Search the source libraries

Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study.

Background: The dependence of the adaptive immune system on circadian rhythm is an emerging field of study with potential therapeutic implications. We aimed to determine whether specific time-of-day patterns of immune checkpoint inhibitor infusions might alter melanoma treatment efficacy. Methods: Melanoma Outcomes Following Immunotherapy (MEMOIR) is a longitudinal study of all patients with melanoma who received ipilimumab, nivolumab, or pembrolizumab, or a combination of these at a single tertiary cancer centre (Winship Cancer Institute of Emory University, Atlanta, GA, USA). For this analysis, we collected deidentified participant-level data from the MEMOIR database for adults (age ≥18 years) diagnosed with stage IV melanoma between 2012 and 2020. Those who received fewer than four infusions were excluded. Standard of care doses were used, with modifications at the treating physicians' discretion. The primary outcome was overall survival, defined as death from any cause and indexed from date of first infusion of immune checkpoint inhibitor. We calculated the association between overall survival and proportion of infusions of immune checkpoint inhibitors received after 1630 h (a composite time cutoff derived from seminal studies of the immune-circadian rhythm to represent onset of evening) using Cox regression and propensity score-matching on age, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase concentration, and receipt of corticosteroids and radiotherapy. Treatment-related adverse events that led to change or discontinuation of immune checkpoint inhibitors were also assessed. Findings: Between Jan 1, 2012, and Dec 31, 2020, 481 patients with melanoma received treatment with immune checkpoint inhibitors at the study centre, of whom 299 had stage IV disease and were included in this study; median follow-up was 27 months (IQR 14 to 47). In the complete unmatched sample, 102 (34%) patients were female and 197 (66%) were male, with a median age of 61 years (IQR 51 to 72). Every additional 20% of infusions of immune checkpoint inhibitors received after 1630 h (among all infusions received by a patient) conferred an overall survival hazard ratio (HR) of 1·31 (95% CI 1·00 to 1·71; p=0·046). A propensity score-matched analysis of patients who did (n=73) and did not (n=73) receive at least 20% of their infusions of immune checkpoint inhibitors after 1630 h (54 [37%] of 146 patients were women and 92 [63%] were men, with a median age of 58 years [IQR 48 to 68]) showed that having at least 20% of infusions in the evening was associated with shorter overall survival (median 4·8 years [95% CI 3·9 to not estimable] vs not reached; HR 2·04 [1·04 to 4·00; p=0·038]). This result remained robust to multivariable proportional hazards adjustment with (HR 1·80 [1·08 to 2·98; p=0·023]) and without (2·16 [1·10 to 4·25; p=0·025]) inclusion of the complete unmatched study sample. The most common adverse events were colitis (54 [18%] of 299 patients), hepatitis (27 [9%]), and hypophysitis (15 [5%]), and there were no treatment-related deaths. Interpretation: Our findings are in line with an increasing body of evidence that adaptive immune responses are less robust when initially stimulated in the evening than if stimulated in the daytime. Although prospective studies of the timing of immune checkpoint inhibitor infusions are warranted, efforts towards scheduling infusions before mid-afternoon could be considered in the multidisciplinary management of advanced melanoma. Funding: National Institutes of Health, American Society for Radiation Oncology and Melanoma Research Alliance, and Winship Cancer Institute.

The Lancet. Oncology · clinical trial · 146 citationsread the source →

Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial.

Objective: To assess the effect of a multimodal group exercise intervention, as an adjunct to conventional care, on fatigue, physical capacity, general wellbeing, physical activity, and quality of life in patients with cancer who were undergoing adjuvant chemotherapy or treatment for advanced disease. Design: Randomised controlled trial. Setting: Two university hospitals in Copenhagen, Denmark. Participants: 269 patients with cancer; 73 men, 196 women, mean age 47 years (range 20-65) representing 21 diagnoses. Main exclusion criteria were brain or bone metastases. 235 patients completed follow-up. Intervention: Supervised exercise comprising high intensity cardiovascular and resistance training, relaxation and body awareness training, massage, nine hours weekly for six weeks in addition to conventional care, compared with conventional care. Main outcome measures: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Medical Outcomes Study Short Form (MOS SF-36), Leisure Time Physical Activity Questionnaire, muscular strength (one repetition maximum), maximum oxygen consumption (Vo(2)max). Statistical methods The general linear model was used for continuous outcome while analysis of associates between categorical outcomes was performed as analysis of marginal homogeneity in contingency tables. Results: Adjusted for baseline score, disease, and demographic covariates, the intervention group showed an estimated improvement at six weeks for the primary outcome, fatigue, of -6.6 points (95% confidence interval -12.3 to -0.9, P=0.02; effect size=0.33, 0.04 to 0.61). Significant effects were seen on vitality (effect size 0.55, 95% CI 0.27 to 0.82), physical functioning (0.37, 0.09 to 0.65), role physical (0.37, 0.10 to 0.64), role emotional (0.32, 0.05 to 0.59), and mental health (0.28, 0.02 to 0.56) scores. Improvement was noted in physical capacity: estimated mean difference between groups for maximum oxygen consumption was 0.16 l/min (95% CI 0.1 to 0.2, P<0.0001) and for muscular strength (leg press) was 29.7 kg (23.4 to 34.9, P<0.0001). No significant effect was seen on global health status/quality of life. Conclusion: A supervised multimodal exercise intervention including high and low intensity components was feasible and could safely be used in patients with various cancers who were receiving adjuvant chemotherapy or treatment for advanced disease. The intervention reduced fatigue and improved vitality, aerobic capacity, muscular strength, and physical and functional activity, and emotional wellbeing, but not quality of life. Trial registration: Current Controlled trials ISRCTN05322922.

BMJ (Clinical research ed.) · randomised controlled trial · 304 citationsread the source →

Job satisfaction and burnout syndrome among intensive-care unit nurses: A systematic review and meta-analysis.

Introduction: The severe conditions often experienced in an intensive care unit, combined with poor working conditions, increase stress and therefore decrease job satisfaction. Sustained stress in the workplace leads to the development of burnout, a syndrome characterised by three dimensions: emotional exhaustion, depersonalisation and perceived lack of personal fulfilment. Objective: To analyse the relationship between burnout syndrome and job satisfaction among ICU personnel. Data sources: The PubMed, CINAHL and Scopus databases were used. Study design: A systematic review and meta-analysis. The study sample consisted of 18 quantitative primary studies conducted in the last five years. Validated questionnaires were used to assess burnout in ICU healthcare workers, the most commonly used being the Maslach Burnout Inventory. Extraction methods: The search equation applied was: "job satisfaction AND nurs* AND burnout AND (ICU OR intensive care units)". The search was performed in October 2022. Principal findings: The search returned 514 results. Only 73 articles met the eligibility criteria. After reading the title and abstract, 20 articles were selected. After reading the full texts, 12 articles remained and after the reverse search, 18 articles were finally selected. The studies reported a 50% prevalence of burnout, all three dimensions of which were heightened by the COVID-19 pandemic. Analysis of the study findings revealed an inverse association between burnout and job satisfaction. Conclusions: Job dissatisfaction of ICU nurses depends on lack of experience, working conditions or working environment among others. ICU nurses with lower job satisfaction have higher levels of burnout. Implications for clinical practice: This meta-analysis shows the potential value of job satisfaction on improving health outcomes related to burnout syndrome for nursing professional in Intensive Care Units. Different factors that could increase job satisfaction and consequently protect them from suffering high levels of burnout, such as salary, permanence in the service, mental health care are the responsibility of the hospital supervisor and, finally, of the own Health System. Knowledge of a risk profile based on the factors influencing job dissatisfaction would enable the implementation of effective workplace interventions to reduce or prevent the risk of burnout. Health policies should focus on protecting the worker, so in addition to improving working conditions, it would be interesting to promote coping skills in order to improve the quality of care and patient safety.

Intensive & critical care nursing · meta-analysis · 75 citationsread the source →

Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year.

Objective: To describe the outcomes of a consecutive series of depressed patients treated with vagus nerve stimulation (VNS) following US Food and Drug Administration (FDA) approval of this intervention. Method: We implanted a VNS device in 15 consecutive outpatients with treatment-resistant major depressive episodes, including 10 with major depressive disorder and 5 with bipolar disorder (DSM-IV criteria), between November 2005 and August 2006. Existing antidepressant treatment remained fixed as far as clinically possible. The primary outcome was change from baseline in the Beck Depression Inventory (BDI) score. Outcomes were assessed at 6 and 12 months postimplant and compared to those of the VNS pivotal efficacy trial that led to FDA approval of VNS. Results: The BDI score decreased significantly compared to baseline at 6 months (P < .05) and 12 months (P < .01), from a mean of 37.8 (SD = 7.8) before VNS activation to a mean of 24.6 (SD = 11.4) at 12 months. By 1 year, 28.6% (n = 4) of the sample responded to VNS and 7.1% (n = 1) remitted according to the BDI. Secondary outcomes on the Hamilton Depression Rating Scale 24-Item showed similar improvement at 1 year, with a 43% response rate (n = 6) and 14.3% remission rate (n = 2). No obvious predictors of response were detected. Side effects of VNS included hoarseness (73%), dyspnea (47%), nausea (40%), pain (33%), and anxiety (20%); no patient terminated treatment due to intolerable side effects. Conclusions: We found that a substantial minority of patients with extremely difficult-to-treat depressive disorders benefited from VNS in an ambulatory clinical practice, with outcomes comparable to those observed in previous VNS efficacy studies and with a similar side effect profile.

The Journal of clinical psychiatry · clinical trial · 93 citationsread the source →

"There Was a Sense That Our Load Had Been Lightened": Evaluating Outcomes of Virtual Ethics Rounds for Veterinary Team Members.

Clinical ethics support services (CESS) are employed in healthcare to improve patient care and help team members develop skills to recognize and navigate ethically challenging situations (ECS). The objective of this study was to evaluate the impact of ethics rounds, one form of CESS, on veterinary team members. An anonymous, online mixed-methods survey incorporating a 15-item instrument designed to assess the outcomes of moral case deliberation originally developed for human healthcare workers (the Euro-MCD 2.0), was developed. The survey was administered to veterinary team members prior to and following participation in a 90-min virtual ethics rounds session. A total of 23 sessions of virtual ethics rounds were held. In total, 213 individuals participated, and 89 completed both surveys (response rate 41.8%). Most respondents were female (n = 70, 81%). Most were veterinarians (n = 51, 59%), followed by other veterinary team members (practice manager, animal attendant) (n = 18, 21%), veterinary nurses or animal health technicians (n = 10, 12%) and veterinary students (n = 8, 9%). Age ranged from 20 to 73 (median 41, IQR 32-52, n = 87). While there was no statistically significant difference between overall modified Euro-MCD 2.0 scores between T1 and T2, there were statistically significant changes in 7 out of 15 Euro-MCD 2.0 items in the domains of moral competence and moral teamwork. Reflexive thematic analysis of free-text responses identified themes including the types, impact and barriers to resolving ECS, the impacts of ethics rounds on veterinary team members and constraints preventing veterinary team members from speaking up in the face of ECS. While participants largely described the impact of ethics rounds as beneficial (for example, by facilitating clarification of thinking about ECS, allowing participants to see ECS from the perspective of others and providing a safe space for discussion), reflecting on ECS could be stressful for participants. Active participation in ethics rounds may be inhibited in the context of power imbalance, or in settings where bullying occurs. Overall, carefully facilitated ethics rounds has the potential to improve the ability of veterinary team members to identify and navigate ECS, and potentially mitigate moral distress.

Frontiers in veterinary science · 8 citationsread the source →

Safety assessment of citrus and olive by-products using a sustainable methodology based on natural deep eutectic solvents.

In this work, the application of betaine-based hydrophilic natural deep eutectic solvents (NADESs) as green extraction solvents was proposed for the first time for the evaluation of twelve pesticides in citrus and olive by-products intended to be applied as potential sources of compounds with neuroprotective activity against Alzheimer Disease. Ultrasound-assisted extraction of selected pesticides was followed by separation and determination using gas chromatography coupled to single quadrupole mass spectrometry. Eight NADESs were tested using different hydrogen bond donors (i.e. citric and lactic acid, fructose, glucose, glycerol, propylene glycol, propionic and butanoic acid). Other factors affecting extraction efficiency were also evaluated using a step-by-step approach. Eight mL of a mixture composed of 60% betaine:propylene glycol NADES at a molar ratio 1:4 and 40% of water, as well as 30 min of ultrasound-assisted extraction were selected as the most adequate conditions. The methodology was validated prior to its application in citrus and olive by-products. Recovery values were between 73 and 115% (RSD% < 20%), while limits of quantification of the method were in the range 8.5-128.8 µg/kg, which demonstrates the suitability of the procedure to determine the selected group of pesticides, usually applied in citrus and olive crops, at the legislated levels. The greenness of the procedure was also evaluated using AGREE calculator. Finally, the whole method was applied for the safety assessment of seven olive leaf samples and seven citrus by-products produced in Spain, finding the presence of several of the evaluated compounds at concentrations higher than the established limits for similar products.

Journal of chromatography. A · 8 citationsread the source →

Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies.

Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3%, 12.3%, 47.8%, 20.5 years (k = 36, median = 25, IQR = 20-34), personality disorders/related traits: 1.9%, 9.6%, 47.7%, 20.5 years (k = 6, median = 25, IQR = 20-33), and mood disorders: 2.5%, 11.5%, 34.5%, 20.5 years (k = 79, median = 31, IQR = 21-46). No significant difference emerged by sex, or definition of age of onset. Median age at onset for specific mental disorders mapped on a time continuum, from phobias/separation anxiety/autism spectrum disorder/attention deficit hyperactivity disorder/social anxiety (8-13 years) to anorexia nervosa/bulimia nervosa/obsessive-compulsive/binge eating/cannabis use disorders (17-22 years), followed by schizophrenia, personality, panic and alcohol use disorders (25-27 years), and finally post-traumatic/depressive/generalized anxiety/bipolar/acute and transient psychotic disorders (30-35 years), with overlap among groups and no significant clustering. These results inform the timing of good mental health promotion/preventive/early intervention, updating the current mental health system structured around a child/adult service schism at age 18.

Molecular psychiatry · meta-analysis · 2420 citationsread the source →

Effectiveness of digital psychological interventions for mental health problems in low-income and middle-income countries: a systematic review and meta-analysis.

