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Tenofovir-diphosphate in peripheral blood mononuclear cells during low, medium and high adherence to emtricitabine/ tenofovir alafenamide vs. emtricitabine/ tenofovir disoproxil fumarate.

Objective: Tenofovir alafenamide (TAF) preferentially loads peripheral blood mononuclear cells (PBMCs), resulting in higher PBMC tenofovir-diphosphate (TFV-DP) vs. tenofovir disoproxil fumarate (TDF). No studies have yet compared TFV-DP in PBMC from lower than daily dosing between prodrugs, which has potential implications for event-driven preexposure prophylaxis and pharmacologic forgiveness. Design: Two separate randomized, directly observed therapy (DOT) crossover studies (DOT-DBS and TAF-DBS) were conducted to mimic low, medium and high adherence. Methods: HIV-negative adults were randomized to two 12-week DOT regimens of 33, 67 or 100% of daily dosing with emtricitabine (F)/TAF 200 mg/25 mg (TAF-DBS) or F/TDF 200 mg/300 mg (DOT-DBS), separated by a 12-week washout. PBMC steady-state concentrations (Css) of TFV-DP and FTC-TP were estimated using nonlinear mixed models and compared between F/TAF and F/TDF. Results: Thirty-five participants contributed to 33% (n = 23), 67% (n = 23) and 100% (n = 23) of daily F/TAF regimens. Forty-four contributed to 33% (n = 15), 67% (n = 16) and 100% (n = 32) of daily F/TDF regimens. PBMC TFV-DP Css were 7.3 [95% confidence interval (95% CI): 6.4-8.2], 7.1 (5.9-8.2) and 6.7- (4.4-8.9) fold higher (P < 0.0001) following F/TAF vs. F/TDF; 593 vs. 81.7, 407 vs. 57.4, and 215 vs. 32.3 fmol/106 cells, respectively. TFV-DP was 2.6 (2.1-3.1) fold higher with 33% F/TAF vs. 100% F/TDF. Estimated half-lives (95% CI) of TFV-DP in PBMC were 2.9 (1.5-5.5) days for F/TAF and 2.1 (1.5-2.9) days for F/TDF. FTC-TP was similar in both studies (P = 0.119). Conclusion: F/TAF produced 6.7 to 7.3-fold higher TFV-DP in PBMC vs. F/TDF across adherence levels, supporting increased potency and pharmacologic forgiveness with F/TAF in the PBMC compartment.

AIDS (London, England) · randomised controlled trial · 27 citationsread the source →

Relapse prevention interventions for smoking cessation.

Background: A number of treatments can help smokers make a successful quit attempt, but many initially successful quitters relapse over time. Several interventions have been proposed to help prevent relapse. Objectives: To assess whether specific interventions for relapse prevention reduce the proportion of recent quitters who return to smoking. Search methods: We searched the Cochrane Tobacco Addiction Group trials register, clinicaltrials.gov, and the ICTRP in February 2018 for studies mentioning relapse prevention or maintenance in their title, abstracts, or keywords. Selection criteria: Randomised or quasi-randomised controlled trials of relapse prevention interventions with a minimum follow-up of six months. We included smokers who quit on their own, were undergoing enforced abstinence, or were participating in treatment programmes. We included studies that compared relapse prevention interventions with a no intervention control, or that compared a cessation programme with additional relapse prevention components with a cessation programme alone. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: We included 77 studies (67,285 participants), 15 of which are new to this update. We judged 21 studies to be at high risk of bias, 51 to be at unclear risk of bias, and five studies to be at low risk of bias. Forty-eight studies included abstainers, and 29 studies helped people to quit and then tested treatments to prevent relapse. Twenty-six studies focused on special populations who were abstinent because of pregnancy (18 studies), hospital admission (five studies), or military service (three studies). Most studies used behavioural interventions that tried to teach people skills to cope with the urge to smoke, or followed up with additional support. Some studies tested extended pharmacotherapy. We focused on results from those studies that randomised abstainers, as these are the best test of relapse prevention interventions. Of the 12 analyses we conducted in abstainers, three pharmacotherapy analyses showed benefits of the intervention: extended varenicline in assisted abstainers (2 studies, n = 1297, risk ratio (RR) 1.23, 95% confidence interval (CI) 1.08 to 1.41, I² = 82%; moderate certainty evidence), rimonabant in assisted abstainers (1 study, RR 1.29, 95% CI 1.08 to 1.55), and nicotine replacement therapy (NRT) in unaided abstainers (2 studies, n = 2261, RR 1.24, 95% Cl 1.04 to 1.47, I² = 56%). The remainder of analyses of pharmacotherapies in abstainers had wide confidence intervals consistent with both no effect and a statistically significant effect in favour of the intervention. These included NRT in hospital inpatients (2 studies, n = 1078, RR 1.23, 95% CI 0.94 to 1.60, I² = 0%), NRT in assisted abstainers (2 studies, n = 553, RR 1.04, 95% CI 0.77 to 1.40, I² = 0%; low certainty evidence), extended bupropion in assisted abstainers (6 studies, n = 1697, RR 1.15, 95% CI 0.98 to 1.35, I² = 0%; moderate certainty evidence), and bupropion plus NRT (2 studies, n = 243, RR 1.18, 95% CI 0.75 to 1.87, I² = 66%; low certainty evidence). Analyses of behavioural interventions in abstainers did not detect an effect. These included studies in abstinent pregnant and postpartum women at end of pregnancy (8 studies, n = 1523, RR 1.05, 95% CI 0.99 to 1.11, I² = 0%) and at postpartum follow-up (15 studies, n = 4606, RR 1.02, 95% CI 0.94 to 1.09, I² = 3%), studies in hospital inpatients (4 studies, n = 1300, RR 0.95, 95% CI 0.81 to 1.11, I² = 0%), and studies in assisted abstainers (10 studies, n = 5408, RR 0.99, 95% CI 0.87 to 1.13, I² = 56%; moderate certainty evidence) and unaided abstainers (5 studies, n = 3561, RR 1.06, 95% CI 0.96 to 1.16, I² = 1%) from the general population. Authors' conclusions: Behavioural interventions that teach people to recognise situations that are high risk for relapse along with strategies to cope with them provided no worthwhile benefit in preventing relapse in assisted abstainers, although unexplained statistical heterogeneity means we are only moderately certain of this. In people who have successfully quit smoking using pharmacotherapy, there were mixed results regarding extending pharmacotherapy for longer than is standard. Extended treatment with varenicline helped to prevent relapse; evidence for the effect estimate was of moderate certainty, limited by unexplained statistical heterogeneity. Moderate-certainty evidence, limited by imprecision, did not detect a benefit from extended treatment with bupropion, though confidence intervals mean we could not rule out a clinically important benefit at this stage. Low-certainty evidence, limited by imprecision, did not show a benefit of extended treatment with nicotine replacement therapy in preventing relapse in assisted abstainers. More research is needed in this area, especially as the evidence for extended nicotine replacement therapy in unassisted abstainers did suggest a benefit.

The Cochrane database of systematic reviews · meta-analysis · 60 citationsread the source →

Coverage of Nonpharmacologic Treatments for Low Back Pain Among US Public and Private Insurers.

Importance: Despite epidemic rates of addiction and death from prescription opioids in the United States, suggesting the importance of providing alternatives to opioids in the treatment of pain, little is known regarding how payers' coverage policies may facilitate or impede access to such treatments. Objective: To examine coverage policies for 5 nonpharmacologic approaches commonly used to treat acute or chronic low back pain among commercial and Medicare Advantage insurance plans, plus an additional 6 treatments among Medicaid plans. Design, setting, and participants: Cross-sectional study of 15 commercial, 15 Medicaid, and 15 Medicare Advantage health plans for the 2017 calendar year in 16 states representing more than half of the US population. Interviews were conducted with 43 senior medical and pharmacy health plan executives from representative plans. Main outcomes and measures: Medical necessity and coverage status for the treatments examined, as well as the use of utilization management tools and cost-sharing magnitude and structure. Results: Commercial and Medicare insurers consistently regarded physical and occupational therapy as medically necessary, but policies varied for other therapies examined. Payers most commonly covered physical therapy (98% [44 of 45 plans]), occupational therapy (96% [43 of 45 plans]), and chiropractic care (89% [40 of 45 plans]), while transcutaneous electrical nerve stimulation (67% [10 of 15 plans]) and steroid injections (60% [9 of 15 plans]) were the most commonly covered among the therapies examined for Medicaid plans only. Despite evidence in the literature to support use of acupuncture and psychological interventions, these therapies were either not covered by plans examined (67% of all plans [30 of 45] did not cover acupuncture) or lacked information about coverage (80% of Medicaid plans [12 of 15] lacked information about coverage of psychological interventions). Utilization management tools, such as prior authorization, were common, but criteria varied greatly with respect to which conditions and what quantity and duration of services were covered. Interviewees represented 6 Medicaid managed care organizations, 2 Medicare Advantage or Part D plans, 9 commercial plans, and 3 trade organizations (eg, Blue Cross Blue Shield Association). Interviews with plan executives indicated a low level of integration between the coverage decision-making processes for pharmacologic and nonpharmacologic therapies for chronic pain. Conclusions and relevance: Wide variation in coverage of nonpharmacologic treatments for low back pain may be driven by the absence of best practices, the administrative complexities of developing and revising coverage policies, and payers' economic incentives. Such variation suggests an important opportunity to improve the accessibility of services, reduce opioid use, and ultimately improve the quality of care for individuals with chronic, noncancer pain while alleviating the burden of opioid addiction and overdose.

JAMA network open · 127 citationsread the source →

Patient outcomes up to 15 years after stroke: survival, disability, quality of life, cognition and mental health.

Background: The global epidemiological shift of disease burden towards long-term conditions means understanding long-term outcomes of cardiovascular disease is increasingly important. More people are surviving stroke to experience its long-term consequences, but outcomes in people living more >10 years after stroke have not been described in detail. Methods: Data were collected for the population-based South London Stroke Register, with participants followed up annually until death. Outcomes were survival, disability, activity, cognitive impairment, quality of life, depression and anxiety. Findings: Of 2625 people having first-ever stroke, 262 (21%) survived to 15 years. By 15 years, 61% (95% CI 55% to 67%) of the survivors were male, with a median age of stroke onset of 58 years (IQR 48-66). 87% of the 15-year survivors were living at home and 33.8% (26.2% to 42.4%) had mild disability, 14.3% (9.2% to 21.4%) moderate disability and 15.0% (9.9% to 22.3%) severe disability. The prevalence of disability increased with time but 1 in 10 of the 15-year survivors had lived with moderate-severe disability since their stroke. At 15 years, the prevalence of cognitive impairment was 30.0% (19.5% to 43.1%), depression 39.1% (30.9% to 47.9%) and anxiety 34.9% (27.0% to 43.8%), and survivors reported greater loss of physical than mental quality of life. Conclusions: One in five people live at least 15 years after a stroke and poor functional, cognitive and psychological outcomes affect a substantial proportion of these long-term survivors. As the global population of individuals with cardiovascular long-term conditions grows, research and health services will need to increasingly focus on preventing and managing the long-term consequences of stroke.

Journal of neurology, neurosurgery, and psychiatry · 214 citationsread the source →

Integrated disease management interventions for patients with chronic obstructive pulmonary disease.

Background: People with chronic obstructive pulmonary disease (COPD) show considerable variation in symptoms, limitations, and well-being; this often complicates medical care. A multi-disciplinary and multi-component programme that addresses different elements of care could improve quality of life (QoL) and exercise tolerance, while reducing the number of exacerbations. Objectives: To compare the effectiveness of integrated disease management (IDM) programmes versus usual care for people with chronic obstructive pulmonary disease (COPD) in terms of health-related quality of life (QoL), exercise tolerance, and exacerbation-related outcomes. Search methods: We searched the Cochrane Airways Group Register of Trials, CENTRAL, MEDLINE, Embase, and CINAHL for potentially eligible studies. Searches were current as of September 2020. Selection criteria: Randomised controlled trials (RCTs) that compared IDM programmes for COPD versus usual care were included. Interventions consisted of multi-disciplinary (two or more healthcare providers) and multi-treatment (two or more components) IDM programmes of at least three months' duration. Data collection and analysis: Two review authors independently assessed trial quality and extracted data. If required, we contacted study authors to request additional data. We performed meta-analyses using random-effects modelling. We carried out sensitivity analyses for the quality of included studies and performed subgroup analyses based on setting, study design, dominant intervention components, and region. Main results: Along with 26 studies included in the 2013 Cochrane Review, we added 26 studies for this update, resulting in 52 studies involving 21,086 participants for inclusion in the meta-analysis. Follow-up periods ranged between 3 and 48 months and were classified as short-term (up to 6 months), medium-term (6 to 15 months), and long-term (longer than 15 months) follow-up. Studies were conducted in 19 different countries. The mean age of included participants was 67 years, and 66% were male. Participants were treated in all types of healthcare settings, including primary (n =15), secondary (n = 22), and tertiary care (n = 5), and combined primary and secondary care (n = 10). Overall, the level of certainty of evidence was moderate to high. We found that IDM probably improves health-related QoL as measured by St. George's Respiratory Questionnaire (SGRQ) total score at medium-term follow-up (mean difference (MD) -3.89, 95% confidence interval (CI) -6.16 to -1.63; 18 RCTs, 4321 participants; moderate-certainty evidence). A comparable effect was observed at short-term follow-up (MD -3.78, 95% CI -6.29 to -1.28; 16 RCTs, 1788 participants). However, the common effect did not exceed the minimum clinically important difference (MCID) of 4 points. There was no significant difference between IDM and control for long-term follow-up and for generic QoL. IDM probably also leads to a large improvement in maximum and functional exercise capacity, as measured by six-minute walking distance (6MWD), at medium-term follow-up (MD 44.69, 95% CI 24.01 to 65.37; 13 studies, 2071 participants; moderate-certainty evidence). The effect exceeded the MCID of 35 metres and was even greater at short-term (MD 52.26, 95% CI 32.39 to 72.74; 17 RCTs, 1390 participants) and long-term (MD 48.83, 95% CI 16.37 to 80.49; 6 RCTs, 7288 participants) follow-up. The number of participants with respiratory-related admissions was reduced from 324 per 1000 participants in the control group to 235 per 1000 participants in the IDM group (odds ratio (OR) 0.64, 95% CI 0.50 to 0.81; 15 RCTs, median follow-up 12 months, 4207 participants; high-certainty evidence). Likewise, IDM probably results in a reduction in emergency department (ED) visits (OR 0.69, 95%CI 0.50 to 0.93; 9 RCTs, median follow-up 12 months, 8791 participants; moderate-certainty evidence), a slight reduction in all-cause hospital admissions (OR 0.75, 95%CI 0.57 to 0.98; 10 RCTs, median follow-up 12 months, 9030 participants; moderate-certainty evidence), and fewer hospital days per person admitted (MD -2.27, 95% CI -3.98 to -0.56; 14 RCTs, median follow-up 12 months, 3563 participants; moderate-certainty evidence). Statistically significant improvement was noted on the Medical Research Council (MRC) Dyspnoea Scale at short- and medium-term follow-up but not at long-term follow-up. No differences between groups were reported for mortality, courses of antibiotics/prednisolone, dyspnoea, and depression and anxiety scores. Subgroup analysis of dominant intervention components and regions of study suggested context- and intervention-specific effects. However, some subgroup analyses were marked by considerable heterogeneity or included few studies. These results should therefore be interpreted with caution. Authors' conclusions: This review shows that IDM probably results in improvement in disease-specific QoL, exercise capacity, hospital admissions, and hospital days per person. Future research should evaluate which combination of IDM components and which intervention duration are most effective for IDM programmes, and should consider contextual determinants of implementation and treatment effect, including process-related outcomes, long-term follow-up, and cost-effectiveness analyses.

