Search the source libraries

Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study.

Background: Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety. Methods: In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion of placebo (n=62) or relaxin 10 microg/kg (n=40), 30 microg/kg (n=43), 100 microg/kg (n=39), or 250 microg/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806. Findings: In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 microg/kg per day group, 42 in the relaxin 30 microg/kg per day group, 37 in the relaxin 100 microg/kg per day group, and 49 in the relaxin 250 microg/kg per day group. Dyspnoea improved with relaxin 30 microg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0.044) and visual analogue scale through day 14 (8214 mm x h [SD 8712] vs 4622 mm x h [9003]; p=0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% CI 0.4-16.8] vs 17.2% [9.6-29.6]; p=0.053). The number of serious adverse events was similar between groups. Interpretation: When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety.

Lancet (London, England) · randomised controlled trial · 314 citationsread the source →

Associations between perfectionism and symptoms of anxiety, obsessive-compulsive disorder and depression in young people: a meta-analysis.

Perfectionism is a transdiagnostic process contributing to the onset and maintenance of anxiety, obsessive-compulsive disorder (OCD) and depression. The aim of this systematic review and meta-analysis was to examine the association between perfectionism, and symptoms of anxiety, OCD and depression among young people aged 6-24 years. A systematic literature search retrieved a total of 4,927 articles, with 121 studies included (Mpooled age = ~17.70 years). Perfectionistic concerns demonstrated significant moderate pooled correlations with symptoms of anxiety (r = .37-.41), OCD (r = .42), and depression (r = .40). Perfectionistic strivings demonstrated significant, small correlations with symptoms of anxiety (r = .05) and OCD (r = .19). The findings highlight the substantial link between perfectionistic concerns and psychopathology in young people, and to a smaller extent perfectionistic strivings, anxiety, and OCD. The results indicate the importance of further research on early intervention for perfectionism to improve youth mental health.

Cognitive behaviour therapy · meta-analysis · 22 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 →

COVID-19 pandemic effects on health worker's mental health: Systematic review and meta-analysis.

Background: Healthcare workers (HCWs) exposed to coronavirus 19 (COVID-19) are at high risk of developing mental health concerns across several domains. The aim of this study is to determine the updated, global frequency of these outcomes. Methods: A multistep literature search was performed from database inception until March 1, 2021. PRISMA/MOOSE-compliant systematic review and PROSPERO protocol were used to identify studies reporting on depression, anxiety, acute stress, post-traumatic symptoms, insomnia, and burnout in HCWs exposed to COVID-19. A quantitative meta-analysis with random effects was conducted to analyze the proportion rate of the mental health disorders. Sensitivity analyses were performed to investigate the effect of the different continents and scales. Meta-regression analyses were conducted to examine the effect of gender, age, and work position. Results: 239 articles were included (n = 271,319 HCWs, mean age = 36.08 ± 8.33 (66.99% female). 33% HCWs exposed to COVID-19 reported depressive symptoms (95% confidence intervals [CI] = 28-38%), 42% anxiety features (95% CI = 35-48), 40% acute stress (95% CI = 32-47), 32% post-traumatic symptoms (95% CI = 26-37%), 42% insomnia (95% CI = 36-48), 37% burnout (95% CI = 31-42). Sensitivity analyses did not show statistically significant differences. Meta-regressions found a statistically significant lower prevalence of post-traumatic symptoms in Asia. Conclusions: HCWs exposed to COVID-19 were found to have a significant prevalence of mental health concerns in all domains analyzed. The effects of COVID-19 on HCWs' mental health could be underestimated and the future consequences dismissed.

European psychiatry : the journal of the Association of European Psychiatrists · meta-analysis · 170 citationsread the source →

Group-based compassion-focused therapy for prolonged grief symptoms in adults - Results from a randomized controlled trial.

Prolonged grief disorder is a debilitating condition, which affects approximately one out of ten who lose a loved one. While existing meta-analyses have synthesized evidence regarding the overall effect of psychological interventions for pathological grief across different types of psychotherapy, it remains clinically relevant to explore whether specific types of psychological interventions are efficacious in the treatment of grief. The present study investigated the efficacy of group-based Compassion-Focused Therapy (CFT) for adults who had lost a spouse or a parent, and who reported clinically relevant levels of prolonged grief symptoms (PGS) at 11 months post-loss. A total of 82 participants were randomized to the CFT group (n = 42) or the waitlist control (n = 40). Time × group interactions showed no statistically significant effects of the intervention on the primary outcome PGS at post-intervention or 6-month follow-up. Likewise, no statistically significant effects were found for any of the secondary outcomes or process variables, with the exception of posttraumatic stress symptoms and self-reassurance. Taken together, in the present study group-based CFT did not emerge as an efficacious treatment for PGS. Possible explanations include that CFT may not target core maintaining processes in PGS and that the group-based, 8-week operationalization of CFT may be less than optimal.

Psychiatry research · randomised controlled trial · 11 citationsread the source →

Effects of a program to prevent social isolation on loneliness, depression, and subjective well-being of older adults: a randomized trial among older migrants in Japan.

Social isolation among the elderly is a concern in developed countries. Using a randomized trial, this study examined the effect of a social isolation prevention program on loneliness, depression, and subjective well-being of the elderly in Japan. Among the elderly people who relocated to suburban Tokyo, 63 who responded to a pre-test were randomized and assessed 1 and 6 months after the program. Four sessions of a group-based program were designed to prevent social isolation by improving community knowledge and networking with other participants and community "gatekeepers." The Life Satisfaction Index A (LSI-A), Geriatric Depression Scale (GDS), Ando-Osada-Kodama (AOK) loneliness scale, social support, and other variables were used as outcomes of this study. A linear mixed model was used to compare 20 of the 21 people in the intervention group to 40 of the 42 in the control group, and showed that the intervention program had a significant positive effect on LSI-A, social support, and familiarity with services scores and a significant negative effect on AOK over the study period. The program had no significant effect on depression. The findings of this study suggest that programs aimed at preventing social isolation are effective when they utilize existing community resources, are tailor-made based on the specific needs of the individual, and target people who can share similar experiences.

Archives of gerontology and geriatrics · randomised controlled trial · 102 citationsread the source →

Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis.

Background: Medicinal cannabinoids, including medicinal cannabis and pharmaceutical cannabinoids and their synthetic derivatives, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been suggested to have a therapeutic role in certain mental disorders. We analysed the available evidence to ascertain the effectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders. Methods: For this systematic review and meta-analysis we searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for studies published between Jan 1, 1980, and April 30, 2018. We also searched for unpublished or ongoing studies on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry. We considered all studies examining any type and formulation of a medicinal cannabinoid in adults (≥18 years) for treating depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder, or psychosis, either as the primary condition or secondary to other medical conditions. We placed no restrictions on language, publication status, or study type (ie, both experimental and observational study designs were included). Primary outcomes were remission from and changes in symptoms of these mental disorders. The safety of medicinal cannabinoids for these mental disorders was also examined. Evidence from randomised controlled trials was synthesised as odds ratios (ORs) for disorder remission, adverse events, and withdrawals and as standardised mean differences (SMDs) for change in symptoms, via random-effects meta-analyses. The quality of the evidence was assessed with the Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO (CRD42017059372, CRD42017059373, CRD42017059376, CRD42017064996, and CRD42018102977). Findings: 83 eligible studies (40 randomised controlled trials, n=3067) were included: 42 for depression (23 randomised controlled trials; n=2551), 31 for anxiety (17 randomised controlled trials; n=605), eight for Tourette syndrome (two randomised controlled trials; n=36), three for ADHD (one randomised controlled trial; n=30), 12 for post-traumatic stress disorder (one randomised controlled trial; n=10), and 11 for psychosis (six randomised controlled trials; n=281). Pharmaceutical THC (with or without CBD) improved anxiety symptoms among individuals with other medical conditions (primarily chronic non-cancer pain and multiple sclerosis; SMD -0·25 [95% CI -0·49 to -0·01]; seven studies; n=252), although the evidence GRADE was very low. Pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study (SMD 0·36 [95% CI 0·10 to 0·62]; n=24). Pharmaceutical THC (with or without CBD) did not significantly affect any other primary outcomes for the mental disorders examined but did increase the number of people who had adverse events (OR 1·99 [95% CI 1·20 to 3·29]; ten studies; n=1495) and withdrawals due to adverse events (2·78 [1·59 to 4·86]; 11 studies; n=1621) compared with placebo across all mental disorders examined. Few randomised controlled trials examined the role of pharmaceutical CBD or medicinal cannabis. Interpretation: There is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis. There is very low quality evidence that pharmaceutical THC (with or without CBD) leads to a small improvement in symptoms of anxiety among individuals with other medical conditions. There remains insufficient evidence to provide guidance on the use of cannabinoids for treating mental disorders within a regulatory framework. Further high-quality studies directly examining the effect of cannabinoids on treating mental disorders are needed. Funding: Therapeutic Goods Administration, Australia; Commonwealth Department of Health, Australia; Australian National Health and Medical Research Council; and US National Institutes of Health.

The lancet. Psychiatry · meta-analysis · 309 citationsread the source →

A randomised controlled trial of the effects of mindfulness practice on medical student stress levels

OBJECTIVE: This study aimed to determine whether the practice of mindfulness reduces the level of stress experienced by senior medical students. METHODS: We carried out a multicentre, single-blinded, randomised controlled trial with intention-to-treat analysis in three clinical schools attached to the University of Tasmania, Hobart, Tasmania. Participants included 66 medical students in their final 2 years of study in 2009. Participants were block-randomised to either an intervention or a usual care control group. The intervention used an audio CD of guided mindfulness practice designed and produced for this trial. Participants were advised to use the intervention daily over the 8 weeks of the trial. All participants completed two self-report questionnaires, at baseline and at 8 weeks, respectively. The intervention group also completed a questionnaire at 16 weeks to provide follow-up data. The primary outcome measure was the difference over time in scores on the Perceived Stress Scale (PSS). The secondary outcome measure referred to differences over time in scores on the subscales of the Depression, Anxiety and Stress Scale (DASS). RESULTS: Mean baseline scores on the PSS and the stress component of the DASS were 15.7 (maximal score of 40) and 13.2 (maximal score of 42), respectively, both of which exceed scores in age-matched normative control data. Using multivariable analysis, participants in the intervention group demonstrated significant reductions in scores on the PSS (- 3.44, 95% confidence interval [CI] - 6.20 to - 0.68; p < 0.05) and the anxiety component of the DASS (- 2.82, 95% CI - 4.99 to - 0.64; p < 0.05). A borderline significant effect was demonstrated on the stress component of the DASS (- 3.69, 95% CI - 7.38 to 0.01; p = 0.05). Follow-up at 8 weeks post-trial revealed that the effect was maintained. CONCLUSIONS: Mindfulness practice reduced stress and anxiety in senior medical students. Stress is prevalent in medical students and can have adverse effects on both student health and patients. A simple, self-administered, evidence-based intervention now exists to manage stress in this at-risk population and should be widely utilised.

Medical Education · randomised controlled trial · 316 citationsread the source →

Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation.

Background: In 2009, the U.S. Preventive Services Task Force recommended biennial mammography screening for women aged 50 to 74 years and selective screening for those aged 40 to 49 years. Purpose: To review studies of screening in average-risk women with mammography, magnetic resonance imaging, or ultrasonography that reported on false-positive results, overdiagnosis, anxiety, pain, and radiation exposure. Data sources: MEDLINE and Cochrane databases through December 2014. Study selection: English-language systematic reviews, randomized trials, and observational studies of screening. Data extraction: Investigators extracted and confirmed data from studies and dual-rated study quality. Discrepancies were resolved through consensus. Data synthesis: Based on 2 studies of U.S. data, 10-year cumulative rates of false-positive mammography results and biopsies were higher with annual than biennial screening (61% vs. 42% and 7% vs. 5%, respectively) and for women aged 40 to 49 years, those with dense breasts, and those using combination hormone therapy. Twenty-nine studies using different methods reported overdiagnosis rates of 0% to 54%; rates from randomized trials were 11% to 22%. Women with false-positive results reported more anxiety, distress, and breast cancer-specific worry, although results varied across 80 observational studies. Thirty-nine observational studies indicated that some women reported pain during mammography (1% to 77%); of these, 11% to 46% declined future screening. Models estimated 2 to 11 screening-related deaths from radiation-induced cancer per 100,000 women using digital mammography, depending on age and screening interval. Five observational studies of tomosynthesis and mammography indicated increased biopsies but reduced recalls compared with mammography alone. Limitations: Studies of overdiagnosis were highly heterogeneous, and estimates varied depending on the analytic approach. Studies of anxiety and pain used different outcome measures. Radiation exposure was based on models. Conclusion: False-positive results are common and are higher for annual screening, younger women, and women with dense breasts. Although overdiagnosis, anxiety, pain, and radiation exposure may cause harm, their effects on individual women are difficult to estimate and vary widely. Primary funding source: Agency for Healthcare Research and Quality.

Annals of internal medicine · systematic review · 267 citationsread the source →

A longitudinal, observational study of the features of transitional healthcare associated with better outcomes for young people with long-term conditions.

Background: Most evidence about what works in transitional care comes from small studies in single clinical specialties. We tested the hypothesis that exposures to nine recommended features of transitional healthcare were associated with better outcomes for young people with long-term conditions during transition from child-centred to adult-oriented health services. Methods: This is a longitudinal, observational cohort study in UK secondary care including 374 young people, aged 14-18.9 years at recruitment, with type 1 diabetes (n = 150), cerebral palsy (n = 106) or autism spectrum disorder with an associated mental health problem (n = 118). All were pre-transfer and without significant learning disability. We approached all young people attending five paediatric diabetes centres, all young people with autism spectrum disorder attending four mental health centres, and randomly selected young people from two population-based cerebral palsy registers. Participants received four home research visits, 1 year apart and 274 participants (73%) completed follow-up. Outcome measures were Warwick Edinburgh Mental Wellbeing Scale, Mind the Gap Scale (satisfaction with services), Rotterdam Transition Profile (Participation) and Autonomy in Appointments. Results: Exposure to recommended features was 61% for 'coordinated team', 53% for 'age-banded clinic', 48% for 'holistic life-skills training', 42% for 'promotion of health self-efficacy', 40% for 'meeting the adult team before transfer', 34% for 'appropriate parent involvement' and less than 30% for 'written transition plan', 'key worker' and 'transition manager for clinical team'. Three features were strongly associated with improved outcomes. (1) 'Appropriate parent involvement', example association with Wellbeing (b = 4.5, 95% CI 2.0-7.0, p = 0.001); (2) 'Promotion of health self-efficacy', example association with Satisfaction with Services (b = - 0.5, 95% CI - 0.9 to - 0.2, p = 0.006); (3) 'Meeting the adult team before transfer', example associations with Participation (arranging services and aids) (odds ratio 5.2, 95% CI 2.1-12.8, p < 0.001) and with Autonomy in Appointments (average 1.7 points higher, 95% CI 0.8-2.6, p < 0.001). There was slightly less recruitment of participants from areas with greater socioeconomic deprivation, though not with respect to family composition. Conclusions: Three features of transitional care were associated with improved outcomes. Results are likely to be generalisable because participants had three very different conditions, attending services at many UK sites. Results are relevant for clinicians as well as for commissioners and managers of health services. The challenge of introducing these three features across child and adult healthcare services, and the effects of doing so, should be assessed.

BMC medicine · cohort or longitudinal · 94 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 →

Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil.

Background: Breastfeeding has clear short-term benefits, but its long-term consequences on human capital are yet to be established. We aimed to assess whether breastfeeding duration was associated with intelligence quotient (IQ), years of schooling, and income at the age of 30 years, in a setting where no strong social patterning of breastfeeding exists. Methods: A prospective, population-based birth cohort study of neonates was launched in 1982 in Pelotas, Brazil. Information about breastfeeding was recorded in early childhood. At 30 years of age, we studied the IQ (Wechsler Adult Intelligence Scale, 3rd version), educational attainment, and income of the participants. For the analyses, we used multiple linear regression with adjustment for ten confounding variables and the G-formula. Findings: From June 4, 2012, to Feb 28, 2013, of the 5914 neonates enrolled, information about IQ and breastfeeding duration was available for 3493 participants. In the crude and adjusted analyses, the durations of total breastfeeding and predominant breastfeeding (breastfeeding as the main form of nutrition with some other foods) were positively associated with IQ, educational attainment, and income. We identified dose-response associations with breastfeeding duration for IQ and educational attainment. In the confounder-adjusted analysis, participants who were breastfed for 12 months or more had higher IQ scores (difference of 3·76 points, 95% CI 2·20-5·33), more years of education (0·91 years, 0·42-1·40), and higher monthly incomes (341·0 Brazilian reals, 93·8-588·3) than did those who were breastfed for less than 1 month. The results of our mediation analysis suggested that IQ was responsible for 72% of the effect on income. Interpretation: Breastfeeding is associated with improved performance in intelligence tests 30 years later, and might have an important effect in real life, by increasing educational attainment and income in adulthood. Funding: Wellcome Trust, International Development Research Center (Canada), CNPq, FAPERGS, and the Brazilian Ministry of Health.