Background: The effectiveness of digital psychological interventions in low-income and middle-income countries (LMICs) remains unclear. We aimed to systematically investigate the available evidence for digital psychological interventions in reducing mental health problems in LMICs. Methods: In this systematic review and meta-analysis, we searched PubMed, PsycINFO, Embase, and Cochrane databases for articles published in English from database inception to March 9, 2020. We included randomised controlled trials investigating digital psychological interventions in individuals with mental health problems in LMICs. We extracted data on demographics, inclusion and exclusion criteria, details of the intervention, including the setting, digital delivery method, control group conditions, number of sessions, therapeutic orientation (eg, cognitive therapy or behaviour therapy), presence or absence of guidance, and length of follow-up, and statistical information to calculate effect sizes. If a study reported insufficient data to calculate effect sizes, the corresponding authors were contacted to provide data that could be aggregated. We did random-effects meta-analyses, and calculated the standardised mean difference in scores of digital psychological interventions versus control conditions (Hedges'g). Quality of evidence was assessed by use of the Grading of Recommendations Assessment, Development, and Evaluation approach. The primary outcome was post-intervention mental health problems, as measured by self-reporting instruments or clinical interviews. This study is registered with PROSPERO, CRD42019137755. Findings: We identified 22 eligible studies that were included in the meta-analysis. The included studies involved a total of 4104 participants (2351 who received a digital psychological intervention and 1753 who were in the control group), and mainly focused on young adults (mean age of the study population was 20-35 years) with depression or substance misuse. The results showed that digital psychological interventions are moderately effective when compared with control interventions (Hedges'g 0·60 [95% CI 0·45-0·75]; Hedges'g with treatment as usual subgroup for comparison 0·54 [0·35-0·73]). Heterogeneity between studies was substantial (I2=74% [95% CI 60-83]). There was no evidence of publication bias, and the quality of evidence according to the GRADE criteria was generally high. Interpretation: Digital psychological interventions, which have been mostly studied in individuals with depression and substance misuse, are superior to control conditions, including usual care, and are moderately effective in LMICs. However, the considerable heterogeneity observed in our analysis highlights the need for more studies to be done, with standardised implementation of digital psychological intervention programmes to improve their reproducibility and efficiency. Digital psychological interventions should be considered for regions where usual care for mental health problems is minimal or absent. Funding: None. Translations: For the Persian, Chinese, Hindi, Portuguese, Bahasa, Turkish, Romanian, Spanish and Thai translations of the abstract see Supplementary Materials section.

The lancet. Psychiatry · meta-analysis · 194 citationsread the source →

Planned early birth versus expectant management (waiting) for prelabour rupture of membranes at term (37 weeks or more).

Background: Prelabour rupture of membranes (PROM) at term is managed expectantly or by planned early birth. It is not clear if waiting for birth to occur spontaneously is better than intervening, e.g. by inducing labour. Objectives: The objective of this review is to assess the effects of planned early birth (immediate intervention or intervention within 24 hours) when compared with expectant management (no planned intervention within 24 hours) for women with term PROM on maternal, fetal and neonatal outcomes. Search methods: We searched Cochrane Pregnancy and Childbirth's Trials Register (9 September 2016) and reference lists of retrieved studies. Selection criteria: Randomised or quasi-randomised controlled trials of planned early birth compared with expectant management (either in hospital or at home) in women with PROM at 37 weeks' gestation or later. Data collection and analysis: Two review authors independently assessed trials for inclusion, extracted the data, and assessed risk of bias of the included studies. Data were checked for accuracy. Main results: Twenty-three trials involving 8615 women and their babies were included in the update of this review. Ten trials assessed intravenous oxytocin; 12 trials assessed prostaglandins (six trials in the form of vaginal prostaglandin E2 and six as oral, sublingual or vaginal misoprostol); and one trial each assessed Caulophyllum and acupuncture. Overall, three trials were judged to be at low risk of bias, while the other 20 were at unclear or high risk of bias. Primary outcomes: women who had planned early birth were at a reduced risk of maternal infectious morbidity (chorioamnionitis and/or endometritis) than women who had expectant management following term prelabour rupture of membranes (average risk ratio (RR) 0.49; 95% confidence interval (CI) 0.33 to 0.72; eight trials, 6864 women; Tau² = 0.19; I² = 72%; low-quality evidence), and their neonates were less likely to have definite or probable early-onset neonatal sepsis (RR 0.73; 95% CI 0.58 to 0.92; 16 trials, 7314 infants;low-quality evidence). No clear differences between the planned early birth and expectant management groups were seen for the risk of caesarean section (average RR 0.84; 95% CI 0.69 to 1.04; 23 trials, 8576 women; Tau² = 0.10; I² = 55%; low-quality evidence); serious maternal morbidity or mortality (no events; three trials; 425 women; very low-quality evidence); definite early-onset neonatal sepsis (RR 0.57; 95% CI 0.24 to 1.33; six trials, 1303 infants; very low-quality evidence); or perinatal mortality (RR 0.47; 95% CI 0.13 to 1.66; eight trials, 6392 infants; moderate-quality evidence). Secondary outcomes: women who had a planned early birth were at a reduced risk of chorioamnionitis (average RR 0.55; 95% CI 0.37 to 0.82; eight trials, 6874 women; Tau² = 0.19; I² = 73%), and postpartum septicaemia (RR 0.26; 95% CI 0.07 to 0.96; three trials, 263 women), and their neonates were less likely to receive antibiotics (average RR 0.61; 95% CI 0.44 to 0.84; 10 trials, 6427 infants; Tau² = 0.06; I² = 32%). Women in the planned early birth group were more likely to have their labour induced (average RR 3.41; 95% CI 2.87 to 4.06; 12 trials, 6945 women; Tau² = 0.05; I² = 71%), had a shorter time from rupture of membranes to birth (mean difference (MD) -10.10 hours; 95% CI -12.15 to -8.06; nine trials, 1484 women; Tau² = 5.81; I² = 60%), and their neonates had lower birthweights (MD -79.25 g; 95% CI -124.96 to -33.55; five trials, 1043 infants). Women who had a planned early birth had a shorter length of hospitalisation (MD -0.79 days; 95% CI -1.20 to -0.38; two trials, 748 women; Tau² = 0.05; I² = 59%), and their neonates were less likely to be admitted to the neonatal special or intensive care unit (RR 0.75; 95% CI 0.66 to 0.85; eight trials, 6179 infants), and had a shorter duration of hospital (-11.00 hours; 95% CI -21.96 to -0.04; one trial, 182 infants) or special or intensive care unit stay (RR 0.72; 95% CI 0.61 to 0.85; four trials, 5691 infants). Women in the planned early birth group had more positive experiences compared with women in the expectant management group. No clear differences between groups were observed for endometritis; postpartum pyrexia; postpartum antibiotic usage; caesarean for fetal distress; operative vaginal birth; uterine rupture; epidural analgesia; postpartum haemorrhage; adverse effects; cord prolapse; stillbirth; neonatal mortality; pneumonia; Apgar score less than seven at five minutes; use of mechanical ventilation; or abnormality on cerebral ultrasound (no events).None of the trials reported on breastfeeding; postnatal depression; gestational age at birth; meningitis; respiratory distress syndrome; necrotising enterocolitis; neonatal encephalopathy; or disability at childhood follow-up. In subgroup analyses, there were no clear patterns of differential effects for method of induction, parity, use of maternal antibiotic prophylaxis, or digital vaginal examination. Results of the sensitivity analyses based on trial quality were consistent with those of the main analysis, except for definite or probable early-onset neonatal sepsis where no clear difference was observed. Authors' conclusions: There is low quality evidence to suggest that planned early birth (with induction methods such as oxytocin or prostaglandins) reduces the risk of maternal infectious morbidity compared with expectant management for PROM at 37 weeks' gestation or later, without an apparent increased risk of caesarean section. Evidence was mainly downgraded due to the majority of studies contributing data having some serious design limitations, and for most outcomes estimates were imprecise. Although the 23 included trials in this review involved a large number of women and babies, the quality of the trials and evidence was not high overall, and there was limited reporting for a number of important outcomes. Thus further evidence assessing the benefits or harms of planned early birth compared with expectant management, considering maternal, fetal, neonatal and longer-term childhood outcomes, and the use of health services, would be valuable. Any future trials should be adequately designed and powered to evaluate the effects on short- and long-term outcomes. Standardisation of outcomes and their definitions, including for the assessment of maternal and neonatal infection, would be beneficial.

The Cochrane database of systematic reviews · meta-analysis · 75 citationsread the source →

Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis.

Background: Depressive disorders are common in children and adolescents. Antidepressants, psychotherapies, and their combination are often used in routine clinical practice; however, available evidence on the comparative efficacy and safety of these interventions is inconclusive. Therefore, we sought to compare and rank all available treatment interventions for the acute treatment of depressive disorders in children and adolescents. Methods: We did a systematic review and network meta-analysis. We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, PsycINFO, ProQuest, CINAHL, LiLACS, international trial registries, and the websites of regulatory agencies for published and unpublished randomised controlled trials from database inception until Jan 1, 2019. We included placebo-controlled and head-to-head trials of 16 antidepressants, seven psychotherapies, and five combinations of antidepressant and psychotherapy that are used for the acute treatment of children and adolescents (≤18 years old and of both sexes) with depressive disorder diagnosed according to standard operationalised criteria. Trials recruiting participants with treatment-resistant depression, bipolar disorder, psychotic depression, treatment duration of less than 4 weeks, or an overall sample size of fewer than ten patients were excluded. We extracted data following a predefined hierarchy of outcome measures, and assessed risk of bias and certainty of evidence using validated methods. Primary outcomes were efficacy (change in depressive symptoms) and acceptability (treatment discontinuation due to any cause). We estimated summary standardised mean differences (SMDs) or odds ratios (ORs) with credible intervals (CrIs) using network meta-analysis with random effects. This study was registered with PROSPERO, number CRD42015020841. Findings: From 20 366 publications, we included 71 trials (9510 participants). Depressive disorders in most studies were moderate to severe. In terms of efficacy, fluoxetine plus cognitive behavioural therapy (CBT) was more effective than CBT alone (-0·78, 95% CrI -1·55 to -0·01) and psychodynamic therapy (-1·14, -2·20 to -0·08), but not more effective than fluoxetine alone (-0·22, -0·86 to 0·42). No pharmacotherapy alone was more effective than psychotherapy alone. Only fluoxetine plus CBT and fluoxetine were significantly more effective than pill placebo or psychological controls (SMDs ranged from -1·73 to -0·51); and only interpersonal therapy was more effective than all psychological controls (-1·37 to -0·66). Nortriptyline (SMDs ranged from 1·04 to 2·22) and waiting list (SMDs ranged from 0·67 to 2·08) were less effective than most active interventions. In terms of acceptability, nefazodone and fluoxetine were associated with fewer dropouts than sertraline, imipramine, and desipramine (ORs ranged from 0·17 to 0·50); imipramine was associated with more dropouts than pill placebo, desvenlafaxine, fluoxetine plus CBT, and vilazodone (2·51 to 5·06). Most of the results were rated as "low" to "very low" in terms of confidence of evidence according to Confidence In Network Meta-Analysis. Interpretation: Despite the scarcity of high-quality evidence, fluoxetine (alone or in combination with CBT) seems to be the best choice for the acute treatment of moderate-to-severe depressive disorder in children and adolescents. However, the effects of these interventions might vary between individuals, so patients, carers, and clinicians should carefully balance the risk-benefit profile of efficacy, acceptability, and suicide risk of all active interventions in young patients with depression on a case-by-case basis. Funding: National Key Research and Development Program of China.

The lancet. Psychiatry · systematic review · 248 citationsread the source →

Populations and Interventions for Palliative and End-of-Life Care: A Systematic Review.

Importance: Evidence supports palliative care effectiveness. Given workforce constraints and the costs of new services, payers and providers need help to prioritize their investments. They need to know which patients to target, which personnel to hire, and which services best improve outcomes. Objective: To inform how payers and providers should identify patients with "advanced illness" and the specific interventions they should implement, we reviewed the evidence to identify (1) individuals appropriate for palliative care and (2) elements of health service interventions (personnel involved, use of multidisciplinary teams, and settings of care) effective in achieving better outcomes for patients, caregivers, and the healthcare system. Evidence review: Systematic searches of MEDLINE, EMBASE, PsycINFO, Web of Science, and Cochrane Database of Systematic Reviews databases (1/1/2001-1/8/2015). Results: Randomized controlled trials (124) met inclusion criteria. The majority of studies in cancer (49%, 38 of 77 studies) demonstrated statistically significant patient or caregiver outcomes (e.g., p < 0.05), as did those in congestive heart failure (CHF) (62%, 13 of 21), chronic obstructive pulmonary disease (COPD; 58%, 11 of 19), and dementia (60%, 15 of 25). Most prognostic criteria used clinicians' judgment (73%, 22 of 30). Most interventions included a nurse (70%, 69 of 98), and many were nurse-only (39%, 27 of 69). Social workers were well represented, and home-based approaches were common (56%, 70 of 124). Home interventions with visits were more effective than those without (64%, 28 of 44; vs. 46%, 12 of 26). Interventions improved communication and care planning (70%, 12 of 18), psychosocial health (36%, 12 of 33, for depressive symptoms; 41%, 9 of 22, for anxiety), and patient (40%, 8 of 20) and caregiver experiences (63%, 5 of 8). Many interventions reduced hospital use (65%, 11 of 17), but most other economic outcomes, including costs, were poorly characterized. Palliative care teams did not reliably lower healthcare costs (20%, 2 of 10). Conclusions: Palliative care improves cancer, CHF, COPD, and dementia outcomes. Effective models include nurses, social workers, and home-based components, and a focus on communication, psychosocial support, and the patient or caregiver experience. High-quality research on intervention costs and cost outcomes in palliative care is limited.

Journal of palliative medicine · systematic review · 135 citationsread the source →

Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.

Background: Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder. Methods: We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291. Findings: We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89-2·41) for amitriptyline and 1·37 (1·16-1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72-0·97) and fluoxetine (0·88, 0·80-0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01-1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19-1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51-0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43-0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30-2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low. Interpretation: All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants. Funding: National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science.

Lancet (London, England) · systematic review · 2220 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 →

Smoking cessation for people with severe mental illness (SCIMITAR+): a pragmatic randomised controlled trial.