The Cochrane database of systematic reviews · meta-analysis · 48 citationsread the source →

Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.

Background: The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods: DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir-ritonavir, lopinavir-ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings: Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77-1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation: No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding: European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation: For the French translation of the abstract see Supplementary Materials section.

The Lancet. Infectious diseases · randomised controlled trial · 264 citationsread the source →

Accuracy of Wristband Fitbit Models in Assessing Sleep: Systematic Review and Meta-Analysis.

Background: Wearable sleep monitors are of high interest to consumers and researchers because of their ability to provide estimation of sleep patterns in free-living conditions in a cost-efficient way. Objective: We conducted a systematic review of publications reporting on the performance of wristband Fitbit models in assessing sleep parameters and stages. Methods: In adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, we comprehensively searched the Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, Embase, MEDLINE, PubMed, PsycINFO, and Web of Science databases using the keyword Fitbit to identify relevant publications meeting predefined inclusion and exclusion criteria. Results: The search yielded 3085 candidate articles. After eliminating duplicates and in compliance with inclusion and exclusion criteria, 22 articles qualified for systematic review, with 8 providing quantitative data for meta-analysis. In reference to polysomnography (PSG), nonsleep-staging Fitbit models tended to overestimate total sleep time (TST; range from approximately 7 to 67 mins; effect size=-0.51, P<.001; heterogenicity: I2=8.8%, P=.36) and sleep efficiency (SE; range from approximately 2% to 15%; effect size=-0.74, P<.001; heterogenicity: I2=24.0%, P=.25), and underestimate wake after sleep onset (WASO; range from approximately 6 to 44 mins; effect size=0.60, P<.001; heterogenicity: I2=0%, P=.92) and there was no significant difference in sleep onset latency (SOL; P=.37; heterogenicity: I2=0%, P=.92). In reference to PSG, nonsleep-staging Fitbit models correctly identified sleep epochs with accuracy values between 0.81 and 0.91, sensitivity values between 0.87 and 0.99, and specificity values between 0.10 and 0.52. Recent-generation Fitbit models that collectively utilize heart rate variability and body movement to assess sleep stages performed better than early-generation nonsleep-staging ones that utilize only body movement. Sleep-staging Fitbit models, in comparison to PSG, showed no significant difference in measured values of WASO (P=.25; heterogenicity: I2=0%, P=.92), TST (P=.29; heterogenicity: I2=0%, P=.98), and SE (P=.19) but they underestimated SOL (P=.03; heterogenicity: I2=0%, P=.66). Sleep-staging Fitbit models showed higher sensitivity (0.95-0.96) and specificity (0.58-0.69) values in detecting sleep epochs than nonsleep-staging models and those reported in the literature for regular wrist actigraphy. Conclusions: Sleep-staging Fitbit models showed promising performance, especially in differentiating wake from sleep. However, although these models are a convenient and economical means for consumers to obtain gross estimates of sleep parameters and time spent in sleep stages, they are of limited specificity and are not a substitute for PSG.

Journal of medical Internet research · meta-analysis · 310 citationsread the source →

Non-pharmacological interventions for assisting the induction of anaesthesia in children.

Background: Induction of general anaesthesia can be distressing for children. Non-pharmacological methods for reducing anxiety and improving co-operation may avoid the adverse effects of preoperative sedation. Objectives: To assess the effects of non-pharmacological interventions in assisting induction of anaesthesia in children by reducing their anxiety, distress or increasing their co-operation. Search methods: In this updated review we searched CENTRAL (the Cochrane Library 2012, Issue 12) and searched the following databases from inception to 15 January 2013: MEDLINE, EMBASE, PsycINFO and Web of Science. We reran the search in August 2014. We will deal with the single study found to be of interest when we next update the review. Selection criteria: We included randomized controlled trials of a non-pharmacological intervention implemented on the day of surgery or anaesthesia. Data collection and analysis: At least two review authors independently extracted data and assessed risk of bias in trials. Main results: We included 28 trials (2681 children) investigating 17 interventions of interest; all trials were conducted in high-income countries. Overall we judged the trials to be at high risk of bias. Except for parental acupuncture (graded low), all other GRADE assessments of the primary outcomes of comparisons were very low, indicating a high degree of uncertainty about the overall findings. Parental presence: In five trials (557 children), parental presence at induction of anaesthesia did not reduce child anxiety compared with not having a parent present (standardized mean difference (SMD) 0.03, 95% confidence interval (CI) -0.14 to 0.20). In a further three trials (267 children) where we were unable to pool results, we found no clear differences in child anxiety, whether a parent was present or not. In a single trial, child anxiety showed no significant difference whether one or two parents were present, although parental anxiety was significantly reduced when both parents were present at the induction. Parental presence was significantly less effective than sedative premedication in reducing children's anxiety at induction in three trials with 254 children (we could not pool results). Child interventions (passive): When a video of the child's choice was played during induction, children were significantly less anxious than controls (median difference modified Yale Preoperative Anxiety Scale (mYPAS) 31.2, 95% CI 27.1 to 33.3) in a trial of 91 children. In another trial of 120 children, co-operation at induction did not differ significantly when a video fairytale was played before induction. Children exposed to low sensory stimulation were significantly less anxious than control children on introduction of the anaesthesia mask and more likely to be co-operative during induction in one trial of 70 children. Music therapy did not show a significant effect on children's anxiety in another trial of 51 children. Child interventions (mask introduction): We found no significant differences between a mask exposure intervention and control in a single trial of 103 children for child anxiety (risk ratio (RR) 0.59, 95% CI 0.31 to 1.11) although children did demonstrate significantly better co-operation in the mask exposure group (RR 1.27, 95% CI 1.06 to 1.51). Child interventions (interactive): In a three-arm trial of 168 children, preparation with interactive computer packages (in addition to parental presence) was more effective than verbal preparation, although differences between computer and cartoon preparation were not significant, and neither was cartoon preparation when compared with verbal preparation. Children given video games before induction were significantly less anxious at induction than those in the control group (mYPAS mean difference (MD) -9.80, 95% CI -19.42 to -0.18) and also when compared with children who were sedated with midazolam (mYPAS MD -12.20, 95% CI -21.82 to -2.58) in a trial of 112 children. When compared with parental presence only, clowns or clown doctors significantly lessened children's anxiety in the operating/induction room (mYPAS MD -24.41, 95% CI -38.43 to -10.48; random-effects, I² 75%) in three trials with a total of 133 children. However, we saw no significant differences in child anxiety in the operating room between clowns/clown doctors and sedative premedication (mYPAS MD -9.67, 95% CI -21.14 to 1.80, random-effects, I² 66%; 2 trials of 93 children). In a trial of hypnotherapy versus sedative premedication in 50 children, there were no significant differences in children's anxiety at induction (RR 0.59, 95% CI 0.33 to 1.04). Parental interventions: Children of parents having acupuncture compared with parental sham acupuncture were less anxious during induction (mYPAS MD -17, 95% CI -30.51 to -3.49) and were more co-operative (RR 1.59, 95% CI 1.01 to 2.53) in a single trial of 67 children. Two trials with 191 parents assessed the effects of parental video viewing but did not report any of the review's prespecified primary outcomes. Authors' conclusions: This review shows that the presence of parents during induction of general anaesthesia does not diminish their child's anxiety. Potentially promising non-pharmacological interventions such as parental acupuncture; clowns/clown doctors; playing videos of the child's choice during induction; low sensory stimulation; and hand-held video games need further investigation in larger studies.

The Cochrane database of systematic reviews · meta-analysis · 100 citationsread the source →

Reduction in saturated fat intake for cardiovascular disease.

Background: Reducing saturated fat reduces serum cholesterol, but effects on other intermediate outcomes may be less clear. Additionally, it is unclear whether the energy from saturated fats eliminated from the diet are more helpfully replaced by polyunsaturated fats, monounsaturated fats, carbohydrate or protein. Objectives: To assess the effect of reducing saturated fat intake and replacing it with carbohydrate (CHO), polyunsaturated (PUFA), monounsaturated fat (MUFA) and/or protein on mortality and cardiovascular morbidity, using all available randomised clinical trials. Search methods: We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid) and Embase (Ovid) on 15 October 2019, and searched Clinicaltrials.gov and WHO International Clinical Trials Registry Platform (ICTRP) on 17 October 2019. Selection criteria: Included trials fulfilled the following criteria: 1) randomised; 2) intention to reduce saturated fat intake OR intention to alter dietary fats and achieving a reduction in saturated fat; 3) compared with higher saturated fat intake or usual diet; 4) not multifactorial; 5) in adult humans with or without cardiovascular disease (but not acutely ill, pregnant or breastfeeding); 6) intervention duration at least 24 months; 7) mortality or cardiovascular morbidity data available. Data collection and analysis: Two review authors independently assessed inclusion, extracted study data and assessed risk of bias. We performed random-effects meta-analyses, meta-regression, subgrouping, sensitivity analyses, funnel plots and GRADE assessment. Main results: We included 15 randomised controlled trials (RCTs) (16 comparisons, 56,675 participants), that used a variety of interventions from providing all food to advice on reducing saturated fat. The included long-term trials suggested that reducing dietary saturated fat reduced the risk of combined cardiovascular events by 17% (risk ratio (RR) 0.83; 95% confidence interval (CI) 0.70 to 0.98, 12 trials, 53,758 participants of whom 8% had a cardiovascular event, I² = 67%, GRADE moderate-quality evidence). Meta-regression suggested that greater reductions in saturated fat (reflected in greater reductions in serum cholesterol) resulted in greater reductions in risk of CVD events, explaining most heterogeneity between trials. The number needed to treat for an additional beneficial outcome (NNTB) was 56 in primary prevention trials, so 56 people need to reduce their saturated fat intake for ~four years for one person to avoid experiencing a CVD event. In secondary prevention trials, the NNTB was 53. Subgrouping did not suggest significant differences between replacement of saturated fat calories with polyunsaturated fat or carbohydrate, and data on replacement with monounsaturated fat and protein was very limited. We found little or no effect of reducing saturated fat on all-cause mortality (RR 0.96; 95% CI 0.90 to 1.03; 11 trials, 55,858 participants) or cardiovascular mortality (RR 0.95; 95% CI 0.80 to 1.12, 10 trials, 53,421 participants), both with GRADE moderate-quality evidence. There was little or no effect of reducing saturated fats on non-fatal myocardial infarction (RR 0.97, 95% CI 0.87 to 1.07) or CHD mortality (RR 0.97, 95% CI 0.82 to 1.16, both low-quality evidence), but effects on total (fatal or non-fatal) myocardial infarction, stroke and CHD events (fatal or non-fatal) were all unclear as the evidence was of very low quality. There was little or no effect on cancer mortality, cancer diagnoses, diabetes diagnosis, HDL cholesterol, serum triglycerides or blood pressure, and small reductions in weight, serum total cholesterol, LDL cholesterol and BMI. There was no evidence of harmful effects of reducing saturated fat intakes. Authors' conclusions: The findings of this updated review suggest that reducing saturated fat intake for at least two years causes a potentially important reduction in combined cardiovascular events. Replacing the energy from saturated fat with polyunsaturated fat or carbohydrate appear to be useful strategies, while effects of replacement with monounsaturated fat are unclear. The reduction in combined cardiovascular events resulting from reducing saturated fat did not alter by study duration, sex or baseline level of cardiovascular risk, but greater reduction in saturated fat caused greater reductions in cardiovascular events.

The Cochrane database of systematic reviews · meta-analysis · 98 citationsread the source →

Physical activity, diet and other behavioural interventions for improving cognition and school achievement in children and adolescents with obesity or overweight.

