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Influence of embryo culture medium (G5 and HTF) on pregnancy and perinatal outcome after IVF: a multicenter RCT.

Study question: Does embryo culture medium influence pregnancy and perinatal outcome in IVF? Summary answer: Embryo culture media used in IVF affect treatment efficacy and the birthweight of newborns. What is known already: A wide variety of culture media for human preimplantation embryos in IVF/ICSI treatments currently exists. It is unknown which medium is best in terms of clinical outcomes. Furthermore, it has been suggested that the culture medium used for the in vitro culture of embryos affects birthweight, but this has never been demonstrated by large randomized trials. Study design, size, duration: We conducted a multicenter, double-blind RCT comparing the use of HTF and G5 embryo culture media in IVF. Between July 2010 and May 2012, 836 couples (419 in the HTF group and 417 in the G5 group) were included. The allocated medium (1:1 allocation) was used in all treatment cycles a couple received within 1 year after randomization, including possible transfers with frozen-thawed embryos. The primary outcome was live birth rate. Participants/materials, setting, methods: Couples that were scheduled for an IVF or an ICSI treatment at one of the six participating centers in the Netherlands or their affiliated clinics. Main results and the role of chance: The live birth rate was higher, albeit nonsignificantly, in couples assigned to G5 than in couples assigned to HTF (44.1% (184/417) versus 37.9% (159/419); RR: 1.2; 95% confidence interval (CI): 0.99-1.37; P = 0.08). Number of utilizable embryos per cycle (2.8 ± 2.3 versus 2.3 ± 1.8; P < 0.001), implantation rate after fresh embryo transfer (20.2 versus 15.3%; P < 0.001) and clinical pregnancy rate (47.7 versus 40.1%; RR: 1.2; 95% CI: 1.02-1.39; P = 0.03) were significantly higher for couples assigned to G5 compared with those assigned to HTF. Of the 383 live born children in this trial, birthweight data from 380 children (300 singletons (G5: 163, HTF: 137) and 80 twin children (G5: 38, HTF: 42)) were retrieved. Birthweight was significantly lower in the G5 group compared with the HTF group, with a mean difference of 158 g (95% CI: 42-275 g; P = 0.008). More singletons were born preterm in the G5 group (8.6% (14/163) versus 2.2% (3/137), but singleton birthweight adjusted for gestational age and gender (z-score) was also lower in the G5 than in the HTF group (-0.13 ± 0.08 versus 0.17 ± 0.08; P = 0.008). Limitations, reasons for caution: This study was powered to detect a 10% difference in live births while a smaller difference could still be clinically relevant. The effect of other culture media on perinatal outcome remains to be determined. Wider implications of the findings: Embryo culture media used in IVF affect not only treatment efficacy but also perinatal outcome. This suggests that the millions of human embryos that are cultured in vitro each year are sensitive to their environment. These findings should lead to increased awareness, mechanistic studies and legislative adaptations to protect IVF offspring during the first few days of their existence. Study funding/competing interests: This project was partly funded by The NutsOhra foundation (Grant 1203-061) and March of Dimes (Grant 6-FY13-153). The authors declare no conflict of interest. Trial registration number: NTR1979 (Netherlands Trial Registry). Trial registration date: 1 September 2009. Date of first patient's enrolment: 18 July 2010.

Human reproduction (Oxford, England) · randomised controlled trial · 104 citationsread the source →

Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial.

Background: The role of nutrition in the treatment of attention-deficit hyperactivity disorder (ADHD) is gaining international attention; however, treatments have generally focused only on diet restriction or supplementing with one nutrient at a time. Aims: To investigate the efficacy and safety of a broad-based micronutrient formula consisting mainly of vitamins and minerals, without omega fatty acids, in the treatment of ADHD in adults. Method: This double-blind randomised controlled trial assigned 80 adults with ADHD in a 1:1 ratio to either micronutrients (n = 42) or placebo (n = 38) for 8 weeks (trial registered with the Australian New Zealand Clinical Trials Registry: ACTRN12609000308291). Results: Intent-to-treat analyses showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales. However, clinicians rated those receiving micronutrients as more improved than those on placebo both globally and on ADHD symptoms. Post hoc analyses showed that for those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo. There were no group differences in adverse events. Conclusions: This study provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile.

The British journal of psychiatry : the journal of mental science · randomised controlled trial · 71 citationsread the source →

Burden of 375 diseases and injuries, risk-attributable burden of 88 risk factors, and healthy life expectancy in 204 countries and territories, including 660 subnational locations, 1990-2023: a systematic analysis for the Global Burden of Disease Study 2023.

Background: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. Methods: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. Findings: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). Interpretation: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. Funding: Gates Foundation and Bloomberg Philanthropies.

Lancet (London, England) · 257 citationsread the source →

An intervention for reducing secondary traumatization and improving professional self-efficacy in well baby clinic nurses following war and terror: a random control group trial.

Background: Due to the terror and war-related situation in Israel, well baby clinic nurses dealing with a large number of traumatized and highly distressed infants, toddlers and their parents have become overwhelmed. Objectives: (1) Assess the level of secondary traumatization, including lack of compassion satisfaction, burnout and compassion fatigue of well baby clinic nurses living under chronic threat of war and terror. (2) Assess the efficacy of an intervention aimed at providing well baby clinic nurses with psycho-educational knowledge pertaining to stress and trauma in infants, young children and parents. This intervention provides the nurses with screening tools for identifying children and parents at risk of developing stress-related problems and equips them with stress management techniques. Design: Quasi-random control trial. Setting: The intervention took place in Israel, in war (North) and terror (South) affected areas. Participants: Ninety well baby clinic nurses from the most war and terror affected areas in Israel were approached, 42 were randomly assigned the experimental intervention and 38 served as a waiting list group. Methods: The intervention was comprised of 12 weekly 6-h sessions. Each session included theoretical knowledge, experiential exercises based on the nurses' work or personal life experience, and the learning of skills accompanied by homework assignments. Participants were assessed on self-report measures of secondary traumatization, professional self-efficacy, hope, sense of mastery and self-esteem before and after the intervention. Results: (1) Well baby clinic nurses were found to have elevated secondary traumatization levels. (2) Compared to the waiting list group, the intervention group improved significantly on the professional self-efficacy measure as well as reducing the level of secondary traumatization. Furthermore, improvement on all secondary traumatization measures covaried with the improvement on the professional self-efficacy assessments. Based on additional informal reports, the improvement was observed to be clinically significant. Conclusions: Training of medical personnel who work with traumatized children and their families and who may also be under the threat of war and terror is essential to both improving their professional functioning, as well as reducing the vulnerability to secondary traumatization.

International journal of nursing studies · randomised controlled trial · 35 citationsread the source →

Attribution, cognition and psychopathology in persistent insomnia disorder: outcome and mediation analysis from a randomized placebo-controlled trial of online cognitive behavioural therapy.

Objectives: Insomnia patients complain that mental events keep them awake. This study investigates how cognitive behavioural therapy (CBT) affects such events and considers how attributional, cognitive and psychopathological symptoms may mediate sleep improvement. Method: A pragmatic, parallel-group randomized controlled trial of 164 adults (120 F: (mean 49 years (18-78 years)) meeting Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for insomnia disorder, assigned to CBT (n=55; 40 F), imagery relief therapy (IRT placebo; n=55; 42 F), or treatment as usual (TAU; n=54; 38 F), was conducted. CBT/IRT comprised six online sessions delivered by an animated therapist, with automated web/e-mail support. CBT users had access to a moderated community. TAU comprised 'usual care'. Participants completed the Sleep Disturbance Questionnaire (SDQ), Glasgow Content of Thoughts Inventory (GCTI), Depression Anxiety and Stress Scales (DASS) and Sleep Condition Indicator (SCI) at baseline, post treatment and 8-week follow-up. Results: The sample was characterised by mental arousal, notably 'trying too hard' to sleep (SDQ), and by 'sleep and sleeplessness' and 'rehearsal and planning' thoughts (GCTI). Treatment effects were observed for all SDQ domains (e.g., CBT vs. IRT: d=0.76 for 'trying too hard'). CBT was also superior to IRT on the GCTI (e.g., 'rehearsal and planning', d=0.62; 'sleep and sleeplessness', d=0.74). CBT vs. TAU comparisons yielded larger effects, whereas placebo effects (IRT vs. TAU) were small to moderate. Hierarchical regression demonstrated partial mediation of SCI improvement by attributional and cognitive factors (R2 = 21-27%) following CBT. Improvement in sleep efficiency appears to be independent of such factors. Conclusion: Online CBT modifies sleep-related attributions, night-time thought content and psychopathology. This process partly mediates improvement in DSM-5-defined insomnia.

Sleep medicine · randomised controlled trial · 64 citationsread the source →

Fall rates in hospital rehabilitation units after individualised patient and staff education programmes: a pragmatic, stepped-wedge, cluster-randomised controlled trial.

Background: Falls are the most frequent adverse events that are reported in hospitals. We examined the effectiveness of individualised falls-prevention education for patients, supported by training and feedback for staff, delivered as a ward-level programme. Methods: Eight rehabilitation units in general hospitals in Australia participated in this stepped-wedge, cluster-randomised study, undertaken during a 50 week period. Units were randomly assigned to intervention or control groups by use of computer-generated, random allocation sequences. We included patients admitted to the unit during the study with a Mini-Mental State Examination (MMSE) score of more than 23/30 to receive individualised education that was based on principles of changes in health behaviour from a trained health professional, in addition to usual care. We provided information about patients' goals, feedback about the ward environment, and perceived barriers to engagement in falls-prevention strategies to staff who were trained to support the uptake of strategies by patients. The coprimary outcome measures were patient rate of falls per 1000 patient-days and the proportion of patients who were fallers. All analyses were by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials registry, number ACTRN12612000877886). Findings: Between Jan 13, and Dec 27, 2013, 3606 patients were admitted to the eight units (n=1983 control period; n=1623 intervention period). There were fewer falls (n=196, 7·80/1000 patient-days vs n=380, 13·78/1000 patient-days, adjusted rate ratio 0·60 [robust 95% CI 0·42-0·94], p=0·003), injurious falls (n=66, 2·63/1000 patient-days vs 131, 4·75/1000 patient-days, 0·65 [robust 95% CI 0·42-0·88], p=0·006), and fallers (n=136 [8·38%] vs n=248 [12·51%] adjusted odds ratio 0·55 [robust 95% CI 0·38 to 0·81], p=0·003) in the intervention compared with the control group. There was no significant difference in length of stay (intervention median 11 days [IQR 7-19], control 10 days [6-18]). Interpretation: Individualised patient education programmes combined with training and feedback to staff added to usual care reduces the rates of falls and injurious falls in older patients in rehabilitation hospital-units. Funding: State Health Research Advisory Council, Department of Health, Government of Western Australia.

Lancet (London, England) · randomised controlled trial · 143 citationsread the source →

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.

Background: Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a new, rare, post-infectious complication of SARS-CoV-2 infection in children. We aimed to describe the 6-month outcomes of PIMS-TS. Methods: This retrospective cohort study comprised children (aged <18 years) who fulfilled the UK Royal College of Paediatrics and Child Health (RCPCH) diagnostic criteria for PIMS-TS and were admitted to Great Ormond Street Hospital (London, UK) between April 4 and Sept 1, 2020. Patients were followed up by a multidisciplinary team of specialists at 6 weeks and 6 months after admission. Biochemical and functional outcomes were analysed. Findings: 46 children were included in this study. The median age at presentation was 10·2 years (IQR 8·8-13·3), 30 (65%) patients were male and 16 (35%) were female, 37 (80%) were from minority ethnic groups, and eight (17%) had pre-existing comorbidities. All patients had elevated markers of systemic inflammation at baseline. None of the patients died. By 6 months, systemic inflammation was resolved in all but one patient. 38 (90%) of 42 patients who had positive SARS-CoV-2 IgG antibodies within 6 weeks of admission remained seropositive at 6 months. Echocardiograms were normal in 44 (96%) of 46 patients by 6 months, and gastrointestinal symptoms that were reported in 45 (98%) of 46 patients at onset were present in six (13%) of 46 patients at 6 months. Renal, haematological, and otolaryngological findings largely resolved by 6 months. Although minor abnormalities were identified on neurological examination in 24 (52%) of 46 patients at 6 weeks and in 18 (39%) of 46 at 6 months, we found minimal functional impairment at 6 months (median Expanded Disability Status Scale score 0 [IQR 0-1]). Median manual muscle test-8 scores improved from 53 (IQR 43-64) during hospital admission to 80 (IQR 68-80) at 6 months, but 18 (45%) of 40 patients showed 6-min walk test results below the third centile for their age or sex at 6 months. PedsQL responses revealed severe emotional difficulties at 6 months (seven [18%] of 38 by parental report and eight [22%] of 38 by self report). 45 (98%) of 46 patients were back in full-time education (virtually or face to face) by 6 months. Interpretation: Despite initial severe illness, few organ-specific sequelae were observed at 6 months. Ongoing concerns requiring physical re-conditioning and mental health support remained, and physiotherapy assessments revealed persisting poor exercise tolerance. Longer-term follow-up will help define the extended natural history of PIMS-TS. Funding: None.

The Lancet. Child & adolescent health · 151 citationsread the source →

Suffering in silence: Stigma, healthcare barriers, and resilience during Sierra Leone's 2025 clade IIb mpox outbreak-A multi-perspective qualitative study.

Mpox was confirmed in Sierra Leone in January 2025, with a public health emergency declared shortly thereafter. By June 2025, the country reported over 4,000 confirmed cases caused by clade IIb. Limited qualitative research has explored the lived experiences of affected populations during mpox outbreaks in African settings. This study explored multi-stakeholder experiences of mpox, including illness trajectories, stigma manifestations, healthcare-seeking behaviours, and health system response challenges. We conducted a multi-perspective qualitative study using thematic framework analysis between March and August 2025 across four districts. Participants included mpox survivors (n = 42), healthcare workers (n = 38), community members (n = 36), and contact tracers (n = 24). Data were collected through 94 semi-structured interviews and 12 focus group discussions. Analysis was guided by a modified Social Ecological Model (SEM) integrating the Health Stigma and Discrimination Framework (HSDF). Five interconnected themes emerged: (1) illness characterised by physical suffering and lasting bodily changes; (2) multi-layered stigma operating across individual, interpersonal, community, and institutional levels; (3) healthcare-seeking shaped by fear of disclosure and economic constraints; (4) healthcare workers' moral distress and professional isolation; (5) adaptive health system response alongside coordination challenges. Stigma operated as a cross-cutting dimension that intersected with all other themes, shaping illness experience, care-seeking behaviour, professional practice, and system-level response simultaneously. It also permeated all dimensions of the mpox outbreak experience, delaying care-seeking, undermining contact tracing, and compounding healthcare worker distress. Compound trauma from sequential epidemic exposure emerged as a distinct burden among frontline workers. These findings point to the need for stigma-informed outbreak response strategies, sustained healthcare worker support mechanisms, and community-centred communication approaches in post-conflict, resource-constrained settings facing recurrent epidemics.

PLOS global public healthread the source →

Effectiveness of brief alcohol interventions in primary care populations.

Background: Excessive drinking is a significant cause of mortality, morbidity and social problems in many countries. Brief interventions aim to reduce alcohol consumption and related harm in hazardous and harmful drinkers who are not actively seeking help for alcohol problems. Interventions usually take the form of a conversation with a primary care provider and may include feedback on the person's alcohol use, information about potential harms and benefits of reducing intake, and advice on how to reduce consumption. Discussion informs the development of a personal plan to help reduce consumption. Brief interventions can also include behaviour change or motivationally-focused counselling. This is an update of a Cochrane Review published in 2007. Objectives: To assess the effectiveness of screening and brief alcohol intervention to reduce excessive alcohol consumption in hazardous or harmful drinkers in general practice or emergency care settings. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and 12 other bibliographic databases to September 2017. We searched Alcohol and Alcohol Problems Science Database (to December 2003, after which the database was discontinued), trials registries, and websites. We carried out handsearching and checked reference lists of included studies and relevant reviews. Selection criteria: We included randomised controlled trials (RCTs) of brief interventions to reduce hazardous or harmful alcohol consumption in people attending general practice, emergency care or other primary care settings for reasons other than alcohol treatment. The comparison group was no or minimal intervention, where a measure of alcohol consumption was reported. 'Brief intervention' was defined as a conversation comprising five or fewer sessions of brief advice or brief lifestyle counselling and a total duration of less than 60 minutes. Any more was considered an extended intervention. Digital interventions were not included in this review. Data collection and analysis: We used standard methodological procedures expected by Cochrane. We carried out subgroup analyses where possible to investigate the impact of factors such as gender, age, setting (general practice versus emergency care), treatment exposure and baseline consumption. Main results: We included 69 studies that randomised a total of 33,642 participants. Of these, 42 studies were added for this update (24,057 participants). Most interventions were delivered in general practice (38 studies, 55%) or emergency care (27 studies, 39%) settings. Most studies (61 studies, 88%) compared brief intervention to minimal or no intervention. Extended interventions were compared with brief (4 studies, 6%), minimal or no intervention (7 studies, 10%). Few studies targeted particular age groups: adolescents or young adults (6 studies, 9%) and older adults (4 studies, 6%). Mean baseline alcohol consumption was 244 g/week (30.5 standard UK units) among the studies that reported these data. Main sources of bias were attrition and lack of provider or participant blinding. The primary meta-analysis included 34 studies (15,197 participants) and provided moderate-quality evidence that participants who received brief intervention consumed less alcohol than minimal or no intervention participants after one year (mean difference (MD) -20 g/week, 95% confidence interval (CI) -28 to -12). There was substantial heterogeneity among studies (I² = 73%). A subgroup analysis by gender demonstrated that both men and women reduced alcohol consumption after receiving a brief intervention. We found moderate-quality evidence that brief alcohol interventions have little impact on frequency of binges per week (MD -0.08, 95% CI -0.14 to -0.02; 15 studies, 6946 participants); drinking days per week (MD -0.13, 95% CI -0.23 to -0.04; 11 studies, 5469 participants); or drinking intensity (-0.2 g/drinking day, 95% CI -3.1 to 2.7; 10 studies, 3128 participants).We found moderate-quality evidence of little difference in quantity of alcohol consumed when extended and no or minimal interventions were compared (-14 g/week, 95% CI -37 to 9; 6 studies, 1296 participants). There was little difference in binges per week (-0.08, 95% CI -0.28 to 0.12; 2 studies, 456 participants; moderate-quality evidence) or difference in days drinking per week (-0.45, 95% CI -0.81 to -0.09; 2 studies, 319 participants; moderate-quality evidence). Extended versus no or minimal intervention provided little impact on drinking intensity (9 g/drinking day, 95% CI -26 to 9; 1 study, 158 participants; low-quality evidence).Extended intervention had no greater impact than brief intervention on alcohol consumption, although findings were imprecise (MD 2 g/week, 95% CI -42 to 45; 3 studies, 552 participants; low-quality evidence). Numbers of binges were not reported for this comparison, but one trial suggested a possible drop in days drinking per week (-0.5, 95% CI -1.2 to 0.2; 147 participants; low-quality evidence). Results from this trial also suggested very little impact on drinking intensity (-1.7 g/drinking day, 95% CI -18.9 to 15.5; 147 participants; very low-quality evidence).Only five studies reported adverse effects (very low-quality evidence). No participants experienced any adverse effects in two studies; one study reported that the intervention increased binge drinking for women and two studies reported adverse events related to driving outcomes but concluded they were equivalent in both study arms. Sources of funding were reported by 67 studies (87%). With two exceptions, studies were funded by government institutes, research bodies or charitable foundations. One study was partly funded by a pharmaceutical company and a brewers association, another by a company developing diagnostic testing equipment. Authors' conclusions: We found moderate-quality evidence that brief interventions can reduce alcohol consumption in hazardous and harmful drinkers compared to minimal or no intervention. Longer counselling duration probably has little additional effect. Future studies should focus on identifying the components of interventions which are most closely associated with effectiveness.

The Cochrane database of systematic reviews · meta-analysis · 409 citationsread the source →

Cost-effectiveness of Treatments for Opioid Use Disorder.

Importance: Opioid use disorder (OUD) is a significant cause of morbidity and mortality in the US, yet many individuals with OUD do not receive treatment. Objective: To assess the cost-effectiveness of OUD treatments and association of these treatments with outcomes in the US. Design and setting: This model-based cost-effectiveness analysis included a US population with OUD. Interventions: Medication-assisted treatment (MAT) with buprenorphine, methadone, or injectable extended-release naltrexone; psychotherapy (beyond standard counseling); overdose education and naloxone distribution (OEND); and contingency management (CM). Main outcomes and measures: Fatal and nonfatal overdoses and deaths throughout 5 years, discounted lifetime quality-adjusted life-years (QALYs), and costs. Results: In the base case, in the absence of treatment, 42 717 overdoses (4132 fatal, 38 585 nonfatal) and 12 660 deaths were estimated to occur in a cohort of 100 000 patients over 5 years, and 11.58 discounted lifetime QALYs were estimated to be experienced per person. An estimated reduction in overdoses was associated with MAT with methadone (10.7%), MAT with buprenorphine or naltrexone (22.0%), and when combined with CM and psychotherapy (range, 21.0%-31.4%). Estimated deceased deaths were associated with MAT with methadone (6%), MAT with buprenorphine or naltrexone (13.9%), and when combined with CM, OEND, and psychotherapy (16.9%). MAT yielded discounted gains of 1.02 to 1.07 QALYs per person. Including only health care sector costs, methadone cost $16 000/QALY gained compared with no treatment, followed by methadone with OEND ($22 000/QALY gained), then by buprenorphine with OEND and CM ($42 000/QALY gained), and then by buprenorphine with OEND, CM, and psychotherapy ($250 000/QALY gained). MAT with naltrexone was dominated by other treatment alternatives. When criminal justice costs were included, all forms of MAT (with buprenorphine, methadone, and naltrexone) were associated with cost savings compared with no treatment, yielding savings of $25 000 to $105 000 in lifetime costs per person. The largest cost savings were associated with methadone plus CM. Results were qualitatively unchanged over a wide range of sensitivity analyses. An analysis using demographic and cost data for Veterans Health Administration patients yielded similar findings. Conclusions and relevance: In this cost-effectiveness analysis, expanded access to MAT, combined with OEND and CM, was associated with cost-saving reductions in morbidity and mortality from OUD. Lack of widespread MAT availability limits access to a cost-saving medical intervention that reduces morbidity and mortality from OUD. Opioid overdoses in the US likely reached a record high in 2020 because of COVID-19 increasing substance use, exacerbating stress and social isolation, and interfering with opioid treatment. It is essential to understand the cost-effectiveness of alternative forms of MAT to treat OUD.

JAMA psychiatry · 85 citationsread the source →

Interactive telemedicine: effects on professional practice and health care outcomes.

Background: Telemedicine (TM) is the use of telecommunication systems to deliver health care at a distance. It has the potential to improve patient health outcomes, access to health care and reduce healthcare costs. As TM applications continue to evolve it is important to understand the impact TM might have on patients, healthcare professionals and the organisation of care. Objectives: To assess the effectiveness, acceptability and costs of interactive TM as an alternative to, or in addition to, usual care (i.e. face-to-face care, or telephone consultation). Search methods: We searched the Effective Practice and Organisation of Care (EPOC) Group's specialised register, CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers to June 2013, together with reference checking, citation searching, handsearching and contact with study authors to identify additional studies. Selection criteria: We considered randomised controlled trials of interactive TM that involved direct patient-provider interaction and was delivered in addition to, or substituting for, usual care compared with usual care alone, to participants with any clinical condition. We excluded telephone only interventions and wholly automatic self-management TM interventions. Data collection and analysis: For each condition, we pooled outcome data that were sufficiently homogenous using fixed effect meta-analysis. We reported risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) for continuous outcomes. Main results: We included 93 eligible trials (N = 22,047 participants), which evaluated the effectiveness of interactive TM delivered in addition to (32% of studies), as an alternative to (57% of studies), or partly substituted for usual care (11%) as compared to usual care alone. The included studies recruited patients with the following clinical conditions: cardiovascular disease (36), diabetes (21), respiratory conditions (9), mental health or substance abuse conditions (7), conditions requiring a specialist consultation (6), co morbidities (3), urogenital conditions (3), neurological injuries and conditions (2), gastrointestinal conditions (2), neonatal conditions requiring specialist care (2), solid organ transplantation (1), and cancer (1).Telemedicine provided remote monitoring (55 studies), or real-time video-conferencing (38 studies), which was used either alone or in combination. The main TM function varied depending on clinical condition, but fell typically into one of the following six categories, with some overlap: i) monitoring of a chronic condition to detect early signs of deterioration and prompt treatment and advice, (41); ii) provision of treatment or rehabilitation (12), for example the delivery of cognitive behavioural therapy, or incontinence training; iii) education and advice for self-management (23), for example nurses delivering education to patients with diabetes or providing support to parents of very low birth weight infants or to patients with home parenteral nutrition; iv) specialist consultations for diagnosis and treatment decisions (8), v) real-time assessment of clinical status, for example post-operative assessment after minor operation or follow-up after solid organ transplantation (8) vi), screening, for angina (1).The type of data transmitted by the patient, the frequency of data transfer, (e.g. telephone, e-mail, SMS) and frequency of interactions between patient and healthcare provider varied across studies, as did the type of healthcare provider/s and healthcare system involved in delivering the intervention. We found no difference between groups for all-cause mortality for patients with heart failure (16 studies; N = 5239; RR:0.89, 95% CI 0.76 to 1.03, P = 0.12; I(2) = 44%) (moderate to high certainty of evidence) at a median of six months follow-up. Admissions to hospital (11 studies; N = 4529) ranged from a decrease of 64% to an increase of 60% at median eight months follow-up (moderate certainty of evidence). We found some evidence of improved quality of life (five studies; N = 482; MD:-4.39, 95% CI -7.94 to -0.83; P < 0.02; I(2) = 0%) (moderate certainty of evidence) for those allocated to TM as compared with usual care at a median three months follow-up. In studies recruiting participants with diabetes (16 studies; N = 2768) we found lower glycated haemoglobin (HbA1c %) levels in those allocated to TM than in controls (MD -0.31, 95% CI -0.37 to -0.24; P < 0.00001; I(2)= 42%, P = 0.04) (high certainty of evidence) at a median of nine months follow-up. We found some evidence for a decrease in LDL (four studies, N = 1692; MD -12.45, 95% CI -14.23 to -10.68; P < 0.00001; I(2 =) 0%) (moderate certainty of evidence), and blood pressure (four studies, N = 1770: MD: SBP:-4.33, 95% CI -5.30 to -3.35, P < 0.00001; I(2) = 17%; DBP: -2.75 95% CI -3.28 to -2.22, P < 0.00001; I(2) = 45% (moderate certainty evidence), in TM as compared with usual care. Seven studies that recruited participants with different mental health and substance abuse problems, reported no differences in the effect of therapy delivered over video-conferencing, as compared to face-to-face delivery. Findings from the other studies were inconsistent; there was some evidence that monitoring via TM improved blood pressure control in participants with hypertension, and a few studies reported improved symptom scores for those with a respiratory condition. Studies recruiting participants requiring mental health services and those requiring specialist consultation for a dermatological condition reported no differences between groups. Authors' conclusions: The findings in our review indicate that the use of TM in the management of heart failure appears to lead to similar health outcomes as face-to-face or telephone delivery of care; there is evidence that TM can improve the control of blood glucose in those with diabetes. The cost to a health service, and acceptability by patients and healthcare professionals, is not clear due to limited data reported for these outcomes. The effectiveness of TM may depend on a number of different factors, including those related to the study population e.g. the severity of the condition and the disease trajectory of the participants, the function of the intervention e.g., if it is used for monitoring a chronic condition, or to provide access to diagnostic services, as well as the healthcare provider and healthcare system involved in delivering the intervention.

The Cochrane database of systematic reviews · meta-analysis · 456 citationsread the source →

Measurement of resident fatigue using rapid number naming.

Objective: Sleep deprivation has a negative effect on neurocognitive performance. The King-Devick test (KDT), which tests speed and accuracy of number-reading, requires integrity of saccades, visual processing, and cognition. This study investigated effects of sleep deprivation in on-call residents using KDT. Methods: A prospective cohort study was conducted among 80 residents. KDT was performed at the beginning and end of an overnight call shift for the residents in the experimental group. A control group was tested at the beginning of 2 consecutive day shifts. Estimates of hours of sleep, Karolinska Sleepiness Scale (KSS)(1 = extremely alert, 9 = extremely sleepy), and time and accuracy of KDT were recorded. Results: 42 residents were tested before and after overnight call shifts and 38 served as controls. Change in test time differed between the groups, with the experimental group performing 0.54(SD = 4.0) seconds slower after their night on call and the control group performing 2.32(SD = 3.0) seconds faster on the second day, p < 0.001. This difference was larger in surgical compared to medical residents. Conclusions: Sleep deprivation was inversely correlated with neurocognitive performance as measured by KDT, with more effect on surgical than medical residents. Further research could investigate whether this test could help determine fatigue level and ability to continue working after a long shift.

Journal of the neurological sciences · cohort or longitudinal · 3 citationsread the source →

Gamification and Oral Health in Children and Adolescents: Scoping Review

BACKGROUND: Oral health is a determinant of overall well-being and quality of life. Individual behaviors, such as oral hygiene and dietary habits, play a central role in oral health. Motivation is a crucial factor in promoting behavior change, and gamification offers a means to boost health-related knowledge and encourage positive health behaviors. OBJECTIVE: This study aims to evaluate the impact of gamification and its mechanisms on oral health care of children and adolescents. METHODS: A systematic search covered multiple databases: PubMed/MEDLINE, PsycINFO, the Cochrane Library, ScienceDirect, and LILACS. Gray literature, conference proceedings, and WHOQOL internet resources were considered. Studies from January 2013 to December 2022 were included, except for PubMed/MEDLINE, which was searched until January 2023. A total of 15 studies were selected following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The eligibility criteria were peer-reviewed, full-text, and empirical research related to gamification in oral health care, reports of impact, and oral health care outcomes. The exclusion criteria encompassed duplicate articles; unavailable full texts; nonoriginal articles; and non-digital game-related, non-oral health-related, and protocol studies. Selected studies were scrutinized for gamification mechanisms and outcomes. Two main questions were raised: "Does gamification in oral health care impact oral health?" and "Does oral health care gamification enhance health promotion and literacy?" The PICO (Patient, Intervention, Comparison, Outcome) framework guided the scoping review. RESULTS: Initially, 617 records were obtained from 5 databases and gray literature sources. After applying exclusion criteria, 15 records were selected. Sample size in the selected studies ranged from 34 to 190 children and adolescents. A substantial portion (11/15, 73%) of the studies discussed oral self-care apps supported by evidence-based oral health. The most clearly defined data in the apps were "brushing time" (11/11, 100%) and "daily amount brushing" (10/11, 91%). Most studies (11/15, 73%) mentioned oral health care behavior change techniques and included "prompt intention formation" (11/26, 42%), "providing instructions" (11/26, 42%), "providing information on the behavior-health link" (10/26, 38%), "providing information on consequences" (9/26, 35%), "modeling or demonstrating behavior" (9/26, 35%), "providing feedback on performance" (8/26, 31%), and "providing contingent rewards" (8/26, 31%). Furthermore, 80% (12/15) of the studies identified game design elements incorporating gamification features in oral hygiene applications. The most prevalent gamification features were "ideological incentives" (10/12, 83%) and "goals" (9/16, 56%), which were found in user-specific and challenge categories, respectively. CONCLUSIONS: Gamification in oral health care shows potential as an innovative approach to promote positive health behaviors. Most studies reported evidence-based oral health and incorporated oral health care behavior change techniques.

Interactive Journal of Medical Research · review · 23 citationsread the source →

Collaborative Care for Opioid and Alcohol Use Disorders in Primary Care: The SUMMIT Randomized Clinical Trial.

Importance: Primary care offers an important and underutilized setting to deliver treatment for opioid and/or alcohol use disorders (OAUD). Collaborative care (CC) is effective but has not been tested for OAUD. Objective: To determine whether CC for OAUD improves delivery of evidence-based treatments for OAUD and increases self-reported abstinence compared with usual primary care. Design, setting, and participants: A randomized clinical trial of 377 primary care patients with OAUD was conducted in 2 clinics in a federally qualified health center. Participants were recruited from June 3, 2014, to January 15, 2016, and followed for 6 months. Interventions: Of the 377 participants, 187 were randomized to CC and 190 were randomized to usual care; 77 (20.4%) of the participants were female, of whom 39 (20.9%) were randomized to CC and 38 (20.0%) were randomized to UC. The mean (SD) age of all respondents at baseline was 42 (12.0) years, 41(11.7) years for the CC group, and 43 (12.2) yearsfor the UC group. Collaborative care was a system-level intervention, designed to increase the delivery of either a 6-session brief psychotherapy treatment and/or medication-assisted treatment with either sublingual buprenorphine/naloxone for opioid use disorders or long-acting injectable naltrexone for alcohol use disorders. Usual care participants were told that the clinic provided OAUD treatment and given a number for appointment scheduling and list of community referrals. Main outcomes and measures: The primary outcomes were use of any evidence-based treatment for OAUD and self-reported abstinence from opioids or alcohol at 6 months. The secondary outcomes included the Healthcare Effectiveness Data and Information Set (HEDIS) initiation and engagement measures, abstinence from other substances, heavy drinking, health-related quality of life, and consequences from OAUD. Results: At 6 months, the proportion of participants who received any OAUD treatment was higher in the CC group compared with usual care (73 [39.0%] vs 32 [16.8%]; logistic model adjusted OR, 3.97; 95% CI, 2.32-6.79; P < .001). A higher proportion of CC participants reported abstinence from opioids or alcohol at 6 months (32.8% vs 22.3%); after linear probability model adjustment for covariates (β = 0.12; 95% CI, 0.01-0.23; P = .03). In secondary analyses, the proportion meeting the HEDIS initiation and engagement measures was also higher among CC participants (initiation, 31.6% vs 13.7%; adjusted OR, 3.54; 95% CI, 2.02-6.20; P < .001; engagement, 15.5% vs 4.2%; adjusted OR, 5.89; 95% CI, 2.43-14.32; P < .001) as was abstinence from opioids, cocaine, methamphetamines, marijuana, and any alcohol (26.3% vs 15.6%; effect estimate, β = 0.13; 95% CI, 0.03-0.23; P = .01). Conclusions and relevance: Among adults with OAUD in primary care, the SUMMIT collaborative care intervention resulted in significantly more access to treatment and abstinence from alcohol and drugs at 6 months, than usual care. Trial registration: clinicaltrials.gov Identifier: NCT01810159.

JAMA internal medicine · randomised controlled trial · 174 citationsread the source →

Group Cognitive Behavioral Therapy and Attention Bias Modification for Childhood Anxiety Disorders: A Factorial Randomized Trial of Efficacy.

Background: The objective of this study is to assess group differences in symptom reduction between individuals receiving group cognitive behavioral therapy (G-CBT) and attention bias modification (ABM) compared to their respective control interventions, control therapy (CT), and attention control training (ACT), in a 2 × 2 factorial design. Methods: A total of 310 treatment-naive children (7-11 years of age) were assessed for eligibility and 79 children with generalized, separation or social anxiety disorder were randomized and received G-CBT (n = 42) or CT (n = 37). Within each psychotherapy group, participants were again randomized to ABM (n = 38) or ACT (n = 41) in a 2 × 2 factorial design resulting in four groups: G-CBT + ABM (n = 21), G-CBT + ACT (n = 21), CT + ABM (n = 17), and CT + ACT (n = 20). Primary outcomes were responder designation as defined by Clinical Global Impression-Improvement (CGI-I) scale (≤2) and change on the Pediatric Anxiety Rating Scale (PARS). Results: There were significant improvements of symptoms in all groups. No differences in response rates or mean differences in PARS scores were found among groups: G-CBT + ABM group (23.8% response; 3.9 points, 95% confidence interval [CI] -0.3 to 8.1), G-CBT + ACT (42.9% response; 5.6 points, 95% CI 2.2-9.0), CT + ABM (47.1% response; 4.8 points 95% CI 1.08-8.57), and CT + ACT (30% response; 0.8 points, 95% CI -3.0 to 4.7). No evidence or synergic or antagonistic effects were found, but the combination of G-CBT and ABM was found to increase dropout rate. Conclusions: We found no effect of G-CBT or ABM beyond the effects of comparison groups. Results reveal no benefit from combining G-CBT and ABM for anxiety disorders in children and suggest potential deleterious effects of the combination on treatment acceptability.

Journal of child and adolescent psychopharmacology · randomised controlled trial · 15 citationsread the source →

A systematic review of influences on implementation of peer support work for adults with mental health problems.

Purpose: The evidence base for peer support work in mental health is established, yet implementation remains a challenge. The aim of this systematic review was to identify influences which facilitate or are barriers to implementation of mental health peer support work. Methods: Data sources comprised online databases (n = 11), journal table of contents (n = 2), conference proceedings (n = 18), peer support websites (n = 2), expert consultation (n = 38) and forward and backward citation tracking. Publications were included if they reported on implementation facilitators or barriers for formal face-to-face peer support work with adults with a mental health problem, and were available in English, French, German, Hebrew, Luganda, Spanish or Swahili. Data were analysed using narrative synthesis. A six-site international survey [Germany (2 sites), India, Israel, Tanzania, Uganda] using a measure based on the strongest influences was conducted. The review protocol was pre-registered (Prospero: CRD42018094838). Results: The search strategy identified 5813 publications, of which 53 were included. Fourteen implementation influences were identified, notably organisational culture (reported by 53% of papers), training (42%) and role definition (40%). Ratings on a measure using these influences demonstrated preliminary evidence for the convergent and discriminant validity of the identified influences. Conclusion: The identified influences provide a guide to implementation of peer support. For services developing a peer support service, organisational culture including role support (training, role clarity, resourcing and access to a peer network) and staff attitudes need to be considered. The identified influences provide a theory base to prepare research sites for implementing peer support worker interventions.

Social psychiatry and psychiatric epidemiology · systematic review · 139 citationsread the source →

Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention.

Importance: Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective: To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence review: Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings: In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and relevance: This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.

JAMA psychiatry · systematic review · 369 citationsread the source →

Gender differences in coping with infertility among couples undergoing counselling for In Vitro Fertilization treatment.

Objective: To identify gender differences in coping responses and the association between coping and psychological distress in couples undergoing In Vitro Fertilization (IVF) treatment at the University of the West Indies (UWI). Methods: All men and women (n = 52) who were offered psychological counselling prior to beginning IVF treatment between October 2003 and May 2004 were invited to complete questionnaires on their coping responses, self-reported distress and socio-demographic data. One female declined. Results: Of the 51 participants, 52% had completed secondary education, 44% tertiary education, and 37% were 38 years or older; 42% of the couples were trying for more than seven years to have a child. Gender differences in coping included more women than men keeping others from knowing their pain (p < 0.01) and more women ruminating about what they did wrong to cause the infertility (p < 0.01). These strategies were also associated with reports of heightened distress (p < 0.05). Talking to others to obtain information was associated with less negative feelings. Coping skills that were commonly used by both genders included seeking medical advice and engaging in wishful thinking. Conclusion: Women coping with infertility may be at risk for self-depreciation and isolation because of their choice of coping strategies and the meaning they ascribe to the infertility. As a result, they are likely to experience more heightened distress than men who are also infertile. Counselling that is specific to gender-needs is indicated.

The West Indian medical journal · 16 citationsread the source →

Peer-supported self-management for people discharged from a mental health crisis team: a randomised controlled trial.

Background: High resource expenditure on acute care is a challenge for mental health services aiming to focus on supporting recovery, and relapse after an acute crisis episode is common. Some evidence supports self-management interventions to prevent such relapses, but their effect on readmissions to acute care following a crisis is untested. We tested whether a self-management intervention facilitated by peer support workers could reduce rates of readmission to acute care for people discharged from crisis resolution teams, which provide intensive home treatment following a crisis. Methods: We did a randomised controlled superiority trial recruiting participants from six crisis resolution teams in England. Eligible participants had been on crisis resolution team caseloads for at least a week, and had capacity to give informed consent. Participants were randomly assigned to intervention and control groups by an unmasked data manager. Those collecting and analysing data were masked to allocation, but participants were not. Participants in the intervention group were offered up to ten sessions with a peer support worker who supported them in completing a personal recovery workbook, including formulation of personal recovery goals and crisis plans. The control group received the personal recovery workbook by post. The primary outcome was readmission to acute care within 1 year. This trial is registered with ISRCTN, number 01027104. Findings: 221 participants were assigned to the intervention group versus 220 to the control group; primary outcome data were obtained for 218 versus 216. 64 (29%) of 218 participants in the intervention versus 83 (38%) of 216 in the control group were readmitted to acute care within 1 year (odds ratio 0·66, 95% CI 0·43-0·99; p=0·0438). 71 serious adverse events were identified in the trial (29 in the treatment group; 42 in the control group). Interpretation: Our findings suggest that peer-delivered self-management reduces readmission to acute care, although admission rates were lower than anticipated and confidence intervals were relatively wide. The complexity of the study intervention limits interpretability, but assessment is warranted of whether implementing this intervention in routine settings reduces acute care readmission. Funding: National Institute for Health Research.

Lancet (London, England) · randomised controlled trial · 92 citationsread the source →

Psychotherapy for depression in older veterans via telemedicine: a randomised, open-label, non-inferiority trial.

Background: Many older adults with major depression, particularly veterans, do not have access to evidence-based psychotherapy. Telemedicine could increase access to best-practice care for older adults facing barriers of mobility, stigma, and geographical isolation. We aimed to establish non-inferiority of behavioural activation therapy for major depression delivered via telemedicine to same-room care in largely male, older adult veterans. Methods: In this randomised, controlled, open-label, non-inferiority trial, we recruited veterans (aged ≥58 years) meeting DSM-IV criteria for major depressive disorder from the Ralph H Johnson Veterans Affairs Medical Center and four associated community outpatient-based clinics in the USA. We excluded actively psychotic or demented people, those with both suicidal ideation and clear intent, and those with substance dependence. The study coordinator randomly assigned participants (1:1; block size 2-6; stratified by race; computer-generated randomisation sequence by RGK) to eight sessions of behavioural activation for depression either via telemedicine or in the same room. The primary outcome was treatment response according to the Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI; defined as a 50% reduction in symptoms from baseline at 12 months), and Structured Clinical Interview for DSM-IV, clinician version (defined as no longer being diagnosed with major depressive disorder at 12 months follow-up), in the per-protocol population (those who completed at least four treatment sessions and for whom all outcome measurements were done). Those assessing outcomes were masked. The non-inferiority margin was 15%. This trial is registered with ClinicalTrials.gov, number NCT00324701. Findings: Between April 1, 2007, and July 31, 2011, we screened 780 patients, and the study coordinator randomly assigned participants to either telemedicine (120 [50%]) or same-room treatment (121 [50%]). We included 100 (83%) patients in the per-protocol analysis in the telemedicine group and 104 (86%) in the same-room group. Treatment response according to GDS did not differ significantly between the telemedicine (22 [22·45%, 90% CI 15·52-29·38] patients) and same-room (21 [20·39%, 90% CI 13·86-26·92]) groups, with an absolute difference of 2·06% (90% CI -7·46 to 11·58). Response according to BDI also did not differ significantly (telemedicine 19 [24·05%, 90% CI 16·14-31·96] patients; same room 19 [23·17%, 90% CI 15·51-30·83]), with an absolute difference of 0·88% (90% CI -10·13 to 11·89). Response on the Structured Clinical Interview for DSM-IV, clinician version, also did not differ significantly (39 [43·33%, 90% CI 34·74-51·93] patients in the telemedicine group and 46 [48·42%, 90% CI 39·99-56·85] in the same-room group), with a difference of -5·09% (-17·13 to 6·95; p=0·487). Results from the intention-to-treat population were similar. MEM analyses showed that no significant differences existed between treatment trajectories over time for BDI and GDS. The criteria for non-inferiority were met. We did not note any adverse events. Interpretation: Telemedicine-delivered psychotherapy for older adults with major depression is not inferior to same-room treatment. This finding shows that evidence-based psychotherapy can be delivered, without modification, via home-based telemedicine, and that this method can be used to overcome barriers to care associated with distance from and difficulty with attendance at in-person sessions in older adults. Funding: US Department of Veterans Affairs.