Background: People with severe mental illnesses such as schizophrenia are three times more likely to smoke than the wider population, contributing to widening health inequalities. Smoking remains the largest modifiable risk factor for this health inequality, but people with severe mental illness have not historically engaged with smoking cessation services. We aimed to test the effectiveness of a combined behavioural and pharmacological smoking cessation intervention targeted specifically at people with severe mental illness. Methods: In the smoking cessation intervention for severe mental illness (SCIMITAR+) trial, a pragmatic, randomised controlled study, we recruited heavy smokers with bipolar disorder or schizophrenia from 16 primary care and 21 community-based mental health sites in the UK. Participants were eligible if they were aged 18 years or older, and smoked at least five cigarettes per day. Exclusion criteria included substantial comorbid drug or alcohol problems and people who lacked capacity to consent at the time of recruitment. Using computer-generated random numbers, participants were randomly assigned (1:1) to a bespoke smoking cessation intervention or to usual care. Participants, mental health specialists, and primary care physicians were unmasked to assignment. The bespoke smoking cessation intervention consisted of behavioural support from a mental health smoking cessation practitioner and pharmacological aids for smoking cessation, with adaptations for people with severe mental illness-such as, extended pre-quit sessions, cut down to quit, and home visits. Access to pharmacotherapy was via primary care after discussion with the smoking cessation specialist. Under usual care participants were offered access to local smoking cessation services not specifically designed for people with severe mental illnesses. The primary endpoint was smoking cessation at 12 months ascertained via carbon monoxide measurements below 10 parts per million and self-reported cessation for the past 7 days. Secondary endpoints were biologically verified smoking cessation at 6 months; number of cigarettes smoked per day, Fagerström Test for Nicotine Dependence (FTND) and Motivation to Quit (MTQ) questionnaire; general and mental health functioning determined via the Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder-7 (GAD-7) questionnaire, and 12-Item Short Form Health Survey (SF-12); and body-mass index (BMI). This trial was registerd with the ISRCTN registry, number ISRCTN72955454, and is complete. Findings: Between Oct 7, 2015, and Dec 16, 2016, 526 eligible patients were randomly assigned to the bespoke smoking cessation intervention (n=265) or usual care (n=261). 309 (59%) participants were male, median age was 47·2 years (IQR 36·3-54·5), with high nicotine dependence (mean 24 cigarettes per day [SD 13·2]), and the most common severe mental disorders were schizophrenia or other psychotic illness (n=343 [65%]), bipolar disorder (n=115 [22%]), and schizoaffective disorder (n=66 [13%]). 234 (88%) of intervention participants engaged with the treatment programme and attended 6·4 (SD 3·5) quit smoking sessions, with an average duration of 39 min (SD 17; median 35 min, range 5-120). Verified quit data at 12 months were available for 219 (84%) of 261 usual care and 223 (84%) of 265 intervention participants. The proportion of participants who had quit at 12 months was higher in the intervention group than in the usual care group, but non-significantly (34 [15%] of 223 [13% of those assigned to group] vs 22 [10%] of 219 [8% of those assigned to group], risk difference 5·2%, 95% CI -1·0 to 11·4; odds ratio [OR] 1·6, 95% CI 0·9 to 2·9; p=0·10). The proportion of participants who quit at 6 months was significantly higher in the intervention group than in the usual care group (32 [14%] of 226 vs 14 [6%] of 217; risk difference 7·7%, 95% CI 2·1 to 13·3; OR 2·4, 95% CI 1·2 to 4·6; p=0·010). The incidence rate ratio for number of cigarettes smoked per day at 6 months was 0·90 (95% CI 0·80 to 1·01; p=0·079), and at 12 months was 1·00 (0·89 to 1·13; p=0·95). At both 6 months and 12 months, the intervention group was non-significantly favoured in the FTND (adjusted mean difference 6 months -0·18, 95% CI -0·53 to 0·17, p=0·32; and 12 months -0·01, -0·39 to 0·38, p=0·97) and MTQ questionnaire (adjusted mean difference 0·58, -0·01 to 1·17, p=0·056; and 12 months 0·64, 0·04 to 1·24, p=0·038). The PHQ-9 showed no difference between the groups (adjusted mean difference at 6 months 0·20, 95% CI -0·85 to 1·24 vs 12 months -0·12, -1·18 to 0·94). For the SF-12 survey, we saw evidence of improvement in physical health in the intervention group at 6 months (adjusted mean difference 1·75, 95% CI 0·21 to 3·28), but this difference was not evident at 12 months (0·59, -1·07 to 2·26); and we saw no difference in mental health between the groups at 6 or 12 months (adjusted mean difference at 6 months -0·73, 95% CI -2·82 to 1·36, and 12 months -0·41, -2·35 to 1·53). The GAD-7 questionnaire showed no difference between the groups (adjusted mean difference at 6 months -0·32 95% CI -1·26 to 0·62 vs 12 months -0·10, -1·05 to 0·86). No difference in BMI was seen between the groups (adjusted mean difference 6 months 0·16, 95% CI -0·54 to 0·85; 12 months 0·25, -0·62 to 1·13). Interpretation: This bespoke intervention is a candidate model of smoking cessation for clinicians and policy makers to address high prevalence of smoking. The incidence of quitting at 6 months shows that smoking cessation can be achieved, but the waning of this effect by 12 months means more effort is needed for sustained quitting. Funding: National Institute for Health Research Health Technology Assessment Programme.

The lancet. Psychiatry · randomised controlled trial · 134 citationsread the source →

Behavioural interventions to promote physical activity in a multiethnic population at high risk of diabetes: PROPELS three-arm RCT.

Background: Type 2 diabetes is a leading cause of mortality globally and accounts for significant health resource expenditure. Increased physical activity can reduce the risk of diabetes. However, the longer-term clinical effectiveness and cost-effectiveness of physical activity interventions in those at high risk of type 2 diabetes is unknown. Objectives: To investigate whether or not Walking Away from Diabetes (Walking Away) - a low-resource, 3-hour group-based behavioural intervention designed to promote physical activity through pedometer use in those with prediabetes - leads to sustained increases in physical activity when delivered with and without an integrated mobile health intervention compared with control. Design: Three-arm, parallel-group, pragmatic, superiority randomised controlled trial with follow-up conducted at 12 and 48 months. Setting: Primary care and the community. Participants: Adults whose primary care record included a prediabetic blood glucose measurement recorded within the past 5 years [HbA1c ≥ 42 mmol/mol (6.0%), < 48 mmol/mol (6.5%) mmol/mol; fasting glucose ≥ 5.5 mmol/l, < 7.0 mmol/l; or 2-hour post-challenge glucose ≥ 7.8 mmol/l, < 11.1 mmol/l] were recruited between December 2013 and February 2015. Data collection was completed in July 2019. Interventions: Participants were randomised (1 : 1 : 1) using a web-based tool to (1) control (information leaflet), (2) Walking Away with annual group-based support or (3) Walking Away Plus (comprising Walking Away, annual group-based support and a mobile health intervention that provided automated, individually tailored text messages to prompt pedometer use and goal-setting and provide feedback, in addition to biannual telephone calls). Participants and data collectors were not blinded; however, the staff who processed the accelerometer data were blinded to allocation. Main outcome measures: The primary outcome was accelerometer-measured ambulatory activity (steps per day) at 48 months. Other objective and self-reported measures of physical activity were also assessed. Results: A total of 1366 individuals were randomised (median age 61 years, median body mass index 28.4 kg/m2, median ambulatory activity 6638 steps per day, women 49%, black and minority ethnicity 28%). Accelerometer data were available for 1017 (74%) and 993 (73%) individuals at 12 and 48 months, respectively. The primary outcome assessment at 48 months found no differences in ambulatory activity compared with control in either group (Walking Away Plus: 121 steps per day, 97.5% confidence interval -290 to 532 steps per day; Walking Away: 91 steps per day, 97.5% confidence interval -282 to 463). This was consistent across ethnic groups. At the intermediate 12-month assessment, the Walking Away Plus group had increased their ambulatory activity by 547 (97.5% confidence interval 211 to 882) steps per day compared with control and were 1.61 (97.5% confidence interval 1.05 to 2.45) times more likely to achieve 150 minutes per week of objectively assessed unbouted moderate to vigorous physical activity. In the Walking Away group, there were no differences compared with control at 12 months. Secondary anthropometric, biomechanical and mental health outcomes were unaltered in either intervention study arm compared with control at 12 or 48 months, with the exception of small, but sustained, reductions in body weight in the Walking Away study arm (≈ 1 kg) at the 12- and 48-month follow-ups. Lifetime cost-effectiveness modelling suggested that usual care had the highest probability of being cost-effective at a threshold of £20,000 per quality-adjusted life-year. Of 50 serious adverse events, only one (myocardial infarction) was deemed possibly related to the intervention and led to the withdrawal of the participant from the study. Limitations: Loss to follow-up, although the results were unaltered when missing data were replaced using multiple imputation. Conclusions: Combining a physical activity intervention with text messaging and telephone support resulted in modest, but clinically meaningful, changes in physical activity at 12 months, but the changes were not sustained at 48 months. Future work: Future research is needed to investigate which intervention types, components and features can help to maintain physical activity behaviour change over the longer term. Trial registration: Current Controlled Trials ISRCTN83465245. 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. 25, No. 77. See the NIHR Journals Library website for further project information.

Health technology assessment (Winchester, England) · randomised controlled trial · 17 citationsread the source →

Effectiveness of Mindfulness Meditation vs Headache Education for Adults With Migraine: A Randomized Clinical Trial.

Importance: Migraine is the second leading cause of disability worldwide. Most patients with migraine discontinue medications due to inefficacy or adverse effects. Mindfulness-based stress reduction (MBSR) may provide benefit. Objective: To determine if MBSR improves migraine outcomes and affective/cognitive processes compared with headache education. Design, setting, and participants: This randomized clinical trial of MBSR vs headache education included 89 adults who experienced between 4 and 20 migraine days per month. There was blinding of participants (to active vs comparator group assignments) and principal investigators/data analysts (to group assignment). Interventions: Participants underwent MBSR (standardized training in mindfulness/yoga) or headache education (migraine information) delivered in groups that met for 2 hours each week for 8 weeks. Main outcomes and measures: The primary outcome was change in migraine day frequency (baseline to 12 weeks). Secondary outcomes were changes in disability, quality of life, self-efficacy, pain catastrophizing, depression scores, and experimentally induced pain intensity and unpleasantness (baseline to 12, 24, and 36 weeks). Results: Most participants were female (n = 82, 92%), with a mean (SD) age of 43.9 (13.0) years, and had a mean (SD) of 7.3 (2.7) migraine days per month and high disability (Headache Impact Test-6: 63.5 [5.7]), attended class (median attendance, 7 of 8 classes), and followed up through 36 weeks (33 of 45 [73%] of the MBSR group and 32 of 44 [73%] of the headache education group). Participants in both groups had fewer migraine days at 12 weeks (MBSR: -1.6 migraine days per month; 95% CI, -0.7 to -2.5; headache education: -2.0 migraine days per month; 95% CI, -1.1 to -2.9), without group differences (P = .50). Compared with those who participated in headache education, those who participated in MBSR had improvements from baseline at all follow-up time points (reported in terms of point estimates of effect differences between groups) on measures of disability (5.92; 95% CI, 2.8-9.0; P < .001), quality of life (5.1; 95% CI, 1.2-8.9; P = .01), self-efficacy (8.2; 95% CI, 0.3-16.1; P = .04), pain catastrophizing (5.8; 95% CI, 2.9-8.8; P < .001), depression scores (1.6; 95% CI, 0.4-2.7; P = .008), and decreased experimentally induced pain intensity and unpleasantness (MBSR group: 36.3% [95% CI, 12.3% to 60.3%] decrease in intensity and 30.4% [95% CI, 9.9% to 49.4%] decrease in unpleasantness; headache education group: 13.5% [95% CI, -9.9% to 36.8%] increase in intensity and an 11.2% [95% CI, -8.9% to 31.2%] increase in unpleasantness; P = .004 for intensity and .005 for unpleasantness, at 36 weeks). One reported adverse event was deemed unrelated to study protocol. Conclusions and relevance: Mindfulness-based stress reduction did not improve migraine frequency more than headache education, as both groups had similar decreases; however, MBSR improved disability, quality of life, self-efficacy, pain catastrophizing, and depression out to 36 weeks, with decreased experimentally induced pain suggesting a potential shift in pain appraisal. In conclusion, MBSR may help treat total migraine burden, but a larger, more definitive study is needed to further investigate these results. Trial registration: ClinicalTrials.gov Identifier: NCT02695498.

JAMA internal medicine · randomised controlled trial · 132 citationsread the source →

Long-term weight loss trajectories following participation in a randomised controlled trial of a weight management programme for men delivered through professional football clubs: a longitudinal cohort study and economic evaluation.

Background: Obesity is a major public health concern requiring innovative interventions that support people to lose weight and keep it off long term. However, weight loss maintenance remains a challenge and is under-researched, particularly in men. The Football Fans in Training (FFIT) programme engages men in weight management through their interest in football, and encourages them to incorporate small, incremental physical activity and dietary changes into daily life to support long-term weight loss maintenance. In 2011/12, a randomised controlled trial (RCT) of FFIT demonstrated effectiveness and cost-effectiveness at 12 months. The current study aimed to investigate long-term maintenance of weight loss, behavioural outcomes and lifetime cost-effectiveness following FFIT. Methods: A longitudinal cohort study comprised 3.5-year follow-up of the 747 FFIT RCT participants. Men aged 35-65 years, BMI ≥ 28 kg/m2 at RCT baseline who consented to long-term follow-up (n = 665) were invited to participate: those in the FFIT Follow Up Intervention group (FFIT-FU-I) undertook FFIT in 2011 during the RCT; the FFIT Follow Up Comparison group (FFIT-FU-C) undertook FFIT in 2012 under routine (non-research) conditions. The primary outcome was objectively-measured weight loss (from baseline) at 3.5 years. Secondary outcomes included changes in self-reported physical activity and diet at 3.5 years. Cost-effectiveness was estimated at 3.5 years and over participants' lifetime. Results: Of 665 men invited, 488 (73%; 65% of the 747 RCT participants) attended 3.5-year measurements. The FFIT-FU-I group sustained a mean weight loss of 2.90 kg (95% CI 1.78, 4.02; p < 0.001) 3.5 years after starting FFIT; 32.2% (75/233) weighed ≥5% less than baseline. The FFIT-FU-C group had lost 2.71 kg (1.65, 3.77; p < 0.001) at the 3.5-year measurements (2.5 years after starting FFIT); 31.8% (81/255) weighed ≥5% less than baseline. There were significant sustained improvements in self-reported physical activity and diet in both groups. The estimated incremental cost-effectiveness of FFIT was £10,700-£15,300 per QALY gained at 3.5 years, and £1790-£2200 over participants' lifetime. Conclusions: Participation in FFIT under research and routine conditions leads to long-term weight loss and improvements in physical activity and diet. Investment in FFIT is likely to be cost-effective as part of obesity management strategies in countries where football is popular. Trial registration: ISRCTN32677491 , 20 October 2011.