Background: The global prevalence of childhood and adolescent obesity is high. Lifestyle changes towards a healthy diet, increased physical activity and reduced sedentary activities are recommended to prevent and treat obesity. Evidence suggests that changing these health behaviours can benefit cognitive function and school achievement in children and adolescents in general. There are various theoretical mechanisms that suggest that children and adolescents with excessive body fat may benefit particularly from these interventions. Objectives: To assess whether lifestyle interventions (in the areas of diet, physical activity, sedentary behaviour and behavioural therapy) improve school achievement, cognitive function (e.g. executive functions) and/or future success in children and adolescents with obesity or overweight, compared with standard care, waiting-list control, no treatment, or an attention placebo control group. Search methods: In February 2017, we searched CENTRAL, MEDLINE and 15 other databases. We also searched two trials registries, reference lists, and handsearched one journal from inception. We also contacted researchers in the field to obtain unpublished data. Selection criteria: We included randomised and quasi-randomised controlled trials (RCTs) of behavioural interventions for weight management in children and adolescents with obesity or overweight. We excluded studies in children and adolescents with medical conditions known to affect weight status, school achievement and cognitive function. We also excluded self- and parent-reported outcomes. Data collection and analysis: Four review authors independently selected studies for inclusion. Two review authors extracted data, assessed quality and risks of bias, and evaluated the quality of the evidence using the GRADE approach. We contacted study authors to obtain additional information. We used standard methodological procedures expected by Cochrane. Where the same outcome was assessed across different intervention types, we reported standardised effect sizes for findings from single-study and multiple-study analyses to allow comparison of intervention effects across intervention types. To ease interpretation of the effect size, we also reported the mean difference of effect sizes for single-study outcomes. Main results: We included 18 studies (59 records) of 2384 children and adolescents with obesity or overweight. Eight studies delivered physical activity interventions, seven studies combined physical activity programmes with healthy lifestyle education, and three studies delivered dietary interventions. We included five RCTs and 13 cluster-RCTs. The studies took place in 10 different countries. Two were carried out in children attending preschool, 11 were conducted in primary/elementary school-aged children, four studies were aimed at adolescents attending secondary/high school and one study included primary/elementary and secondary/high school-aged children. The number of studies included for each outcome was low, with up to only three studies per outcome. The quality of evidence ranged from high to very low and 17 studies had a high risk of bias for at least one item. None of the studies reported data on additional educational support needs and adverse events. Compared to standard practice, analyses of physical activity-only interventions suggested high-quality evidence for improved mean cognitive executive function scores. The mean difference (MD) was 5.00 scale points higher in an after-school exercise group compared to standard practice (95% confidence interval (CI) 0.68 to 9.32; scale mean 100, standard deviation 15; 116 children, 1 study). There was no statistically significant beneficial effect in favour of the intervention for mathematics, reading, or inhibition control. The standardised mean difference (SMD) for mathematics was 0.49 (95% CI -0.04 to 1.01; 2 studies, 255 children, moderate-quality evidence) and for reading was 0.10 (95% CI -0.30 to 0.49; 2 studies, 308 children, moderate-quality evidence). The MD for inhibition control was -1.55 scale points (95% CI -5.85 to 2.75; scale range 0 to 100; SMD -0.15, 95% CI -0.58 to 0.28; 1 study, 84 children, very low-quality evidence). No data were available for average achievement across subjects taught at school. There was no evidence of a beneficial effect of physical activity interventions combined with healthy lifestyle education on average achievement across subjects taught at school, mathematics achievement, reading achievement or inhibition control. The MD for average achievement across subjects taught at school was 6.37 points lower in the intervention group compared to standard practice (95% CI -36.83 to 24.09; scale mean 500, scale SD 70; SMD -0.18, 95% CI -0.93 to 0.58; 1 study, 31 children, low-quality evidence). The effect estimate for mathematics achievement was SMD 0.02 (95% CI -0.19 to 0.22; 3 studies, 384 children, very low-quality evidence), for reading achievement SMD 0.00 (95% CI -0.24 to 0.24; 2 studies, 284 children, low-quality evidence), and for inhibition control SMD -0.67 (95% CI -1.50 to 0.16; 2 studies, 110 children, very low-quality evidence). No data were available for the effect of combined physical activity and healthy lifestyle education on cognitive executive functions. There was a moderate difference in the average achievement across subjects taught at school favouring interventions targeting the improvement of the school food environment compared to standard practice in adolescents with obesity (SMD 0.46, 95% CI 0.25 to 0.66; 2 studies, 382 adolescents, low-quality evidence), but not with overweight. Replacing packed school lunch with a nutrient-rich diet in addition to nutrition education did not improve mathematics (MD -2.18, 95% CI -5.83 to 1.47; scale range 0 to 69; SMD -0.26, 95% CI -0.72 to 0.20; 1 study, 76 children, low-quality evidence) and reading achievement (MD 1.17, 95% CI -4.40 to 6.73; scale range 0 to 108; SMD 0.13, 95% CI -0.35 to 0.61; 1 study, 67 children, low-quality evidence). Authors' conclusions: Despite the large number of childhood and adolescent obesity treatment trials, we were only able to partially assess the impact of obesity treatment interventions on school achievement and cognitive abilities. School and community-based physical activity interventions as part of an obesity prevention or treatment programme can benefit executive functions of children with obesity or overweight specifically. Similarly, school-based dietary interventions may benefit general school achievement in children with obesity. These findings might assist health and education practitioners to make decisions related to promoting physical activity and healthy eating in schools. Future obesity treatment and prevention studies in clinical, school and community settings should consider assessing academic and cognitive as well as physical outcomes.

The Cochrane database of systematic reviews · meta-analysis · 77 citationsread the source →

Effectiveness of brief alcohol interventions in primary care populations.

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

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

Global patterns of mortality in international migrants: a systematic review and meta-analysis.

Background: 258 million people reside outside their country of birth; however, to date no global systematic reviews or meta-analyses of mortality data for these international migrants have been done. We aimed to review and synthesise available mortality data on international migrants. Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, and Google Scholar databases for observational studies, systematic reviews, and randomised controlled trials published between Jan 1, 2001, and March 31, 2017, without language restrictions. We included studies reporting mortality outcomes for international migrants of any age residing outside their country of birth. Studies that recruited participants exclusively from intensive care or high dependency hospital units, with an existing health condition or status, or a particular health exposure were excluded. We also excluded studies limited to maternal or perinatal outcomes. We screened studies using systematic review software and extracted data from published reports. The main outcomes were all-cause and International Classification of Diseases, tenth revision (ICD-10) cause-specific standardised mortality ratios (SMRs) and absolute mortality rates. We calculated summary estimates using random-effects models. This study is registered with PROSPERO, number CRD42017073608. Findings: Of the 12 480 articles identified by our search, 96 studies were eligible for inclusion. The studies were geographically diverse and included data from all global regions and for 92 countries. 5464 mortality estimates for more than 15·2 million migrants were included, of which 5327 (97%) were from high-income countries, 115 (2%) were from middle-income countries, and 22 (<1%) were from low-income countries. Few studies included mortality estimates for refugees (110 estimates), asylum seekers (144 estimates), or labour migrants (six estimates). The summary estimate of all-cause SMR for international migrants was lower than one when compared with the general population in destination countries (0·70 [95% CI 0·65-0·76]; I2=99·8%). All-cause SMR was lower in both male migrants (0·72 [0·63-0·81]; I2=99·8%) and female migrants (0·75 [0·67-0·84]; I2=99·8%) compared with the general population. A mortality advantage was evident for refugees (SMR 0·50 [0·46-0·54]; I2=89·8%), but not for asylum seekers (1·05 [0·89-1·24]; I2=54·4%), although limited data was available on these groups. SMRs for all causes of death were lower in migrants compared with the general populations in the destination country across all 13 ICD-10 categories analysed, with the exception of infectious diseases and external causes. Heterogeneity was high across the majority of analyses. Point estimates of all-cause age-standardised mortality in migrants ranged from 420 to 874 per 100 000 population. Interpretation: Our study showed that international migrants have a mortality advantage compared with general populations, and that this advantage persisted across the majority of ICD-10 disease categories. The mortality advantage identified will be representative of international migrants in high-income countries who are studying, working, or have joined family members in these countries. However, our results might not reflect the health outcomes of more marginalised groups in low-income and middle-income countries because little data were available for these groups, highlighting an important gap in existing research. Our results present an opportunity to reframe the public discourse on international migration and health in high-income countries. Funding: Wellcome Trust, National Institute for Health Research, Medical Research Council, Alliance for Health Policy and Systems Research, Department for International Development, Fogarty International Center, Grand Challenges Canada, International Development Research Centre Canada, Inter-American Institute for Global Change Research, National Cancer Institute, National Heart, Lung and Blood Institute, National Institute of Mental Health, Swiss National Science Foundation, World Diabetes Foundation, UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, and European Society for Clinical Microbiology and Infectious Diseases (ESCMID) Study Group Research Funding for the ESCMID Study Group for Infections in Travellers and Migrants.

Lancet (London, England) · meta-analysis · 198 citationsread the source →

Long-term trends in child maltreatment in England and Wales, 1858-2016: an observational, time-series analysis.

Background: It is unclear whether child maltreatment is increasing or decreasing in England and Wales. More evidence is needed, from multiple sources and over longer periods of time, to explore trends in child maltreatment. We investigated whether the annual incidence of child maltreatment has changed over time, using official record data and time-series methods to establish long-term trends. Methods: In this observational time-series analysis, we used six data sources (Government records for child mortality, police-recorded child homicides, crimes against children, child protection, and children in care; and NSPCC data) to estimate the incidence of child maltreatment in England and Wales and examine long-term trends. We included nationally representative data that could estimate the incidence of child maltreatment for more than 25 years. Our primary outcomes were the number of victims (age <20 years) or perpetrators (age >16 years) of child maltreatment per 12-month period in England, including or excluding Wales. We fitted Poisson regression models with year as the exposure and the number of victims or perpetrators of child maltreatment as the outcome (adjusted for population age-structure and size). When a linear trend was not appropriate, we fitted generalised additive models with penalised splines to visualise trends. Findings: The incidence of child mortality by homicide or assault decreased by 90% (2·7 per 100 000 children) between 1858 and 2016 and the incidence of people guilty of child cruelty or neglect decreased by 83% (6·7 per 100 000 adults) between 1893 and 2016, whereas child protection registrations increased by 182% (328·7 per 100 000 children) between 1988 and 2016. Crimes against children and children entering care increased between 2000 and 2016. In 2016, 40 children died by homicide, with twice as many adolescent (15-19 years) deaths than infant (age <1 year) deaths. In 2016, 67 700 children were placed on the child protection register and neglect and emotional abuse were the most common reasons. Interpretation: Although long-term trends have decreased, child maltreatment remains a major public health problem in England and Wales. Further research is needed to establish whether adolescents are a particularly vulnerable age group and whether neglect and emotional abuse are increasing. Future child protection policies and practices should respond to these areas of growing need. Funding: Andrew W Mellon Foundation and Clarendon through The Oxford Research Centre in the Humanities, Oxford.

The Lancet. Public health · cohort or longitudinal · 22 citationsread the source →

A co-designed mHealth programme to support healthy lifestyles in Māori and Pasifika peoples in New Zealand (OL@-OR@): a cluster-randomised controlled trial.

Background: The OL@-OR@ mobile health programme was co-designed with Māori and Pasifika communities in New Zealand, to support healthy lifestyle behaviours. We aimed to determine whether use of the programme improved adherence to health-related guidelines among Māori and Pasifika communities in New Zealand compared with a control group on a waiting list for the programme. Methods: The OL@-OR@ trial was a 12-week, two-arm, cluster-randomised controlled trial. A cluster was defined as any distinct location or setting in New Zealand where people with shared interests or contexts congregated, such as churches, sports clubs, and community groups. Members of a cluster were eligible to participate if they were aged 18 years or older, had regular access to a mobile device or computer, and had regular internet access. Clusters of Māori and of Pasifika (separately) were randomly assigned (1:1) to either the intervention or control condition. The intervention group received the OL@-OR@ mHealth programme (smartphone app and website). The control group received a control version of the app that only collected baseline and outcome data. The primary outcome was self-reported adherence to health-related guidelines, which were measured with a composite health behaviour score (of physical activity, smoking, alcohol intake, and fruit and vegetable intake) at 12 weeks. The secondary outcomes were self-reported adherence to health-related behaviour guidelines at 4 weeks; self-reported bodyweight at 12 weeks; and holistic health and wellbeing status at 12 weeks, in all enrolled individuals in eligible clusters; and user engagement with the app, in individuals allocated to the intervention. Adverse events were not collected. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12617001484336. Findings: Between Jan 24 and Aug 14, 2018, we enrolled 337 Māori participants from 19 clusters and 389 Pasifika participants from 18 clusters (n=726 participants) in the intervention group and 320 Māori participants from 15 clusters and 405 Pasifika participants from 17 clusters (n=725 participants) in the control group. Of these participants, 227 (67%) Māori participants and 347 (89%) Pasifika participants (n=574 participants) in the intervention group and 281 (88%) Māori participants and 369 (91%) Pasifika participants (n=650 participants) in the control group completed the 12-week follow-up and were included in the final analysis. Relative to baseline, adherence to health-related behaviour guidelines increased at 12 weeks in both groups (315 [43%] of 726 participants at baseline to 329 [57%] of 574 participants in the intervention group; 331 [46%] of 725 participants to 369 [57%] of 650 participants in the control group); however, there was no significant difference between intervention and control groups in adherence at 12 weeks (odds ratio [OR] 1·13; 95% CI 0·84-1·52; p=0·42). Furthermore, the proportion of participants adhering to guidelines on physical activity (351 [61%] of 574 intervention group participants vs 407 [63%] of 650 control group participants; OR 1·03, 95% CI 0·73-1·45; p=0·88), smoking (434 [76%] participants vs 501 [77%] participants; 1·12, 0·67-1·87; p=0·66), alcohol consumption (518 [90%] participants vs 596 [92%] participants; 0·73, 0·37-1·44; p=0·36), and fruit and vegetable intake (194 [34%] participants vs 196 [30%] participants; 1·08, 0·79-1·49; p=0·64) did not differ between groups. We found no significant differences between the intervention and control groups in any secondary outcome. 147 (26%) intervention group participants engaged with the OL@-OR@ programme (ie, set at least one behaviour change goal online). Interpretation: The OL@-OR@ mobile health programme did not improve adherence to health-related behaviour guidelines amongst Māori and Pasifika individuals. Funding: Healthier Lives He Oranga Hauora National Science Challenge.