The Lancet. Global health · 382 citationsread the source →

Supported Employment for Veterans With Traumatic Brain Injury: Patient Perspectives.

Objectives: To quantify the need for, and interest in, supported employment (SE) among recent military veterans with traumatic brain injury (TBI); and to examine characteristics associated with veterans' interest in SE. Design: Stratified random sample of Iraq and Afghanistan War veterans confirmed to have TBI through the Veterans Health Administration (VHA) screening and evaluation system. Setting: Community-based via mailed survey. Participants: We recruited 1800 veterans with clinician-confirmed TBI (mild TBI: n=1080; moderate/severe TBI: n=720) through multiple mailings. Among 1451 surveys that were not returned undeliverable, N=616 (42%) responded. Interventions: Not applicable. Main outcome measures: Veterans rated their interest in SE after reading a script describing the program. Additional measures assessed mental health and pain-related comorbidities, employment, financial/housing difficulties, demographics, and military service characteristics. Estimates were weighted to represent the population of veterans with VHA clinician-confirmed TBI. Results: Unemployment was reported by 45% (95% confidence interval [CI], 43-47) of veterans with TBI. Although 42% (95% CI, 40-44) reported they would be interested in using SE if it were offered to them, only 12% had heard of SE (95% CI, 11-14) and <1% had used it. TBI severity and comorbidities were not associated with veterans' interest in SE. However, those who were unemployed, looking for work, experiencing financial strain, or at risk for homelessness were more likely to be interested in SE. Conclusions: Our research highlights an important gap between veterans' vocational needs and interests and their use of SE. Systematically identifying and referring those with employment and financial/housing difficulties may help close this gap.

Archives of physical medicine and rehabilitation · 20 citationsread the source →

Focused psychosocial interventions for children in low-resource humanitarian settings: a systematic review and individual participant data meta-analysis.

Background: Results from studies evaluating the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in humanitarian settings in low-income and middle-income countries have been inconsistent, showing varying results by setting and subgroup (eg, age or gender). We aimed to assess the effectiveness of these interventions, and to explore which children are likely to benefit most. Methods: We did a systematic review and meta-analysis of individual participant data (IPD) from 3143 children recruited to 11 randomised controlled trials of focused psychosocial support interventions versus waiting list. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, PsycArticles, Web of Science, and the main local low-income and middle-income countries (LMICs) databases according to the list of databases relevant to LMIC developed collaboratively by Cochrane and WHO Library, up to November, 2016. We included randomised controlled trials that assessed the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in LMICs, compared with waiting lists (eg, inactive controls). We excluded quasi-randomised trials, studies that did not focus on psychosocial support interventions, and studies that compared two active interventions without control conditions. We requested anonymised data from each trial for each of the prespecified variables for each child who was randomly assigned. The main outcomes considered were continuous scores in post-traumatic stress disorder (PTSD) symptoms, depressive symptoms, and anxiety symptoms assessed with rating scales administered immediately (0-4 weeks) after the intervention. We harmonised all individual items from rating scales using item response theory methods. This study is registered with PROSPERO, number CRD42013006960. Findings: We identified a beneficial effect of focused psychosocial support interventions on PTSD symptoms (standardised mean difference [SMD] -0·33, 95% CI -0·52 to -0·14) that was maintained at follow-up (-0·21, -0·42 to -0·01). We also identified benefits at the endpoint for functional impairment (-0·29, -0·43 to -0·15) and for strengths: coping (-0·22, -0·43 to -0·02), hope (-0·29, -0·48 to -0·09), and social support (-0·27, -0·52 to -0·02). In IPD meta-analyses focused on age, gender, displacement status, region, and household size we found a stronger improvement in PTSD symptoms in children aged 15-18 years (-0·43, -0·63 to -0·23), in non-displaced children (-0·40, -0·52 to -0·27), and in children living in smaller households (<6 members; -0·27, -0·42 to -0·11). Interpretation: Overall, focused psychosocial interventions are effective in reducing PTSD and functional impairment, and in increasing hope, coping, and social support. Future studies should focus on strengthening interventions for younger children, displaced children, and children living in larger households. Funding: European Commission FP7th Framework Programme for Research (Marie Curie International Outgoing Fellowship) and the National Institute on Aging.

The Lancet. Global health · meta-analysis · 99 citationsread the source →

Predicting general and cancer-related distress in women with newly diagnosed breast cancer.

Background: Psychological distress can impact medical outcomes such as recovery from surgery and experience of side effects during treatment. Identifying the factors that explain variability in distress would guide future interventions aimed at decreasing distress. Two factors that have been implicated in distress are illness perceptions and coping, and are part of the Self-Regulatory Model of Illness Behaviour (SRM). The model suggests that coping mediates the relationship between illness perceptions and distress. Despite this; very little research has assessed this relationship with cancer-related distress, and none have examined women with screen-detected breast cancer. This study is the first to examine the relative contribution of illness perceptions and coping on general and cancer-related distress in women with screen-detected breast cancer. Methods: Women recently diagnosed with breast cancer (N = 94) who had yet to receive treatment completed measures of illness perceptions (Revised Illness Perception Questionnaire), cancer-specific coping (Mental Adjustment to Cancer Scale), general anxiety and depression (Hospital Anxiety and Depression scale), and cancer-related distress. Results: Hierarchical regression analyses revealed that medical variables, illness perceptions and coping predicted 50% of the variance in depression, 42% in general anxiety, and 40% in cancer-related distress. Believing in more emotional causes to breast cancer (β = .22, p = .021), more illness identity (β = .25, p = .004), greater anxious preoccupation (β = .23, p = .030), and less fighting spirit (β = -.31, p = .001) predicted greater depression. Greater illness coherence predicted less cancer-related distress (β = -.20, p = .043). Greater anxious preoccupation also led to greater general anxiety (β = .44, p < .001) and cancer-related distress (β = .37, p = .001). Mediation analyses revealed that holding greater beliefs in a chronic timeline, more severe consequences, greater illness identity and less illness coherence increases cancer-specific distress (ps < .001) only if women were also more anxiously preoccupied with their diagnosis. Conclusions: Screening women for anxious preoccupation may help identify women with screen-detected breast cancer at risk of experiencing high levels of cancer-related distress; whilst illness perceptions and coping could be targeted for use in future interventions to reduce distress.

BMC cancer · 28 citationsread the source →

Breaking the cycle of loneliness: A randomized controlled trial of the anti-inflammatory naproxen in lonely, middle-aged adults.

Background: Loneliness poses a major public health concern linked to many adverse health outcomes. One proposed pathway linking loneliness to poor health is inflammation, and there is growing evidence of a bidirectional relationship between the two. Additionally, both chronic loneliness and inflammation are associated with similar negative psychological consequences, such as heightened social threat sensitivity and negative cognitive biases. Given the relationship between loneliness and inflammation, it is possible that reducing inflammation may reduce loneliness and the negative psychological processes associated with it. Thus, this study investigated the effects of a non-steroidal inflammatory drug (NSAID) on loneliness, inflammatory activity, depressive and anhedonic symptoms, and affect during a social interaction. Methods: A parallel group randomized controlled trial examined the effect of an NSAID (naproxen) in a sample of highly lonely, healthy middle-aged adults. Participants took naproxen (400 mg; n=40 analyzed) or placebo (n=42 analyzed) daily for 2 weeks, completing a baseline, post-intervention, and follow-up session (2 weeks post-intervention). Participants reported on loneliness, depressive, and anhedonic symptoms at all three timepoints. Additionally, at baseline and post-intervention, participants provided a blood sample to assess inflammatory gene expression and completed a social interaction task to explore affective and affiliative behaviors in response to a conversation. Results: There were no significant treatment by time effects on any of the outcomes, except for inflammatory gene expression, which decreased in the naproxen-treated group. However, baseline perceived stress levels moderated treatment effects for several outcomes. Those with the highest baseline stress reported reductions in loneliness and anhedonia in the naproxen group. Similarly, during the social interaction task, those with higher baseline stress showed reduced negative affect and increased social approach behavior in the naproxen group. Surprisingly, those with lower baseline stress reported increases in loneliness and marginal increases in anhedonia in the naproxen-treated group. All observed effects were maintained 2-weeks after the intervention period. Conclusion: The observed relationships suggest that naproxen may benefit highly lonely individuals with concurrent elevated levels of perceived stress.

Brain, behavior, and immunityread the source →

Absence of association between maternal adverse events and long-term gut microbiome outcomes in the Australian autism biobank.

Introduction: Maternal immune activation (MIA) and prenatal maternal stress (MatS) are well-studied risk factors for psychiatric conditions such as autism and schizophrenia. Animal studies have proposed the gut microbiome as a mechanism underlying this association and have found that risk factor-related gut microbiome alterations persist in the adult offspring. In this cross-sectional study, we assessed whether maternal immune activation and prenatal maternal stress were associated with long-term gut microbiome alterations in children using shotgun metagenomics. Methods: This cross-sectional study included children diagnosed with autism (N = 92), siblings without a diagnosis (N = 42), and unrelated children (N = 40) without a diagnosis who were recruited into the Australian Autism Biobank and provided a faecal sample. MIA exposure was inferred from self-reported data and included asthma/allergies, complications during pregnancy triggering an immune response, auto-immune conditions, and acute inflammation. Maternal stress included any of up to 9 stressful life events during pregnancy, such as divorce, job loss, and money problems. Data were analysed for a total of 174 children, of whom 63 (36%) were born to mothers with MIA and 84 (48%) were born to mothers who experienced maternal stress during pregnancy (where 33 [19%] experienced both). Gut microbiome data was assessed using shotgun metagenomic sequencing of the children's faecal samples. Results: In our cohort, MIA, but not MatS, was associated with ASD. Variance component analysis revealed no associations between any of the gut microbiome datasets and neither MIA nor MatS. After adjusting for age, sex, diet and autism diagnosis, there was no significant difference between groups for bacterial richness, α-diversity or β-diversity. We found no significant differences in species abundance in the main analyses. However, when stratifying the cohort by age, we found that Faecalibacterium prausnitzii E was significantly decreased in MIA children aged 11-17. Discussion: Consistent with previous findings, we found that children who were born to mothers with MIA were more likely to be diagnosed with autism. Unlike within animal studies, we found negligible microbiome differences associated with MIA and maternal stress. Given the current interest in the microbiome-gut-brain axis, researchers should exercise caution in translating microbiome findings from animal models to human contexts and the clinical setting.

Brain, behavior, & immunity - health · 3 citationsread the source →

Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections: a systematic review and meta-analysis with comparison to the COVID-19 pandemic.

Background: Before the COVID-19 pandemic, coronaviruses caused two noteworthy outbreaks: severe acute respiratory syndrome (SARS), starting in 2002, and Middle East respiratory syndrome (MERS), starting in 2012. We aimed to assess the psychiatric and neuropsychiatric presentations of SARS, MERS, and COVID-19. Methods: In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature databases (from their inception until March 18, 2020), and medRxiv, bioRxiv, and PsyArXiv (between Jan 1, 2020, and April 10, 2020) were searched by two independent researchers for all English-language studies or preprints reporting data on the psychiatric and neuropsychiatric presentations of individuals with suspected or laboratory-confirmed coronavirus infection (SARS coronavirus, MERS coronavirus, or SARS coronavirus 2). We excluded studies limited to neurological complications without specified neuropsychiatric presentations and those investigating the indirect effects of coronavirus infections on the mental health of people who are not infected, such as those mediated through physical distancing measures such as self-isolation or quarantine. Outcomes were psychiatric signs or symptoms; symptom severity; diagnoses based on ICD-10, DSM-IV, or the Chinese Classification of Mental Disorders (third edition) or psychometric scales; quality of life; and employment. Both the systematic review and the meta-analysis stratified outcomes across illness stages (acute vs post-illness) for SARS and MERS. We used a random-effects model for the meta-analysis, and the meta-analytical effect size was prevalence for relevant outcomes, I2 statistics, and assessment of study quality. Findings: 1963 studies and 87 preprints were identified by the systematic search, of which 65 peer-reviewed studies and seven preprints met inclusion criteria. The number of coronavirus cases of the included studies was 3559, ranging from 1 to 997, and the mean age of participants in studies ranged from 12·2 years (SD 4·1) to 68·0 years (single case report). Studies were from China, Hong Kong, South Korea, Canada, Saudi Arabia, France, Japan, Singapore, the UK, and the USA. Follow-up time for the post-illness studies varied between 60 days and 12 years. The systematic review revealed that during the acute illness, common symptoms among patients admitted to hospital for SARS or MERS included confusion (36 [27·9%; 95% CI 20·5-36·0] of 129 patients), depressed mood (42 [32·6%; 24·7-40·9] of 129), anxiety (46 [35·7%; 27·6-44·2] of 129), impaired memory (44 [34·1%; 26·2-42·5] of 129), and insomnia (54 [41·9%; 22·5-50·5] of 129). Steroid-induced mania and psychosis were reported in 13 (0·7%) of 1744 patients with SARS in the acute stage in one study. In the post-illness stage, depressed mood (35 [10·5%; 95% CI 7·5-14·1] of 332 patients), insomnia (34 [12·1%; 8·6-16·3] of 280), anxiety (21 [12·3%; 7·7-17·7] of 171), irritability (28 [12·8%; 8·7-17·6] of 218), memory impairment (44 [18·9%; 14·1-24·2] of 233), fatigue (61 [19·3%; 15·1-23·9] of 316), and in one study traumatic memories (55 [30·4%; 23·9-37·3] of 181) and sleep disorder (14 [100·0%; 88·0-100·0] of 14) were frequently reported. The meta-analysis indicated that in the post-illness stage the point prevalence of post-traumatic stress disorder was 32·2% (95% CI 23·7-42·0; 121 of 402 cases from four studies), that of depression was 14·9% (12·1-18·2; 77 of 517 cases from five studies), and that of anxiety disorders was 14·8% (11·1-19·4; 42 of 284 cases from three studies). 446 (76·9%; 95% CI 68·1-84·6) of 580 patients from six studies had returned to work at a mean follow-up time of 35·3 months (SD 40·1). When data for patients with COVID-19 were examined (including preprint data), there was evidence for delirium (confusion in 26 [65%] of 40 intensive care unit patients and agitation in 40 [69%] of 58 intensive care unit patients in one study, and altered consciousness in 17 [21%] of 82 patients who subsequently died in another study). At discharge, 15 (33%) of 45 patients with COVID-19 who were assessed had a dysexecutive syndrome in one study. At the time of writing, there were two reports of hypoxic encephalopathy and one report of encephalitis. 68 (94%) of the 72 studies were of either low or medium quality. Interpretation: If infection with SARS-CoV-2 follows a similar course to that with SARS-CoV or MERS-CoV, most patients should recover without experiencing mental illness. SARS-CoV-2 might cause delirium in a significant proportion of patients in the acute stage. Clinicians should be aware of the possibility of depression, anxiety, fatigue, post-traumatic stress disorder, and rarer neuropsychiatric syndromes in the longer term. Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), UK Medical Research Council, NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London.

The lancet. Psychiatry · meta-analysis · 1531 citationsread the source →

A meta-analysis of disordered eating and its association with self-criticism and self-compassion.

Objective: Future treatments for eating disorders (ED) need to be enhanced by targeting maintaining mechanisms. Literature suggests self-criticism and self-critical perfectionism act as key mechanisms exacerbating ED, and self-compassion protects against self-criticism. This meta-analysis examines associations between self-criticism and self-critical perfectionism on disordered eating (DE), and reviews how self-compassion and self-criticism relate to each other with respect to DE. Method: Searches across three databases yielded 135 studies across 42,952 participants. Heterogeneity, publication bias, and quality assessments were analyzed. Moderation analyses between self-criticism measures, self-compassion measures, between clinical and nonclinical samples, and between cross-sectional and experimental studies were also conducted. Results: Random-effects models showed a medium positive link between self-criticism and DE (r = .37), and 10 subgroups pertaining to various measures of self-criticism utilized in literature showed small to large positive links with DE (r = .20-.52). Preliminary evidence also suggests negative relationships between self-compassion and DE (r = -.40 to -.43) and negative relationships between self-compassion and self-criticism (r = -.04 to -.88). Discussion: Greater levels of self-criticism is linked with greater levels of DE and reduced levels of self-compassion, suggesting a need to tackle self-criticism and nurture self-compassion in standard treatments for ED. Understanding these interactions better in conjunction with dismantling intervention studies can help develop more effective and efficient interventions targeting self-criticism and self-compassion for people with DE. Public significance statement: Higher levels of self-criticism are linked with higher levels of DE and lower self-compassion. Self-compassion interventions could be more effective and efficient in reducing ED symptoms if self-criticism is tackled early in such treatments.