The international journal of behavioral nutrition and physical activity · randomised controlled trial · 25 citationsread the source →

Cognitive behavioural therapy for adults with dissociative seizures (CODES): a pragmatic, multicentre, randomised controlled trial.

Background: Dissociative seizures are paroxysmal events resembling epilepsy or syncope with characteristic features that allow them to be distinguished from other medical conditions. We aimed to compare the effectiveness of cognitive behavioural therapy (CBT) plus standardised medical care with standardised medical care alone for the reduction of dissociative seizure frequency. Methods: In this pragmatic, parallel-arm, multicentre randomised controlled trial, we initially recruited participants at 27 neurology or epilepsy services in England, Scotland, and Wales. Adults (≥18 years) who had dissociative seizures in the previous 8 weeks and no epileptic seizures in the previous 12 months were subsequently randomly assigned (1:1) from 17 liaison or neuropsychiatry services following psychiatric assessment, to receive standardised medical care or CBT plus standardised medical care, using a web-based system. Randomisation was stratified by neuropsychiatry or liaison psychiatry recruitment site. The trial manager, chief investigator, all treating clinicians, and patients were aware of treatment allocation, but outcome data collectors and trial statisticians were unaware of treatment allocation. Patients were followed up 6 months and 12 months after randomisation. The primary outcome was monthly dissociative seizure frequency (ie, frequency in the previous 4 weeks) assessed at 12 months. Secondary outcomes assessed at 12 months were: seizure severity (intensity) and bothersomeness; longest period of seizure freedom in the previous 6 months; complete seizure freedom in the previous 3 months; a greater than 50% reduction in seizure frequency relative to baseline; changes in dissociative seizures (rated by others); health-related quality of life; psychosocial functioning; psychiatric symptoms, psychological distress, and somatic symptom burden; and clinical impression of improvement and satisfaction. p values and statistical significance for outcomes were reported without correction for multiple comparisons as per our protocol. Primary and secondary outcomes were assessed in the intention-to-treat population with multiple imputation for missing observations. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN05681227, and ClinicalTrials.gov, NCT02325544. Findings: Between Jan 16, 2015, and May 31, 2017, we randomly assigned 368 patients to receive CBT plus standardised medical care (n=186) or standardised medical care alone (n=182); of whom 313 had primary outcome data at 12 months (156 [84%] of 186 patients in the CBT plus standardised medical care group and 157 [86%] of 182 patients in the standardised medical care group). At 12 months, no significant difference in monthly dissociative seizure frequency was identified between the groups (median 4 seizures [IQR 0-20] in the CBT plus standardised medical care group vs 7 seizures [1-35] in the standardised medical care group; estimated incidence rate ratio [IRR] 0·78 [95% CI 0·56-1·09]; p=0·144). Dissociative seizures were rated as less bothersome in the CBT plus standardised medical care group than the standardised medical care group (estimated mean difference -0·53 [95% CI -0·97 to -0·08]; p=0·020). The CBT plus standardised medical care group had a longer period of dissociative seizure freedom in the previous 6 months (estimated IRR 1·64 [95% CI 1·22 to 2·20]; p=0·001), reported better health-related quality of life on the EuroQoL-5 Dimensions-5 Level Health Today visual analogue scale (estimated mean difference 6·16 [95% CI 1·48 to 10·84]; p=0·010), less impairment in psychosocial functioning on the Work and Social Adjustment Scale (estimated mean difference -4·12 [95% CI -6·35 to -1·89]; p<0·001), less overall psychological distress than the standardised medical care group on the Clinical Outcomes in Routine Evaluation-10 scale (estimated mean difference -1·65 [95% CI -2·96 to -0·35]; p=0·013), and fewer somatic symptoms on the modified Patient Health Questionnaire-15 scale (estimated mean difference -1·67 [95% CI -2·90 to -0·44]; p=0·008). Clinical improvement at 12 months was greater in the CBT plus standardised medical care group than the standardised medical care alone group as reported by patients (estimated mean difference 0·66 [95% CI 0·26 to 1·04]; p=0·001) and by clinicians (estimated mean difference 0·47 [95% CI 0·21 to 0·73]; p<0·001), and the CBT plus standardised medical care group had greater satisfaction with treatment than did the standardised medical care group (estimated mean difference 0·90 [95% CI 0·48 to 1·31]; p<0·001). No significant differences in patient-reported seizure severity (estimated mean difference -0·11 [95% CI -0·50 to 0·29]; p=0·593) or seizure freedom in the last 3 months of the study (estimated odds ratio [OR] 1·77 [95% CI 0·93 to 3·37]; p=0·083) were identified between the groups. Furthermore, no significant differences were identified in the proportion of patients who had a more than 50% reduction in dissociative seizure frequency compared with baseline (OR 1·27 [95% CI 0·80 to 2·02]; p=0·313). Additionally, the 12-item Short Form survey-version 2 scores (estimated mean difference for the Physical Component Summary score 1·78 [95% CI -0·37 to 3·92]; p=0·105; estimated mean difference for the Mental Component Summary score 2·22 [95% CI -0·30 to 4·75]; p=0·084), the Generalised Anxiety Disorder-7 scale score (estimated mean difference -1·09 [95% CI -2·27 to 0·09]; p=0·069), and the Patient Health Questionnaire-9 scale depression score (estimated mean difference -1·10 [95% CI -2·41 to 0·21]; p=0·099) did not differ significantly between groups. Changes in dissociative seizures (rated by others) could not be assessed due to insufficient data. During the 12-month period, the number of adverse events was similar between the groups: 57 (31%) of 186 participants in the CBT plus standardised medical care group reported 97 adverse events and 53 (29%) of 182 participants in the standardised medical care group reported 79 adverse events. Interpretation: CBT plus standardised medical care had no statistically significant advantage compared with standardised medical care alone for the reduction of monthly seizures. However, improvements were observed in a number of clinically relevant secondary outcomes following CBT plus standardised medical care when compared with standardised medical care alone. Thus, adults with dissociative seizures might benefit from the addition of dissociative seizure-specific CBT to specialist care from neurologists and psychiatrists. Future work is needed to identify patients who would benefit most from a dissociative seizure-specific CBT approach. Funding: National Institute for Health Research, Health Technology Assessment programme.

The lancet. Psychiatry · randomised controlled trial · 192 citationsread the source →

Digital smartphone intervention to recognise and manage early warning signs in schizophrenia to prevent relapse: the EMPOWER feasibility cluster RCT.

Background: Relapse is a major determinant of outcome for people with a diagnosis of schizophrenia. Early warning signs frequently precede relapse. A recent Cochrane Review found low-quality evidence to suggest a positive effect of early warning signs interventions on hospitalisation and relapse. Objective: How feasible is a study to investigate the clinical effectiveness and cost-effectiveness of a digital intervention to recognise and promptly manage early warning signs of relapse in schizophrenia with the aim of preventing relapse? Design: A multicentre, two-arm, parallel-group cluster randomised controlled trial involving eight community mental health services, with 12-month follow-up. Settings: Glasgow, UK, and Melbourne, Australia. Participants: Service users were aged > 16 years and had a schizophrenia spectrum disorder with evidence of a relapse within the previous 2 years. Carers were eligible for inclusion if they were nominated by an eligible service user. Interventions: The Early signs Monitoring to Prevent relapse in psychosis and prOmote Wellbeing, Engagement, and Recovery (EMPOWER) intervention was designed to enable participants to monitor changes in their well-being daily using a mobile phone, blended with peer support. Clinical triage of changes in well-being that were suggestive of early signs of relapse was enabled through an algorithm that triggered a check-in prompt that informed a relapse prevention pathway, if warranted. Main outcome measures: The main outcomes were feasibility of the trial and feasibility, acceptability and usability of the intervention, as well as safety and performance. Candidate co-primary outcomes were relapse and fear of relapse. Results: We recruited 86 service users, of whom 73 were randomised (42 to EMPOWER and 31 to treatment as usual). Primary outcome data were collected for 84% of participants at 12 months. Feasibility data for people using the smartphone application (app) suggested that the app was easy to use and had a positive impact on motivations and intentions in relation to mental health. Actual app usage was high, with 91% of users who completed the baseline period meeting our a priori criterion of acceptable engagement (> 33%). The median time to discontinuation of > 33% app usage was 32 weeks (95% confidence interval 14 weeks to ∞). There were 8 out of 33 (24%) relapses in the EMPOWER arm and 13 out of 28 (46%) in the treatment-as-usual arm. Fewer participants in the EMPOWER arm had a relapse (relative risk 0.50, 95% confidence interval 0.26 to 0.98), and time to first relapse (hazard ratio 0.32, 95% confidence interval 0.14 to 0.74) was longer in the EMPOWER arm than in the treatment-as-usual group. At 12 months, EMPOWER participants were less fearful of having a relapse than those in the treatment-as-usual arm (mean difference -4.29, 95% confidence interval -7.29 to -1.28). EMPOWER was more costly and more effective, resulting in an incremental cost-effectiveness ratio of £3041. This incremental cost-effectiveness ratio would be considered cost-effective when using the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year gained. Limitations: This was a feasibility study and the outcomes detected cannot be taken as evidence of efficacy or effectiveness. Conclusions: A trial of digital technology to monitor early warning signs that blended with peer support and clinical triage to detect and prevent relapse is feasible. Future work: A main trial with a sample size of 500 (assuming 90% power and 20% dropout) would detect a clinically meaningful reduction in relapse (relative risk 0.7) and improvement in other variables (effect sizes 0.3-0.4). Trial registration: This trial is registered as ISRCTN99559262. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 27. See the NIHR Journals Library website for further project information. Funding in Australia was provided by the National Health and Medical Research Council (APP1095879).

Health technology assessment (Winchester, England) · randomised controlled trial · 24 citationsread the source →

Elevated C-reactive protein levels, psychological distress, and depression in 73, 131 individuals.

CONTEXT The pathogenesis of depression is not fully understood, but studies suggest that low-grade systemic inflammation contributes to the development of depression. OBJECTIVE To test whether elevated plasma levels of C-reactive protein (CRP) are associated with psychological distress and depression. DESIGN We performed cross-sectional and prospective analyses of CRP levels in 4 clinically relevant categories using data from 2 general population studies. SETTING The Copenhagen General Population and the Copenhagen City Heart studies. PARTICIPANTS We examined 73 131 men and women aged 20 to 100 years. MAIN OUTCOME MEASURES We ascertained psychological distress with 2 single-item self-reports and depression using self-reported antidepressant use, register-based prescription of antidepressants, and register-based hospitalization with depression. RESULTS In cross-sectional analyses, increasing CRP levels were associated with increasing risk for psychological distress and depression (P = 3 × 10-8 to P = 4 × 10-105 for trend). For self-reported use of antidepressants, the odds ratio was 1.38 (95% CI, 1.23-1.55) for CRP levels of 1.01 to 3.00 mg/L, 2.02 (1.77-2.30) for 3.01 to 10.00 mg/L, and 2.70 (2.25-3.25) for greater than 10.00 mg/L compared with 0.01 to 1.00 mg/L. For prescription of antidepressants, the corresponding odds ratios were 1.08 (95% CI, 0.99-1.17), 1.47 (1.33-1.62), and 1.77 (1.52-2.05), respectively; for hospitalization with depression, 1.30 (1.01-1.67), 1.84 (1.39-2.43), and 2.27 (1.54-3.32), respectively. In prospective analyses, increasing CRP levels were also associated with increasing risk for hospitalization with depression (P = 4 × 10-8 for trend). CONCLUSIONS Elevated levels of CRP are associated with increased risk for psychological distress and depression in the general population.

JAMA psychiatry · 350 citationsread the source →

Baseline comprehensive geriatric assessment is associated with toxicity and survival in elderly metastatic breast cancer patients receiving single-agent chemotherapy: results from the OMEGA study of the Dutch breast cancer trialists' group.

Aim: To evaluate the association between baseline comprehensive geriatric assessment (CGA) or the Groningen Frailty Indicator (GFI) and toxicity in elderly metastatic breast cancer (MBC) patients treated with first-line palliative chemotherapy. Patients and methods: MBC patients (≥65 years) were randomized between pegylated liposomal doxorubicine or capecitabine. CGA included instrumental activities of daily living (IADL), cognition using the mini-mental state examination (MMSE), mood using the geriatric depression scale (GDS), comorbidity using the Charlson index, polypharmacy and nutritional status using the body mass index. Frailty on CGA was defined as one or more of the following: IADL ≤ 13, MMSE ≤ 23, GDS ≥ 5, BMI ≤ 20, ≥5 medications or Charlson ≥2. The cut-off for frailty on the GFI was ≥4. Results: Of the randomized 78 patients (median age 75.5 years, range 65.8-86.8 years), 73 were evaluable for CGA; 52 (71%) had one or more geriatric conditions. Grade 3-4 chemotherapy-related toxicity was experienced by 19% of patients without geriatric conditions compared to 56% of patients with two geriatric conditions and 80% of those with three or more (p = 0.002). Polypharmacy was the only individual factor significantly associated with toxicity (p = 0.001). GFI had a sensitivity of 69% and a specificity of 76% for frailty on CGA, and was not significantly associated with survival or toxicity. Conclusion: In this study of elderly patients with MBC, the number of geriatric conditions correlated with grade 3-4 chemotherapy-related toxicity. Therefore, in elderly patients for whom chemotherapy is being considered, a CGA could be a useful addition to the decision-making process.

Breast (Edinburgh, Scotland) · randomised controlled trial · 91 citationsread the source →

Does active referral by a doctor or 12-Step peer improve 12-Step meeting attendance? Results from a pilot randomised control trial.