The Lancet. Digital health · randomised controlled trial · 45 citationsread the source →

Uptake of antiretroviral therapy and male circumcision after community-based HIV testing and strategies for linkage to care versus standard clinic referral: a multisite, open-label, randomised controlled trial in South Africa and Uganda.

Background: Male circumcision decreases HIV acquisition by 60%, and antiretroviral therapy (ART) almost eliminates HIV transmission from HIV-positive people who are virally suppressed; however, coverage of these interventions has lagged behind targets. We aimed to assess whether community-based HIV testing with counsellor support and point-of-care CD4 cell count testing would increase uptake of ART and male circumcision. Methods: We did this multisite, open-label, randomised controlled trial in six research-naive communities in rural South Africa and Uganda. Eligible HIV-positive participants (aged ≥16 years) were randomly assigned (1:1:1) in a factorial design to receive lay counsellor clinic linkage facilitation, lay counsellor follow-up home visits, or standard-of-care clinic referral, and then (1:1) either point-of-care CD4 cell count testing or referral for CD4 testing. HIV-negative uncircumcised men (aged 16-49 years) who could receive secure mobile phone text messages were randomly assigned (1:1:1) to receive text message reminders, lay counsellor visits, or standard clinic referral. The study biostatistician generated the randomisation schedule via a computer-generated random number program with varying block sizes (multiples of six or three) stratified by country. Primary outcomes for HIV-positive people were obtaining a CD4 cell count, linkage to an HIV clinic, ART initiation, and viral suppression at 9 months, and for HIV-negative uncircumcised men were visiting a circumcision facility and uptake of male circumcision at 3 months. We assessed social harms as a safety outcome throughout the study. We did the primary analyses by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02038582. Findings: Between June 6, 2013, and March 11, 2015, 15 332 participants were tested. 2339 (15%) participants tested HIV positive, of whom 1325 (57%) were randomly assigned to receive lay counsellor clinic linkage facilitation (n=437), lay counsellor follow-up home visits (n=449), or standard clinic referral (n=439), and then point-of-care CD4 cell testing (n=206, n=220, and n=213, respectively) or referral for CD4 testing (n=231, n=229, and n=226, respectively). 12 993 (85%) participants tested HIV negative, of whom 750 (6%) uncircumcised men were randomly assigned to receive clinic referral (n=230), text message reminders (n=288), or lay counsellor follow-up visits (n=232). 1218 (93%) of 1303 HIV-positive participants were linked to care, but only 488 (37%) participants initiated ART. Overall, 635 (50%) of 1272 HIV-positive individuals achieved viral suppression at 9 months: 219 (52%) of 419 participants in the clinic facilitation group, 202 (47%) of 431 participants in the lay counsellor follow-up group, and 214 (51%) of 422 participants in the clinic referral group, with no significant differences between groups (p=0·668 for clinic facilitation and p=0·273 for lay counsellor follow-up vs clinic referral). 523 (72%) of 734 HIV-negative men visited a circumcision facility, with no difference between groups. 62 (28%) of 224 men were circumcised in the male circumcision clinic referral group compared with 137 (48%) of 284 men in the text message reminder group (relative risk 1·72, 95% CI 1·36-2·17; p<0·0001) and 106 (47%) of 226 men in the lay counsellor follow-up group (1·67, 1·29-2·14; p=0·0001). No cases of study-related social harm were reported, including probing about partnership separation, unintended disclosure, gender-based violence, and stigma. Interpretation: All the community-based strategies achieved high rates of linkage of HIV-positive people to HIV clinics, roughly a third of whom initiated ART, and of those more than 80% were virally suppressed at 9 months. Uptake of male circumcision was almost two-times higher in men who received text message reminders or lay counsellor visits than in those who received standard-of-care clinic referral. Clinic barriers to ART initiation should be addressed in future strategies to increase the proportion of HIV-positive people accessing treatment and achieving viral suppression. Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health.

The lancet. HIV · randomised controlled trial · 65 citationsread the source →

Effects of digital cognitive behavioural therapy for insomnia on insomnia severity: a large-scale randomised controlled trial.

Background: Although several large-scale randomised controlled trials have shown the efficacy of digital cognitive behavioural therapy for insomnia (dCBT-I), there is a need to validate widespread dissemination of dCBT-I using recommended key outcomes for insomnia. We investigated the effect of a fully automated dCBT-I programme on insomnia severity, sleep-wake patterns, sleep medication use, and daytime impairment. Methods: We did a parallel-group superiority randomised controlled trial comparing dCBT-I with online patient education about sleep. The interventions were available through a free-to-access website, publicised throughout Norway, which incorporated automated screening, informed consent, and randomisation procedures, as well as outcome assessments. Adults (age ≥18 years) who had regular internet access and scored 12 or higher on the Insomnia Severity Index (ISI) were eligible for inclusion, and were allocated (1:1) to receive dCBT-I (consisting of six core interactive sessions to be completed over 9 weeks) or patient education (control group). Participants were masked to group assignment and had no contact with researchers during the intervention period. The primary outcome was the change in ISI score from baseline to 9-week follow-up, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02558647) and is ongoing, with 2-year follow-up assessments planned. Findings: Between Feb 26, 2016, and July 1, 2018, 5349 individuals commenced the online screening process, of which 1497 were ineligible or declined to participate, 2131 discontinued the screening process, and 1721 were randomly allocated (868 to receive dCBT-I and 853 to receive patient education). At 9-week follow-up, 584 (67%) participants in the dCBT-I group and 534 (63%) in the patient education group completed the ISI assessment. The latent growth model showed that participants in the dCBT-I group had a significantly greater reduction in ISI scores from baseline (mean score 19·2 [SD 3·9]) to 9-week follow-up (10·4 [6·2]) than those in the patient education group (from 19·6 [4·0] to 15·2 [5·3]; estimated mean difference -4·7 (95% CI -5·4 to -4·1; Cohen's d -1·21; p<0·001). Compared with patient education, the number needed to treat with dCBT-I was 2·7 (95% CI 2·4 to 3·2) for treatment response (ISI score reduction ≥8) and 3·2 (2·8 to 3·8) for insomnia remission (ISI score <8). No adverse events were reported to the trial team. Interpretation: dCBT-I is effective in reducing the severity of symptoms associated with the insomnia disorder. These findings support the widespread dissemination of dCBT-I. Future research is needed to identify the moderators of response and to improve targeting. Funding: Norwegian Research Council; Liaison Committee for Education, Research and Innovation in Central Norway.

The Lancet. Digital health · randomised controlled trial · 95 citationsread the source →

Health Care Workers' Need for Headspace: Findings From a Multisite Definitive Randomized Controlled Trial of an Unguided Digital Mindfulness-Based Self-help App to Reduce Healthcare Worker Stress.

Background: Health care workers experience high stress. Accessible, affordable, and effective approaches to reducing stress are lacking. In-person mindfulness-based interventions can reduce health care worker stress but are not widely available or accessible to busy health care workers. Unguided, digital, mindfulness-based self-help (MBSH) interventions show promise and can be flexibly engaged with. However, their effectiveness in reducing health care worker stress has not yet been explored in a definitive trial. Objective: This study aimed to investigate the effectiveness of an unguided digital MBSH app (Headspace) in reducing health care worker stress. Methods: This was a definitive superiority randomized controlled trial with 2182 National Health Service staff in England recruited on the web and allocated in a 1:1 ratio to fully automated Headspace (n=1095, 50.18%) or active control (Moodzone; n=1087, 49.82%) for 4.5 months. Outcomes were subscales of the Depression, Anxiety, and Stress (primary outcome) Scale short form; Short Warwick Edinburgh Mental Well-being Scale; Maslach Burnout Inventory; 15-item Five-Facet Mindfulness Questionnaire minus Observe items; Self-Compassion Scale-Short Form; Compassionate Love Scale; Penn State Worry Questionnaire; Brooding subscale of the Ruminative Response Scale; and sickness absence. Results: Intention-to-treat analyses found that Headspace led to greater reductions in stress over time than Moodzone (b=-0.31, 95% CI -0.47 to -0.14; P<.001), with small effects. Small effects of Headspace versus Moodzone were found for depression (b=-0.24, 95% CI -0.40 to -0.08; P=.003), anxiety (b=-0.19, 95% CI -0.32 to -0.06; P=.004), well-being (b=0.14, 95% CI 0.05-0.23; P=.002), mindfulness (b=0.22, 95% CI 0.09-0.34; P=.001), self-compassion (b=0.48, 95% CI 0.33-0.64; P<.001), compassion for others (b=0.02, 95% CI 0.00-0.04; P=.04), and worry (b=-0.30, 95% CI -0.51 to -0.09; P=.005) but not for burnout (b=-0.19, -0.04, and 0.13, all 95% CIs >0; P=.65, .67, and .35), ruminative brooding (b=-0.06, 95% CI -0.12 to 0.00; P=.06), or sickness absence (γ=0.09, 95% CI -0.18 to 0.34). Per-protocol effects of Headspace (454/1095, 41.46%) versus Moodzone (283/1087, 26.03%) over time were found for stress, self-compassion, and compassion for others but not for the other outcomes. Engagement (practice days per week) and improvements in self-compassion during the initial 1.5-month intervention period mediated pre- to postintervention improvements in stress. Improvements in mindfulness, rumination, and worry did not mediate pre- to postintervention improvements in stress. No serious adverse events were reported. Conclusions: An unguided digital MBSH intervention (Headspace) can reduce health care workers' stress. Effect sizes were small but could have population-level benefits. Unguided digital MBSH interventions can be part of the solution to reducing health care worker stress alongside potentially costlier but potentially more effective in-person mindfulness-based interventions, nonmindfulness courses, and organizational-level interventions. Trial registration: International Standard Randomised Controlled Trial Number ISRCTN15424185; https://tinyurl.com/rv9en5kc.

JMIR mHealth and uHealth · randomised controlled trial · 52 citationsread the source →

Effect of Varenicline Combined With Medical Management on Alcohol Use Disorder With Comorbid Cigarette Smoking: A Randomized Clinical Trial.

Importance: Individuals with alcohol use disorder have high rates of cigarette smoking. Varenicline tartrate, an approved treatment for smoking cessation, may reduce both drinking and smoking. Objectives: To test the efficacy of varenicline with medical management for patients with alcohol use disorder and comorbid smoking seeking alcohol treatment, and to evaluate the secondary effects on smoking abstinence. Design, setting, and participants: This phase 2, randomized, double-blind, parallel group, placebo-controlled trial was conducted at 2 outpatient clinics from September 19, 2012, to August 31, 2015. Eligible participants met alcohol-dependence criteria and reported heavy drinking (≥5 drinks for men and ≥4 drinks for women) 2 or more times per week and smoking 2 or more times per week; 131 participants were randomized to either varenicline or placebo stratified by sex and site. All analyses were of the intention-to-treat type. Data analysis was conducted from February 5, 2016, to September 29, 2017. Interventions: Varenicline tartrate, 1 mg twice daily, and matching placebo pills for 16 weeks. Medical management emphasized medication adherence for 4 weeks followed by support for changing drinking. Main outcomes and measures: Percentage of heavy drinking days (PHDD) weeks 9 to 16, no heavy drinking days (NHDD) weeks 9 to 16, and prolonged smoking abstinence weeks 13 to 16. Results: Of 131 participants, 39 (29.8%) were women and 92 (70.2%) were men, the mean (SD) age was 42.7 (11.7) years, and the race/ethnicity self-identified by most respondents was black (69 [52.7%]). Sixty-four participants were randomized to receive varenicline, and 67 to receive placebo. Mean change in PHDD between varenicline and placebo across sex and site was not significantly different. However, a significant treatment by sex by time interaction for PHDD (F1,106 = 4.66; P = .03) revealed that varenicline compared with placebo resulted in a larger decrease in log-transformed PHDD in men (least square [LS] mean difference in change from baseline, 0.54; 95% CI, -0.09 to 1.18; P = .09; Cohen d = 0.45) but a smaller decrease in women (LS mean difference, -0.69; 95% CI, -1.63 to 0.25; P = .15; Cohen d = -0.53). Thirteen of 45 men (29%) had NHDD taking varenicline compared with 3 of 47 men (6%) taking placebo (Cohen h = 0.64; 95% CI, 0.22-1.03), whereas 1 of 19 women (5%) had NHDD compared with 5 of 20 women (25%) taking placebo (Cohen h = -0.60; 95% CI, -1.21 to 0.04). Taking varenicline, 8 of 64 participants (13%) achieved prolonged smoking abstinence; no one (0 of 67) quit smoking taking placebo (P = .003; Cohen h = 0.72; 95% CI, 0.38-1.07). Conclusions and relevance: Varenicline with medical management resulted in decreased heavy drinking among men and increased smoking abstinence in the overall sample. Varenicline could be considered to promote improvements in men with these dual behavioral health risks. Trial registration: clinicaltrials.gov Identifier: NCT01553136.

JAMA psychiatry · randomised controlled trial · 77 citationsread the source →

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial.

Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression. Objective: To investigate the effect of psilocybin therapy in patients with MDD. Design, setting, and participants: This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population). Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay. Main outcomes and measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR). Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score). Conclusions and relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression. Trial registration: ClinicalTrials.gov Identifier: NCT03181529.

JAMA psychiatry · randomised controlled trial · 900 citationsread the source →

Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial.