The International journal of eating disorders · meta-analysis · 22 citationsread the source →

Pregabalin abuse and dependence in Germany: results from a database query.

Purpose: Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures and generalised anxiety disorder in many countries and currently under study for other indications. Supported by case reports and the results of a limited number of studies there is an ongoing debate on the potential of PRG to cause addictive behaviours. However, currently available evidence on this issue is sparse, and any definitive assessment of PRG's potential for abuse and dependence is not yet in sight. The aim of our study was to identify the number of cases of PRG abuse or dependence reported to the database of a German medical regulatory body and to obtain insights into further usage-specific parameters. Methods: We conducted a query of the entire database of the German Federal Institute for Drugs and Medical Devices (BfArM) regarding reports of PRG abuse or dependence and analysed these cases on the basis of several parameters. Results: A total of 55 reports of PRG abuse or dependence were identified (mean age 36 years, 64 % of reports involved males). The first reports were submitted to BfArM in 2008, and the reporting frequency has increased up to the present. Mean daily PRG dosage was 1424 mg. Current or previous polytoxicomania was present in 40 and 42 % of cases, respectively. Psychiatric diagnoses other than substance-related disorders were reported in 13 (24 %) cases. In about one-third of the patients withdrawal syndromes subsequent to discontinuation of PRG were reported. Conclusions: Cases of PRG abuse or dependence have been reported to the BfArM since 2008, with a marked increase of such reports in subsequent years. Male sex and a history of polytoxicomania may be possible risk factors for the development of addictive behaviours related to PRG.

European journal of clinical pharmacology · 74 citationsread the source →

Neighborhood safety, collective efficacy, and obesity in women with young children.

Objective: To test the hypothesis that mothers of young children would have a higher prevalence of obesity if they lived in neighborhoods that they perceived as unsafe or as having a low level of collective efficacy. Research methods and procedures: Using data from the Fragile Families and Child Wellbeing Study, a cross-sectional analysis was conducted of 2445 women living in 20 large (population > or = 200,000) U.S. cities. BMI was measured on 72% and self-reported on 28%. Perception of neighborhood safety was assessed with the Neighborhood Environment for Children Rating Scales. The collective efficacy measure was adapted from the Project on Human Development in Chicago Neighborhoods. Results: Thirty percent of the women were married, 38% lived below the U.S. poverty threshold, and 66% reported no education beyond high school. Approximately one-half of the women were non-Hispanic black, and one-fourth were Hispanic (any race). After adjustment for sociodemographic factors (household income, education, race/ethnicity, age, and marital status), smoking, depression, and television time, the prevalence of obesity (BMI > or = 30 kg/m2) increased across tertiles of neighborhood safety from safest to least safe (37% vs. 41% vs. 46%, p = 0.004) but did not differ across tertiles of collective efficacy from highest to lowest (41% vs. 40% vs. 42%, p = 0.67). Discussion: In a national sample of women with young children, obesity was more prevalent among those who perceived their neighborhoods to be unsafe.

Obesity (Silver Spring, Md.) · 85 citationsread the source →

Efficacy and cost-effectiveness of therapist-guided internet cognitive behavioural therapy for paediatric anxiety disorders: a single-centre, single-blind, randomised controlled trial.

Background: Paediatric anxiety disorders are associated with substantial disability and long-term adverse consequences, but only a small proportion of affected children have access to evidence-based treatment. Internet-delivered cognitive behavioural therapy (ICBT) could help increase accessibility but needs further rigorous assessment. We aimed to assess the efficacy and cost-effectiveness of ICBT in the treatment of paediatric anxiety disorders. Methods: We did a single-blind randomised controlled trial in a clinical research unit within the Child and Adolescent Mental Health Services in Stockholm (Sweden). Eligible participants were children aged 8-12 years with a diagnosis of a principal anxiety disorder (seperation anxiety disorder, generalised anxiety disorder, specific phobia, social anxiety disorder, or panic disorder) of at least moderate severity. We randomly allocated participants (1:1) to ICBT or internet-delivered child-directed play, an active comparator aimed to improve parent-child relationships and increase a child's self-esteem without directly targeting anxiety. Block sizes for the randomisation varied between four and six and were generated using a computer random-number generator, and the allocation was concealed from the researchers by opaque sealed envelopes. Both treatment programmes comprised 12 modules presented over 12 weeks with weekly asynchronous online therapist support, and consisted of texts, films, illustrations, and exercises. The primary outcome was severity rating of the principal anxiety disorder 12-weeks post-treatment, via the Anxiety Disorder Interview Schedule for Diagnostic and Statistical Manual of Mental Disorders-IV (a rating of at least 4 corresponds to meeting the criteria for the principal diagnosis), assessed by clinicians masked to treatment allocation. All participants were included in the primary analysis (intention-to-treat). This trial is registered at ClinicalTrials.gov, number NCT02350257. Findings: Between March 11, 2015, and Oct 21, 2016, 131 participants were recruited and allocated to either ICBT (n=66) or internet-delivered child-directed play (n=65). The clinician-assessed severity rating of the principal anxiety disorder improved significantly after the 12-weeks treatment period for participants in both ICBT (within-group effect size 1·22, 95% CI 0·78-1·65) and the active control (0·72, 0·44-1·00) groups. However, greater improvement was seen with ICBT than with the active control (estimated mean difference 0·79, 95% CI 0·42-1·16, p=0·002; between-group effect size 0·77, 95% CI 0·40-1·15). 29 (48%) participants in the ICBT group no longer had their principal diagnosis, compared to nine (15%) in the active control group (odds ratio 5·41, 95% CI 2·26 to 12·90, p<0·0001); the number needed to treat for ICBT to gain one additional participant in remission was three (95% CI 2·85 to 3·15). ICBT resulted in an average societal-cost saving of €493·05 (95% CI 477·17 to 508·92) per participant. No severe adverse events were reported. Interpretation: ICBT is an efficacious and cost-effective treatment for paediatric anxiety disorders that should be considered for implementation in routine clinical care. Funding: The Swedish Research Council for Health, Working Life and Welfare, and Stockholm County Council.

The Lancet. Child & adolescent health · randomised controlled trial · 51 citationsread the source →

Effectiveness of paediatric occupational therapy for children with disabilities: A systematic review.

Introduction: Paediatric occupational therapy seeks to improve children's engagement and participation in life roles. A wide variety of intervention approaches exist. Our aim was to summarise the best-available intervention evidence for children with disabilities, to assist families and therapists choose effective care. Methods: We conducted a systematic review (SR) using the Cochrane methodology, and reported findings according to PRISMA. CINAHL, Cochrane Library, MEDLINE, OTSeeker, PEDro, PsycINFO were searched. Two independent reviewers: (i) determined whether studies met inclusion: SR or randomised controlled trial (RCT); an occupational therapy intervention for children with a disability; (ii) categorised interventions based on name, core components and diagnostic population; (iii) rated quality of evidence and determined the strength of recommendation using GRADE criteria; and (iv) made recommendations using the Evidence Alert Traffic Light System. Results: 129 articles met inclusion (n = 75 (58%) SRs; n = 54 (42%)) RCTs, measuring the effectiveness of 52 interventions, across 22 diagnoses, enabling analysis of 135 intervention indications. Thirty percent of the indications assessed (n = 40/135) were graded 'do it' (Green Go); 56% (75/135) 'probably do it' (Yellow Measure); 10% (n = 14/135) 'probably don't do it' (Yellow Measure); and 4% (n = 6/135) 'don't do it' (Red Stop). Green lights were: Behavioural Interventions; Bimanual; Coaching; Cognitive Cog-Fun & CAPS; CO-OP; CIMT; CIMT plus Bimanual; Context-Focused; Ditto; Early Intervention (ABA, Developmental Care); Family Centred Care; Feeding interventions; Goal Directed Training; Handwriting Task-Specific Practice; Home Programs; Joint Attention; Mental Health Interventions; occupational therapy after toxin; Kinesiotape; Pain Management; Parent Education; PECS; Positioning; Pressure Care; Social Skills Training; Treadmill Training and Weight Loss 'Mighty Moves'. Conclusion: Evidence supports 40 intervention indications, with the greatest number at the activities-level of the International Classification of Function. Yellow light interventions should be accompanied by a sensitive outcome measure to monitor progress and red light interventions could be discontinued because effective alternatives existed.

Australian occupational therapy journal · systematic review · 163 citationsread the source →

Emergence and rapid regional spread of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae.

Unlabelled: Exposure network analysis and molecular epidemiologic methods were used to analyze the emergence and regional spread of Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae over a 1-year period. Although 40 patients and 26 health care facilities were affected, 1 long-term acute care hospital played a critical role in the convergence of patients at high risk, amplification by cross-infection, and dissemination of these multidrug-resistant bacteria. Background: Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are an emerging antibiotic resistance threat with demonstrated epidemic potential. Methods: We conducted an outbreak investigation of KPC-producing Enterobacteriaceae among patients of acute and long-term acute care hospitals (LTACHs) in 4 adjacent counties in Indiana and Illinois from 1 January 2008 through 31 December 2008 (cases). The study used traditional and molecular epidemiologic methods and an adaptation of social network analysis ("exposure network analysis"). Results: Clinical records for 40 (95%) of 42 patients were available. Patients were mostly older with multiple comorbid conditions. Eleven patients (27.5%) died during the index hospitalization or were discharged to hospice; 23 (57.5%) were discharged to a nursing home, and 4 (10.0%) were discharged to home. One LTACH (LTACH-A) was central to the regional outbreak: 24 (60%) of 40 cases were linked to LTACH-A, and at least 10 patients (25%) acquired KPC there. Of 16 cases not linked to LTACH-A, 12 (75%) were linked to 3 nursing homes. Only 4 patients (10%) definitely acquired KPC during an acute care hospital stay. Molecular typing revealed the 31 available KPC-positive K. pneumoniae isolates to be similar and to cluster with epidemic multilocus sequence type 258; 2 KPC-positive Escherichia coli isolates were unique. Conclusions: We observed extensive transfer of KPC-positive patients throughout the exposure network of 14 acute care hospitals, 2 LTACHs, and 10 nursing homes. Although few cases were identified at most institutions, many facilities were affected. Successful control of KPC-producing Enterobacteriaceae will require a coordinated, regional effort among acute and long-term health care facilities and public health departments.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America · 176 citationsread the source →

Psychopathology among offspring of parents with schizophrenia: relationship to premorbid impairments.

Introduction: A broad range of psychopathology, including externalizing disorders is seen in offspring at genetic risk for schizophrenia. However, it is unclear whether such psychopathology may underlie a higher predisposition to the premorbid antecedents of schizophrenia. We examined the prevalence and correlates of psychopathology in an ongoing study of offspring genetically at risk for schizophrenia. Methods: Seventy five consenting high risk offspring (HR: offspring, age 15.68+/-3.27 years; male/female 34/41) and 82 matched comparison subjects (40 males and 42 females; age 15.92+/-3.0 years) participated in this study. Diagnoses were ascertained using structured psychiatric interviews and consensus meetings, including all available clinical information. Results: Sixty (60%) of the HR offspring had one or more lifetime diagnosis of axis I psychiatric disorder. HR subjects with axis I psychopathology had significantly more soft neurological signs, poorer premorbid adjustment, and higher schizotypy scores as measured by Chapman psychosis proneness scales. Among those with psychopathology, HR subjects with externalizing disorders showed the most abnormal scores in schizotypy. Discussion: A substantial proportion of HR offspring of parents with schizophrenia manifest a broad range of childhood psychiatric disorders. Psychopathology, especially externalizing disorders such as attention deficit hyperactivity disorder (ADHD) may represent a subgroup with an increased risk for schizophrenia spectrum disorders. This possibility needs to be examined by prospective follow-up studies, and would be of considerable importance to early diagnosis and intervention efforts in schizophrenia.

Schizophrenia research · 87 citationsread the source →

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study.

Background: Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. Methods: SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40-65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed. Findings: Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean -1·87 [SE 0·42; p<0·001], -2·07 [SE 0·42; p<0·001]) and week 12 (-2·39 [SE 0·44; p<0·001], -2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (-0·15 [0·06; p=0·012], -0·19 [0·06; p=0·002]) and week 12 (-0·24 [0·08; p=0·002], -0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation. Interpretation: Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. Funding: Astellas Pharma.

Lancet (London, England) · randomised controlled trial · 172 citationsread the source →

The UK Lung Cancer Screening Trial: a pilot randomised controlled trial of low-dose computed tomography screening for the early detection of lung cancer.

Background: Lung cancer kills more people than any other cancer in the UK (5-year survival < 13%). Early diagnosis can save lives. The USA-based National Lung Cancer Screening Trial reported a 20% relative reduction in lung cancer mortality and 6.7% all-cause mortality in low-dose computed tomography (LDCT)-screened subjects. Objectives: To (1) analyse LDCT lung cancer screening in a high-risk UK population, determine optimum recruitment, screening, reading and care pathway strategies; and (2) assess the psychological consequences and the health-economic implications of screening. Design: A pilot randomised controlled trial comparing intervention with usual care. A population-based risk questionnaire identified individuals who were at high risk of developing lung cancer (≥ 5% over 5 years). Setting: Thoracic centres with expertise in lung cancer imaging, respiratory medicine, pathology and surgery: Liverpool Heart & Chest Hospital, Merseyside, and Papworth Hospital, Cambridgeshire. Participants: Individuals aged 50-75 years, at high risk of lung cancer, in the primary care trusts adjacent to the centres. Interventions: A thoracic LDCT scan. Follow-up computed tomography (CT) scans as per protocol. Referral to multidisciplinary team clinics was determined by nodule size criteria. Main outcome measures: Population-based recruitment based on risk stratification; management of the trial through web-based database; optimal characteristics of CT scan readers (radiologists vs. radiographers); characterisation of CT-detected nodules utilising volumetric analysis; prevalence of lung cancer at baseline; sociodemographic factors affecting participation; psychosocial measures (cancer distress, anxiety, depression, decision satisfaction); and cost-effectiveness modelling. Results: A total of 247,354 individuals were approached to take part in the trial; 30.7% responded positively to the screening invitation. Recruitment of participants resulted in 2028 in the CT arm and 2027 in the control arm. A total of 1994 participants underwent CT scanning: 42 participants (2.1%) were diagnosed with lung cancer; 36 out of 42 (85.7%) of the screen-detected cancers were identified as stage 1 or 2, and 35 (83.3%) underwent surgical resection as their primary treatment. Lung cancer was more common in the lowest socioeconomic group. Short-term adverse psychosocial consequences were observed in participants who were randomised to the intervention arm and in those who had a major lung abnormality detected, but these differences were modest and temporary. Rollout of screening as a service or design of a full trial would need to address issues of outreach. The health-economic analysis suggests that the intervention could be cost-effective but this needs to be confirmed using data on actual lung cancer mortality. Conclusions: The UK Lung Cancer Screening (UKLS) pilot was successfully undertaken with 4055 randomised individuals. The data from the UKLS provide evidence that adds to existing data to suggest that lung cancer screening in the UK could potentially be implemented in the 60-75 years age group, selected via the Liverpool Lung Project risk model version 2 and using CT volumetry-based management protocols. Future work: The UKLS data will be pooled with the NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek: Dutch-Belgian Randomised Lung Cancer Screening Trial) and other European Union trials in 2017 which will provide European mortality and cost-effectiveness data. For now, there is a clear need for mortality results from other trials and further research to identify optimal methods of implementation and delivery. Strategies for increasing uptake and providing support for underserved groups will be key to implementation. Trial registration: Current Controlled Trials ISRCTN78513845. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 40. See the NIHR Journals Library website for further project information.

Health technology assessment (Winchester, England) · randomised controlled trial · 206 citationsread the source →

Laparoscopic ileocaecal resection versus infliximab for terminal ileitis in Crohn's disease: a randomised controlled, open-label, multicentre trial.