Background: Active engagement in 12-Step self-help groups (SHG) is associated with improvements in substance use outcomes during and after treatment, yet levels of participation in SHG meetings in the U.K. remain low. Method: An RCT investigating the impact of active referral to SHG, delivered by doctors or 12-Step peers during inpatient treatment on both inpatient and post-treatment meeting attendance was conducted. 151 inpatients with alcohol, opiate, crack-cocaine or benzodiazepine dependence undergoing detoxification, received one of two active referral interventions: 12-Step peer intervention (PI), doctor intervention (DI), or no intervention (NI). 83% of the sample was followed up, 2-3 months following discharge. Results: Active referral interventions significantly increased attendance at 12-Step meetings during inpatient treatment (88% versus 73%, p<.05). Rates of post-discharge meeting attendance were PI=64%, DI=48%, NI=33%, with those in the PI group significantly (OR=3.6; CI=1.3, 9.8) more likely to have attended. Inpatient meeting attenders were three times as likely to have attended meetings post-discharge (59% versus 20%, p<.01), and post-discharge meeting attenders reported significantly higher abstinence rates (60.8% versus 39.2%, p<.05) at follow-up. However, abstinence rates did not differ significantly across intervention groups (44% [PI], 41% [DI] and 36% [NI]). Conclusion: Attendance at 12-Step SHGs is associated with greater rates of abstinence and active referral, especially by 12-Step peers, increases 12-Step SHG attendance rates. However, improved clinical outcomes among attendees might not occur until stronger recovery peer support networks are established. These results show promise for the benefit of incorporating Twelve Step Facilitation into U.K. treatment settings.

Drug and alcohol dependence · randomised controlled trial · 43 citationsread the source →

Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial.

Background: Obesity is associated with a reduction in life expectancy and an increase in mortality from cardiovascular diseases, cancer, and other causes. We therefore assessed the efficacy and safety of two doses of phentermine plus topiramate controlled-release combination as an adjunct to diet and lifestyle modification for weight loss and metabolic risk reduction in individuals who were overweight and obese, with two or more risk factors. Methods: In this 56-week phase 3 trial, we randomly assigned overweight or obese adults (aged 18-70 years), with a body-mass index of 27-45 kg/m(2) and two or more comorbidities (hypertension, dyslipidaemia, diabetes or prediabetes, or abdominal obesity) to placebo, once-daily phentermine 7·5 mg plus topiramate 46·0 mg, or once-daily phentermine 15·0 mg plus topiramate 92·0 mg in a 2:1:2 ratio in 93 centres in the USA. Drugs were administered orally. Patients were randomly assigned by use of a computer-generated algorithm that was implemented through an interactive voice response system, and were stratified by sex and diabetic status. Investigators, patients, and study sponsors were masked to treatment. Primary endpoints were the percentage change in bodyweight and the proportion of patients achieving at least 5% weight loss. Analysis was by intention to treat. This study is registered with Clinical Trials.gov, number NCT00553787. Findings: Of 2487 patients, 994 were assigned to placebo, 498 to phentermine 7·5 mg plus topiramate 46·0 mg, and 995 to phentermine 15·0 mg plus topiramate 92·0 mg; 979, 488, and 981 patients, respectively, were analysed. At 56 weeks, change in bodyweight was -1·4 kg (least-squares mean -1·2%, 95% CI -1·8 to -0·7), -8·1 kg (-7·8%, -8·5 to -7·1; p<0·0001), and -10·2 kg (-9·8%, -10·4 to -9·3; p<0·0001) in the patients assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively. 204 (21%) patients achieved at least 5% weight loss with placebo, 303 (62%; odds ratio 6·3, 95% CI 4·9 to 8·0; p<0·0001) with phentermine 7·5 mg plus topiramate 46·0 mg, and 687 (70%; 9·0, 7·3 to 11·1; p<0·0001) with phentermine 15·0 mg plus topiramate 92·0 mg; for ≥10% weight loss, the corresponding numbers were 72 (7%), 182 (37%; 7·6, 5·6 to 10·2; p<0·0001), and 467 (48%; 11·7, 8·9 to 15·4; p<0·0001). The most common adverse events were dry mouth (24 [2%], 67 [13%], and 207 [21%] in the groups assigned to placebo, phentermine 7·5 mg plus topiramate 46·0 mg, and phentermine 15·0 mg plus topiramate 92·0 mg, respectively), paraesthesia (20 [2%], 68 [14%], and 204 [21%], respectively), constipation (59 [6%], 75 [15%], and 173 [17%], respectively), insomnia (47 [5%], 29 [6%], and 102 [10%], respectively), dizziness (31 [3%], 36 [7%], 99 [10%], respectively), and dysgeusia (11 [1%], 37 [7%], and 103 [10%], respectively). 38 (4%) patients assigned to placebo, 19 (4%) to phentermine 7·5 mg plus topiramate 46·0 mg, and 73 (7%) to phentermine 15·0 mg plus topiramate 92·0 mg had depression-related adverse events; and 28 (3%), 24 (5%), and 77 (8%), respectively, had anxiety-related adverse events. Interpretation: The combination of phentermine and topiramate, with office-based lifestyle interventions, might be a valuable treatment for obesity that can be provided by family doctors. Funding: Vivus.

Lancet (London, England) · randomised controlled trial · 667 citationsread the source →

Mental Health Outcomes in Transgender and Nonbinary Youths Receiving Gender-Affirming Care.

Importance: Transgender and nonbinary (TNB) youths are disproportionately burdened by poor mental health outcomes owing to decreased social support and increased stigma and discrimination. Although gender-affirming care is associated with decreased long-term adverse mental health outcomes among these youths, less is known about its association with mental health immediately after initiation of care. Objective: To investigate changes in mental health over the first year of receiving gender-affirming care and whether initiation of puberty blockers (PBs) and gender-affirming hormones (GAHs) was associated with changes in depression, anxiety, and suicidality. Design, setting, and participants: This prospective observational cohort study was conducted at an urban multidisciplinary gender clinic among TNB adolescents and young adults seeking gender-affirming care from August 2017 to June 2018. Data were analyzed from August 2020 through November 2021. Exposures: Time since enrollment and receipt of PBs or GAHs. Main outcomes and measures: Mental health outcomes of interest were assessed via the Patient Health Questionnaire 9-item (PHQ-9) and Generalized Anxiety Disorder 7-item (GAD-7) scales, which were dichotomized into measures of moderate or severe depression and anxiety (ie, scores ≥10), respectively. Any self-report of self-harm or suicidal thoughts over the previous 2 weeks was assessed using PHQ-9 question 9. Generalized estimating equations were used to assess change from baseline in each outcome at 3, 6, and 12 months of follow-up. Bivariate and multivariable logistic models were estimated to examine temporal trends and investigate associations between receipt of PBs or GAHs and each outcome. Results: Among 104 youths aged 13 to 20 years (mean [SD] age, 15.8 [1.6] years) who participated in the study, there were 63 transmasculine individuals (60.6%), 27 transfeminine individuals (26.0%), 10 nonbinary or gender fluid individuals (9.6%), and 4 youths who responded "I don't know" or did not respond to the gender identity question (3.8%). At baseline, 59 individuals (56.7%) had moderate to severe depression, 52 individuals (50.0%) had moderate to severe anxiety, and 45 individuals (43.3%) reported self-harm or suicidal thoughts. By the end of the study, 69 youths (66.3%) had received PBs, GAHs, or both interventions, while 35 youths had not received either intervention (33.7%). After adjustment for temporal trends and potential confounders, we observed 60% lower odds of depression (adjusted odds ratio [aOR], 0.40; 95% CI, 0.17-0.95) and 73% lower odds of suicidality (aOR, 0.27; 95% CI, 0.11-0.65) among youths who had initiated PBs or GAHs compared with youths who had not. There was no association between PBs or GAHs and anxiety (aOR, 1.01; 95% CI, 0.41, 2.51). Conclusions and relevance: This study found that gender-affirming medical interventions were associated with lower odds of depression and suicidality over 12 months. These data add to existing evidence suggesting that gender-affirming care may be associated with improved well-being among TNB youths over a short period, which is important given mental health disparities experienced by this population, particularly the high levels of self-harm and suicide.

JAMA network open · cohort or longitudinal · 346 citationsread the source →

Intrinsic functional connectivity differentiates minimally conscious from unresponsive patients.

Despite advances in resting state functional magnetic resonance imaging investigations, clinicians remain with the challenge of how to implement this paradigm on an individualized basis. Here, we assessed the clinical relevance of resting state functional magnetic resonance imaging acquisitions in patients with disorders of consciousness by means of a systems-level approach. Three clinical centres collected data from 73 patients in minimally conscious state, vegetative state/unresponsive wakefulness syndrome and coma. The main analysis was performed on the data set coming from one centre (Liège) including 51 patients (26 minimally conscious state, 19 vegetative state/unresponsive wakefulness syndrome, six coma; 15 females; mean age 49 ± 18 years, range 11-87; 16 traumatic, 32 non-traumatic of which 13 anoxic, three mixed; 35 patients assessed >1 month post-insult) for whom the clinical diagnosis with the Coma Recovery Scale-Revised was congruent with positron emission tomography scanning. Group-level functional connectivity was investigated for the default mode, frontoparietal, salience, auditory, sensorimotor and visual networks using a multiple-seed correlation approach. Between-group inferential statistics and machine learning were used to identify each network's capacity to discriminate between patients in minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Data collected from 22 patients scanned in two other centres (Salzburg: 10 minimally conscious state, five vegetative state/unresponsive wakefulness syndrome; New York: five minimally conscious state, one vegetative state/unresponsive wakefulness syndrome, one emerged from minimally conscious state) were used to validate the classification with the selected features. Coma Recovery Scale-Revised total scores correlated with key regions of each network reflecting their involvement in consciousness-related processes. All networks had a high discriminative capacity (>80%) for separating patients in a minimally conscious state and vegetative state/unresponsive wakefulness syndrome. Among them, the auditory network was ranked the most highly. The regions of the auditory network which were more functionally connected in patients in minimally conscious state compared to vegetative state/unresponsive wakefulness syndrome encompassed bilateral auditory and visual cortices. Connectivity values in these three regions discriminated congruently 20 of 22 independently assessed patients. Our findings point to the significance of preserved abilities for multisensory integration and top-down processing in minimal consciousness seemingly supported by auditory-visual crossmodal connectivity, and promote the clinical utility of the resting paradigm for single-patient diagnostics.

Brain : a journal of neurology · cohort or longitudinal · 283 citationsread the source →

Analysis of persistent organic pollutants in marine sediments using a novel microwave assisted solvent extraction and liquid-phase microextraction technique.

A simple and novel analytical method for quantifying persistent organic pollutants (POPs) in marine sediments has been developed using microwave assisted solvent extraction (MASE) and liquid-phase microextraction (LPME) using hollow fibre membrane (HFM). POPs studied included twelve organochlorine pesticides (OCP) and eight polychlorinated biphenyl (PCB) congeners. MASE was used for the extraction of POPs from 1 g of sediment using 10 ml of ultrapure water at 600 W for 20 min at 80 degrees C. The extract was subsequently subjected to a single step LPME-HFM cleanup and enrichment procedure. Recovery varied between 73 and 111% for OCPs; and 86-110% for PCBs, and exceeded levels achieved for conventional multi-step Soxhlet extraction coupled with solid-phase extraction. The method detection limit for each POP analyte ranged from 0.07 to 0.70 ng g(-1), and peak areas were proportional to analyte concentrations in the range of 5-500 ng g(-1). Relative standard deviations of less than 20% was obtained, based on triplicate sample analysis. The optimized technique was successfully applied to POP analysis of marine sediments collected from the northeastern and southwestern areas of Singapore's coastal environment.

Journal of chromatography. A · cohort or longitudinal · 54 citationsread the source →

Demoralization and depression in patients with advanced cancer: validation of the German version of the demoralization scale.

Context: The concept of demoralization has been widely used to describe states of existential distress and a self-perceived incapacity to deal effectively with a specific stressful situation. Objectives: To evaluate the psychometric properties of the German adaptation of the Demoralization Scale (DS) in patients with advanced cancer. Methods: Participants with heterogeneous tumor sites were recruited in several treatment and rehabilitation facilities. Concurrent and divergent validity of the DS was analyzed through associations with and group differences between measures of distress, depression, anxiety, and meaning-related life attitudes. Results: From a total sample of 1102 patients, 516 individuals (45%) with advanced cancer were enrolled (male 53%, median age 58 years [range 18-88], breast cancer 21%, prostate cancer 17%). The total mean score of the DS was 29.8 (SD=10.41). Four factors were extracted by exploratory factor analysis, which accounted for 59% of the variation (Cronbach α=0.84): loss of meaning and purpose (α=0.88), disheartenment (α=0.88), dysphoria (α=0.80), and sense of failure (α=0.76). DS dimensions shared between 12% and 62% of the variance. Demoralization was significantly associated with anxiety (r=0.71), depression (r=0.61), and distress (r=0.42). Fifty-seven percent of patients had high distress, 24% depression, and 11% high anxiety. According to different cutoff values, between 16% and 39% were seriously demoralized and 73% had moderate levels of demoralization. Between 5% and 20% of patients were seriously demoralized but not clinically depressed; 60% of patients with moderate levels of demoralization had no depression. Conclusion: Results provide further evidence that the DS is a valid and reliable instrument of high clinical relevance in patients with advanced cancer.

Journal of pain and symptom management · 104 citationsread the source →

Alteration in body water compartments following intermittent fasting in Ramadan.

Concerning the health outcomes of intermittent fasting in Ramadan, loss of fat-free mass (FFM) and changes in the content of body water are of paramount importance. In this study, we aimed to assess the concomitant alterations in body water compartment and composition following Ramadan fasting in healthy individuals. We conducted an open-label cohort with longitudinal follow-up, involving 73 healthy medical staff who planned to fast for at least 20 consecutive days during Ramadan. The primary outcomes of the cohort were changes in parameters related to body composition and water content, which were measured using bioelectrical impedance analysis by InBody S10 (InBody, Seoul, South Korea). Based on the results, the participants' weight decreased significantly by approximately 1,030 g after the fasting period (p < 0.001). There was a significant reduction in the fat mass of an average 828 g (p < 0.001), which accounted for more than 80% of the weight loss. The decline in FFM was not significant (190 g; p = 0.234). The amount of total body water (TBW) and extracellular water (ECW) did not change, while intracellular water (ICW) decreased significantly by about 160 mL (p = 0.027). A strong correlation was observed between the reduction of phase angle and the increase in ECW/TBW ratio (R = -0.71, p < 0.001). Overall, our findings revealed a minimal amount of weight loss after Ramadan fasting, which was mainly due to the loss of fat mass. The parallel decrease in ICW and phase angle indicated impaired cell membrane integrity, with subsequent movement of water from the intracellular to the extracellular compartment.

Frontiers in nutrition · 2 citationsread the source →

Breaking Bad News: A Survey of Radiology Residents' Experiences Communicating Results to Patients.