The lancet. Psychiatry · randomised controlled trial · 123 citationsread the source →

The Social Epidemiology of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Social epidemiology is defined as the study of the distribution of health outcomes and their social determinants (1). It builds on the classic epidemiologic triangle of host, agent, and environment to focus explicitly on the role of social determinants in infectious disease transmission and progression. These determinants are the “features of and pathways by which societal conditions affect health” (2, p. 697). Early studies of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) focused on individual characteristics and behaviors in determining HIV risk, an approach that Fee and Krieger (3) refer to as “biomedical individualism.” Biomedical individualism is the basis of risk factor epidemiology; by contrast, the social epidemiology perspective emphasizes social conditions as fundamental causes of disease (4) (table 1). Social epidemiologists examine how persons become exposed to risk or protective factors and under what social conditions individual risk factors are related to disease. Social factors are thus the focus of analysis and are not simply adjusted for as potentially confounding factors or used as proxies for unavailable individual-level data. Social factors are indeed critical to understanding nonuniform infectious disease patterns that emerge as a result of the dependent nature of disease transmission or the idea that an outcome in one person is dependent upon outcomes and exposures in others (5, 6). Contact patterns that enhance HIV/AIDS vulnerability may be conceptualized at multiple levels. Figure 1 distinguishes determinants of HIV/AIDS at three levels: individual, social, and structural. Individual factors include biologic, demographic, and behavioral risk factors that may influence the risk of HIV acquisition and disease progression. Social-level factors include critical pathways by which community and network structures link persons to society. These structures are central to understanding the diffusion and differential distribution of HIV/AIDS in population subgroups. Structural-level factors include social and economic factors, as well as laws and policies. These factors, in turn, affect HIV transmission dynamics and the differential distribution of HIV/AIDS. Infectious disease epidemiology provides models of the mechanisms through which social determinants affect HIV transmission (7). For example, the basic reproductive number of an infectious disease, R0 (8), describes secondary infections that arise from a primary infection. In the equation R0 = βCD, β is the probability of infection per contact, C is the number of contacts, and D is the duration of infectivity. The goal of intervention efforts is to reduce the empirical value of these terms by modifying the social conditions under which individual risk factors lead to disease. Examples of factors that affect the component terms of R0 in HIV epidemiology are presented in table 2. In this review, we present existing evidence linking social and structural determinants to HIV/AIDS. In addition, we discuss the implications of these findings for future social epidemiology research on HIV/AIDS as well as the design of more effective HIV/AIDS interventions. We searched the published literature to identify conceptual and empirical research reports on the social epidemiology of HIV/AIDS. Five databases were searched: PsycINFO (American Psychological Association, Washington, DC), PubMed (MEDLINE; National Institutes of Health, Bethesda, Maryland), Social Science Citation Index (Web of Science; Thomson ISI, Stamford, Connecticut), Sociological Abstracts (CSA, Bethesda, Maryland), and Digital Dissertations (ProQuest; UMI, Ann Arbor, Michigan). Searches were designed to include the factors we specified in our framework as social or structural factors (figure 1). Searches were limited to published articles in the English language for the period 1981–2003. The following keywords were included in each search: AIDS/acquired immunodeficiency syndrome, HIV, and epidemiol*. Additional searches were conducted by using combinations of keywords listed in Appendix table 1 corresponding with our framework. We identified four categories of social-level factors of importance to HIV/AIDS epidemiology: cultural context, social networks, neighborhood effects, and social capital. Each uses different conceptual and methodological approaches to examine the effects of social forces on population HIV/AIDS vulnerability. Anthropologist Edward Tylor defined culture as “that complex whole which includes knowledge, belief, art, law, morals, custom, and any other capabilities and habits acquired by man as a member of society” (9, p. 1). Anthropologic and epidemiologic approaches may be integrated in a variety of ways to identify features of the social environment that affect HIV/AIDS risk. One way to explore how the social environment affects HIV/AIDS epidemiology is through the use of mixed research methods. Mixed-methods study designs integrate qualitative and quantitative research methods either sequentially or concurrently (10). In sequential study designs, qualitative methods may be used to explore a topic under study or to explain quantitative epidemiologic findings. Concurrent study designs are meant to confirm, cross-validate, or corroborate findings within a single study. A common type of concurrent mixed methods study is “triangulation,” and this approach has been used extensively in rapid assessments of illicit drug use and HIV/AIDS (11–13). Mixed methods approaches are particularly well suited to the investigation of the often hidden and stigmatizing behavioral and social factors underlying HIV epidemics. One exemplary study combining qualitative methods with quantitative methods was conducted by Beyrer et al. (14) to examine the role of overland heroin trafficking routes in shaping explosive HIV/AIDS epidemics among injection drug users in Southeast Asia. Piecing together data from a variety of sources, including existing epidemiologic data, key informant interviews, and laboratory data, this study revealed that distinct HIV subtypes emerged and recombined along drug trafficking routes originating in Myanmar, one of the world’s largest heroin producers. Along these trafficking routes, communities of injection drug users formed, facilitating the spread of HIV into local communities in Laos, Thailand, Vietnam, India, and China (refer, for example, to Panda et al. (15)). This illustration highlights the broader understanding of HIV/AIDS epidemiology that can be achieved by examining the interplay between contextual factors and social and behavioral factors. Investigation of social networks in HIV/AIDS began with the mapping of relationships between one of the first identified AIDS cases, an airline steward, and a large number of his male sex partners in the early 1980s (16). Social network analysis generates measures of the quality, density, position, and structure of relationships between persons, including dyads (partnerships), personal networks (“egocentric” networks), and larger communities (“sociometric” networks) (17, 18). Social networks can influence health outcomes in direct and indirect ways, including 1) social influence, 2) social engagement and participation, 3) prevalence of infectious disease and network member mixing, 4) access to material goods and informational resources, and 5) social support (19). Researchers have demonstrated that patterns in the structure of relationships—rather than differences in individual risk behaviors alone—explain observed HIV patterns (20, 21). The theoretical foundation for examining social networks in HIV research is closely tied to advances in sexually transmitted disease (STD) epidemiology. A key concept from STD epidemiology is the notion of the “core group,” a small group of disease transmitters responsible for a large proportion of cases (22). Friedman et al. (23) found that individuals’ locations within sociometric risk networks were associated with HIV risk among a group of injection drug users in New York City. Other concepts from STD epidemiology, such as partner concurrency, bridging, and mixing patterns, are also important in understanding HIV risk (24–29). Specific network characteristics that have been associated with HIV/AIDS include the size of subgroups and their distribution in a network (23), the centrality of HIV-positive persons within networks (30), partner selection patterns (24, 31–33), and concurrent sexual partnerships (28). Inclusion of these variables has been shown to improve transmission estimates in mathematical modeling (34, 35). Social and normative influences have also been associated with individual HIV risks (36, 37). Network-related social and normative influences are predictive of illicit drug use (38) and condom use behavior (37, 39), highlighting the importance of network-based interventions for HIV prevention (18). Kelly et al. (40, 41) developed a popular opinion leader model that has been effective in reducing HIV risk in several populations, including men who have sex with men and women in low-income housing (42). The success of this model has led to its adaption for international use by the National Institute of Mental Health Collaborative HIV/STD Prevention Trial in China, India, Peru, Russia, and Zimbabwe. Neighborhoods represent the intersection of social networks and physical spatial locations, a confluence Wallace (43) has called the “sociogeographic networks” through which infectious diseases spread. Early interest in the role of neighborhood social environment in disease transmission was sparked by a study in Colorado Springs, Colorado, in which researchers found that gonorrhea was highly focused geographically in core residential neighborhoods (44). Both direct and indirect mechanisms may determine how neighborhood-level factors shape population HIV/AIDS patterns. Direct mechanisms are those that increase the likelihood of a person coming into contact with someone who is HIV positive, for example, through residential segregation and the social isolation of marginalized populations. Indirect mechanisms include those that increase population vulnerability to HIV/AIDS, such as exposure to poor socioeconomic conditions, high unemployment, or the proliferation of illicit drug markets. A range of neighborhood-level factors have been examined in relation to infectious disease, including poverty and income (45, 46), residential segregation (47), and neighborhood physical environment (48, 49). Current research in neighborhood and area effects on health emphasizes the importance of moving beyond documentation of associations to analyze the social and epidemiologic mechanisms through which neighborhood effects might operate (50–54). Increasing concentrations of affluence and poverty are contributing to what demographer Douglas Massey has called “a radical change in the geographic basis of human society” (55, p. 395). Powerful social and economic forces in US cities are increasing neighborhood segregation by class and race/ethnicity (56, 57). Resulting social disorganization and loss of resources and services in poor neighborhoods are in turn shaping HIV/AIDS patterns at the neighborhood level. In a number of studies in New York City, for example, Wallace (58–63) has examined the complex interplay of public policies such as “planned shrinkage” with HIV epidemic dynamics in the Bronx, documenting the “synergy of plagues” that has accompanied rapid social change and the destruction of essential protective networks in poor communities. Using AIDS surveillance data, ecologic studies conducted in various US cities have also consistently found significant associations between income and poverty measures and neighborhood-level AIDS incidence and prevalence rates, and these findings have been consistent across census block groups (46), census tracts (64), and zip codes (65, 66). 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Epidemiologic Reviews · meta-analysis · 394 citationsread the source →

Therapist-delivered Internet psychotherapy for depression in primary care: a randomised controlled trial.

Background: Despite strong evidence for its effectiveness, cognitive-behavioural therapy (CBT) remains difficult to access. Computerised programs have been developed to improve accessibility, but whether these interventions are responsive to individual needs is unknown. We investigated the effectiveness of CBT delivered online in real time by a therapist for patients with depression in primary care. Methods: In this multicentre, randomised controlled trial, 297 individuals with a score of 14 or more on the Beck depression inventory (BDI) and a confirmed diagnosis of depression were recruited from 55 general practices in Bristol, London, and Warwickshire, UK. Participants were randomly assigned, by a computer-generated code, to online CBT in addition to usual care (intervention; n=149) or to usual care from their general practitioner while on an 8-month waiting list for online CBT (control; n=148). Participants, researchers involved in recruitment, and therapists were masked in advance to allocation. The primary outcome was recovery from depression (BDI score <10) at 4 months. Analysis was by intention to treat. This trial is registered, number ISRCTN 45444578. Findings: 113 participants in the intervention group and 97 in the control group completed 4-month follow-up. 43 (38%) patients recovered from depression (BDI score <10) in the intervention group versus 23 (24%) in the control group at 4 months (odds ratio 2.39, 95% CI 1.23-4.67; p=0.011), and 46 (42%) versus 26 (26%) at 8 months (2.07, 1.11-3.87; p=0.023). Interpretation: CBT seems to be effective when delivered online in real time by a therapist, with benefits maintained over 8 months. This method of delivery could broaden access to CBT. Funding: BUPA Foundation.

Lancet (London, England) · randomised controlled trial · 214 citationsread the source →

Long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial.

Background: For men with localised prostate cancer, surgery provides a survival benefit compared with watchful waiting. Treatments are associated with morbidity. Results for functional outcome and quality of life are rarely reported beyond 10 years and are lacking from randomised settings. We report results for quality of life for men in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) after a median follow-up of more than 12 years. Methods: All living Swedish and Finnish men (400 of 695) randomly assigned to radical prostatectomy or watchful waiting in SPCG-4 from 1989 to 1999 were included in our analysis. An additional 281 men were included in a population-based control group matched for region and age. Physical symptoms, symptom-induced stress, and self-assessed quality of life were evaluated with a study-specific questionnaire. Longitudinal data were available for 166 Swedish men who had answered quality-of-life questionnaires at an earlier timepoint. Findings: 182 (88%) of 208 men in the radical prostatectomy group, 167 (87%) of 192 men in the watchful-waiting group, and 214 (76%) of 281 men in the population-based control group answered the questionnaire. Men in SPCG-4 had a median follow-up of 12·2 years (range 7-17) and a median age of 77·0 years (range 61-88). High self-assessed quality of life was reported by 62 (35%) of 179 men allocated radical prostatectomy, 55 (34%) of 160 men assigned to watchful waiting, and 93 (45%) of 208 men in the control group. Anxiety was higher in the SPCG-4 groups (77 [43%] of 178 and 69 [43%] of 161 men) than in the control group (68 [33%] of 208 men; relative risk 1·42, 95% CI 1·07-1·88). Prevalence of erectile dysfunction was 84% (146 of 173 men) in the radical prostatectomy group, 80% (122 of 153) in the watchful-waiting group, and 46% (95 of 208) in the control group and prevalence of urinary leakage was 41% (71 of 173), 11% (18 of 164), and 3% (six of 209), respectively. Distress caused by these symptoms was reported significantly more often by men allocated radical prostatectomy than by men assigned to watchful waiting. In a longitudinal analysis of men in SPCG-4 who provided information at two follow-up points 9 years apart, 38 (45%) of 85 men allocated radical prostatectomy and 48 (60%) of 80 men allocated watchful waiting reported an increase in number of physical symptoms; 50 (61%) of 82 and 47 (64%) of 74 men, respectively, reported a reduction in quality of life. Interpretation: For men in SPCG-4, negative side-effects were common and added more stress than was reported in the control population. In the radical prostatectomy group, erectile dysfunction and urinary leakage were often consequences of surgery. In the watchful-waiting group, side-effects can be caused by tumour progression. The number and severity of side-effects changes over time at a higher rate than is caused by normal ageing and a loss of sexual ability is a persistent psychological problem for both interventions. An understanding of the patterns of side-effects and time dimension of their occurrence for each treatment is important for full patient information. Funding: US National Institutes of Health; Swedish Cancer Society; Foundation in Memory of Johanna Hagstrand and Sigfrid Linnér.

The Lancet. Oncology · randomised controlled trial · 277 citationsread the source →

The Surgeon as the Second Victim? Results of the Boston Intraoperative Adverse Events Surgeons' Attitude (BISA) Study.

Background: An intraoperative adverse event (iAE) is often directly attributable to the surgeon's technical error and/or suboptimal intraoperative judgment. We aimed to examine the psychological impact of iAEs on surgeons as well as the surgeons' attitude about iAE reporting. Study design: We conducted a web-based cross-sectional survey of all surgeons at 3 major teaching hospitals of the same university. The 29-item questionnaire was developed using a systematic closed and open approach focused on assessing the surgeons' personal account of iAE incidence, emotional response to iAEs, available support systems, and perspective about the barriers to iAE reporting. Results: The response rate was 44.8% (n = 126). Mean age of respondents was 49 years, 77% were male, and 83% performed >150 procedures/year. During the last year, 32% recalled 1 iAE, 39% recalled 2 to 5 iAEs, and 9% recalled >6 iAEs. The emotional toll of iAEs was significant, with 84% of respondents reporting a combination of anxiety (66%), guilt (60%), sadness (52%), shame/embarrassment (42%), and anger (29%). Colleagues constituted the most helpful support system (42%) rather than friends or family; a few surgeons needed psychological therapy/counseling. As for reporting, 26% preferred not to see their individual iAE rates, and 38% wanted it reported in comparison with their aggregate colleagues' rate. The most common barriers to reporting iAEs were fear of litigation (50%), lack of a standardized reporting system (49%), and absence of a clear iAE definition (48%). Conclusions: Intraoperative AEs occur often, have a significant negative impact on surgeons' well-being, and barriers to transparency are fear of litigation and absence of a well-defined reporting system. Efforts should be made to support surgeons and standardize reporting when iAEs occur.

Journal of the American College of Surgeons · cohort or longitudinal · 110 citationsread the source →

Young adult outcomes in the follow-up of the multimodal treatment study of attention-deficit/hyperactivity disorder: symptom persistence, source discrepancy, and height suppression.

Background: The Multimodal Treatment Study (MTA) began as a 14-month randomized clinical trial of behavioral and pharmacological treatments of 579 children (7-10 years of age) diagnosed with attention-deficit/hyperactivity disorder (ADHD)-combined type. It transitioned into an observational long-term follow-up of 515 cases consented for continuation and 289 classmates (258 without ADHD) added as a local normative comparison group (LNCG), with assessments 2-16 years after baseline. Methods: Primary (symptom severity) and secondary (adult height) outcomes in adulthood were specified. Treatment was monitored to age 18, and naturalistic subgroups were formed based on three patterns of long-term use of stimulant medication (Consistent, Inconsistent, and Negligible). For the follow-up, hypothesis-generating analyses were performed on outcomes in early adulthood (at 25 years of age). Planned comparisons were used to estimate ADHD-LNCG differences reflecting persistence of symptoms and naturalistic subgroup differences reflecting benefit (symptom reduction) and cost (height suppression) associated with extended use of medication. Results: For ratings of symptom severity, the ADHD-LNCG comparison was statistically significant for the parent/self-report average (0.51 ± 0.04, p < .0001, d = 1.11), documenting symptom persistence, and for the parent/self-report difference (0.21 ± 0.04, p < .0001, d = .60), documenting source discrepancy, but the comparisons of naturalistic subgroups reflecting medication effects were not significant. For adult height, the ADHD group was 1.29 ± 0.55 cm shorter than the LNCG (p < .01, d = .21), and the comparisons of the naturalistic subgroups were significant: the treated group with the Consistent or Inconsistent pattern was 2.55 ± 0.73 cm shorter than the subgroup with the Negligible pattern (p < .0005, d = .42), and within the treated group, the subgroup with the Consistent pattern was 2.36 ± 1.13 cm shorter than the subgroup with the Inconsistent pattern (p < .04, d = .38). Conclusions: In the MTA follow-up into adulthood, the ADHD group showed symptom persistence compared to local norms from the LNCG. Within naturalistic subgroups of ADHD cases, extended use of medication was associated with suppression of adult height but not with reduction of symptom severity.

Journal of child psychology and psychiatry, and allied disciplines · cohort or longitudinal · 179 citationsread the source →

Healthy lifestyle and life expectancy at age 30 years in the Chinese population: an observational study.

Background: The improvement of life expectancy is one of the aims of the Healthy China 2030 blueprint. We aimed to investigate the extent to which healthy lifestyles are associated with life expectancy in Chinese adults. Methods: We used the prospective China Kadoorie Biobank (CKB) study to examine the relative risk of mortality associated with individual and combined lifestyle factors (never smoking or quitting not for illness, no excessive alcohol use, being physically active, healthy eating habits, and healthy body shape). Participants with coronary heart disease, stroke, cancer, or missing values for body-mass index were excluded. For analysis of chronic respiratory diseases, participants with chronic obstructive pulmonary disease or asthma were excluded. We estimated the national prevalence of lifestyle factors using data from the China Nutrition and Health Surveillance (CNHS; 2015) and derived mortality rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (2015). All three data sources were combined to estimate the life expectancy of individuals at age 30 years following different levels of lifestyle factors by using the life table method. The cause-specific decomposition of the life expectancy differences was analysed using Arriaga's method. Findings: After the exclusion of CKB participants with coronary heart disease, stroke, cancer, or missing BMI data at baseline, 487 209 were included in the primary analysis. Participants with COPD or asthma at baseline were additionally excluded for chronic respiratory disease-related analysis, leaving 451 233 participants with data available for analysis. Data from 171 127 adults aged 30-84 years from the CNHS 2015 were used to estimate the sex-specific and age-specific prevalence of lifestyle-related factors. There were 42 496 deaths documented over a median follow-up of 11·1 years (IQR 10·2-12·1) in CKB. The adjusted hazard ratios (aHRs) of participants adopting five versus 0-1 low-risk factors was 0·38 (95% CI 0·34-0·43) for all-cause mortality, aHR 0·37 (0·30-0·46) for cardiovascular disease mortality, aHR 0·47 (0·39-0·56) for cancer mortality, and aHR 0·30 (0·14-0·64) for chronic respiratory disease mortality. The life expectancy at age 30 years for individuals with 0-1 low-risk factors was on average 41·7 years (95% CI 41·5-42·0) for men and 47·3 years (46·6-48·0) for women. For individuals with all five low-risk factors, the life expectancy at age 30 was 50·5 years (95% CI 48·5-52·4) for men and 55·4 years (53·5-57·4) for women; meaning a difference of 8·8 years (95% CI 6·8-10·7) for men and 8·1 years (6·5-9·9) for women. The estimated extended life expectancy for men and women was mainly attributable to reduced death from cardiovascular disease (2·4 years [27% of the total extended life expectancy] for men and 3·7 years [46%] for women), cancer (2·6 years [30%] for men and 0·9 years [11%] for women), and chronic respiratory disease (0·6 years [7%] for men and 1·2 years [15%] for women). Interpretation: Our findings suggest that increasing the adoption of these five healthy lifestyle factors through public health interventions could be associated with substantial gains in life expectancy in the Chinese population. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Kadoorie Charitable Foundation, UK Wellcome Trust.

The Lancet. Public health · cohort or longitudinal · 129 citationsread the source →

Hand Posturing Is a Nonverbal Indicator of Catastrophic Thinking for Finger, Hand, or Wrist Injury.

Background: Prior research documents that greater psychologic distress (anxiety/depression) and less effective coping strategies (catastrophic thinking, kinesophobia) are associated with greater pain intensity and greater limitations. Recognition and acknowledgment of verbal and nonverbal indicators of psychologic factors might raise opportunities for improved psychologic health. There is evidence that specific patient words and phrases indicate greater catastrophic thinking. This study tested proposed nonverbal indicators (such as flexion of the wrist during attempted finger flexion or extension of uninjured fingers as the stiff and painful finger is flexed) for their association with catastrophic thinking. Questions/purposes: (1) Do patients with specific protective hand postures during physical examination have greater pain interference (limitation of activity in response to nociception), limitations, symptoms of depression, catastrophic thinking (protectiveness, preparation for the worst), and kinesophobia (fear of movement)? (2) Do greater numbers of protective hand postures correlate with worse scores on these measures? Methods: Between October 2014 and September 2016, 156 adult patients with stiff or painful fingers within 2 months after sustaining a finger, hand, or wrist injury were invited to participate in this study. Six patients chose not to participate as a result of time constraints and one patient was excluded as a result of inconsistent scoring of a possible hand posture, leaving 149 patients for analysis. We asked all patients to complete a set of questionnaires and a sociodemographic survey. We used Patient Reported Outcomes Measurement Information System (PROMIS) Depression, Upper Extremity Physical Function, and Pain Interference computer adaptive test (CAT) questionnaires. We used the Abbreviated Pain Catastrophizing Scale (PCS-4) to measure catastrophic thinking in response to nociception. Finally, we used the Tampa Scale of Kinesophobia (TSK) to assess fear of movement. The occurrence of protective hand postures during the physical examination was noted by both the physician and researcher. For uncertainty or disagreement, a video of the physical examination was recorded and a group decision was made. Results: Patients with one or more protective hand postures did not score higher on the PROMIS Pain Interference CAT (hand posture: 59 [56-64]; no posture: 59 [54-63]; difference of medians: 0; p = 0.273), Physical Function CAT (32 ± 8 versus 34 ± 8; mean difference: 2 [confidence interval {CI}, -0.5 to 5]; p = 0.107), nor the Depression CAT (48 [41-55] versus 48 [42-53]; difference of medians: 0; p = 0.662). However, having at least one hand posture was associated with a higher degree of catastrophic thinking (PCS scores: 13 [6-26] versus 10 [3-16]; difference of medians: 3; p = 0.0104) and a higher level of kinesophobia (TSK: 40 ± 6 versus 38 ± 6; mean difference: -2 [CI, -4 to -1]; p = 0.0420). Greater catastrophic thinking was associated with a greater number of protective hand postures on average (rho: 0.20, p = 0.0138). Conclusions: Protective hand postures and (based on prior research) specific words and phrases are associated with catastrophic thinking and kinesophobia, less effective coping strategies that hinder recovery. Surgeons can learn to recognize these signs and begin to treat catastrophic thinking and kinesophobia starting with compassion, empathy, and patience and be prepared to add formal support (such as cognitive-behavioral therapy) to help facilitate recovery. Level of evidence: Level III, diagnostic study.

Clinical orthopaedics and related research · cohort or longitudinal · 35 citationsread the source →

The impact of Ramadan during COVID-19 confinement on weight, dietary, and lifestyle habits in the Kingdom of Saudi Arabia: a cross-sectional study.

Severe procedures were undertaken globally because of the COVID-19 pandemic to overcome the spread of the disease and to prevent catastrophic results affecting the health care system including social distancing, lockdowns, and quarantines. Despite the widely known health benefits of Ramadan fasting, there was a general concern regarding the lifestyle of people during Ramadan 2020 that accompanied the period of COVID-19 pandemic and the home confinement applied. The main objective for the current cross-sectional investigation was to investigate the influence of Covid-19 lockdown during Ramadan fasting on weight change on 481 participants in Saudi Arabia. Identifying the contributing risk factors to weight gain were also addressed. Around 42% of the participants had gained weight and around 38% of the participants had lost weight. Physical activity level was shown to be considered as a protective factor against weight gain (OR = 1.03 with P = 0.008), while increasing the number of meals and not adapting healthy cooking methods can both be considered as contributing factors to weight gain (OR = 1.03 with P = 0.009, and OR = 1.03 with P = 0.004, respectively). Assessing these changes during Ramadan of COVID-19 quarantine provided valuable perspective on the health and wellbeing of Saudi Arabia citizens. These findings should be considered in future studies to explore the persistence of Covid-19 related weight status and habit change.

BMC public health · 3 citationsread the source →

Improving newborn preventive services at the birth hospitalization: a collaborative, hospital-based quality-improvement project.

Objective: The goal was to test the effectiveness of a statewide, collaborative, hospital-based quality-improvement project targeting preventive services delivered to healthy newborns during the birth hospitalization. Methods: All Vermont hospitals with obstetric services participated. The quality-improvement collaborative (intervention) was based on the Breakthrough Series Collaborative model. Targeted preventive services included hepatitis B immunization; assessment of breastfeeding; assessment of risk of hyperbilirubinemia; performance of metabolic and hearing screens; assessment of and counseling on tobacco smoke exposure, infant sleep position, car safety seat fit, and exposure to domestic violence; and planning for outpatient follow-up care. The effect of the intervention was assessed at the end of an 18-month period. Preintervention and postintervention chart audits were conducted by using a random sample of 30 newborn medical charts per audit for each participating hospital. Results: Documented rates of assessment improved for breastfeeding adequacy (49% vs 81%), risk for hyperbilirubinemia (14% vs 23%), infant sleep position (13% vs 56%), and car safety seat fit (42% vs 71%). Documented rates of counseling improved for tobacco smoke exposure (23% vs 53%) and car safety seat fit (38% vs 75%). Performance of hearing screens also improved (74% vs 97%). No significant changes were noted in performance of hepatitis B immunization (45% vs 30%) or metabolic screens (98% vs 98%), assessment of tobacco smoke exposure (53% vs 67%), counseling on sleep position (46% vs 68%), assessment of exposure to domestic violence (27% vs 36%), or planning for outpatient follow-up care (80% vs 71%). All hospitals demonstrated preintervention versus postintervention improvement of > or = 20% in > or = 1 newborn preventive service. Conclusions: A statewide, hospital-based quality-improvement project targeting hospital staff members and community physicians was effective in improving documented newborn preventive services during the birth hospitalization.

Pediatrics · cohort or longitudinal · 30 citationsread the source →

Radiomics in nuclear medicine: robustness, reproducibility, standardization, and how to avoid data analysis traps and replication crisis.

Radiomics in nuclear medicine is rapidly expanding. Reproducibility of radiomics studies in multicentre settings is an important criterion for clinical translation. We therefore performed a meta-analysis to investigate reproducibility of radiomics biomarkers in PET imaging and to obtain quantitative information regarding their sensitivity to variations in various imaging and radiomics-related factors as well as their inherent sensitivity. Additionally, we identify and describe data analysis pitfalls that affect the reproducibility and generalizability of radiomics studies. After a systematic literature search, 42 studies were included in the qualitative synthesis, and data from 21 were used for the quantitative meta-analysis. Data concerning measurement agreement and reliability were collected for 21 of 38 different factors associated with image acquisition, reconstruction, segmentation and radiomics-specific processing steps. Variations in voxel size, segmentation and several reconstruction parameters strongly affected reproducibility, but the level of evidence remained weak. Based on the meta-analysis, we also assessed inherent sensitivity to variations of 110 PET image biomarkers. SUVmean and SUVmax were found to be reliable, whereas image biomarkers based on the neighbourhood grey tone difference matrix and most biomarkers based on the size zone matrix were found to be highly sensitive to variations, and should be used with care in multicentre settings. Lastly, we identify 11 data analysis pitfalls. These pitfalls concern model validation and information leakage during model development, but also relate to reporting and the software used for data analysis. Avoiding such pitfalls is essential for minimizing bias in the results and to enable reproduction and validation of radiomics studies.

European journal of nuclear medicine and molecular imaging · review · 207 citationsread the source →

Telemedicine Applications for Cancer Rehabilitation: Scoping Review.

Background: Cancer is a significant public health issue worldwide. Treatments such as surgery, chemotherapy, and radiation therapy often cause psychological and physiological side effects, affecting patients' ability to function and their quality of life (QoL). Physical activity is crucial to cancer rehabilitation, improving physical function and QoL and reducing cancer-related fatigue. However, many patients face barriers to accessing cancer rehabilitation due to socioeconomic factors, transportation issues, and time constraints. Telerehabilitation can potentially overcome these barriers by delivering rehabilitation remotely. Objective: The aim of the study is to identify how telemedicine is used for the rehabilitation of patients with cancer. Methods: This scoping review followed recognized frameworks. We conducted an electronic literature search on PubMed for studies published between January 2015 and May 2023. Inclusion criteria were studies reporting physical therapy telerehabilitation interventions for patients with cancer, including randomized and nonrandomized controlled trials, feasibility studies, and usability studies. In total, 21 studies met the criteria and were included in the final review. Results: Our search yielded 37 papers, with 21 included in the final review. Randomized controlled trials comprised 47% (n=10) of the studies, with feasibility studies at 33% (n=7) and usability studies at 19% (n=4). Sample sizes were typically 50 or fewer participants in 57% (n=12) of the reports. Participants were generally aged 65 years or younger (n=17, 81%), with a balanced gender distribution. Organ-specific cancers were the focus of 66% (n=14) of the papers, while 28% (n=6) included patients who were in the posttreatment period. Web-based systems were the most used technology (n=13, 61%), followed by phone call or SMS text messaging-based systems (n=9, 42%) and mobile apps (n=5, 23%). Exercise programs were mainly home based (n=19, 90%) and included aerobic (n=19, 90%), resistance (n=13, 61%), and flexibility training (n=7, 33%). Outcomes included improvements in functional capacity, cognitive functioning, and QoL (n=10, 47%); reductions in pain and hospital length of stay; and enhancements in fatigue, physical and emotional well-being, and anxiety. Positive effects on feasibility (n=3, 14%), acceptability (n=8, 38%), and cost-effectiveness (n=2, 9%) were also noted. Functional outcomes were frequently assessed (n=19, 71%) with tools like the 6-minute walk test and grip strength tests. Conclusions: Telerehabilitation for patients with cancer is beneficial and feasible, with diverse approaches in study design, technologies, exercises, and outcomes. Future research should focus on developing standardized methodologies, incorporating objective measures, and exploring emerging technologies like virtual reality, wearable or noncontact sensors, and artificial intelligence to optimize telerehabilitation interventions. Addressing these areas can enhance clinical practice and improve outcomes for remote rehabilitation with patients.

JMIR cancer · review · 17 citationsread the source →

Compassion fatigue, moral distress, and work engagement in surgical intensive care unit trauma nurses: a pilot study.

Preparation for replacing the large proportion of staff nurses reaching retirement age in the next few decades in the United States is essential to continue delivering high-quality nursing care and improving patient outcomes. Retaining experienced critical care nurses is imperative to successfully implementing the orientation of new inexperienced critical care nurses. It is important to understand factors that affect work engagement to develop strategies that enhance nurse retention and improve the quality of patient care. Nurses' experience of moral distress has been measured in medical intensive care units but not in surgical trauma care units, where nurses are exposed to patients and families faced with sudden life-threatening, life-changing patient consequences. This pilot study is a nonexperimental, descriptive, correlational design to examine the effect of compassion satisfaction, compassion fatigue, moral distress, and level of nursing education on critical care nurses' work engagement. This is a partial replication of Lawrence's dissertation. The study also asked nurses to describe sources of moral distress and self-care strategies for coping with stress. This was used to identify qualitative themes about the nurse experiences. Jean Watson's theory of human caring serves as a framework to bring meaning and focus to the nursing-patient caring relationship.A convenience sample of 26 of 34 eligible experienced surgical intensive care unit trauma nurses responded to this survey, indicating a 77% response rate. Twenty-seven percent of the nurses scored high, and 73% scored average on compassion satisfaction. On compassion fatigue, 58% scored average on burnout and 42% scored low. On the secondary traumatic stress subscale, 38% scored average, and 62% scored low. The mean moral distress situations subscale score was 3.4, which is elevated. The mean 9-item Utrecht Work Engagement Scale total score, measuring work engagement, was 3.8, which is considered low. Content analysis was used to identify themes of Role Conflict With Management/Rules, Death and Suffering, Dealing With Violence in the Intensive Care Unit, Dealing With Family, Powerlessness, Physical Distress, and Medical Versus Nursing Values. Additional themes identified were caring, helping families, long-time interdependent relationships of colleagues, and satisfaction in trauma nursing. As work engagement increased, compassion satisfaction significantly increased, and burnout significantly decreased. Results of this study support moral distress as a clinically meaningful issue for surgical intensive care unit nurses. Moral distress scales were elevated, whereas work engagement scales were low. This finding was congruent with Lawrence's study and may reflect ongoing need for greater supports for experienced intensive care unit nurses, from both education and management. Future recommendations for research include examining the interaction of these variables in larger samples to examine additional explanatory factors as well as strategies for self-care, motivation, and behavior change.

Dimensions of critical care nursing : DCCN · 125 citationsread the source →

Pathophysiology of the risk factors associated with osteoporosis and their correlation to the T-score value in patients with osteopenia and osteoporosis in the United Arab Emirates

INTRODUCTION Osteoporosis is a bone disorder, characterized by loss of bone strength because of an imbalance between the bone resorption and the mechanisms of bone formation, leading to increased fragility and fractures. Pathophysiological mechanisms underlying this disorder include an inadequate formation response during the remodeling process of bone formation, which is an essential factor in osteoporosis pathogenesis. This inadequacy is due to the activation of large numbers of osteoclasts as a response to initiation of hematopoietic precursor cells with failure of normal interaction with the osteoblastic lineage. This will lead to excessive bone resorption that may result in complete loss of trabecular structure and loss of template for new bone formation. The time required for osteoblastic replacement is longer than the resorption phase of bone remodeling by osteoclasts. Therefore, any increase in bone remodeling will lead to damaged architecture and loss of bone mass.[1] Recently, it has been estimated that more than 200 million people worldwide have osteoporosis. On the basis of a statistics from the International Osteoporosis Foundation in 2017, one in five men and one in three women over the age of 50 years will experience fractures during their lifetime because of osteoporosis. Furthermore, it has been found that an osteoporotic fracture occurs every 3s, with the most common fractures occurring at the hip, spine, and wrist.[23] Osteoporotic fractures may be the first manifestation of the disease, which is why it is called a silent disease. Risk factors of osteoporosis, decreased bone mineral density (BMD), and increased fragility fractures may be modifiable or non-modifiable. Among the modifiable factors are low body mass index (BMI), vitamin D deficiency, low calcium intake, excessive caffeine and alcohol consumption, smoking, sedentary life and low physical activity, endocrine disorders (such as estrogen deficiency and insulin-dependent diabetes mellitus or hyperparathyroidism), some drugs (such as corticosteroids), and previous history of fragility fractures. The non-modifiable factors include female gender, family history, race, and early menopause.[45] According to the World Health Organization (WHO) diagnostic criteria, osteoporosis is diagnosed by BMD at the hip or spine, which is below the young normal mean reference population by 2.5 standard deviations (SDs) or more. This is called the T-score, and osteopenia is diagnosed by BMD less than or equal to 1 SD.[6] The guidelines for osteoporosis screening vary greatly in various publications. In general, most organizations recommend that all adults older than 50 years of age with a history of fracture must receive BMD screening.[7] Dual-energy X-ray absorptiometry (DXA) at the hip or spine is the best test for measuring central BMD. An association is present between the T-score values in DXA in patients with osteoporosis or osteopenia and the risk of fractures. A fracture risk assessment tool (FRAX) was designed. It is estimated that for every 1 SD decline in spine BMD, the risk of having a spine fracture increases 2.3 times and the risk of having a hip fracture increases 2.6 times.[89] As the most common bone disease in humans, the prevalence of osteoporosis is steadily increasing due to a growing elderly population, and thus represents a major public health concern with reduced bone strength and a higher risk of fractures.[68] The prevalence of osteoporosis is steadily escalating due to increased life expectancy as a result of developed health services. According to the 2016 WHO report, in the United Arab Emirates (UAE), life expectancy at birth for men was 76 years and for women it was 79 years.[10] The UAE population projection showed that in 2011, 7% of the population were 50 years of age or over and less than 1% were 70 years of age or over. By 2050, it is estimated that 12% of the population will be 50 years or over and 2% will be 70 years or over.[11] MATERIALS AND METHODS Study design The study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines. Ethical approval number UG-H-18-11-7-10 was obtained from the Research Ethics Committee of the college. The study was conducted on a population sample of national and nonnational people in the UAE. Both men and women were recruited in the study. Data were collected from the patients in six governmental and private hospitals. Research tools A total of 200 male and female participants between the age of 25 and 80 years were recruited in the study. Eighty percent of the sample were women and 20% were men. After obtaining the required consent, each participant was asked to fill a structured questionnaire consisting of 25 questions, which was used as the primary tool for data collection. The questions were formulated both in Arabic and English, it required 3–4min to be completed. BMD of the participants was assessed in the International Radiology Centre and correlated with their data in the questionnaires. DXA scan was used for the measurement of BMD. Data collection and data analysis After ensuring strict confidentiality, data were collected between March 20, 2016 and May 20, 2016. The following information was obtained: Demographic data (gender, age, race, BMI, and occupation) Family history of osteoporosis or osteoporotic fractures Social history and lifestyle, physical activity, and exposure to the sun Dietary habits such as calcium, caffeine, and soft drinks intake Medical history of diseases and medicines. For female participants, number of pregnancies, lactation, and age at menopause were included The following criteria were used to evaluate osteoporosis: Normal BMD: if T-score between +2.5 and –1 Osteopenia: if T-score between –1 and –2.5 Osteoporosis: if T-score below –2.5 The filled questionnaires were coded and data were analyzed statistically using the Statistical Package for the Social Sciences (SPSS) software (version 24; IBM Corporation, Newyork, USA). Spearman’s correlation test was carried out to assess the association between different variables in the study. A P value of less than 0.05 was considered significant. RESULTS Sociodemographic data The sociodemographic background of the study participants is listed in Table 1. A total of 200 participants were included in the study. The control group and the osteoporotic group consisted of 100 participants each, 20% of them were men, whereas 80% of the respondents were women. Table 1: Background demographic data of the respondentsBody mass index The patients with osteoporosis have significantly lower BMI than the control group (P < 0.05). Results showed that 72% of them have a BMI less than 25 kg/m2 (P < 0.05) [Table 2] [Figure 1].Table 2: Body mass index of the respondentsFigure 1: Body mass index (kg/m2) of the respondentsSmoking behavior Regarding smoking behavior, a significant value was evident between smoking and osteoporosis (P < 0.01) as 54% of the patients with osteoporosis were current smokers, whereas 72% of the controls had never smoked before [Table 3] [Figure 2].Table 3: Smoking behavior and intake of milk, coffee, and soft drinks by the respondentsFigure 2: Intake of milk and caffeine and smoking behavior by the respondentsDietary calcium intake The intake of milk and dairy products by the participants was used to assess the dietary calcium intake. The patients with osteoporosis have a significant low calcium intake (P < 0.01), whereas non-osteoporotic control significantly consume more milk and dairy products (P < 0.01). A positive correlation was found between the intake of milk and dairy products and the T-score value of the participants (P < 0.05) [Table 3] [Figures 2 and 3].Figure 3: Correlation between milk intake and T-score in patients with osteoporosisCaffeine consumption Caffeine intake was evaluated in this study by the amount of coffee, tea, or soft drinks consumed by the participants each day. The results showed that the patients with osteoporosis significantly consume more caffeine (P < 0.01). A negative correlation is present between the amount of caffeine intake and T-score value of the participants (P < 0.05) [Table 3] [Figures 2, 4, and 5].Figure 4: Correlation between tea/coffee intake and T-score in patients with osteoporosisFigure 5: Correlation between soft drinks intake and T-score in patients with osteoporosisExercise behavior and exposure to the sun Results showed a significant positive correlation between the duration of exercise and the T-score value of the participants (P < 0.05) [Table 4] [Figure 6].Table 4: Exercise behavior and exposure to sun of the respondentsFigure 6: Correlation between exercise duration and T-score in patients with osteoporosisRegarding the exposure to the sun, the results showed that 96% of the patients with osteoporosis were exposed to the sun for less than 15min, three to four times a week or not exposed at all, whereas most of the normal controls (72%) exposed their bodies to the sun for 16–30min/day, three to four times a week [Table 4] [Figure 7].Figure 7: Sun exposure behavior of the respondentsDiseases and medications Results of the study revealed that 46% of the patients with osteoporosis were diabetic, 42% of them were treated by antidiabetics, 18% had arthritis and 38% had been treated previously by corticosteroids [Table 5].Table 5: Distribution of patients with osteoporosis by their diseases and medicationsNumber of pregnancies and breastfeeding Female participants constituted 80% of the study sample, 75% of the females with osteoporosis were menopausal, 75% of them had three or more pregnancies, and 82.5% of them breastfed their children, whereas these values for the control group participants are 30%, 28%, and 33%, respectively. Results showed a significant positive correlation between the age at menopause and the T-score value of females with osteoporosis (P < 0.05) [Table 6] [Figure 8]. The distribution of patients according to the joint affected by Osteoporosis or Osteopenia is shown in [Figure 9] and [Table 7].Table 6: Distribution of female patients with osteoporosis by number of pregnancies and breastfeedingFigure 8: Correlation between age at menopause and T-score in female patients with osteoporosisFigure 9: Distribution of patients having osteopenia or osteoporosis in wrists, hips, or spineTable 7: Distribution of patients having osteoporosis and/or osteopenia in hips, wrists, and spineDISCUSSION To maintain normal bone structure, a remodeling process that consists of osteoclasts, removing old bone, and osteoblasts, synthesizing new bone, occurs. Hematopoietic progenitors produce osteoclasts, whereas mesenchymal stem cells called marrow stromal fibroblasts produce osteoblasts. This process is controlled by certain circulating hormones, growth factors, and locally produced cytokines through their effects on apoptosis of osteoblasts and osteoclasts. Estrogen deficiency or glucocorticoid excess leads to bone loss because of changes in the production of bone cells. This is caused by the prolongation of the life span of osteoclasts and the shortening of the life span of osteoblasts. On the contrary, drugs that aim to treat or prevent osteoporosis prevent apoptosis of osteoblasts and/or stimulate the apoptosis of osteoclasts.[12] The pathogenesis of osteoporosis is the consequence of various hormonal, genetic, dietary, lifestyle, and physical factors. Genetic factors mainly affect the BMD and bone formation, whereas low levels of estrogen increase parathyroid hormone, and local cytokines are mainly responsible for bone remodeling imbalance.[13] Age and gender In this study, 76% of the patients with osteoporosis were women at or above 50 years of age. Osteoporosis is usually considered a disease of the elderly with low BMD. In a recent study, most of the patients with osteoporosis were in the age groups of 45–49 and 50–54 years.[14] Previous studies showed that women were at an increased risk of developing osteoporosis because of their faulty behavior of physical inactivity, sun-avoidance behavior, low intake of dairy products, and poor diets.[151617] Body mass index The results of this study showed a significant number of patients of osteoporosis with BMI <25 kg/m2, where P < 0.05. Women that have low BMI are at a higher risk of developing osteoporosis. It is reported that one unit change in BMI has a larger effect on the risk of developing osteoporosis than most other modifiable risk factors. To help reduce the risk of osteoporosis, patients should be advised to maintain a weight within the normal range.[1516] The risk of osteoporotic fractures increases in adults who have low BMI of less than 20 kg/m2.[18] On the contrary, patients who are obese (BMI >30 kg/m2) are also at a high risk of developing osteoporosis and fractures because of the risk of repeated falls and the weakness of the skeletal muscles due to loss of its mass as a result of aging.[19] Exercise and physical activity The results of this study showed a significant correlation between the exercise time and the T-score value. Previous studies concluded that physical activity and exercises stimulate skeletal growth and bone strength.[45] Estrogen Estrogen deficiency has a critical effect on the pathogenesis of osteoporosis. The results of this study showed a significant positive correlation between the age at menopause and the T-score value of the female patients. Estrogen has a crucial role in bone formation and physiology. It stimulates the production of T cell cytokines, affects the osteoblastic cell by altering its production of receptor activator of nuclear factor-Kappa B ligand (RANKL) or Osteoprotegerin (OPG), inhibits the differentiation of osteoclasts by direct action, and stimulates the formation of bone performed by osteoblasts and osteocytes, which allows them to enhance their ability to respond to mechanical forces.[2021] Estrogen produces its effect through a specific cell surface receptor called the estrogen receptor alpha (ERα). This receptor binds and then transports estrogen into the nucleus of the cell where certain genes are then activated by the receptor–hormone complex. ERα receptors and estrogen receptor–related receptor alpha (ERRα) are found on the surface of osteoblasts. ERRα may play a supporting role in the regulation of bone cells.[22] Previous studies also suggest that sex hormone–binding globulin may play a significant role in regulating bone cells as well because it facilitates entry of estrogen into cells.[23] Because of the natural drop of estrogen level in postmenopausal women, they are at the highest risk of developing osteoporosis. A previous study showed that it is an increase in bone resorption that might be the driving force for bone loss during estrogen deficiency in postmenopausal women not impaired bone formation as was previously thought.[1] However, other studies indicated that both markers of bone resorption and formation also increased, leading to accelerated bone remodeling at menopause.[2425] Calcium intake and vitamin D Calcium and vitamin D are two pivotal contributors of bone formation and mineralization. The results of this study showed that the patients with osteoporosis have a significant low calcium intake, whereas controls significantly consume more milk and dairy products (P < 0.01). This significant result showed the importance of calcium intake. Results also established a positive correlation between calcium intake and the T-score value of the participants. Vitamin D plays an important role in maintaining calcium homeostasis and bone integrity as it is essential for intestinal calcium absorption.[26] It is estimated that over one billion people around the world have vitamin D deficiency.[2728] Sun exposure is considered as the source of vitamin D, the present results showed a significant value (P < 0.01) as 74% of the patients with osteoporosis exposed their bodies to the sun for 5min or less, three to four times per week, whereas 72% of controls exposed their bodies to the sun for 15–30min, 3 to 4 times a week. A previous study conducted in the UAE showed that 58.2% of the UAE nationals were vitamin D deficient compared to 45% of the patients from other nationalities.[29] In spite of living in sunny areas, such as UAE, Saudi Arabia, and India, young populations have a high prevalence of vitamin D deficiency because of insufficient knowledge and practice of vitamin D and its health implications.[3031] Decreased blood calcium level will lead to secondary hyperparathyroidism. This decrease may result from impaired intestinal calcium absorption due to vitamin D deficiency, aging, or other diseases. Calcitriol, the active form of vitamin D, stimulates the intestinal absorption of calcium and phosphorus. It has an inhibitory effect on the synthesis of parathyroid hormone as well. Therefore, calcitriol deficiency will lead to secondary hyperparathyroidism as well.[32] There is a clear evidence that the risk of having an osteoporotic fracture increases when vitamin D levels are below 50 nmol.[3334] However, a recent study showed that pathological macrophages produced by vitamin D receptor signaling play an important role in the development of myelofibrosis.[35] Smoking The results of this study showed that nicotine has a significant effect on the incidence of osteoporosis (P < 0.01). Smoking has been identified as a modifiable risk factor for low BMD and increased osteoporotic fracture risk.[3637] Smoking behavior should be evaluated when assessing the fracture risk and FRAX.[1638] The role of smoking in decreasing BMD is complicated; smoking is shown to be associated with other risk factors for osteoporosis such as decreased physical activity, low BMI, and poor diet.[38] Nicotine has both direct and indirect effects on BMD. The direct effect is on bone cell proliferation and is described to be biphasic, small doses have a stimulatory effect, whereas toxic large doses have an antiproliferative effect on the proliferation of osteoblasts.[39] This effect on osteoblasts is receptor mediated by the nicotinic acetylcholine receptors, where nicotine in low doses upregulates gene expression of alkaline phosphatase, type 1 collagen, and osteocalcin.[40] Nicotine produces an increased level of tumor necrosis factor α (TNFα) secretion that reduces bone formation by osteoblasts and increases bone resorption by osteoclasts. TNFα has a powerful osteoclastogenic effect through its stimulating effect on RANKL production and by intensifying osteoclasts production.[41] It is strongly supported that RANK/RANKL/OPG systems have a role in regulating bone resorption and the formation of osteoclasts.[42] The main predisposing factor for chronic obstructive pulmonary disease (COPD) has been found to be smoking. The most important factor in managing COPD continues to be the termination of smoking.[43] It has been shown in numerous studies that smokers with COPD have elevated levels of pro-inflammatory cytokines in the form of interleukin-6. In addition, TNFα levels are much higher in COPD smokers than in asymptomatic smokers. This indicates that COPD affects local and systemic inflammatory responses, which in turn affects bone remodeling.[4445] Nicotine has an indirect effect on BMD, which is caused by releasing calcitropic hormones and glucocorticoids, which leads to an increase in bone resorption.[43] Furthermore, smoking has been linked to an increase in the level of cortisol[4446] as well as a decrease in the level of estradiol.[47] Nicotine also harms intestinal calcium absorption, which might lessen the effectiveness of dietary calcium supplements.[48] Also, toxic carcinogenic metabolites of nicotine have also been found to increase osteoclast formation in rats.[49] Moreover, one hip fracture in eight postmenopausal women with osteoporosis is attributable to smoking. This correlation could not be explained by early menopause, low BMI, lower levels of exercise, or by the actions of nicotine on estrogen. This indicates that there is an independent negative effect of nicotine on BMD, which means that smokers lose bone at a faster rate than nonsmokers.[50] CONCLUSION Prevalence of osteoporosis is high in the UAE and is expected to grow due to increased life expectancy and faulty lifestyle of inadequate dietary habits, sun exposure, exercise behavior, and smoking. More intervention should be directed toward changing the modifiable risk factors in the patients with osteoporosis, and more studies should be directed toward osteoporosis in the UAE. Limitations of the study To make the study a polycentric research, it would require greater number of participants from all the emirates of the UAE. Financial support and sponsorship This work is self-funded by the authors. Conflicts of interest There are no conflicts of interest.