Background: Vascular-targeted photodynamic therapy, a novel tissue-preserving treatment for low-risk prostate cancer, has shown favourable safety and efficacy results in single-arm phase 1 and 2 studies. We compared this treatment with the standard of care, active surveillance, in men with low-risk prostate cancer in a phase 3 trial. Methods: This randomised controlled trial was done in 47 European university centres and community hospitals. Men with low-risk, localised prostate cancer (Gleason pattern 3) who had received no previous treatment were randomly assigned (1:1) to vascular-targeted photodynamic therapy (4 mg/kg padeliporfin intravenously over 10 min and optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light 753 nm with a fixed power of 150 mW/cm for 22 min 15 s) or active surveillance. Randomisation was done by a web-based allocation system stratified by centre with balanced blocks of two or four patients. Best practice for active surveillance at the time of study design was followed (ie, biopsy at 12-month intervals and prostate-specific antigen measurement and digital rectal examination at 3-month intervals). The co-primary endpoints were treatment failure (histological progression of cancer from low to moderate or high risk or death during 24 months' follow-up) and absence of definite cancer (absence of any histology result definitely positive for cancer at month 24). Analysis was by intention to treat. Treatment was open-label, but investigators assessing primary efficacy outcomes were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT01310894. Findings: Between March 8, 2011, and April 30, 2013, we randomly assigned 206 patients to vascular-targeted photodynamic therapy and 207 patients to active surveillance. Median follow-up was 24 months (IQR 24-25). The proportion of participants who had disease progression at month 24 was 58 (28%) of 206 in the vascular-targeted photodynamic therapy group compared with 120 (58%) of 207 in the active surveillance group (adjusted hazard ratio 0·34, 95% CI 0·24-0·46; p<0·0001). 101 (49%) men in the vascular-targeted photodynamic therapy group had a negative prostate biopsy result at 24 months post treatment compared with 28 (14%) men in the active surveillance group (adjusted risk ratio 3·67, 95% CI 2·53-5·33; p<0·0001). Vascular-targeted photodynamic therapy was well tolerated. The most common grade 3-4 adverse events were prostatitis (three [2%] in the vascular-targeted photodynamic therapy group vs one [<1%] in the active surveillance group), acute urinary retention (three [2%] vs one [<1%]) and erectile dysfunction (two [1%] vs three [1%]). The most common serious adverse event in the vascular-targeted photodynamic therapy group was retention of urine (15 patients; severe in three); this event resolved within 2 months in all patients. The most common serious adverse event in the active surveillance group was myocardial infarction (three patients). Interpretation: Padeliporfin vascular-targeted photodynamic therapy is a safe, effective treatment for low-risk, localised prostate cancer. This treatment might allow more men to consider a tissue-preserving approach and defer or avoid radical therapy. Funding: Steba Biotech.

The Lancet. Oncology · randomised controlled trial · 236 citationsread the source →

Promoting school climate and health outcomes with the SEHER multi-component secondary school intervention in Bihar, India: a cluster-randomised controlled trial.

Background: School environments affect health and academic outcomes. With increasing secondary school retention in low-income and middle-income countries, promoting quality school social environments could offer a scalable opportunity to improve adolescent health and wellbeing. Methods: We did a cluster-randomised trial to assess the effectiveness of a multi-component whole-school health promotion intervention (SEHER) with integrated economic and process evaluations in grade 9 students (aged 13-14 years) at government-run secondary schools in the Nalanda district of Bihar state, India. Schools were randomly assigned (1:1:1) to three groups: the SEHER intervention delivered by a lay counsellor (the SEHER Mitra [SM] group), the SEHER intervention delivered by a teacher (teacher as SEHER Mitra [TSM] group), and a control group in which only the standard government-run classroom-based life-skills Adolescence Education Program was implemented. The primary outcome was school climate measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Students were assessed at the start of the academic year (June, 2015) and again 8 months later at the end of the academic year (March, 2016) via self-completed questionnaires. This study is registered with ClinicalTrials.gov, number NCT02484014. Findings: Of the 112 eligible schools in the Nalanda district, 75 were randomly selected to participate in the trial. We randomly assigned 25 schools to each of the three groups. One school subsequently dropped out of the TSM group, leaving 24 schools in this group. The baseline survey included a total of 13 035 participants, and the endpoint survey included 14 414 participants. Participants in the SM-delivered intervention schools had substantially higher school climate scores at endpoint survey than those in the control group (BBSCQ baseline-adjusted mean difference [aMD] 7·57 [95% CI 6·11-9·03]; effect size 1·88 [95% CI 1·44-2·32], p<0·0001) and the TSM-delivered intervention (aMD 7·57 [95% CI 6·06-9·08]; effect size 1·88 [95% CI 1·43-2·34], p<0·0001). There was no effect of the TSM-delivered intervention compared with control (aMD -0·009 [95% CI -1·53 to 1·51], effect size 0·00 [95% CI -0·45 to 0·44], p=0·99). Compared with the control group, participants in the SM-delivered intervention schools had moderate to large improvements in the secondary outcomes of depression (aMD -1·23 [95% CI -1·89 to -0·57]), bullying (aMD -0·91 [95% CI -1·15 to -0·66]), violence victimisation (odds ratio [OR] 0·62 [95% CI 0·46-0·84]), violence perpetration (OR 0·68 [95% CI 0·48-0·96]), attitude towards gender equity (aMD 0·41 [95% CI 0·21-0·61]), and knowledge of reproductive and sexual health (aMD 0·29 [95% CI 0·06-0·53]). Similar results for these secondary outcomes were noted for the comparison between SM-delivered intervention schools and TSM-delivered intervention schools (depression: aMD -1·23 [95% CI -1·91 to -0·55]; bullying: aMD -0·83 [95% CI -1·08 to -0·57]; violence victimisation: OR 0·49 [95% CI 0·35-0·67]; violence perpetration: OR 0·49 [95% CI 0·34-0·71]; attitude towards gender equity: aMD 0·23 [95% CI 0·02-0·44]; and knowledge of reproductive and sexual health: aMD 0·22 [95% CI -0·02 to 0·47]). However, no effects on these secondary outcomes were observed for the TSM-delivered intervention schools compared with the control group (depression: aMD -0·03 [95% CI -0·70 to 0·65]; bullying: aMD -0·08 [95% CI -0·34 to 0·18]; violence victimisation: OR 1·27 [95% CI 0·93-1·73]; violence perpetration: OR 1·37 [95% CI 0·95-1·95]; attitude towards gender equity: aMD 0·17 [95% CI -0·09 to 0·38]; and knowledge of reproductive and sexual health: aMD 0·06 [95% CI -0·18 to 0·32]). Interpretation: The multi-component whole-school SEHER health promotion intervention had substantial beneficial effects on school climate and health-related outcomes when delivered by lay counsellors, but no effects when delivered by teachers. Future research should focus on the evaluation of the scaling up of the SEHER intervention in diverse contexts and delivery agents. Funding: John D. and Catherine T. MacArthur Foundation, USA and the United Nations Population Fund India Office.

Lancet (London, England) · randomised controlled trial · 121 citationsread the source →

A meta-analysis of randomised placebo-controlled treatment trials for depression and anxiety in Parkinson's disease.

Background: Psychopharmacotherapy currently constitutes the first-line treatment for depression and anxiety in Parkinson's disease (PD) however the efficacy of antidepressant treatments in PD is unclear. Several alternative treatments have been suggested as potentially more viable alternatives including dopamine agonists, repetitive transcranial magnetic stimulation, and cognitive behavioural therapy (CBT). Method: A meta-analysis of randomised placebo-controlled trials for depression and/or anxiety in PD was conducted to systematically examine the efficacy of current treatments for depression and anxiety in PD. Results: Nine trials were included. There was only sufficient data to calculate a pooled effect for antidepressant therapies. The pooled effect of antidepressants for depression in PD was moderate but non-significant (d = .71, 95% CI = -1.33 to 3.08). The secondary effect of antidepressants on anxiety in PD was large but also non-significant (d = 1.13, 95% CI = -.67 to 2.94). Two single-trials of non-pharmacological treatments for depression in PD resulted in significant large effects; Omega-3 supplementation (d = .92, 95% CI = .15 to 1.69) and CBT (d = 1.57, 95% CI = 1.06 to 2.07), and warrant further exploration. Conclusions: There remains a lack of controlled trials for both pharmacological and non-pharmacological treatments for depression and anxiety in PD which limits the conclusions which can be drawn. While the pooled effects of antidepressant therapies in PD were non-significant, the moderate to large magnitude of each pooled effect is promising. Non-pharmacological approaches show potential for depression in PD however more research is required.

PloS one · meta-analysis · 86 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 →

A randomized controlled comparison of guided self-help cognitive behavioral therapy and behavioral weight loss for binge eating disorder.

We performed a randomized controlled study to test the relative efficacy of guided self-help (gsh) cognitive-behavioral therapy (CBTgsh) and behavioral weight loss treatment (BWLgsh) treatments for binge eating disorder (BED). To provide an additional partial control for non-specific influences of attention, a third control (CON) treatment condition was included. We tested the treatments using a guided self-help approach given the promising results from initial studies using minimal therapist guidance. Ninety consecutive overweight patients (19 males, 71 females) with BED were randomly assigned (5:5:2 ratio) to one of three treatments: CBTgsh (N=37), BWLgsh (N=38), or CON (N=15). The three 12-week treatment conditions were administered individually following guided self-help protocols. Overall, 70 (78%) completed treatments; CBTgsh (87%) and CON (87%) had significantly higher completion rates than BWLgsh (67%). Intent-to-treat analyses revealed that CBTgsh had significantly higher remission rates (46%) than either BWLgsh (18%) or CON (13%). Weight loss was minimal and differed little across treatments. The findings suggest that CBT, administered via guided self-help, demonstrates efficacy for BED, but not for obesity. The findings support CBT administered via guided self-help as a first step in the treatment of BED and provide evidence for its specific effects.

Behaviour research and therapy · randomised controlled trial · 124 citationsread the source →

Cognitive behavioural treatment for women who have menopausal symptoms after breast cancer treatment (MENOS 1): a randomised controlled trial.

Background: Hot flushes and night sweats (HFNS) affect 65-85% of women after breast cancer treatment; they are distressing, causing sleep problems and decreased quality of life. Hormone replacement therapy is often either undesirable or contraindicated. Safe, effective non-hormonal treatments are needed. We investigated whether cognitive behavioural therapy (CBT) can help breast cancer survivors to effectively manage HFNS. Methods: In this randomised controlled trial, we recruited women from breast clinics in London, UK, who had problematic HFNS (minimum ten problematic episodes a week) after breast-cancer treatment. Participants were randomly allocated to receive either usual care or usual care plus group CBT (1:1). Randomisation was done in blocks of 12-20 participants, stratifying by age (younger than 50 years, 50 years or older), and was done with a computer-generated sequence. The trial statistician and researchers collecting outcome measures were masked to group allocation. Group CBT comprised one 90 min session a week for 6 weeks, and included psycho-education, paced breathing, and cognitive and behavioural strategies to manage HFNS. Assessments were done at baseline, 9 weeks, and 26 weeks after randomisation. The primary outcome was the adjusted mean difference in HFNS problem rating (1-10) between CBT and usual care groups at 9 weeks after randomisation. Analysis of the primary endpoint was done by modified intention to treat. The trial is registered, ISRCTN13771934, and was closed March 15, 2011. Findings: Between May 5, 2009, and Aug 27, 2010, 96 women were randomly allocated to group CBT (n=47) or usual care (n=49). Group CBT significantly reduced HFNS problem rating at 9 weeks after randomisation compared with usual care (mean difference -1·67, 95% CI -2·43 to -0·91; p<0·0001) and improvements were maintained at 26 weeks (mean difference -1·76, -2·54 to -0·99; p<0·0001). We recorded no CBT-related adverse events. Interpretation: Group CBT seems to be a safe and effective treatment for women who have problematic HFNS after breast cancer treatment with additional benefits to mood, sleep, and quality of life. The treatment could be incorporated into breast cancer survivorship programmes and delivered by trained breast cancer nurses. Funding: Cancer Research UK.

The Lancet. Oncology · randomised controlled trial · 190 citationsread the source →

Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: the Project ENABLE II randomized controlled trial.

Context: There are few randomized controlled trials on the effectiveness of palliative care interventions to improve the care of patients with advanced cancer. Objective: To determine the effect of a nursing-led intervention on quality of life, symptom intensity, mood, and resource use in patients with advanced cancer. Design, setting, and participants: Randomized controlled trial conducted from November 2003 through May 2008 of 322 patients with advanced cancer in a rural, National Cancer Institute-designated comprehensive cancer center in New Hampshire and affiliated outreach clinics and a VA medical center in Vermont. Interventions: A multicomponent, psychoeducational intervention (Project ENABLE [Educate, Nurture, Advise, Before Life Ends]) conducted by advanced practice nurses consisting of 4 weekly educational sessions and monthly follow-up sessions until death or study completion (n = 161) vs usual care (n = 161). Main outcome measures: Quality of life was measured by the Functional Assessment of Chronic Illness Therapy for Palliative Care (score range, 0-184). Symptom intensity was measured by the Edmonton Symptom Assessment Scale (score range, 0-900). Mood was measured by the Center for Epidemiological Studies Depression Scale (range, 0-60). These measures were assessed at baseline, 1 month, and every 3 months until death or study completion. Intensity of service was measured as the number of days in the hospital and in the intensive care unit (ICU) and the number of emergency department visits recorded in the electronic medical record. Results: A total of 322 participants with cancer of the gastrointestinal tract (41%; 67 in the usual care group vs 66 in the intervention group), lung (36%; 58 vs 59), genitourinary tract (12%; 20 vs 19), and breast (10%; 16 vs 17) were randomized. The estimated treatment effects (intervention minus usual care) for all participants were a mean (SE) of 4.6 (2) for quality of life (P = .02), -27.8 (15) for symptom intensity (P = .06), and -1.8 (0.81) for depressed mood (P = .02). The estimated treatment effects in participants who died during the study were a mean (SE) of 8.6 (3.6) for quality of life (P = .02), -24.2 (20.5) for symptom intensity (P = .24), and -2.7 (1.2) for depressed mood (P = .03). Intensity of service did not differ between the 2 groups. Conclusion: Compared with participants receiving usual oncology care, those receiving a nurse-led, palliative care-focused intervention addressing physical, psychosocial, and care coordination provided concurrently with oncology care had higher scores for quality of life and mood, but did not have improvements in symptom intensity scores or reduced days in the hospital or ICU or emergency department visits. Trial registration: clinicaltrials.gov Identifier: NCT00253383.