Background: Treatment of patients with ileocaecal Crohn's disease who have not responded to conventional therapy is commonly scaled up to biological agents, but surgery can also offer excellent short-term and long-term results. We compared laparoscopic ileocaecal resection with infliximab to assess how they affect health-related quality of life. Methods: In this randomised controlled, open-label trial, in 29 teaching hospitals and tertiary care centres in the Netherlands and the UK, adults with non-stricturing, ileocaecal Crohn's disease, in whom conventional therapy has failed were randomly allocated (1:1) by an internet randomisation module with biased-coin minimisation for participating centres and perianal fistula to receive laparoscopic ileocaecal resection or infliximab. Eligible patients were aged 18-80 years, had active Crohn's disease of the terminal ileum, and had not responded to at least 3 months of conventional therapy with glucocorticosteroids, thiopurines, or methotrexate. Patients with diseased terminal ileum longer than 40 cm or abdominal abscesses were excluded. The primary outcome was quality of life on the Inflammatory Bowel Disease Questionnaire (IBDQ) at 12 months. Secondary outcomes were general quality of life, measured by the Short Form-36 (SF-36) health survey and its physical and mental component subscales, days unable to participate in social life, days on sick leave, morbidity (additional procedures and hospital admissions), and body image and cosmesis. Analyses of the primary outcome were done in the intention-to-treat population, and safety analyses were done in the per-protocol population. This trial is registered at the Dutch Trial Registry (NTR1150). Findings: Between May 2, 2008, and October 14, 2015, 73 patients were allocated to have resection and 70 to receive infliximab. Corrected for baseline differences, the mean IBDQ score at 12 months was 178·1 (95% CI 171·1-185·0) in the resection group versus 172·0 (164·3-179·6) in the infliximab group (mean difference 6·1 points, 95% CI -4·2 to 16·4; p=0·25). At 12 months, the mean SF-36 total score was 112·1 (95% CI 108·0-116·2) in the resection group versus 106·5 (102·1-110·9) in the infliximab group (mean difference 5·6, 95% CI -0·4 to 11·6), the mean physical component score was 47·7 (45·7-49·7) versus 44·6 (42·5-46·8; mean difference 3·1, 4·2 to 6·0), and the mean mental component score was 49·5 (47·0-52·1) versus 46·1 (43·3-48·9; mean difference 3·5, -0·3 to 7·3). Mean numbers of days of sick leave were 3·4 days (SD 7·1) in the resection group versus 1·4 days (4·7) in the infliximab group (p<0·0001), days not able to take part in social life were 1·8 days (6·3) versus 1·1 days (4·5; p=0·20), days of scheduled hospital admission were 6·5 days (3·8) versus 6·8 days (3·2; p=0·84), and the number of patients who had unscheduled hospital admissions were 13 (18%) of 73 versus 15 (21%) of 70 (p=0·68). Body-image scale mean scores in the patients who had resection were 16·0 (95% CI 15·2-16·8) at baseline versus 17·8 (17·1-18·4) at 12 months, and cosmetic scale mean scores were 17·6 (16·6-18·6) versus 18·6 (17·6-19·6). Surgical intervention-related complications classified as IIIa or worse on the Clavien-Dindo scale occurred in four patients in the resection group. Treatment-related serious adverse events occurred in two patients in the infliximab group. During a median follow-up of 4 years (IQR 2-6), 26 (37%) of 70 patients in the infliximab group had resection, and 19 (26%) of 73 patients in the resection group received anti-TNF. Interpretation: Laparoscopic resection in patients with limited (diseased terminal ileum <40 cm), non-stricturing, ileocaecal Crohn's disease in whom conventional therapy has failed could be considered a reasonable alternative to infliximab therapy. Funding: Netherlands Organisation for Health Research and Development.

The lancet. Gastroenterology & hepatology · randomised controlled trial · 228 citationsread the source →

Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease: A Randomized Clinical Trial.

Importance: Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective: To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, setting, and participants: Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions: Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main outcomes and measures: Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form- physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results: Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was -2.5 units (95% CI, -3.7 to -1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, -0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and relevance: Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety. Trial registration: clinicaltrials.gov Identifier: NCT01795859.

JAMA · randomised controlled trial · 177 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 →

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). Length of survival an AIDS has also been with neighborhood measures of income and the of highly a of health at the population may also a role in shaping HIV/AIDS patterns, associations between HIV/AIDS and income at the neighborhood have not been well segregation by race/ethnicity is neighborhood-level that may an important role in HIV/AIDS may affect infectious disease patterns through the and isolation of persons in one increasing the probability of transmission within that For example, found that measures of residential isolation were protective for at risk of disease. Indirect effects of segregation are associated with of neighborhood and with for those in poor neighborhoods segregation may to understanding disease we of studies examining neighborhood segregation in relation to HIV/AIDS that have been The physical environment of neighborhoods has also been examined in relation to infectious disease. et al. examined gonorrhea and neighborhood physical environment in New by using an of physical to explore and to this the of physical such as and a in social in a of community this concept to public et al. found a significant between neighborhood physical and gonorrhea rates, a by a ecologic study of US physical environment may HIV risk by illicit drug use such as injection behaviors and of the mechanisms through which the observed associations may be and associations between the physical environment and HIV/AIDS is research is to support the design of neighborhood-level HIV/AIDS interventions. has differences are not result from social and economic by policies. are and to p. The of evidence ecologic associations between neighborhood-level factors and infectious disease that to be to identify of and defined social as of social structures that that is the of that in its not be p. Social may affect health through 1) the of 2) access to services and 3) of in a and 4) participation, to policies that are more to published studies have explicitly examined social in the of HIV/AIDS. In the and examined income and social as of STD and AIDS found social to be the of STD and AIDS In et al. examined one of social participation, as a for understanding community influences on HIV infection. found that in of and was in other social groups groups with high of social HIV risk. findings from these studies are and We identified categories of factors to HIV/AIDS epidemiology: structural and the and and Each is in the that highlights a of by often and forces that through as is more the the of p. is in patterns of on sexual and HIV A of how structural might influence HIV/AIDS risk is presented in 2. The and uses of race/ethnicity in epidemiologic research have been the of analysis and Social epidemiologists race/ethnicity as an of social forces than physical has that race/ethnicity is a for exposure to which may be defined as the and individual that and of p. The study of disease is of central importance in the study of HIV/AIDS In the for example, the of HIV HIV/AIDS and of also high HIV/AIDS with of behavioral risk factors at the individual have not observed HIV/AIDS or STD by race/ethnicity individual pathways by which HIV/AIDS in a group complex of economic and social patterns, of illicit and health Social epidemiology is and evidence as to what factors and these HIV/AIDS and found that sexual networks for in sexually transmitted infection in the National Health and Social et al. found that risk network structure in a of injection drug users in differences in HIV prevalence between and and structural factors key in shaping the patterns that to HIV/AIDS For example, the effects of sex from the of men may be relationships and sexual segregation by race/ethnicity also to shape social and risk networks in ways that to disease patterns. residential segregation was and associated with gonorrhea at the in the patterns might be observed for HIV/AIDS. is in the proportion of women among HIV/AIDS cases the for of HIV-positive in through and for of HIV-positive in HIV infections in women are at an and women are and more to HIV infection. theoretical for understanding in HIV/AIDS have been including and human beyond as a risk these approaches structural for in HIV/AIDS. focus has been on women in the of sex or transmission women HIV from their partner and reducing acquisition of HIV among men is key to reducing the spread of HIV to women the of and and than their male partners upon of HIV-positive in of of and HIV risks by women The effects of include individual to HIV and a of to HIV prevention The for and Prevention estimates that one of those with HIV not their HIV and have central in shaping to HIV/AIDS the effects of these social forces on the differential distribution of HIV/AIDS have not been well has been examined at the individual in studies of and and to of and in a that the of to p. et al. have defined as and that are at to have AIDS or HIV and at the and communities with which these are p. and have that a conceptual framework for understanding is our of and to as social that can be in relation to broader of and p. in et al. that HIV transmission and with AIDS the of or structural interventions change the in which and communities HIV infection The effective have been those in which communities have to and by increasing community of HIV Social interventions to and to affect community The for this is found in diffusion which on social networks, opinion and change these are by cultural through the in social networks within communities are essential for and behavior change to to HIV/AIDS structures refer to as well as to the and with their and et al. that laws can affect health in 1) may be a through which social determinants affect health direct and 2) may to social conditions associated with health outcomes indirect of direct effects of on HIV risk are on access to injection which have been associated with HIV incidence of an indirect of structures is the of laws on income which may social conditions that increase HIV vulnerability. key social determinants of HIV/AIDS, including poverty and income and community social change may affect HIV/AIDS patterns through population and and the and structures of Each of these factors may be as modifying between and persons in populations. the HIV infection than populations, of HIV prevalence in the or and may affect HIV transmission studies of have into 1) studies of the spread of HIV along and 2) studies of the that vulnerability to HIV/AIDS can the spread of HIV subtypes and to patterns of and evidence linking patterns and Beyrer et al. (14) found that distinct HIV subtypes were associated with different illicit drug trafficking routes in Southeast Asia. has to the spread of HIV in India, and In addition, studies have identified the importance of in the of for HIV/AIDS is a classic of an health have examined the role of in population HIV/AIDS patterns that might for the effects of on HIV/AIDS patterns include sexual and drug use patterns to in patterns, and of and persons, and on the health sex that men have also been associated with high HIV/AIDS prevalence at the This ecologic is to be by the effects of cultural at the local of the effects might have on and network patterns. the of resources in the public and and the environment a central role in the and of HIV/AIDS epidemics. of importance to HIV/AIDS include health social and illicit drug HIV/AIDS is a high on the health of and policies are to be contributing to increasing HIV/AIDS The complex and between policies and HIV/AIDS are to be policies affect health and by poverty in the distribution of and health have that structural designed to and in have a on the HIV/AIDS by increasing and and reducing in the health and social services as to how policies can be designed to to in HIV/AIDS Structural-level health policies and can to in HIV/AIDS HIV prevention have on individual behavior the of the HIV prevention is with of the for that the social and economic of HIV/AIDS The condom is an exemplary of an effective structural HIV prevention to the environment in which HIV risk behaviors the of may also affect in HIV/AIDS transmission by reducing among HIV-positive Social policies a critical role in the of those to HIV/AIDS, such as or Social policies such as and public affect access to resources and can also affect HIV transmission and access to quantitative research has social change to population health outcomes qualitative research has the importance of social in shaping risk In for example, et al. the effects of the and of which Social and Social on the basis of drug and in this study into the drug of income of and in behaviors in an to HIV to studies of the associations between social policies and HIV/AIDS are to the human of policies of with the of those to HIV/AIDS and to identify drug also has a significant on HIV/AIDS. drug particularly of is HIV epidemics in the The on has focused on to the of which of prevention and measures policies for those trafficking or illicit have in of persons for drug The direct of patterns to be For example, et al. found that on policies such as the of and of those with use from Social were associated with in is a risk factor for HIV risk behaviors have been shown to associated with of and HIV risk of in have access to can increase HIV/AIDS risk and by social and risk networks, or and increasing poverty and social in in risk behaviors in of have been For example, et al. found that the in was associated with among injection drug users in of the of heroin trafficking from In the of the of has also been associated with HIV/AIDS forces are often and of men from In a study for the found that a in the size of the from to as a proportion of population reduce HIV among by 1 to the of in are to reduce HIV in with HIV/AIDS prevention and for The of social epidemiology to the HIV/AIDS have in This is in to a that from a that risk factors for disease to one that the that patterns of disease in p. and methodological in the have this our understanding of multiple causes of risk in modeling geographic and databases linking public health data with on social factors enhance our to and in ways that more closely the of HIV/AIDS epidemics. social epidemiology research in HIV/AIDS determine how we can design more effective of interventions at multiple of social A number of key which of the larger social environment in HIV/AIDS transmission and disease are model complex and be has these include data variables and of analysis at multiple contextual effects, and complex with and p. approaches are for the effective of social-level interventions. persons are with HIV/AIDS, and an HIV infections in effective are high drug and in are to of an HIV more These the to underlying social and structural determinants of HIV/AIDS through policies and This was by from the National Institute on The of the New York of for for and A framework for the social epidemiology of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome The the the nature of the between of In are between factors at that to observed epidemic patterns. sexually transmitted infection. 2. through which various of structural might influence the risk of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome of how epidemiology is examined by using different research HIV, human immunodeficiency acquired immunodeficiency In this a is between three approaches to social epidemiology: a a social of disease and an This table is on by Krieger of how epidemiology is examined by using different research HIV, human immunodeficiency acquired immunodeficiency In this a is between three approaches to social epidemiology: a a social of disease and an This table is on by Krieger terms in the equation for the basic reproductive and factors that affect the empirical estimates of the terms in the of HIV, human immunodeficiency acquired immunodeficiency terms in the equation for the basic reproductive and factors that affect the empirical estimates of the terms in the of HIV, human immunodeficiency acquired immunodeficiency keywords used to databases for published literature on the social epidemiology of of Bethesda, HIV, human immunodeficiency acquired immunodeficiency keywords used to databases for published literature on the social epidemiology of of Bethesda, HIV, human immunodeficiency acquired immunodeficiency

Epidemiologic Reviews · meta-analysis · 394 citationsread the source →

Interventions for treating femoral shaft fractures in children and adolescents.

Background: Fractures of the femoral shaft in children are relatively uncommon but serious injuries that disrupt the lives of children and their carers and can result in significant long-term disability. Treatment involves either surgical fixation, such as intramedullary nailing or external fixation, or conservative treatment involving prolonged immobilisation, often in hospital. Objectives: To assess the effects (benefits and harms) of interventions for treating femoral shaft fractures in children and adolescents. Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (accessed 16 August 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013 Issue 7), MEDLINE (1946 to August Week 1 2013), EMBASE (1980 to 2012 week 9), CINAHL (16 August 2013), clinical trials registries, conference proceedings and reference lists; and contacted trial authors and experts in the field. Selection criteria: Randomised and quasi-randomised controlled trials comparing conservative and surgical interventions for diaphyseal fractures of the femur in children under 18 years of age. Our primary outcomes were functional outcome measures, unacceptable malunion, and serious adverse events. Data collection and analysis: Two authors independently screened and selected trials, assessed risk of bias and extracted data. We assessed the overall quality of the evidence for each outcome for each comparison using the GRADE approach. We pooled data using a fixed-effect model. Main results: We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically-treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatmentThe three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatmentThe three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight-bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight-bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. Authors' conclusions: There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time. There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials.

The Cochrane database of systematic reviews · meta-analysis · 23 citationsread the source →

Mapping information exposure on social media to explain differences in HPV vaccine coverage in the United States.

Background: Together with access, acceptance of vaccines affects human papillomavirus (HPV) vaccine coverage, yet little is known about media's role. Our aim was to determine whether measures of information exposure derived from Twitter could be used to explain differences in coverage in the United States. Methods: We conducted an analysis of exposure to information about HPV vaccines on Twitter, derived from 273.8 million exposures to 258,418 tweets posted between 1 October 2013 and 30 October 2015. Tweets were classified by topic using machine learning methods. Proportional exposure to each topic was used to construct multivariable models for predicting state-level HPV vaccine coverage, and compared to multivariable models constructed using socioeconomic factors: poverty, education, and insurance. Outcome measures included correlations between coverage and the individual topics and socioeconomic factors; and differences in the predictive performance of the multivariable models. Results: Topics corresponding to media controversies were most closely correlated with coverage (both positively and negatively); education and insurance were highest among socioeconomic indicators. Measures of information exposure explained 68% of the variance in one dose 2015 HPV vaccine coverage in females (males: 63%). In comparison, models based on socioeconomic factors explained 42% of the variance in females (males: 40%). Conclusions: Measures of information exposure derived from Twitter explained differences in coverage that were not explained by socioeconomic factors. Vaccine coverage was lower in states where safety concerns, misinformation, and conspiracies made up higher proportions of exposures, suggesting that negative representations of vaccines in the media may reflect or influence vaccine acceptance.

Vaccine · 148 citationsread the source →

Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling.

Background: Treatment with statins improves clinical outcome, but the exact mechanisms of pleiotropic statin effects on vascular function in human atherosclerosis remain unclear. We examined the direct effects of atorvastatin on tetrahydrobiopterin-mediated endothelial nitric oxide (NO) synthase coupling in patients with coronary artery disease. Methods and results: We first examined the association of statin treatment with vascular NO bioavailability and arterial superoxide (O(2)(·-)) in 492 patients undergoing coronary artery bypass graft surgery. Then, 42 statin-naïve patients undergoing elective coronary artery bypass graft surgery were randomized to atorvastatin 40 mg/d or placebo for 3 days before surgery to examine the impact of atorvastatin on endothelial function and O(2)(·-) generation in internal mammary arteries. Finally, segments of internal mammary arteries from 26 patients were used in ex vivo experiments to evaluate the statin-dependent mechanisms regulating the vascular redox state. Statin treatment was associated with improved vascular NO bioavailability and reduced O(2)(·-) generation in internal mammary arteries. Oral atorvastatin increased vascular tetrahydrobiopterin bioavailability and reduced basal and N-nitro-l-arginine methyl ester-inhibitable O(2)(·-) in internal mammary arteries independently of low-density lipoprotein lowering. In ex vivo experiments, atorvastatin rapidly improved vascular tetrahydrobiopterin bioavailability by upregulating GTP-cyclohydrolase I gene expression and activity, resulting in improved endothelial NO synthase coupling and reduced vascular O(2)(·-). These effects were reversed by mevalonate, indicating a direct effect of vascular hydroxymethylglutaryl-coenzyme A reductase inhibition. Conclusions: This study demonstrates for the first time in humans the direct effects of statin treatment on the vascular wall, supporting the notion that this effect is independent of low-density lipoprotein lowering. Atorvastatin directly improves vascular NO bioavailability and reduces vascular O(2)(·-) through tetrahydrobiopterin-mediated endothelial NO synthase coupling. These findings provide new insights into the mechanisms mediating the beneficial vascular effects of statins in humans. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01013103.