Journal of Pharmacy And Bioallied Sciences · 11 citationsread the source →

Health of men, women, and children in post-trafficking services in Cambodia, Thailand, and Vietnam: an observational cross-sectional study.

Background: Trafficking is a crime of global proportions involving extreme forms of exploitation and abuse. Yet little research has been done of the health risks and morbidity patterns for men, women, and children trafficked for various forms of forced labour. Methods: We carried out face-to-face interviews with a consecutive sample of individuals entering 15 post-trafficking services in Cambodia, Thailand, and Vietnam. We asked participants about living and working conditions, experience of violence, and health outcomes. We measured symptoms of anxiety and depression with the Hopkins Symptoms Checklist and post-traumatic stress disorder with the Harvard Trauma Questionnaire, and used adjusted logistic regression models to estimate the effect of trafficking on these mental health outcomes, controlling for age, sector of exploitation, and time in trafficking. Findings: We interviewed 1102 people, of whom 1015 reached work destinations. Participants worked in various sectors including sex work (329 [32%]), fishing (275 [27%]), and factories (136 [13%]). 481 (48%) of 1015 experienced physical violence, sexual violence, or both, with 198 (35%) of 566 women and girls reporting sexual violence. 478 (47%) of 1015 participants were threatened and 198 (20%) were locked in a room. 685 (70%) of 985 who had data available worked 7 days per week and 296 (30%) of 989 worked at least 11 hours per day. 222 (22%) of 983 had a serious injury at work. 61·2% (95% CI 58·2-64·2) of participants reported symptom of depression, 42·8% (39·8-45·9) reported symptoms of anxiety, and 38·9% (36·0-42·0) reported symptoms of post-traumatic stress disorder. 5·2% (4·0-6·8) had attempted suicide in the past month. Participants who experienced extremely excessive overtime at work, restricted freedom, bad living conditions, threats, or severe violence were more likely to report symptoms of depression, anxiety, and post-traumatic stress disorder. Interpretation: This is the first health study of a large and diverse sample of men, women, and child survivors of trafficking for various forms of exploitation. Violence and unsafe working conditions were common and psychological morbidity was associated with severity of abuse. Survivors of trafficking need access to health care, especially mental health care. Funding: Anesvad Foundation and International Organization for Migration International Development Fund.

The Lancet. Global health · 87 citationsread the source →

Heart rate variability

IN FOCUSHeart rate variabilityHarald M. StaussHarald M. StaussDepartment of Exercise Science, University of Iowa, Iowa City, Iowa 52242Published Online:01 Nov 2003https://doi.org/10.1152/ajpregu.00452.2003MoreSectionsPDF (59 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the rhythm of the heart has not only fascinated cardiologists but also inspired poets and musicians. Indeed, the periodic beat of the heart was used to define the speed of music. In music notation, the traditional Italian term "moderato" originally referred to one beat of the measure per walking pace (76-80 paces/min) or heartbeat (∼72 beats/min). The use of the heartbeat to define the speed of music may imply that the periodicity of the beat of the heart is very constant. However, this is not necessarily the case. In fact, loss of heart rate variability can indicate severe cardiovascular diseases and reliably predict poor outcome of such conditions (18, 22, 27, 47a). This In Focus article reviews sources of heart rate variability, its role as a prognostic marker for cardiovascular diseases, and its application in estimation of cardiac autonomic nervous system activity. All of these topics have been addressed intensely in articles published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology during the last two years. In healthy subjects, the sinoatrial node located at the posterior wall of the right atrium initiates each beat of the heart. Due to the unstable membrane potential of the myocytes located in this region, action potentials are generated periodically at a fairly constant frequency. This relatively constant frequency generated by the autorhythmicity of the sinoatrial node is modulated by many factors that add variability to the heart rate signal at different frequencies. According to the Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology (47a) these frequencies are classified into 1) ultra-low frequencies (ULF; >5-h cycle length) that include the circadian rhythm (6, 9, 34, 54); 2) very low frequencies (VLF; >25-s cycle length) that are supposed to be affected by temperature regulation (1, 7, 34, 52, 54) and humoral systems (9, 36); 3) low frequencies (LF; >6-s cycle length in humans) that are sensitive to changes in cardiac sympathetic (and presumably parasympathetic) nerve activity (27, 30); and 4) high frequencies (HF; 2.5- to 6.0-s cycle length in humans) that are synchronized to the respiratory rhythm (5) and are primarily modulated by cardiac parasympathetic innervation (38).The most prominent oscillation in the ULF band of the heart rate spectrum is the circadian rhythm. The autonomic nervous system contributes significantly to circadian heart rate variability. Using long-term recordings in conscious rabbits, Barrett et al. (6) demonstrated a strong circadian rhythm in heart rate, mean arterial blood pressure, renal blood flow, and renal sympathetic nerve activity. The importance of this study is that it clearly demonstrates that sympathetic nerve discharges exhibit a strong circadian rhythmicity. The paraventricular nucleus of the hypothalamus (PVN) appears to play a central role in mediating the circadian rhythm of autonomic nervous system activity. First, GABAergic and glutamatergic neurons project from the suprachiasmatic nuclei of the hypothalamus (SCN) to spinal-projecting neurons of the PVN (12). The SCN is the major central oscillator that triggers the day/night cycle. It receives photic input from the retina (47) and drives many neuroendocrine, metabolic, autonomic, and behavioral circadian rhythms (14, 16, 21, 31, 35, 44, 46, 50). In addition, microinjections of the inhibitory neurotransmitter GABA into the PVN of anesthetized rats elicit dose-dependent decreases in renal sympathetic nerve activity, whereas bicuculline (a GABA antagonist) increases renal sympathetic nerve activity (56). Second, from the PVN, neurons project to the nucleus of the solitary tract (that integrates inputs from the baroreceptors), the nucleus ambiguus (origin of preganglionic parasympathetic neurons to the heart), the rostroventrolateral medulla (location of sympathetic premotor neurons), and the intermediolateral cell column of the thoracolumbar spinal cord (location of preganglionic sympathetic neurons). Thus PVN neurons can modulate autonomic nervous system activity by sending inputs to major sites of autonomic nervous system regulation. As an example, a pivotal role of the PVN for sympathoexcitation during parturition was recently demonstrated in sheep. The increase in sympathetic nerve activity that accompanies birth in maternal animals was prevented by stereotactic lesioning of the PVN (43). Taken together, a major component of the circadian heart rate variability is elicited by diurnal fluctuations in autonomic nervous system activity, generated by corresponding fluctuations of neuronal activity within the PVN, which depend on circadian inputs originating from the SCN.It has been suggested that thermoregulation affects VLF heart rate variability (10, 26). Cooling the heart causes bradycardia, a mechanism used in heart surgeries. Conversely, fever is known to increase heart rate. Raising body core temperature from 36.0 to 36.6°C caused an increase in heart rate by almost 40 beats/min in male subjects (1), whereas acutely reducing ambient temperature from thermoneutral conditions (35°C) to 29, 23, and 17°C, reduced heart rate from 400 to 250 beats/min in 8-day-old rats (7). In addition, lowering temperature in the isolated working rat heart from 37 to 31°C reduced heart rate from 332 to 215 beats/min and markedly increased heart rate variability (28), indicating that parts of the temperature effects on heart rate and heart rate variability are independent from the autonomic nervous system. In contrast to the tachycardia that accompanies acute elevations in temperature, chronically raising ambient temperature in adult rodents from a standard housing temperature of 21-23°C to thermoneutral conditions (29-30°C) reduced heart rate by roughly 50 beats/min in rats (34) and by 200-300 beats/min in mice (54). The authors of these articles (34, 54) suggested that standard housing temperatures are associated with cold stress that causes parallel activation of brown adipose tissue, cardiac, and vasomotor sympathetic drives that elicits nonshivering thermogenesis and tonically elevates heart rate and arterial blood pressure. These and other studies indicate that both direct effects of temperature on pacemaker activity of the sinus node (28) and indirect effects mediated via the autonomic nervous system (11, 25, 51, 55) mediate temperature effects on heart rate and heart rate variability. Thus fluctuation in temperature is an important source of heart rate variability that should not be underestimated. In a more recent study, this was taken into account by core body temperature correction of heart rate variability (3).Endocrine factors affecting heart rate variability include thyroxine, reproductive hormones, the renin-angiotensin system, steroids, and others. Chronic subcutaneous infusion of angiotensin II in rats markedly increased blood pressure and heart rate variability, expressed as standard deviation (9). In contrast, chronic corticosterone treatment is likely to reduce baroreflex-mediated heart rate variability, because baroreceptor-heart rate (39) and baroreceptor-renal sympathetic nerve activity reflex sensitivity (41) were blunted in chronically corticosterone-treated rats. Furthermore, an interaction between angiotensin II and glucocorticoids was recently described. Intracerebro-ventricular microinjections of angiotensin II AT1 receptor antagonists caused marked decreases in mean blood pressure and heart rate in rats chronically treated with corticosterone but not in control animals (40). This interaction is likely to take place in the central nervous system, because peripheral angiotensin II AT1 receptor blockade did not alter the effects of betamethasone treatment on blood pressure, heart rate, and baroreceptor-heart rate reflex sensitivity in newborn lambs (42).Adenosine is a substance less known to affect heart rate variability. It is produced locally in the heart (53) and binds to A1-adenosinergic receptors, which are among the earliest expressed G protein-coupled receptors in the heart (36). The A1-adenosinergic agonist N6-cyclopentyladenosine dose dependently reduced heart rate in murine embryos, whereas 1,3-dipropyl-8-cyclopentylxanthine, an A1-adenosinergic antagonist, increased heart rate (36). Adenosine also exerts central nervous system effects in various brain areas (15, 20). Microinjections of adenosine into the nucleus of the solitary tract of awake rats caused dose-dependent changes in heart rate: low doses (0.01 nmol) produced a bradycardic response, whereas high doses (2.5-5.0 nmol) elicited a tachycardic response (15). Thus adenosine may indeed be involved in the regulation of heart rate and modulate heart rate variability via local cardiac and central nervous system effects. It has been proposed that the intrinsic cardiac nervous system plays an active role in regulating cardiac function (4, 37, 45, 57). This nervous system consists of sympathetic and parasympathetic neurons and interconnecting local circuits (37). Neurons in the canine right atrial ganglionated plexus (RAGP) spontaneously generate activity even after chronic cardiac autonomic denervation (45). Right atrial neurons in patients undergoing coronary artery bypass surgery generated spontaneous activity that was unrelated to the cardiac cycle but sensitive to changes in systemic arterial pressure, indicating that these neurons receive pressure-sensitive sensory inputs (4). In addition, it has been suggested that substance P acts as a neuromodulator and neurotransmitter in intracardiac ganglia of the guinea pig, modulates the response to vagal inputs, and triggers action potentials at the site of parasympathetic ganglia independent of acetylcholine (57). Furthermore, the right atrial (RAGP) and the posterior atrial ganglionated plexus (PAGP) appear to have different functions. Ablation of the PAGP reduced vagally mediated bradycardia by 26%, whereas RAGP ablation completely abolished this response. Inhibition of sympathetically mediated tachycardia by vagal stimulation was attenuated by ablation of either plexus (37). Thus parasympathetic efferent neurons are primarily located in the RAGP, whereas prejunctional parasympathetic-sympathetic interactions also involve neurons within the PAGP (37). The spontaneous activity of neurons in the intrinsic cardiac nervous system, even after cardiac denervation (45), suggests an active role of this system in regulating heart rate. However, the impact of the intrinsic cardiac nervous system on heart rate variability remains to be elucidated. The importance of the autonomic nervous system for heart rate variability in humans becomes apparent in patients following cardiac transplantation, in whom heart rate variability is markedly reduced (49). Although reinnervation is possible after months and years, initially transplanted hearts can be considered to be denervated. Thus the reduced heart rate variability in cardiac transplanted patients (49) underlines the importance of an intact autonomic innervation for spontaneously occurring heart rate variability. A major component of the chronotropic effect of the autonomic nervous system is linked to cAMP. Intracellular cAMP increases the inward current of Na+ (funny current, If), which determines the rate of the slow diastolic depolarization that precedes each action potential. The activity of adenylate cyclase and thus intracellular cAMP levels are increased by stimulation of sympathetic β1-adrenergic receptors and decreased (via a Gi protein) by stimulation of parasympathetic muscarinic receptors. Thus cardiac sympathetic innervation increases the rate of the slow diastolic depolarization and accelerates heart rate, while cardiac parasympathetic innervation elicits opposite effects. Interestingly, parasympathetic-mediated changes in heart rate occur much faster than sympathetic-mediated effects on heart rate (27, 30, 47a). As a result, cardiac sympathetic nervous system activity can only affect LF components of heart rate variability, whereas the parasympathetic nervous system can also modulate HF components. A hitherto unsolved question in this context is if the rapid heart rate response to parasympathetic stimulation compared with the slow effect of sympathetic inputs is due to 1) different kinetics of β1-adrenergic vs. muscarinic receptors, 2) different kinetics of adenylate cyclase vs. phosphodiesterase, the enzyme that cleaves cAMP, or 3) fast parasympathetic-mediated opening of KACh channels (via muscarinic receptors and a GK protein). Support for the latter possibility comes from experiments in the rabbit sinoatrial node that demonstrated that activation of KACh channels contributes to the initial slowing of heart rate as a result of vagal stimulation (8).On the basis of the different frequency response characteristics of sympathetic and parasympathetic modulation of heart rate, frequency analysis of heart rate variability is often used as a tool to determine "autonomic balance" or sympathetic and parasympathetic nervous system activity (27, 47a). As an example, the wavelet transform was recently used to determine cardiac autonomic responses to reperfusion in patients with thrombolysis after coronary thrombosis. Depending on the location of the infarct, marked alterations in LF or HF spectral power of heart rate or in the LF/HF ratio was observed in all successful reperfusions (48).The HF component corresponds to the frequency of respiration and is driven by the vagus as indicated by the strong respiratory pattern of cardiac vagal motoneurons in the nucleus ambiguus (38). The LF component has been ascribed to sympathetic modulation of cardiac pacemaker activity, because a variety of studies demonstrated that acute interventions that increase sympathetic nervous system activity, such as orthostatic perturbations (17, 19, 33), mental stress (32), or handgrip exercise (13, 24) increases LF spectral power of heart rate (27, 30). In addition to acute perturbations of cardiac sympathetic nerve activity, feedback oscillations generated by the baroreceptor reflex also appear to contribute to LF spectral power of heart rate as it was demonstrated that sinoaortic denervation markedly reduces the LF component (27, 30). Despite the strong modulation of heart rate by the autonomic nervous system, the LF and HF spectral components of heart rate variability may not always be very reliable markers for cardiac sympathetic and parasympathetic "tone" (30). In a recent study, muscle sympathetic nerve activity was recorded together with heart rate variability during application of lower body negative pressure that is known to increase muscle sympathetic nerve activity (17, 33). At higher levels of lower body negative pressure (-15 mmHg), both muscle sympathetic nerve activity and relative LF spectral power of heart rate increased significantly, whereas HF spectral power decreased (17). These findings suggest that LF spectral power reflects cardiac sympathetic "tone." However, no correlation within subjects was found between changes in LF/HF ratio and muscle sympathetic nerve activity (17). Thus heart rate variability does not reliably reflect the sympathetic response to orthostatic stress. Respiration-related fluctuation of heart rate (respiratory sinus arrhythmia) is probably the most often investigated component of heart rate variability, as it is believed that this component reflects respiration-driven vagal modulation of sinus arrhythmia (27). In a recent study, Rentero et al. (38) recorded the electrical activity from cardiac vagal motoneurons in the nucleus ambiguus. Firing of these neurons was modulated by the central respiratory cycle. This and other studies support the view that respiratory sinus arrhythmia is generated by central coupling of the respiratory oscillator with autonomic centers in the brain stem. However, a mechanical cardiopulmonary coupling as a source of respiration-related heart rate variability has also been suggested (5). The Bainbridge reflex causes a tachycardia in response to hypervolemia. This reflex is initiated by atrial mechanoreceptors and uses efferent sympathetic and parasympathetic pathways to modulate heart rate in response to changes in central venous pressure (23). Thus respiratory changes in central blood volume cause corresponding respiratory fluctuations in cardiac autonomic nervous system activity via the Bainbridge reflex. Only the parasympathetic component of the efferent pathway of the reflex can contribute to respiratory sinus arrhythmia, because sympathetic actions on heart rate are too damped to follow the respiratory frequency. The gain and phase of the transfer function between respiratory changes in lung volume and R-R intervals of the ECG were calculated in human subjects during graded changes in central blood volume (5). At the respiratory frequency, the phase was -180 degree, indicating that an inspiratory increase in central blood volume was associated with a decrease in R-R interval (increase in heart rate). Furthermore, the gain of the transfer function at the respiratory frequency steadily increased with increasing central volumes (except at the highest volume). Both of these findings confirm the presence of the Bainbridge reflex in humans (5). Thus, in addition to the central coupling of respiratory oscillators with cardiovascular centers, the Bainbridge reflex may contribute to respiration-related heart rate variability by mechanical cardiopulmonary coupling. There is general agreement that low heart rate variability is an unfavorable prognostic marker for cardiovascular diseases, such as diabetic autonomic neuropathy, hypertension, myocardial infarction, and heart failure (18, 22, 27, 29, 47a). Heart rate variability (variance of R-R intervals) was reduced in patients with mild hypertension (29) compared with normal values (1,134 ± 202 vs. 3,466 ± 1,018 ms2) provided by the Task Force (47a). In the rat model of myocardial infarction-induced congestive heart failure, Francis and colleagues (18) reported loss of spontaneous heart rate variability 6 wk after coronary artery ligation. Interestingly, reduced heart rate variability was also observed in a rat model of depression that is based on chronic (4 wk) mild stress application (22). Because depression is an independent risk factor for coronary artery disease, this finding may realistically model a human disease process. The reduction in heart rate variability was abolished by β-adrenergic receptor blockade, indicating that the reduced heart rate variability in this model of depression is related to elevated cardiac sympathetic tone (22).In summary, heart rate variability is generated by multiple factors not exclusively limited to the autonomic nervous system. Specific frequency components of heart rate variability mirror acute perturbations of the autonomic nervous system but do not always reflect autonomic nervous system activity. Simple statistics of heart rate variability, such as the standard deviation of R-R intervals in the ECG, can reliably predict the prognosis of cardiovascular diseases.I thank Dr. R. McAllen for critically reviewing the manuscript. References 1 Aoki K, Stephens DP, and Johnson JM. Diurnal variation in cutaneous vasodilator and vasoconstrictor systems during heat stress. 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Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Clinically and experimentally, primary tumor formation and metastasis are distinct processes — locally growing tumors can progress without the development of metastases. This observation prompted the hypothesis that the molecular processes regulating tumorigenicity and metastasis are distinguishable and could be targeted therapeutically. During the process of transformation and subsequent progression to a malignant phenotype, both genetic and epigenetic alterations alter a cell's ability to perceive and respond to signals that regulate normal tissue homeostasis. A minority of tumorigenic cells accrue the full complement of alterations that enables them to disseminate from the primary tumor, survive insults from the immune system and biophysical forces, and respond to growth-promoting and/or inhibitory signals from the distant tissues and thrive there. Identification of genes and proteins that specifically inhibit the ability of cells to form metastases (e.g., metastasis suppressors) is providing new insights into the molecular mechanisms that regulate this complex process. This review will highlight: (a) the functional identification of metastasis suppressors, (b) the signaling cascades and cellular phenotypes which are controlled or modulated by metastasis suppressors, and (c) opportunities for translation and clinical trials that are based on mechanistic studies regarding metastasis suppressors. The identification of nm23, the first metastasis suppressor gene, provided functional evidence for the existence of genes that specifically regulate metastasis (1, 2). Subsequent to this initial discovery, researchers used in vivo studies to identify additional metastasis suppressors. These pioneering studies used an unbiased approach to identify such candidates by demonstrating that ectopic expression of the putative suppressor gene inhibited the development of spontaneous macroscopic metastases without significantly affecting primary tumor growth (3–5). Recently, this definition has been extended to include genes which specifically inhibit metastatic colonization (i.e., experimental metastasis formation using i.v. injection). The use of in vivo assays is required because in vitro assays are often of inadequate complexity to sufficiently model the entire process of metastasis. Furthermore, there are currently no in vitro models that allow the study of preferential growth within different target tissues. Table 1 lists the proteins which have bona fide metastasis suppressor activity in vivo (i.e., suppression of metastasis following ectopic expression into metastatic cell lines). It is interesting to note that metastasis suppressor activity for many of these genes would not have been predicted a priori based on their known cellular function(s). Furthermore, the unbiased, functional strategy identified novel genes for which no cellular function was known at the time of discovery. Metastasis suppressors can impart their suppressive activity at one or more of the steps in the metastatic cascade (6). For example, in vivo studies showed that metastatic cancer cells which express ectopic KISS1, JNKK1/MKK4, MKK6, MKK7, TXNIP, nm23-H1, or SSeCKS proteins could successfully disseminate and lodge at secondary sites, but are suppressed in their ability to colonize (i.e., form overt metastases) target tissues (7–12). After lodging at secondary sites, disseminated cells may die, persist as nondividing cells, or initiate growth (13). Such pivotal cellular decisions depend on both the expression of a specific gene profile as well as the activation status of key signaling pathways and the cumulative inputs of timing, amplitude, and duration of signaling responses. In short, cells expressing metastasis suppressors grow at primary sites, but fail to proliferate at secondary or metastatic sites, suggesting differential responses to site-specific external signals. Although the observation that a gene of interest functions as a metastasis suppressor is an excellent starting point, research is now focused on the biochemical and molecular mechanisms by which metastasis suppressor proteins execute their in vivo functions. Metastasis suppressors vary widely in their cellular locations and biochemical functions. Such proteins could display either extracellular (e.g., KISS1) or intracellular localization patterns. Within the cell, they are located in various cellular compartments, from the plasma membrane (e.g., cadherin, KAI1, CD44), cytoskeleton (e.g., RhoGDI2, gelsolin), cytosol (e.g., JNKK1/MKK4, nm23-H1, RKIP), mitochondria (e.g., caspase 8), and nucleus (e.g., BRMS1, CRSP3, TXNIP) (14–21).Cells respond to external stimuli by using a limited number of signaling pathways. Signaling specificity is achieved, at least in part, by combinatorial spatiotemporal activation of signaling proteins. The summation of these signaling events, enabled by a cell-specific gene expression profile, is a tailored, situation-appropriate response. During the process of transformation and progression to a malignant phenotype, both genetic and epigenetic alterations influence a cell's ability to perceive and respond to signals which regulate normal tissue homeostasis. The accumulation of such alterations during progressive rounds of cell division could endow a minority of tumorigenic cells with the ability to disseminate from the primary tumor. It is likely that as a result of these changes, metastatic cells are no longer bound by tissue-of-origin–derived signaling specificity and acquire the ability to modulate their responses to the changing environments encountered throughout the metastatic cascade. Current data supports a model in which ectopic expression of metastasis suppressor proteins may restore, at least in part, the endogenous signaling repertoire of earlier, more benign cellular generations, thereby blocking metastasis formation. In this light, metastasis formation can be viewed as the result of a cell's ability to respond to multiple growth milieus as opposed to being restricted to growth in the microenvironment of the tissue of origin. Defining pathways regulating metastatic growth requires the integration and interpretation of data obtained over experimental settings ranging from the molecular interactions of specific proteins, to communication between signaling networks within single cells, and ultimately cellular interactions among populations of cells that yield a particular disease state. This line of inquiry is a particular challenge in studies of metastasis regulation because of the complexity and diversity of downstream events that take place in metastasis formation. The majority of metastasis suppressors identified participate in highly conserved eukaryotic signal transduction pathways. Based on their known biochemical functions, we have divided the metastasis suppressors into four general signaling categories: cytoskeletal signaling, mitogenic pathways, stress-activated pathways, and survival pathways (Fig. 1). Although it may seem straightforward to place a metastatic suppressor into a linear signaling pathway, it is important to be mindful that these pathways are, in fact, dynamic networks that exist in series and parallel leading to crosstalk and interplay; phenomena known as emergent properties. The cytoskeleton is a dynamic structure that enables motility, deformability, and flexibility, while maintaining cellular architecture. For most nonhematopoietic cells, motility is an ancillary function; however, as a nonhematopoietic cell transitions from the benign to the invasive to the metastatic state, motility becomes an increasingly paramount ability. Without a dynamic actin cytoskeleton, a tumor cell would be incapable of intravasation or extravasation, and the cellular deformability is necessary to complete the metastatic cascade. Not surprisingly, several proteins involved in cellular motility have been implicated as metastasis suppressors. The Rho family of GTP-binding proteins, which include Rho, Rac, and Cdc42, are central players in the regulation of actin dynamics. The Rho-GTPase family consists of small 20 to 30 kDa monomeric GTP-binding proteins that bind GDP/GTP and hydrolyze GTP, leading to the activation of downstream effector molecules (22). In this signaling scheme, metastasis suppressors have been identified as upstream inhibitors of the Rho family (23), or downstream effectors (24). RhoGDIs inhibit Rho family members by impeding the dissociation of GDP from Rho proteins, thereby locking the Rho protein in its inactive state, preventing Rho proteins from interacting with effector targets, and/or sequestering Rho-GTPases in the cytosol (25). RHOGDI2 was shown to suppress experimental lung metastasis but not affect in vitro growth or in vivo tumorigenicity. The Src-suppressed C kinase substrate is a protein kinase C substrate with protein scaffolding properties that have been shown to be a negative regulator of Rho family members (26). Reexpression of Src-suppressed C kinase substrate suppressed secondary lung metastases in nude mice and increased cell-cell adhesion, yet had little effect on primary tumor growth (10). Furthermore, Src-suppressed C kinase substrate reexpression at physiologic levels suppresses podosome formation and correlates with the induction of normal actin cytoskeletal structures and cell morphology, but not with the inhibition of Src kinase activity in cells (26).The finding that RhoGDI displayed the ability to suppress metastasis suggested that the downstream molecules it inhibits may have metastasis-promoting activities. This hypothesis seems to hold true in that mice deficient in RhoC, a target of RhoGDI, displayed a marked decrease in metastasis potential (27). Furthermore, specific inhibition of a downstream effector of Rho, ROCK, decreased tumor cell invasiveness in vitro and reduced the dissemination of tumor cells implanted in the peritoneal cavity in vivo (28). RhoGDI2 has also been shown to regulate secreted growth factors such as endothelin 1 (ET-1), which contribute to metastasis and will be discussed below (29). This prometastasic activation of effectors downstream of the Rho family is not universal. Gelsolin is a downstream effector of Rac that regulates the length of actin via its filament severing and capping activities. Overexpression of gelsolin has been shown to inhibit metastasis in vivo (24). Counterintuitively, gelsolin is an indispensable protein of podosomes, which are thought to play an active role in tissue invasion and matrix remodeling through their regulation of matrix metalloprotease (MMP) activity (30, 31).Cell interactions with the extracellular matrix and with neighboring cells trigger numerous responses that have essential roles in the regulation of behavior and fate. Integrin-mediated cell adhesions provide bidirectional links between the microenvironment and the cytoskeleton. This crosstalk between a cell and its local environment occurs whether the cell is benign, malignant, or metastatic. In this light, the cytoskeleton serves as a conduit for the integration and processing of intracellular and extracellular information; however, changes in the cytoskeletal program during pathologic progression may alter how this information is integrated and processed. Two metastasis suppressors have been shown to have interactions with integrins. Connective tissue growth factor is a 38-kDa cysteine-rich heparin-binding protein which is a secreted growth factor that can bind to integrins on the cell surface (32). Ectopic expression of connective tissue growth factor inhibited metastatic colonization by lung cancer cells (33). In contrast, the KAI1 metastasis suppressor protein is a member of the tetraspanin family of proteins and has been shown to interact with a myriad of cell surface proteins including other tetraspans (i.e., CD9, CD81), integrins β1 and β2, MHCII growth factor receptors, and intracellular signaling proteins such as protein kinase C (34). It has been hypothesized that KAI1 modulates integrin and growth receptor signaling by accelerating the rate of internalization via a protein kinase C–dependent pathway, thereby modulating cell adhesion and cell migration (34). Furthermore, KAI1 has been shown to decrease the integrin- and ligand-induced activation of the receptor tyrosine kinase c-Met, and independently decreases integrin-induced Src activation. Both c-Met and Src are thought to be required for invasion (35). A final observation with respect to the involvement of integrins in metastasis suppressor activity concerns caspase-8 function. Loss of caspase-8 in neuroblastoma cells leads to increased survival and an increased incidence of metastasis. The induction of caspase-8-mediated apoptosis seems to be due to unligated integrins because decreased expression of unligated integrins enhanced cell survival (36–38).Claudin-4 is a component of tight junctions which form the most apical component of intercellular junctional complexes where they establish cell polarity and cellular functions such as permeability (39, 40). These intercellular junctions not only carry out adhesive functions but also contain crucial components of signaling pathways that regulate epithelial proliferation and differentiation. Complementary in vitro and in vivo studies identified claudin-4 as an inhibitor of invasion and metastasis in pancreatic cancer cells and a target of transforming growth factor-β and extracellular signal-regulated kinase (ERK) signaling (40, 41).RECK, a membrane glycoprotein that encodes a GPI-anchored glycoprotein harboring three protease inhibitor–like domains, has been shown to negatively regulate MMP-2, MMP-9, and MT1-MMPs in vitro, suggesting that it is an important regulator of extracellular matrix remodeling. Furthermore, RECK-null mouse embryos displayed markedly elevated MMP activity. Interestingly, RECK is down-regulated by Ras signaling, a commonly altered pathway in many malignant cells (42).The role of some putative metastasis suppressors is more complex. There are several of a protein as a metastasis suppressor in one model and a potential tumor suppressor in For example, is a glycoprotein that responses of the cell to their cellular Although it has been in the that of has been shown to suppress metastasis in the cancer system other have that may metastatic activity a of the invasion and of and has been suggested to be a is not the only protein to have an role in metastasis. are a of that cell-cell adhesion in various tissues in a function is controlled by its Both and seem to inhibit cell migration and the in vivo metastatic potential of cells other studies have suggested that may invasion It is important to note that cancer cells of tissue used in several of the The tissue specificity of metastasis suppressor function is with the and integration information through signal transduction is a secreted protein and is hypothesized to processing by The are known as or not be secreted in to its metastatic suppressor activity has yet to be at the identification of upstream of identified a metastasis suppressor activity for CRSP3, a of the receptor of cells with suppressed metastasis and was with an of providing a potential between these and metastasis regulation stress-activated protein and pathways in parallel to the protein kinase In to the of with and have been with cell and apoptosis in to and changes, and growth factor specifically either or The protein is a kinase that has been shown to and the and in to a of extracellular can function as a metastasis suppressor in both and cancer Complementary in vitro and in vivo assays showed that the kinase activity of is required for the suppression of overt metastases and is to Subsequent studies identified metastasis suppressor for and in and interest is the finding that in cancer signals through the of the pathway to suppress metastasis in cancer signals through the of the pathway to suppress metastasis In vivo studies that both and suppress the formation of overt metastases by the ability of disseminated cells to colonize the lung identification of a metastasis suppressor function for protein also or protein mechanistic between the to cellular and of metastatic ability. is an endogenous inhibitor of a component of a system that has been implicated in cancer progression The levels of in cells are by endogenous as the in to to and including The primary of cellular is the is through of membrane or in to to with molecular or thereby highly or a of events that result in cell and of metastasis. this and ectopic expression of modulates these events to suppress metastasis formation is currently pathway is by mitogenic such as growth growth or which receptor tyrosine and The of mitogenic factors to cell surface a series of that with the activation of various factors and proteins and regulation may at in this is through both the of a kinase for a as well as protein expression levels of regulation are by intracellular localization and with scaffolding or proteins. These events may be important for regulating metastatic In the of metastasis the protein with the by to and the kinase suppressor of Ras a protein that has a role in the regulation of Ras activity and activation of the pathway has been shown to regulate signaling, suggesting that metastasis suppression activity may be by the inhibition of signaling kinase inhibitor protein was identified as a metastasis suppressor gene in functions as a negative upstream regulator of signaling and kinase interact with at sites, and of either inhibits of the Both be in to inhibition may suppress metastasis by of metastasis suppressors, and are with the signaling The signaling pathway a key role in many of cell survival and 1 are of an inhibitory and a and signals from various cellular proteins such as and an integration for the activation of and downstream to a that a of downstream targets, the and also regulates a of target proteins that cell proliferation and survival The levels of are and several particular interest is the which to signaling metastasis suppressor protein has been with the of cells showed decreases in endogenous levels of (i.e., of This finding is with a model in which changes in signaling the ability of disseminated cells to survive in the and grow at secondary In contrast, expression of the metastasis suppressor is modulated by clinical is the finding that expression correlates significantly with in both and cancer and that the in as a significantly of and cancer survival either evidence from the cell molecular and genetic studies that the metastatic process requires many steps to The of only one in this of in vivo events the process and a This enabled the identification of metastasis suppressor proteins. the of the however, the is not as straightforward because which signaling in the metastatic process are is not have insights into this by metastatic colonization as the in the metastatic cascade that is from a of A clinical will this to of invasive are with metastatic and (i.e., These that many with invasive disease disseminated cancer cells at preventing the of disseminated cells into the metastatic (i.e., the process of would a for cancer This approach more at preventing cancer cells from the primary tumor for the that this process has place the is first with In where this process has not yet local such as and can the the for additional at the an for metastasis preventing the growth of disseminated tumor cells into an overt clinical metastasis or the metastases. the approach not the in hold disease in providing increased of the with both of these is the identification of at for disease that they may at metastatic that can be to this include both tumor as well as molecular of the primary tumor to the development of metastasis a it has been to of the disseminated tumor cells at a secondary as the and as being distinct from that at the primary with to the tumor tumor cells distinct in the primary and secondary sites, and these interactions can or include locally and as well as cell-cell interactions in environments such as the and these with the of metastasis suppressor protein one can to there are to metastasis suppressor proteins. The of these on of the leading to of metastasis suppressor protein For example, the gene is it that of a normal gene would be the In contrast, was secondary to suppressed for example, at the endogenous gene seem we will provide an of approach from that have the of the first identified metastasis a of metastasis suppressor protein function in disseminated tumor In many cancer is with metastasis that occurs A study used gene to and whether this would cancer metastasis in an model of this A cell line of metastatic potential to the by in vivo was used to the of reexpression on metastasis. of these cells, an expressing was This in expression of the gene in most of the tumor cells in in and was with a in the number of metastases and a of This of of the of induction as a approach The of this approach are also to the of which is a disease that the In with gene is and the with i.v. development from the also the of the metastasis gene but the approach reexpression of the endogenous gene as a the was to a that would expression and allow at to on at of the This of would a that is and with an and have been to For example, was to expression in a cell line elevated the expression of cells out an of the the that elevated the expression of metastatic cell is a used at in and as well as at in cancer Furthermore, elevated expression and inhibited colonization and this effect was through The effect of on the of expression was in an in vivo model system for the of metastases the cell line to lung mice to or in of mice to of The number of metastases mouse was reduced by to on the metastases in reduced by to in the inhibited the number and of metastases in this This in metastases was with reexpression in the lung a of in with metastases and and tumors is of gene expression alterations with of metastasis suppressor protein A would be that functional of metastasis suppressor proteins is with gene expression changes, and cellular Recently, this with the that of metastasis suppressor proteins is with the of was used to a novel These studies focused on RhoGDI2, a suppressor of metastasis in an model of cancer metastasis reduced expression was to be with decreased survival for with cancer that RhoGDI2 as a on the expression of genes and to identify such genes in a of the lung metastasis model and primary clinical of RhoGDI2 protein is currently they to proteins or pathways downstream of These genes required to be following the of RhoGDI2 protein from the cells, and be of being inhibited by or to the changes in gene expression following of RhoGDI2 expression in metastatic cells, several proteins including This finding was by the between RhoGDI2 expression levels and of in tumor (29). Furthermore, inhibition of the endothelin with of the endothelin receptor such as to metastatic suppression in cells deficient for RhoGDI2 (29). The endothelin has been shown to regulate tissue cell cell and remodeling also has on cells in the and lung important of cancer metastasis In to such may growth factor and factor and growth factor one in the proliferation of and cells tumor also a role for in metastases from and and supports a model in which cells, in providing a microenvironment for these that trials with endothelin may be for with cancer following of the primary The for its use in the from the effect these have had in preventing experimental metastasis. These however, not the of these in metastatic but this is yet to be The molecular shown between and RhoGDI2 is because of endothelin receptor A such as with clinical In fact, in with in a the most events and that is well In this there was no at to in other of was not by this the of this effector approach to other metastasis suppressor proteins could identify potential novel for in other for and during the of key of this