JAMA · randomised controlled trial · 1314 citationsread the source →

A communication strategy and brochure for relatives of patients dying in the ICU.

Background: There is a need for close communication with relatives of patients dying in the intensive care unit (ICU). We evaluated a format that included a proactive end-of-life conference and a brochure to see whether it could lessen the effects of bereavement. Methods: Family members of 126 patients dying in 22 ICUs in France were randomly assigned to the intervention format or to the customary end-of-life conference. Participants were interviewed by telephone 90 days after the death with the use of the Impact of Event Scale (IES; scores range from 0, indicating no symptoms, to 75, indicating severe symptoms related to post-traumatic stress disorder [PTSD]) and the Hospital Anxiety and Depression Scale (HADS; subscale scores range from 0, indicating no distress, to 21, indicating maximum distress). Results: Participants in the intervention group had longer conferences than those in the control group (median, 30 minutes [interquartile range, 19 to 45] vs. 20 minutes [interquartile range, 15 to 30]; P<0.001) and spent more of the time talking (median, 14 minutes [interquartile range, 8 to 20] vs. 5 minutes [interquartile range, 5 to 10]). On day 90, the 56 participants in the intervention group who responded to the telephone interview had a significantly lower median IES score than the 52 participants in the control group (27 vs. 39, P=0.02) and a lower prevalence of PTSD-related symptoms (45% vs. 69%, P=0.01). The median HADS score was also lower in the intervention group (11, vs. 17 in the control group; P=0.004), and symptoms of both anxiety and depression were less prevalent (anxiety, 45% vs. 67%; P=0.02; depression, 29% vs. 56%; P=0.003). Conclusions: Providing relatives of patients who are dying in the ICU with a brochure on bereavement and using a proactive communication strategy that includes longer conferences and more time for family members to talk may lessen the burden of bereavement. (ClinicalTrials.gov number, NCT00331877.)

The New England journal of medicine · randomised controlled trial · 820 citationsread the source →

Hypnosis decreases presurgical distress in excisional breast biopsy patients.

Background: Excisional breast biopsy is associated with presurgical psychological distress. Such distress is emotionally taxing, and may have negative implications for postsurgical side effects and satisfaction with anesthesia. We investigated the ability of a brief hypnosis session to reduce presurgical psychological distress in excisional breast biopsy patients. Methods: Ninety patients presenting for excisional breast biopsy were randomly assigned to receive either a 15-minute presurgery hypnosis session (n = 49, mean age: 46.4 (95% CI: 42.3-50.4)) or a 15-minute presurgery attention control session (n = 41, mean age: 45.0 (95% CI: 40.8-49.2)). The hypnosis session involved suggestions for increased relaxation and decreased distress. The attention control session involved nondirective empathic listening. Presurgery distress was measured using visual analog scales (VAS) and the short version of the Profile of Mood States (SV-POMS). Data were analyzed using analysis of variance and chi2 procedures. Results: Groups did not differ in terms of the following: demographics (age, education, ethnicity, marital status, all P's > 0.28); medical variables (presurgery diagnosis, previous excisional biopsy, previous breast cancer, all P's > 0.11); or preintervention distress (SV-POMS P > 0.74) assessed on the day of surgery. Postintervention, and before surgery, patients in the hypnosis group had significantly lower mean values for presurgery VAS emotional upset (16.5 vs 38.2, P < 0.0001, d = .85), VAS depressed mood (6.6 vs 19.9, P < 0.02, d = .67), and SV-POMS anxiety (10.0 vs 5.0, P < 0.0001, d = 0.85); and significantly higher levels for VAS relaxation (75.7 vs 54.2, P < 0.001, d = -0.76) than attention controls. Conclusions: The study results indicate that a brief presurgery hypnosis intervention can be an effective means of controlling presurgical distress in women awaiting diagnostic breast cancer surgery.

Anesthesia and analgesia · randomised controlled trial · 52 citationsread the source →

Determining the relative importance of the mechanisms of behavior change within Alcoholics Anonymous: a multiple mediator analysis.

Aims: Evidence indicates that Alcoholics Anonymous (AA) participation reduces relapse risk but less is known about the mechanisms through which AA confers this benefit. Initial studies indicate self-efficacy, negative affect, adaptive social networks and spiritual practices are mediators of this effect, but because these have been tested in isolation, their relative importance remains elusive. This study tested multiple mediators simultaneously to help determine the most influential pathways. Design: Prospective, statistically controlled, naturalistic investigation examined the extent to which these previously identified mechanisms mediated AA attendance effects on alcohol outcomes controlling for baseline outcome values, mediators, treatment, and other confounders. Setting: Nine clinical sites within the United States. Participants: Adults (n = 1726) suffering from alcohol use disorder (AUD) initially enrolled in a randomized study with two arms: aftercare (n = 774); and out-patient (n = 952) comparing three out-patient treatments (Project MATCH). Measurements: AA attendance during treatment; mediators at 9 months; and outcomes [percentage of days abstinent (PDA) and drinks per drinking day (DDD)] at 15 months. Findings: Among out-patients the effect of AA attendance on alcohol outcomes was explained primarily by adaptive social network changes and increases in social abstinence self-efficacy. Among more impaired aftercare patients, in addition to mediation through adaptive network changes and increases in social self-efficacy, AA lead to better outcomes through increasing spirituality/religiosity and by reducing negative affect. The degree to which mediators explained the relationship between AA and outcomes ranged from 43% to 67%. Conclusion: While Alcoholics Anonymous facilitates recovery by mobilizing several processes simultaneously, it is changes in social factors which appear to be of primary importance.

Addiction (Abingdon, England) · randomised controlled trial · 119 citationsread the source →

What Are the Minimal and Substantial Improvements in the HOOS and KOOS and JR Versions After Total Joint Replacement?

Background: Patient-reported outcome measures (PROMs) are a gold standard for measuring therapeutic outcomes in research. Extending their use to inform clinical care decisions, determine the appropriateness of therapeutic choices, and assess healthcare quality is attractive but will require our professional community to establish valid estimates of minimal and substantial clinical improvements. Questions/purposes: The purposes of this study were (1) to assess the validity of estimates for the minimal clinically important difference (MCID) calculated using distribution- and anchor-based methods by determining whether they exceed the minimal detectable change (MDC) for the Hip Disability and Osteoarthritis Outcome Score (HOOS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) domains, the HOOS, joint replacement (JR) and the KOOS, JR among patients who underwent THA or TKA; (2) to determine substantial clinical benefit thresholds for the HOOS and KOOS domains, the HOOS, JR, and the KOOS, JR among patients who underwent THA or TKA; and (3) to assess the proportions of patients who underwent THA or TKA who achieved an MCID for the HOOS and KOOS domains, HOOS, JR, and KOOS, JR based on distribution-based and anchor-based methods as well as the percentages of patients who achieved substantial clinical benefit using the anchor-based method. Methods: Medicare patients enrolled in our institutional joint replacement registry who subsequently underwent THA (n = 2323) or TKA (n = 2630) between 2007 and 2012 completed HOOS or KOOS preoperatively and 2 years postoperatively. Short-form joint replacement (JR) versions of each PROM were derived from the full PROMs. Of all eligible patients, 78% (3161 of 4080) of THAs and 74% of TKAs (3815 of 5156) consented to join the registry and completed a baseline survey, 88% (2796 of 3161) of THAs and 85% (3230 of 3815) of TKAs were eligible for followup survey administration, and 83% of THAs (2323 of 2796) and 81% (2630 of 3230) of TKAs returned 2-year surveys. For each HOOS domain, KOOS domain, HOOS, JR, and KOOS, JR, we calculated the calibration variation of the instrument (MDC) with confidence intervals (CIs) reflecting 80% (MDC80), 90% (MDC90), and 95% (MDC95) certainty; we calculated the smallest difference joint health patients might detect (MCID) using distribution- and anchor-based approaches and the difference that can be considered a large improvement in joint health (substantial clinical benefit) using an anchor-based approach. Results: Patients undergoing THA were 57% female with a mean (± SD) age of 73 ± 6 years, whereas patients undergoing TKA were 63% female with a mean age of 74 ± 6 years. Depending on the CI chosen for the MDC, values ranged from 7 to 16 for the HOOS and KOOS domains and the JRs. The MCIDs ranged from 6 to 9 for the distribution-based approach and 7 to 36 for the anchor-based approach. All HOOS and KOOS domains and all JR scores are scores from 0 (worst joint health) to 100 (best joint health). The MCIDs calculated using the distribution-based approach were not valid, because they were lower than the MDC for all HOOS/KOOS domains and both JRs at every confidence level. The anchor-based receiver operating characteristic approach, on the other hand, resulted in MCIDs exceeding MDC80 for seven of eight HOOS/KOOS domains and MDC95 for both JR scores. For all domains and JR versions, substantial clinical benefits ranged from 15 to 36, exceeding MDC95 in all domains and JR scores. Across HOOS and KOOS domains as well as the JR, the proportion of patients undergoing THA who achieved an MCID ranged from 77% to 95% with the distribution-based method and from 67% to 96% using the anchor-based method. The proportion achieving substantial clinical benefit ranged from 67% to 85%. Conclusions: The MDC and MCID differ greatly based on assumptions and methods used. The MCID anchor-based approach had superior construct and face validity compared with the MCID distribution-based approach, which never exceeded even small MDCs. Achieving consensus about standard definitions of meaningful improvement will be necessary to maximize utility of these PROMs to inform clinical care or performance measurement. Level of evidence: Level III, diagnostic study.

Clinical orthopaedics and related research · cohort or longitudinal · 400 citationsread the source →

Heterogeneity of phenotypes in severe asthmatics. The Belgian Severe Asthma Registry (BSAR).

Unlabelled: The Belgian severe asthma registry is a web-based registry encompassing demographic, clinical, functional and inflammatory data of severe asthmatics (SA), aiming at improving awareness, knowledge on its natural history and subphenotypes, and offering tools to optimize care of this asthma population. Methods: The cross-sectional analyses of this registry included 350 SA as defined by the ATS (2000) from 9 Belgian centres, with at least one year follow up. Results: Mean age was 55 ± 14 yrs. SA were more frequently female (57%) and atopic (70%). Late-onset asthma (≥40 yr) was observed in 31% of SA. Current smokers represented 12% while 31% were ex-smokers. In addition to high doses ICS + LABA, 65% of patients were receiving LTRA, 27% anti-IgE and 24% maintenance oral corticosteroids (8 mg (Interquartile range-IQR:4-8) methylprednisolone). Despite impaired airflow (median FEV1:67%; IQR: 52-81) only 65% had a post-bronchodilator FEV1/FVC ratio <70%. The median blood eosinophil count was 240/mm³. The median FENO was 26 ppb (IQR: 15-43) and 22% of SA had FENO ≥ 50 ppb. Induced sputum was successful in 86 patients. Eosinophilic asthma (sputum Eos ≥ 3%) was the predominant phenotype (55%) while neutrophilic (sputum Neu ≥ 76%) and paucigranulocytic asthma accounted for 22% and 17% respectively. Comorbidities included rhinitis and chronic rhinosinusitis (49%), nasal polyposis (19%), oesophageal reflux (36%), overweight and obesity (47%) and depression (19%). In addition, 8% had aspirin-induced asthma and 3% ABPA. Asthma was not well-controlled in 83% according to ACT < 20 and 77% with ACQ > 1.5. Conclusion: In this cohort of patients with severe asthma, the majority displayed indices of persistent airflow limitation and eosinophilic inflammation despite high-dose corticosteroids, suggesting potential for eosinophil-targeted biotherapies.

Respiratory medicine · cohort or longitudinal · 199 citationsread the source →

Physical activity, diet and other behavioural interventions for improving cognition and school achievement in children and adolescents with obesity or overweight.