Purpose: The practice of radiology often includes routine communication of diagnostic test results directly to patients in breast imaging and interventional radiology. There is increasing interest in expanding direct communication throughout radiology. Though these conversations can substantially affect patient well-being, there is limited evidence indicating that radiology residents are specifically taught methods to effectively convey imaging results to patients. Our purpose is to evaluate resident experience communicating imaging results to patients. Materials and methods: An IRB-approved study with a total of 11 pilot-tested questions was used. Surveyed programs included radiology residents (PGY2-PGY5) at 2 urban residency programs. Online surveys were administered using SurveyMonkey and e-mailed to residents at both programs (starting November 20, 2015, completed March 31, 2016). Demographics were obtained with survey proportions compared using logistic regression (P < 0.05, statistically significant). Results: A total of 73 residents responded (93.6% response rate) with similar response rates at each institution (P = 0.689). Most were male (71.2%) with 17.8% planning to go into breast imaging (21.9%, interventional radiology (IR)). Furthermore, 83.6% described no training in communicating radiology results to patients; 91.8% of residents communicated results with patients (87.7% diagnostic imaging tests and 57.5% biopsies). Residents most commonly communicated results in person (75.3%) followed by phone (64.4%), and 79.4% agreed or strongly agreed that additional training relaying results would be helpful. Conclusions: A large majority of radiology residents have communicated test results to patients, yet few have received training in how to communicate these results. A large majority of residents expressed interest in obtaining additional communication training. Additional research is required to determine ideal methods to educate residents on communicating test results.

Current problems in diagnostic radiology · 13 citationsread the source →

Psychological and physiological effects of emotion focused training for self-compassion and self-protection.

Emotion Focused Training for Self-Compassion and Self-Protection (EFT-SCP) is a novel intervention developed on the basis of the latest findings on self-criticism from Emotion-focused therapy and existing programs designed to cultivate compassion. EFTSCP is designed to encourage participants to cultivate self-compassion and protective anger as a way of reducing selfcriticism. Our goal was to investigate the effect of this group-based intervention on self-criticism, self-protection, and self-compassion. A total of 73 students were assigned to the EFT-SCP intervention (n=19), no-treatment control (n=34) or to an active control group (n=20). The intervention group met weekly for 1.5 hours and were instructed to incorporate EFT-SCP tasks into their daily life for 12 weeks. Whilst the no-treatment group did not undergo an intervention, the active control group completed an adapted expressive writing task once a week. In addition to the assessment of heart rate variability during imagery tasks, participants also completed self-reported measures of self-compassion and self-criticism before and after the intervention. Compared with both control groups, the intervention group showed a significant increase in heart rate variability following EFT-SCP (during self-critical imagery, P=.049; probability of superiority was .63, and during self-compassionate imagery P=.007; probability of superiority was .62, both effect sizes were medium) and significant decreases in selfcriticism (Hated Self P=.017; .34 and Inadequate Self P<.001; .33) and self-uncompassionate responding (P<.001; .39). All three effect sizes were small. Participating in EFT-SCP had a positive effect on psychological and physiological outcomes.

Research in psychotherapy (Milano) · 8 citationsread the source →

Maternal Stress, Depression, Anxiety, and Participation in Care in Neonatal Semi-Intensive and Intensive Care Units: Results of a Cross-Sectional Study in Two Sri Lankan Hospitals.

Background/Objectives: Admission of a newborn to a neonatal intensive care unit (NICU) places mothers under considerable psychological strain, yet there is limited research from resource-limited settings regarding this aspect. This study represents the Sri Lankan arm of the multicentre study titled "Empowering Parents in the NICU". It aimed to determine the prevalence and associated factors of stress, depression, and anxiety among mothers of neonates admitted to neonatal units and to assess mothers' participation in neonatal care. Methods: A cross-sectional study was conducted in two tertiary neonatal units in Sri Lanka. Maternal stress, depression, and anxiety were measured using the Parental Stressor Scale: NICU, Edinburgh Postnatal Depression Scale, and State-Trait Anxiety Inventory. Maternal involvement in care was assessed using the Index of Parental Participation (IPP-NICU). Univariate and multivariate logistic regression analyses were performed. Results: A total of 300 mothers were enrolled. The prevalence of stress, depression, and state anxiety was 73%, 87%, and 77.7%, respectively. Overall, 94.3% experienced at least one psychological condition, while 59% experienced all three. Only 13% achieved an IPP-NICU score ≥ 20 (maximum: 30). Mothers of infants admitted to NICUs, compared with those in semi-intensive care, showed significantly higher rates of depression. Tamil and Muslim mothers demonstrated lower rates of state anxiety compared to Sinhalese mothers. An IPP-NICU score ≥ 20 was associated with reduced stress and anxiety. Conclusions: High psychological morbidity is observed among mothers of neonates managed in neonatal units, emphasising the need for routine maternal mental health screening and promoting maternal participation in neonatal care.

Children (Basel, Switzerland)read the source →

Contribution of risk factors to excess mortality in isolated and lonely individuals: an analysis of data from the UK Biobank cohort study.

Background: The associations of social isolation and loneliness with premature mortality are well known, but the risk factors linking them remain unclear. We sought to identify risk factors that might explain the increased mortality in socially isolated and lonely individuals. Methods: We used prospective follow-up data from the UK Biobank cohort study to assess self-reported isolation (a three-item scale) and loneliness (two questions). The main outcomes were all-cause and cause-specific mortality. We calculated the percentage of excess risk mediated by risk factors to assess the extent to which the associations of social isolation and loneliness with mortality were attributable to differences between isolated and lonely individuals and others in biological (body-mass index, systolic and diastolic blood pressure, and handgrip strength), behavioural (smoking, alcohol consumption, and physical activity), socioeconomic (education, neighbourhood deprivation, and household income), and psychological (depressive symptoms and cognitive capacity) risk factors. Findings: 466 901 men and women (mean age at baseline 56·5 years [SD 8·1]) were included in the analyses, with a mean follow-up of 6·5 years (SD 0·8). The hazard ratio for all-cause mortality for social isolation compared with no social isolation was 1·73 (95% CI 1·65-1·82) after adjustment for age, sex, ethnic origin, and chronic disease (ie, minimally adjusted), and was 1·26 (95% CI 1·20-1·33) after further adjustment for socioeconomic factors, health-related behaviours, depressive symptoms, biological factors, cognitive performance, and self-rated health (ie, fully adjusted). The minimally adjusted hazard ratio for mortality risk related to loneliness was 1·38 (95% CI 1·30-1·47), which reduced to 0·99 (95% CI 0·93-1·06) after full adjustment for baseline risks. Interpretation: Isolated and lonely people are at increased risk of death. Health policies addressing risk factors such as adverse socioeconomic conditions, unhealthy lifestyle, and lower mental wellbeing might reduce excess mortality among the isolated and the lonely. Funding: Academy of Finland, NordForsk, and the UK Medical Research Council.

The Lancet. Public health · 295 citationsread the source →

20 years review of antenatal diagnosis of haemoglobin Bart's disease and treatment with intrauterine transfusion.

Objective: To review prenatal diagnosis and outcome of alpha thalassaemia major through universal antenatal screening. Method: This was a retrospective study on ultrasound features, antenatal diagnosis, in-utero intervention and long term outcome of pregnancies at risk of Haemoglobin Bart's hydrops foetalis syndrome attending prenatal diagnosis from 2000 to 2019 at Tsan Yuk Hospital in Hong Kong. Results: Among 390 foetuses from 373 at-risk pregnancies, 122 (31%) prenatal invasive procedures were performed and 65 affected foetuses were diagnosed antenatally. For foetuses with ultrasound features of anaemia, the diagnostic yield of BHFS was 73%. Cardiomegaly carried a positive predictive value of 65.2% while its absence had the highest negative predictive value (96.0%). Three women having affected foetuses continued pregnancy and received intrauterine transfusion beginning 20 weeks of gestation. All babies were born alive and non-hydropic. They were managed with regular transfusion and cured by haematopoietic stem cell transplantation. Conclusions: Absence of ultrasound features of anaemia had high negative predictive value for alpha thalassaemia major. Couple at risk of having affected foetus could be offered serial ultrasound surveillance. Invasive testing for pregnancies with features of foetal anaemia provided high diagnostic yield. Intrauterine transfusion corrected foetal anaemia and allowed long term transfusion free survival without significant neurological sequelae following postnatal transplant therapy.

Prenatal diagnosis · 4 citationsread the source →

College student interest in teletherapy and self-guided mental health supports during the COVID-19 pandemic.

Objective The COVID-19 pandemic has worsened college students' mental health while simultaneously creating new barriers to traditional in-person care. Teletherapy and online self-guided mental health supports are two potential avenues for addressing unmet mental health needs when face-to-face services are less accessible, but little is known about factors that shape interest in these supports. Participants: 1,224 U.S. undergraduate students (mean age = 20.7; 73% female; 40% White) participated. Methods: Students completed an online questionnaire assessing interest in teletherapy and self-guided supports. Predictors included age, sex, race/ethnicity, sexual minority status, and anxiety and depression symptomatology. Results: Interest rates were 20% and 25% for at-cost supports (teletherapy and online self-help, respectively) and 70% and 72% for free supports (teletherapy and online self-help, respectively). Patterns emerged by age, anxiety symptom severity, and race/ethnicity. Conclusions: Results may inform universities' efforts to optimize students' engagement with nontraditional, digital mental health supports, including teletherapy and self-guided programs. The SARS-CoV2 (COVID-19) pandemic has taken a severe toll on public health, with effects reaching far beyond unprecedented illness and mortality. Levels of mental health difficulties appear to be rising broadly as the pandemic has progressed, both in the general U.S. population and among college students specifically.1,2 The COVID-19 pandemic and its repercussions may undermine college student mental health in myriad ways.2 Concurrently, students now face the potential for serious illness, loss of loved ones, financial strain, social isolation, loss of on-campus resources, and sudden disruption of routines-creating a "perfect storm" for the emergence or exacerbation of psychological distress.

Journal of American college health : J of ACH · 17 citationsread the source →

Morally injurious combat events as an indirect risk factor for postconcussive symptoms among veterans: The mediating role of posttraumatic stress.

Objective: Psychosocial factors, including combat-related distress (e.g., posttraumatic stress disorder [PTSD]), contribute to postconcussive symptoms (PCS) among veterans with mild traumatic brain injury (mTBI). However, research on risk factors for PCS has focused solely on life-threatening combat experiences, neglecting the morally injurious dimension of combat-related trauma and associated implications for treatment. Morally injurious events (MIEs) are associated with PTSD symptoms among veterans, a robust risk factor of PCS. Nonetheless, the interplay between MIEs, PTSD symptoms, and PCS remains poorly understood. We sought to investigate MIEs as an indirect risk factor for PCS among Veterans with mTBI. Method: This cross-sectional study of 145 veterans with mTBI used path analysis to investigate whether PTSD symptoms mediated the relationship between MIEs (transgressions and betrayals) and PCS (mood-behavioral, vestibular-sensory, and cognitive domains) among 145 veterans with mTBI. We used the Moral Injury Event Scale, PTSD Checklist-Civilian Version, and Neurobehavioral Symptom Inventory to measure MIEs, PTSD, and PCS, respectively. Results: Perceived transgressions were indirectly associated with mood-behavioral (β = .21, p = .005), vestibular-sensory (β = .17, p = .005), and cognitive PCS (β = .20, p = .005), as mediated by PTSD. Greater transgressions were associated with more severe PTSD (β = .27, p = .003), and greater PTSD was associated with more severe mood-behavioral (β = .79, p < .001), vestibular-sensory (β = .64, p < .001), and cognitive PCS (β = .73, p < .001). Betrayals were not indirectly associated with PCS. Conclusions: Findings offer preliminary support for responses to MIEs being a modifiable risk factor for PCS among veterans. Interventions designed to foster veterans' recovery by targeting the unique emotions and beliefs associated with MIEs may be indicated. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Psychological trauma : theory, research, practice and policy · 2 citationsread the source →

A Professional Development Workshop to Facilitate Self-Forgiveness.

Background: Evidence suggests that forgiving one's self, others, and events improves relationships and self-esteem; reduces anxiety, depression, and stress; lowers blood pressure; improves cardiovascular health; and boosts immune function. Objective: We determined the efficacy of a workshop to facilitate forgiveness in medical education professionals. Methods: A 1-hour self-forgiveness workshop conducted by 4 facilitators was presented at a medical education conference in 2018. The workshop included a didactic presentation on forgiveness and Internal Family Systems, small group discussion on self-forgiveness concepts, a 15-minute guided imagery audio meditation on self-forgiveness, and postintervention small group discussion. The 18-item Heartland Forgiveness Scale (HFS), which measures forgiveness for self, others, and situations, was completed preintervention and postintervention (score range, 18-126). Results: There were 91 participants, including graduate medical education managers and directors (61%), deans/clerkship directors (19%), and academic faculty/others (20%). Participants were from the South (20%), West (17%), Midwest (31%), and Northeast (32%) US regions. Baseline HFS scores showed that 53% were forgiving, 47% were neutral, and no participants had unforgiving tendencies. Total HFS score significantly increased (90.31 pre versus 95.7 post, P = .013), with significant increases in forgiveness of self (53% pre versus 73% post; P = .012; odds ratio = 2.47) and forgiveness of others (49% pre versus 69% post; P = .020; odds ratio = 2.3). Preintervention group discussion topics focused on guilt, shame, and barriers to forgiving, while postintervention discussions centered on challenges and benefits. Conclusions: A brief guided meditation intervention with focused discussions was feasible and improved the immediate tendency to forgive.

Journal of graduate medical education · 2 citationsread the source →

Quality of life, psychological burden, needs, and satisfaction during specialized inpatient palliative care in family caregivers of advanced cancer patients.

Background: This pilot study aimed to investigate quality of life, psychological burden, unmet needs, and care satisfaction in family caregivers of advanced cancer patients (FCs) during specialized inpatient palliative care (SIPC) and to test feasibility and acceptance of the questionnaire survey. Methods: During a period of 12 weeks, FCs were recruited consecutively within 72 h after the patient's admission. They completed validated scales on several outcomes: quality of life (SF-8), distress (DT), anxiety (GAD-7), depression (PHQ-9), supportive needs (FIN), palliative care outcome (POS), and satisfaction with care (FAMCARE-2). We used non-parametric tests, t-tests and correlation analyses to address our research questions. Results: FCs showed high study commitment: 74 FCs were asked to participate whereof 54 (73%) agreed and 51 (69%) returned the questionnaire. Except for "bodily pain", FCs' quality of life (SF-8) was impaired in all subscales. Most FCs (96%) reported clinically significant own distress (DT), with sadness, sorrows and exhaustion being the most distressing problems (80-83%). Moderate to severe anxiety (GAD-7) and depression (PHQ-9) were prevalent in 43% and 41% of FCs, respectively. FCs scored a mean number of 16.3 of 20 needs (FIN) as very or extremely important (SD 3.3), 20% of needs were unmet in >50% of FCs. The mean POS score assessed by FCs was 16.6 (SD 5.0) and satisfaction (FAMCARE-2) was high (73.4; SD 8.3). Conclusions: This pilot study demonstrated feasibility of the questionnaire survey and showed relevant psychosocial burden and unmet needs in FCs during SIPC. However, FCs' satisfaction with SIPC seemed to be high. A current multicenter study evaluates these findings longitudinally in a large cohort of FCs.