Clinical Cancer Research · review · 131 citationsread the source →

Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation

HomeStrokeVol. 43, No. 10Modulation of Neural Plasticity as a Basis for Stroke Rehabilitation Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBModulation of Neural Plasticity as a Basis for Stroke Rehabilitation Marcela Pekna, MD, PhD, Milos Pekny, MD, PhD and Michael Nilsson, MD, PhD Marcela PeknaMarcela Pekna From the Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. , Milos PeknyMilos Pekny From the Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. and Michael NilssonMichael Nilsson From the Center for Brain Repair and Rehabilitation, Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden. Originally published23 Aug 2012https://doi.org/10.1161/STROKEAHA.112.654228Stroke. 2012;43:2819–2828Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2012: Previous Version 1 IntroductionCurrent understanding of the mechanisms underlying neural plasticity changes after stroke stems from experimental models as well as clinical studies and provides the foundation for evidence-based neurorehabilitation. In this review, we first describe the main structural and functional constituents of neural plasticity that are believed to contribute to recovery of function after stroke. Next, we discuss selected behavioral manipulations and adjuvant therapies that can stimulate neural plasticity and improve recovery of function, particularly when applied in combination with task-specific physiotherapy and in a stimulating environment. Neural Plasticity After Brain and Spinal Cord InjuryExperience-Dependent Plasticity of the Cerebral CortexCerebral cortex is an assembly of neuronal cells that are highly interconnected. The morphology as well as function of these complex and spatially distributed networks are modulated or even controlled by the glial component of the central nervous system (CNS). The ability to adapt in response to the changing environment is the most fundamental property of the nervous tissue and constitutes the basis for learning. Neural plasticity is the neurobiological basis for the ability to adapt and learn in an experience-dependent manner.1 At the structural level, neural plasticity could be defined in terms of dendritic and axonal arborization, spine density, synapse number and size, receptor density, and in some brain regions also the number of neurons. These structural constituents of neural plasticity jointly determine the complexity of neuronal networks and their activity and contribute to recovery of function after stroke and other CNS injury. Spontaneous Recovery of Function After StrokeLoss of function attributable to stroke is caused by cell death in the infarcted region as well as cell dysfunction in the areas surrounding the infarct. In addition, the function of remote brain regions, including the contralateral areas that are connected to the area of tissue damage, is compromised because of hypometabolism, neurovascular uncoupling, and aberrant neurotransmission, jointly called diaschisis.1 Some recovery of function occurs spontaneously after stroke in humans as well as in animal models. It is believed that this functional recovery involves 3, to some extent overlapping, phases: (1) reversal of diaschisis, activation of cell genesis, and repair; (2) changing the properties of existing neuronal pathways; and (3) neuroanatomical plasticity leading to the formation of new neuronal connections.1 The basic processes underlying phases 2 and 3 also are involved in normal learning and it has been recognized that functional improvement after CNS injury is a relearning process.2Cortical Map RearrangementsAs stated, the brain, and especially the cerebral cortex, has a capacity to alter the structure and function of neurons and to reorganize its neural networks in response to the changes in input and output demands. Thus, when the normal input to a particular area of the primary somatosensory cortex is lost because of injury, rapid structural and functional reorganization results in this area being activated by sensory stimulation of the surrounding intact body regions. Thus, spinal cord injuries lead to both unmasking of existing latent connections as well as changes in somatosensory cortex anatomy attributable to the growth of new lateral connections.3–5 Similarly, the motor maps in the primary motor cortex change in response to task-specific training or after injury. Training human subjects or animals to perform a specific task leads to an increase in the area of motor cortex that controls the muscles used during the task.2 Injury to the motor cortex leads to the recruitment of motor areas that were not making significant contribution to the lost function before the injury. For example, in macaque monkeys, recovery of dexterity after unilateral motor cortex lesion is mediated by the ipsilesional premotor cortex. Inactivation of this region abolishes recovered movement, whereas it does not affect the performance in uninjured monkeys.6 The notion that the activity of cortical areas recruited after injury plays a role in functional recovery in humans is supported by a study showing that in well-recovered stroke patients, the ipsilesional dorsal motor cortex shows increase in activity.7 Even stronger evidence stems from clinical studies showing that, when the function within such a newly recruited area is disrupted using transcranial magnetic stimulation, the recovered movement of the limb affected by stroke is impaired.8–11 Functional redundancy attributable to substantial degree of overlap within and across brain regions can also contribute to the ability of the brain to adapt to injury.2Contralateral Hemisphere InvolvementThe contralesional hemisphere has the capacity to contribute to movement on the ipsilateral side but does not make any significant contribution in healthy subjects.12 However, significant increases in contralesional motor cortex activity can be observed in stroke patients during movement of the affected foot or arm.13–15 These and other studies have demonstrated that in the early phase of stroke recovery process, there is an increased activation of the motor areas in both hemispheres but is substantially more pronounced on the contralesional side. The contralesional activation is often reduced in the later stage of recovery. Although there is no general consensus concerning the role of contralesional somatosensory and motor area activation in recovery of function, it appears that the best recovery is associated with an early recruitment of the supplementary motor areas on the ipsilesional side, whereas persistent activation of the contralesional prefrontal and parietal cortex predicts a slower and less complete recovery and also is often associated with larger infarct.16,17 Notably, a recent functional magnetic resonance imaging study has shown that the pattern of brain activation present in the early phase after stroke could be predictive of subsequent recovery of motor functions.18Contralesional Axonal Remodeling of the Corticospinal SystemWhereas the capacity for functional and structural rearrangements has been studied for decades and is well-documented for the neural networks within the cerebral cortex, the plasticity responses induced by stroke at the level of the spinal cord have been demonstrated only recently. Using a rat stroke model, Liu et al19 showed that the spontaneous behavioral motor recovery highly correlates with the remodeling of corticospinal tract axons in the cervical spinal cord as well as the reorganization of pyramidal neurons in the cerebral cortex of both hemispheres. Consistent with conclusions from human imaging studies, they further showed that functional recovery is highly correlated with contralesional cortical wiring only in the acute phase, with a negative correlation later.19 Although the capacity for remodeling of the corticospinal tract axons at the spinal cord level remains to be demonstrated in stroke patients, these findings add a new dimension to the rehabilitative efforts for improved functional recovery after stroke. Cell GenesisIn the adult human brain, neural stem cells keep producing new neurons, astrocytes, and oligodendrocytes in 2 defined regions, the dentate gyrus of the hippocampus and the subventricular zone, albeit at a much lower rate than during earlier ontogenetic stages.20 A structure analogous to the rostral migratory stream in rodents connecting the subventricular zone with the olfactory bulb exists also in the human brain.21 Having originated from dividing neural stem cells, differentiating cells migrate through the rostral migratory stream to the olfactory bulb. In the rodent stroke models, some of these cells divert from the rostral migratory stream and reach the ischemic penumbra, where some of them transiently persist and others turn into neurons and astrocytes.22 We do not know yet the functional significance of the adult mammalian neurogenesis because no animal models exist in which neurogenesis could be specifically inhibited without simultaneous inhibitory or modulatory effects on other plasticity responses. However, an enriched environment applied to adults of various vertebrate species stimulates both baseline and ischemia-triggered neurogenesis. Thus, it is possible that newly formed neurons, astrocytes, or oligodendrocytes positively affect brain plasticity and functional recovery after stroke. In a mouse CNS, gap junctional coupling occurs between introduced neural stem cells and residential neuronal cells, and is essential for the neuroprotective effect of neural stem cells on the endogenous neuronal cells.23 Thus, apart from the plasticity-promoting "trophic" effects of newly born and partially differentiated neuroectodermal cells, these cells also might protect the ischemic penumbra by a direct cell–cell transfer of signaling and other molecules. Angiogenesis, the formation of new vessels, plays an important role in remodeling of ischemic brain tissue after stroke through enhanced perfusion as well as blood flow–independent mechanisms.24Increasing Neural Plasticity Through Behavioral Manipulations and Adjuvant TherapiesEvidence accumulated during the past 2 decades together with recent advances in the field of stroke recovery clearly show that the effects of neurorehabilitation can be enhanced by behavioral manipulations and combination with adjuvant therapies that stimulate the endogenous neural plasticity. However, the dose, timing after stroke, and coupling with appropriate physical therapy may be critical for the outcome. Enriched Environment and Multimodal StimulationA large number of animal studies have demonstrated that experience in an enriched environment (housing conditions that facilitate enhanced sensory, cognitive and motor stimulation) stimulates all the structural and functional components of neural plasticity and cognitive performance in healthy animals as well as promotes recovery of sensorimotor function after experimental stroke.25,26 Human equivalents of the environmental enrichment are multimodal stimulation and multisensory training protocols. These have been shown to be more effective for learning in healthy subjects.27–29 However, we are only beginning to understand how to translate the positive effects of enriched environment in experimental animal research to humans. Specific examples of multisensory neurorehabilitation are mirror therapy and action observation, motor imagery and mental training, virtual reality training, and music-related therapies. In mirror therapy, the illusion of movement in the affected limb is created by the reflection of the moving unaffected limb while the affected arm is hidden behind the mirror. The strongest evidence in support of the effectiveness of this approach has come from a study of subacute stroke patients who received 30 minutes of mirror therapy program per day consisting of wrist and finger flexion and extension movements in addition to a conventional program for 4 weeks. Compared with a control group who received a sham instead of mirror therapy, the mirror training patients showed a more improved distal hand functioning at the end of therapy period and at 5-month follow-up.30 Similarly, severely hemiparetic patients who received mirror therapy regained more distal function after 6 weeks of training 30 minutes per day, 5 days per week, for 6 weeks.31 However, little is known about which patients are likely to benefit from mirror therapy and how such a therapy should be preferentially applied.32 Action observation for 4 weeks also led to enhanced motor performance in stroke patients, and this functional improvement was still present at 8 weeks of follow-up.33 Action observation on motor training in combination with concurrent physical training of the observed action enhanced the positive effects of task practice alone.34Mental training is based on conscious activation of brain regions and networks involved in movement preparation and execution. In a placebo-controlled trial of chronic stroke patients, therapist-guided mental practice was associated with increased dexterity and changes in patterns of cortical activation.35 Because motor imagery is not dependent on the actual ability to execute movements, mental training can be used early in the rehabilitation process and even in severely paretic patients, although it can be difficult in patients with left parietal or left lateral prefrontal lesions.36Virtual reality technologies provide multimodal, interactive, and realistic 3-dimensional environments with a high level of control of the sensory input to suit each user's needs. The evidence of the effectiveness of virtual reality training in stroke rehabilitation thus far is limited, with most studies underpowered and lacking controls.37 However, recent reports show that Nintendo Wii gaming technology represents a potentially effective alternative to promote motor recovery,38 and a rehabilitation gaming system facilitates the functional recovery of the upper extremities as compared with intense occupational therapy or nonspecific interactive games for stroke patients who received this adjuvant therapy in combination with conventional rehabilitation.39A number of studies suggest that listening to music can enhance a variety of cognitive functions, such as attention, learning, communication, and memory, both in healthy subjects and in various patient groups.40–42 Music also can affect the mood and motivation of the subject, and thus could be an easy-to-conduct and inexpensive means to facilitate cognitive and emotional recovery in numerous neurological and psychiatric disorders. A recent study of listening to music after stroke demonstrated that patients who listened to self-selected music had better cognitive recovery and mood compared with those who listened to self-selected audio books or those with no listening material.43 Further, listening to music or speech in the acute phase after ischemic stroke induced long-term plastic changes in early sensory processing that correlated with improvement in verbal memory and focused attention.44 Patients with chronic poststroke visual neglect who performed tasks while listening to music of their choice showed enhanced visual awareness of contralesional targets relative to when tasks were performed either with unpreferred music or in silence.45Noninvasive Brain StimulationNoninvasive brain stimulation can be performed using repetitive transcranical magnetic stimulation and transcranial direct current stimulation (tDCS). These therapies have the potential to enhance neuroplasticity during stroke rehabilitation, thereby supporting recovery of motor and cognitive impairments.46,47 The differences between tDCS and transcranial magnetic stimulation are based on presumed mechanisms of action in which transcranial magnetic stimulation acts both as a neurostimulator and a neuromodulator, whereas tDCS acts as a neuromodulator. Depending on the frequency, duration of the stimulation, the strength of the magnetic field, and the shape of the coil, transcranial magnetic stimulation can activate or suppress the activity in different cortical regions. The tDCS delivers weak polarizing currents to the cerebral cortex, which induce sustained changes in neural cell membrane potential, leading to either hyperpolarization or depolarization. The basic cellular mechanisms underpinning the effects of noninvasive brain stimulation are only partially known. Animal studies indicate that the effects of transcranial magnetic stimulation could be analogous to other interventions inducing long-term potentiation or long-term depression in the hippocampus. Different neurotransmitters and neuromodulators such as γ-aminobutyric acid, glutamate, dopamine, and serotonin are altered in defined regions of the brain after stimulation with both repetitive transcranial magnetic stimulation and tDCS. Further, immediate early genes like c-fos and genes coding for neurotrophic factors like brain-derived neurotrophic factor are expressed in the rat brain after repetitive transcranial magnetic stimulation.46,47In humans, both repetitive transcranial magnetic stimulation and tDCS are shown to induce long-term effects on cortical excitability that last for months after the intervention,47 which may, in turn, lead to long-lasting behavioral modifications. These effects are believed to engage mechanisms of neural plasticity, rendering noninvasive brain stimulation well-suited to promote recovery of cognition and motor functions, especially in combination with other types of rehabilitative interventions. Results from several studies show, for example, that active stimulation of either the affected or the unaffected motor cortex in combination with physical and occupational therapy improves motor outcome after stroke.48Pharmacological Modulators of Neural PlasticityRecently, several promising approaches that promote the recovery of function after stroke through the stimulation of neural plasticity have been identified through experimental animal research. Importantly, some of these compounds are already in clinical use for other indications or are already being tested in clinical trials.D-AmphetamineThere is large body of laboratory work showing that administration of amphetamine, a potent psychomotor stimulant that induces neuronal release of norepinephrine, dopamine, and serotonin, coupled with motor practice can enhance motor recovery in animal models of stroke or other brain injury and these functional improvements are associated with increased axonal plasticity and the formation of new anatomic pathways.49,50Several double-blind placebo-controlled clinical studies have evaluated the effects of amphetamine on poststroke motor recovery in humans.49 A meta-analysis concluded that there is no indication for the routine use of amphetamines to improve recovery after stroke.51 Given the potentially critical differences in trial designs, however, the interpretation of the results of this meta-analysis is not clear.49 As pointed out by Goldstein,49 several principles pertinent to the trial design have been elucidated by the animal studies. First, the dose–effect relationship for amphetamine-promoted motor recovery has an inverted "U" shape. The drug is relatively ineffective at lower and higher doses. Second, the effects of certain drugs (eg, amphetamine) on recovery are dependent on concomitant behavioral experience. Third, the timing of the drug administration/experience intervention is critical and also varies with the number and frequency of treatment sessions. Fourth, some drugs (eg, haloperidol) impair recovery. Thus, the clinical value of D-amphetamine in combination with physiotherapy remains to be determined through new clinical trials. The National Institute of Health–sponsored Amphetamine-Enhanced Stroke Recovery trial to evaluate the impact of the timing and duration of therapy was started in 2003. Regrettably, this trial was put on hold in 2009 pending application for further funding and the data remain unanalyzed. Recently, a pilot randomized clinical trial involving 16 patients showed that 10 mg amphetamine administered 2 days per week before physiotherapy augments the positive effects of physiotherapy on recovery of activities of daily living and arm function.52LevodopaLevodopa (L-3,4-dihydroxyphenylalanine) is the precursor of dopamine that is further converted to norepinephrine. Delayed treatment with levodopa in combination with physiotherapy improves functional motor recovery in ischemic stroke patients.53 Although the positive effects of levodopa (and amphetamine) on recovery are mostly ascribed to the increased levels of norepinephrine at the synapse,53,54 there is also experimental evidence in support of the role of astrocytes and dopamine signaling in recovery-enhancing of of receptor is in brain tissue from that were in enriched environment after cerebral A more of the of receptor in recovery after stroke showed that the of receptor is in the cells, particularly astrocytes, in the region of animals with recovery of neurological The receptor is in membrane of astrocytes and neurons and plays an essential role in membrane and Importantly, a potent and receptor enhanced functional recovery in rat models of stroke when administered within 2 days after stroke promising is in a stroke clinical phase increases in the of induced by long-term changes and and changes that and cellular In the brain, serotonin are neuroprotective through their effects and improve cognitive by neurogenesis in the A clinical for motor recovery after acute ischemic stroke demonstrated in a larger of patients with to after ischemic stroke that physiotherapy in combination with early treatment with motor recovery and the number of dependent patients compared with physiotherapy These results for even larger and more with an on functional outcome Because serotonin are not a of experimental and studies are to further the understanding of their of acid, is the most effective drug for the treatment of with a of after brain improved functional outcome in through a combination of its effects on and increased plasticity and The clinical and of in treatment of stroke remain to be is a of after unilateral stroke neurons on the side of the brain to new to areas of the and spinal cord and improved behavioral outcome in altered in neurons contralateral to stroke and enhanced the ability of these neurons to connections on the side of the spinal with a receptor or with environmental enrichment the effects of these 2 treatment on the of use after These results that the combination of behavioral and adjuvant therapies may have or even effect in the recovery of function after stroke. A treatment was and in Because is in clinical for it appears to be a particularly for brain plasticity and outcome in stroke is a that plasticity and recovery after CNS injury through treatment enhanced functional recovery and reorganization of the corticospinal tract and axonal plasticity in the uninjured hemisphere to areas after cortical as well as increased dendritic and spine of pyramidal neurons in the contralesional sensorimotor of the receptor system or the use of that the signaling through the receptor have effects on axonal plasticity and recovery of function after experimental A recent study showed that also leads to the improvement of chronic neurological and of neuronal plasticity and that this therapy may be used to function even when administered for 2 weeks weeks after in using the or could be their into the brain after administration because of the to the to clinical of based on receptor may have been by a of a active receptor that the after A phase clinical trial to subjects with acute spinal cord injury has been and a phase trial is in stroke, the zone shows increased neuroplasticity which sensorimotor to from However, this important for rehabilitation, is by neuronal mediated by γ-aminobutyric and is caused by an in the ability of astrocytes to γ-aminobutyric is a drug that acts as for the of γ-aminobutyric treatment with 3 days after stroke the γ-aminobutyric and in an early and sustained recovery of function in In stroke was increased in with from stroke showing that in the acute phase is neuroprotective and the timing of drug is critical for the treatment These results provide a basis for the of to promote recovery after 5 5 is an that the of a 5 is expressed in cells of blood as well as in neural of 5 leads to and is used for the treatment of 5 administered for 6 to days after stroke improved functional recovery in and experimental through improved cerebral blood enhanced and In studies, use of caused functional improvement in a patient with and in a patient with treatment with mg to be in patients with to subacute ischemic or from the growth factor have shown effects on neural plasticity and recovery of function after stroke. For example, growth a with is both neuroprotective and positive effects on neurogenesis and although an early administration of growth factor can promote and a growth factor used for the treatment of was shown to be neuroprotective when administered within the first 2 after however, in combination with tissue administered the induces

Stroke · review · 256 citationsread the source →

Dysfunctional beliefs about symptoms and illness in patients with hypochondriasis.

Background: The cognitive model and empirical research underline the importance of dysfunctional beliefs about bodily symptoms and illness in health anxiety and hypochondriasis. However, specificity of such beliefs has not yet been adequately demonstrated for patients with hypochondriasis. Objective: This study examined whether dysfunctional beliefs about bodily symptoms and illness are elevated in comparison to patients with anxiety disorders and, therefore, specific for patients with hypochondriasis. Method: Patients with hypochondriasis (n = 38), patients with anxiety disorders (n = 40), and healthy controls (n = 42) completed the Symptom and Outcomes Scale (SOS) measuring participants' estimation of the likelihood of various symptoms being indicative of a particular illness. Additionally, participants' general psychopathology (Brief Symptom Inventory), depressive (Beck Depression Inventory-II), and anxiety symptoms (Beck Anxiety Inventory) were evaluated. Results: In comparison to patients with anxiety disorders and healthy controls, patients with hypochondriasis estimated bodily symptoms to be more likely an indicator for a catastrophic illness. Patients with anxiety disorders took a middle position between patients with hypochondriasis and healthy controls. Regarding the estimation of the likelihood of symptoms indicating a minor illness, no differences were found between the three groups. Conclusions: Dysfunctional beliefs about symptoms and illness are important and specific for patients with hypochondriasis, which is in line with the cognitive model. In order to reduce misinformation about serious illnesses in patients with hypochondriasis, more attention should be paid to psychoeducational strategies.

Psychosomatics · 31 citationsread the source →

A Clinical-Psychological Perspective on Somatization Among Immigrants: A Systematic Review.

Background: Somatic and psychopathological conditions (e.g., anxiety, depression, post-traumatic stress disorder, and somatization) are frequent among immigrants belonging to various ethnic groups. Worldwide findings on the epidemiology regarding specific mental conditions still vary with respect to different migration samples and migration contexts. This inconsistency also holds true in the incidence of somatization among migrants. We carried out a systematic review analyzing the relationship between migration and somatization by providing a qualitative data synthesis of original research articles on the topic. Methods: According to PRISMA guidelines, we conducted a systematic search of the literature on PubMed, Scopus, ISI Web of Science, PsycINFO, Google Scholar, and ScienceDirect. The articles were selected using multiple combinations of relevant search terms (e.g., defined somatization and related disorders, and migration status). Each database was searched systematically from January 2000 to December 2017. Results: The initial search identified 338 records, of which 42 research reports met the predefined inclusion criteria and were analyzed. Most studies (n = 38; 90%) were cross-sectional. The main findings of this study are that migrants with somatization exhibited more psychological distress, had an increased perceived need for healthcare service utilization, and reported more post-migration living difficulties and/or post-traumatic stress disorder than those without somatization. It was also found that specific individual features mediate the association between somatization and migration. The prevalence and correlates of somatization were found to vary across the immigrant groups, depending on cultural variation in reasons for migration, stress exposure, explanatory models of illness, coping, and other individual variables. Conclusion: Somatization is a challenge for health professionals due to its vague nature. In this regard, clinical management of immigrant patients should include further efforts to address emotional distress, with special attention to social, cultural, and linguistic differences.

Frontiers in psychology · 39 citationsread the source →

Embrace Hope: An End-of-Life Intervention to Support Neurological Critical Care Patients and Their Families

Because of the acute nature of most neurological events, families are often faced with rapid processing of the illness with little time to realize that their loved one is going to die. Watching the dying process of patients in acute care settings can be unsettling for both patients’ families and staff. The neurocritical care unit at Riverside Methodist Hospital in Columbus, Ohio, wanted to offer help to families and patients traveling this difficult path. To support this goal, an organized, intentional, and flexible end-of-life intervention was needed. Using subjective data gathered from our neurocritical care staff and client families, we developed a plan of care called “Embrace Hope” to help patients and their families through the dying process. Embrace Hope is a structured multi-disciplinary delineation of end-of-life interactions that include educational and support information to be received immediately or at some point after the patient has died. In this article, we provide an overview of the specific items that made up the Embrace Hope intervention, and we use DJ’s story as an example of how the new intervention was applied. More than 50% of deaths in the United States occur in hospitals.1 More than 4 million patients are admitted to intensive care units in the United States annually, and of those admitted, approximately 500 000 or 10% to 20% die.2,3 As the population ages and technological support advances, needs related to end-of-life care increase. In an attempt to address this growing need, multiple organizations gathered in January 2005 to support a national consensus project for end-of-life care. The global goal of this group was to establish care standards for the period around the end of life. To achieve this goal, the group’s focus included symptom management and support of patients and their families during the dying process via adequate communication and decision making. This multiorganizational group identified the need to increase structural support in institutional settings and to identify areas for palliative care.1In a study performed by Teno et al,4 a mortality follow-back survey of approximately 1500 surrogates (next of kin) occurred. The focus of the study was to evaluate the dying experience of persons in the United States at home and in an institutional setting. Results indicated that people in the United States who died in institutions died with unmet needs for symptom amelioration, physician communication, emotional support, and respectful treatment.4A 2-year prospective observational study5 with more than 4300 end-of-life patients occurred from 1989 to 1991. The objectives of this study were to improve end-of-life decision making and reduce the frequency of a mechanically supported, painful, and prolonged process of dying. The study was focused on obtaining information from dying patients about treatment preferences and patterns of decision making among critically ill patients. Results of this study indicated shortcomings in practitioner communication, frequency of aggressive treatment, and family report of patients experiencing severe to moderate pain at the end of life.5 Of the patients included in the study, 38% had spent at least 10 days in the intensive care unit.5Mosenthal et al6 did a prospective, observational study of 42 trauma deaths before an intervention and 52 trauma deaths after an intervention. In that study, care was evaluated before a structured palliative care intervention was integrated into standard intensive care. Results from after the intervention indicated an ability to integrate palliative care interventions within this environment leading to earlier consensus on goals of care for dying trauma patients.6In 2001, the Society of Critical Care Medicine (SCCM) published recommendations for end-of-life treatment in the intensive care unit. The recommendations acknowledged the emerging perspective that palliative and intensive care are not mutually exclusive.7 Although some patients benefit from the transition to other care settings, others are so dependent on critical care technology that transfer is not possible. Therefore, SCCM recommended a series of interventions necessary for clinicians in intensive care units to ensure transition to death. Examples include preparing the team, ensuring patients’ comfort, offering a variety of ventilator withdrawal techniques, and learning communication skills to support patients’ families.7The American Academy of Critical Care Medicine in 2008 released a consensus document for end-of-life recommendations that update the 2001 version. Acknowledging that 95% of patients may not be able to make decisions themselves because of illness, patient- and family-centered decision making was acknowledged as the comprehensive ideal for end-of-life care. With this concept as the foundation, conflict resolution, family communication strategies, interdisciplinary team rounds, and practical considerations for withdrawal of care were discussed.8In 2006, the American Association of Critical-Care Nurses printed protocols for end-of-life issues in critical care. In this document, 5 major areas for end-of-life care were highlighted: symptom management, family issues, withdrawing or withholding support, communication and conflict resolution techniques, and caring for the caregiver.9Although the literature is compelling, situations similar to DJ’s were what prompted the NCC staff to focus on improving end-of-life care within our unit. About a year before DJ’s death, the unit had experienced 3 deaths of patients within 4 days, leaving the unit staff emotionally drained. As several bedside staff lamented that emotional support provided to families currently was perhaps not enough, an informal debriefing session began between multidisciplinary staff, bedside nurses, and advanced practice nurses. A vision of providing optimal end-of-life care to our patients and families through an organized intervention was formed. Driven by the desire of NCC staff and the needs of patients and their families in end-of-life situations, a multidisciplinary team gathered, literature was reviewed, and the concept of an end-of-life intervention that would enable families to embrace hope despite life-changing and life-ending circumstances was born. Although neuroscience practice involves aggressively treating patients and supporting their families during acute illness, death is also a reality. Because of the acute nature of most neurological events, families are often faced with rapid processing of the illness with little time to transition into the realization that their loved one is going to die. Additional stress occurs as catastrophic neurological injuries often leave patients incapable of making end-of-life decisions. These choices are then deferred to families that may never have discussed final wishes with their loved one. In these situations, practitioners are faced with the challenge of not only actively caring for patients, but also supporting families as they transition through the grieving process. Therefore, practitioners must learn to balance the difficult task of resuscitation with the art of compassionate end-of-life care. In order to ensure that the literature supported a comprehensive approach to our end-of-life care, a multidisciplinary team was selected to review the literature and assist in creating a unit-specific process.7–9 The team consisted of several bedside nurses, a patient care technician, a unit clerk, a case manager, a neurological social worker, a palliative care social worker, palliative care and hospice nurses, a unit-based family communication liaison, an intensivist, a neurosurgeon, 2 pastoral care representatives, and a neurological nurse practitioner team leader. Before moving forward, permission for monthly meetings was sought from and granted by the unit’s leaders. The name of the intervention, Embrace Hope, was selected. Despite the devastation of the death of their loved one, our goal was to provide immediate comfort as well as lasting memories that were not clouded by awkward or disorganized interactions with hospital staff. We wanted to relay our respect for their loved one, while giving families the freedom to customize the death to meet their family’s preferences by providing resources to support hope for the future. Building on the research that outlined a “good death” as one that provides physical and emotional support, creates shared decision making, and treats the dying person/family with respect, the group worked to create interventions that would span the continuum.10 The following sections provide an overview of this formalization process while using DJ’s case study to provide examples of the interventions designed to support NCC families. Appreciating the literature support for a multidisciplinary approach to end-of-life care,7–9 the group began work to solidify this approach. It became clear after the first several meetings that the group first needed to designate the roles and responsibilities among the involved disciplines. The goal was to optimize multidisciplinary skill sets and minimize duplication of tasks while spreading the emotional toll and workload between the involved disciplines. A flowsheet was developed to visually guide physicians, nurses, nurse practitioners, unit clerks, pastoral caregivers, social workers, communication liaisons, palliative caregivers, and hospice staff into potential roles at each phase of the Embrace Hope process. The Embrace Hope intervention did not begin until the physician indicated that the patient’s clinical condition had deteriorated to a futile situation. Often several conversations were necessary for family members to process the news and be able to make a decision about withdrawal of life support. These initial conversations were presented by either the attending physician or the nurse practitioner as directed by the attending physician. Early in the process of flowcharting the intervention, it became clear that many items could be accomplished by a number of staff. Through debate, the group reached consensus on lead individuals for given tasks indicated by an asterisk on the diagram. This person was responsible for driving the completion on this item or communicating the need for a replacement if he or she were unavailable. Having multiple people qualified for each item ensured that the process would not break down if death occurred during off hours or if other clinical situations pulled someone in a different direction. As outlined by the Academy of Critical Care Medicine, competent practitioners require specific end-of-life education.7 The Institute of Medicine states that poor end-of-life care sometimes happens because health care professionals are not trained well.11 The NCC end-of-life team believed similarly and proactively sought to train providers on end-of-life care. To achieve this educational foundation, 4 hours of content was crafted by the multidisciplinary team. Management of the NCC required that all full-time and part-time patient care technicians and nursing staff participate in the training. A total of 5 repeat sessions were taught by members of the Embrace Hope team at various times of day to accommodate day and off-shift schedules. One session was taped so that new hires could also receive the training. Nurse and technician training included content on the components of the Embrace Hope structured process, symptom onset/management during terminal stages, communication techniques during grief, cultural considerations of dying, and institutional resources available to support end-of-life care. Content from the 2001 End-of-Life Nursing Education Consortium was used in all educational sections except the institution-specific topics.12 Physician education was 1 hour and included a brief overview of the Embrace Hope intervention and evidence-based symptom management given by the palliative care physician. The suggestions related to symptom management that were presented corresponded to recommendations and guidelines from the SCCM and the American Academy of Critical Care Medicine.7,8In a busy intensive care unit, it is important for all team members to be engaged in the end-of-life process. As outlined in the SCCM guidelines, ensuring an environment conducive to emotional and physical intimacy is also a goal.7 To create this environment, minimization of potential disruptions of family time with the patient were needed. To this end, 2 types of signs were created that notified hospital workers of the situation. The first sign contains the words “Please See Nurse Prior to Entering Room.” This paper sign was stored with other Embrace Hope paperwork to facilitate placement on the patient’s door after the end-of-life decision has been made. The second form of notification is a magnet with the letters EH, for Embrace Hope. This magnet is placed next to the patient’s name on the unit’s communication board. These 2 simple measures ensure that staff at all levels of service will be aware that additional sensitivity with activities is needed for these patients and their families. As stated in the SCCM end-of-life recommendations, attention to detail can make an enormous difference in how the patient and the patient’s family perceive the final moments.7 The Embrace Hope care team developed a number of interventions to assist staff in supporting patients’ family members as they transitioned through the grieving process. The process began in the family conference room. This closed room contained multiple chairs and couches, tissue boxes, water, phone access, and a wall quilt to create a private, comfortable setting to receive updates. This attention to detail addresses the family’s physical comfort as they emotionally process the death of their loved one.7Once the family’s physical needs were tended to, an organized rollout of the end-of-life tools needed to be created to support efficient and compassionate execution by staff. The team decided on a fabric envelope that would be stocked with intervention materials and centrally stored (Figure 1). The concept of the envelope came from a pastoral intern who was included on the team and who had experience with a similar item in a hospital in Toledo, Ohio. A local fabric dealer, Boone Fabrics in Columbus, Ohio, was approached and graciously agreed to donate fabric on an ongoing basis. Cloth pouches were created by Riverside Methodist Hospital’s sewing guild. The fabric design was selected for the huggable nature of the product that also afforded room to place cards, pictures, and additional mementos that may have accumulated throughout the patient’s stay in the NCC. Paperwork to be completed by the staff or given to the family was separated into 2 sections. The first section was to be used right away, and the family could refer to the second section immediately or after they returned home. In January 2006, the Joint Commission outlined a national safety goal to improve handoffs of patients.13 Although this concept is not generally thought to apply to a withdrawal situation, staff in the NCC decided that a communication handoff would be to end-of-life care. the number of staff that be involved in providing various a paper was created and to support an organized transition for staff and for patients’ families (Figure The is with the bedside paperwork and can be on by staff from care not a the that all components of the Embrace Hope intervention are the order of or the providing the care. The of items that are completed from to but in This time is emotional for all family and staff involved in the care of the This focus care and staff to that all the necessary have been for the leaving more time to the additional to provide comfort is to the patient and the patient’s family in what a “good death” to This process by staff the family’s cultural and that families are more clinicians time to and the their for their loved one during the dying also an important in end-of-life and not be as In order to respect and the of each family’s cultural and the NCC staff developed a cultural needs Through subjective data from staff, it was clear that these conversations was for some NCC nurses. To minimize this a structured was created to begin the process of the family in what they needed from to support the respectful death they As we for a process, The Of was developed by using the pastoral care cultural and (Figure The addresses 3 specific about and what is most important to the at this this is by the nurse but as other with the additional often The and use of family preferences assist all staff in the plan of care to make the through death a experience for the patient’s and care for dying patients and their families can be to staff and from the on what to next may and family that on preparing the patient and the patient’s family for the withdrawal process is With DJ’s physical and needs for the the staff focused on and DJ’s family about what to as time To assist with this a (Figure was designed by the Embrace Hope team to help families simple that can occur during the transition from life to death. some families, this may be their first experience of this experience may emotional or may death as a from others may focus on to help during this Although each patient’s is the signs and of the dying process as and in and In situations withdrawal or withholding of care is this is and by the staff to the patient’s an initial of this the Embrace Hope that death required a educational given the of This also was created (Figure death, or withholding care are the circumstances death, practical comfort measures are during this review and families are to participate in their loved care as they were taught about what to during the dying process, and staff during this With this support and the goal was to support families in offering the of that can be so as they on this time in their To this end, are are or within the and for families to provide care or in are the and project plan of the Embrace Hope intervention, the multidisciplinary team on many to what they could to families memories of their loved one. The team decided that that family members could in their or that could be placed in the to would be that could be The developed into family members a of as a of their loved a of from a dying loved one was a practice in the The was then and placed into or made into other our this was in the and with death. this the team decided to use a the of the families that we would be the team decided to make it to and document from the family to the of so would and respect for cultural or that may of the or of the patient’s of as the of the patient’s and the number of to 1 or 2 to minimize the of this the of potential process was to provide lasting memories for families as One of these was to offer to create a of a loved one (Figure the hospital is and are only grieving of can be and the of one we loved can of how that person our life. A created by an Embrace Hope team was included in the of the to the hope that can in were to each with available in a additional be The of the printed was down so that it did not the loved in and was to support the and improve The of the paper to the that became the process. This and in a of art of the of the grieving process as families home to their they are with of loved In with recommendations for the members of the Embrace Hope team wanted to support this transition to home after a loved death. The first was to provide a with practical items and support items included how to create an create and from support and their phone were also included for these were to be after the of care had and the concept of the family’s new to these practical the staff wanted to to the families that we to their loved one. To 2 items are from the and until after the families have These items are a for the family (Figure and a of 1). The concept supported in the SCCM the quilt as the of the items in the and is on the unit for a period of 1 to 2 after the patient’s death. This time staff time to sign the the 2 after the death the that will occur during a time to be with the was a of in a The was selected by the Embrace Hope team as a that would and in of their family concept of Embrace Hope was but of the process was at In to the of care, a process to the of support needed to the for the families is the most of this who a group of our hospital the A was created as a for the and is in a for ongoing items needed for families, as of cards, “Embrace Hope” for and additional tools are also in the at the unit are available in One can be for from of the Embrace Hope intervention in the a for a order for withdrawal of care was (Figure before and after the Embrace Hope intervention were completed by staff nurses, and indicated in staff ability to provide a “good “good death” was as a death that was from pain and with a patient’s and with and clinical the end-of-life intervention was practitioners also a in to their ability to provide end-of-life care A total of patient’s next of kin) were also about the end-of-life care provided in the NCC. surrogates completed before the intervention and surrogates completed after the intervention. in the emotional support and care provided were on was by surrogates in to symptom communication, and emotional support provided by NCC staff (Figure We to research but that work is of the Embrace Hope intervention and the process of the withdrawal order within the NCC has prompted other units within the hospital to create similar to support their patients. the palliative care unit and several other critical care units are the process to the available and the needs of their specific of work and on supporting patients and their families at the end of care can be provided within the of critical care the skill sets of an multidisciplinary team a structured intervention that caring while a for team staff from the intervention that providing a structured intervention to an end-of-life plan that a in the of staff. In the words of one in the memories of those who Through the transition of critical care to caring our desire is to our to enable more memories for families of intensive care patients end-of-life care so that they can Embrace Hope.

Critical Care Nurse · case report · 20 citationsread the source →

Prevalence and correlates of stress and burnout among U.S. healthcare workers during the COVID-19 pandemic: A national cross-sectional survey study.

Background: COVID-19 has put extraordinary stress on healthcare workers. Few studies have evaluated stress by worker role, or focused on experiences of women and people of color. Methods: The "Coping with COVID" survey assessed US healthcare worker stress. A stress summary score (SSS) incorporated stress, fear of exposure, anxiety/depression and workload (Omega 0.78). Differences from mean were expressed as Cohen's d Effect Sizes (ESs). Regression analyses tested associations with stress and burnout. Findings: Between May 28 and October 1, 2020, 20,947 healthcare workers responded from 42 organizations (median response rate 20%, Interquartile range 7% to 35%). Sixty one percent reported fear of exposure or transmission, 38% reported anxiety/depression, 43% suffered work overload, and 49% had burnout. Stress scores were highest among nursing assistants, medical assistants, and social workers (small to moderate ESs, p < 0.001), inpatient vs outpatient workers (small ES, p < 0.001), women vs men (small ES, p < 0.001), and in Black and Latinx workers vs Whites (small ESs, p < 0.001). Fear of exposure was prevalent among nursing assistants and Black and Latinx workers, while housekeepers and Black and Latinx workers most often experienced enhanced meaning and purpose. In multilevel models, odds of burnout were 40% lower in those feeling valued by their organizations (odds ratio 0.60, 95% CIs [0.58, 0.63], p< 0.001). Interpretation: Stress is higher among nursing assistants, medical assistants, social workers, inpatient workers, women and persons of color, is related to workload and mental health, and is lower when feeling valued.

EClinicalMedicine · 352 citationsread the source →

The Relationship Between Sleep, Cognition, and Dementia Risk in People With Focal Epilepsy.

Background and objectives: Sleep disruption and cognitive impairment are important comorbidities of focal epilepsy. However, the nature to which sleep affects cognition and long-term dementia risk in focal epilepsy, compared with other brain conditions, remains unclear. We examined the relationship between sleep, cognition, and dementia risk in patients with focal epilepsy compared with healthy controls and stroke patients. Methods: We conducted an analysis of the prospective UK Biobank cohort study, with baseline assessments performed between 2006 and 2010 and follow-up until 2021. Study groups were mutually exclusive participants with focal epilepsy and stroke at baseline assessment and healthy controls. Sleep characteristics included reports of sleep duration, obstructive sleep apnea, insomnia, napping, and dozing. Main outcomes were risk of incident all-cause dementia and Alzheimer disease from Cox proportional hazard modeling and comparison of executive function measures and brain total hippocampal and gray matter volumes using generalized linear modeling. Results: We examined a sample of 482,207 participants, aged between 38 and 72 years (mean [SD] 57.6 [8.1] years; 53.8% female), without dementia at baseline and a nested imaging subsample of 42,345 participants. Optimal sleep duration (6-8 hours) was associated with better executive function in control, focal epilepsy, and stroke groups. The impact of optimal sleep was significantly higher in individuals with focal epilepsy compared with controls (interaction term, p = 0.009), but not in the stroke group (interaction term, p = 0.574). Nonoptimal sleep was associated with worse executive function up to 8 years before the diagnosis of focal epilepsy. A 5-fold increased risk of developing dementia was seen in individuals with focal epilepsy and nonoptimal sleep (hazard ratio [HR] 5.15, 95% CI 3.77-7.04, p < 0.001) compared with healthy controls with optimal sleep. This was greater than in stroke individuals with poor sleep (HR 3.48, 95% CI 2.82-4.26, p < 0.001). Optimal sleep compared with nonoptimal sleep modified the dementia risk in in individuals focal epilepsy, with a significantly greater improvement compared with healthy controls (interaction term p = 0.017), while no significant difference was seen in the stroke group (interaction term p = 0.991). Discussion: Optimal sleep modified both cognitive performance and dementia risk in individuals with focal epilepsy compared with stroke patients and healthy controls. Based on self-reported sleep data, these findings suggest that improving sleep may be an impactful intervention to improve cognition and reduce dementia risk particularly in focal epilepsy.

Neurology · 1 citationsread the source →

Awe/Gratitude as an Experiential Aspect of Spirituality and Its Association to Perceived Positive Changes During the COVID-19 Pandemic.

Background: While the COVID-19 pandemic has affected the lives of almost all people worldwide, many people observed also positive changes in their attitudes and behaviors. This can be seen in the context of posttraumatic growth. These perceived changes refer to five main categories: Nature/Silence/Contemplation, Spirituality, Relationships, Reflection on life, and Digital media usage. A previous study with persons recruited in June 2020 directly after the lockdown in Germany showed that the best predictors of these perceived changes related to the Corona pandemic were the ability to mindfully stop and pause in distinct situations, to be "spellbound at the moment" and to become "quiet and devout," indicating moments of wondering awe, with subsequent feelings of gratitude. Now, we intended to analyze (1) by whom and how strongly awe/gratitude was experienced during the COVID-19 pandemic, and (2) how these feelings relate to perceived changes and experienced burden, and (3) whether or not feelings of awe/gratitude contribute to participants' well-being or may buffer perceived burden in terms of a resilience factor. Methods: Online survey with standardized questionnaires [i.e., WHO-Five Well-being Index (WHO5), Life satisfaction (BMLSS), Awe/Gratitude scale (GrAw-7), and Perceived Changes Questionnaire (PCQ)] among 2,573 participants (68% women; mean age 48.7 ± 14.2 years, 74% with a Christian affiliation) from Germany recruited between June and November 2020. Results: Awe/Gratitude scored significantly higher particularly among women (Cohen's d = 0.40), older persons (d = 0.88), persons who rely on their faith as a "stronghold in difficult times" (d = 0.99), those with higher well-being (d = 0.70), and lower perceptions of loneliness (d = 0.49). With respect to perceived changes during the pandemic, more intense feelings of Awe/Gratitude were particularly related to Nature/Silence/Contemplation (r = 0.41), Spirituality (r = 0.41), and Relationships (r = 0.33). Regression analyses revealed that the best predictors of Awe/Gratitude (R 2 = 0.40) were the frequency of meditation, female gender, life satisfaction and well-being, faith as a stronghold, and perceived burden and also life reflection, while Nature/Silence/Contemplation and Relationships had a further, but weaker, impact on Awe/Gratitude as a dependent variable. Awe/Gratitude was moderately associated with well-being (r = 0.32) and would predict 9% of participants' well-being variance. The best predictors of participants' well-being were multidimensional life satisfaction and low perceived burden (related to the pandemic), and further Awe/Gratitude and Nature/Silence/Contemplation; these would explain 47% of variance in well-being scores. However, Awe/Gratitude cannot be regarded as a buffer of the negative aspects of the COVID-19 pandemic, as it is only marginally (though negatively) related to perceived burden (r = -0.15). Mediation analysis showed that Awe/Gratitude mediates 42% of the link between well-being as a predictor on Nature/Silence/Contemplation as an outcome and has a direct effect of β = 0.15 (p < 0.001) and an indirect effect of β = 0.11 (p < 0.001). Further, Awe/Gratitude mediates 38% (p < 0.001) of the link between Nature/Silence/Contemplation as a predictor on well-being as the outcome; the direct effect is β = 0.18 (p < 0.001), and the indirect effect is β = 0.11 (p < 0.001). Conclusions: The general ability to experience Awe/Gratitude particularly during the COVID-19 pandemic may sensitize to perceive the world around (including nature and concrete persons) more intensely, probably in terms of, or similar to, posttraumatic growth. As this awareness toward specific moments and situations that deeply "touch" a person was higher in persons with more intense meditation or prayer practice, one may assume that these practices may facilitate these perceptions in terms of a training. However, the experience of Awe/Gratitude does not necessarily buffer against adverse events in life and cannot prevent perceived burden due to the corona pandemic, but it facilitates to, nevertheless, perceive positive aspects of life even within difficult times. As Awe/Gratitude is further mediating the effects of Nature/Silence/Contemplation on well-being, intervention programs could help to train these perceptions, as these self-transcendent feelings are also related to prosocial behaviors with respectful treatment of others and commitment to persons in needs, and well-being.

Frontiers in psychiatry · 28 citationsread the source →

Extracellular Vesicle Proteins and MicroRNAs Are Linked to Chronic Post-Traumatic Stress Disorder Symptoms in Service Members and Veterans With Mild Traumatic Brain Injury.

Symptoms of post-traumatic stress disorder (PTSD) are common in military populations, and frequently associated with a history of combat-related mild traumatic brain injury (mTBI). In this study, we examined relationships between severity of PTSD symptoms and levels of extracellular vesicle (EV) proteins and miRNAs measured in the peripheral blood in a cohort of military service members and Veterans (SMs/Vs) with chronic mTBI(s). Participants (n = 144) were divided into groups according to mTBI history and severity of PTSD symptoms on the PTSD Checklist for DSM-5 (PCL-5). We analyzed EV levels of 798 miRNAs (miRNAs) as well as EV and plasma levels of neurofilament light chain (NfL), Tau, Amyloid beta (Aβ) 42, Aβ40, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNFα), and vascular endothelial growth factor (VEGF). We observed that EV levels of neurofilament light chain (NfL) were elevated in participants with more severe PTSD symptoms (PCL-5 ≥ 38) and positive mTBI history, when compared to TBI negative controls (p = 0.024) and mTBI participants with less severe PTSD symptoms (p = 0.006). Levels of EV NfL, plasma NfL, and hsa-miR-139-5p were linked to PCL-5 scores in regression models. Our results suggest that levels of NfL, a marker of axonal damage, are associated with PTSD symptom severity in participants with remote mTBI. Specific miRNAs previously linked to neurodegenerative and inflammatory processes, and glucocorticoid receptor signaling pathways, among others, were also associated with the severity of PTSD symptoms. Our findings provide insights into possible signaling pathways linked to the development of persistent PTSD symptoms after TBI and biological mechanisms underlying susceptibility to PTSD.

Frontiers in pharmacology · 35 citationsread the source →

Prolonged grief disorder among asylum seekers in Germany: the influence of losses and residence status.

Background: Besides the high exposure to traumatic events, many refugees to Europe experienced tremendous interpersonal losses. Objective: The aim of this study was to investigate the rate and potential risk factors of prolonged grief disorder (PGD) in recently fled asylum seekers who lived in collective accommodations in Germany. Method: Three groups of asylum seekers from different countries (N = 99) completed the Traumatic Grief Inventory Self-Report Version (TGI-SR), Posttraumatic Stress Disorder Checklist-5 (PCL-5), and Patient Health Questionnaire depression module (PHQ-9). Individuals in Group 1 were waiting for asylum decisions (n = 29), Group 2 members were in appeal against rejected asylum claims (n = 32), and Group 3 members had been permitted temporary residence status (n = 38). Results: The loss of a loved person was reported by 92% of participants. The criteria for provisional PGD diagnosis according to Prigerson criteria were met by 20% of participants, 16% fulfilled the criteria for DSM-5 persistent complex bereavement disorder. Probable posttraumatic stress disorder (45%) and depression (42%) rates were high. The total number of lost nuclear family members and PTSD symptoms were associated with higher and temporary residence status was predicted lower PGD symptom levels. Conclusions: These results show that a substantial proportion of asylum seekers suffer from PGD. This points to the need to screen for problematic grief in the current refugee population in Europe.

European journal of psychotraumatology · 35 citationsread the source →

Virtual Reality-Based Early Neurocognitive Stimulation in Critically Ill Patients: A Pilot Randomized Clinical Trial.

This study focuses on the application of a non-immersive virtual reality (VR)-based neurocognitive intervention in critically ill patients. Our aim was to assess the feasibility of direct outcome measures to detect the impact of this digital therapy on patients' cognitive and emotional outcomes. Seventy-two mechanically ventilated adult patients were randomly assigned to the "treatment as usual" (TAU, n = 38) or the "early neurocognitive stimulation" (ENRIC, n = 34) groups. All patients received standard intensive care unit (ICU) care. Patients in the ENRIC group also received adjuvant neurocognitive stimulation during the ICU stay. Outcome measures were a full neuropsychological battery and two mental health questionnaires. A total of 42 patients (21 ENRIC) completed assessment one month after ICU discharge, and 24 (10 ENRIC) one year later. At one-month follow-up, ENRIC patients had better working memory scores (p = 0.009, d = 0.363) and showed up to 50% less non-specific anxiety (11.8% vs. 21.1%) and depression (5.9% vs. 10.5%) than TAU patients. A general linear model of repeated measures reported a main effect of group, but not of time or group-time interaction, on working memory, with ENRIC patients outperforming TAU patients (p = 0.008, ηp2 = 0.282). Our results suggest that non-immersive VR-based neurocognitive stimulation may help improve short-term working memory outcomes in survivors of critical illness. Moreover, this advantage could be maintained in the long term. An efficacy trial in a larger sample of participants is feasible and must be conducted.