Background: The global prevalence of childhood and adolescent obesity is high. Lifestyle changes towards a healthy diet, increased physical activity and reduced sedentary activities are recommended to prevent and treat obesity. Evidence suggests that changing these health behaviours can benefit cognitive function and school achievement in children and adolescents in general. There are various theoretical mechanisms that suggest that children and adolescents with excessive body fat may benefit particularly from these interventions. Objectives: To assess whether lifestyle interventions (in the areas of diet, physical activity, sedentary behaviour and behavioural therapy) improve school achievement, cognitive function (e.g. executive functions) and/or future success in children and adolescents with obesity or overweight, compared with standard care, waiting-list control, no treatment, or an attention placebo control group. Search methods: In February 2017, we searched CENTRAL, MEDLINE and 15 other databases. We also searched two trials registries, reference lists, and handsearched one journal from inception. We also contacted researchers in the field to obtain unpublished data. Selection criteria: We included randomised and quasi-randomised controlled trials (RCTs) of behavioural interventions for weight management in children and adolescents with obesity or overweight. We excluded studies in children and adolescents with medical conditions known to affect weight status, school achievement and cognitive function. We also excluded self- and parent-reported outcomes. Data collection and analysis: Four review authors independently selected studies for inclusion. Two review authors extracted data, assessed quality and risks of bias, and evaluated the quality of the evidence using the GRADE approach. We contacted study authors to obtain additional information. We used standard methodological procedures expected by Cochrane. Where the same outcome was assessed across different intervention types, we reported standardised effect sizes for findings from single-study and multiple-study analyses to allow comparison of intervention effects across intervention types. To ease interpretation of the effect size, we also reported the mean difference of effect sizes for single-study outcomes. Main results: We included 18 studies (59 records) of 2384 children and adolescents with obesity or overweight. Eight studies delivered physical activity interventions, seven studies combined physical activity programmes with healthy lifestyle education, and three studies delivered dietary interventions. We included five RCTs and 13 cluster-RCTs. The studies took place in 10 different countries. Two were carried out in children attending preschool, 11 were conducted in primary/elementary school-aged children, four studies were aimed at adolescents attending secondary/high school and one study included primary/elementary and secondary/high school-aged children. The number of studies included for each outcome was low, with up to only three studies per outcome. The quality of evidence ranged from high to very low and 17 studies had a high risk of bias for at least one item. None of the studies reported data on additional educational support needs and adverse events. Compared to standard practice, analyses of physical activity-only interventions suggested high-quality evidence for improved mean cognitive executive function scores. The mean difference (MD) was 5.00 scale points higher in an after-school exercise group compared to standard practice (95% confidence interval (CI) 0.68 to 9.32; scale mean 100, standard deviation 15; 116 children, 1 study). There was no statistically significant beneficial effect in favour of the intervention for mathematics, reading, or inhibition control. The standardised mean difference (SMD) for mathematics was 0.49 (95% CI -0.04 to 1.01; 2 studies, 255 children, moderate-quality evidence) and for reading was 0.10 (95% CI -0.30 to 0.49; 2 studies, 308 children, moderate-quality evidence). The MD for inhibition control was -1.55 scale points (95% CI -5.85 to 2.75; scale range 0 to 100; SMD -0.15, 95% CI -0.58 to 0.28; 1 study, 84 children, very low-quality evidence). No data were available for average achievement across subjects taught at school. There was no evidence of a beneficial effect of physical activity interventions combined with healthy lifestyle education on average achievement across subjects taught at school, mathematics achievement, reading achievement or inhibition control. The MD for average achievement across subjects taught at school was 6.37 points lower in the intervention group compared to standard practice (95% CI -36.83 to 24.09; scale mean 500, scale SD 70; SMD -0.18, 95% CI -0.93 to 0.58; 1 study, 31 children, low-quality evidence). The effect estimate for mathematics achievement was SMD 0.02 (95% CI -0.19 to 0.22; 3 studies, 384 children, very low-quality evidence), for reading achievement SMD 0.00 (95% CI -0.24 to 0.24; 2 studies, 284 children, low-quality evidence), and for inhibition control SMD -0.67 (95% CI -1.50 to 0.16; 2 studies, 110 children, very low-quality evidence). No data were available for the effect of combined physical activity and healthy lifestyle education on cognitive executive functions. There was a moderate difference in the average achievement across subjects taught at school favouring interventions targeting the improvement of the school food environment compared to standard practice in adolescents with obesity (SMD 0.46, 95% CI 0.25 to 0.66; 2 studies, 382 adolescents, low-quality evidence), but not with overweight. Replacing packed school lunch with a nutrient-rich diet in addition to nutrition education did not improve mathematics (MD -2.18, 95% CI -5.83 to 1.47; scale range 0 to 69; SMD -0.26, 95% CI -0.72 to 0.20; 1 study, 76 children, low-quality evidence) and reading achievement (MD 1.17, 95% CI -4.40 to 6.73; scale range 0 to 108; SMD 0.13, 95% CI -0.35 to 0.61; 1 study, 67 children, low-quality evidence). Authors' conclusions: Despite the large number of childhood and adolescent obesity treatment trials, we were only able to partially assess the impact of obesity treatment interventions on school achievement and cognitive abilities. School and community-based physical activity interventions as part of an obesity prevention or treatment programme can benefit executive functions of children with obesity or overweight specifically. Similarly, school-based dietary interventions may benefit general school achievement in children with obesity. These findings might assist health and education practitioners to make decisions related to promoting physical activity and healthy eating in schools. Future obesity treatment and prevention studies in clinical, school and community settings should consider assessing academic and cognitive as well as physical outcomes.

The Cochrane database of systematic reviews · meta-analysis · 69 citationsread the source →

Evaluation of Parental Dental Fear and Anxiety (DFA) on Adolescent Dental Treatment

INTRODUCTION Dental anxiety is a negative state of mind of a dental patient, which is shown to be excessive and unreasonable.[1] Dental fear is a normal emotional response to particularly alarming stimuli in situations related to dental treatment.[1] Dental fear and anxiety (DFA) are often used together to describe different types of fear experienced in the dental environment.[2] American Academy of Pediatrics divides adolescents into three age groups: early 11–14 years, middle 15–17 years, and late 18–21 years.[3] Five specific pathways for DFA were seen in adolescent dental patients. One of which being the parental pathway plays an important role in the transmission of fear hindering their child’s dental treatment.[4] Parental DFA is usually an excessive perturbing of the things that could go wrong in child’s oral health and is an important factor that has an impact on adolescents receiving dental treatment and maintenance of their oral health. It is necessary to recognize and know how parental DFA affects the dental treatment of adolescents. Thus, this review aimed at evaluating the parental influence of DFA on dental treatment of adolescents. MATERIALS AND METHODS DATA EXTRACTION AND LITERATURE SEARCH STRATEGY A broad search of literature published between 2005 and 2021 from electronic databases through Scopus, PubMed, Google Scholar, and Web of Science was performed. These studies were conducted in different countries as mentioned in Table 1. This review article includes eight cross-sectional studies, three longitudinal studies, and one descriptive study. The age group of children included ranged from 10 to 19 years. Table 1: Summary study design, data collection, dental fear and anxiety assessment scales used analysis, and interpretation of reviewed articlesThe search was carried out using the following keywords: dental anxiety, parental dental anxiety, adolescent, and dental treatment. The terms used to formulate the search strategies were parent OR mother OR father AND dental fear OR dental anxiety AND adolescent AND dental treatment. Data extracted were independently reviewed and disagreements were solved by discussion. A flowchart representing the method of article selection for the review is shown in Figure 1.Figure 1: Flowchart representing the method of article selectionINCLUSION CRITERIA We included the studies in which parental dental anxiety was a major criterion affecting different dental health conditions. Articles referring to adolescents (10–19 years) facing different oral health problems were also included in the study. EXCLUSION CRITERIA Abstracts that were not giving relevant data, data from unpublished articles, parental dental anxiety in medically compromised and specially challenged adolescents, and articles that did not include the adolescent age group were excluded from the study. RESULTS Approximately 83 publications were found related. Screening identified 10 articles that fulfilled the criteria of inclusion; full-text versions were retrieved and their references were screened for further relevant articles. Checking the subreference list, another two relevant articles were found. Thus, 12 articles were considered for this review that met the final inclusion criteria. Of 12 articles reviewed, 8 studies[56789101112] used validated assessment scales as mentioned by authors for measuring parental DFA. The authors have not specified the validation of assessment scales used for the other four studies.[13141516] The various DFA assessment scales used in the reviewed articles are mentioned in Table 2. Summary study design, data collection, analysis, and interpretation of reviewed articles are mentioned in Table 1.Table 2: Tabular representation of dental fear and anxiety assessment scales usedDISCUSSION Dental anxiety being primarily a negative parental factor was found to affect children from assessing regular dental care. Among the reviewed articles based on the outcome, we found that three articles explained about a relationship between parental DFA and adolescent dental treatment,[67,13] and the remaining nine articles explained about the correlation between parental DFA scores with adolescent DFA scores.[6891011,13141516] No significant association was observed between parental DFA and adolescent DFA scores in two of the studies,[78] whereas two studies showed positive association only during early adolescence.[914] Other five studies showed a significant positive correlation of parental DFA with their children’s dental anxiety,[10111215,16] of which three studies also suggested fathers as mediating role in transmission of DFA to their children.[1011,15] RELATIONSHIP BETWEEN PARENTAL DENTAL FEAR AND ANXIETY AND ADOLESCENT DENTAL TREATMENT Adolescent dental treatment utilization mainly depends on parental/caretaker’s decision-making and their dental care obtaining habits. In childhood and even adolescence, this becomes very crucial for the development of good oral health behavior like regular visits to the dentist and preventive dental care.[17] Another postulated process is “social learning” wherein, media, friends, and relatives portray dentists in negative light or image leading to formation of DFA. These processes of information transmission and vicarious experience lead to negative portrayal of dentists and pessimistic expectations about the dentist’s role. All these predispose to DFA.[18] The absence of anxiety among parents would have a positive influence on a child.[19] Parental dental anxiety along with family income, economic stability, parental oral health literacy, and oral health practices is found to be a few factors that affect adolescent’s oral health-related quality of life (QOL).[202122] Dental anxiety being primarily a negative parental factor was found to affect children from accessing regular dental care, whereas parental self-dental utilization being a positive parental factor showed a positive impact on a child’s dental utilization.[23] Parents with higher anxiety levels were found to start brushing their children’s teeth at an earlier age; hence, a significant correlation was found between parent’s anxiety levels and the age at which the child starts to brush.[24] Dental health status of children was found to be better with more a positive attitude of parents toward dentistry.[25] Among the articles reviewed, two articles were found to have parental DFA during fixed orthodontic treatment of the adolescents which included the use of extraoral appliances. These two studies used different anxiety measurement scales for assessing parental DFA before and during the treatment procedures.[513] Poorer QOL is seen in families of adolescents with malocclusion as compared with the families of adolescents without any occlusal variation; the impact may have effects on parental or guardian’s emotions.[26] Both of the studies assessed state and trait dental anxiety of parents (STAI scale). State anxiety is transient, fluctuates, and varies in intensity. Trait anxiety is a personality trait; it is stable with time.[2728] The result showed that parent’s trait anxiety levels did not change during orthodontic treatment.[513] State anxiety was found to be within normal range and changed according to intensity of pressure.[13] There was an incidence of high levels of state anxiety and depression in both parents and patients under treatment with extra oral orthodontic appliances after 1 year of active treatment. Among patients waiting for orthodontic treatment and among their parents no statistically significant differences were noted in their trait anxiety levels.[5] The extra oral appliances had a negative effect on patient’s and parent’s anxiety levels which might indirectly affect the ongoing dental treatment. It was therefore recommended for clinicians to have alternate treatment modalities in mind to address this challenge.[5] Apart from orthodontic treatment, adolescents are also found commonly with traumatic dental injuries (TDIs) involving dentine/pulp or fracture of the root. A family’s QOL in such conditions was assessed using the family impact scale (FIS). This scale had four subscales, in which parental emotion was one of the subscales assessed. Parental emotion had a significant negative impact on the severity of TDI and severe untreated TDI of an adolescent can be a source of family distress.[629,30] EVIDENCE OF ASSOCIATION OF DENTAL FEAR AND ANXIETY BETWEEN PARENTS AND THEIR ADOLESCENTS Previous studies have shown that parents exhibit an influence on their children’s DFA through modeling and information.[31] The DFA experienced in childhood may lead into adulthood causing a predictor for dental treatment avoidance in adulthood.[3233] Among the reviewed articles, we found a correlation between the parental dental DFA scores with their adolescent’s DFA scores. Parent’s DFA and children’s DFA were assessed using the same dental anxiety measuring scale in nine of the studies,[6891011,13141516] and three studies[57,12] used different scales to measure anxiety levels in parents and children’s. Two of the studies showed no significant association between the anxiety level of adolescents and that of their parents.[78] One of the studies suggested that when a child reached adolescence, parental DFA does not directly contribute to child DFA. Other factors such as the presence of a sibling and family structure (single-parent family, nuclear) are found to play a significant role.[7] Lending support to the former findings, there was no relation between anxiety levels of adolescents (12–17 years) and that of their parents, whereas in the same study a positive association was found when the child is 8–11 years of age.[8] Two studies suggested a positive association in early adolescence.[914] In one of these two studies, mother’s and adolescents dental fear scores had a significant association at the age of 12 years and 18 years in given treatment scenarios such as “feeling about having their teeth scraped and polished, having teeth drilled and having an injection in gum,” whereas there was no significant association between dental fear scores of mother’s and adolescence at 15 years of age.[9] In another study reviewed, in early adolescence (11–12 years), there was a statistically significant association between parental and adolescent dental fear but in mid-adolescence (15–16 years) there was only an association with parental dental fear with their daughters.[14] It was found in the Finnish population, by eliminating dental fear among 30 years and elderly population, 41% of irregular attendees could become regular attenders.[34] In contrast, other five studies showed a significant positive correlation of parental DFA with their children’s dental anxiety.[10111215,16] Fearful parents of adolescents of age (11–16 years) assumed that their child had fear irrespective of whether the child had fear or not.[16] Three of these studies, where parental DFA was assessed in both the parents, suggested that the father also has a mediating role in the transmission of DFA to the children of age group 11–17 years,[10] 7–15 years,[11] and 7–12 years,[15] respectively. Father’s DFA is one of the best predictors of adolescence DFA[1035] and it is also found that child’s dental anxiety is best predicted by the parent’s fear of pain.[12] Previous studies have suggested that children experience fear and anxiety in their early life due to a lack of cognitive ability without having a clear perception of fearful situation and have been influenced by their parent’s fear and anxiety.[36] It is still unclear of the association of DFA between parents and late adolescents.[9] It was found that limited studies were found in the area of adolescent oral health. In the available literature, definite assessment methods were not used to assess the anxiety levels among parents. Furthermore, studies focused on late adolescence are indicated to establish the changes in oral health due to parental DFA. Adolescence is the transitional phase between childhood and adulthood and is a crucial period where they develop decision-making and independence; this has an impact on dental treatment-seeking behavior. The influence of parental dental anxiety might worsen the scenario. Parental DFA is seen to have a direct impact on the treatment itself.[56,20] Previously reviewed articles show a strong association of parental DFA and child’s DFA below 8 years of age.[37] In this study, we found parental DFA showed a positive association with their adolescent’s DFA, which thus hinders their dental treatment. There is a need to give attention to psychological parameters before and during the treatment of both parents and adolescents. Therefore, identifying parental dental anxiety prior to the treatment and intervention helps to reduce or eliminate DFA in children and further improves their dental treatment utilization. This study adds value in sensitizing dental professionals toward addressing parental concerns while treating adolescents and recommendations for appropriate implementations in teaching curricula and policies regarding the same. There is more potential to understand the background of parental DFA in single parents and in mother and father alone and also the factors that made them vulnerable. Parental education/counselling regarding various dental treatment procedures using appropriate methods such as focus group discussion will help to reduce DFA among the parental populations. ACKNOWLEDGEMENT We thank Health Sciences Library, Manipal Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India and Department of Psychiatry, Kasturba Medical College and Hospital, Manipal, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka, India. FINANCIAL SUPPORT AND SPONSORSHIP This study was self-funded. CONFLICTS OF INTEREST There are no conflicts of interest. AUTHORS CONTRIBUTIONS Idea and conceptualization: Ramprasad Vasthare. Literature search: Thrisha Hegde, Bhavyashri P. Manuscript writing: Thrisha Hegde, Bhavyashri P, Ramprasad Vasthare, Karthik M, Ravindra Munoli. Editing of the review: Ramprasad Vasthare, Thrisha Hegde, Bhavyashri P, Karthik M, Ravindra Munoli. Intellectual inputs: Ramprasad Vasthare, Ravindra Munoli, Karthik M. ETHICAL POLICY AND INSTITUTIONAL REVIEW BOARD STATEMENT Not applicable as this was a narrative review. PATIENT DECLARATION OF CONSENT Not applicable. DATA AVAILABILITY STATEMENT Data of literature search is available on appropriate request to the corresponding author.