Circulation · randomised controlled trial · 179 citationsread the source →

Experiential virtual scenarios with real-time monitoring (interreality) for the management of psychological stress: a block randomized controlled trial.

Background: The recent convergence between technology and medicine is offering innovative methods and tools for behavioral health care. Among these, an emerging approach is the use of virtual reality (VR) within exposure-based protocols for anxiety disorders, and in particular posttraumatic stress disorder. However, no systematically tested VR protocols are available for the management of psychological stress. Objective: Our goal was to evaluate the efficacy of a new technological paradigm, Interreality, for the management and prevention of psychological stress. The main feature of Interreality is a twofold link between the virtual and the real world achieved through experiential virtual scenarios (fully controlled by the therapist, used to learn coping skills and improve self-efficacy) with real-time monitoring and support (identifying critical situations and assessing clinical change) using advanced technologies (virtual worlds, wearable biosensors, and smartphones). Methods: The study was designed as a block randomized controlled trial involving 121 participants recruited from two different worker populations-teachers and nurses-that are highly exposed to psychological stress. Participants were a sample of teachers recruited in Milan (Block 1: n=61) and a sample of nurses recruited in Messina, Italy (Block 2: n=60). Participants within each block were randomly assigned to the (1) Experimental Group (EG): n=40; B1=20, B2=20, which received a 5-week treatment based on the Interreality paradigm; (2) Control Group (CG): n=42; B1=22, B2=20, which received a 5-week traditional stress management training based on cognitive behavioral therapy (CBT); and (3) the Wait-List group (WL): n=39, B1=19, B2=20, which was reassessed and compared with the two other groups 5 weeks after the initial evaluation. Results: Although both treatments were able to significantly reduce perceived stress better than WL, only EG participants reported a significant reduction (EG=12% vs. CG=0.5%) in chronic "trait" anxiety. A similar pattern was found for coping skills: both treatments were able to significantly increase most coping skills, but only EG participants reported a significant increase (EG=14% vs CG=0.3%) in the Emotional Support skill. Conclusions: Our findings provide initial evidence that the Interreality protocol yields better outcomes than the traditionally accepted gold standard for psychological stress treatment: CBT. Consequently, these findings constitute a sound foundation and rationale for the importance of continuing future research in technology-enhanced protocols for psychological stress management. Trial registration: ClinicalTrials.gov: NCT01683617; http://clinicaltrials.gov/show/NCT01683617 (Archived by WebCite at http://www.webcitation.org/6QnziHv3h).

Journal of medical Internet research · randomised controlled trial · 68 citationsread the source →

Meditation or exercise for preventing acute respiratory infection: a randomized controlled trial.

Purpose: This study was designed to evaluate potential preventive effects of meditation or exercise on incidence, duration, and severity of acute respiratory infection (ARI) illness. Methods: Community-recruited adults aged 50 years and older were randomized to 1 of 3 study groups: 8-week training in mindfulness meditation, matched 8-week training in moderate-intensity sustained exercise, or observational control. The primary outcome was area-under-the-curve global illness severity during a single cold and influenza season, using the Wisconsin Upper Respiratory Symptom Survey (WURSS-24) to assess severity. Health care visits and days of missed work were counted. Nasal wash collected during ARI illness was assayed for neutrophils, interleukin-8, and viral nucleic acid. Results: Of 154 adults randomized into the study, 149 completed the trial (82% female, 94% white, mean age 59.3 ± 6.6 years). There were 27 ARI episodes and 257 days of ARI illness in the meditation group (n = 51), 26 episodes and 241 illness days in the exercise group (n = 47), and 40 episodes and 453 days in the control group (n = 51). Mean global severity was 144 for meditation, 248 for exercise, and 358 for control. Compared with control, global severity was significantly lower for meditation (P = .004). Both global severity and total days of illness (duration) trended toward being lower for the exercise group (P=.16 and P=.032, respectively), as did illness duration for the meditation group (P=.034). Adjusting for covariates using zero-inflated multivariate regression models gave similar results. There were 67 ARI-related days of-work missed in the control group, 32 in the exercise group (P = .041), and 16 in the meditation group (P <.001). Health care visits did not differ significantly. Viruses were identified in 54% of samples from meditation, 42% from exercise, and 54% from control groups. Neutrophil count and interleukin-8 levels were similar among intervention groups. Conclusions: Training in meditation or exercise may be effective in reducing ARI illness burden.

Annals of family medicine · randomised controlled trial · 91 citationsread the source →

Effect of early limited formula on duration and exclusivity of breastfeeding in at-risk infants: an RCT.

Background and objectives: Recent public health efforts focus on reducing formula use for breastfed infants during the birth hospitalization. No previous randomized trials report the effects of brief early formula use. The objective of the study was to determine if small formula volumes before the onset of mature milk production might reduce formula use at 1 week and improve breastfeeding at 3 months for newborns at risk for breastfeeding problems. Methods: We randomly assigned 40 exclusively breastfeeding term infants, 24 to 48 hours old, who had lost ≥5% birth weight to early limited formula (ELF) intervention (10 mL formula by syringe after each breastfeeding and discontinued when mature milk production began) or control (continued exclusive breastfeeding). Our outcomes were breastfeeding and formula use at 1 week and 1, 2, and 3 months. Results: Among infants randomly assigned to ELF during the birth hospitalization, 2 (10%) of 20 used formula at 1 week of age, compared with 9 (47%) of 19 control infants assigned during the birth hospitalization to continue exclusive breastfeeding (P = .01). At 3 months, 15 (79%) of 19 infants assigned to ELF during the birth hospitalization were breastfeeding exclusively, compared with 8 (42%) of 19 controls (P = .02). Conclusions: Early limited formula may reduce longer-term formula use at 1 week and increase breastfeeding at 3 months for some infants. ELF may be a successful temporary coping strategy for mothers to support breastfeeding newborns with early weight loss. ELF has the potential for increasing rates of longer-term breastfeeding without supplementation based on findings from this RCT.

Pediatrics · randomised controlled trial · 62 citationsread the source →

Mild dehydration impairs cognitive performance and mood of men.

The present study assessed the effects of mild dehydration on cognitive performance and mood of young males. A total of twenty-six men (age 20·0 (sd 0·3) years) participated in three randomised, single-blind, repeated-measures trials: exercise-induced dehydration plus a diuretic (DD; 40 mg furosemide); exercise-induced dehydration plus placebo containing no diuretic (DN); exercise while maintaining euhydration plus placebo (EU; control condition). Each trial included three 40 min treadmill walks at 5·6 km/h, 5 % grade in a 27·7°C environment. A comprehensive computerised six-task cognitive test battery, the profile of mood states questionnaire and the symptom questionnaire (headache, concentration and task difficulty) were administered during each trial. Paired t tests compared the DD and DN trials resulting in >1 % body mass loss (mean 1·59 (sd 0·42) %) with the volunteer's EU trial (0·01 (sd 0·03) %). Dehydration degraded specific aspects of cognitive performance: errors increased on visual vigilance (P = 0·048) and visual working memory response latency slowed (P = 0·021). Fatigue and tension/anxiety increased due to dehydration at rest (P = 0·040 and 0·029) and fatigue during exercise (P = 0·026). Plasma osmolality increased due to dehydration (P < 0·001) but resting gastrointestinal temperature was not altered (P = 0·238). In conclusion, mild dehydration without hyperthermia in men induced adverse changes in vigilance and working memory, and increased tension/anxiety and fatigue.

The British journal of nutrition · randomised controlled trial · 162 citationsread the source →

Anxiety and depression in COVID-19 survivors: Role of inflammatory and clinical predictors.

Infection-triggered perturbation of the immune system could induce psychopathology, and psychiatric sequelae were observed after previous coronavirus outbreaks. The spreading of the Severe Acute Respiratory Syndrome Coronavirus (COVID-19) pandemic could be associated with psychiatric implications. We investigated the psychopathological impact of COVID-19 in survivors, also considering the effect of clinical and inflammatory predictors. We screened for psychiatric symptoms 402 adults surviving COVID-19 (265 male, mean age 58), at one month follow-up after hospital treatment. A clinical interview and a battery of self-report questionnaires were used to investigate post-traumatic stress disorder (PTSD), depression, anxiety, insomnia, and obsessive-compulsive (OC) symptomatology. We collected sociodemographic information, clinical data, baseline inflammatory markers and follow-up oxygen saturation levels. A significant proportion of patients self-rated in the psychopathological range: 28% for PTSD, 31% for depression, 42% for anxiety, 20% for OC symptoms, and 40% for insomnia. Overall, 56% scored in the pathological range in at least one clinical dimension. Despite significantly lower levels of baseline inflammatory markers, females suffered more for both anxiety and depression. Patients with a positive previous psychiatric diagnosis showed increased scores on most psychopathological measures, with similar baseline inflammation. Baseline systemic immune-inflammation index (SII), which reflects the immune response and systemic inflammation based on peripheral lymphocyte, neutrophil, and platelet counts, positively associated with scores of depression and anxiety at follow-up. PTSD, major depression, and anxiety, are all high-burden non-communicable conditions associated with years of life lived with disability. Considering the alarming impact of COVID-19 infection on mental health, the current insights on inflammation in psychiatry, and the present observation of worse inflammation leading to worse depression, we recommend to assess psychopathology of COVID-19 survivors and to deepen research on inflammatory biomarkers, in order to diagnose and treat emergent psychiatric conditions.

Brain, behavior, and immunity · 1041 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 →

Economic impact of workplace productivity losses due to allergic rhinitis compared with select medical conditions in the United States from an employer perspective.

Objective: To evaluate the cost of lost productivity in the workplace due to allergic rhinitis compared to other selected medical conditions from an employer perspective. Setting and participants: A total of 8267 US employees at 47 employer locations who volunteered to participate in health/wellness screenings. Measurements: The Work Productivity Short Inventory was used to assess the impact of a predefined group of health conditions on workplace productivity for the previous 12 months. Both absenteeism and presenteeism (lost productivity while at work) were recorded. Costs were calculated using a standard hourly wage. Results: Allergic rhinitis was the most prevalent of the selected conditions; 55% of employees reported experiencing allergic rhinitis symptoms for an average of 52.5 days, were absent 3.6 days per year due to the condition, and were unproductive 2.3 h per workday when experiencing symptoms. The mean total productivity (absenteeism + presenteeism) losses per employee per year were 593 US dollars for allergic rhinitis, 518 US dollars for high stress, 277 US dollars for migraine, 273 US dollars for depression, 269 US dollars for arthritis/rheumatism, 248 US dollars for anxiety disorder, 181 US dollars for respiratory infections, 105 US dollars for hypertension or high blood pressure, 95 US dollars for diabetes, 85 US dollars for asthma, and 40 US dollars for coronary heart disease. The mean total productivity loss per employee per year due to caregiving was 102 US dollars for pediatric respiratory infections, 85 US dollars for pediatric allergies, 49 US dollars for Alzheimer's disease, and 42 US dollars for otitis media/earache. Conclusions: Allergies are major contributors to the total cost of health-related absenteeism and presenteeism. Payers and employers need to consider this when determining health benefits for employees.

Current medical research and opinion · cohort or longitudinal · 188 citationsread the source →

Behavioural consequences of withdrawal from three different administration schedules of amphetamine.

Different administration schedules of amphetamine (AMPH) lead to different behavioural consequences, neurochemical changes and gene expression patterns in a variety of brain areas during drug withdrawal. However, direct comparisons of these different effects within the same experiment are rare in the literature. Accordingly, in this study, rats were tested in relevant behavioural paradigms during withdrawal from three different administration schedules of AMPH. The intermittent schedule (INT) consisted of one daily injection of 1.5 mg/kg AMPH for 6 days. The escalating administration schedule consisted of three daily injections for 6 days with increasing dosages from 1 to 5 mg/kg AMPH during the first five injections and 5 mg/kg for the following 13 injections (ESC-5). A second more severe escalating administration schedule (three injections per day for 3 days escalating from 1 to 9 mg/kg AMPH and a final 10 mg/kg AMPH injection on day 4, ESC-10) was also investigated. Control animals received saline injections according to the three administration schedules. Rats pretreated with AMPH according to the ESC-10 administration schedule exhibited a transient reduction of locomotor activity on day 1, but not day 5, of withdrawal, as well as a permanent disruption of prepulse inhibition (PPI) on days 4, 20, and 40 of withdrawal. There was no effect on anxiety measured by the elevated plus-maze on withdrawal day 2, and all the AMPH pretreated animals exhibited a similar magnitude of behavioural sensitization following an AMPH challenge irrespective of administration schedule on withdrawal day 42. These data suggest that, based on their persistent disruption of PPI, animals withdrawn from AMPH ESC-10 might model specific symptoms of schizophrenic patients.

Behavioural brain research · cohort or longitudinal · 24 citationsread the source →

A mixed-methods evaluation of a peer-led, co-produced, asset-based intervention for early diagnosis of prostate cancer for Black men: the PROCAN-B study.

Objective: To pilot a culturally tailored, peer-led, co-produced asset-based intervention workshop to encourage early diagnosis of prostate cancer for Black men. Design: Mixed-methods pilot study. Setting: Community centres in the North-East of England and Scotland. Participants: The intervention was delivered in November 2023 with Black African and Caribbean men (n=21), and again in February 2024 (n=41). Participants were highly educated and aged between 42 and 63 years. The intervention was qualitatively evaluated with 40 of the intervention participants. Intervention: Underpinned by the Integrated Screening Action Model (I-SAM), we co-produced a culturally tailored, peer-led 2-hour workshop consisting of multiple components, including small group discussions about barriers to accessing prostate cancer care, general practitioner (GP) health education, activities to facilitate effective communication with the GP and reception staff and videos with testimonials from survivors, women and religious leaders. Primary outcomes: Knowledge, attitudes and intention to engage in prostate cancer testing were examined through a pre- and post-survey design. Intervention acceptability was qualitatively explored through focus groups. Results: Participants (n=41) reported that the workshop increased their confidence in engaging with healthcare providers to discuss prostate cancer testing (I-SAM component: psychological capability). Knowledge (I-SAM component: psychological capability: Z=4.939, p<0.001) and intention to undergo prostate cancer testing (I-SAM component: decided to act): Z=3.975, p<0.001) significantly increased post-intervention. Focus group data showed participants enjoyed the workshop and found it acceptable and informative. They particularly liked that the workshop was delivered exclusively by people who shared participants' cultural and racial backgrounds. Culturally tailored and faith-based messages made the intervention relevant to participants and facilitated trust-building. Conclusion: Asset-based strategies, focusing on community strengths, including faith-based health promotion, can promote health behaviours in a culturally and spiritually meaningful way. The PROCAN-B intervention effectively targeted components within the I-SAM and shows potential to increase prostate cancer awareness and build confidence to engage in behaviours conducive to early diagnosis. However, the sample was small, and more robust effectiveness testing is needed.

BMJ openread the source →

Effects of expressive writing of positive emotions on mental health among patients with ovarian cancer undergoing postoperative chemotherapy.

Purpose: Patients with ovarian cancer often experience significant psychological distress during postoperative chemotherapy, including anxiety and depression. Expressive writing of positive emotions has shown potential in improving psychological health and fostering post-traumatic growth (PTG) in cancer patients. However, its application to ovarian cancer patients undergoing chemotherapy remains under-explored. Methods: A quasi-experimental study was conducted with 82 ovarian cancer patients undergoing postoperative chemotherapy at a tertiary hospital in Changchun, China. Patients were divided into an experimental group (n = 40) receiving expressive writing intervention and a control group (n = 42) receiving routine care. Outcomes were assessed using the Post-Traumatic Growth Inventory (PTGI), Self-Rating Anxiety Scale (SAS), and Self-Rating Depression Scale (SDS) at baseline and after a 6-week intervention. Results: After the intervention, the experimental group exhibited significantly higher PTGI scores (mean ± SD: 73.43 ± 6.95) compared to the control group (63.19 ± 5.91, P < 0.001), with improvements observed across all five PTG dimensions (P < 0.05). The experimental group also showed a greater reduction in SAS (mean ± SD: 38.25 ± 4.31 vs. 45.12 ± 5.17, P < 0.001) and SDS scores (mean ± SD: 42.10 ± 3.86 vs. 48.75 ± 4.62, P < 0.001). Conclusions: Expressive writing of positive emotions significantly enhances PTG and reduces anxiety and depression in ovarian cancer patients undergoing chemotherapy. This intervention offers a cost-effective and feasible approach for psychological support in clinical settings.

European journal of oncology nursing : the official journal of European Oncology Nursing Society · 4 citationsread the source →

Social Isolation and Loneliness Among San Francisco Bay Area Older Adults During the COVID-19 Shelter-in-Place Orders.