Journal of personalized medicine · 29 citationsread the source →

Combat sports and wellbeing: advancing health and inclusion in athletes and practitioners. An opinion paper

Historically, combat sports have been predominantly conceptualized within the framework of elite competition, emphasizing physical aptitude, technical proficiency, and strategic execution (1-3). Despite their traditional and peculiar constitutions and developments, disciplines such as judo, karate, taekwondo, wrestling, fencing, boxing, and mixed martial arts have commonly been associated with high-performance athletes striving for competitive excellence on national and international stages (1, 4-6). However, contemporary discourse increasingly recognizes their expansive role in contributing to physical and psychological well-being, and social inclusion of the practitioners (7, 8). This paradigmatic shift underscores the capacity of combat sports to function as inclusive and accessible modalities for fostering multidimensional health benefits across diverse populations, including individuals with disabilities and other marginalized groups (9-13).The interdisciplinary exploration of physical activity and health highlights the intricate interrelationship between structured sports engagement and holistic well-being (14). Whilst conventional team and individual sports have long been acknowledged for their physiological and psychosocial benefits, combat sports exhibit distinct characteristics that might amplify these advantages (15, 16). Within combat sports, the synergistic interplay of rigorous physical conditioning, the cognitive engagement, adherence to rules, competition dynamics, respect, externalizing emotions regulation, are intertwined with pedagogical and philosophical values, thus presenting a unique framework for enhancing psychological resilience, cognitive adaptability, and emotional control. Consequently, the systematic practice of combat sports has been increasingly examined as a way of promoting mental health, stress modulation, and social cohesion (17, 18).The inclusive nature of many combat sports programmes further accentuates their relevance in dismantling stereotypes, facilitating integration, and fostering equity and social integration (19-21). In fact, they demonstrated significant adaptability to accommodate individuals with disabilities (e.g., physical impairments, developmental, emotional, intellectual disorders), thereby ensuring equitable access and fostering empowerment (9, 22). Adapted judo, para-taekwondo, and other modified combat disciplines provide individuals with disabilities a structured platform to engage in physical activity, cultivate self-efficacy, and develop meaningful social connections within a supportive and adaptive environment (23). From a public health perspective, the integration of combat sports within community-based health initiatives offers a compelling opportunity to engage populations that may not traditionally participate in structured physical activity programmes (7, 8, 19). The distinctive accessibility of combat sports, which cater to practitioners of all skill levels (e.g., from novices to elite athletes) sets them apart from many other sports. While their structured progression, adaptability, and emphasis on holistic development make them a viable option for lifelong and intergenerational participation (19, 24, 25), the mentorship and pedagogical frameworks cultivate positive role modeling, discipline, and intrinsic motivation, which are integral for sustaining long-term adherence to health-promoting behaviors (8).Furthermore, the intersection between combat sports and mental health has increasingly emerged as a focal point within academic and clinical research (17) with empirical evidence suggesting an association between participation and enhanced self-regulation and self-efficacy, and reduction in anxiety and depressive symptomatology (8, 26, 27). In necessitating sustained focus, adaptability, and emotional equilibrium, combat sports inherently require cognitive and affective demands, which align closely with established psychological frameworks that underpin mental well-being (28, 29). Moreover, the integration of mindfulness techniques, stress management strategies, and resilience-building paradigms within combat sports training substantiates their potential as a non-pharmacological intervention for addressing various mental health challenges (e.g., autism spectrum and oppositional defiant disorders) (30, 31).Despite these advantages, the discourse surrounding combat sports and well-being necessitates a critical examination of inherent risks and potential challenges. Issues related to injury risk, hypercompetitive environments, eating disorders, sexual harassment, and the psychological stressors associated with high-intensity training warrant careful scrutiny (32-36). The implementation of evidence-based injury prevention protocols, the establishment of ethically responsible coaching methodologies, and the promotion of safe training environments are imperative to ensure that the benefits of combat sports are maximized while minimizing adverse outcomes. Against this backdrop, this opinion paper seeks to examine the role of combat sports in advancing health and social inclusion among athletes and practitioners. Through a synthesis of contemporary empirical findings, theoretical paradigms, and applied insights, this paper aims to contribute to the evolving discourse on the potential of combat sports as a catalyst for holistic well-being. By delineating the multidimensional impact of combat sports on physical, psychological, and social health, this paper endeavors to underscore their transformative potential as an instrument for fostering individual and community well-being within different populations. DiscussionWhilst an expanding body of research and an evolution in scholarly discourse is recognizing the combat sports’ broader implications for holistic well-being (30, 37), a rigorous evaluation of the investigation methodologies, the validity of hypotheses, and the translational potential of recent findings is necessary to contextualize their significance within the sports and public health sciences, considering their strengths, weaknesses, opportunities, and threats (Figure 1).----------------------------------------ADD FIGURE 1 ABOUT HERE----------------------------------------Empirical evidence robustly shows the positive impact of combat sports on physical fitness, motor coordination, and cardiovascular health (3, 38). These benefits are attributed to the high-intensity, intermittent nature of combat sports training, which enhances aerobic and anaerobic endurance, muscular strength, and neuromuscular control (39). However, concerns regarding injury risk, particularly in striking and contact-intensive disciplines such as boxing, taekwondo, and mixed martial arts, necessitate continued research into injury mitigation strategies, particularly those targeting concussion and repetitive head trauma (6, 35, 40, 41). Moreover, many combat sports have developed styles with reduced or simulated contact to minimize injury risk. For example, the French "boxe éducative" emphasizing technique and control, penalizing any violent behaviors (42) and the value and application of kata (i.e., forms; prearranged, pattern practices) to learning and adopting judo technique in a safe way educating the athlete culturally, to enrich her/him as a person (43).Beyond physical health, recent studies highlight the psychological benefits of combat sports, including reductions in anxiety and depression and improvements in self-efficacy, emotional regulation, resilience, and stress management (27, 44-47). Therefore, combat sports-based interventions for individuals with mental health conditions have yielded promising outcomes (23). Despite these encouraging findings, variability in study designs, participant demographics, and intervention protocols limits their external validity, underscoring the need for further rigorously controlled investigations. Furthermore, some authors claimed that combat sport athletes might present symptoms of low energy availability and high anxiety levels associated with competition- and injury-related psychological stressors, deficits in executive functions and neuropsychological impairments associated with occurrence of concussions, disordered eating and eating disorders associated with weight-loss, and might suffer offensive, frightening, hostile, degrading, humiliating experiences, or sexual harassment, which urge safeguarding actions (32-36).The role of combat sports in fostering social inclusion has gained empirical support, particularly in programmes aimed at individuals with disabilities and marginalized communities (25, 48). For instance, a recent systematic review shows that judo interventions adapted for intellectual disabilities help improve social integration and self-perception and enhance participants' quality of life (49). The development of para-combat sports demonstrates enhanced physical and motor abilities while providing psychosocial benefits to various populations with different disabilities, promoting social integration, self-perception, and community belonging (50, 51). However, longitudinal research is needed to assess the long-term retention rates and sustainability of these benefits. Furthermore, there is a need of studies focused on the most appropriate adapted rules to achieve a fairer competition for ensuring a sense of success in individuals with physical, emotional, mental, hearing or visual impairments participating in adapted sports competitions at local, national, and international levels. Methodological approaches in combat sports research encompass experimental, longitudinal, qualitative, and systematic review designs. While randomized controlled trials remain the gold standard for establishing causality, their application in combat sports research is constrained by ethical concerns, logistical challenges, and the inherently dynamic nature of training environments (52, 53). Consequently, many studies rely on observational designs, which, despite their value in identifying associations, are susceptible to confounding variables and biases (24, 54).Qualitative methodologies have provided critical insights into the lived experiences of combat sports practitioners, offering perspectives on psychological and social dimensions that are often overlooked in quantitative studies (28). Ethnographic research has been particularly instrumental in elucidating the role of combat sports in shaping identity, discipline, and personal development (55). However, limitations in reproducibility and generalizability highlight the need for mixed-methods approaches to generate a more comprehensive understanding of combat sports' impact (25, 56).Additionally, the incorporation of biometric and neurocognitive assessments, such as heart rate variability analysis, functional MRI, and salivary cortisol measurements, has advanced our understanding of the physiological and psychological mechanisms underlying combat sports participation (47, 57, 58). Despite their objective precision, these techniques often face challenges related to cost, accessibility, and limited sample sizes, necessitating the development of scalable and cost-effective methodologies for broader research application. Finally, recent studies show that virtual reality (VR) technology and digital platforms are increasingly becoming part of combat sports training methods. Due to COVID-19 restrictions, martial arts schools and organizations implemented hybrid or online training models, which allowed athletes to stay engaged. VR boxing programmes provide users with virtual sparring simulations to enhance their motor skills without needing physical interaction. Initial results indicate that VR training enhances response behavior in karate athletes (59). Digital adaptations offer great potential, especially for people with limited mobility or remote locations. However, further studies are necessary to prove their enduring effects on physical health and psychological and social aspects (59-61).Strengths and Weaknesses of Scientific HypothesesThe hypothesis that combat sports confer multidimensional health benefits is strongly supported by empirical evidence spanning physiological, psychological, and social domains (8, 62-64). The integration of physical exertion, cognitive engagement, and structured discipline inherent in combat sports aligns with established theories of exercise psychology, neuroplasticity, and social identity formation (65, 66). This multidimensional perspective provides a robust theoretical foundation for advocating combat sports as a health-promoting activity. Nevertheless, several limitations warrant consideration. The heterogeneity of disciplines, which vary highly in intensity, contact level, and training methodologies, is often inadequately addressed in research, leading to overgeneralized conclusions (17, 39). Often underexamined, individual differences in personality, motivation, and previous trauma history may strongly moderate the psychological outcomes of combat sports participation (35, 67, 68).Additionally, a research focus is needed on concerns regarding the potential for adverse psychological effects (e.g., anxiety, depression, disordered eating behaviors, burnout, and decreased self-esteem), particularly in competitive environments where performance pressure, extreme weight-cutting practices, and aggressive coaching styles are prevalent (69, 70). Indeed, a balanced perspective that considers both benefits and risks is essential for the development of evidence-based recommendations (10, 71).Future DirectionsTo enhance the field, future research should prioritize well-structured longitudinal studies that assess the long-term impact of combat sports participation on physical, psychological, and social health. Standardization of outcome measures, intervention protocols, and participant demographics would facilitate cross-study comparisons and strengthen the reliability of findings (72, 73). Moreover, interdisciplinary collaborations incorporating sports science, psychology, and sociology could provide a more holistic perspective on combat sports' broader implications on practitioners (74).From a policy perspective, to yield valuable insights into combat sports’ practical applications research should investigate their efficacy within public health, educational, and rehabilitation initiatives, particularly for underserved and vulnerable populations (23, 75, 76).Furthermore, while safety remains a primary concern, advancements in protective equipment, training methodologies, education for athletes, coaches, referees and tournament directors, and regulatory frameworks should be continually evaluated to optimize benefits while mitigating risks (40, 41, 58, 77, 78). Ethical considerations, particularly concerning athlete well-being and inclusive participation, should remain a central focus in both research and practical implementation (17, 34, 36).Therefore, key research challenges to be addressed are: 1. Injury risk and safety: a need for injury prevention strategies, especially for concussions and head trauma in striking sports. 2. Psychological wellbeing: risks of stress, anxiety, burnout, and negative self-perception in competitive environments. 3. Inclusion and accessibility: a need for more research on long-term social and psychological benefits for marginalized groups and individuals with disabilities. 4. Methodological limitations: lack of standardized protocols, variability in study designs, and limited reproducibility of findings. 5. Ethical and regulatory issues: concerns over coaching practices, extreme weight-cutting, and athlete wellbeing in high-pressure environments. 6. Technological innovations: more research required on the effectiveness of VR and digital training tools in combat sports. 7. Public health and policy: exploration of combat sports' role in health initiatives, rehabilitation, and educational programs. ConclusionThe evolving discourse on combat sports highlights their potential as a multidimensional tool for well-being promotion. While a substantial body of evidence supports their benefits, a critical examination of methodological limitations, scientific hypotheses, and practical applications is essential for further refine our understanding and enhance their effectiveness. Finally, this article makes a significant contribution not only to the field of martial arts but also to public health and sports psychology. Its interdisciplinary approach calls for scientific collaboration and methodological rigor, reinforces the need for evidence-based policies and can serve as a valuable guide for researchers and policymakers looking to integrate combat sports into strategies for promoting health and social inclusion.

Frontiers in Psychology · 12 citationsread the source →

Psychosexual health in gynecological cancer

The literature surrounding psychosexual health and cancer patients has primarily considered the functional aspects of the disease and its treatment at the major expense of the emotional sequelae. Sexual health is defined by WHO as: "a state of physical, emotional, mental, and social well-being in relation to sexuality; it is not merely the absence of disease, dysfunction or infirmity. Sexual health requires a positive and respectful approach to sexuality and sexual relationships, as well as the possibility of having pleasurable and safe sexual experiences, free of coercion, discrimination and violence" [1]. A principle goal of WHO is to assist its member states in achieving the highest attainable standard of health care for all, including sexual and reproductive health [2]. Global statistics show that the world's female population is carrying an overwhelming burden of need in this area. Over 200 million women cannot access modern contraception, and millions of women suffer rape, domestic violence, and sexual abuse, not only in the context of wars and criminal activities, but also in their own homes [2]. Although the physical sequelae of these disasters can be treated, such as treatment for sexually transmitted infections, the emotional impact can frequently be hidden, ignored, or may not reveal its impact until many years after the event. Any illness or traumatic life event, past or present, can lead to sexual problems in the lifetime of a woman, and gynecological cancer is no exception. It is the root cause or trigger for sexual difficulties in at least 50% of women affected [3]. In 2012, the estimated number of women living with gynecological cancers was over three million, which means that potentially 1.5 million gynecological cancer survivors could be affected by an associated sexual difficulty [4]. Within the context of gynecological cancer, many of these problems can be alleviated if recognized and acknowledged early in the cancer journey, therefore contributing dramatic improvements to a woman's overall well-being. It is now estimated that half of the population of either sex will develop cancer at some time in their life. Globally, 40% − 45% of women will have a sexual problem at some stage, with the prevalence increasing with age [5]. Between 10% and 90% of women with any cancer will have sexual problems [6] and over 50% of women with gynecological cancer will have either temporary or persistent sexual difficulties [3]. As diagnosis and treatments improve, the number of women surviving cancer will increase, and survivorship issues including quality of life have become increasingly important. Sexuality is a key component of most subjective measurable quality of life indicators [7]. Sexual function and enjoyment are important components of survivorship and should not be ignored. The most common sexual problems can be divided into two groups: problems of function and/or problems of desire. There is, however, a complex interplay of organic disorders with emotional and psychosocial issues, and these divisions are merely artificial. Formal definitions of female sexual dysfunction have been adopted, including the US classifications in the Diagnostic and Statistical Manual of Mental Disorders [8], although having a sexual difficulty does not constitute having a mental health disorder. Basson et al. [9] published a useful classification of the problems. Such classifications are useful for research purposes, but may often be less helpful when treating women. The predominant functional female sexual problem is pain on sexual intercourse, or dyspareunia. Deep dyspareunia describes intracoital pelvic pain, and superficial dyspareunia is pain on vaginal entry. Either could signify organic disease, and should be appropriately investigated. If no pathology is demonstrated, and the pain persists, then an emotional cause must be considered and pursued. Vaginismus, or involuntary spasm of the pubococcygeal and related musculature, can prevent sexual intercourse taking place. Good history taking can clarify whether there has been any penetration of the vagina, not only penile, but by fingers, sex toys, or tampons. If not, this is diagnostic of primary vaginismus, and apart from close inspection of the vulva and offer of gentle digital vaginal examination to determine the extent of the vaginismus, no further clinical investigation is warranted. Women with gynecological cancer are more likely to have secondary vaginismus caused by pain experienced from the disease or its treatment, and fear of the pain occurring during sex [10]. Loss of libido or loss of sexual interest on the other hand is a problem of desire. There are no physiological markers for loss of desire when its origins are psychogenic, with psychosocial contributions, past and present relationships, traumas, and emotional factors all inhibiting the woman's wish to be sexual. One of the key ways to determine the origins of the sexual difficulty is to ask about the sexual and emotional relationship between the woman and her partner before the cancer diagnosis. It should not be assumed that problems are all due to the cancer, as long-standing relationship problems may be disclosed, and need to be incorporated into any counselling. The exception to this is the woman who suddenly becomes menopausal following cancer treatment, who had no problems with sex or desire prior to her cancer therapy. Appropriate standard therapy for her menopausal symptoms should be considered; however, the impact of a cancer diagnosis will be life changing, and drug treatment of hormonal deprivation symptoms may not be sufficient without some psychological or counselling support, or may be contraindicated as in the case of breast and endometrial cancer [11]. A diagnosis of gynecological cancer is overwhelming. While the instinctive professional response from clinicians is to ensure long-term survival, sexual issues are important for quality of life and should be considered in the decision-making process [12]. Sexual dysfunction is one of the most common and distressing consequences of cancer treatment [13]. Many treatments are shown to have sexual impacts, both positive and negative, and should be discussed fully with the woman pre-treatment so that she can make an autonomous decision about her care. Early offer of discussion of sexual issues in the cancer journey can lead to better sexual outcomes. Cervical cancer is the most common gynecological cancer worldwide. Cervical cancer survivors are at risk of sexual pain disorders, no matter which modality of treatment is used. A small study of patients who underwent radical vaginal trachelectomy for early stage cervical cancer showed sexual dysfunction, including loss of libido, for up to one year following treatment; however, by 12 months, sexual activity had reached that of healthy women [14]. Following radical hysterectomy for locally advanced cervical cancer, there was no significant difference in sexual activity and enjoyment between women with benign or malignant disease; however, the cancer group had worse problems than healthy controls with body image and vaginal functioning [15]. In women with advanced cervical cancer given chemoradiotherapy, pain during intercourse was in fact reduced after treatment [16]. This may have been a result of the resolution of bleeding, discharge, and pelvic pain. However, the anxiety surrounding cancer remains for many women. Women surviving up to 15 years following cervical cancer treatment showed poorer quality of life than healthy controls, and those who had received radiotherapy were significantly more affected by sexual dysfunction than those who had surgery alone [17]. Despite this however, orgasm may be unimpaired following radiation [18]. Many additional needs were expressed by women with cervical cancer; however, sexuality and intimacy came to the fore as a predominant issue for survivorship [19]. It has been known for some time that the physical and emotional impact of ovarian cancer can be devastating, leading to sexual as well as global quality of life issues [20]. One study has shown a prevalence of 63% for sexual difficulties among women with a diagnosis of ovarian cancer [3]. The effects of chemotherapy and surgery, combined with the anxiety about survival can have a dramatic negative effect on the woman's libido, and even women who undertake risk-reducing salpingo-oophorectomy can suffer sexual dysfunction [21]. Many of these women are totally unprepared for the devastating effects of sudden menopause, with hot flushes, vaginal dryness, and loss of libido replacing a previously healthy sex life. This could be helped by more realistic counselling before the procedure, and increased postoperative emotional support. One study has shown that women who had surgery for endometrial cancer had no differences in their own sexual experience postoperatively, but compared with healthy controls, they had more sexual difficulties overall [22]. Women with Lynch syndrome who opt for preventive surgery tend to be happy overall with the surgery, but are often unprepared for the physical adverse effects of menopause [23]. In contrast, Moldovan et al. [24] has reported that, despite sometimes debilitating menopausal symptoms, there were no significant sexual difficulties associated with the procedure. Vulvectomy is a common treatment for vulvar malignancy. This is increasingly affecting younger women, who are HIV positive. Women with vulvar cancer can have many years of difficulties with sex due to often distressing vulvar symptoms and bleeding. Following treatment they still suffer severe dyspareunia and body image distortion due to the effects of treatment. Although a recent study showed no differences in psychosocial and sexual functioning before and after vulvectomy, it was acknowledged that women with vulvar malignancy have a high risk for sexual problems compared with healthy controls [25]. Factors associated with postoperative sexual difficulties are increased age, poor overall physical and mental health well-being, and extent of the surgical excision [25]. This often elderly group of patients is usually neglected from the psychosexual point of view. The majority of the literature related to sexuality and cancer stems from high-resource countries. Although most of these studies encompass all women, there is a lack of good published evidence on the treatment of the sexual sequelae of cancer in relation to ethnic minority groups, within a majority culture [26]. Furthermore, data from low- and middle-income countries are scant. Much of the literature focuses on sexual distress and activity in relation to HIV and AIDS which, of course, is a global priority; however, this focus on infection transmission should not take away from the emotional needs of the woman who suffers from gynecological cancer. Sexuality research around the globe must be perceived and researched in terms of cultural, spiritual, ethnic, and religious contexts. Sexual problems in women with gynecological cancer may be associated with adverse effects of surgical, hormonal, and chemical treatments, as well as by the cancer itself. Fortunately, emotional, sexual, and quality of life outcomes improve as less morbid, more minimally invasive surgical treatments for gynecological cancers develop [12]. Chemotherapy-induced ovarian failure in cancer patients is associated with all the possible symptoms of a sudden menopause, combined with the emotional impact not only of the cancer, but loss of physical well-being and fertility all at the same time. Vaginal dryness can be a major problem to those women who wish to have sex [27], and appropriate vaginal moisturizers and lubricants can help. The issue of vaginal estrogen is still debated, but should be discussed with the patient, weighing up the risk − benefit ratio for each individual. Vaginal estrogen will, in most cases, alleviate the dryness, but there may be concerns about using hormones, especially in relation to breast cancer where the evidence is unclear. The scientific data, however, support the safety of low dose vaginal estrogen therapy [28]. It is not well understood that following a few weeks of vaginal estrogen, the vagina thickens and cornifies and estrogen is not absorbed as a result. Newer treatments such as selective estrogen receptor modulators have been used in place of vaginal estrogen in women without cancer [29], and may prove good alternatives in the future [30]. There are non-hormonal vaginal moisturizers and lubricants to make sexual intercourse more comfortable. Unfortunately, some commercial sexual lubricants can be hyperosmolar and could cause epithelial disruption, facilitating HIV transmission [31]. Simple lubricants such as olive oil or liquid glycerin have been used successfully in interventions to alleviate pain on intercourse due to vaginal dryness, combining their use with physiotherapy and psychosexual counselling. Treatments with pelvic external beam radiotherapy and/or with brachytherapy may cause vaginal shortening, tightening, and lack of pliability. The use of vaginal dilators to overcome these complications is widespread, despite lack of conclusive evidence, either for or against, either with or without a coating of estrogen cream [32]. Unsurprisingly, the intrusion of inserting a plastic (or sometimes glass) tube into a tender vagina after treatment is a task that may carry a deep psychological and emotional impact [33], and will have resultant poor compliance. Radiation oncologists agree that information about dilator use should be given before treatment [34], and that sufficient patient information and support are essential to improve compliance. Sensitivity to emotions and women's views and personal values in relation to sexuality are essential supports to encouraging dilator use [35]. Any of the above problems cannot fail to have an emotional impact on the woman and on her partner. Many sexual difficulties are automatically blamed on the organic disruption caused by cancer and its treatments; however, once any clearly indicated treatments have been given, in a sizable proportion of cases, the sexual difficulty will remain unresolved. Many sexual difficulties are psychogenic, and no amount of skilled clinical treatments will help if not linked closely to appropriate counselling, psychological, or psychosexual therapy. This form of intervention will enable the woman to expose and reflect on her sexual difficulties, in the context of her life and relationship not only since the cancer, but beforehand. This is often a time when past problems, such as childhood abuse, or problems with her current partner will surface. Some partners are disgusted by the physical impacts of cancer, and the relationship will suffer. On the other hand, some partners become more supportive and the cancer leads to stronger relationships [36]. Classic psychosexual therapy, using brief, focused psychotherapeutic techniques is the mainstay of treatment. It can be used with an individual or a couple, of any sexual orientation or cultural or religious background. This is a way of listening reflectively to the patient, so that they can gain their own insights into their sexual problem. The issue of genital examination is considered if relevant, as it enables the woman to connect with her genital area, and may trigger deep-seated thoughts or anxieties that the woman had blocked emotionally. This, of course, is a technique used only by clinicians who are qualified to examine the patient [37]. Clinical psychologists and counsellors trained in psychosexual work also treat women with sexual problems. Globally, because the availability of trained personnel differs, many simple innovative treatment interventions have been tried. A brief intervention using a well-accepted treatment, cognitive behavioral therapy (CBT), combined with sexual health education had positive results on patients who had risk-reducing salpingo-oophorectomy [21]. Psychosexual interventions work [38], and like all psychodynamic interventions only require a trained counsellor and a means of allowing access to the patient. The internet has enabled access to health care for many people around the world who are not able to travel long and difficult land journeys to direct provision of health care. An online intervention with a professional moderator has proven acceptable to gynecological cancer patients with a sexual difficulty [39], and another internet-based sexual difficulties intervention with counselling sessions proved more successful in improving sexuality issues than without a counsellor; however, there was no difference between the two groups in relation to emotional distress and quality of life [40]. Elsewhere, telephone interventions are being used, also with some success; however, it is clear that the knowledge, skills, and training of the health professional providing the intervention are relevant to the patient outcome. Multidisciplinary care should form the backbone of treatment of sexual difficulties in women with gynecological cancer, incorporating physical, psychoeducational, and psychosexual input. Team discussions, including clinicians, psychosexual therapists, and physiotherapists are well within the capabilities of many cancer centers, remembering that the patient and her partner are the focal point and should always be consulted. It is impossible to diagnose and treat a sexual problem if one does not acknowledge that it exists. Many studies in the past have identified lack of willingness of doctors and nurses to discuss sex, but sadly recent research has shown that not much has changed. For instance, in a cohort sample of 1154 US obstetrician − gynecologists, 60% did not ask patients about sexual problems [41]. Too often clinicians make value judgements about their patients including whether sexuality is an important part of their lives. Such assumptions may include biases about age, appearance, sexual preferences, and marital status of people who have sex. People with cancer and their partners have unmet sexual information and support needs [42], often due to the unwillingness of healthcare professionals to discuss sexual issues, even though they recognize it may be important to the patient. There are many barriers to talking about sex, affecting both the patient and the clinician, such as cultural background, and age and gender discrepancies between doctor and patient. There may be simple barriers, such as lack of privacy in a consultation, as often cancer patients are accompanied by family or close friends. Patients often state that they feel it is trivial to take up the doctor's time with non-life-threatening issues such as sex. Clinicians often cite lack of training as a reason that they are uncomfortable talking about sex and poor provision of this training has been noted [13]. Different models of communication skills training have been used and those undertaking the training have shown greater empathy and were more inclined to use open questions [43]. This technique of speaking to the patient in an open rather than interrogative manner can easily facilitate discussion of intimate issues. An even greater challenge in communication is the recognition that individuals are sexual beings up to the end of life. To some women in the palliative phase, sexual touch and closeness to their partner is of vital importance. Sadly this is rarely recognized and addressed by palliative care physicians [44]. It is important to remember that a minority of the female population identifies as lesbian, and that about 8% of the population is bisexual. While this should make no difference to the quality of sexual health care they receive, lesbians and bisexuals find it difficult to disclose their sexuality to clinicians, often inhibited by their cultural or religious background, and fears of facing discrimination [45]. If the clinician asks the patient at the outset if they have a sexual partner, and whether the partner is male or female, it will greatly enhance the quality of the doctor − patient interaction. Lesbian partners in particular can be very supportive during the cancer journey, and should be given the opportunity to be present if the patient wishes. Despite the recognized need for treatment of sexual problems in menopause and gynecological cancer, there is poor provision of specialist training to ensure that this important area of service provision is met [46]. Undergraduate teaching is important, but it is only by recognizing psychosexual medicine in formal gynecology or oncology training, as a compulsory requirement of the course, that this situation will begin to be addressed. Innovative online programs [47] can make a major impact on global training opportunities and give trainees around the world an opportunity to gain some skills and insight into treating sexual difficulties in a nonjudgmental way. Owing to the global prevalence of sexual problems associated with gynecological cancer, it should be within every gynecologist's or oncologist's duty of care to the patient to be aware of and have some understanding of how to diagnose and facilitate treatment for sexual problems in a nonjudgmental manner. This is true holistic medicine, recognizing not only the cancer, but the woman behind the symptoms, and requires awareness of the emotional, social, and relationship aspects of the patient's life. The ability of any person to enjoy a sexual life free of coercion, shame, disease, or pain in a consensual manner is a fundamental element of the human rights of women, and should be an unequivocally accepted as part of her gynecological cancer care. To make a difference, even in the absence of expensive and sophisticated cancer treatments, just acknowledging, listening, and offering support to the woman with sexual difficulties related to cancer will ultimately have a major benefit to her quality of life. The author has no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

International Journal of Gynecology & Obstetrics · 17 citationsread the source →

Charting the Future of Cancer Health Disparities Research: A Position Statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute

The academic field of cancer health disparities was stimulated by the U.S. civil rights movement. Concerns about civil rights led to concerns about equality in health care. The first publications to make the observation that black Americans have higher rates of death as a result of certain cancers compared with white Americans were published by the early 1970s (1, 2). The discipline concerned with these differences was first called “minority health research” and later “special populations health” or “special populations research.” The National Cancer Institute (NCI) defines cancer health disparities as adverse differences in cancer incidence, cancer prevalence, cancer mortality, cancer survivorship, and burden of cancer or related health conditions that exist among specific population groups in the United States (3). However, with greater and renewed acknowledgment of health disparities as rooted within the context of historical and contextual inequities in the United States, many health disparities are considered health inequities (4).The National Cancer Act of 1971 created the Surveillance, Epidemiology, and End Results (SEER) program within the NCI. This program began collecting incidence, mortality, and survival data by race in the early 1970s from a number of population-based registries around the United States. The SEER program improved documentation of differences in outcomes and analyzed them through its black–white studies (5). These studies especially demonstrated differences in treatment patterns, with a higher proportion of blacks receiving inappropriate cancer care compared with whites. The discipline grew from a focus on black–white differences to encompass differences in outcomes for a number of racial and ethnic groups, as well as for cohorts defined by age, sex, socioeconomic status (SES), and other social determinants of health. There is now even greater appreciation for disparities among communities, whether rural versus urban or even by state or region. The definition of health outcomes also broadened beyond death rates. The field of health disparities was once simply a description of population differences and a call for cultural competence among health care providers. Today, the field is transdisciplinary, integrating basic science, clinical science, policy, epidemiology, and the social sciences. It involves people trained in diverse nonmedical fields, such as education, economics, sociology, religion, geography, and anthropology. The field is also dynamic. It changes as better and more granular statistics, greater understanding of causes of health disparities, and new challenges to mitigate these underlying causes have emerged. As an example, in the 1970s, the breast cancer death rate for black and white American women was the same. Today, the death rate is substantially higher for blacks compared with whites (6). Policy changes have also created opportunities and challenges. The Affordable Care Act has allowed for Medicaid expansion in each state. Expansion has been adopted by 32 states and the District of Columbia. This will create a new challenge, because poor residents of some states have expanded access to care and residents of other states do not. It is essential that any future policy changes should be carefully designed to increase, rather than decrease, equitable access to care throughout the cancer continuum. Population categorizations also are being redefined. The Asian category includes Korean Americans and Pakistani Americans. The Pacific Islander category, often merged with the Asian category, includes native Hawaiians and Samoans. These populations are incredibly heterogeneous and have dramatically different cancer statistics. In 2015, representatives from four leading cancer organizations, the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology (ASCO), and the NCI, began to meet to discuss the state of health disparities in the United States. These discussions involved the state of cancer health disparities research and what could be done to move it forward. The discussions were purposely not meant as a comprehensive review of cancer health disparities research. Rather, the meeting and the resulting document aimed to identify issues in health disparities research and make specific recommendations to improve the way disparities research is conducted and disseminated. This statement presents a unified strategy among four of the leading cancer organizations in the United States to promote cooperation among investigators in all areas of the cancer health disparities research community, to ensure that cancer research benefits all populations and patients regardless of race, ethnicity, age, gender identity, sexual orientation, SES, or the communities in which they live. Disparities in outcomes across the cancer continuum have been identified in numerous medically underserved populations, including racial and ethnic minorities and patients of lower SES. In addition to individual social status, social contextual and community factors, such as neighborhood safety, social cohesion, availability of healthy foods, and residential segregation, play an important role in health of both individuals and populations. All of these factors can intersect to generate larger disparities (7, 8).To understand and fully address cancer health disparities, complete, consistent, and accurate collection of patient, community, and structural factors that put people at risk for disparate outcomes is essential. Unfortunately, cancer health disparities research has often been fraught with missing, inaccurate, or overly simplified patient-level data, and most research has failed to consider the community-level factors described above (9–11).For the most part, the manner in which data are collected and integrated in disparities research is suboptimal. The literature is characterized by variable methodology for collection of the factors that put patients and communities at risk for disparate care and outcomes. For example, although race and ethnicity are distinct constructs, they are often conflated such that a person is identified as Hispanic without identification of his or her race. Many studies that investigate cancer care or outcomes according to socioeconomic position have only area-level data on socioeconomic position, whereas others use only composite measures. While valuable in many cases in identifying disparities, such measures fall short in providing the richness of data needed to understand an individual's socioeconomic position. Health literacy and numeracy are rarely assessed in practice and are not available in administrative and research databases. Finally, methods for uniform data collection of information on sexual orientation and gender identity are in their infancy, despite calls for such data collection from the Institute of Medicine, among others (12).Disparities in cancer incidence are pronounced and longstanding. Drivers of these disparities are multifactorial and multilevel, and they include sociodemographic factors, access to health care, risk factor profiles and lifestyle/health habits, cultural perceptions, biologic differences, and genetic predisposition. Disparities in cancers for which single etiologic factors account for a substantial proportion of disease (e.g., human papillomavirus and cervical cancer, or Helicobacter pylori and stomach cancer) can be reasonably understood and explained, but disparities for many of the common etiologically heterogeneous cancers, such as breast, prostate, and colorectal cancers, remain much less well understood. Multilevel approaches are needed to advance knowledge relevant to addressing disparities in cancer incidence rates. One approach is to design and implement observational studies focused on a population in which disparities exist to advance knowledge about etiology and to inform novel prevention strategies. A successful example of such an effort is the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a multicenter consortium that has combined data and biospecimens from 7,500 African American patients with breast cancer and 17,000 healthy controls, representing the largest study of breast cancer in African American women in the United States (14). It has yielded a number of insights on multilevel risk factors specific to the major molecular subtypes of breast cancer among African American women (15–17).There is also a need for studies focused on identifying the genetic contributors to cancer health disparities. Recent work has focused on the prioritization of candidate variants relevant to prostate cancer risk within the context of genetic ancestry (based on ancestry informative markers) across those with European, African, Japanese, or Latino ancestry (18). Furthermore, the African Ancestry Prostate Cancer Genome-Wide Association Studies (GWAS) Consortium has reported on susceptibility loci for aggressive prostate cancer specific to men of African ancestry (19).Although some cancer risk factors are well established, the biologic mechanisms through which their impact on cancer risk varies across different populations remain incompletely understood. For example, variations in diet are hypothesized to be the primary driver of the dramatic variations in colorectal cancer incidence rates observed across populations. Recent research has evaluated the impact that different diets have on microbiota composition and function, which in turn affects the production of metabolites that either promote mucosal health or are proinflammatory/neoplastic in the gut. A study that compared Americans with African ancestry (who have a relatively high incidence of colorectal cancer) with rural South Africans (who have a comparatively very low colorectal cancer incidence rate) demonstrated that a typical U.S. diet with high meat and fat intake increases mucosal proliferation rates (a marker of cancer risk) when fed to both populations, whereas typical high-fiber South African diets were associated with low proliferation rates when fed to both groups. This demonstrates that diet can have a profound and fairly immediate impact on the gut microbiome that can either promote or suppress tumors (20).Cancer outcome disparities are well documented for racial and ethnic minorities, and presentation at more advanced stages of cancer explains much of this difference. However, even when controlling for the stage of cancer at diagnosis, the survival disparities persist. What is most concerning is that rather than improving over time, for cancers such as colon cancer, the stage-specific disparities are actually worsening (21). The reason for this growing disparity is not completely clear but involves socioeconomic issues such as education status and the level of insurance and access to medical care. Even in studies that normalize socioeconomic issues (with the limitations cited in the Defining Measures section), disparities that disproportionally affect U.S. minority populations can still be demonstrated for several cancers and may highlight the not-so-well-understood interplay between genetic predisposition and environmental exposure, such as lifestyle and diet, that modifies cancer risk (22, 23). Ultimately, growing postdiagnosis survival disparities are caused by the interplay of system, social, biologic, and environmental factors. Documenting and addressing each of these and their interactions are key to eliminating these disparities. The role of system-level and social determinants in explaining cancer health disparities is best demonstrated by recognizing that disparities vary widely across the United States; some states show almost no disparities, whereas others show striking ones (24). We also know that disparities in treatment of cancer differ and that when treatment differences are accounted for, either through the use of standardized therapies on a clinical trial or through multivariable modeling, cancer-specific survival disparities often disappear. We also have clear examples of successful system-level reform (21, 25, 26). We know, therefore, this is a solvable problem. The key step toward improving care and reducing cancer health disparities requires accurate measurement of meaningful variables, fed back in real time to key stakeholders in the system, followed by meaningful action and continued monitoring to ensure that the action was successful. Determining meaningful measurement across the cancer spectrum may vary by sociocultural factors and require patient and stakeholder input. These system-based practices formed the core of a recent Institute of Medicine report, “Systems Practices for the Care of Socially At-Risk Populations” (27). Systems can be thought of at a macro level, such as state, county, or city governments, all the way down to the individual practice or physician level. Implementation science can inform the best approaches to ensure delivery of high-quality cancer care. Cancers can start as a result of chronic inflammation, and inflammation can modify the behavior of cancer. Biomarkers, such as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that can be detected from inflammation-laden cancers, are associated with worse patient outcome and increased metastasis and appear to be more common among African Americans. Microsatellite-unstable (MSI) cancers, which have an overall good prognosis, may be half as common among African Americans compared with whites (28). Both EMAST and MSI have implications for (1) chemotherapeutic response and (2) immunotherapeutic response. In terms of race, these aspects have not been studied. Furthermore, there is much evidence that the microbiome can influence (1) inflammation, (2) response to chemotherapy, and (3) cancer or precancerous lesion formation; also, the microbiome itself can be determined by diet and other factors. These aspects have not been examined with race in mind. Additionally, driver genes may be different within the same type of cancer from patients with different genetic backgrounds, which have implications for correct, definitive therapeutic approaches (29).Most studies that use human specimens to study aspects of cancer and race or ethnicity come from limited individual collections with sparse clinical–epidemiologic information, with rare exception. The exceptions tend to be NCI-funded projects, such as the North Carolina Colon Cancer Study, in which peer review and thoughtful input about how the collection was made with controls, surveys, and linked information to make the collection more meaningful, comprehensive in information, potentially useful for other future studies, and possessed of longevity. However, these types of collections or biorepositories, which include tumor and nontumor specimens, have not been created from diverse samples representative of the U.S. Census population. Current models of health care delivery are highly focused on the use of technology and innovation to improve patient outcomes across disease processes, as demonstrated by the focus on precision medicine in cancer treatment (32–36). Although oncology attempts to embrace this approach, the impact of innovative treatments has been hampered by poor translation of innovation into health care systems and patients from diverse community settings (37, 38). As precision medicine in cancer is accelerated as part of the Beau Biden Cancer Moonshot and other initiatives, the importance of community engagement to ensure that all patients benefit from these advances cannot be overlooked. Cancer health disparities must be taken into consideration in the design, execution, and evaluation of all such programs. Community-engaged research (CER) has been documented as an effective, beneficial method for engaging communities and formulating research that has relevance and impact for both researchers and affected communities (39–42). Involving relevant community stakeholders in research at the planning stages allows for a deeper understanding of community needs, allows researchers to have an iterative method for evaluating research questions in an active realistic milieu, and simultaneously creates a valuable vehicle for active dissemination of the research findings into the communities they are intended to serve. CER offers the potential to improve processes and outcomes in several areas, including care delivery, continuity of care, managing comorbidities, and supportive care (42).Unfortunately, there is a dearth of support for oncology health professionals who choose to work in CER, given its necessity for infrastructure and relationship building, the complex personal interactions with communities and community organizations, and the need to establish long-term benefits to the community after the research project is completed. Importantly, CER requires not only a broad range of expertise across multiple disciplines, but also investigators skilled in a team science approach (43). The benefit of this type of team science has been touted across disciplines; however, its implementation has been limited (44).A lack of workforce diversity has been identified as a barrier to improving access to care for underserved minority groups as well as to advancing research on health disparities (45, 46). Organizations, including ASCO and the American Society of Hematology, have sought to increase workforce diversity in oncology through awards and mentoring programs that expose minorities to in oncology at the medical and In the to Cancer Health Disparities and the American Association for Cancer several programs aimed at the of researchers in cancer and cancer health disparities research. of these types are needed to an oncology workforce that the diversity of the patients it CER not often with most and will require on of the research in both and such an it will remain to create a between CER and the that in cancer are the most important and available to evidence for care and of patients with cancer and individuals at risk for cancer that advanced new approaches from clinical care and diverse oncology the of clinical is to evidence that is both and future must include research questions that consider the multifactorial and multilevel that populations with the cancer This to advance disparities research within the cancer clinical within a new of for in cancer clinical and common for providing trial information have been to for rural patients and patients with lower SES, limited low health and The high and of chronic and of risk factors for chronic such as and must inform to these populations fully in cancer As an example, African Americans a burden of the that from studies, and it is to which could be reasonably as or could be or within the study In addition to those from cancer prevention and treatment also has that populations often are later in the and do not support and rates are key that influence the outcome of clinical cancer studies, those in which minorities have higher disease such as breast, prostate, and cancers In and treatment and rates lower rates exist for those patients who from to and Many such as and to the However, community engagement is to address the and challenges that the clinical CER has been demonstrated to promote building, and the and dissemination of information needed for and long-term As an example, the evaluated the of community health to promote and in and rural populations and that community health can be trained to as research and can be for of and cancer clinical trial and require an of often to be collected at multiple time thought should be given to how best to the of and the study (e.g., and needed to support collection and of specimens from and that to field of cancer health disparities has into a complex science and an field of cancer research. Unfortunately, the to this research has not been and the infrastructure needed to it to the level, can be is The of this which has been by from these four organizations, is to the of advances in this is that this statement will be by both and organizations to inform specific made to improve cancer health disparities eliminating identified disparities in cancer incidence, of care, and recommendations for action have a new in cancer health disparities that has the potential to benefit from across and the in cancer incidence and disparities that affects minorities and the medically it is that in this of cancer research when are being there will be opportunities to this new knowledge to all populations, and cancer health disparities for and future has in a or role for and and as a of the for has research from and has other from the has in a or role for and has research his from and and has and from and has from has in a or role for the and and has research from or other in and has from and has and from for both and an immediate or other in and and has research her from potential of were by the other and and of and of for all aspects of the the of and the for their of this to and