BMC palliative care · 109 citationsread the source →

Modifiable risk factors of maternal postpartum weight retention: an analysis of their combined impact and potential opportunities for prevention.

Background/objectives: Pregnancy triggers a physiological change in weight status. Postpartum weight retention in the childbearing years can substantially alter a woman's weight gain trajectory, with several potential contributing factors identified. Most research has relied on women's recall of pre-pregnancy weight during pregnancy or later, and not considered risk factors in combination. Using measured pre-pregnancy weight, this study aimed to examine the associations of maternal postpartum weight retention with parity, pre-pregnancy BMI, excessive gestational weight gain (GWG), maternal serum vitamin D concentration and dietary Glycaemic Index in early and late pregnancy, and breastfeeding duration, including analysis of the combined impact of potentially modifiable risk factors. Subjects/methods: Prospective cohort study of 12 583 non-pregnant women aged 20-34 years in Southampton (UK) who were assessed prior to pregnancy, with those who subsequently became pregnant followed up in early and late gestation, and after delivery (n=2559 in the final sample). Linear regression models examined potential predictors of weight retention in adjusted individual and multivariate analyses, and as a risk factor score. Results: Compared with pre-pregnancy weight, 73% of women retained some weight at 6 months postpartum (mean (s.d.): 3.5 (6.2) kg). In the adjusted multivariate model, women who were primiparous, had a lower pre-pregnancy BMI, excessive GWG, a lower early pregnancy vitamin D concentration and breastfed for <6 months had greater weight retention 6 months postpartum (P<0.05 for all variables). For each additional modifiable risk factor (excessive GWG, low vitamin D concentration in early pregnancy and short breastfeeding duration; scale 0-3), women retained an additional 2.49 kg (95% CI: 2.16, 2.82; P<0.001). Conclusions: Having a greater number of modifiable risk factors was associated with greater weight retention 6 months postpartum. Initiatives supporting women to target these risk factors in the years prior to, during and after pregnancy could impact on their weight gain trajectory and later risk of adverse weight-related outcomes.

International journal of obesity (2005) · 47 citationsread the source →

Exploring Proof of Concept for a Novel Web-Based Self-Management Support Intervention for Polycystic Ovary Syndrome: Multimethod Study.

Background: Polycystic ovary syndrome (PCOS) is a common chronic hormonal condition affecting 8%-13% of women and individuals assigned female at birth. Symptoms may include subfertility, menstrual, skin, and metabolic problems, with long-term health risks including diabetes and cardiovascular disease. PCOS has a significant negative impact on mental health, quality of life, and well-being. We explored proof of concept for a web-based self-management support intervention, "Hope PCOS," designed to reduce anxiety and depression and increase positive well-being for women living with PCOS. Objective: We aim to pilot the intervention to test feasibility for web-based recruitment and delivery, acceptability, and potential to reduce anxiety and depression and increase positive well-being. Methods: Women with PCOS were recruited via social media with support from a patient advocacy charity and offered places on a 6-session cohort of the intervention. In a pre-post design, participants reported depression (Patient Health Questionnaire 9-Items), anxiety (Generalized Anxiety Disorder 7-Items), well-being (Warwick-Edinburgh Mental Wellbeing Scale), hope (SHS [State Hope Scale]), and gratitude (GQ-6 [Gratitude Questionnaire]) at baseline and 6 weeks. All participants who accessed 3 or more sessions were invited to a follow-up qualitative interview to explore user experience. Data from 8 interviews were thematically analyzed, and pre-post data were explored with descriptive statistics. Results: A total of 63 eligible women responded and were given access to the intervention. Three withdrew, leaving a baseline sample of 60, aged 20-58 (median 30, IQR 25-36) years. Further, 48 of the 60 started, of whom 46% (22/48) completed at least 3 sessions, and 29% (14/48) completed all 6. Additionally, 8 women (aged 25-38, median 29, IQR 26-35) years who completed between 3 and 6 sessions reported acceptability and experiences in exit interviews, including prioritizing self-care, developing a self-management mindset, setting motivating goals, improved mental health, self-compassion, reduced shame, openness about PCOS, preparedness for future health concerns, and continuing practice to consolidate behavior change. Furthermore, 11 women aged 25-43 (median 31, IQR 27-37) years, who completed 1-6 sessions (median 6, IQR 6-6), completed pre- and postintervention outcomes. Descriptive quantitative analysis indicated decreases in anxiety and depression and increases in hope agency, hope pathways, and gratitude. There was a meaningful (≥3 points) increase in well-being. Among patients with baseline and follow-up data, 73% (8/11) met clinical caseness for depression at baseline and 36% (4/11) post intervention. Conclusions: We explored proof of concept. Web-based recruitment and delivery online were feasible. We detected early signs of acceptability and potential benefits for anxiety, depression, and positive well-being that warrant testing in a controlled trial. Future research should assess the feasibility of a randomized controlled trial to evaluate effectiveness, acceptability, and cost-effectiveness.

JMIR formative researchread the source →

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

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

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

Spirituality and mental health

INTRODUCTION All along, the majority position of Psychiatry has been that Psychiatry has nothing to do with religion and spirituality. Religious beliefs and practices have long been thought to have a pathological basis, and psychiatrists over a century have understood them in this light. Religion was considered as a symptom of mental illness. Jean Charcot and Sigmund Freud linked religion with neurosis. DSM3 portrayed religion negatively by suggesting that religious and spiritual experiences are examples of psychopathology. But recent research reports strongly suggest that to many patients, religion and spirituality are resources that help them to cope with the stresses in life, including those of their illness. Many psychiatrists now believe that religion and spirituality are important in the life of their patients. The importance of spirituality in mental health is now widely accepted. As John Turbott[1] puts it, rapprochement between religion and psychiatry is essential for psychiatric practice to be effective. The Royal College of Psychiatrists, London, has a special group on Psychiatry and Spirituality. The American College of Graduate Medical Education mandates in its special requirements for residency training in Psychiatry, that all programs must provide training in religious and spiritual factors that can influence mental health. The World Psychiatric Association recently established a section on psychiatry and religion. Lukoff et al.[2] proposed that the diagnostic entities of religious and psychospiritual problems should be incorporated in DSM4 which has been accepted. DSM4, V 62.89 includes three categories—normal religious and spiritual experiences; religious and spiritual problems leading to mental disturbances; and mental disturbances with a religious and spiritual context. I understand that the Indian Psychiatric Society has formed a task force on spirituality and mental health which is urging the Medical council of India to include taking the spiritual history as part of psychiatric evaluation. Even so the importance of religion and spirituality are not sufficiently recognized by the psychiatric community. Religion does not have a place in most of the psychiatry text books. Only very few psychiatrists make use of religion and spirituality in the therapeutic situation. This paper makes an attempt to bring out the importance of spirituality in mental health. WHAT IS SPIRITUALITY? Spirituality is a globally acknowledged concept. It involves belief and obedience to an all powerful force usually called God, who controls the universe and the destiny of man. It involves the ways in which people fulfill what they hold to be the purpose of their lives, a search for the meaning of life and a sense of connectedness to the universe. The universality of spirituality extends across creed and culture. At the same time, spirituality is very much personal and unique to each person. It is a sacred realm of human experience. Spirituality produces in man qualities such as love, honesty, patience, tolerance, compassion, a sense of detachment, faith, and hope. Of late, there are some reports which suggest that some areas of the brain, mainly the nondominant one, are involved in the appreciation and fulfillment of spiritual values and experiences.[3–5] SPIRITUALITY AND RELIGION Religion is institutionized spirituality. Thus, there are several religions having different sets of beliefs, traditions, and doctrines. They have different types of community-based worship programs. Spirituality is the common factor in all these religions. It is possible that religions can lose their spirituality when they become institutions of oppression instead of agents of goodwill, peace and harmony. They can become divisive instead of unifying. History will tell us that this had happened from time to time. It has been said that more blood has been shed in the cause of religion than any other cause. The medieval holy wars of Europe; the religion-based terrorism and conflicts of modern times are examples. We must remember that the institutions of religion are supposed to help us to practice spirituality in our lives. They need periodical revivals to put spirituality in place. SPIRITUAL DIMENSION IS IMPORTANT IN MENTAL HEALTH Mental health has two dimensions—absence of mental illness and presence of a well-adjusted personality that contributes effectively to the life of the community. Ability to take responsibility for one's own actions, flexibility, high frustration tolerance, acceptance of uncertainty, involvement in activities of social interest, courage to take risks, serenity to accept the things which we cannot change, courage to change the things which we can change, the wisdom to know the difference between the above, acceptance of handicaps, tempered self-control, harmonious relationships to self, others, including Nature and God, are the essential features of mental health. Spirituality is an important aspect of mental health. St. Augustine prayed “O God, thou created us in thy image and our hearts will be restless until they find their rest in Thee.” Though Sigmund Freud looked upon religion as an illusion and neurosis, Carl Jung considered the psyche as a carrier of truth, powerfully rooted in the unconscious mind. Religion is important, directly and indirectly, in the etiology, diagnosis, symptomatology, treatment and prognosis of psychiatric disturbances. Lack of spirituality can interfere with interpersonal relationships, which can contribute to the genesis of psychiatric disturbance. Psychiatric symptoms can have a religious content. For example, the loss of interest in religious activities is a common symptom of depression. Too much and distorted religious practices are common in schizophrenia. It is well recognized that some religious states and experiences are misdiagnosed as symptoms of psychiatric illness. Visions and possession states are examples. The spiritual background of the patient will help in the diagnosis of psychiatric disturbance. They are important in the treatment of psychiatric disturbance because spiritual matters can be profitably incorporated in psychotherapy. Spirituality is important in the prognosis of psychiatric conditions. In the spiritual perspective, a differentiation must be made between cure and healing. Cure is the removal of symptoms. Healing is the healing of the whole person. Adversity often produces maturity. Hence in psychotherapy, the patient must be helped to accept the handicap and transform the handicap to a life of usefulness. SOME SIGNIFICANT CLINICAL AND RESEARCH FINDINGS Recent studies show that religious beliefs and practices are supportive to cope with stresses in life and are beneficial to mental health. Thomas Ashby Wills,[6] Professor of Epidemiology and population health at Albert Einstein College of Medicine developed a scale that determines how important is religion to people. This was administered to 1182 children in New York. It was found that religiosity kept children from smoking, drinking and drug abuse by buffering the impact of life stresses. Gene H. Brody,[7] a research professor of child and family development at the University of Georgia, Athens, found that parents who were more involved in church activities were more likely to have harmonious marital relationships and better parenting skills. That in turn enhanced children's competence, self-regulation, psychosocial adjustment and school performance. Miller et al.[8] made a 10-year follow up study on depressed mothers and their offsprings and reported that maternal religiosity and mother-child concordance in religiosity were protective against depression in the offspring. They also reported that low level of religiosity was associated with substance abuse in the offsprings.[9] J. Scott Tonigan,[10] a research professor of psychiatry at the University of New Mexico, followed up 226 patients of alcohol dependence and reported that spirituality predicts behavior such as honesty and responsibility which in turn promoted alcohol abstinence. Wagner and King[11] conducted a study involving three groups—one group of patients who had psychotic illness, one group of formal care givers, and a third group of informal caregivers. The existential needs were the most important for the patient group, while the other groups considered material needs such as housing and work as more important. Neeleman and King[12] surveyed the psychiatric practices of 231 psychiatrists in London. 73% had no religious affiliation, 28% had belief in God, 61% believed that religion can protect against mental illness, and 48% asked patients about their religious practices. Baetz et al.[13] surveyed 1204 psychiatrists and 157 psychiatric patients in Canada. 54% of psychiatrists believed in God, 47% asked patients regarding their religious beliefs, and 55% consulted clergy for the management of patients. Among the patients, 71% believed in God, and 24% preferred psychiatrists who were religious. In an Australian survey, a large majority of patients with psychiatric illness wanted their therapists to be aware of their spiritual beliefs and needs and believed that their spiritual practices helped them to cope better.[14] Mathai and North[15] constructed a questionnaire, consisting of 5 questions and gave it to 70 parents of children attending child and adolescent mental health clinic. They reported that majority of the parents believed that spiritual concerns were important and that therapists should consider their spiritual beliefs in the management of the problems of the children. In USA, Curlin et al.[16] conducted a study of psychiatrists and compared them with physicians from other specialities in their religious affiliations and found that psychiatrists showed less religious affiliations. Several empirical studies on psychiatrists' religious characteristics have indicated that psychiatrists are significantly less religious than the general population, their patients and other physicians.[17],[18] In a 12-year follow up of all articles appearing in American Journal of Psychiatry and Archives of General Psychiatry, 72% of the religious commitment variables were beneficial to mental health; participation in religious services, social support, prayer and relationship with God were beneficial in 92% of citations.[19] Similar findings were reported in a review of the Journal of Family Practice.[20] In a British epidemiological study, church going and active religion were found to be protective to vulnerability for depression by Brown and Prudo.[21] In a detailed study on suicide in Netherlands, Kerkoff [quoted by Sims[22]] reported that there was a decline in suicidal rate, which was concurrent with a religious revival. A study on the factors in the course and outcome of schizophrenia was conducted in the Department of psychiatry, Christian Medical College, Vellore.. It was a collaborative study among three centers—Vellore, Madras and Lucknow. A two-year and five-year follow up showed that those patients who spent more time in religious activities tended to have a better prognosis.[23],[24] The above reports strongly suggest that religious beliefs and practices of psychiatric patients should be given importance. The sense of hope and spiritual support that patients get by discussing religious matters help them to cope better. They also suggest that the importance of religion and spirituality is not sufficiently recognized by the psychiatric community. Mental health workers must take it seriously since psychiatry cannot afford to ignore the importance of spirituality and religion in psychiatry. Sims[22] gives two case histories which drives home this fact. One is the case of Jim who suffered from Korsakov's psychosis. He was so deteriorated that he mistook his wife for a hat. In the ward, others considered him as desolate individual. But his behavior in the chapel was normal. In absolute concentration and attention, he would partake Holy Communion. He did not forget anything nor did he show any signs of Korsakov's psychosis. The other patient had chronic schizophrenia. He used to hear a voice commanding him to jump out of the window. His simple devout mother had taught him to resist the voice by praying to God. His mind was destroyed, but the capacity for spiritual life was present. Unfortunately, on the final occasion, he was too late to pray and he lost his life. Sims makes a comment, “It is unfortunate that we as psychiatrists can be so crass as to neglect this area of life which is clearly important to many of our patients.” Andresen,[25] in an editorial, has pointed out that our civilization's “loss of soul” may cause psychiatric symptoms such as depression, obsessions, addictions, and violence. She has suggested that it is the responsibility of psychiatrists to remind the medical fraternity the necessity of putting back the soul in medical ethics and the fact that spirituality is of vital importance for the mental health of people. WHAT CAN WE DO? As pointed out earlier, spiritual values and religious practices are important in the lives of our patients. Many of their problems may centre round existential preoccupations. It is therefore important that we incorporate spirituality and religious practices in our treatment protocol. We must propagate the Bio-psycho-socio-spiritual model in our approach in psychiatry. Harold Koening,[26] in his paper Religion and Mental health: what should psychiatrists do?, has made some suggestions in this area. Psychiatric history should be catered to the patients' spiritual orientation and religious practices. When we take psychiatric history, we usually ask for the denomination the patient belongs. We do not try to find out how the patient experiences religion. What does religion and spirituality mean to the patient. The psychiatric history should gather information about patient's religious background and experiences in the past and what role religion plays in coping with life stresses. Has patient had any past negative religious experiences? Has he got spiritual and social support from the congregation which he attends? How active is he in the religious congregation? Some religious beliefs can be in conflict with the proposed treatment. Some religious groups are against any type of treatment. Some religious conflicts and frustrations may be contributing to the present psychiatric problem. Sexual abuse by religious workers, traumatic events which turned the patient away from religious beliefs and activities, unanswered prayers, etc. are examples. There are some questionnaires that can be used to take a history of spirituality and religious experiences.[152728] Discussion with the patient on spiritual matters and religious experiences will strengthen the therapeutic relationship. It can also lead to reversal effect of a personal growth of the therapist. We should respect and support patients' religious beliefs if these help them to cope better or do not adversely affect their mental health. For example, if a patient says that his discipline of fasting and prayer helps him to cope better, then this has to be encouraged. We should also challenge the beliefs that can adversely affect mental health. This has to be done very tactfully. It is better to be neutral till we understand the patients and the issues involved well and a good therapeutic relationship is formed. Patients may wish to discuss with the therapist regarding their subjective experiences and existential needs. We should spend time in listening to them. Partnership with the religious workers is an useful area. Leavy and King[29] in their paper, The devil in the detail: partnership between psychiatry and faith based organizations, brings out the importance of such a partnership. They have reported that in UK, the clergy continue to have a central role in several communities and the utility of their involvement in the care of people with mental health problems is increasing. They have argued the importance of examining the form and parameters of partnership between the mental health team and the faith-based communities. For this partnership to be effective, the mental health workers must be spiritually oriented and the religious workers must be better informed about mental health and illness. As referred to earlier, some religious experiences are often misdiagnosed as symptoms of mental illness and vice versa, some psychiatric symptoms are explained as spiritual experiences. According to Sims,[22] phenomena such as faith, prayer and magic can lend themselves to description and definition using Jasperian phenomenology which can lead to a clear differentiation of normal and pathological religious experiences. This emphasizes the importance of psycho-pastoral partnership. One example of such a partnership is the Bangalore psycho-pastoral association, which runs a very efficient half-way home for psychiatric patients. Recognizing the importance of this, the World Council of Churches has formed an Advisory group on mental health and faith communities, which has been active in the exploration of strategies for an effective partnership between mental health services and faith communities. There can be problems in such a partnership. The religious workers may be reluctant to get involved in secular programs, leaving their spiritual fortress. Some of them can have incorrect ideas about the causes of mental illness, which can interfere with the treatment program. Some others can be against medical treatment. Mental health workers can also be prejudiced against the patients' religious beliefs and practices. As referred to earlier, research findings suggest that majority of psychiatrists do not give importance to the spiritual and religious experiences of patients. According to Neelman and Persaud,[30] this may be due to the following factors. Psychiatrists are by and large less religious than other physicians; psychiatrists often come to know of spirituality through the pathological religious symptoms of patients, which make them prejudiced against spirituality; psychiatrists tend to have a biological approach to mental illness, which ignores spiritual dimension; and psychiatrists may think that religion and spirituality cause dependence and guilt feelings. All these can be minimized with dialogue and periodical orientation programs. As John Turbott[31] puts it, psychiatry as a whole can only benefit if the concepts and vocabulary of religion and spirituality are more widely known and discussed among its practitioners. It is also true that conflicts and problems arise more with religious experiences and not with spirituality Praying with the patient is a controversial area. Many psychiatrists will argue that it is a dangerous ground upon which to tread. If at all it is done, it should be done only after a strong therapeutic relationship is established and only if the patient asks for it. Praying for the patient can be beneficial. Research. Although there is substantial body of literature that describes the connection between mental health and spirituality, we must develop theoretical models to understand their relationship in practice. The statistical findings reported earlier were mainly the results of surveys. High-quality evidence-based research is required to make the clinical applications more objective and effective. There are ample opportunities to do research in this area. Phenomena such as meditation, religious faith, and concepts are all What are their to normal life and psychiatric What are the which influence spiritual experiences? If spirituality is to mental health and if religious beliefs and experiences are important in the life of the psychiatric it is only that we should include religious concepts in psychotherapy. For example, some and can be profitably used to help the patient to cope with life situation. The spiritual concepts are incorporated in the treatment of out of the to spirituality. describes a which is called This is a treatment spiritual values to behavior which was developed and promoted at the University of areas are meaning and purpose and The patient is through to meaning and This with examining the of life such as and the patient to the patient is to the of of and in life. The the patient's that and and The involves a on after examining and one's in life. meaning is by meaning for each This is by and factors life and illness The are of and The use of meditation, and with of beliefs and on symptoms form the of the treatment. When the patient negative is the treatment about each about The are depression and adolescent show that produces