Background/objectives: Physical distancing during the COVID-19 pandemic may have unintended, detrimental effects on social isolation and loneliness among older adults. Our objectives were to investigate (1) experiences of social isolation and loneliness during shelter-in-place orders, and (2) unmet health needs related to changes in social interactions. Design: Mixed-methods longitudinal phone-based survey administered every 2 weeks. Setting: Two community sites and an academic geriatrics outpatient clinical practice. Participants: A total of 151 community-dwelling older adults. Measurements: We measured social isolation using a six-item modified Duke Social Support Index, social interaction subscale, that included assessments of video-based and Internet-based socializing. Measures of loneliness included self-reported worsened loneliness due to the COVID-19 pandemic and loneliness severity based on the three-item University of California, Los Angeles (UCLA) Loneliness Scale. Participants were invited to share open-ended comments about their social experiences. Results: Participants were on average aged 75 years (standard deviation = 10), 50% had hearing or vision impairment, 64% lived alone, and 26% had difficulty bathing. Participants reported social isolation in 40% of interviews, 76% reported minimal video-based socializing, and 42% minimal Internet-based socializing. Socially isolated participants reported difficulty finding help with functional needs including bathing (20% vs 55%; P = .04). More than half (54%) of the participants reported worsened loneliness due to COVID-19 that was associated with worsened depression (62% vs 9%; P < .001) and anxiety (57% vs 9%; P < .001). Rates of loneliness improved on average by time since shelter-in-place orders (4-6 weeks: 46% vs 13-15 weeks: 27%; P = .009), however, loneliness persisted or worsened for a subgroup of participants. Open-ended responses revealed challenges faced by the subgroup experiencing persistent loneliness including poor emotional coping and discomfort with new technologies. Conclusion: Many older adults are adjusting to COVID-19 restrictions since the start of shelter-in-place orders. Additional steps are critically needed to address the psychological suffering and unmet medical needs of those with persistent loneliness or barriers to technology-based social interaction.

Journal of the American Geriatrics Society · 234 citationsread the source →

Clinical Presentation of Left Atrial Cardiac Myxoma

Introduction Cardiac myxoma is the most frequent “benign” tumor of the heart and presents an important diagnostic challenge (4,43,47). Myxomas may resemble many cardiovascular or systemic diseases, and can arise in any of the cardiac chambers, although 75% occur in the left atrium. Most cases of atrial myxomas are now diagnosed in living patients, allowing successful surgical extirpation (1,3,30,44,53). Before the introduction of angiocardiography in 1951, cardiac myxoma diagnosis was made only at autopsy (22). The first successful surgical removal of an atrial myxoma was performed in 1954 (35,47). In 1959, the first M-mode echocardiogram of a left atrial myxoma was reported (16). Indeed, the introduction of echocardiography has provided an important noninvasive means of diagnosis for cardiac myxomas (55). Thus, the diagnosis of small myxomas (less than 5 cm in size and asymptomatic) is becoming easier. We report here the experience of a French cardiovascular center in the clinical presentation of left atrial myxomas. The large number of patients in this series allowed us to perform an analytic, clinicopathologic study. Patients and Methods We reviewed the 112 cases of left atrial myxoma seen at 1 institution (Hôpital Louis Pradel, Lyons, France) over a 40-year period (1959–1998). In all cases the diagnosis was established before surgical removal. The patients’ medical records were reviewed, and data concerning clinical presentation, diagnostic methods, and postoperative course were collected. Histopathologic slides were reviewed for all cases by the same pathologist (RL). Other locations where cardiac myxoma occurred during that time period were the right atrium (15 cases), left ventricle (2 cases), and right ventricle (1 case). Follow-up information was obtained by contacting either the patients or the attending physicians, and a standardized questionnaire was completed for each case. Statistical analysis A chi-square test, or the Fisher exact test when required, was performed for all qualitative variables, and odds ratios (OR) with 95% confidence intervals (95% CI) were computed. For ordinal variables a Wilcoxon rank sum test was used. Data analysis was performed using SAS (Statistical Analysis System, SAS Institute Inc., Cary, NC). The variables studied in the statistical analysis were 1) sex and age, period of diagnosis (before or after echocardiography was available), delay to diagnosis (delay between the first symptoms and diagnosis), possible systematic (serendipitous) discovery; 2) size of the tumor (> or < 5 cm), tumor surface appearance (smooth or villous); 3) the main symptoms: cardiac (cardiac failure, malaise or syncope, chest pain or palpitations), embolic (cerebral, coronary, or peripheral artery), systemic (fever, weight loss, or pseudo-connective tissue disease signs), or neurologic (stroke, vertigo, epilepsy, coma, or other signs); 4) cardiac auscultation modifications (pseudo-mitral signs, “tumor plop”, nonspecific other signs); 5) possible chest X-ray abnormalities (left cardiac failure signs, cardiomegaly, pleural effusion, left atrium enlargement, visible myxoma when calcified), electrocardiogram (ECG) alterations (arrhythmias or conduction disturbances, ST-segment and T-wave shifts, left atrial hypertrophy, and nonspecific signs), or serologic test abnormalities (elevated erythrocyte sedimentation rate [ESR], anemia). Results Patient characteristics The study group included 72 women, (64% of the whole sample; median age, 53 yr; range, 23–84 yr) and 40 men (36% of the sample; median age, 58 yr, range, 5–77 yr). Forty-six patients (41% of the sample, 31 women, 15 men) were less than 50 years old, 47 (42%, 31 women, 16 men) were between 50 and 70 years, and 19 (17%, 10 women, 9 men) were older than 70. Age distribution was homogenous in men, but most female patients were between 40 and 60 years old (Figure 1).Fig. 1: Age distribution of 112 patients with left atrial myxoma. The clinical and laboratory features of left atrial myxoma in our series are presented in Table 1. The different frequencies of clinical and laboratory signs according to sex and age are detailed in Table 2. Male patients were more at risk than females for embolic complications and for neurologic symptoms; females were more at risk than males to develop systemic symptoms such as fever; younger patients (age <50 yr) had more neurologic symptoms and cardiac auscultation abnormalities than older patients (age >50 yr).TABLE 1: Clinical and laboratory features of left atrial myxoma (112 cases)TABLE 2: Frequencies of clinical and laboratory signs by sex and age*We divided the patients into 2 groups according to the pre-and post-echocardiography periods: 1) between 1959 and 1977, when the only diagnostic methods were angiocardiography and cardiac cathe-terization, only 14 patients (12.5%) underwent surgery; 2) since 1977, with 2-dimensional echocardiography use (transthoracic, then transesophageal), about 5 patients per year have undergone surgery for left atrial myxoma (98 patients, 87.5%). The sex ratio and age ranges are similar in these 2 patient groups, but other differences can be identified (Table 3). Before 1977, most patients were diagnosed on the basis of serologic or blood test abnormalities (particularly elevated ESR) and radiologic abnormalities; chest X-ray evidence of cardiac failure or left atrium enlargement was particularly prevalent in patients diagnosed before 1977 compared with those diagnosed after 1977 (p = 0.006 and p = 0.02, respectively).TABLE 3: Symptoms by year of diagnosis*Delay before surgery In our series, the time interval between symptoms onset and diagnosis (surgical removal) varied from 0 to 126 months (median, 4 mo). The median delay before surgery was 5.5 months before 1977, and 3 months after 1977; the difference is not significant. The median delay to diagnosis increased significantly when cardiac symptoms were present; there was no significant difference for the other symptoms (Table 4).TABLE 4: Delay to diagnosis by year and by principal clinical symptoms*Initial symptoms ( Figure 2) For 11 patients, the left atrial myxoma diagnosis was a mere chance, or serendipitous, discovery (“systematic findings” in Figure 2). Among these patients, in 9 cases echocardiography (8 cases) or computed tomography (CT) (1 case) was performed for another indication and allowed a diagnosis of myxoma. For 2 patients, echocardiography had been systematically performed during follow-up for surgery on a right atrial myxoma. Fig. 2: Initial symptoms of left atrial myxoma (112 cases).The most common initial symptoms of left atrial myxoma in our series were related to mitral valve obstruction: dizziness and occasionally syncope, palpitations, dyspnea, cough, pulmonary edema, or congestive heart failure were observed in 58 patients. Eight patients showed atypical paroxysmal clinical manifestations: chest pain, hemoptysis, limb claudication, thoracic noise, shortness of breath, or syncope when reclining. Embolic manifestations suggested myxoma in 18 patients. Constitutional or general systemic signs appeared as initial manifestations for 17 patients: myalgia, muscle weakness, arthralgia, fever, weight loss, fatigue, and Raynaud syndrome. Clinical features at diagnosis All patients presented with at least 1 or more symptoms of the classic triad: 1) obstructive cardiac signs; 2) embolic signs; and 3) constitutional or systemic manifestations (See Table 1). 1) Intracardiac obstruction signs occurred in 75 patients. Pulmonary edema or progressive congestive cardiac failure (dyspnea, orthopnea) were the most common symptoms (n = 48). Malaise or syncope occurred in 16 cases. Two patients experienced cardiac arrest before surgery and fully recovered after resuscitation. Other nonspecific cardiac symptoms were present in 34 patients: cough, thoracic pain, palpi-tations, myocardial infarction due to coronary embolism. Malaise, palpitations, or thoracic pain could vary with body postural changes. 2) Signs of embolism were present in 33 patients, either with 1 (n = 25) or several (n = 8) locations. Embolic locations were the central nervous system (n = 24), in 1 case in the retinal artery, the upper and lower extremities (n = 15), and the coronary arteries (n = 4). 3) Thirty-eight patients presented with systemic or constitutional symptoms. These symptoms were obviously nonspecific, including fever (n = 22), weight loss or fatigue (n = 20), and immunologic diseases mimicking symptoms such as myalgia, muscle weakness, arthralgia, or Raynaud syndrome (n = 6). 4) Other clinical presentations 4.1) Twenty-nine patients had neurologic symptoms, particularly transient or permanent motor or sensory neurologic deficiencies (n = 23), when cerebral emboli were present (stroke). Three of these patients developed multiple cerebral aneurysms, induced by cerebral emboli. Three patients had epileptic fits, or multilocular sclerosis mimicking symptoms. Six patients also suffered from other neurologic manifestations, such as vertigo or coma. One patient with streptococcal meningitis underwent surgery for a supposed antibiotic-resistant endocarditis suggested by echocardiographic findings, but surgery uncovered an incidental noninfected myxoma. 4.2) One patient had fever and positive blood cultures for Streptococcus viridans. 4.3) Three patients were investigated for liver abnormalities connected in fact with right cardiac failure. 4.4) For 3 patients, the main symptoms were abdominal pain or hemoptysis. Physical examination (cardiac auscultation) On cardiac auscultation 72 patients (64%) had abnormal findings, 18 (16%) of them with postural changes or with time examination modifications. These murmurs looked like significant mitral stenosis findings: apical diastolic or presystolic murmur (n = 60, 53%). A tumor plop was heard in 17 patients (15%), all before 1989. Other auscultatory features were changes in preexisting murmurs, gallops, or modification of the first (split) or second heart sound (n = 12, 11%). A significant was observed between cardiac auscultation abnormalities and 1) systemic symptoms (fever, weight loss or and 2) cardiac symptoms and signs (cardiac failure, (Table no between auscultatory signs and embolic or neurologic symptoms was between clinical The most frequent laboratory was in patients Table 1). in men, in was observed in 15 patients. blood or was present in patients. The between these serologic abnormalities and systemic manifestations was significant Table there was no significant between serologic signs and or neurologic symptoms. abnormalities of the patients (n = had abnormal Table 1). atrial was the most frequent (n = or or conduction were Other were ST-segment abnormalities (n = or nonspecific abnormalities (n = hypertrophy, The of abnormalities with systemic manifestations and cardiac signs was significant Table was no significant with embolic or neurologic symptoms. were abnormal in patients Table 1). included pulmonary or congestive heart failure signs (n = and nonspecific (n = atrial enlargement (n = that made the tumor visible (n = and pleural were (n = The of radiologic abnormalities with systemic and cardiac manifestations was significant Table X-ray abnormalities were significantly less frequent in patients with embolic or neurologic methods Before 1977, all cases were diagnosed by angiocardiography with left heart (n = 1977, echocardiography was the diagnostic (n = only M-mode echocardiography was (Figure 3). 2-dimensional and particularly echocardiography the methods in many cases. For 2 patients the diagnosis was established by or 3: A myxoma is seen in the left The diagnosis of myxoma was obtained after surgical tumor for all cases. On the tumor from 1 cm to 15 The size was for was than 5 cm in and in cases had been during The weight of the from 15 to In our series of the myxomas were with a cm), and were the left atrial myxomas in our series, the and from the left atrial with only a other left and small mitral valve The myxoma surface was studied in was or in of these (n = and (Figure 4) in the other cases (n = The less common or (Figure 5) myxomas had a surface that of multiple or and with a to (Figure 4: left atrial myxoma after left atrial were on the of myxoma in an of an The myxoma had a or an and a were the The surface of the tumor was by a of was observed in of the cases. We with a myxoma from with a and or different of 1) (Figure with or by then by 2) (Figure with many or in the of the cases were left atrial of them with and with were myxomas with All were observed in patients with myxoma and atrial myxoma with with myxoma in atrial myxoma with or myxoma in significant could be between myxoma size or 5 and diagnosis or or of or serologic symptoms or signs (Table 6). a myxoma size cm was significantly with cardiac symptoms, auscultatory signs, and and chest X-ray of myxomas appeared to be more and the delay to diagnosis was for small than for large Table of clinical features to myxoma size was significantly with neurologic symptoms, embolic and cardiac auscultation there was no significant between and or X-ray signs or symptoms; discovery; or delay in diagnosis (Table of clinical features to myxoma surface course All patients had patients during the 1 patient in during a second surgical for a of myxoma years after the first surgical a on in with cardiac and on the second postoperative from a in from mitral by a mitral and a in from meningitis with the the incidental tumor had been 1 patient a mitral valve endocarditis was with the myxoma. The most frequent postoperative was transient or atrial in patients A permanent cardiac for was for only 2 patients. Follow-up the postoperative patients were to patients to and not our Among the other patients, 4 and were during the follow-up Patients presented with peripheral fully The follow-up for patients with multiple cerebral is 14 years a In the present series, were for a median of 3 years 1 yr). Six patients had a of myxoma. Three patients with myxoma in the left and 17 years Three other patients had One of them suffered 2 in the left 16 and months The other 2 patients with had an initial myxoma in the right for 1 of them the was in the left atrium 3 years and for the other the were multiple in the left atrium and years and then in the right atrium years We report here the series of patients with left atrial myxoma diagnosed in a to our The patients presented over a 40-year ratio is with other in this ratio from to Myxomas can occur in all but are most frequent between the and of occur in although there is no for this female due in to In our series, younger age is significantly with neurologic signs or cardiac auscultation and is with neurologic or embolic symptoms in men and systemic symptoms in Clinical features The clinical features of these are by and there are no signs and symptoms that the of a myxoma In a of there are no symptoms at all in our there is no significant between the size of the tumor or 5 and the of discovery or atrial myxomas when the mitral or systemic 1) symptoms occur in of patients in our cases as mitral valve in mitral atrial and of fever are only of patients had in our study. Cardiac obstruction can be by progressive congestive cardiac failure on or or by syncope, or to mitral valve obstruction by the myxoma or coronary arteries The of obstruction may vary with body and these postural changes are particularly of myxoma (35,47). Cardiac failure the most frequent in our In our the of cardiac signs increased the diagnosis to that clinical symptoms are by another more common disease due to 2) emboli are the second of the classic in of myxoma patients in our study. than of emboli to the central nervous system in our but any may be to a of symptoms and cases emboli in the upper and lower coronary and more emboli may to aneurysms, as of cardiac myxomas as in 3 patients in our was 12, yr, We that the of an or surface is significantly with cerebral and peripheral 3) Constitutional signs are the of the classic these symptoms are may occur in to of cases The is lower in our series studied a at a cardiovascular These signs and symptoms myalgia, muscle weakness, arthralgia, fever, weight loss, and are obviously nonspecific and may occur in a of or or immunologic diseases tissue manifestations have also been reported in myxoma patients Cardiac auscultation Cardiac auscultatory may vary between and may on body presystolic or diastolic murmurs, significant mitral may be heard in more than of the patients in our The auscultatory of myxoma is “tumor is a heart sound of heard after the second heart sound may be with a heart sound or a mitral The tumor plop is in only of patients in our We established a significant between cardiac auscultation abnormalities and cardiac or systemic symptoms. and are abnormal in only of the patients those with systemic symptoms significant was in our The main but nonspecific laboratory abnormalities are and elevated or is or may occur by on the has also been common are and that the and of a by the tumor may be for systemic and manifestations has been with of in patients with myxoma that to after surgical removal A between the size of the tumor and the of has also been suggested have also been in myxoma tissue myxoma tissue in cases by and are nonspecific but observed in our atrial in of patients, the alterations by the is (less than of cases) in to the in mitral valve We observed a significant between signs and the of cardiac or systemic symptoms. also nonspecific features in the patients and are not for when the tumor is in our a left atrium enlargement and signs of pulmonary may be In our series, chest X-ray abnormalities were significantly with cardiac or systemic symptoms, but there were radiologic signs when the myxoma was by embolic or neurologic In cardiac signs or symptoms are more prevalent with large and may that embolic becoming are diagnosed before the the size 5 that to cardiac and radiologic data a positive between small tumor size and embolic Table 6). methods is the and diagnostic of is and not any risk of tumor and and cardiac examination may be by the echocardiography is less with an to but echocardiography the for surgery is only on echocardiographic evidence of the in our series angiocardiography has not been since coronary in patients over 40 years old is in to coronary disease Other diagnostic methods and The of and over echocardiography is that of and thoracic are also more in tumor and tumor and size data that most left atrial myxomas arise from the atrial or the on the of and on the appearance is or with a or or is and the surface is either or and in our myxomas with constitutional symptoms, or In the such as and surface are seen in older that In our series, there was no significant between and The size and weight of myxomas but in our the of symptoms was in patients with on could or myxomas and or myxomas according to the of the that all occurred in patients with and myxomas. the of cardiac myxomas have been The of most is that myxomas are of is no that myxomas are myxomas may have a of that at first may be the of multiple surface or is not with or any of presentation, and is important not to an on the basis of these atypical are cardiac not be with myxomas The to the tumor are to be and analysis has that myxoma as tumor = and are and may be for and cases with is as is the showed that was by is also a for the that myxomas arise from the to A study that myxomas with a between tumor size and the of this a in Myxomas may to the but these not have any The myxoma tissue emboli may may the and may or may but any cerebral tissue years the may to Three patients in our series had embolic that into the with of multiple aneurysms, any or during and follow-up The of for myxomas is surgical removal the diagnosis is of the tumor is Embolic complications or are in patients: of patients in the time of our series, not due to cardiac but 2 patients had cardiac arrest in the before surgery with successful resuscitation. surgery is a as most are can be The may according to In our series, was 3 patients during the postoperative period before and another patient in of meningitis not to myxoma. The most frequent postoperative was transient or with an of Cardiac myxomas occur but or cases have been The reported rate ranges from to in the in our are reported from as as a months to as as years after of the myxoma in our The of is not but risk or of tumor of the a of tumor in the In most cases of of the to be the of Patients with abnormalities are at risk of and from 2 or more of the cardiac and myxomas or of the with and are as or The risk of for and myxomas is about and is only for In our series, 3 cases the cardiac myxoma the time of myxoma patients are younger than myxoma patients. myxomas of the 2 patient groups are not A to has been identified The is In the the rate is and after of myxomas ranges from 0 to in our may surgical removal in our A patients may permanent cardiac for conduction 2 patients in our In of the of a tumor that with mitral valve to in heart failure, the mitral valve is In our only 1 patient mitral valve for endocarditis with left atrial myxoma. the myxoma patients to be and cases. echocardiogram is over the period at diagnosis The mitral valve other and heart more common than and occur in patients with myocardial infarction or systemic symptoms are present (fever, weight loss, the diagnosis heart and tissue disease or The of embolic and constitutional symptoms is due more to but may also myxoma. The of or syndrome to the 2 diseases, as these are in myxoma. myxomas are occasionally the clinical of myxoma and endocarditis more of cardiac myxomas reported 40 cases with a presentation similar to is no clinical between and noninfected myxoma cardiac symptoms and the rate of systemic or cerebral constitutional symptoms significantly in patients with myxoma (fever, elevated and men are more than series of 112 cases of left atrial myxoma clinical that this tumor may a of clinical symptoms not only such as cardiac but also or neurologic is made only on clinical there are no signs or symptoms. but or cases have been that and of the by the tumor may be for or including the is the of for diagnosis and follow-up of this myxomas are be in the diagnosis of mitral valve disease and congestive heart failure, in patients with is also for any patient with embolic embolic in in the of signs or symptoms of endocarditis or to a of myxoma as the embolic The obtained by be are to the clinical features of in in myxoma or be studied for embolic myxomas with of could be performed to for the ratio and age We a series of 112 cases of left atrial myxoma diagnosed in a French and 40 age range, yr) over 40 years, from 1959 to Symptoms of mitral valve the first of the classic of myxoma presentation, were present in 75 patients with cardiac failure or Symptoms of the second frequent presentation in the classic were observed in 33 cases with 1 or several cerebral emboli with are at risk than females of embolic The of the classic of constitutional symptoms with fever, weight loss, or symptoms tissue due to and patients have more neurologic symptoms, and female patients have more systemic symptoms. patients (64%) had cardiac auscultation valve disease and more the tumor plop The most frequent was left atrial were The number of myxoma patients diagnosed after 1977 the introduction of echocardiography as a noninvasive diagnostic there was no significant in the time from onset of symptoms to between patients seen in the before and after The tumor from 1 to 15 cm with a weight of between 15 and The myxoma surface was or in of the and in the other cases. Myxomas in patients with embolism have a those in patients with cardiac symptoms, auscultation signs, tumor and electrocardiogram or radiologic signs of left atrium and are significantly the The is and only 4 occurred our 112 cases over a median follow-up of 3 The rate is but follow-up and echocardiography are for patients. The surgical were performed during the 40-year period by We are to for the