Cancer Research · 84 citationsread the source →

Understanding nutrition, depression and mental illnesses

INTRODUCTION Few people are aware of the connection between nutrition and depression while they easily understand the connection between nutritional deficiencies and physical illness. Depression is more typically thought of as strictly biochemical-based or emotionally-rooted. On the contrary, nutrition can play a key role in the onset as well as severity and duration of depression. Many of the easily noticeable food patterns that precede depression are the same as those that occur during depression. These may include poor appetite, skipping meals, and a dominant desire for sweet foods.[1] Nutritional neuroscience is an emerging discipline shedding light on the fact that nutritional factors are intertwined with human cognition, behavior, and emotions. The most common mental disorders that are currently prevalent in numerous countries are depression, bipolar disorder, schizophrenia, and obsessive-compulsive disorder (OCD).[2] The dietary intake pattern of the general population in many Asian and American countries reflects that they are often deficient in many nutrients, especially essential vitamins, minerals, and omega-3 fatty acids.[3] A notable feature of the diets of patients suffering from mental disorders is the severity of deficiency in these nutrients.[3] Studies have indicated that daily supplements of vital nutrients are often effective in reducing patients' symptoms.[4] Supplements containing amino acids have also been found to reduce symptoms, as they are converted to neurotransmitters which in turn alleviate depression and other mental health problems.[4] On the basis of accumulating scientific evidence, an effective therapeutic intervention is emerging, namely nutritional supplement/treatment. These may be appropriate for controlling and to some extent, preventing depression, bipolar disorder, schizophrenia, eating disorders and anxiety disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), autism, and addiction.[4] Most prescription drugs, including the common antidepressants lead to side effects.[4] This usually causes the patients to skip taking their medications. Such noncompliance is a common occurrence encountered by psychiatrists. An important point to remember here is that, such noncompliant patients who have mental disorders are at a higher risk for committing suicide or being institutionalized. In some cases, chronic use or higher doses may lead to drug toxicity, which may become life threatening to the patient.[4] An alternate and effective way for psychiatrists to overcome this noncompliance is to familiarize themselves about alternative or complementary nutritional therapies. Although further research needs to be carried out to determine the best recommended doses of most nutritional supplements in the cases of certain nutrients, psychiatrists can recommend doses of dietary supplements based on previous and current efficacious studies and then adjust the doses based on the results obtained by closely observing the changes in the patient.[4] When we take a close look at the diet of depressed people, an interesting observation is that their nutrition is far from adequate. They make poor food choices and selecting foods that might actually contribute to depression. Recent evidence suggests a link between low levels of serotonin and suicide.[5] It is implicated that lower levels of this neurotransmitter can, in part, lead to an overall insensitivity to future consequences, triggering risky, impulsive and aggressive behaviors which may culminate in suicide, the ultimate act of inwardly directed impulsive aggression. Depression is a disorder associated with major symptoms such as increased sadness and anxiety, loss of appetite, depressed mood, and a loss of interest in pleasurable activities. If there is no timely therapeutic intervention, this disorder can lead to varied consequences. Patients who are suffering from depression exhibit suicidal tendency to a larger degree and hence are usually treated with antidepressants and/or psychotherapy.[6] Deficiencies in neurotransmitters such as serotonin, dopamine, noradrenaline, and γ-aminobutyric acid (GABA) are often associated with depression.[6–11] As reported in several studies, the amino acids tryptophan, tyrosine, phenylalanine, and methionine are often helpful in treating many mood disorders including depression.[12–17] When consumed alone on an empty stomach, tryptophan, a precursor of serotonin, is usually converted to serotonin. Hence, tryptophan can induce sleep and tranquility. This implies restoring serotonin levels lead to diminished depression precipitated by serotonin deficiencies.[8] Tyrosine and sometimes its precursor phenylalanine are converted into dopamine and norepinephrine.[18] Dietary supplements containing phenyl alanine and/or tyrosine cause alertness and arousal. Methionine combines with adenosine triphosphate (ATP) to produce S-adenosylmethionine (SAM), which facilitates the production of neurotransmitters in the brain.[19–22] The need of the present paradigm is, more studies shedding light on the daily supplemental doses of these neurochemicals that should be consumed to achieve antidepressant effects. Researchers attribute the decline in the consumption of omega-3 fatty acids from fish and other sources in most populations to an increasing trend in the incidence of major depression.[23] The two omega-3 fatty acids, eicosapentaenoic acid (EPA) which the body converts into docosahexanoic acid (DHA), found in fish oil, have been found to elicit antidepressant effects in human. Many of the proposed mechanisms of this conversion involve neurotransmitters. For instance, antidepressant effects may be due to bioconversion of EPA to leukotrienes, prostaglandins, and other chemicals required by the brain. Others hypothesize that both EPA and DHA influence neuronal signal transduction by activating peroxisomal proliferator-activated receptors (PPARs), inhibiting G-proteins and protein kinase C, in addition to calcium, sodium, and potassium ion channels. Whichever may be the case, epidemiological data and clinical studies have clearly shown that omega-3 fatty acids can effectively treat depression.[24] In depressed patients, daily consumption of dietary supplements of omega-3 fatty acid that contain 1.5-2 g of EPA has been shown to stimulate mood elevation. Nevertheless, doses of omega-3 higher than 3 g do not show better effects than placebos and may be contraindicative in cases, such as those taking anticlotting drugs.[25] In addition to omega–3 fatty acids, vitamin B (e.g., folate) and magnesium deficiencies have been linked to depression.[26–28] Randomized, controlled trials that involve folate and vitamin B12 suggest that patients treated with 0.8 mg of folic acid/day or 0.4 mg of vitamin B12/day will exhibit decreased depression symptoms.[27] In addition, the results of several case studies where patients were treated with 125-300 mg of magnesium (as glycinate or taurinate) with each meal and at bedtime led to rapid recovery from major depression in < 7 days for most of the patients. Previous research has revealed the link between nutritional deficiencies and some mental disorders.[232529–32] The most common nutritional deficiencies seen in patients with mental disorders are of omega–3 fatty acids, B vitamins, minerals, and amino acids that are precursors to neurotransmitters.[20232427283033] Accumulating evidence from demographic studies indicates a link between high fish consumption and low incidence of mental disorders; this lower incidence rate being the direct result of omega–3 fatty acid intake.[233132] One to two grams of omega-3 fatty acids taken daily is the generally accepted dose for healthy individuals, but for patients with mental disorders, up to 9.6 g has been shown to be safe and effective.[34–36] Majority of Asian diets are usually also lacking in fruits and vegetables, which further lead to mineral and vitamin deficiencies. The significance of various nutrients in mental health, with special relevance to depression has been discussed below. CARBOHYDRATES Carbohydrates are naturally occurring polysaccharides and play an important role in structure and function of an organism. In higher organisms (human), they have been found to affect mood and behavior. Eating a meal which is rich in carbohydrates triggers the release of insulin in the body. Insulin helps let blood sugar into cells where it can be used for energy and simultaneously it triggers the entry of tryptophan to brain. Tryptophan in the brain affects the neurotransmitters levels. Consumption of diets low in carbohydrate tends to precipitate depression, since the production of brain chemicals serotonin and tryptophan that promote the feeling of well being, is triggered by carbohydrate rich foods. It is suggested that low glycemic index (GI) foods such as some fruits and vegetables, whole grains, pasta, etc. are more likely to provide a moderate but lasting effect on brain chemistry, mood, and energy level than the high GI foods - primarily sweets - that tend to provide immediate but temporary relief. PROTEINS Proteins are made up of amino acids and are important building blocks of life. As many as 12 amino acids are manufactured in the body itself and remaining 8 (essential amino acids) have to be supplied through diet. A high quality protein diet contains all essential amino acids. Foods rich in high quality protein include meats, milk and other dairy products, and eggs. Plant proteins such as beans, peas, and grains may be low in one or two essential amino acids. Protein intake and in turn the individual amino acids can affect the brain functioning and mental health. Many of the neurotransmitters in the brain are made from amino acids. The neurotransmitter dopamine is made from the amino acid tyrosine and the neurotransmitter serotonin is made from the tryptophan.[5] If there is a lack of any of these two amino acids, there will not be enough synthesis of the respective neurotransmitters, which is associated with low mood and aggression in the patients. The excessive buildup of amino acids may also lead to brain damage and mental retardation. For example, excessive buildup of phenylalanine in the individuals with disease called phenylketonuria can cause brain damage and mental retardation. ESSENTIAL FATTY ACIDS Omega-3 fatty acids The brain is one of the organs with the highest level of lipids (fats). Brain lipids, composed of fatty acids, are structural constituents of membranes. It has been estimated that gray matter contains 50% fatty acids that are polyunsaturated in nature (about 33% belong to the omega-3 family), and hence are supplied through diet. In one of the first experimental demonstrations of the effect of dietary substances (nutrients) on the structure and function of the brain, the omega-3 fatty acids (specially alpha-linolenic acid, ALA) were the member to take part. An important trend has been observed from the findings of some recent studies that lowering plasma cholesterol by diet and medications increases depression. Among the significant factors involved are the quantity and ratio of omega-6 and omega-3 polyunsaturated fatty acids (PUFA) that affect serum lipids and alter the biochemical and biophysical properties of cell membranes. It has been hypothesized that sufficient long chain PUFAs, especially DHA, may decrease the development of depression.[37] The structural and functional components of membrane in cells of brain which is a lipid-rich organ, include polar phospholipids, spingolipids, and cholesterol. The glycerophospholipids in brain consist of high proportion of PUFA derived from the essential fatty acids (EFAs), linoleic acid and α-linolenic acid. The main PUFA in the brain are DHA, derived from the omega-3 fatty acid α-linolenic acid, arachidonic acid (AA) and docosa tetraenoic acid, both derived from omega-6 fatty acid linoleic acid. Experimental studies have revealed that diets lacking omega-3 PUFA lead to considerable disturbance in neural function.[38] Studies by Marszalek and Lodish indicate that despite their abundance in the nervous system, DHA and AA cannot be synthesized by mammals de novo and hence they or their precursors have to be supplied through the diet and transported to the brain. During late gestation and the early postnatal period, neurodevelopment occurs at significantly rapid rates which make the supply of adequate quantity of PUFAs, particularly DHA, imperative to ensure neurite outgrowth in addition to appropriate development of brain and retina.[39] Bruinsma and Taren of University of Arizona College of Public Health, Tucson, USA explored the involvement of dieting-related psychological factors as potential confounders.[40] They discussed studies that have both supported and contested the proposition that lowering plasma cholesterol by diet and medications contributes to depression. Research findings point out that an imbalance in the ratio of the EFAs, namely the omega-6 and omega-3 fatty acids, and/or a deficiency in omega-3 fatty acids, may be responsible for the heightened depressive symptoms associated with low plasma cholesterol. These relationships may explain the inconsistency in the results of trials on cholesterol-lowering interventions and depression. On similar lines, dieting behaviors have been associated with alterations in moods.[41] Dietary omega-3 fatty acids play a role in the prevention of some disorders including depression. Their deficiency can accelerate cerebral aging by preventing the renewal of membranes. However, the respective roles of the vascular component on one hand (where the omega-3s are active) and the cerebral parenchyma itself on the other, have not yet been clearly resolved. The role of omega–3 in certain diseases such as dyslexia and autism is suggested. It was omega–3 fatty acids that participated in the first coherent experimental demonstration of the effect of dietary substances (nutrients) on the structure and function of the brain. Experiments were first of all carried out on x-vivo cultured brain cells (1), then on in vivo brain cells (2), finally on physicochemical, biochemical, physiological, neurosensory, and behavioral parameters (3). These findings indicated that the nature of polyunsaturated fatty acids (in particular omega–3) present in formula milks for infants (both premature and term) determines the visual, cerebral, and intellectual abilities.[16] VITAMINS B-complex vitamins Nutrition and depression are intricately and undeniably linked, as suggested by the mounting evidence by researchers in neuropsychiatry. According to a study reported in Neuropsychobiology,[42] supplementation of nine vitamins, 10 times in excess of normal recommended dietary allowance (RDA) for 1 year improved mood in both men and women. The interesting part was that these changes in mood after a year occurred even though the blood status of nine vitamins reached a plateau after 3 months. This mood improvement was particularly associated with improved vitamin B2 and B6 status. In women, baseline vitamin B1 status was linked with poor mood and an improvement in the same after 3 months was associated with improved mood. Thiamine is known to modulate cognitive performance particularly in the geriatric population.[43] Vitamin B12 (Cynocobalamin) Clinical trials have indicated that Vitamin B12 delays the onset of signs of dementia (and blood abnormalities), if it is administered in a precise clinical timing window, before the onset of the first symptoms. Supplementation with cobalamin enhances cerebral and cognitive functions in the elderly; it frequently promotes the functioning of factors related to the frontal lobe, in addition to the language function of people with cognitive disorders. Adolescents who have a borderline level of vitamin B12 deficiency develop signs of cognitive changes.[43] Folate It has been observed that patients with depression have blood folate levels, which are, on an average, 25% lower than healthy controls.[44] Low levels of folate have also been identified as a strong predisposing factor of poor outcome with antidepressant therapy. A controlled study has been reported to have shown that 500 mcg of folic acid enhanced the effectiveness of antidepressant medication.[45] Folate's critical role in brain metabolic pathways has been well recognized by various researchers who have noted that depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency.[46] It is not clear yet whether poor nutrition, as a symptom of depression, causes folate deficiency or primary folate deficiency produces depression and its symptoms. MINERALS Calcium A recent study showed that selective serotonin uptake inhibitors (SSRIs) inhibit absorption of calcium into bones. In addition to this, the SSRIs can also lower blood pressure in people, resulting in falls which may lead to broken bones. Indiscriminate prescription of SSRIs by doctors and ingestion by patients at risk of depression or other mental health problems may put them at increased risk of fractures. Compounded by the fact that they may be aging and already taking other medications, may also predispose them to osteoporosis.[47] Chromium Many studies on the association of chromium in humans depression have been recorded[4849] which indicate the significance of this micronutrient in mental health. Iodine Iodine plays an important role in mental health. The iodine provided by the thyroid hormone ensures the energy metabolism of the cerebral cells. During pregnancy, the dietary reduction of iodine induces severe cerebral dysfunction, eventually leading to cretinism. Iron Iron is necessary for oxygenation and to produce energy in the cerebral parenchyma (through cytochrome oxidase), and for the synthesis of neurotransmitters and myelin. Iron deficiency is found in children with attention-deficit/hyperactivity Iron in the are critical during the development of the and in with the in the with its associated deficiency is associated with disturbance in the development of cognitive Research findings out that as many as men are This in and more with of more depression than during other times in their These indicate the of in the of depression since its deficiency is known to cause and depression. Iron deficiency is for instance, with depression, and rapid a was first and by in while an of the mineral The role of has been well known in a into its its for bipolar disorder with and The therapeutic use of also its as an in depression, disorder, disorder, eating disorders, and in certain of adequate has to be taken while the mood in the can be used in patients with and The use of during and in and geriatric population needs observation about its In a of the of identified at studies, which indicate that low intake is associated with mood studies with with other populations that mood and in the of studies have shown that levels are lower in those with clinical intervention research that can influence the effectiveness of antidepressant also the brain cells the potential damage by studies have revealed the potential of the for physical development and mental development may be due to deficiency of When children and with poor nutritional status are to alterations of mental and behavioral they can be by dietary but to certain It has been observed that, of diet and meal pattern can have or immediate or effects. Dietary deficiencies of and nutrients vitamins, and such as during aging may precipitate brain which may be due to for of diet and depression which is a of to a factor that is often linked to increased and premature of aging may play an important role in this, by reducing food intake or reducing food intake in to such factors as in and poor use of prescription drugs, and and occurring in the in both and due to to They suggest changes associated with mental disorders such as dementia and depression, and and as to the of depression, people are the alternative and complementary are by the for and as a of and health and that are not currently to be a part of health need to be aware that it is likely that a of their patients with bipolar disorder might use these interventions to be and safe or to research in and brain indicates the of pathways that can provide a of the association between nutritional nervous system, and function an psychological health status. These findings may lead to of the therapeutic of dietary intervention health and health depression and other psychological disorders.

Indian Journal of Psychiatry · editorial or comment · 409 citationsread the source →

The impact of end-stage kidney disease (ESKD) on close persons: a literature review

Kidney disease is defined as end-stage when a patient's glomerular filtration rate has fallen to <15 ml/min/ 1.73 m2 [1]. Mortality associated with end-stage kidney disease (ESKD) is high [2]. The incidence of treated ESKD is rising in the western world, with a corresponding increase in the incidence of diabetes and cardiovascular disease, especially in ethnic minority groups. Survival on dialysis has been shown to be poorer in the older age group, especially in patients with increased comorbidity and in those whose functional status at the start of dialysis is poor [3]. Whilst renal transplant rates vary between different countries [4], the liberalization in the acceptance of older people into renal replacement therapy (RRT) programmes, together with changes in population demographics and the fact that kidney transplantation is less suitable for this group of older patients, means that dialysis may be the only treatment option available for an increasing number of patients aged 65 years and over [5]. Recent health policy changes in the OECD countries [6,7] acknowledge that end of life care may be more appropriate for some of these people, and maximum conservative management programmes (where residual renal function is supported, haemoglobin levels maintained and symptoms relieved) have been introduced into many renal units, particularly in the United Kingdom [6]. The onset of ESKD and subsequent recommendation of dialysis as a treatment option involves a change in lifestyle for both patients and close persons [8]. Even before end-stage disease is reached, as renal function deteriorates, patients frequently require additional support, and it is often family members who provide this [9]. In the UK it is estimated that 9 out of 10 carers of patients with either physical or neurological disabilities will be close relatives. In particular when home haemodialysis is undertaken, family members have been involved in supporting patients [10,11]. Studies have shown that good family support is associated with successful adaptation to dialysis and compliance with dietary restrictions [12,13]. Conversely, one of the main factors associated with patients discontinuing dialysis is patients’ perception that they have become a ‘burden’ to close family members [14]. There is therefore a need for health professionals to be aware of the important contribution that close persons make to the care of renal patients, to communicate effectively with them and to provide bereavement support for this group when appropriate [15]. The literature on close persons of patients with renal disease has identified two main areas of impact. Firstly, both haemodialysis and peritoneal dialysis may have a disruptive influence on family members’ social lives [16] and the structure of the week may be geared towards dialysis sessions. Secondly, some patients become frail and lose functional independence, leaving family members to provide greater physical support. Family members may have health and social care needs of their own that need to be addressed [16,17]. Qyinan [18] reported that close persons commonly felt overwhelmed and stressed, although this review was limited to an evidence base of four articles and considered home dialysis only. Campbell [19] used findings from the general carer literature to illustrate demands of ageing partners with ESKD. In other chronic illnesses such as stroke [20] or in palliative care for cancer and mental health [21], interventions aimed at providing family members with training to support patients with their rehabilitation, or to address unmet needs as a result of the patient's illness, have been developed and evaluated. Results have been mixed. In the case of stroke, carers in the intervention group experienced less depression and anxiety and better quality of life [20], whilst in the palliative care study, no statistically significant differences were found between the intervention and control group on carers’ psychological outcomes [21]. However, before such interventions can be developed in ESKD, it is important to understand better the emotional and physical needs of close persons. This review aims to identify all studies involving close persons caring for ESKD patients, to describe the main findings and critique the methodology. Specific attention has been paid to (a) studies exploring the impact of ESKD on close persons, in particular for those close persons where the patients are either withdrawing from dialysis or being provided with end of life care and (b) studies looking at the provision of health care for close persons. A literature search for relevant articles was conducted in five databases: Medline (1950–2006), Embase (1991–2006), CINAHL (1982–2006), PsycINFO (1970–2006) and AMED (1985–2006), employing the following key words: carers, caregivers, end-stage kidney disease, end-stage renal disease, haemodialysis, peritoneal dialysis and renal replacement therapy. These keywords were used both in word search options and exploded as thesaurus terms to obtain the maximum number of articles. The abstracts for each article were read to check for inclusion into the main review, using the following criteria: Published in peer-reviewed journals. Research studies with an introduction, a methodology and results section and a conclusion. Involve close persons, defined as either a family member or the person identified by the patient as an informal carer. By an informal carer, we mean a person who provides the majority of a patient's physical and emotional care needs and who is neither a volunteer nor in the employment of statutory services. Use a sample of close persons caring for adult ESKD patients (over 18 years). Non-English language articles were considered if the English translation of the abstract met the above criteria. Using these criteria, 334 articles were identified from the five databases (139 in Medline, 121 in Embase, 80 in CINAHL, 8 in AMED and 34 in PsycINFO). J.L. went through the abstracts of each of the 382 articles, of which 37 initially met the inclusion criteria. One was later excluded on closer inspection, as it was specifically a validation study of a fatigue severity scale. Of the remaining 36 studies, 16 exclusively looked at family members, 12 specifically at the patient-family dyad and 3 at the family-health professional dyad. Whilst the latter two types of studies did not concentrate solely on family concerns, we decided to include them in the analysis, because these findings further contribute to the limited number of studies in this field. Thirty-six studies were included in the review. Both J.L. and G.S. first went through the remaining 36 studies independently and extracted the following information for each study: the number of carers in the study sample, the RRT population they were caring for, authors’ definition of a carer, demographic details of the sample, patients’ dialysis history, caring history, study design, outcome measures used and main findings. J.L. and G.S. then met together to discuss these findings and obtain an initial consensus before meeting with A.B. and L.J. to obtain a final consensus. We undertook an exploration of the aims of these studies, their study design, the sample of participants and the outcome measures highlighted in the quantitative studies. The three main themes explored were (a) the impact of caring for a patient with ESKD on dialysis on close persons, in particular quality of life, psychological morbidity, close person responsibilities—which authors often referred to as ‘burden’ or ‘carer burden’—and their life situation; (b) the coping strategies employed by these close persons and (c) factors that influence psychological morbidity. No studies of health provision for close persons of patients with ESKD were identified. Four studies looking at end of life issues explored the following themes for close persons: (a) their perceptions of patients’ terminal symptoms; (b) their reasons for why patients decided to stop dialysis; (c) the long-term impact of patient death following dialysis cessation and (d) their perceptions of advance directives. End of life care may be provided by the renal multi-disciplinary team alone, or it may involve referral for specialist palliative care advice. Such advice is likely to include symptom control, attention to spiritual and psychological issues for patients and, where possible, involvement of their families in decision-making. Whilst most studies were interested in the direct impact on close persons only, one triangulated close person data with patient data. The majority of studies reviewed used a cross-sectional design; there was only one longitudinal study. Whilst most were quantitative (24/36), there were some qualitative studies (11/36) and one used a mixed methods approach. The total sample was predominantly female, with mean ages ranging from 41 to 68 years (analysis possible in only 18 studies). Sample sizes also tended to be small, with a median sample of 55 participants for the quantitative and 15 participants for the qualitative studies. Most of the sample was recruited in studies where associated patients were undergoing haemodialysis or peritoneal dialysis. Three studies also involved kidney transplant patients. Only five studies looked at close persons dealing with end of life issues or with patients withdrawing from dialysis. Many studies did not focus on close persons in their potential role as ‘informal carers’. Thirteen studies actively sought close persons who also considered themselves to be informal carers, of which eight provided full definitions of what they meant by this term. All studies included spouses as part of their sample, of which eight specifically concentrated on this group alone. Adult children were included in seven of these studies and parents in five. A wide variety of outcome measures were used to rate health-related quality of life, anxiety, depression, coping strategies and patient disease severity. Some studies used standardized outcome measures; others used simple self-rated tools. The most commonly used standardized measures were the Zarit Burden Interview [22] to evaluate the sense of carer responsibility (3/8), the Beck Depression Scale [23] to evaluate depression (2/5), SF-36 [24] to evaluate health-related quality of life (3/8), Jalowiec Coping Scale [25] to evaluate close persons’ use of coping strategies (3/3) and End-Stage Renal Disease Severity Index [26] to evaluate patients’ disease severity (2/4). A breakdown of the country of origin for each study showed that over half originated from either the USA (11/36) or Canada (7/36), with five originating from Australia and only seven from the European Union, of which only one was conducted in the UK. The remaining six studies came from the following countries: Japan (2/36), Brazil (2/36), China (1/36) and Turkey (1/36). The 36 studies have shown mixed results. They have mainly explored the following areas associated with caring for an ESKD patient: the impact on close persons and their social life and the factors affecting close persons’ psychological health. There have been very few studies looking at palliative care issues and these have primarily concentrated on dealing with end of life issues rather than the provision of supportive care in the pre-terminal phase. In only one study, close persons rated their quality of life as excellent and reported few pressures resulting from their carer responsibilities [27], whilst in all others, ESKD and dialysis were shown to increase the close person's sense of responsibility and lead to a poorer quality of life when compared with age-matched controls [28]. Close persons found living with an ESKD patient on dialysis stressful [29] and experienced increased fatigue [30]. The dominating effect of caring for an ESKD patient often led close persons to neglect their own health. For those who took time to have a break from their carer responsibilities, there were health benefits [31]. Other issues that close persons reported included isolation through the loss of social activity [30–36], life restrictions [36–38], increased workload, negative economic consequences [39,40], changed relationship with the patient [30,34] and sexual problems for spouses [41]. Impact on family life (quantitative and mixed methods studies) CAPD = Continuous Ambulatory Peritoneal Dialysis; CBI = Caregivers Burden Interview; FES = Family Environment Scale; HD = Haemodialysis; IIRS = Illness Intrusiveness Ratings Scale; MAES = Marital Attitudes Evaluation Scale; NGQ = Norris & Groves Questionnaire; PAF = Physicians’ Assessment Form; PAIS = Psychosocial Adjustment to Illness Scale; SF-36 = Short-Form 36; SwQoL = Swedish Health-Related Quality of Life Survey; VAS = Visual Analogue Scale; ZBI = Zarit Burden Interview. Impact on family life (quantitative and mixed methods studies) CAPD = Continuous Ambulatory Peritoneal Dialysis; CBI = Caregivers Burden Interview; FES = Family Environment Scale; HD = Haemodialysis; IIRS = Illness Intrusiveness Ratings Scale; MAES = Marital Attitudes Evaluation Scale; NGQ = Norris & Groves Questionnaire; PAF = Physicians’ Assessment Form; PAIS = Psychosocial Adjustment to Illness Scale; SF-36 = Short-Form 36; SwQoL = Swedish Health-Related Quality of Life Survey; VAS = Visual Analogue Scale; ZBI = Zarit Burden Interview. Impact on family life (qualitative studies) CAPD = continuous ambulatory peritoneal dialysis; HD = haemodialysis; PD = peritoneal dialysis. Impact on family life (qualitative studies) CAPD = continuous ambulatory peritoneal dialysis; HD = haemodialysis; PD = peritoneal dialysis. The treatment modality may also have an impact on family members. Studies have highlighted that spouses of transplant patients were more assertive, self-sufficient and able to handle the physical, social and existential aspects of the illness better than dialysis spouses [33,42]. Despite these pressures, close persons recognized that they play a positive role in promoting patients’ well-being [11,43]. They recognized that health care professionals were important in providing support to discuss their problems [39] and would like to have more information about the care being provided to patients [44]. However, they also reported poor communication with professionals, felt that their needs were not always addressed [30,39,45] and felt themselves uneducated and poorly equipped to deal with the regimented lifestyle associated with the dialysis regimen [14]. Whilst some studies have shown that close persons display few signs of psychological distress [40,46–49], others have identified the following: Caring and psychological health ABS = Affect Balance Scale; BDI = Beck Depression Inventory; BI = Barthel Index; CAPD = Continuous Ambulatory Peritoneal Dialysis; CAS = Clinical Anxiety Scale; CBI = Caregivers Burden Interview; CBS = Caregiver Burden Scale; CES-D = Center for Epidemiologic Studies Depression Scale; CID = Cognitive Index of Depression; DAS = Adjustment Scale; = = Anxiety and Scale; = Questionnaire; = Depression Questionnaire; = Questionnaire; = End-Stage Renal Disease Severity Index; = End-Stage Renal Disease Severity = Family Questionnaire; = Scale; = = Index; HD = haemodialysis; = Scale; = Impact on Family Scale; = Jalowiec Coping Scale; = Scale; = of control of = Marital Adjustment = Marital Questionnaire; = Scale of = Psychosocial Adjustment to Illness PD = peritoneal dialysis; = Scale; = for and Family Scale; = Quality of Life Index; = Scale; = Inventory; SF-36 = Short-Form 36; = = Anxiety Inventory; = with Life Scale; = ZBI = Zarit Burden Interview. Caring and psychological health ABS = Affect Balance Scale; BDI = Beck Depression Inventory; BI = Barthel Index; CAPD = Continuous Ambulatory Peritoneal Dialysis; CAS = Clinical Anxiety Scale; CBI = Caregivers Burden Interview; CBS = Caregiver Burden Scale; CES-D = Center for Epidemiologic Studies Depression Scale; CID = Cognitive Index of Depression; DAS = Adjustment Scale; = = Anxiety and Scale; = Questionnaire; = Depression Questionnaire; = Questionnaire; = End-Stage Renal Disease Severity Index; = End-Stage Renal Disease Severity = Family Questionnaire; = Scale; = = Index; HD = haemodialysis; = Scale; = Impact on Family Scale; = Jalowiec Coping Scale; = Scale; = of control of = Marital Adjustment = Marital Questionnaire; = Scale of = Psychosocial Adjustment to Illness PD = peritoneal dialysis; = Scale; = for and Family Scale; = Quality of Life Index; = Scale; = Inventory; SF-36 = Short-Form 36; = = Anxiety Inventory; = with Life Scale; = ZBI = Zarit Burden Interview. A negative between close persons’ psychological health and their sense of carer responsibility their use of coping strategies strategies that the symptoms of the of the the close person's age and the social and changes as a result of ESKD A positive between good mental health and the following a of of dialysis the of dialysis patients are on of social support and sense of carer responsibility The sense of carer responsibilities are if patients are in of living have less or comorbidity This was further in studies in patients home haemodialysis or transplant where close persons not anxiety or depression felt less by their carer responsibility and a quality of life to the age-matched population were found between levels of responsibility and other outcomes such as quality of life and The use of coping was found to have a negative with a positive with the number of years on dialysis Close persons were more likely to have negative towards patients if they no of the dialysis and a high of involvement with the caring whilst living in a We identified five studies that explored end of life only one specifically on close persons. This study the long-term impact of death on families when dialysis was found that most families felt that patients a good death as at and with close people and most family members showed only levels of However, carers and those with levels of caring responsibility for the did End of life care HD = End of life care HD = The remaining four studies on patient outcomes such as reasons for withdrawing from dialysis the quality of death the of close persons in ESKD patients’ to and care and use of advance as a in advance by patients, which the of treatment to be by health care a patient is to provide to that person's of These studies found that close persons that whilst most patients a many patients were to be in and from fatigue care family members in that patients’ were and most recognized the of living which they felt were health care professional Close persons were poorly for caring for a dialysis and patients did not to be a on their families [14]. They were also poor at both patients’ and for or dialysis No studies were identified for carers of patients with supportive care those on maximum conservative management The main of most studies included in this review is the of and of the demographic over half of the studies demographic details of close persons’ ages and or details of their relationship to patients of other relevant demographic such as employment status or social is and only seven studies the time that close persons as Whilst all studies the of dialysis half reported the of time a patient has been on with very few patients’ functional although carer studies in other that this has an impact on carers’ quality of life In only 18 9 qualitative and mixed methods study details of their sample of the quantitative studies included in the used cross-sectional and were predominantly Such studies are in exploring between are limited as they not to be only five studies provide the full details of sample it is therefore not possible to rates or the sample The sample sizes were with a median of 55 and details of were reported in only one study. the of the used to the different outcomes it to between the different studies. We identified that most studies poor of their methods and a of of their data Most used of family members with five studies using only one details of their studies with their studies with their one a of their their approach. One study no details of their the studies were poorly that the was and authors were as to to use qualitative data with the and of the qualitative data demographic of data and poor use of supporting This study reviewed the literature exploring the of close persons of patients with ESKD, from which can be the quality of and for the of in this Firstly, studies exploring end of life issues are with only four identified. these four studies are they that health are the time for informal carers to discuss patients’ about end of life care and, long-term distress of close persons resulting from the patients’ However, about such end of life issues close persons, and we studies in this Secondly, definitions of close persons were there were some differences identified between the different groups. the literature the that most close persons are to patients, the in to patients who were and those with family and relationship were not not all close persons to on the role of the informal carer, and the of this role can be a as illness review did not identify differences between informal carers and family carers in the outcome measures used included both the of differences may in their with ‘informal carers’ a more members’ may be as being more this needs further issues that need to be addressed the use of methodology were identified in the Most quantitative studies were and with no intervention studies being identified. Studies of demographic details and rates and all were cross-sectional with sample sizes that used standardized Whilst the use of standardized measures the of the the findings from cross-sectional studies are limited in that they can only between We the use of longitudinal methods in that would that between key be explored in more This would also into the long-term of close persons. In those studies using qualitative most used with poor and of demographic and social and Many authors used the ‘burden’ or ‘carer such terms may influence of the relationship between close person and was not they were by close persons to use the ‘burden’ or it was a by the authors to describe the responsibilities of Such and the of study findings the half of the studies originated from either the USA (11/36) or Canada This it to the results of these studies their to in the of health care provision in other there is evidence that the psychological health of close persons them to to care which in can the mental health of patients, we to identify studies in review that looked specifically at health close persons of patients with ESKD. review has identified in the literature that need to be is therefore to the relationship between health and close persons in to We would like to acknowledge for this review and for support in this of

Clinical Kidney Journal · editorial or comment · 83 citationsread the source →

PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCE OF INTEREST TO CLINICIANS?

Major depressive disorder (MDD) is a common and costly disorder which is usually associated with severe and persistent symptoms leading to important social role impairment and increased mortality 1,2. It is one of the most important causes of disability worldwide 3. The high rate of inadequate treatment of the disorder remains a serious concern 1. This review is aimed at summarizing the solid evidence on the etiology and pathophysiology of MDD that is likely relevant for clinical psychiatry. Neurobiological findings are regarded as solid when they are consistent and convergent, i.e., they have been confirmed by several studies using the same method and fit into results from studies using different methodological approaches. Family, twin, and adoption studies provide very solid and consistent evidence that MDD is a familial disorder and that this familiality is mostly or entirely due to genetic factors 4. This important finding suggests that parental social behavior and other familial environmental risk factors are not as important in the pathogenesis of MDD as previously assumed and should not be the major focus of the treatment of the disorder. The above-mentioned studies consistently show that the influence of genetic factors is around 30–40% 4. Non-genetic factors, explaining the remaining 60–70% of the variance in susceptibility to MDD, are individual-specific environmental effects (including measurement error effects and gene-environment interactions). These effects are mostly adverse events in childhood and ongoing or recent stress due to interpersonal adversities, including childhood sexual abuse, other lifetime trauma, low social support, marital problems, and divorce 5,6. These results suggest that there is a huge potential in the prevention of MDD by means of psychosocial interventions (e.g., in schools, at workplace). In addition, these results mirror the clinical practice of empirically validated psychotherapies to treat depression 7,8,9, including interpersonal, psychodynamic and cognitive behavioral psychotherapies and cognitive behavioural analysis system of psychotherapy, which all focus directly or indirectly on interpersonal difficulties and skills. This does not exclude the fact that unidentified non-genetic, non-psychosocial risk factors may also play important roles in some patients (e.g., climatic change, medical conditions). Stress sensitivity in depression is partly gender-specific. While men and women are, in general, equally sensitive to the depressogenic effects of stressful life events, their responses vary depending upon the type of stressor. Specifically, men are more likely to have depressive episodes following divorce, separation, and work difficulties, whereas women are more sensitive to events in their proximal social network, such as difficulty getting along with an individual, serious illness, or death 10. These findings point to the importance of gender-sensitive psychosocial approaches in the prevention and treatment of MDD. In contrast to the very solid evidence from epidemiological studies on broad risk factor domains, there is no solid evidence for specific genes and specific gene-by-environment interactions in the pathogenesis of MDD. Genome-wide association studies have indicated that many genes with small effects are involved in complex diseases, increasing the difficulty in identifying such genes 11. While there has been progress in the search for risk genes for several complex diseases despite this methodological problem 12, psychiatric conditions have turned out to be very resistant to robust gene identification. For example, based on a community-based prospective study, it has been proposed that a specific genetic variation in the promoter region of the serotonin transporter (a target of antidepressant drugs) interacts with stressful life events in the pathogenesis of depression 13. Although there is high clinical and neurobiological plausibility of this interaction, a recent meta-analysis yielded no evidence that the serotonin transporter gene alone or in interaction with psychological stress was associated with the risk of depression 14. The limited success of genetic studies of depression has been related to use of current classification schemas including ICD-10 and DSM-IV. These diagnostic manuals are based on clusters of symptoms and characteristics of clinical course that do not necessarily describe homogenous disorders but instead reflect common final pathways of different pathophysiolgical processes 15,16. The clinician should be aware that family history will continue to be the most solid source of information to estimate the genetic risk of MDD. Corticotropin-releasing hormone (CRH) is released from the hypothalamus in response to the perception of psychological stress by cortical brain regions. This hormone induces the secretion of pituitary corticotropin, which stimulates the adrenal gland to release cortisol into the plasma. The physiologic response to stress is partly gender-specific: women show generally greater stress responsiveness than men, which is consistent with the greater incidence of major depression in women 17. Moreover, men show greater cortisol responses to achievement challenges, whereas women show greater cortisol responses to social rejection challenges 18. Although MDD is considered as a stress disorder, most subjects treated for MDD have no evidence of dysfunctions of the hypothalamic-pituitary-adrenal axis (HPA) 19. However, some subjects with MDD do show abnormalities of that axis and of the extrahypothalamic CRH system 20. Altered stress hormone secretion appeared to be most prominent in depressed subjects with a history of childhood trauma 21. Elevated cortisol may act as a mediator between major depression and its physical long-term consequences such as coronary heart disease, type II diabetes, and osteoporosis 22. The importance of HPA axis dysfunction for the efficacy of antidepressants is a matter of debate 23. This axis is regulated through a dual system of mineralocorticoid (MR) and glucocorticoid (GR) receptors. Decreased limbic GR receptor function 24,25 and increased functional activity of the MR system 26 suggest an imbalance in the MR/GR ratio in stress-related conditions such as MDD. Epigenetic regulation of the glucocorticoid receptors has been associated with childhood abuse 27. Such environmental programming of gene expression may represent one possible mechanism that links early life stress to abnormal HPA axis function and increased risk of MDD in adults. While the CRH stimulation test (dex/CRH test) 28 is a sensitive measure of the HPA axis dysfunction in depression, the specificity of this test for MDD is low. However, non-suppression in the dex/CRH test has consistently predicted increased risk for depressive relapse during clinical remission 23. Additionally, the measurement of waking salivary cortisol concentration has been shown to be a simple and sensitive test for HPA axis hyperactivity in depression 29. Hypercortisolemia is almost exclusively found in subjects with severe and psychotic depression, in whom glucocorticoid antagonists may have some therapeutic effect 30. There is convergent evidence for CRH to play a major role in the pathogenesis of certain types of depression. Levels of CRH in the cerebrospinal fluid are elevated in some depressed subjects 31. Post-mortem studies reported an increased number of CRH secreting neurons in limbic brain regions in depression 32, likely reflecting a compensatory response to increased CRH concentrations 33. In addition, CRH produces a number of physiological and behavioral alterations that resemble the symptoms of major depression, including decreased appetite, disrupted sleep, decreased libido, and psychomotor alterations 34. There is also preliminary evidence that CRH1 receptor antagonists reduce symptoms of depression and anxiety 35. “Sickness behavior” as a result of an activation of the inflammatory response system shares many symptoms with depression, including fatigue, anhedonia, psychomotor retardation, and cognitive impairment. Sickness is mediated by pro-inflammatory cytokines such as interleukin-1α, tumor necrosis factor-α, and interleukin-6, which activate the HPA axis and impair the central serotonin system 36. The prevalence of depression as an unwanted effect of recombinant interferons is around 30% 37. In animals, blocking pro-inflammatory cytokine-mediated signaling produces antidepressant-like effects 38. Clinical data suggest that cytokines may play a role in the pathophysiology of a subgroup of depressed subjects, particularly those with comorbid physical conditions 36. The antidepressant enhancing effect of acetylsalicylic acid 39 points to the possible clinical relevance of psychoneuroimmunology in clinical depression research. Taken together, the laboratory tests with the highest potential to be clinically useful in the care of depressed individuals are based on abnormalities of the neuroendocrine and neuroimmune systems. Despite the large amount of basic science data suggesting that the HPA axis is importantly involved in the pathophysiology of depression, the effect of pharmacological modulation of this neuroendocrine system as antidepressant therapy has been disappointing. The link between childhood trauma and a permanently altered physiologic stress system points to the use of specific psychotherapies in the treatment of depressed patients with a history of early life trauma 40. Most of the serotonergic, noradrenergic and dopaminergic neurons are located in midbrain and brainstem nuclei and project to large areas of the entire brain. This anatomy suggests that monoaminergic systems are involved in the regulation of a broad range of brain functions, including mood, attention, reward processing, sleep, appetite, and cognition. Almost every compound that inhibits monoamine reuptake, leading to an increased concentration of monoamines in the synaptic cleft, has been proven to be a clinically effective antidepressant 19. Inhibiting the enzyme monoamine oxidase, which induces an increased availability of monoamines in presynaptic neurons, also has antidepressant effects. These observations led to the pharmacologically most relevant theory of depression, referred to as the monoamine-deficiency hypothesis. The monoamine-deficiency theory posits that the underlying pathophysiological basis of depression is a depletion of the neurotransmitters serotonin, norepinephrine or dopamine in the central nervous system. Serotonin is the most extensively studied neurotransmitter in depression. The most direct evidence for an abnormally reduced function of central serotonergic system comes from studies using tryptophan depletion, which reduces central serotonin synthesis. Such a reduction leads to the development of depressive symptoms in subjects at increased risk of depression (subjects with MDD in full remission, healthy subjects with a family history of depression) 41,42, possibly mediated by increased brain metabolism in the ventromedial prefrontal cortex and subcortical brain regions 42. Experimentally reduced central serotonin has been associated with mood congruent memory bias, altered reward-related behaviors, and disruption of inhibitory affective processing 16, all of which add to the clinical plausibility of the serotonin deficiency hypothesis. There is also evidence for abnormalities of serotonin receptors in depression, with the most solid evidence pointing to the serotonin-1A receptor, which regulates serotonin function. Decreased availability of this receptor has been found in multiple brain areas of patients with MDD 43, although this abnormality is not highly specific for MDD and has been found in patients with panic disorder 44 and temporal lobe epilepsy 45, possibly contributing to the considerable comorbidity among these conditions. However, there is no explanation for the mechanism of serotonin loss in depressed patients, and studies of serotonin metabolites in plasma, urine and cerebrospinal fluid, as well as post-mortem research on the serotonergic system in depression, have yielded inconsistent results. There is preliminary evidence that an increased availability of the brain monoamine oxidase, which metabolizes serotonin, may cause serotonin deficiency 46. In addition, loss-of-function mutations in the gene coding for the brain-specific enzyme tryptophan hydroxylase-2 may explain the loss of serotonin production as a rare risk factor for depression 47. Dysfunction of the central noradrenergic system has been hypothesized to play a role in the pathophysiology of MDD, based upon evidence of decreased norepinephrine metabolism, increased activity of tyrosine hydroxylase, and decreased density of norepinephrine transporter in the locus coeruleus in depressed patients 48. In addition, decreased neuronal counts in the locus coeruleus, increased alpha-2 adrenergic receptor density, and decreased alpha-1 adrenergic receptor density have been found in the brains of depressed suicide victims post-mortem 49. Since there is no method to selectively deplete central norepinephrine and no imaging tool to study the central norepinephrine system, solid evidence for abnormalities of this system in depression is lacking. While the classical theories of the neurobiology of depression mainly focused on serotonin and norepinephrine, there is increasing interest in the role of dopamine 50. Dopamine reuptake inhibitors (e.g., nomifensine) and dopamine receptor agonists (e.g., pramipexole) had antidepressant effects in placebo-controlled studies of MDD 51. In the cerebrospinal fluid and jugular vein plasma, levels of dopamine metabolites were consistently reduced in depression, suggesting decreased dopamine turnover 52. Striatal dopamine transporter binding and dopamine uptake were reduced in MDD, consistent with a reduction in dopamine neurotransmission 53. Degeneration of dopamine projections to the striatum in Parkinson's disease was associated with a major depressive syndrome in about one half of cases, which usually preceded the appearance of motor signs 54. Experimentally reduced dopaminergic transmission into the accumbens has been associated with anhedonic symptoms and performance deficits on a reward processing task in subjects at increased risk of depression 55,56. These findings are consistent with the clinical observation that depressed patients have a blunted reaction to positive reinforcers and an abnormal response to negative feedback 57. Almost all established antidepressants target the monoamine systems 58. However, full and partial resistance to these drugs and their delayed onset of action suggest that dysfunctions of monoaminergic neurotransmitter systems found in MDD represent the downstream effects of other, more primary abnormalities. Despite this limitation, the monoamine-deficiency hypothesis has proved to be the most clinically relevant neurobiological theory of depression. New findings on the role of dopamine in depression emphasize the scientific potential of this theory, and promising reports of antidepressant effects of drugs that modulate the dopaminergic system (e.g., pramipexole, modafinil) in difficult-to-treat depression underline its clinical relevance 51,59. Although many historical attempts to localize mental functions have failed, they have considerably contributed to a modern neuroscientific understanding of mental disorders 60. The development of neuroimaging techniques has opened up the potential to investigate structural and functional abnormalities in living depressed patients. Unfortunately, the diversity of imaging techniques used, the relatively small and heterogeneous study samples studied, and the limited overlap of results across imaging paradigms 61 make it difficult to reliably identify neuronal regions or networks with consistently abnormal structure or function in MDD. Functional imaging studies have provided the most limited overlap of findings. This may be due to methodological limitations and/or the complexity of neurocircuitry involved in MDD. A recent meta-analytic study found the best evidence for abnormal brain activity in MDD in lateral frontal and temporal cortices, insula, and cerebellum. In these brain regions activity was decreased at rest, they showed a relative lack of activation during induction of negative emotions, and an increase in activity following treatment with serotonin reuptake inhibitors. Opposite changes may exist in ventromedial frontal areas, striatum and possibly other subcortical brain regions 61. More solid evidence has been provided by structural imaging and post-mortem studies. A recent meta-analytic study on brain volume abnormalities in MDD revealed relatively large volume reductions in the ventromedial prefrontal cortex, particularly in the left anterior cingulate and in the orbitofrontal cortex. Moderate volume reductions were found in the lateral prefrontal cortex, hippocampus and striatum 62. Post-mortem studies consistently identified a reduction in glia cell density in dorsal, orbital and subgenual prefrontal cortices, as well as in the amygdala 63,64. Overall, functional, structural and post-mortem studies suggest that structural and functional abnormalities in the left subgenual cingulate cortex are the most solid neuroanatomical finding in MDD. Volume reduction in this region was found early in illness and in young adults at high familial risk for MDD 65, suggesting a primary neurobiological abnormality associated with the etiology of the illness. Humans with lesions that include the subgenual prefrontal cortex showed abnormal autonomic responses to social stimuli 66, and rats with left-sided lesions in this region had increased sympathetic arousal and corticosterone responses to restraint stress 67. Most importantly, chronic deep brain stimulation to reduce the potentially elevated activity in the subgenual cingulated cortex produced clinical benefits in patients with treatment-resistant depression 68. In summary, despite the considerable heterogeneity of findings from neuroimaging studies, there is convergent evidence for the presence of abnormalities in the subgenual prefrontal cortex in some patients with MDD. Neuroanatomical research in depression is of great clinical interest, since novel antidepressant treatments such as deep brain stimulation can target specific brain regions. In addition, there are promising leads for neuroimaging findings to predict the likelihood of responses to specific treatments 69. Risk factors for depressive episodes change during the course of the illness. The first depressive episode is usually “reactive”, i.e., triggered by important psychosocial stressors, while subsequent episodes become increasingly “endogenous”, i.e., triggered by minor stressors or occurring spontaneously 70. There is consistent evidence that the volume loss of the hippocampus and other brain regions is related to the duration of depression 71, suggesting that untreated depression leads to hippocampal volume loss, possibly resulting in increased stress sensitivity 72 and increased risk of recurrence 73. Glucocorticoid neurotoxicity, glutamatergic toxicity, decreased neurotrophic factors, and decreased neurogenesis have been proposed as possible mechanisms explaining brain volume loss in depression. There is no solid evidence on of these since there are no imaging to directly and neurotrophic processes in neurotrophic factor has considerable Specifically, studies have shown between and in hippocampal as well as expression of following antidepressant treatment The clinician should be aware of the potentially effect of depression and treat depressed patients as early and as A of studies consistently showed reductions in acid concentrations in the prefrontal and cortex in depression This may reflect stress since psychological stress to presynaptic of prefrontal neurotransmission low concentration may reflect reduction in the density and of In addition, chronic stress may reduce receptor possibly through changes in evidence of the hypothesis of depression the lack of effects of drugs on depressive symptoms and prefrontal concentration in subjects with MDD of evidence suggest a dysfunction of the neurotransmitter system in a of the receptor produced and large antidepressant effects in patients with treatment-resistant MDD inhibitors of release (e.g., antidepressant abnormal levels were found in depressed subjects as by and there is evidence for abnormal signaling in post-mortem Since is the major neurotransmitter involved in almost every brain the of the specific role of in depression (e.g., there are promising leads that the receptor is involved in MDD and are diagnostic for MDD, suggesting regulation in depressed patients. In addition, some depressive symptoms may show psychomotor of of positive and negative and a subgroup of patients with MDD may have a disorder In healthy young subjects, changes in the of the had specific effects on subsequent mood In depressed patients, of can have antidepressant on these abnormalities have been hypothesized to be associated with MDD The association between of the and in cortisol in some subjects with and the effect of antidepressants on of and to the of this hypothesis Despite of the many promising the and genetic of this hypothesis are It remains to be antidepressant effects of such as directly to of on these abnormalities have been hypothesized to be associated with MDD The association between of the and in cortisol in some subjects with and the effect of antidepressants on of and to the of this hypothesis Despite of the many promising the and genetic of this hypothesis are It remains to be antidepressant effects of such as directly to of The and of the neurobiological of depression are in 1. The many theories of depression and the relatively low response rate of all antidepressant treatments a hypothesis of and suggest that depression is a clinically and heterogeneous disorder. This research on of the response to therapeutic interventions using such as neuroimaging and neuroendocrine tests in with for with to stress sensitivity and antidepressant The of of therapeutic will for the development of that has the potential to interventions and to up pathways in the of novel therapeutic approaches.