Indian Journal of Psychiatry · editorial or comment · 106 citationsread the source →

Body mass, weight control behaviours, weight perception and emotional well being in a multiethnic sample of early adolescents.

Objective: To investigate weight perception, dieting and emotional well being across the range of body mass index (BMI) in a population-based multiethnic sample of early adolescents. Design: Cross-sectional population-based survey. Subjects: In total, 2789 adolescents 11-14 years of age from three highly deprived regional authorities in East London, in 2001. Measurements: Data were collected by student-completed questionnaire on weight perception, dieting history, mental and physical health, health behaviours, social capital and sociodemographic factors. Height and weight were measured by trained researchers. Overweight was defined as BMI > or =85th centile and obesity as BMI > or =98th centile. Underweight was defined as BMI< or =15th centile. Results: In all, 73% were from ethnic groups other than white British. Valid BMI were available for 2522 subjects (90.4%) of whom 14% were obese. Only 20% of overweight boys and 51% of overweight girls assessed their weight accurately. Accuracy of weight perception did not vary between ethnic groups. In all, 42% of girls and 26% of boys reported current dieting to lose weight. Compared with white British teenagers, a history of dieting was more common among Bangladeshi, Indian and mixed ethnicity boys and less likely among Pakistani girls. Self-esteem was not associated with BMI in girls but was significantly lower in obese boys than those of normal weight (P=0.02). Within ethnic subgroups, self-esteem was significantly lower in overweight white British boys (P=0.03) and obese Bangladeshi boys (P=0.01) and Bangladeshi girls (P=0.04), but significantly higher in obese black African girls (P=0.01) than those of normal weight. Obese young people had a higher prevalence of psychological distress (P=0.04), except among Bangladeshi teenagers, where overweight and obese young people had less psychological distress than those of normal weight (P=0.02). Birth outside the UK was associated with reduced risk of obesity in girls (P=0.02) but not with history of dieting, weight perception or psychological factors in either gender. Conclusion: High levels of current dieting for weight control and inaccurate perception of body mass are common across all ethnic groups. However, dieting history and the associations of obesity with self-esteem and psychological distress vary between ethnic groups. Interventions to prevent or treat obesity in black or minority ethnicity groups must consider cultural differences in the relationship between body mass, self-esteem and psychological distress.

International journal of obesity (2005) · 99 citationsread the source →

The association between comorbidity and outcome in pathological gambling: a prospective follow-up of recent quitters.

A naturalistic sample of pathological gamblers (N = 101) who recently quit gambling was followed prospectively for a year (follow-up rate 80%). Lifetime mood disorders were identified in 61% of participants and 73% and 48% had lifetime alcohol use and drug use disorders, respectively. Current prevalence rates, however, were much lower. Current mood disorders were found for 20% and 7% had a current alcohol disorder and 7% a current drug use disorder. Age of onset for substance use disorders was earlier than gambling disorders but mood disorders were equally likely to predate or follow gambling disorders. Lifetime mood disorder was associated with a longer time to achieve 3 months of stable abstinence. Participants who were currently in treatment or attending Gamblers Anonymous and the small number of participants with current alcohol disorders were also more likely to achieve abstinence earlier. The results underscore the importance of increasing our understanding of the role of comorbid disorders in the recovery process from gambling problems.

Journal of gambling studies · 71 citationsread the source →

High-throughput sequencing and characterization of the small RNA transcriptome reveal features of novel and conserved microRNAs in Panax ginseng.

microRNAs (miRNAs) play vital regulatory roles in many organisms through direct cleavage of transcripts, translational repression, or chromatin modification. Identification of miRNAs has been carried out in various plant species. However, no information is available for miRNAs from Panax ginseng, an economically significant medicinal plant species. Using the next generation high-throughput sequencing technology, we obtained 13,326,328 small RNA reads from the roots, stems, leaves and flowers of P. ginseng. Analysis of these small RNAs revealed the existence of a large, diverse and highly complicated small RNA population in P. ginseng. We identified 73 conserved miRNAs, which could be grouped into 33 families, and 28 non-conserved ones belonging to 9 families. Characterization of P. ginseng miRNA precursors revealed many features, such as production of two miRNAs from distinct regions of a precursor, clusters of two precursors in a transcript, and generation of miRNAs from both sense and antisense transcripts. It suggests the complexity of miRNA production in P. ginseng. Using a computational approach, we predicted for the conserved and non-conserved miRNA families 99 and 31 target genes, respectively, of which eight were experimentally validated. Among all predicted targets, only about 20% are conserved among various plant species, whereas the others appear to be non-conserved, indicating the diversity of miRNA functions. Consistently, many miRNAs exhibited tissue-specific expression patterns. Moreover, we identified five dehydration- and ten heat-responsive miRNAs and found the existence of a crosstalk among some of the stress-responsive miRNAs. Our results provide the first clue to the elucidation of miRNA functions in P. ginseng.

PloS one · 49 citationsread the source →

A multicomponent yoga-based, breath intervention program as an adjunctive treatment in patients suffering from generalized anxiety disorder with or without comorbidities

OBJECTIVES: The aim of this study is to evaluate the efficacy and tolerability of Sudarshan Kriya Yoga (SKY) course in generalized anxiety disorder (GAD) outpatients, who after eight weeks of an appropriate dose of traditional therapy had not yet achieved remission. SUBJECTS: The adult participants (18-65 years) were outpatients with a primary diagnosis of GAD with or without comorbidities on the Mini-International Neuropsychiatric Interview (MINI). Participants had a minimum of eight weeks standard treatment with an appropriate dose of a standard prescription anxiolytic, a clinician global impression-severity (CGI-S) score of 5-7, a Hamilton anxiety scale (HAM-A) total score ≥20 including a score of >2 on the anxious mood and tension items. MATERIALS AND METHODS: Forty-one patients were enrolled in an open-label trial of the SKY course as an adjunct to standard treatment of GAD at the START Clinic for Mood and Anxiety Disorders, a tertiary care mood and anxiety disorder clinic in Toronto. The SKY course was administered over five days (22 h total). Subjects were encouraged to practice the yoga breathing techniques at home for 20 min per day after the course and were offered group practice sessions for 2 h once a week led by certified yoga instructors. The primary outcome measure was the mean change from pre-treatment on the HAM-A scale. Psychological measures were obtained at baseline and four weeks after completing the intervention. RESULTS: Thirty-one patients completed the program (mean age 42.6 ± 13.3 years). Among completers, significant reductions occurred in the pre- and post-intervention mean HAM-A total score (t=4.59; P<0.01) and psychic subscale (t=5.00; P≤0.01). The response rate was 73% and the remission rate 41% as measured on the HAM-A. CONCLUSION: The results of this small pilot trial suggest that the SKY course represents a potentially valuable adjunct to standard pharmacotherapy in patients with GAD or treatment-resistant GAD, and warrants further investigation. In particular, changes in worry and body symptoms showed significant improvements that may further our understanding of the mechanism of change in the tolerance of anxiety and worry.

International Journal of Yoga · 87 citationsread the source →

Development and validation of the Eating Pathology Symptoms Inventory (EPSI).

Many current measures of eating disorder (ED) symptoms have 1 or more serious limitations, such as inconsistent factor structures or poor discriminant validity. The goal of this study was to overcome these limitations through the development of a comprehensive multidimensional measure of eating pathology. An initial pool of 160 items was developed to assess 20 dimensions of eating pathology. The initial item pool was administered to a student sample (N = 433) and community sample (N = 407) to determine the preliminary structure of the measure using exploratory and confirmatory factor analyses. The revised measure was administered to independent samples of patients recruited from specialty ED treatment centers (N = 158), outpatient psychiatric clinics (N = 303), and students (N = 227). Analyses revealed an 8-factor structure characterized by Body Dissatisfaction, Binge Eating, Cognitive Restraint, Excessive Exercise, Restricting, Purging, Muscle Building, and Negative Attitudes Toward Obesity. Scale scores showed excellent convergent and discriminant validity; other analyses demonstrated that the majority of scales were invariant across sex and weight categories. Eating Pathology Symptoms Inventory scale scores had excellent internal consistency (median coefficient alphas ranged from .84-.89) and reliability over a 2- to 4-week period (mean retest r = .73). The current study represents one of the most comprehensive scale development projects ever conducted in the field of EDs and will enhance future basic and treatment research focused on EDs.

Psychological assessment · 339 citationsread the source →

Whither the Attenuated Psychosis Syndrome?

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

Schizophrenia Bulletin · 97 citationsread the source →