Medicine · review · 878 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. Am J Physiol Regul Integr Comp Physiol 281: R591-R595, 2001.Link | ISI | Google Scholar3 Aoyagi N, Ohashi K, and Yamamoto Y. Frequency characteristics of long-term heart rate variability during constant-routine protocol. Am J Physiol Regul Integr Comp Physiol 285: R171-R176, 2003.Link | ISI | Google Scholar4 Arora RC, Hirsch GM, Johnson Hirsch K, Hancock Friesen C, and Armour JA. Function of human intrinsic cardiac neurons in situ. Am J Physiol Regul Integr Comp Physiol 280: R1736-R1740, 2001.Link | ISI | Google Scholar5 Barbieri R, Triedman JK, and Saul JP. Heart rate control and mechanical cardiopulmonary coupling to assess central volume: a systems analysis. Am J Physiol Regul Integr Comp Physiol 283: R1210-R1220, 2002.Link | ISI | Google Scholar6 Barrett CJ, Navakatikyan MA, and Malpas SC. Long-term control of renal blood flow: what is the role of the renal nerves? Am J Physiol Regul Integr Comp Physiol 280: R1534-R1545, 2001.Link | ISI | Google Scholar7 Blumberg MS, Knoot TG, and Kirby RF. Neural and hormonal control of arterial pressure during cold exposure in un-anesthetized week-old rats. Am J Physiol Regul Integr Comp Physiol 281: R1514-R1521, 2001.Link | ISI | Google Scholar8 Boyett MR, Kodama I, Honjo H, Arai A, Suzuki R, and Toyama J. Ionic basis of the chronotropic effect of acetylcholine on the rabbit sinoatrial node. Cardiovasc Res 29: 867-878, 1995.Crossref | PubMed | ISI | Google Scholar9 Braga and of on fluctuations and changes in blood pressure. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and elicited of heart rate variability. J Physiol | ISI | Google and modulation of sympathetic nerve activity to muscle in Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and and GABA mediate suprachiasmatic nucleus inputs to spinal-projecting paraventricular Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and is not associated with of the exercise reflex in Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google C, and Y. The effect of on the circadian control of human core body temperature is Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and of adenosine receptors in the does not affect the in awake rats. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google JK, A, and circadian and during two Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and sympathetic nerve and heart rate spectral effects of lower body negative pressure. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google Francis Johnson and of heart failure after myocardial in the Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google A, and of lower body pressure on muscle sympathetic nerve activity response to Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and Adenosine initial depression of in the rat in Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google R, and and circadian phase in a diurnal the Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and Johnson alterations and autonomic in an model of Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google MA, and The interaction of the Bainbridge and in the conscious Res | ISI | Google A, and handgrip exercise arterial control of sympathetic in Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and nerve regulation to is in rats. Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and in heart rate variability. J Physiol | ISI | Google and function and cardiovascular interactions and Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and interval variability in isolated working rat hearts at various conditions and Res | PubMed | Google A, A, and and autonomic of in patients with mild Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google Malpas SC. Neural on cardiovascular and Am J Physiol Heart Physiol 2002.Link | ISI | Google and thermoregulation in and rats in a Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and effects on reflex responses to mental stress in Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and reflex during orthostatic in Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and and responses to and are in rats. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and and in a by cycle. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and of humoral heart rate regulation in the Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google Armour and within the intrinsic cardiac nervous system contribute to chronotropic regulation. Am J Physiol Regul Integr Comp Physiol 285: 2003.Link | ISI | Google Rentero N, A, and McAllen of cardiac vagal motoneurons in rat nucleus ambiguus. Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and modulate control of heart rate in conscious rats. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and central actions of angiotensin to increase arterial pressure. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and modulate control of renal sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and modulation of cardiovascular and autonomic function in role of Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and Inhibition of sympathetic responses at birth in by of the paraventricular Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and JP. pattern of during acute and chronic in conscious adult rats. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google Armour and of chronic cardiac on of canine intracardiac neurons in Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and levels and circadian rhythm of activity in the a model of Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and nerve response of suprachiasmatic nucleus and Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · review · 309 citationsread the source →

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 →

Anxiety, depression and post-traumatic stress disorder in refugees resettling in high-income countries: systematic review and meta-analysis.

Background: The number of refugees is at its highest since the Second World War and on the rise. Many refugees suffer from anxiety, depression and post-traumatic stress disorder (PTSD), but exact and up-to-date prevalence estimates are not available. Aims: To report the pooled prevalence of anxiety and mood disorders and PTSD in general refugee populations residing in high-income countries and to detect sources of heterogeneity therein. Method: Systematic review with meta-analyses and meta-regression. Results: Systematic searches (final search date 3 August 2019) yielded 66 eligible publications that reported 150 prevalence estimates (total sample N = 14 882). Prevalence rates were 13 and 42% (95% CI 8-52%) for diagnosed and self-reported anxiety, 30 and 40% (95% CI 23-48%) for diagnosed and self-reported depression, and 29 and 37% (95% CI 22-45%) for diagnosed and self-reported PTSD. These estimates are substantially higher relative to those reported in non-refugee populations over the globe and to populations living in conflict or war settings, both for child/adolescent and adult refugees. Estimates were similar over different home and resettlement areas and independent of length of residence. Conclusions: Our data indicate a challenging and persisting disease burden in refugees due to anxiety, mood disorders and PTSD. Knowing this is relevant for the development of public health policies of host countries. Scalable interventions, tailored for refugees, should become more readily available.

BJPsych open · 225 citationsread the source →

Lower breathing frequencies in personalized slow-paced breathing enhance relaxation and reduce arousal.

Among all vital functions, breathing is uniquely under both autonomic and volitional control. This dual control enables conscious recognition and regulation of arousal. While breathwork affects arousal and relaxation, research rarely investigates the impact of specific parameters or individual differences. In a randomized crossover trial (N = 42), university students practiced three 5-min, personalized slow-paced breathing protocols at 40%, 60%, and 80% of their spontaneous breathing frequency. Lower frequencies enhanced subjective relaxation and reduced physiological arousal, as indicated by decreased heart rate, increased heart rate variability, and increased peripheral skin temperature. Lower frequencies also induced a greater shift in prefrontal neurophysiological arousal, with decreased relative delta power and increased relative alpha and beta power. In addition, prior experience with relaxation techniques strengthened subjective benefits, whereas higher anxious-depressive symptoms were associated with greater perceived stress after slow-paced breathing. Personalization and parameter-based optimization of breathing protocols may enhance relaxation during practice and strengthen self-regulatory capacity.

iScienceread the source →

Pregnancy in Adolescence - A Challenge Beyond Public Health Policies

Recent Sustainable Development Goals were established by the United Nations (2015–2030), including the broad goal of “good health and wellbeing” for all. Good health and wellbeing (item 3), quality education (item 4), gender equality (item 5) and reduced inequalities (item 10) are among the 17 items of the list.[ 1 ] These four cited goals are directly linked to the unresolved issue of pregnancy during adolescence, and point to fact that well-directed work needs to be done in this area. According to the United Nations Population Fund (UNFPA), around 16 million girls between the ages of 15 and 19, and 1 million girls under the age of 15, give birth every year around the world. In addition, ∼ 95% of these deliveries are concentrated in developing countries, and it is estimated that by 2035 births will be ∼ 20 million, making pregnancy in adolescence one of the major public health problems.[ 2 ] [ 3 ] In Brazil, the 2015 National Household Sample Program (PNAD, in the Portuguese acronym) compared the specific fertility rate of women aged 15 to 19 between the years of 2004 and 2014, and this indicator changed from 78.8 to 60.5 children per thousand women in this age group. The participation of adolescents in the total fertility rate remained high, going from 18.4 to 17.4% in the same period.[ 4 ] Maternity during adolescence draws attention to political debates and issues that have been studied in different areas of knowledge. In the area of public health, teenage pregnancy is considered a major problem due to the high prevalence and perinatal risks. Adolescent pregnancies may be considered high risk, especially those of adolescents under the age of 15, and they often fall outside the statistics data.[ 5 ] Childbirth and complications of pregnancy are the leading causes of hospitalization and death among adolescent women in developing countries. Anemia, preeclampsia and postpartum hemorrhage may occur in greater proportions than in adult pregnant women.[ 6 ] A recent study among pregnant Brazilian adolescents found that 42% of them suffered from anemia.[ 7 ] Preterm birth, low birth weight, low Apgar score and perinatal mortality are also more frequent among the children of teenagers.[ 6 ] The nutritional aspects should also be considered a problem in the association of gestation with adolescence, since these are two periods of great metabolic transformations overlapping. Adolescents in general present an accelerated increase in their overall metabolism, and often have poor nutritional habits and make poor food choices, a behavior that generates deficiencies in the intake of some micronutrients, higher rates of overweight and obesity, in addition to a greater frequency of pathological eating disorders, such as bulimia and anorexia.[ 8 ] Obesity may be associated with early menarche, which is one of the risk factors for early pregnancy. During pregnancy, teenagers can experiment excessive gestational weight gain, and that may result in post-pregnancy weight retention and obesity in adult life. Overweightness and obesity affect ∼ 30–40% of Brazilian women in reproductive age with physical and psychological repercussions leading to an increased risk of non-communicable diseases and a cycle of morbidity and poor health condition in the broadest sense.[ 9 ] [ 10 ] [ 11 ] [ 12 ] Besides the aforementioned medical risks, there is an increase in the social risk related to the physical, emotional, economic, and social dependence of these girls. There is also a greater risk of violence, in all its forms, associated with the lack of autonomy of these mothers in making their own decisions. Lack of autonomy can compromise the aspects related to the evolution of the gestation, as well as various aspects of the mother's future life. Examples of this condition include the later onset of prenatal follow-up,[ 6 ] and the higher prevalence of “delays” in obstetric care, related to the occurrence of maternal near miss, both of which are higher among adolescents.[ 13 ] Unwanted pregnancy is an important cause of morbidity in adolescence, and the use of effective contraception is one of the fundamental pillars that prevent the occurrence of this problem.[ 14 ] In the United States, teenage pregnancy rates are the highest among high-income countries.[ 15 ] However, there has been a reduction since 1990, which could be associated with educational programs that address responsible sexuality and contraceptive use among adolescents. Such educational programs would have been responsible for 86% of this decline.[ 16 ] The use of a “double method” or “double protection,” which consists of the use of a condom associated with another effective method, and a more widespread use of long-acting reversible contraceptives (LARCs) accompanied this reduction.[ 17 ] Any reversible method of contraception can be used for adolescents. Neither the age nor the number of previous pregnancies constitutes a medical reason to contraindicate any of them. It is important to remember that, whatever the choice, it should be based on current scientific information, respecting the eligibility criteria of each method established by the World Health Organization (WHO) and the recommendations of the Brazilian Ministry of Health.[ 18 ] [ 19 ] A Brazilian study shows that after childbirth, the most used contraceptive method was depot medroxyprogesterone acetate (DMPA). To improve contraception and reduce the chance of unintended pregnancies among adolescents, we should promote the use of LARCs.[ 20 ] A recent systematic review of the Cochrane Library compiled studies with a higher quality of information elaboration and consistency, and concluded that it is necessary to integrate educational interventions and offer contraceptive methods in order to reduce the phenomenon of teenage pregnancy.[ 21 ] The abstention from formal education among adolescent pregnant women is relevant, and many of them do not have the opportunity to resume their education once they give birth due to the time they spend in the care of their newborns.[ 22 ] The lower schooling of adolescents at the time of their first pregnancy can be attributed to this serious condition of social deprivation (dropping out of school), and could be one of the reasons behind the etiology of the problem, being the cause, and not the consequence. Disruption of studies in the puerperal period are often unavoidable due to lack of support for these girls and their babies. This all adds to the negative social and economic impact on the adolescents, their families, and society as a whole, for it hinders them from using their potential to invest in their education, find a job and ear an income. The absence from school also increases the chances of a recurring pregnancy still during adolescence. On the other hand, adolescents who do not become pregnant are more likely to finish high school.[ 22 ] In addition to formal education, adolescent sexual education is required. It is widely quoted by the WHO / and The Joint United Nations Program on HIV/AIDS (UNAIDS) that “Sexual education does not lead to increased sexual activity or stimulation of early sexual activity,” and a sexual orientation and education policy is necessary to enable “educated and empowered women and girls to make decisions about their own health,” thereby ensuring their reproductive rights, according to Dr. Margaret Chan, Director-General of the WHO. In this context, the role of the gynecologist-obstetrician is to guide and ensure safe and effective contraception and protection from sexually transmitted diseases. For pregnant teenagers, they could perform prenatal care, preferably with a multidisciplinary team composed of motivated professionals aiming at pregnancy care, as well as health promotion in the general sense. In the puerperal period, it is necessary to pay special attention to contraception, because the risk of another pregnancy is greater then. It is also important to recruit all possible support, so that these young mothers can resume their life plans. More than an organic look at the risks involved in gestation among adolescents, the meaning of pregnancy varies according to the social context in which the teenager is inserted. The restricted perspective of personal growth by these young women, the lack of educational incentive and labor market, make them find in pregnancy and in the social role of being a mother a life goal. In this sense, it is perceived that dealing with the reality of pregnancy in adolescence involves dealing with contradictions and ethical dilemmas that go beyond the clinical protocols of care. Adolescent pregnancy requires critical insight. It is a public health problem, and it presents different dimensions as a human and social phenomenon in different cultures, but its occurrence can often disrupt personal growth and development, and jeopardize future opportunities for many girls. Finally, it is a question of gender and vulnerability that reflects all kinds of inequity.