World Psychiatry · editorial or comment · 607 citationsread the source →

Atypical Antipsychotics: CATIE Study, Drug-Induced Movement Disorder and Resulting Iatrogenic Psychiatric-Like Symptoms, Supersensitivity Rebound Psychosis and Withdrawal Discontinuation Syndromes

Chronic illness can result in chronicity of clinical practice. As we have moved away from prescribing classical antipsychotics and tricyclic antidepressants, issues remain with the use of atypical antipsychotics and second-generation antidepressants that need to be addressed, namely, iatrogenic discontinuation syndromes and supersensitivity psychiatric symptoms. An optimal maintenance drug treatment consists of regular attempts to reduce the dose by finding a minimal therapeutic dose, regularly asking the question of when to reduce or withdraw treatment and for which patients, and moreover, why it is difficult to decrease a given drug treatment. Recently, Falloon [1] proposed that maintenance pharmacotherapy in schizophrenia will depend on finally finding minimally effective doses through ‘extensive training in stress management’. In the long-term treatment of major depression, Fava [2] has hypothesized that antidepressants can aggravate the course of depressive illness. Lambert [3] recently suggested that ‘antipsychotic-switching syndromes’, which include discontinuation syndromes, are a ‘major barrier’ to adjusting antipsychotic treatment. In this paper, we propose that to achieve optimal maintenance treatment with antipsychotics, and to reduce or withdraw antipsychotics effectively, we must distinguish syndromes associated with discontinuing antipsychotics, such as supersensitivity psychosis, from true relapse. While the prevalence and incidence of drug-induced movement disorder(s) (DIMD) has continuously decreased with atypical antipsychotics, DIMD persist as do psychiatric and psychiatric-like symptoms associated with DIMD, and these must also be identified and evaluated. Persistent DIMD have been found to be a predictor of the later emergence of tardive dyskinesia (TD) and supersensitivity psychosis [4]. At present, we need to determine the relative risk of iatrogenic discontinuation syndromes, DIMD and DIMD psychiatric symptoms resulting from atypical antipsychotics. Although atypical antipsychotics are now most commonly prescribed, a debate has emerged on the differences between classical and atypical antipsychotics following the results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study [5]. The question that comes to the forefront is why recent studies are no longer finding well-established differences between these two generations in terms of efficacy and DIMD. Reasons to explain why recent schizophrenia studies have found reduced drug and placebo differences were examined at the International Society for CNS Clinical Trials and Methodology Annual Mid-Year Conference [6]. While the fact must be considered that patients included in recent studies have less severe illness with symptoms that are better controlled than in past studies (likely due to earlier treatment), the issue that psychiatric symptoms specific to schizophrenia are not being adequately measured nor differentiated from psychiatric and psychiatric-like symptoms associated with DIMD is crucial to answering this question. For example, it is hard to believe that in a recent review of psychomotor slowing in schizophrenia, the authors, when evaluating its effect on measurement and treatment research to improve cognition in schizophrenia (MATRICS), nearly completely ignored the influence of akinesia and DIMD on neuropsychological tests in schizophrenia and the importance of accurate DIMD measurements [7]. As we pursue this ongoing discussion, we recommend the discontinuation of all classical antipsychotics due to their neurotoxic association with a high prevalence of DIMD and increases in basal ganglia volumes [8], and now address how to prescribe atypical antipsychotics most effectively, by taking into account DIMD-associated psychiatric symptoms and iatrogenic discontinuation syndromes. The first widely prescribed atypical antipsychotic, risperidone, was first approved in Canada in 1993 following the publication of the Canadian Multicenter Risperidone Study, which reported clear advantages of risperidone over haloperidol and the placebo, and significantly less appearance of DIMD with risperidone than haloperidol [9]. DIMD includes the 4 types of movement disorders induced by antipsychotics: parkinsonism, dystonia, dyskinesia and akathisia [10]. These findings were confirmed by the American Risperidone Study [11] and several other studies reporting greater efficacy of risperidone over classical antipsychotics in terms of cost-efficiency [12] and the clinical management of patients with schizophrenia [13,14,15,16,17]. However, the CATIE study [5] challenged these results. The CATIE study found that of the 4 atypical antipsychotics studied, olanzapine was the only atypical to be more efficacious than the classical antipsychotic perphenazine, and to be highly superior to risperidone for discontinuation of treatment, due to lack of efficacy [5]. Olanzapine is known to produce less DIMD compared to risperidone, therefore one would expect psychiatric symptoms caused by DIMD to be less frequent with olanzapine than risperidone. The expected higher rate of DIMD-induced emergent psychiatric symptoms associated with risperidone would explain the CATIE results, showing risperidone to be significantly less efficacious than olanzapine [5], despite risperidone being known to be at least as efficacious as olanzapine for true schizophrenic symptoms. Furthermore, the rating scales used to measure DIMD did not find the well-established differences between the 5 antipsychotics for DIMD rates [5]. Thus, we propose that DIMD and DIMD-induced psychiatric symptoms were confounded with true schizophrenic symptoms in the CATIE study. DIMD-associated psychiatric symptoms could be classified into 3 types: (1) emergent psychiatric symptoms caused by DIMD, such as akinesia inducing depression, akathisia inducing anxiety; (2) iatrogenic psychiatric-like symptoms resulting from confounding DIMD with psychiatric symptoms, such as akinesia confounded with psychomotor retardation, akathisia with agitation; (3) supersensitivity psychosis symptoms associated with DIMD. In the CATIE study, quetiapine (mean dose = 543.4 mg/day), which shares a low rate of DIMD with olanzapine, was also found to be significantly less efficacious compared to olanzapine, but in contrast to risperidone, this lack of efficacy could be due to psychiatric symptoms related to supersensitivity psychosis explained by quetiapine’s loose binding properties at the D2 receptor [18]. Patients taking quetiapine had a completion rate of 18% out of 329 patients, whereas in our 3-year prospective study of quetiapine monotherapy with a lower mean dose of 487 mg/day (thus less likely to develop therapeutic tolerance), the completion rate was 21.7% out of 23 patients; 6 of 7 patients who relapsed, after a minimum 3 months of stabilized quetiapine treatment, met the criteria for supersensitivity psychosis [19]. Without distinguishing these DIMD-associated psychiatric symptoms from symptoms due to the original illness, the major impact of atypical antipsychotics is on the reduction of DIMD and TD [10, 20,] and their beneficial effects on psychosis are masked by DIMD emergent psychiatric symptoms, including supersensitivity psychosis. We will review 4 multicenter trials, which include a total of 14,497 patients, to illustrate how psychiatric and schizophrenic symptoms are confounded with DIMD-associated psychiatric symptoms.TD epidemiology has changed significantly since the introduction of atypical antipsychotics, with a constant decline in its prevalence [10]. TD, classified as a DIMD, is a hyperkinetic, involuntary and purposeless movement disorder [10, 20]. Considered as the most significant side effect of classical antipsychotics, TD has been associated with antipsychotics and gastrointestinal neuroleptics, and usually occurs after several years of treatment. Persistent TD can also occur after short-term exposure to classical antipsychotics and gastrointestinal neuroleptics even at low doses and for as few as 2 months [8,21,22,23], while reversible and withdrawal dyskinesias share properties with levodopa-induced dyskinesia [24]. We conducted several epidemiological studies of TD [4,25,26,27] and in 1975, using the National Institute of Mental Health (NIMH) psychopharmacology criteria, we found a 31% prevalence of TD in 261 outpatients with schizophrenia [25]. We also evaluated these patients according to the Schooler and Kane research diagnostic criteria and found a 22% prevalence of TD. This variability of findings related to defining criteria complicates comparisons across studies [10]. In a 5-year follow-up study of 169 of the same patients [4, 25], 45% met the research diagnostic criteria for TD. In 1975, 131 of the 261 patients did not meet the research diagnostic for TD, and in 1980 treatment-emergent TD was found in 46 of the patients who did not have it in 1975, for a 5-year cumulative incidence rate of 35% and a mean annual incidence rate of 8.4%. When corrected for remissions, the mean annual incidence rate decreased to 2.9%. This incidence rate, which includes both patients who developed and remitted from TD over time, is similar to results found by other studies during the same time period [28, 29]. The cumulative incidence of treatment-emergent TD in the study by Kane et al. [29] was 12% after 4 years and 40% after 8 years of neuroleptic exposure, which is similar to our finding of an annual incidence rate (corrected for remissions) of 3% for classical antipsychotics. In a study carried out in 130 lithium-treated affective disorder patients previously, but less, exposed to antipsychotics, we found a TD prevalence of 9.2% [26], which was a quarter of the incidence reported in our previous studies on patients with schizophrenia who had greater exposure to antipsychotics. In this time period of classical antipsychotics, 2 meta-analyses (including mostly patients with schizophrenia) reported mean TD prevalences of 23% [30] and 20% [31]. In view of the fact that 58% of patients treated with classical antipsychotics will develop treatment-emergent TD after 10–15 years of treatment [4], and the known beneficial neuroprotective effects of atypical antipsychotics on TD [32] and on increased basal ganglia volumes induced by classical antipsychotics [8], we recommend the discontinuation of all classical antipsychotics due to their neurotoxic effects. In the time period of both classical and atypical antipsychotics, the following multicenter studies (n = 3,753) evaluated the incidence and prevalence of TD, using the same definitions, Extrapyramidal Symptom Rating Scale [20] and training videotapes as in the previous time period. In the first study, an annual TD incidence of 0.68% was reported prospectively in 725 patients with schizophrenia, treated with the long-acting injectable atypical antipsychotic risperidone [27, 33]. Treatment-emergent TD was found in 12 of 587 patients without dyskinesia at the baseline [33]; however, expert case assessment determined 7 cases (1.19%) of withdrawal dyskinesia (3 cases resolved, 4 cases unchanged), 1 case (0.17%) of reversible dyskinesia and 4 cases (0.68%) of persistent treatment-emergent TD. Of the patients with baseline dyskinesia, 28.4% improved, no longer met TD criteria and maintained this response [33]. This annual treatment-emergent TD incidence of 0.68% with atypical antipsychotics is only 22% of the annual incidence of 3% reported with classical antipsychotics [4]. In the second study, the Schizophrenia International Suicide Prevention Trial (67 centers in 11 countries) [34], 980 patients with schizophrenia, or schizoaffective disorders, taking an atypical alone (25.6%), a classical alone (31.5%) or both a classical and an atypical antipsychotic (42.9%) were included from March 19, 1998, to February 14, 1999, and TD was found at the baseline in 115 (12%) patients [27, 35]. Thus, after 10 years in the time period of both classical and atypical antipsychotics, the overall prevalence of TD decreased by at least twofold compared to our previous 1979–1988 studies with classical antipsychotics [4, 25], using the same definitions, Extrapyramidal Symptom Rating Scale and training videotapes. In the third study (baseline data from three Ris-Consta multicenter studies) [27, 36] carried out 1 year later, 2,048 patients were included from March 21, 1999, to December 15, 2000, and TD was found at the baseline in 209 patients (10.2%), using the same methodology. This study showed a further decrease in the prevalence of TD after an additional year of atypical use. This changing epidemiology of TD with atypical antipsychotics is confirmed by Correll et al. [37] in a systematic review of 1-year prospective studies with atypical antipsychotics, and by Jeste et al. [38] in a 1-year study of elderly patients treated with risperidone. In conclusion, following the introduction of atypical antipsychotics, the prevalence and incidence of TD have significantly decreased. However, the risk for TD still exists with both atypical and classical antipsychotics, and there is a need for continued surveillance of emerging cases of TD in patients taking antipsychotics [39], especially as the current debate continues on the differences in efficacy between these two generations of antipsychotics following results from studies such as the CATIE [5, 39]. Furthermore, Kane [39] has pointed out that newly trained clinicians using mostly atypical antipsychotics may not have had the same exposure to TD as previously trained clinicians.A high prevalence of all 4 types of DIMD (parkinsonism, dystonia, dyskinesia and akathisia) remains. In the Schizophrenia International Suicide Prevention Trial (n = 980), a prevalence of 57.5% of DIMD (n = 551 patients) was found [27, 35]. In the Ris-Consta studies (n = 2,048) [27, 36], 970 patients (47.4%) had DIMD at the baseline, which consisted of 778 patients with parkinsonism (38.0%), 285 patients with akathisia (14%) and 209 patients with TD (10.2%). Thus, nearly 1 patient out of 2 had a definite DIMD in this time period of classical and atypical antipsychotics. In addition, DIMD have been consistently associated with significant psychiatric symptoms as measured by the positive and negative syndrome scale (PANSS) [40, 41]. In the InterSept study (n = 980), which included patients with schizophrenia and schizoaffective disorder who were at risk of suicide, suicidality was associated at baseline with DIMD, parkinsonism, TD and akathisia, and depression was associated with TD and akathisia [27, 35]. Based on these results, we recommend routinely assessing DIMD in patients with schizophrenia with suicidal and depressive symptoms. In the Ris-Consta studies (n = 2,048), baseline DIMD were also significantly associated with the PANSS total score, positive, negative and anxiety/depression symptoms [27, 36]. Greater anxiety and depression were seen in patients with severer DIMD, akathisia and parkinsonism. Higher PANSS negative symptom rating was associated with parkinsonism and higher PANSS total scores were associated with akathisia. In this time period, these last two studies (n = 3,028) show that DIMD persists with atypical antipsychotics, and that patients with DIMD have significantly higher PANSS scores compared to patients without DIMD.These results are in agreement with findings from 2 other multicenter studies: the American CATIE study [5] and the European Schizophrenia Outpatient Health Outcomes (SOHO) study [42]. In the CATIE baseline data, patients with TD (n = 212) were found to have significantly more psychopathology than patients without TD (n = 1,098) as measured by the PANSS total score and PANSS general psychopathology subscale [43]. In the 3-year prospective SOHO study, emergent cases of TD were associated with greater overall psychopathology. An increase in clinical global impression overall symptom severity was longitudinally associated with cases of TD in patients without TD at the baseline (n = The SOHO and the CATIE studies have also examined other for TD. the CATIE and SOHO studies found that other DIMD were associated with TD the CATIE study showed that patients with TD had more parkinsonism akathisia while the SOHO study found that baseline symptoms TD our findings in a prospective study of TD [4]. In to reporting that the incidence of TD was lower in patients taking atypical compared to classical antipsychotics after 6 months the SOHO study showed that the incidence of TD was associated with the incidence of of drug-induced in is crucial to that there is a of DIMD with atypical antipsychotics, which are not and confounded with psychiatric symptoms rating scales used routinely in clinical to DIMD do not DIMD from psychiatric symptoms from the 4 multicenter (n = 14,497 patients) into this the CATIE the [27, the Ris-Consta [27, 36] and the SOHO studies have all confirmed the association of DIMD with psychiatric symptoms. most of the studies included in this measure psychiatric symptoms according to the we propose the following of PANSS psychiatric symptoms associated with emergent psychiatric symptoms caused by DIMD, such as depression and suicidality example, akinesia is known to produce depression, psychomotor and suicidal while akathisia psychomotor and suicidal and TD is also associated with suicidal iatrogenic psychiatric-like symptoms resulting from confounding and DIMD with psychiatric symptoms, such as confounding and with and retardation, akathisia with anxiety and and and dyskinesias with and schizophrenic psychiatric schizophrenic symptoms associated with DIMD caused by supersensitivity psychosis, which we are now to first reported drug-induced associated with TD a in and increased receptor after long-term treatment with classical antipsychotics, and we this supersensitivity psychosis. We that TD and supersensitivity psychosis with the decrease or withdrawal of an antipsychotic, given risk not and at the same The debate continues on how to most withdraw antipsychotic [1] and and psychiatric syndromes associated with types of syndromes have been with the discontinuation of (1) withdrawal syndromes and major (2) syndromes anxiety and which have been reported with and (3) supersensitivity syndromes such as TD and supersensitivity psychosis These discontinuation syndromes all produce psychiatric symptoms that can be confounded with true of the original illness. In a recent review of the on psychosis the importance of between antipsychotic withdrawal effects related to the course of the original illness and drug-induced effects such as supersensitivity psychosis. due to the discontinuation of a drug can be differentiated from the course of original illness and more long-term maintenance treatment could be reduced and in patients The long-term maintenance with second-generation antidepressants and of a major depressive disorder is of the in and during long-term maintenance treatment. The has also recently been to produce a persistent disorder following withdrawal to be related to supersensitivity When discontinuing antipsychotics and antidepressants, the of supersensitivity syndromes and other iatrogenic discontinuation syndromes must be to high doses or of outpatients and with schizophrenia treated with a classical antipsychotic treatment also included 1 but no antidepressants, no and no showed a prevalence of 22% for supersensitivity psychosis The prevalence of TD using Schooler and Kane criteria, was that found for supersensitivity psychosis. cases of supersensitivity psychosis increased the prevalence of supersensitivity psychosis to psychosis was associated with a higher maintenance dose of classical antipsychotics, high and schizophrenia with a The higher antipsychotic dose and higher associated with supersensitivity psychosis to the of supersensitivity and these results that lower doses of antipsychotics could the appearance of supersensitivity psychosis. In this study, there was no found between TD and supersensitivity psychosis, due to TD being associated with schizophrenia and supersensitivity psychosis with higher antipsychotic dose was not to be a risk for TD, whereas increased was associated with TD but not associated with supersensitivity psychosis. is that most patients in this study were treated with which has a high for the D2 which could to both a high incidence of supersensitivity psychosis and DIMD as the drug is known to produce a high incidence of symptoms psychosis, in its masked and withdrawal is known to occur 6 following the decrease or withdrawal of an antipsychotic or 3 months for a long-acting injectable We have proposed that TD and supersensitivity psychosis can result from the of in the caused by following in D2 with high for The of supersensitivity psychosis and TD share can both occur after long-term use of antipsychotics and can and difficult to with of the antipsychotic stress both TD and supersensitivity psychosis and both can be by and by and TD was to be the predictor of supersensitivity psychosis in our and follow-up study of supersensitivity psychosis [4, TD and supersensitivity psychosis may or may not occur in the same time but TD is associated with supersensitivity psychosis when it occurs during withdrawal of antipsychotics These two supersensitivity syndromes have been difficult to study due to the fact that antipsychotics can their appearance further with supersensitivity psychosis is that symptoms the original illness and true however, supersensitivity psychosis can be as it more after of the antipsychotic than true occurs with high doses of antipsychotics and not with antipsychotic treatment and therapeutic to antipsychotic treatment after drug response time, as therapeutic there is further of supersensitivity and further syndromes, TD, can (1) or (2) persistent or (3) reversible or symptoms can persist for several months or years and can still be reversible or When persistent and supersensitivity symptoms symptoms, being severer than the original symptoms, but these supersensitivity symptoms persist in contrast to symptoms and may include symptoms atypical antipsychotics, it has been proposed that supersensitivity psychosis occurs more with antipsychotics with from the D2 receptor The 2 atypical antipsychotics most associated with supersensitivity psychosis are quetiapine and which both have loose binding properties at the D2 receptor An additional which and severe in the withdrawal of is its effect as an receptor Thus, for the withdrawal would be by the receptor following of at this drug in the of the a and psychosis results cases of supersensitivity psychosis have also been reported with olanzapine psychosis was found to be associated with quetiapine in our 3-year study of quetiapine in 23 outpatients with schizophrenia and schizoaffective disorder who had previously been treated with classical antipsychotics risperidone, and had symptoms and of side effects [19]. As in our of the CATIE study, 7 patients after a minimum of 3 months of stabilized treatment and 6 of these patients met the criteria for supersensitivity psychosis [19]. the 11 of patients with baseline TD relapsed, the that TD to supersensitivity psychosis and have been to be efficacious in of patients with supersensitivity psychosis We also recommend the use of in supersensitivity and anxiety disorder induced by the discontinuation of the An can be used in with an antipsychotic or an in to more decrease or withdraw these and find the minimal therapeutic dose for patients who still need long-term treatment. a minimal therapeutic dose with an has an additional for a drug olanzapine, as the dose will significant side In in the of Mental Health psychiatric 35% of patients with a of schizophrenia and For severe cases of schizophrenia, the use of or is in to drug to antipsychotic While is less than or it is superior to for anxiety and the of optimal minimal maintenance drug treatment. proposed the beneficial results of treatment in schizophrenia is their effect We have also related their beneficial effects to an of a We recommend treatment as a first for from treatment, can also be prescribed as with as it has a In a and that and had than other in addition, emerging that may improve DIMD has also been to be effective as an to antipsychotic monotherapy in patients with schizophrenia who treatment We that of cases of schizophrenia can be related to supersensitivity psychosis. In patients for maintenance treatment is a minimal therapeutic dose can be with the use of an that will patients from antipsychotic or conclusion, DIMD-induced psychiatric symptoms and supersensitivity syndromes will to to results such as found in the CATIE study which show that olanzapine is the only atypical antipsychotic more efficacious than a classical The proposed for psychiatric and psychiatric-like symptoms associated with DIMD may to the of all classical antipsychotics and the use of higher doses and longer than of atypical antipsychotics. research is in to develop to distinguish between true and iatrogenic discontinuation syndromes and to to more withdraw antipsychotics and antidepressants by and supersensitivity syndromes, for the antipsychotics and quetiapine and for the may to further of DIMD, TD and supersensitivity psychosis as we to more differences in the of As most of antipsychotics and second-generation antidepressants are not routinely or for more differences in drug will also to prescribe minimal therapeutic doses of antipsychotics and antidepressants for greater efficacy and better in the maintenance has and the last 3 years from and

Psychotherapy and Psychosomatics · editorial or comment · 168 citationsread the source →

Female child sexual abuse within the family in a Hungarian County.

Background: The aim of the study was to analyze the characteristics of intrafamiliar female child sexual abuse and to explore common features that may be utilized as targets for possible methods of prevention. We also described the medical and legal approaches to handling child neglect. Methods: This was a descriptive, cross-sectional study on 52 sexually abused girls under the age of 18 at the Department of Obstetrics and Gynecology, Medical and Health Science Center of Debrecen. We prospectively recorded the data of all cases. Intrafamiliar events were defined if the victim and perpetrator belonged to the same family. Legal outcomes were also recorded. Results: During the 16-year period, 209 cases of sexual abuse were seen in our clinic, 52 of them had been involved in child sexual abuse within the family. This accounts for 25% of adolescent cases. Eighty-six percent of the victims were pupils, 50% of them were between 11 and 14 years of age. The perpetrator was the victim's father in 44%, and the stepfather in 40%. There was a slight difference between the type of abuse among the pre- and postpubertal group of victims, but statistically it was not significant. The abuse occurred on multiple occasions in 52%. The occurrence rate of assault was the highest in the summer season (58%), mostly in the afternoon (42%) and it took place almost exclusively at home (98%). The mother accompanied the victim in 38% of the cases and the police in 40%. Vaginal penetration was the type of abuse in 75%, and sexual perversion in 25%. Six victims were physically injured, the presence of sperm could be confirmed on vulvovaginal smears in 2 cases. One pregnancy conceived. Nine cases were reported to the police and as a result of legal proceedings, 5 perpetrators have been sentenced. Conclusion: The majority of crimes take place within the family and are disclosed after multiple episodes. The small proportion of reported sexual assaults is the consequence of the lack of harmony between the Hungarian conditions of emergency care and the criminal law. Prevention calls for attention at all levels of child education, observation at off-school times, early involvement of health professionals, applying standardized medical guidelines and the modification of jurisdiction.

Gynecologic and obstetric investigation · 7 citationsread the source →

Moderate versus severe early life stress: associations with stress reactivity and regulation in 10-12-year-old children.

Early life stress (ELS) is expected to increase reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis; however, several recent studies have shown diminished cortisol reactivity among adults and children with ELS exposure. The goal of this study was to examine cortisol activity in 10-12-year-old internationally adopted children to determine if moderate and severe ELS have different impacts on the HPA axis. Salivary cortisol and two measures of autonomic activity were collected in response to the Trier Social Stress Test for Children (TSST-C). Three groups reflecting moderate, severe, and little ELS were studied: early adopted children who came predominantly from foster care overseas (early adopted/foster care (EA/FC), n=44), later adopted children cared for predominantly in orphanages overseas (late adopted/post-institutionalized (LA/PI), n=42) and non-adopted (NA) children reared continuously by their middle- to upper-income parents in the United States (n=38). Diminished cortisol activity was noted for the EA/FC group (moderate ELS), while the LA/PI group (severe ELS) did not differ from the NA group. Overall, few children showed cortisol elevations to the TSST-C in any group. The presence/absence of severe growth delay at adoption proved to be a critical predictive factor in cortisol activity. Regardless of growth delay, however, LA/PI children exhibited higher sympathetic tone than did NA children. These results suggest that moderate ELS is associated with diminished cortisol activity; however, marked individual differences in cortisol activity among the LA/PI children suggest that child factors modify the impact of severe ELS. Lack of effects of severe ELS even for growth delayed children may reflect the restorative effects of adoption or the generally low responsiveness of this age group to the TSST-C.

Psychoneuroendocrinology · 247 citationsread the source →

Pomegranate phenolics from the peels, arils, and flowers are antiatherogenic: studies in vivo in atherosclerotic apolipoprotein e-deficient (E 0) mice and in vitro in cultured macrophages and lipoproteins.

We have analyzed in vivo and in vitro the antiatherogenic properties and mechanisms of action of all pomegranate fruit parts: peels (POMxl, POMxp), arils (POMa), seeds (POMo), and flowers (POMf), in comparison to whole fruit juice (PJ). Atherosclerotic E 0 mice consumed POM extracts [200 microg of gallic acid equivalents (GAE)/mouse/day] for 3 months. Blood samples, peritoneal macrophages (MPM), and aortas were then collected. All POM extracts possess antioxidative properties in vitro. After consumption of PJ, POMxl, POMxp, POMa, or POMf by E (0) mice, the atherosclerotic lesion area was significantly decreased by 44, 38, 39, 6, or 70%, respectively, as compared to placebo-treated group, while POMo had no effect. POMf consumption reduced serum lipids, and glucose levels by 18-25%. PJ, POMxl, POMxp, POMf, or POMa consumption resulted in a significant decrement, by 53, 42, 35, 27, or 13%, respectively, in MPM total peroxides content, and increased cellular paraoxonase 2 (PON2) activity, as compared to placebo-treated mice. The uptake rates of oxidized-LDL by E (0)-MPM were significantly reduced by approximately 15% after consumption of PJ, POMxl, or POMxp. Similar results were obtained on using J774A.1 macrophage cell line. Finally, pomegranate phenolics (punicalagin, punicalin, gallic acid, and ellagic acid), as well as pomegranate unique complexed sugars, could mimic the antiatherogenic effects of pomegranate extracts. We conclude that attenuation of atherosclerosis development by some of the POM extracts and, in particular, POMf, could be related to the combined beneficial effects on serum lipids levels and on macrophage atherogenic properties.

Journal of agricultural and food chemistry · 145 citationsread the source →

Prediction and prevention of schizophrenia: what has been achieved and where to go next?

Since the traditional clinical paradigm has been replaced by the modern molecular one, medicine set off into new directions. “Prediction”, “prevention” and “personalization” are the programmatic key words of this new approach. Like other medical disciplines, psychiatry has broadened its focus from diagnosis and treatment to the detection and estimation of the risk of disease development, the prediction of its onset and strategies to avoid its manifestation 1,2,3,4. Although treatment of schizophrenia has greatly advanced over the last decades, a significant number of patients continue to take an unfavorable chronic course 5,6. This makes schizophrenia the leading cause for permanent occupational disability among people under 40 years of age in Germany 7, and the 8th most common cause for disability adjusted life years (DALYs) lost among the 15 to 34-year olds worldwide 8, despite its low prevalence. Moreover, schizophrenia involves tremendous direct and indirect societal costs 9 and a huge burden on patients and their families 8,10. It is becoming increasingly clear that schizophrenia is a complex disorder with polygenic heredity and that its pathogenesis is greatly influenced by interactions between different genes and between genes and environment. Associations to variants of the genes for dysbindin and neuregulin-1, the genetic locus G72 and the DAOA (D-amino acid oxidase activator) gene have now been repeatedly confirmed. As with all other complex diseases, research is focusing now on characterizing the polygenetic predisposition and clarifying its influence on the development of the phenotype 11. Research methods range from molecular genetics via proteome research to cell biology, neurophysiology, brain structural and functional imaging and neuropsychology. With all these methods, several indicators for an increased risk of schizophrenia have been identified. However, the currently recognized neurobiological risk factors are not sufficiently predictive to allow the development and application of “selective” prevention measures targeting asymptomatic persons at risk. For neuro-psychological risk factors, this has just become evident in the large-scale attempt of the North American Prodrome Longitudinal Study (NAPLS) group to improve their multivariate model by integrating the examined neurocognitive variables 12. There are also established environmental risk factors for schizophrenia, such as pregnancy or birth complications, growing up in a large city, IQ low but normal and drug consumption. However, with odds ratios around 2, each of these factors appears to increase the lifetime risk of the disease only slightly 13. Thus, the currently known risk factors, either alone or taken together, cannot be used for prediction and prevention without knowledge of the complete predispositional basis and the gene-gene and gene-environment interactions, which are probably numerous. In view of this situation, it may be argued that the current efforts towards prediction and prevention are still premature and that further progress of etiological research is needed. However, a different perspective has emerged from the work of the centers for early recognition and prevention, established first in Melbourne, Australia and in Cologne, Germany in the mid 1990s, and later on in many other places around the world. This resulted from retrospective research of the early course of psychosis, in which the pathophysiologically active disturbances in brain development extend beyond early abnormalities in behavior into psychopathologically definable early risk and ultra high risk (UHR) symptoms, depending on the individual combination of stressors and resilience factors. First episode psychosis (FEP) research has shown that the outbreak of the disease is preceded in about 70% to nearly 100% of cases by an initial prodrome, which lasts for an average of five to six years. Even in highly developed health care systems, an average of one year thereafter elapses from the first manifestation of psychotic positive symptoms to the initiation of adequate treatment 14,15. The period over which the FEP remains untreated (duration of untreated psychosis, DUP) correlates with: delayed and incomplete remission of the symptoms; necessity of more protracted treatment and greater risk of relapse; lower compliance, greater burden on the family, and a higher level of “expressed emotion”; increased risk of depression and suicide; greater impact on the individual's employment or education; increased drug abuse and delinquent behavior; markedly increased costs of treatment 16. These correlations have recently been confirmed by a meta-analysis 17, with coefficients ranging from 0.285 to 0.434 (95% CI). This does not only provide strong arguments in favor of treating the FEP as early as possible, but has also led to a systematic effort to decrease the incidence of psychosis through indicated prevention. Two important studies concerning the early stage prior to the conversion to FEP have demonstrated that the earliest and most common symptoms, which generally dominate during the prodrome, are unspecific and cannot be distinguished from impairment in mood, drive, contact, and concentration of depressive episodes. These are the Age-Beginning-Course (ABC) study of schizophrenia, a retrospective study with optimized methods 14, and the Cologne Early Recognition (CER) Study, a long-term prospective study with an average follow-up period just below 10 years 18. These studies also found striking cognitive impairments in the form of self-experienced disturbances in thought, speech, and perception processes. This subgroup of so-called basic symptoms, which were found in more than a quarter of patients, had high specificity and a high positive predictive power, accompanied by only low rates of false positive predictions 19,20,21. Basic symptoms were first operationalized in the Bonn Scale for the Assessment of Basic Symptoms (BSABS). Shorter versions of the scale for adults and for children and adolescents — the Schizophrenia Proneness Instrument, Adult version (SPI-A) and the Schizophrenia Proneness Instrument, Child and Youth version (SPI-CY) — were later developed from dimensional analyses 22,23,24. While the BSABS only allows an assessment of the current state, the SPI-A and the SPI-CY also allow severity ratings according to the maximum frequency of occurrence within the past 3 months. In the CER study, 385 patients who were presumably in the prodromal phase of schizophrenia were followed up for an average of 9.6 (±7.6) years past baseline. Twenty percent of the initial criterion-positive cases (1 of 66 basic symptoms) who agreed to be followed up developed schizophrenia after 12 months, a further 17% after 24 months, a further 13% after 36 months, and finally a total of 70% after an average of 4.5 years. Thus, only 30% did not convert to schizophrenia. The overall presence/absence of at least one basic symptom correctly predicted presence/absence of a subsequent transition to schizophrenia in 78.1% of cases. From further analyses, two partially overlapping basic symptom criteria for defining at risk mental states (ARMS) for psychosis, primarily schizophrenia, were developed (Table 1). The first criterion, which consists of ten cognitive-perceptive basic symptoms and is abbreviated as COPER, was based on findings concerning the predictive accuracy of individual basic symptoms 18,25. The second was based on a methodological re-analysis of the same data set, in which a cluster of nine cognitive basic symptoms had repeatedly been selected as the most predictive. This cluster was called “cognitive disturbances” (COGDIS). In terms of general predictive accuracy, the two criteria slightly differed in the CER study, as COGDIS tended to be more conservative than COPER, i.e. to perform better in ruling in subsequent schizophrenia at the cost of performing worse in ruling it out. The transition rate throughout the average follow-up period of roughly 10 years was 65% for COPER and 79% for COGDIS, with the majority of transitions occurring within the first 3 years past baseline. In a second prospective study 26, conducted with the SPI-A and with a systematic follow-up of 24 months, 38% of the initially included 146 at-risk subjects developed a frank psychosis, mainly schizophrenia, within 12.3 (±10.4) months on average (1–48; median=9) according to COPER. Thus, the positive results of the CER study were confirmed. Again, COGDIS appeared to be more specific but less sensitive than COPER. As a consequence of these findings, predictive basic symptoms have been established as a set of criteria for risk assessment in international research on the early recognition of psychosis. In particular, the German Research Network on Schizophrenia used these symptoms, together with a combined criterion of functional deterioration and biological risk, in defining an “early at-risk of psychosis state” (ERPS), thereby suggesting a clinical risk staging model (Figure 1). Early and late initial prodromal state: a clinical staging approach The positive symptoms typical of schizophrenia — such as delusions, hallucinations or formal thought disorders — often first appear in an attenuated or transient form during the initial prodromal phase. These symptoms provide a valid prediction of conversion into FEP, particularly in the short term. Warning signs of this sort have been used as ultra-high risk (UHR) criteria 27,28. Notwithstanding their differences across studies, these criteria are generally composed of three alternative elements: attenuated positive symptoms (APS), brief limited intermittent psychotic symptoms (BLIPS), or a combination of one or more risk factors (always including genetic risk) and functional decline within a certain recent period. For the ascertainment of the UHR criteria, the Melbourne group gradually developed a specific instrument, the Comprehensive Assessment of At Risk Mental States (CAARMS) 29. Based on the Australian definition of the UHR criteria, the Structured Interview for Prodromal Syndromes (SIPS), the Scale for Prodromal Syndromes (SOPS) and, subsequently, the Criteria of Prodromal Syndromes (COPS) were developed 30,31. Different UHR-related approaches to an early detection of FEP, particularly schizophrenia, were developed by the Hillside Recognition and Prevention (RAP) program in New York 32 and the Basel Früherkennung von Psychosen (FEPSY) study 33. There have been at least 15 prediction studies using UHR criteria, some of which with large samples 34,35,36,37,38,39,40,41. The 12-month rates of transition into FEP published so far range between approximately 13% and 50%. A substantial variance is even observed with comparable observation periods in the same center 34,35. Yet, as the annual incidence for all forms of psychosis in the general population is only about 0.034% 42, even the lowest conversion rates still indicate a dramatic increase in the relative risk of illness, at least in the help-seeking samples of specialized centers. Table 2 depicts the predictive accuracy measures published so far, with the last five listed studies representing secondary predictor analyses of samples meeting at risk criteria. As a result, in the German Research Network on Schizophrenia, the UHR approach was combined with the basic symptom approach and applied in a slightly modified form for the definition of “late at-risk of psychosis state” (LRPS) (Figure 1). This clinical staging model, which suggests a syndromal sequence for the development of FEP progressing from unspecific prodromal symptoms to predictive basic symptoms, and then to APS, to BLIPS and to full-blown psychotic symptoms, was recently strongly supported 15. Universal or selective prevention measures target healthy population groups or clinically still healthy risk carriers, respectively 43. Indicated prevention, instead, targets individuals with basic symptoms and UHR symptoms. Even at the early stages when these individuals seek advice and help at the early recognition and prevention centers, they must be regarded as ill and in need of treatment. Furthermore, the impending deterioration of psychosocial performance in schizophrenia often already occurs in the initial prodromal phase, even prior to the conversion into FEP 14,15. These clinical and psychosocial impairments justify defining the interventions in EPRS and LPRS as indicated prevention, pursuing the following three objectives: a) improvement in the current burden of prodromal symptoms; b) avoidance or perhaps delay in the development of psychosocial handicap; c) prevention of or at least delay or attenuation of psychosis. Five international intervention studies have attempted to find out whether or to what extent these three objectives can be reached 44,45,46,47,48,49,50,51 (Table 3). The preventive measures used were either cognitive behavioral therapy (CBT), adapted to the requirements of the persons at risk, or atypical antipsychotics (risperidone, olanzapine, and amisulpride). These were randomized controlled studies, but there were problems with the blinding condition in the two CBT interventions. This and other methodological shortcomings currently limit conclusions and have encouraged the research groups working in this area to set up new, optimized intervention studies. For example, the protocol of the ongoing parallel group PREVENT study includes careful comparative analyses and superiority and inferiority tests of the psychological and pharmacological treatments 52. A staging of risk, thereby implying a temporal dimension, was considered for the first time in the two intervention studies of the German Research Network on Schizophrenia. One of these studies covered ERPS and only offered CBT as a preventive measure 49,50. The other study was designed for LRPS and used only preventive treatment with amisul-pride 51. When the symptom development in the initial prodromal state follows the sequence shown in Figure 1, it would be beneficial for scientific and especially ethical reasons to focus on psychological interventions in ERPS, which are well tolerated and highly accepted. As soon as the first attenuated or transient psychotic symptoms occur, it seems justifiable to apply well tolerated antipsychotics with few side effects. This differential prevention strategy is now pursued in all German early recognition centers and is also increasingly gaining support in other countries. Another pharmacological option is aripiprazole, tested in a pilot study in UHR states 53. Its possible preventive effects are currently being analyzed in the PREVENT study. Antidepressants were used in a naturalistic, non-randomized observational study of an adolescent sample employing only the APS criterion for inclusion, but, for methodological reasons, this study does not allow any conclusion about differential preventive effects of these medications 54. A critical evaluation of the achievements over the past 15 years through continuous efforts to enhance prediction and prevention of psychoses, particularly of schizophrenia, reveals quite impressive results. However, the results achieved thus far need to be evaluated in the light of the ambitious, initially mentioned objectives of modern predictive and preventive medicine. Once predictive basic symptoms and UHR symptoms have occurred, the underlying pathophysiological process might have already progressed. For such a complex disease with a long-term course and a pre-dispositional basis, this kind of risk identification and risk-oriented prevention may possibly come too late. A more substantial reduction in incidence could be reached with selective and universal prevention measures. Therefore, symptom-based prediction and prevention need to be further developed into the direction of selective prevention for symptom-free risk carriers. In the future, it is necessary to strive for: a) an improvement of risk enrichment with the inclusion of biological risk factors; b) a stronger individualization of the risk estimation by stratification; c) the inclusion of sub-psychotic mental states, as cross-sectionally by current at risk criteria, in the the application of prevention strategies more with the of the the initial prodromal phase for as as then most of the follow-up periods shown in Table 2 are not to the transition A significant number of later may be as and, the predictive of the risk may be 12. Therefore, the first and most important is to out new, optimized large-scale studies with follow-up periods the of the initial prodromal phase, as in the CER study 18. The risk enrichment can also be advanced through the inclusion of following the of recent research on the prediction of through the cognitive impairment This condition a risk for with a conversion rate comparable to the risk for the patients certain imaging and the predictive risk enrichment may be possible for using brain but also impairments of and which are with the psychosis risk and are more and in cases with a later transition to schizophrenia and other new large-scale studies with sufficiently observation periods could whether the risk enrichment can be achieved by of such The of this strategy is on the progress of research on biological and environmental risk factors and their interactions, as is currently attempted in the Network of schizophrenia study In other medical disciplines, such as or a risk which does not in a of is using for multivariate clinical staging by risk In the of study, this approach was into psychosis prediction research for the first time A clinical model was developed based on a including six variables positive disturbances Assessment of in the past and years of Based on the individual a multivariate for further the risk of transition to psychosis into risk was each a increased relative risk to the general with each This model was argued to improve the prediction of psychosis by a of the individual risk in terms of and a more risk estimation or clinical staging of risk, in studies, could the development of risk adapted inclusion criteria for randomized preventive In the first application of this approach in the only clinical and variables were It remains to be whether a model including or environmental variables would increase the predictive accuracy even In studies have to whether such can also be applied to the prediction of psychosis within different time The currently ongoing of the has a about the inclusion of a risk for psychosis in to prevention initially argued this and to the that the application of as criteria could that the high rate of predictions in would be to increase up to in general This is and prior to whether to the in the of the The on the predictive of at risk criteria, thereby the persons meeting at risk criteria already from mental and functional for which they seek Moreover, they psychological and cognitive with and functional the majority of help-seeking at risk persons general criteria for mental disorder a clinically significant behavioral or psychological with disability and have to be considered as i.e. as people with the need and to be these in there are reasons for the inclusion of a clinical in the as by current at risk criteria, not as a prodromal risk for first psychosis, but as an to medical the of such an diagnosis would have the of the by the current mental state to a and Although an increased risk of psychosis would continue to be a of such a the psychological and medical focus would be from an to and At this current state of the criteria would be the for the inclusion of this A for the and of a new of international and studies would be with this inclusion in and later on also in A new prevention approach is by the of and studies a of the onset of psychosis the with the first results are for and The transition rate was lower in an group of UHR adolescents than in a group and this was at a an was evaluated in 10 patients in an pilot and a significant improvement in different was In an study, time was in an UHR group with as with a group suggesting a of This was the first study imaging data on effects in individuals at risk. The preventive of is currently in the process of in the Australian Prodrome study With the of schizophrenia is the first mental disorder to which the prediction and prevention program of modern medicine has been The results are and justify the that in the years to come it be possible to provide preventive strategies to the individual risk of of each In to a reduction in risk assessment has to be by neurobiological and psychosocial risk factors, and indicated prevention has to be further developed towards selective prevention. This a new of large sample studies for prediction as well as prevention, with observation In these studies, of risk selected to predictive must be psychological and pharmacological interventions need to be on a long-term basis, more prevention strategies have to be In to be to and such studies, it would be to mental states, as by the currently used risk symptoms, in the of the

World Psychiatry · 127 citationsread the source →

Maternal depression and child development

Maternal depression is considered a risk factor for the socioemotional and cognitive development of children [1]. The current prevalence of depression in Canada averages at 6%, which is similar to the rates in other western countries [2] (the female-to-male ratio average is 2:1 [3]). However, the prevalence of postpartum depression is approximately 13% [4]. Women of childbearing age are particularly at risk for depression, and many of them experience high levels of social morbidity and depressive symptoms that are often unrecognized and untreated. Mothers already at risk for depression are particularly fragile during the first months postpartum. Maternal depression has consequences on the child’s development. Because physicians who care for infants and children encounter mothers repeatedly, it is important that they have the knowledge and skills for the detection of symptoms of maternal depression. The objectives of this statement are: To review the present knowledge on the consequences of maternal depression on the development of children at various ages; To review the evidence-based literature on the treatment of maternal depression and its impact on newborns, infants and children; and To review the role of the child’s physician in the detection of symptoms of maternal depression, and the coordination of appropriate support and management. A literature search for the past 15 years was conducted using the MEDLINE database, and by reviewing the bibliographies of the retrieved articles. Of particular interest were the prospective longitudinal cohort studies in which mothers were recruited during their pregnancy or postpartum period, and the children were assessed at regular intervals. Postpartum psychiatric disorders are generally divided into three categories: postpartum blues, postpartum psychosis and postpartum depression. Postpartum blues is a relatively common emotional disturbance with crying, confusion, mood lability, anxiety and depressed mood. The symptoms appear during the first week postpartum, last for a few hours to a few days and have few negative sequelae. At the other end of the spectrum, postpartum psychosis refers to a severe disorder beginning within four weeks postpartum, with delusions, hallucinations and gross impairment in functioning. Postpartum depression begins in or extends into the postpartum period and core features include dysphoric mood, fatigue, anorexia, sleep disturbances, anxiety, excessive guilt and suicidal thoughts [5]. The diagnosis requires that symptoms be present for at least one month and result in some impairment in the woman’s functioning [6]. Women who have experienced postpartum depression have a 50% to 62% risk for future depressions [7]. Other risk factors for postpartum depression include a history of mood disorders, depression symptoms during the pregnancy and a family history of psychiatric disorders [4]. Stress factors, such as negative life events, poor marital relationships, having a special needs infant or medically ‘fragile’ infant, lack of social support, drug abuse, and personal and family psychopathology, have been associated with postpartum depression in some studies, but other studies have found no association [6]. Postpartum depression tends to be milder than episodes of depression that occur at other times, with lower levels of anxiety, agitation, insomnia and somatic symptoms [8]. However, the duration seems to be the same in postpartum and nonpostpartum depression, and lasts several months [6]. The consequences on the child of maternal postpartum depression are not restricted to infancy, but can extend into toddlerhood, preschool age and even school age. Maternal depression that occurs later influences the development of the school-age child and the adolescent. Table 1 summarizes the consequences of maternal depression from prenatal issues to adolescence. Consequences of maternal depression Consequences of maternal depression The associations between maternal depression, maternal behaviour and child outcomes are complex, and not all studies have found a relationship between maternal depression and indicators of poor parenting. Variations in the type, severity, chronicity and timing of maternal depression [9], heterogeneity in sampling (community versus high-risk multiproblem samples), and potentiating risk factors, such as family adversity, low social support and financial stress [10], all contribute to differences in outcomes in children. On the other hand, stress factors can be responsible for adverse child outcomes in the absence of maternal depression. On a daily basis, infants repeatedly participate in interactive routines with their mothers. Maternal depression compromises the dyad’s capacity to mutually regulate the interaction, through two interactive patterns, intrusiveness or withdrawal. Intrusive mothers display a hostile affect, and disrupt the infant’s activity. The infants experience anger, turn away from the mother to limit her intrusiveness and internalize an angry and protective style of coping. Withdrawn mothers are disengaged, unresponsive, affectively flat and do little to support the infant’s activity. The infants are unable to cope or self-regulate this negative state, and develop passivity, withdrawal and self-regulatory behaviours (eg, looking away or sucking on thumb) [11],[12]. Infants of postnatally depressed mothers have been reported to show patterns of dysregulated attention and arousal. In a study by Murray [13], cognitive performance regarding the independent existence of objects was worse for infants of 61 postnatally depressed mothers than the infants of 42 nondepressed mothers, even after adjustment for contextual adversity. Depressed mothers are less likely to offer contingent stimulation to their infants [14], and this disrupts their performance on nonsocial learning tasks [15]. Another factor that may interfere with learning is the negative affect shown by infants of depressed mothers, even when they are interacting with nondepressed adults [16]. It has been documented that an infant’s own negative affect interferes with learning and the ability to process information [17]. Depressed mothers generally show less attentiveness and responsiveness to their children’s needs. They are also poor models for negative mood regulation and problem solving. Longitudinal studies have compared the behaviours of depressed and nondepressed mothers, and the outcome of their children. They showed that depressed mothers were less likely to set limits on their children and to follow through if they did set limits [18]. Children of depressed mothers appeared more passively noncompliant, with less mature expressions of age-appropriate autonomy [19]. They were rated by their dysphoric mothers as being more vulnerable, and having more internalizing (depressed) and externalizing problems (aggressive and destructive), which are associated with lower interaction ratings [20]. They were also more likely to respond negatively to friendly approaches, more likely to engage in low-level physical play and less likely to engage in individual creative play than control children [21]. These aspects of child behaviour were associated with postnatal depression, even when taking adverse situations such as marital conflict, and demographic variables, such as maternal age, ethnicity, socioeconomic status, marital status, child’s age and number of siblings, into account. Studies on large samples all agree on the negative impact of maternal postpartum depression on a child’s cognitive development. Early experience with insensitive maternal interactions (as in maternal postpartum depression) appears to be predictive of poorer cognitive functioning [22]. Boys may be more sensitive than girls to the effects of the mother’s illness. In a study by Sharp et al [23], only boys showed a decrease on standardized tests of intellectual attainment (mainly on indexes of abstract intelligence, reasoning about opposites and analogies) and the “draw-a-child” task. Other aspects of cognitive development, such as cognitive-linguistic functioning [24], have also been shown to be negatively affected, and there were also deficits on the perceptual and performance scale [25]. Outcome effects were independent of birth order, maternal education, family income, marital status and social support. Various studies have shown that school-age children of depressed mothers display impaired adaptive functioning, including internalizing and externalizing problems. Although the studies reviewed by Beardslee et al [26] were uncontrolled studies, a more recent review by Downey and Coyne [27] included studies using control groups (matched for age of parents, occupational status, ethnicity, marital status, and number and age of children), standardized diagnostic criteria to identify parental depression and valid measures of psychological functioning in children. Billings and Moos [28] showed that family stress and low support added to the prediction of child disturbance beyond that accounted for by having a depressed parent. However, the study of Lee and Gotlib [29] comparing children of depressed psychiatric mothers and nondepressed psychiatric mothers showed that the child’s adjustment was more strongly related to the severity of maternal psychopathology than to diagnosis status. Children of depressed parents are also at higher risk of psychopathology, including affective (mainly depression), anxiety and conduct disorders. Hammen et al [30] compared children from four groups of mothers (mothers with unipolar disorder, bipolar disorder and chronic medical illness, and normal mothers) with no differences in ethnicity, age, socioeconomic status or educational level. They showed that, even with the effects of chronic stress statistically controlled, there were still differences in the psychosocial outcome variables among groups, and there was particular impairment in children of unipolar mothers [30]. Other studies [31]–[34], in which there were no demographic differences (age, marital status and socioeconomic level) between depressed and nondepressed parents, have confirmed an increased risk of psychopathology in the children of depressed parents. It seems that onset of a major depression disorder before 30 years of age in parents increases the risk of their children developing depression quite early during childhood [33],[34]. It is somewhat difficult to delineate which behavioural disorders are due to maternal depression and other environmental factors, and which are due to genetic susceptibility. There seems to be an association between attention deficit/hyperactivity disorder (ADHD) in children and maternal mental health, as shown by a cross-sectional study by Lesesne et al [35]. Using the 1998 National Health Interview Study on 9529 mother-child dyads, they found an association between an activity-limiting depression, anxiety or emotional problem in mothers, and ADHD in their children aged four to 17 years, even after adjusting for the child’s age, sex, race, household income and type of family structure [35]. In a longitudinal study of 132 children by Hay et al [36], lower IQ scores, attentional problems, difficulties in mathematical reasoning and special educational needs were significantly more frequent in children whose mothers were depressed at three months postpartum than in controls. In addition, boys were more affected than girls. However, academic difficulties in children of depressed mothers were not mediated by parental IQ, sociodemographic variables or the mother’s mental health after the postpartum depressive episode. Generally, adolescence is a vulnerable period for affective illness and major depressive disorder, which are observed twice as often in girls than in boys [37]. Two cross-sectional studies showed that adolescents with a depressed parent suffered from psychosocial maladjustment [38] and experienced a significantly higher rate of affective disorder than adolescents of nonaffective psychiatric control parents [39]. Longitudinal studies have consistently reported higher rates of major depression and other psychopathology (anxiety disorders, conduct disorders and substance abuse disorders) in adolescents with an affectively ill parent than in control families with similar demographic characteristics (age, ethnicity, socioeconomic status and educational level). Hammen et al [40] followed a cohort of 92 children/adolescents between the ages of eight and 16 years over a three-year They found that children/adolescents with mothers from unipolar depression higher rates of affective disorders, with frequent the disorders in children/adolescents with mothers from bipolar depression were less et al families with children between and years over a They observed higher rates of major depression, disorder and in the of depressed parents than in the major depression onset was between the ages of 15 and Beardslee et al at an of a health with children between the ages of and At the of the children/adolescents with an affectively ill parent at least one of an affective illness compared with in the control years the rates of affective disorders were and and of affectively ill parents onset and a number of in school-age ADHD and learning into adolescence [35]. It has been in many studies that some children with depressed do not display behavioural and that some factors may or the effects of parental depression contextual risk factors, marital life social support lower social and lower maternal are factors that may parental depression and parenting. In a study of mothers with major depressive disorder the child’s et al showed that contextual risk factors mediated the between maternal depression and child behaviour problems. The role of and in child development are to be on mothers, the for the infant is the However, in their study of to et al showed that infants of depressed mothers with their nondepressed who the effects of the mother’s depression on infant interaction In addition, a cross-sectional study of families with children between the ages of and years showed that in families in which the mother was children showed lower social and emotional if the also a psychiatric The role of has been in the of marital to a review by Downey and Coyne marital to children externalizing problems, and increases their risk for depression by and parental depression. differences have been in some studies with boys being more vulnerable and by maternal depression than girls. of the child also to the of parental depression. It has been shown that mothers more negative of their child’s less in their parental and more often A child with a more and be more to their depressed mother’s negative behaviour and not show a of Other of in children include social and cognitive skills that them attention from adults other than their depressed parents and their depressed of and It seems that an of the illness and by the child that or is not to for the behaviour is important to the development of in a child Although the interaction between parents and their child is beyond the of the present it has been that parents of children higher depression than control parents and that is a of maternal depression Because many depressive episodes occur during childbearing years, the to be between the mother’s and a who from depression with is at high risk of [7]. during pregnancy is associated with prenatal poor higher low birth substance abuse and The morbidity of depression during pregnancy be the risk of have been by that are associated with a low risk of and the However, et al did not in major or in taking compared with controls. Another study on taking showed an in when the was during the In the period, it seems that behavioural and rate to are in infants to in et al compared children of mothers with a during children of mothers with and control children of nondepressed mothers who did not during adjusting for the duration and severity of maternal depression, duration of number of depressive episodes after maternal IQ and socioeconomic status, the study showed that and no adverse effects on the IQ, development or behaviour of children between 15 and months of age In a et al compared children to depressed mothers who not to during pregnancy and children to mothers with Although the on the indexes were similar in groups of children to children to lower on the indexes and the factors of the of the of is the of It is important that a depressed mother who to be the is in the postnatal period, there is a risk of with negative consequences on the emotional and behavioural development of the On the other hand, all are in of the information from and to a review by and the and are the of or have been in children or through To infant when postpartum depressed mothers, it is important to all maternal of and and to the of environmental and maternal illness is interaction with the infant or other it is to on the of treatment it is to the of the be on the mother’s and experience of adverse effects with a particular risk of interactions with and adverse effects associated with a particular on mothers and their Maternal be to for the that control of the depressive is and the in pregnancy be in the postnatal The infant’s to can be by the of and it and approximately to after the mother has the Although there is no on the of during pregnancy and be considered in the of a as by the of et al be considered in who have to severe symptoms and who have not to show that and appear to be quite during pregnancy and the postnatal period, and may be during pregnancy and Because of the consequences of maternal depression on an infant’s development, many studies have postnatal mothers. have on the mother’s mood state, her to or of the infant’s and the negative about the infant’s behaviours [16]. to the of by mothers to their infants or by mothers to and their attention support and have been in depressed and as as their and development treatment have been an interactive treatment at problems by the mother in the of her infant that support, and education, with of depressed mothers and their a and in a infant over a period to of months mothers from the showed more interaction and their infants and scores, as as more interaction behaviours than in the control children and adolescents from families with a depressed parent may from a on about the illness within the family and on the development of in the In a study by Beardslee et al families who an to child and a parent with an affective disorder were to a or a parents information about the and symptoms of childhood and depression, and the for within the However, the cognitive to the life of the in the showed more behaviour and among parents and including higher levels of from parents to children about the illness and by the child of the affective illness et al compared with interaction The treatment on the mother’s of her infant and her relationship with the infant, and aspects of the mother’s own childhood and early already the interaction to identify behaviours and to of an infant’s a of there was a in The sleep and difficulties maternal to increased and control In addition, maternal and infants more less and showed more on and problems experienced by depressed postpartum mothers. In a study of depressed postpartum depressive symptoms and social adjustment in the compared with the control on the has also been in the of postpartum depression in with at least one risk factor for postpartum depression and are and is the in Canada seems to be for to depression, it has many drug interactions There are no on its and it be as during pregnancy on its during are a it was observed that was in at a low and the lower limit of in the infant’s A prospective study of found no differences in the of in over the first of life compared with a control to the of the on the Health to of for depression using the Health or the of of from the Health However, it is strongly that a high of for depression among their In their statement the adults for depression in that have in to treatment and of of In their for the of on the that the physical and mental health of the parents in their and review the of attention to their own mental health needs. In a of three et al reported that more than of mothers the impact of depression on the child’s health and and that more than of mothers the role in and to However, a recent study showed that maternal depression was by health care et al reported that in their ability to maternal depression and their of knowledge and The role in maternal depression be one of followed by for and There be a about family history of depression and about episodes of maternal depression. have been and to postpartum depression of that may information about postpartum depression are in Table depression is the can and with the mother’s physician or an appropriate to psychiatric between the mother’s physician and the child’s physician is to information about postpartum depression are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in to information about postpartum depression are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in many mothers, care may be their with health care The child’s physician may be the first to of the and difficulties of a the child’s physician can the depressed mother her mood affect her and contribute to the child’s problems. of include infant sleep problems, child social and family It is important to a high of of maternal depression when child behaviour problems are during a medical for the depression of the mother over behavioural for the Because postpartum depression can have effects on mothers and children and its prevalence occurs at approximately three it has been to for postpartum depression at the and care In school-age children and the of difficulties in child adjustment and impaired functioning at and in school the physician to the of maternal depression. in families with a history of depression, one in that may depressed or display other psychopathology, at adolescence. These often and for a for the The child’s physician has a role in to the appropriate for the and the parent. that children of depressed mothers are at risk for and behavioural problems, as as their for developing a depressive disorder the physician conduct regular of the offer and them early for more and of and behavioural disorders. Postpartum depression occurs in approximately 13% of and often it is there is often a of between and psychiatric and treatment of the lack of The infant of a depressed mother is at risk for developing negative affect and dysregulated attention and arousal. and of depressed mothers are at risk for developing poor internalizing and externalizing problems, and difficulties in cognitive functioning and in social interactions with parents and and children of depressed parents are at risk for impaired adaptive functioning and psychopathology, including conduct disorders, affective disorders and anxiety disorders. They are also at risk for ADHD and learning risk factors such as marital and life may parental depression and child behaviour problems. On the other hand, some children develop through an social cognitive skills and of the illness. with during pregnancy and is but no major or physical and to the or the infant have been The of the mother’s depression to the low of on the or the the of the and development of infants and the physician to of mother-child interaction and behavioural and problems in the such they in the of maternal depression, a few and with the mother’s physician or psychiatric Mothers who have during pregnancy be that of the to that there is no increased risk of or Mothers who have during pregnancy be about the of their child studies have not shown adverse for differences whose to be Mothers who have during be that of the to that there are no or in children to such through Mothers be that on are and that such not be during pregnancy and on of and of of The in this statement do not an of treatment or to be taking into individual may be are current at of

Paediatrics & Child Health · 312 citationsread the source →

Whither the Attenuated Psychosis Syndrome?

After 4 years of debate, a decision has been made. The attenuated psychosis syndrome (APS) will not be a coded diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Formerly known as the psychosis risk syndrome, the proposed diagnosis was based on criteria developed in the mid-1990s that were informed by a comprehensive review of retrospective studies on the prodromal phase of nonaffective psychosis.1 These criteria aimed to identify prospectively people in the prodrome of schizophrenia and other psychotic disorders and have been variously titled “ultra high risk (UHR),” “clinical high risk (CHR),” “at risk mental state (ARMS),” and the “prodromal stage,” and included a group with attenuated (subthreshold) positive psychotic symptoms.2 The criteria are associated with rates of onset of psychotic disorder substantially higher than in the general population3 and other clinical populations.4 A recent meta-analysis reported the rate of onset of a psychotic disorder to be 36% after 3 years.5 About 73% of those developing a psychotic disorder fulfill criteria for schizophrenia spectrum psychoses.6 It should be noted that these data are from treated samples consisting of patients referred to specialist clinical services. Despite the consistent finding that there is a high risk of developing a psychotic disorder associated with the APS group,5 there has been considerable controversy around the idea of formally codifying it into a DSM5 diagnosis. Indeed, we, the authors of this communication, all active researchers in the area, have had differences in opinion about the merits of including APS as a new diagnosis in the DSM.7–12 One issue debated was the tension between the possibility of early intervention to prevent progression of disorder vs potential unnecessary diagnosis and treatment of what might be a self-limiting phase. The possibility of stigma and discrimination was also raised.10,11 Some speculated that a formal diagnosis would be assumed to equate to an indication for antipsychotic medication and so increase the likelihood of antipsychotic prescription.11 Others argued that the absence of an APS diagnosis has led to some clinicians using the term psychosis NOS (not otherwise specified), which may lead to antipsychotic prescription. The APS as an alternative to this diagnosis could then actually reduce antipsychotic prescribing.9,12 Importantly, an APS diagnosis will enable evidence-based treatments to be developed, including psychological therapies, and could therefore decrease antipsychotic use.12 Ultimately, the decision to exclude APS as a coded diagnosis was made not in response to any of the above issues or in the light of data addressing the principal disputes but because data on the diagnostic reliability of APS in clinical practice were limited and inconclusive. Following this decision, some critics have been quick to denounce the whole APS/ultra high-risk/clinical high-risk/prodromal concept.13–15 We, therefore, feel it is timely, as a group involved in high-risk (prodromal) research, to document some points of consensus between us and highlight areas for future research. Attempts to recognize the prodrome of schizophrenia prospectively have been active for nearly 20 years.2 Many samples of persons meeting high-risk criteria have been seen and evaluated. A strong consensus exists that individuals meeting APS criteria (which includes a criterion for help-seeking) are symptomatic and in need of clinical care.16–18 People meeting the criteria do in fact fulfill the broad definition of mental disorder: “a clinically significant behavioral and psychological syndrome or pattern … that is associated with present distress … or disability … or with a significantly increased risk of suffering death, pain, disability, or an important loss of freedom,”19 (p. xxi). Thus, treatment is clearly justified, regardless of the justification of reduction of risk or prevention. We agree that this treatment should include monitoring of mental state, supportive therapy, and attention to current practical needs. Cognitive therapy and omega-3 fatty acids may also be helpful. On current evidence, antipsychotic medication is no more effective than other more benign treatments and so is typically not recommended.20 A second point of consensus is that people meeting APS criteria have a greatly increased risk of developing a psychotic disorder within a brief time frame.3,5,21,22 Despite evidence that the transition rate (conversion from high-risk state to first-episode psychosis) may be declining in the short term23 and the finding of low rate of psychosis in recent intervention trials,24,25 its magnitude is similar to other risk syndromes,26,27 and still in the order of hundreds fold above the risk of the general population. Given this, we agree that regular assessment of mental state to detect first episode of psychosis is indicated. The monitoring of mental state and early detection of psychosis allow prompt treatment and the minimization of the duration of untreated psychosis, which, if prolonged, is harmful to both patients and their families and is known to be associated with a poor outcome.28,29 Finally, we agree that more research into the APS is needed. We support the Psychotic Disorders Workgroup in its recommendation to include the APS as a category in the appendix (Section 3) of DSM-5 as a condition for further study. Collectively, we have devoted many hours into thinking about this condition. Through our research and clinical experience with these patients, we have evolved our thinking and our conceptualization of APS. Initially, the high-risk criteria were developed, as the name suggests, to detect individuals at high risk of psychotic disorder. However, the use of the criteria should not be thought of as identifying and treating an asymptomatic group at risk of a poor outcome, analogous to detecting and treating hyperlipidemia to prevent myocardial infarction (MI). APS patients are symptomatic and distressed. Thus, angina may be a more apt analogy. However, better still is to think of the criteria as detecting chest pain. The condition is distressing, symptomatic, and leads to help seeking. It may indicate the early signs or risk for a serious cardiac disease such as MI, a serious but noncardiac disease, such as pneumonia or a benign self-limiting condition such as esophageal spasm or costochondritis. Likewise, APS may indicate the early signs or risk for illnesses such as nonaffective and affective psychotic disorder, presence or risk for a serious but nonpsychotic illness such as severe unipolar depression, or it may indicate something that is not serious and which may resolve, with or without treatments such as psychological support, stress reduction family interventions, and practical help. This way of conceptualizing APS leads to many different paths for research. Suggestions for the future research agenda follow. Investigation of different outcomes in both the short and long term including psychotic disorders, nonpsychotic disorders, persistence or remission of APS, and social and cognitive functioning is needed. Refining risk factors for these different outcomes is another avenue of research. It may be that added criteria are necessary to enrich the sample for schizophrenia, such as basic and negative symptoms and decline in cognitive and social skills.30,31 Other methods of enrichment for other outcomes can also be studied, including multiple subclinical symptoms plus depression,32 presence of personality disorder, family history of mental disorder, and childhood trauma and adversity.33 Examining recovery and remission of the high-risk state as outcomes is another area that is currently understudied. Searching for predictors of these positive outcomes can then lead to adding such factors to ascertainment criteria as exclusions, which would result in a reduced false positive rate and increased positive predictive power. Examining associated neurobiological,34–36 cognitive,37 physiological,38 metabolic,39 and genetic40,41 associations with the APS and its different outcomes is needed so that subgroups can be more sharply delineated. Longitudinal follow-up is needed to elucidate whether the biological markers that are observed in the APS group are indicative of a trait vulnerability to psychotic disorder or whether they are state markers. Comparison with other psychiatric groups without APS will determine whether biological findings are specific to APS and represent a continuum with psychotic disorders such as schizophrenia or whether they are associated with general psychiatric distress. Research is also needed as to what harms and benefits are associated with an APS diagnosis. This should include assessing any perceived stigma, and comparison made with the stigma, stereotypes, and wish for social distance associated with overt psychiatric symptoms that may occur prior to help seeking and diagnosis. Whether clinical care that provides information, treatment, and hope of a good outcome can minimize stigma should also be studied. The effects of creating a new diagnosis, on patients, their families, and the wider health system, needs to be better understood. While reliability of assessment has been demonstrated in previous studies using structured interviews,42,43 the clinical utility and reliability of assessment in routine practice needs to be assessed and improved and the impact of the proposed diagnosis on prescribing practice examined. Investigation of factors that lead APS patients to seek help will also be useful. Currently, it is unclear how much of the distress that leads to seeking help is related to the psychotic-like symptoms or to associated nonpsychotic mental disorders, such as depression and anxiety.44 Little is known about the prevalence of APS in adolescent and adult clinical populations and in the general community and this also needs further study. Further intervention research is also needed. Omega-3 fatty acids have shown promise in reducing symptoms as well as decreasing the risk of transition to psychotic disorder in one study.45 This requires replication. Other novel treatments such as psychological treatments, vitamin D, glycine, and other neuroprotective agents are also worth testing. Finally, with increasing the knowledge of risk factors for different outcomes (see above), the APS model could also be extended to a more general a strategy for early intervention in a range of mental disorders. It may be that many disorders develop from initial nonspecific symptoms and syndromes, from a background of specific and nonspecific risk factors (such as genes and early environment). Worsening of symptoms and acquisition of new symptoms may occur, together with progressive neurobiological abnormalities, and related neurobehavioral deficits, until clear-cut recognizable mental disorders appear.46 Progression of symptoms and neurobiological abnormalities could continue after “threshold” diagnosis, with development of chronic symptoms, relapses, and ongoing functional deterioration. Transition from one stage to the next is not inevitable, either due to different risk and resilience factors or due to nonspecific or specific intervention. Thus, preventive possibilities exist across this spectrum of evolving illness. This concept of a pluripotent risk syndrome opens up a range of research possibilities. Studying genetic and environmental risk factors and gene and environment interactions for different outcomes, further work on resilience and protective factors, and examination of different trajectories are all future avenues of research. Whether any specific markers for particular course and outcome can be detected early is another area and leads to the possibility of early specific treatments. Novel methods such as multimodal imaging and neurocognitive analysis, single subject methods to predict individual disease course are also possible. APS concept remains a useful one. It identifies people with significant mental health problems that justify treatment in their own right, as well as having a higher likelihood of developing a psychotic disorder (mostly schizophrenia) within a few years. Research into this group will increase our understanding of psychotic-like symptoms and their trajectories and the emerging phase of psychotic disorders. The APS concept is consistent with the continuum view of psychosis and is probably a reflection of biologic reality. Outcomes other than psychotic disorder are also clearly worthy of study. The placement of APS in the DSM-5 appendix should be a clarion call to the field to focus attention on these patients and families in need. National Health and Medical Research Council (Australia) Senior Research Fellowship (#566593), and the Colonial Foundation (to A.R.Y.); National Institute for Mental Health (NIMH) grants (#5U01MH081857 and #5R01 MH061523 to B.A.C.); German Research Foundation, NARSAD, the German Ministry of Education and Research, the Faculty of Medicine of the University of Cologne (to A.B.); the National Institute for Health Research (NIHR) Birmingham and Black Country Collaboration for Leadership in Applied Health Research and Care (to M.B.); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London (to P.F.-P., P.M., and L.V.); the German Research Foundation, the European Commission, the German Ministry of Education and Research, and the Faculty of Medicine of the University of Cologne (to J.K.); the University of Basel (to S.B. and A.R.-R.), Swiss National Foundation, Stanley Foundation, European Union FP7, Österreichische Forschungsförderungsgesellschaft, Foundation Alamaya (to A.R.-R.); NIMH (U01 MH081928, P50 MH080272), Massachusetts Department of Mental Health, R21 MH093294, R01 MH096027 (to L.S.); and NIMH and the Norwegian Research Council (to T.H.M.). A.B. and J.K. have received investigator-initiated grant support from Bristol Myers Squibb. A.B. has received speaker fees and travel support from Bristol Myers Squibb, Eli Lilly, Janssen Cilag, and Servier. P.D.M. has received unrestricted research grant support from Janssen Cilag, honoraria for educational events and consultancies from Janssen-Cilag and Roche, and unrestricted Research Grant Support from Astra Zeneca. As these sources of funding have not influenced the content of this article, all authors have declared that there are no conflicts of interest in relation to the subject of this article.

Schizophrenia Bulletin · 97 citationsread the source →

Adjustment disorders: the state of the art

The diagnostic category of adjustment disorder was introduced in the DSM-III-R 1. Prior to that, it was called transient situational disturbance. The DSM-IV 2 and ICD-10 3 descriptions of adjustment disorder are broadly similar. The main features are the following: a) the symptoms arise in response to a stressful event; b) the onset of symptoms is within 3 months (DSM-IV) or 1 month (ICD-10) of exposure to the stressor; c) the symptoms must be clinically significant, in that they are distressing and in excess of what would be expected by exposure to the stressor and/or there is significant impairment in social or occupational functioning (the latter is mandatory in ICD-10); d) the symptoms are not due to another axis I disorder (or bereavement in DSM-IV); e) the symptoms resolve within 6 months once the stressor or its consequences are removed. Adjustment disorders are divided into subgroups based on the dominant symptoms of anxiety, depression or behaviour. Since its introduction, the category of adjustment disorder has been the subject of criticism on three fronts. The first was that it constituted an attempt to medicalize problems of living and did not conform to the criteria for traditional disorders such as having a specific symptom profile 4. The second was that it was a “wastebasket diagnosis” which was assigned to those who failed to meet the criteria for other disorders 5. The third was on its diagnostic instability 6 and that its main utility was to serve as a “justification” for diagnosis-based reimbursement operating in the healthcare system of the US. Despite this, the category has been retained in the further classifications, in large measure due to its clinical utility. Adjustment disorder continues to be diagnosed in a range of clinical settings. Consultation-liaison psychiatry is the context in which the diagnosis is most likely to be made. Around 12% of referrals are so diagnosed in university hospitals in the US 7, a figure that resembles that in European hospitals 8. Nevertheless, the frequency with which adjustment disorder is now diagnosed seems to be declining, in parallel with an increase in the diagnosis of major depression 9, possibly due to the availability of psychotropic drugs, especially selective serotonin reuptake inhibitors (SSRIs), that are safer in those who are medically ill than the older agents. So, changes in the prevalence of adjustment disorders may reflect a change in the “culture of prescribing”, stimulating changes in the “culture of diagnosis” 10. Adjustment disorder has been reported to be almost three times as common as major depression (13.7 vs. 5.1%) in acutely ill medical in-patients 11 and to be diagnosed in up to one third of cancer patients experiencing a recurrence 12. In obstetric/gynaecology consultation-liaison 13, adjustment disorders predominated over other mood disorders. Among those assessed in an emergency department following self harm, a diagnosis of adjustment disorder was made in 31.8% of those interviewed, while a diagnosis of major depression was made in 19.5% of cases 14. None of the major epidemiological studies carried out in the community, such as the Epidemiological Catchment Area Study 15, the National Comorbidity Survey Replication 16 or the National Psychiatric Morbidity Surveys 17 included adjustment disorder among the conditions examined. An exception was the Outcome of Depression International Network (ODIN) study 18, which found a prevalence of only 1% for adjustment disorder in five European countries. A possible reason for this was that mild depression was included in the depressive episode category, inflating that category at the expense of adjustment disorder. By contrast, a study of elderly people from the general population 19 found the prevalence of adjustment disorder to be 2.3%, similar to that of major depression. Adjustment disorder is reported to be very common in primary care, but relevant epidemiological studies in this setting are rare and report rates of the disorder range from 1 to 18% 20,21 among consulters with mental health problems. Concerning psychiatric settings, a study of intake diagnoses into outpatient clinics 22, combining clinical evaluation and the use of the Structured Clinical Interview for DSM-IV (SCID, 23), found that adjustment disorder was the most common clinical diagnosis, made in 36% of patients, whereas the diagnosis was made in about 11% of cases using SCID. Among psychiatric inpatients, 9% of consecutive admissions to an acute public sector unit were diagnosed with adjustment disorder 24. Quantifying the prevalence of adjustment disorder in child and adolescent populations is difficult, due to changes in the diagnostic criteria over time 25. In the younger age groups, unlike adults, adjustment disorder carries with it significant morbidity and a poor outcome, frequently developing into major psychiatric illness 25,26. A general population study in Puerto Rico 27 found a rate of 4.2% among 14–16 year old people, while the total psychiatric morbidity was 17.8%. A similar rate was found in children aged 8–9 in Finland 28. Among outpatients, figures of 5.9–7% have been reported 29,30. In child liaison psychiatry, over one third of those with recent onset diabetes were so diagnosed 31, making it the most common psychiatric disorder to follow this well defined stressor. The current diagnosis of adjustment disorder assumes that there is a stressor which acts as a trigger and that the condition is self-limiting. So, adjustment disorder is closer to the definition of a discrete disorder as proposed by Kendell 32 than most other disorders in psychiatry, since its etiology and course are encapsulated within the diagnosis, while the definition of many other mental disorders is cross-sectional and based on symptoms alone. Yet, the current classifications impose a hierarchical model that assumes equivalence in how adjustment disorder and other diagnoses are construed. As currently classified, adjustment disorder is a sub-threshold diagnosis, that is trumped once the symptom threshold for another diagnosis is met. There is an inherent belief that a sub-threshold condition is less severe than a full-blown disorder such as major depression, the diagnosis by which adjustment disorder is most often superseded. Yet, the evidence for this is lacking, and there is empirical data 33 that, when measures of symptom severity or social functioning are examined, there is no difference between those with mood disorders and adjustment disorder. Furthermore, up to 25% of adolescents with a diagnosis of adjustment disorder engage in suicidal behaviour 34, while among adults with this disorder the figure is 60% 35. Adjustment disorder is the diagnosis in up to one third of young people who die by suicide 36, while among all suicide deaths in the developing world it is the most common diagnosis 37. These data show that, far from being a mild condition, adjustment disorder has a significant impact on behaviour. On the other hand, the current classifications fail to distinguish between adaptive and maladaptive reactions to stress. The DSM-IV tries to address this problem by stating that a diagnosis of adjustment disorder is only made when the distress is of clinical significance 38. There are two components to this: the distress must be in excess of what would normally be expected and/or there is an impairment in social or occupational function. In relation to the first of these, one of the most insightful critics of the DSM-IV, J. Wakefield 39, points out that it would allow the top third in the normal distribution of mood reactivity to be classified as disordered, and that it does not take into account the contextual factors that might cause this excess in distress. For example, the loss of a job for one person might be manageable while for another it could heap poverty on a family resulting in distress that might not be inappropriate under the circumstances. Cultural differences in the expression of emotion also need to be considered. In liaison psychiatry, where the diagnosis of adjustment disorder is most frequently made, a knowledge of “normal” coping with illness in that specific culture is essential and the diagnostic process will be guided by the extent to which an individual's symptoms are in excess of this. Some might argue that the fact of visiting a doctor indicates abnormal distress, yet the tendency to consult is also determined by factors additional to illness, including cultural and personal attitudes to symptoms. So, the mere fact of a consultation should not of itself be taken as a proxy measure of excessive distress. Neither should the decision to refer to psychiatric services, since this too is governed by factors that are not always related to symptom severity (e.g., a wish “to do something” under pressure from a patient in the face of continuing distress). Because adjustment disorder is a diagnosis made in the context of a stressor, there is a danger that any distress following such an event might be labelled as a disorder 40. Clinical judgement, therefore, plays a large part in making the diagnosis of adjustment disorder in the current criterion vacuum and future classifications should accord weight to culture, context and personal circumstances in differentiating normal from pathological distress. The second criterion, requiring impairment in functioning, is arguably a more robust indicator of disorder, since it is this which leads to treatment seeking. For example, the inability to work is potentially a significant indicator of impairment. However, there may be situations where functioning is reduced in the presence of non-pathological reactions. For instance, if the circumstances are especially traumatic, such as the loss of a child, the period of impaired function may be longer than anticipated in those with non-pathological responses. The evaluation of functioning in children places special demands on the assessor, since it has to be set against the demands of the developmental stage, and the degree of dependency and autonomy in key relationships. The presence of pre-existing impairment and extant vulnerabilities, such as learning disability and developmental disorders, must also be considered when making the evaluation. The ICD-10, contrary to the DSM-IV, requires the presence of both excessive symptoms and functional impairment for the diagnosis of adjustment disorder, thus narrowing the application of this category. Because of the hierarchical nature of ICD-10 and DSM-IV, adjustment disorder cannot be diagnosed once the criteria for another condition are met. The condition that most frequently trumps adjustment disorder is major depression/depressive episode. This is evident from studies that compare the clinical with the research approach. For example, in a study of those presenting because of self-harm, a clinical diagnosis of adjustment disorder was made in 31.8% and one of major depression in 19.5% of cases, but using SCID the proportions changed to 7.8% and 36.4% respectively 14. However, there is a point of departure between the two conditions when other variables are considered. Suicidal behaviour occurs earlier in the course of adjustment disorder as compared to major depression 41 and the interval from suicidal communication to completion of suicide is shorter 42. The socio-demographic profile and childhood risk variables differ between the two groups 41. Among adolescents dying by suicide, there is much less evidence of prior emotional or behavioural problems 42. In addition, the readmission rates for those with adjustment disorder are significantly lower than for those with major depression, generalized anxiety or dysthymia 43 and hospitalization is also shorter 6. This highlights the need for the clearer operationalization of adjustment disorder in future classifications. A further but lesser area of potential overlap is with post-traumatic stress disorder (PTSD). The conflation is not so much related to the symptoms of these disorders but to the stressors themselves. There has been an expansion in the stressors that are deemed to trigger PTSD, from those that are potentially life threatening, as originally described, to events that are less traumatic, such as financial problems or watching distressing images on television – a phenomenon called “criterion creep” 44. In clinical practice, a diagnosis of PTSD is often made reflexively 45 once such an event is identified, although adjustment disorder might be a more appropriate diagnosis. Overall, it is clear from the data available that adjustment disorder is sufficiently severe and distinct from other disorders, especially major depression, to from its to that of a full-blown and mental disorder. for the DSM-IV have been The Clinical Interview and the International Interview do not adjustment disorder at The for Clinical in do adjustment disorder, but only at the of the in 13, which with and This the criteria for all other disorders have been and there are no specific with to adjustment disorder to the on clinical The SCID also a with adjustment disorder, but the to that this diagnosis is not made if the criteria for any other mental disorder are with the of it to a In of the very threshold for major depression, in studies using SCID and to be of adjustment disorder, major depression will often adjustment disorder, of the context in which the symptoms have The International Interview also a on adjustment disorder as in that disorder is trumped when any other diagnosis is made. So, while have epidemiological research in psychiatry, the that they are having been for use by cannot be This is especially for a diagnosis such as adjustment disorder, which on clinical judgement, context and course than symptoms alone. As a of the problems with the current of diagnostic have been made to for adjustment disorder. Because there is symptom overlap with major depression, there is a that which for depression might people with adjustment disorder. A of have been for this including the Depression which has been to be an for adjustment disorder and major depression but when compared to SCID has and A study of health with an diagnosis but one which the of adjustment disorder most found with the to a using a coping measure have also been The and Depression has been for in cancer patients, but it does not distinguish between major depression and adjustment disorder problems when the Interview and the were for to for adjustment disorder. The of might have a in adjustment disorder from major depression and has been in one study that disorder more symptoms and a to the mood changes compared to disorder of this is Adjustment disorder cannot be diagnosed in the of a stressor. The event must be and in time to the onset of symptoms. The longer the time period between the event and the onset of the less likely is the diagnosis to be adjustment disorder. For this a period between the event and symptom onset of 3 months in DSM-IV and 1 month in ICD-10 is must be when this is for two those who are often significance to that in were in at the in an at may to an of the The 3 month may to be and it is to the empirical data on which this is Concerning the of there is to the in adjustment disorder from major depression. of those with a diagnosis of adjustment disorder have recent life of those with major depression also report such with more related to problems and to occupational or family stressors in the adjustment disorder while significant, are to be clinically in an since they are not as to major depression or adjustment disorder. the events range in severity from those that are as such as a with a to those that are more This will be by In the to the on adjustment disorder, the ICD-10 that and risk plays a than in other such as PTSD or acute stress reactions. However, it is on what evidence this is By contrast, the DSM-IV is on this The that a model is of and is arguably the most There have been studies adjustment disorder against other disorders to allow about the of and is in the current of The relevant studies be classified in two those adjustment disorder and those diagnoses to adjustment disorder. The prevalence of disorder among those with adjustment disorder in to those with other depressive disorders seems to be not although studies are and Among as a to adjustment disorder in a has also been examined, and was found to be a risk for adjustment disorder while was with the severity of the disorder using that a diagnosis of adjustment disorder, such as or depression, are also of although there is a that these conditions may not be to adjustment disorder due to differences in the in the earlier classifications. such study found that the was between and a symptom and evidence of The in relation to and a of symptoms were by in studies of and The of clear criteria for adjustment disorder in DSM-IV or ICD-10 that weight is to clinical than in most other current of anxiety, poor having onset following a recent stressful event are likely of a diagnosis of adjustment disorder, although it must be in that major depression also is often more when the person is with the such as when about while at other times mood is normal and The of the person from the stressful is with a general in symptoms. In the of those who adjustment disorder in response to illness, changes in mood are related to changes in the illness The more the symptoms are loss of mood reactivity the less likely is the diagnosis of adjustment disorder. A family of depression might also a depressive episode. to the symptom threshold for major depression, it is to a diagnosis of this condition than adjustment disorder. the National for Clinical on depression a period of so as to allow for the of under pressure from the patient and or the “to do a diagnosis of major depression (or generalized may be made and also arise when the stressor, and the is and has of may be on as there is no of if the symptoms are likely to or if they are now of the trigger and major depression. The of a response to should the that this is an adjustment disorder, so that are than in of A further is that what to be a stressor (e.g., a diagnosis of a may be with symptoms as of the diagnosis the patient (e.g., the of treatment to that stressors symptoms might to an diagnosis of major depression. The of the consequences of the stressor in symptoms is in the DSM-IV definition of adjustment disorder. on the of adjustment disorder are by DSM-IV and ICD-10 The are broadly similar in the two classifications from adjustment disorder with they have The is the most common in adults, while the with of or of and are more diagnosed among children and The between adjustment disorder and a normal stress response is based on the severity of symptoms and the impact on functioning into account the nature of the stressor; the personal and context in which it has cultural with to such responses. PTSD and acute stress disorder the presence of a stressor of a that would be for almost and the symptom is also although both of these have been 40. not to such events by developing PTSD and the that other disorders follow to be considered. For those not the PTSD diagnostic but with significant symptoms and/or functional adjustment disorder should be considered a possible may to be an adjustment disorder, because of the sub-threshold of the symptoms or the of functional might be an axis I disorder in that only as a a period of the of an diagnosis of adjustment disorder may be at especially if there are symptoms in of of the stressor. studies have the disorders that are with adjustment disorder, an that is by the fact that the criteria for this disorder axis I Yet, a recent study 19 found that almost of patients with major depression or and adjustment disorder were not significantly The between and adjustment disorder is also of since it may the instability of the adjustment disorder diagnosis. may be for of symptoms such as anxiety and depression, which are in adjustment disorder. such as are and may with mood changes to This may in one study 6 patients with an diagnosis of adjustment disorder were on as having a primary diagnosis of The evidence for the treatment of adjustment disorder is due to the of A further problem is that these are so that of may fail to any due to In are as being the most with the exception that, when stressors are measures may be However, there is a for children and adolescents diagnosed with adjustment disorder, since there is evidence that a of adolescents major mental disorders. measures may be to the person in the stressful A person being at work might to an system or may the of the A person in an might a A person on too much work may from family such as social or in a or may distress. or in groups, the range including and symptoms of the of and and the that the stressor has for the might also symptoms. In who engage in self-harm, in that do not may be of and to behaviour has the evidence was found to be of in older patients a including and was in patients with adjustment disorder to was when to patients with adjustment disorder who stress and among with adjustment disorder In a study of cancer patients similar were found in those with adjustment disorder and other psychiatric Some of these have been in specific medically ill groups, such as those with or in coping have been it is if adjustment disorder, were studies (e.g., and and of life than symptoms were the measures in (e.g., The of adjustment disorder of treatment of anxiety and The use of to these is common are by especially if there has been no from there is evidence to Nevertheless, those with and anxiety may have a when are such as in those with a of There are to the treatment of adjustment disorder and these are on with the anxiety A study a with a found that the of were although more to the including from and other and a on symptoms. A study found that and were while a study of cancer patients with and mood found to a study in primary the response of patients with major depression and with adjustment disorder to using reported changes in functional disability based on Overall, the adjustment disorder was as likely to to However, as this was a the of the is study compared and in with adjustment disorder assigned to an a or and found that all significantly Overall, these studies for the of and arguably for any specific in the of adjustment disorder, but further studies are Adjustment disorders are common mental disorders, especially in consultation-liaison prevalence seems to be in children and in they are with significant morbidity and a than in Suicidal behaviour is common in both adolescents and adults with these disorders, and adjustment disorder is the diagnosis in up to one third of young people who die by There are major problems with the diagnostic criteria for adjustment disorder in both ICD-10 and The most of these is the as This has in being the subject of Furthermore, current classifications fail to on these disorders from normal adaptive reactions to and the diagnosis of major depression in people with reactions to for adjustment disorders are although are likely to be the

World Psychiatry · 157 citationsread the source →