Revista Brasileira Ginecologia e Obstetrícia · editorial or comment · 27 citationsread the source →

Long work hours, prolonged daytime naps, and decreased cognitive performance in older adults.

In the United States, labor force market projections show significant growth in older ages. With postponed retirement and age-related health changes, attention to work times and recuperative strategies related to cognitive performance remains necessary for safe practice. The purpose of this study was to explore the relationships between long work hours, daytime naps, and cognitive performance in older adults. Cross-sectional data were obtained from 2013-2014 waves of the National Health and Aging Trends Study. A total sample of 308 workers were identified that had data on work hours, sleep-related parameters, and cognitive functioning. Around 42% of older adults were 70 to 74 years of age, and almost 73% of the sample worked < 40 hours/week. Workers on average slept 6.87 ± 1.27 hours, and nearly 43% reported daytime napping, with most naps being brief (≤ 45 minutes). Around 78% of the sample showed no signs of cognitive impairment. After controlling for covariates, older adults who worked ≥ 40 hours/week, compared to older adults who worked < 40 hours, had 2.07 (95%CI 1.03-4.18) increased odds for decreased cognitive performance. Older adults who took prolonged daytime naps (> 45 minutes), compared to those who took no naps, had 2.20 (95%CI 1.00-4.83) increased odds for decreased cognitive performance. No significant relationship was found between those who took brief daytime naps, compared to those who took no naps, and cognitive performance. Future research is needed to elucidate further the possible longitudinal effects of work times and daytime naps, which are modifiable, on cognitive performance in the aging workforce.

Chronobiology international · 9 citationsread the source →

Artificial Intelligence and Radiologist Burnout.

Importance: Understanding the association of artificial intelligence (AI) with physician burnout is crucial for fostering a collaborative interactive environment between physicians and AI. Objective: To estimate the association between AI use in radiology and radiologist burnout. Design, setting, and participants: This cross-sectional study conducted a questionnaire survey between May and October 2023, using the national quality control system of radiology in China. Participants included radiologists from 1143 hospitals. Radiologists reporting regular or consistent AI use were categorized as the AI group. Statistical analysis was performed from October 2023 to May 2024. Exposure: AI use in radiology practice. Main outcomes and measures: Burnout was defined by emotional exhaustion (EE) or depersonalization according to the Maslach Burnout Inventory. Workload was assessed based on working hours, number of image interpretations, hospital level, device type, and role in the workflow. AI acceptance was determined via latent class analysis considering AI-related knowledge, attitude, confidence, and intention. Propensity score-based mixed-effect generalized linear logistic regression was used to estimate the associations between AI use and burnout and its components. Interactions of AI use, workload, and AI acceptance were assessed on additive and multiplicative scales. Results: Among 6726 radiologists included in this study, 2376 (35.3%) were female and 4350 (64.7%) were male; the median (IQR) age was 41 (34-48) years; 3017 were in the AI group (1134 [37.6%] female; median [IQR] age, 40 [33-47] years) and 3709 in the non-AI group (1242 [33.5%] female; median [IQR] age, 42 [34-49] years). The weighted prevalence of burnout was significantly higher in the AI group compared with the non-AI group (40.9% vs 38.6%; P < .001). After adjusting for covariates, AI use was significantly associated with increased odds of burnout (odds ratio [OR], 1.20; 95% CI, 1.10-1.30), primarily driven by its association with EE (OR, 1.21; 95% CI, 1.10-1.34). A dose-response association was observed between the frequency of AI use and burnout (P for trend < .001). The associations were more pronounced among radiologists with high workload and lower AI acceptance. A significant negative interaction was noted between high AI acceptance and AI use. Conclusions and relevance: In this cross-sectional study of radiologist burnout, frequent AI use was associated with an increased risk of radiologist burnout, particularly among those with high workload or lower AI acceptance. Further longitudinal studies are needed to provide more evidence.

JAMA network open · 41 citationsread the source →

Associations between religious and spiritual variables and neuroimmune activity in survivors of breast cancer: a feasibility study.

Purpose: Chronic stress is associated with neuroimmune inflammation and adverse outcomes in breast cancer survivors. Some breast cancer survivors rely on religious and spiritual (R/S) variables to manage stress after breast cancer treatment. A spiritually based psychoneuroimmunological (PNI) model of health suggests that R/S variables influence neuroimmune activity; however, these associations are not well-established. A pilot study was conducted to assess the feasibility of studying associations between R/S variables and neuroimmune biomarkers in breast cancer survivors. Method: Salivary alpha-amylase (sAA) and interleukin-6 (IL-6) were sampled among women previously treated for breast cancer. The primary aim was to assess feasibility and acceptability of the sampling protocol. A secondary aim explored associations between sAA, IL-6, R/S variables, and health outcomes. Result: Forty-one women completed the study. Biomarker sampling yielded 246 acceptable specimens used for analysis. SAA was detectable in 96% of specimens and IL-6 was detectable in 44% of specimens. The R/S variables with the strongest associations to sAA were spiritual self-rank (rs = .39; p < .05) and forgiveness (rs = .40; p < .05). The R/S variable with the strongest association to salivary IL-6 was positive congregational support (rs = .42; p < .05). Conclusion: Feasibility and acceptability of the sampling protocol were confirmed. Reference ranges for sAA and IL-6 for female breast cancer survivors are presented. Results suggest that spiritual beliefs and religious practices are associated with neuroimmune activity, adding credence to a spiritually based PNI model of health. Findings lay the foundations for future R/S-based interventions to promote health and well-being in breast cancer survivors.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 3 citationsread the source →

Synergistic adversities and behavioral problems in traumatized children and adolescents.

Objective: This study investigated synergy of commonly co-occurring pairs of childhood traumas/adversities to determine: 1) if synergistic pairings differ by gender and/or age grouping; and 2) if some traumas/adversities were more synergistically reactive. Methods: A sample of 10,355 clinic-referred youth (1.5-18 years) from the National Child Traumatic Stress Network Core Data Set was divided by gender and categorized into salient age groups (1.5-5 years, 6-12 years, and 13-18 years). Attributable Proportion (AP), a biomedically relevant metric, was calculated to assess additive synergy for behavior problems on the CBCL. Results: Overall, only four pairs of adversities were synergistic. Three involved sexual abuse with physical abuse, parental loss, and domestic violence. When the sample was analyzed by Gender X Age group, however, a more complicated picture emerges. Twelve of the twenty-one possible pairings (57 %) show additive synergy in one or more categories. The mean AP accounted for approximately 40 % of outcome variance. Males had more synergistic pairings (16) than females (7). The average synergistic effect was higher for males (42 % of variance) than females (36 % of variance). The vast majority of synergy occurs in the 6-12 and 13-18 age groups. Sexual abuse was the most synergistically reactive trauma, pairing most frequently (16) followed by physical abuse (10) or neglect (9). Conclusion: Sexual abuse was malignantly synergistic, frequently pairing with other adversities, followed by physical abuse, neglect, and domestic violence. The findings underscore that all ACEs are not equal in their contributions to commonly assessed outcomes. The findings also have considerable implications for prevention, intervention, and future research.

Child abuse & neglect · 27 citationsread the source →

Evaluating a Middle-School Digital Citizenship Curriculum (Screenshots): Quasi-Experimental Study.

Background: Screenshots is an in-school curriculum that seeks to develop positive digital social skills in middle school students with the long-term goal of improving their health and well-being. The program imparts knowledge and teaches skills upon which young adolescents can build a set of beliefs and behaviors that foster respectful interactions, prosocial conflict resolutions, and safe and secure use of communication technology. Intervening in this way can improve young people's mental health by limiting their exposure to cyberbullying and other forms of negative online interactions. This study reports on an evaluation of the Screenshots program conducted with seventh graders in a public school system in a midsized New England city. Objective: This study aims to determine the effectiveness of the Screenshots program in increasing participants' knowledge about key concepts of digital citizenship and in shifting beliefs and intended behaviors to align with prosocial and safe online interactions. In addition, the study examines whether the program has varying effects on males' and females' conflict and bullying resolution strategies. Methods: This quasi-experimental evaluation was conducted in four middle schools in which one group of seventh graders received the Screenshots curriculum and another did not. Before and after the curriculum, all students completed a questionnaire that measured their knowledge of and beliefs about digital citizenship and related online behavioral concepts, their attitudes regarding strategies for stopping online bullying, and their intended online conflict resolution behaviors. Results: The sample included 92 students who received the curriculum and 71 students who were included in the comparison group. Pre- to postinstruction retention rates ranged from 52% (33/63) to 84% (21/25), varying by school and condition. The results showed an increase in knowledge about key curricular concepts for some students (F1,32=9.97; P=.003). In response to some individual items, students decreased their belief supportive of a negative online behavior (F1,76=9.00; P=.004) and increased their belief consistent with an online safety behavior (F1,42=4.39; P=.04) compared with the comparison group. Gender moderated the results related to conflict resolution, with males from one school reducing their endorsement of an aggressive option (F2,40=5.77; P=.006) and males from another school increasing their reported tendency to pursue a nonaggressive option (F2,28=3.65; P=.04). On average, participants reported learning something new from the classes. Conclusions: This study represents a rare evaluation of an in-school digital citizenship program and demonstrates the effectiveness of Screenshots. Students' increased knowledge of key curricular concepts represents a foundation for developing future beliefs and healthy behaviors. Differences in how adolescent males and females experience and perpetrate online aggression likely explain the conflict resolution findings and emphasize the need to examine gender differences in response to these programs. Students' high ratings of the relevance of Screenshots' content reinforce the need for this type of intervention.

JMIR mental health · 13 citationsread the source →

Loneliness and the Social Brain: How Perceived Social Isolation Impairs Human Interactions.

Loneliness is a painful condition associated with increased risk for premature mortality. The formation of new, positive social relationships can alleviate feelings of loneliness, but requires rapid trustworthiness decisions during initial encounters and it is still unclear how loneliness hinders interpersonal trust. Here, a multimodal approach including behavioral, psychophysiological, hormonal, and neuroimaging measurements is used to probe a trust-based mechanism underlying impaired social interactions in loneliness. Pre-stratified healthy individuals with high loneliness scores (n = 42 out of a screened sample of 3678 adults) show reduced oxytocinergic and affective responsiveness to a positive conversation, report less interpersonal trust, and prefer larger social distances compared to controls (n = 40). Moreover, lonely individuals are rated as less trustworthy compared to controls and identified by the blinded confederate better than chance. During initial trust decisions, lonely individuals exhibit attenuated limbic and striatal activation and blunted functional connectivity between the anterior insula and occipitoparietal regions, which correlates with the diminished affective responsiveness to the positive social interaction. This neural response pattern is not mediated by loneliness-associated psychological symptoms. Thus, the results indicate compromised integration of trust-related information as a shared neurobiological component in loneliness, yielding a reciprocally reinforced trust bias in social dyads.

Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 77 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 →

Establishing Clinically Relevant Severity Levels for the Central Sensitization Inventory.

Objectives: The aim of this study was to create and validate severity levels for the central sensitization inventory (CSI), a valid and reliable patient-reported outcome instrument designed to identify patients whose presenting symptoms may be related to a central sensitivity syndrome (CSS; eg, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome), with a proposed common etiology of central sensitization (CS). Methods: Based on CSI score means and standard deviations from previously published subject samples, the following CSI severity levels were established: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100. The concurrent validity of the CSI severity levels was then confirmed in a separate chronic pain patient sample (58% with a CSS diagnosis and 42% without) by demonstrating associations between CSI scores and (1) the number of physician-diagnosed CSSs; (2) CSI score distributions in both CSS and non-CSS patient samples; (3) patient-reported history of CSSs; and (4) patient-reported psychosocial measures, which are known to be associated with CSSs. Results: Compared to the non-CSS patient subsample, the score distribution of the CSS patient subsample was skewed toward the higher severity ranges. CSI mean scores moved into higher severity levels as the number of individual CSS diagnoses increased. Patients who scored in the extreme CSI severity level were more likely to report previous diagnoses of fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, tension/migraine headaches, and anxiety or panic attacks (P < 0.01). CSI severity levels were also associated with patient-reported depressive symptoms, perceived disability, sleep disturbance, and pain intensity (P ≤ 0.02). Conclusion: This study provides support for these CSI severity levels as a guideline for healthcare providers and researchers in interpreting CSI scores and evaluating treatment responsiveness.

Pain practice : the official journal of World Institute of Pain · 199 citationsread the source →

Psychological distress, depression, anxiety, and life satisfaction following COVID-19 infection: evidence from 11 UK longitudinal population studies.

Background: Evidence on associations between COVID-19 illness and mental health is mixed. We aimed to examine whether COVID-19 is associated with deterioration in mental health while considering pre-pandemic mental health, time since infection, subgroup differences, and confirmation of infection via self-reported test and serology data. Methods: We obtained data from 11 UK longitudinal studies with repeated measures of mental health (psychological distress, depression, anxiety, and life satisfaction; mental health scales were standardised within each study across time) and COVID-19 status between April, 2020, and April, 2021. We included participants with information available on at least one mental health outcome measure and self-reported COVID-19 status (suspected or test-confirmed) during the pandemic, and a subset with serology-confirmed COVID-19. Furthermore, only participants who had available data on a minimum set of covariates, including age, sex, and pre-pandemic mental health were included. We investigated associations between having ever had COVID-19 and mental health outcomes using generalised estimating equations. We examined whether associations varied by age, sex, ethnicity, education, and pre-pandemic mental health, whether the strength of the association varied according to time since infection, and whether associations differed between self-reported versus confirmed (by test or serology) infection. Findings: Between 21 Dec, 2021, and July 11, 2022, we analysed data from 54 442 participants (ranging from a minimum age of 16 years in one study to a maximum category of 90 years and older in another; including 33 200 [61·0%] women and 21 242 [39·0%] men) from 11 longitudinal UK studies. Of 40 819 participants with available ethnicity data, 36 802 (90·2%) were White. Pooled estimates of standardised differences in outcomes suggested associations between COVID-19 and subsequent psychological distress (0·10 [95% CI 0·06 to 0·13], I2=42·8%), depression (0·08 [0·05 to 0·10], I2=20·8%), anxiety (0·08 [0·05 to 0·10], I2=0·0%), and lower life satisfaction (-0·06 [-0·08 to -0·04], I2=29·2%). We found no evidence of interactions between COVID-19 and sex, education, ethnicity, or pre-pandemic mental health. Associations did not vary substantially between time since infection of less than 4 weeks, 4-12 weeks, and more than 12 weeks, and were present in all age groups, with some evidence of stronger effects in those aged 50 years and older. Participants who self-reported COVID-19 but had negative serology had worse mental health outcomes for all measures than those without COVID-19 based on serology and self-report. Participants who had positive serology but did not self-report COVID-19 did not show association with mental health outcomes. Interpretation: Self-reporting COVID-19 was longitudinally associated with deterioration in mental health and life satisfaction. Our findings emphasise the need for greater post-infection mental health service provision, given the substantial prevalence of COVID-19 in the UK and worldwide. Funding: UK Medical Research Council and UK National Institute for Health and Care Research.

The lancet. Psychiatry · 52 citationsread the source →