Journal of International Society of Preventive and Community Dentistry · review · 16 citationsread the source →

Pervasive refusal syndrome as part of the refusal-withdrawal-regression spectrum: critical review of the literature illustrated by a case report.

Pervasive refusal syndrome (PRS) is a rare child psychiatric disorder characterized by pervasive refusal, active/angry resistance to help and social withdrawal leading to an endangered state. Little has been written about PRS. A literature search yielded only 15 relevant articles, all published between 1991 and 2006. This article presents a critical review of the published literature, illustrated by a case report of an 11-year-old girl. PRS most often affects girls (75%). The mean age of the known population is 10.5 years. A premorbid high-achieving, perfectionist, conscientious personality seems to play an important role in the aetiology of PRS, as can a psychiatric history of parents or child and environmental stressors. PRS shows a symptom overlap with many other psychiatric disorders. However, none of the current DSM diagnoses can account for the full range of symptoms seen in PRS, and the active/angry resistance can be considered as the main distinguishing feature. Treatment should be multidisciplinary and characterized by patience, gentle encouragement and tender loving care. Hospitalization, ideally in a child and adolescent psychiatric unit, is almost always required. Although the recovery process is painfully slow (average duration of therapy 12.8 months), most children recover fully (complete recovery in 67% of known cases). In our opinion, it is important to increase knowledge of PRS, not only because of its disabling, potential life-threatening character, but also because there is hope for recovery through suitable treatment. We therefore propose an incorporation of PRS into the DSM and ICD classifications. However, an adaptation of the current diagnostic criteria is needed. We also consider PRS closely related to regression, which is why we introduce a new concept: "the refusal-withdrawal-regression spectrum".

European child & adolescent psychiatry · review · 19 citationsread the source →

Socioeconomic inequalities in adolescent health 2002-2010: a time-series analysis of 34 countries participating in the Health Behaviour in School-aged Children study.

Background: Information about trends in adolescent health inequalities is scarce, especially at an international level. We examined secular trends in socioeconomic inequality in five domains of adolescent health and the association of socioeconomic inequality with national wealth and income inequality. Methods: We undertook a time-series analysis of data from the Health Behaviour in School-aged Children study, in which cross-sectional surveys were done in 34 North American and European countries in 2002, 2006, and 2010 (pooled n 492,788). We used individual data for socioeconomic status (Health Behaviour in School-aged Children Family Affluence Scale) and health (days of physical activity per week, body-mass index Z score [zBMI], frequency of psychological and physical symptoms on 0-5 scale, and life satisfaction scored 0-10 on the Cantril ladder) to examine trends in health and socioeconomic inequalities in health. We also investigated whether international differences in health and health inequalities were associated with per person income and income inequality. Findings: From 2002 to 2010, average levels of physical activity (3·90 to 4·08 days per week; p<0·0001), body mass (zBMI -0·08 to 0·03; p<0·0001), and physical symptoms (3·06 to 3·20, p<0·0001), and life satisfaction (7·58 to 7·61; p=0·0034) slightly increased. Inequalities between socioeconomic groups increased in physical activity (-0·79 to -0·83 days per week difference between most and least affluent groups; p=0·0008), zBMI (0·15 to 0·18; p<0·0001), and psychological (0·58 to 0·67; p=0·0360) and physical (0·21 to 0·26; p=0·0018) symptoms. Only in life satisfaction did health inequality fall during this period (-0·98 to -0·95; p=0·0198). Internationally, the higher the per person income, the better and more equal health was in terms of physical activity (0·06 days per SD increase in income; p<0·0001), psychological symptoms (-0·09; p<0·0001), and life satisfaction (0·08; p<0·0001). However, higher income inequality uniquely related to fewer days of physical activity (-0·05 days; p=0·0295), higher zBMI (0·06; p<0·0001), more psychological (0·18; p<0·0001) and physical (0·16; p<0·0001) symptoms, and larger health inequalities between socioeconomic groups in psychological (0·13; p=0·0080) and physical (0·07; p=0·0022) symptoms, and life satisfaction (-0·10; p=0·0092). Interpretation: Socioeconomic inequality has increased in many domains of adolescent health. These trends coincide with unequal distribution of income between rich and poor people. Widening gaps in adolescent health could predict future inequalities in adult health and need urgent policy action. Funding: Canadian Institutes of Health Research.

Lancet (London, England) · 301 citationsread the source →

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial.

Background: The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation. Methods: This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275. Findings: Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (β-estimate -2·11 [95% CI -3·15 to -1·06]; p<0·0001) and head circumference (-0·42 [-0·67 to -0·18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4·27 [95% CI 3·12 to 5·84]; p<0·0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning β-estimate 3·57 [95% CI 1·95 to 5·18], p<0·0001; total intelligence quotient -7·35 [-9·31 to -5·39], p<0·0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2·73 [1·19 to 4·28], p=0·00055; externalising 1·63 [0·19 to 3·08], p=0·027; and total behavioural problems 2·95 [1·44 to 4·46], p=0·00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (β-estimate -1·88 [95% CI -3·69 to -0·07]; p=0·042), externalising (-1·73 [-3·43 to -0·03]; p=0·046), and total emotional and behavioural problems (-2·44 [-4·22 to -0·67]; p=0·0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes. Interpretation: Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition. Funding: European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.

The Lancet. Child & adolescent health · 46 citationsread the source →

Changes in life satisfaction among unaccompanied asylum-seeking and refugee minors who participated in teaching recovery techniques (TRT).

Background: Unaccompanied asylum-seeking and refugee minors report low life satisfaction and high levels of mental health problems, nevertheless they often do not seek or receive help for their problems. Teaching Recovery Techniques (TRT) is a low-threshold, five sessions intervention developed to reduce distressing war- and disaster-related trauma reactions among children and youth. In this study, we investigate if TRT can contribute to increased life satisfaction among unaccompanied asylum-seeking and refugee minors. Methods: Asylum-seeking and resettled unaccompanied minors participated in TRT carried out in 15 locations throughout Norway, n = 147, mean age = 16.61 (SD = 1.80), 88% boys, and 67% from Afghanistan. Life satisfaction was measured by the Cantril Ladder before the intervention, and two- and eight weeks post-intervention. We also included indices of intervention compliance and contextual variables, such as asylum status. We applied a pre- and post-intervention design with linear mixed model analyses to investigate change in life satisfaction. Results: Life satisfaction significantly increased from pre- to post- intervention, but not for youth whose asylum application had been rejected or who were still awaiting a decision. Indices of intervention compliance were associated with an increase in life satisfaction. Conclusions: TRT is a potential useful intervention to enhance life satisfaction among unaccompanied asylum-seeking and refugee minors and can be a measure to support positive development among youth at risk for mental health problems. However, TRT initiatives should consider the participant's stage of asylum process, because harsh immigration policies may overburden the coping capacity. Without further adaptation, TRT seems most useful for youth granted residence. The manual has been revised to include asylum-related stressors. Trial registration: ClinicalTrials.gov (16/54,571, registered 30.01.2019).

Child and adolescent psychiatry and mental health · 4 citationsread the source →

People Have Mixed Reactions to Both Physiological and Psychological Explanations of Disproportionate Pain.

Background: There are two general frameworks that conceptualize pain that is more intense or persistent than expected based on measurable pathologic findings: the psychological (unhelpful thoughts and emotions) and the physiological (purported nervous system dysfunction, such as central sensitization). Some clinicians believe people will be more receptive to a physiological conceptualization. Prior quantitative research demonstrated that carefully crafted psychological explanations are rated similarly to crafted physiological explanations, with relatively mixed reactions. This qualitative study was undertaken in parallel with that quantitative study to help develop effective communication and treatment strategies by identifying specific thoughts and feelings (themes) regarding the physiological and psychological conceptualizations of disproportionate pain that make people more or less comfortable considering comprehensive, biopsychosocial treatment approaches. Question/purpose: What themes arise in patient thoughts and feelings regarding physiological and psychological conceptualizations of pain that is more intense or persistent than expected? Methods: We sought to understand the experience of considering pain as a biopsychosocial experience (phenomenology approach) by studying the thoughts and feelings that arise as people seeking care for arm and back pain engage with physiological and psychological conceptualizations of pain that is more intense or persistent than one would expect based on the pathology. We recruited 29 patients presenting for upper extremity or back pain specialty care at one of two urban offices, intentionally recruiting people of various ages, genders, backgrounds, socioeconomic status, as well as type and duration of pain (purposive sampling). The 29 patients included 18 women and 11 men (16 married, 15 non-White, 20 with arm pain) with a median (interquartile range) age of 62 years (42 to 67). The interviews were conducted by a trained woman orthopaedic surgeon interviewer using a semistructured interview guide soliciting participants' thoughts and feelings about a physiological explanation (nerves in the central nervous system stuck in the on position can make pain more intense) and a psychological explanation (unhelpful thoughts and feelings of distress can make pain more intense) for pain more intense or persistent than expected. The interviews were transcribed and themes were identified as the data were collected. Based on current experimental evidence, including what is known about the physiological effects of thoughts, feelings, and context (placebo/nocebo effects), we assumed an underlying physiological basis for pain that is variably experienced and expressed (mixed postpositive/interpretive approach). Themes were identified in the interview transcripts systematically by two coders and then discussed with the entire research team to arrive at consensus. We stopped enrolling patients when the authors agreed that additional themes did not arise in five consecutive interviews. Results: The following themes and interpretations were derived from the analysis: Neither the physiological nor the psychological explanation for disproportionate pain (1) avoided the stigma associated with mental health, (2) was consistently understood, (3) provided a consistent sense of control, (4) consistently provided hope, and (5) represented the stress and emotion of disproportionate or persistent pain. The physiological explanation also generated mixed reactions regarding whether or not it: (1) was a useful point of conversation, (2) was reassuring or frightening, and (3) supported physiological or psychological treatments. The psychological explanation made some people feel worse. Conclusion: People have mixed reactions to both physiological and psychological explanations of disproportionate pain. As such, without direction on content, communication might be most effective by focusing on relational aspects, such as emotional connection and trust. Clinical relevance: Although there is room to improve the content of strategies for explaining more pain than expected to patients, our findings extend the discoveries of others in highlighting the need for tailored relational communication strategies that prioritize feeling heard, validated, and accompanied.

Clinical orthopaedics and related research · 17 citationsread the source →

Trends in testing of sexually transmissible infections (STIs), sexual health knowledge and behaviours, and pornography use in cross-sectional samples of young people in Victoria, Australia, 2015-21.

Background: Sexually transmissible infections (STI) are prevalent and increasing among young Australians. This study examined trends in STI testing, sexual health knowledge/behaviours, and pornography use in young people aged 15- 29years in Victoria, Australia between 2015 and 2021. Methods: Seven online cross-sectional surveys were conducted in a convenience sample of young people, recruiting a total of 7014 participants (67% female). Logistic regression analyses determined trends over time in binary outcomes. Results: There was a decrease in reports of lifetime vaginal sex over time, while lifetime anal sex remained stable. Among those who had ever had vaginal sex, results showed an increase in the use of long-acting reversible contraceptives on the last occasion of vaginal sex. There was no change in STI testing or condom use with all partner types. Knowledge of STIs and sexual health changed over time: the proportion knowing that chlamydia can make women infertile decreased over time, while knowledge that taking the pill does not reduce fertility increased. There was no change in pornography use after adjusting for demographic variables. Conclusions: Although uptake of long-acting contraceptives increased, STI knowledge and testing, as well as consistent condom use, remained low. Public health interventions should continue to address these critical components of STI prevention.

Sexual health · 8 citationsread the source →

Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.

Background: Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods: We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings: In 2019, there were 12·2 million (95% UI 11·0-13·6) incident cases of stroke, 101 million (93·2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6·55 million (6·00-7·02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11·6% [10·8-12·2] of total deaths) and the third-leading cause of death and disability combined (5·7% [5·1-6·2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70·0% (67·0-73·0), prevalent strokes increased by 85·0% (83·0-88·0), deaths from stroke increased by 43·0% (31·0-55·0), and DALYs due to stroke increased by 32·0% (22·0-42·0). During the same period, age-standardised rates of stroke incidence decreased by 17·0% (15·0-18·0), mortality decreased by 36·0% (31·0-42·0), prevalence decreased by 6·0% (5·0-7·0), and DALYs decreased by 36·0% (31·0-42·0). However, among people younger than 70 years, prevalence rates increased by 22·0% (21·0-24·0) and incidence rates increased by 15·0% (12·0-18·0). In 2019, the age-standardised stroke-related mortality rate was 3·6 (3·5-3·8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3·7 (3·5-3·9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62·4% of all incident strokes in 2019 (7·63 million [6·57-8·96]), while intracerebral haemorrhage constituted 27·9% (3·41 million [2·97-3·91]) and subarachnoid haemorrhage constituted 9·7% (1·18 million [1·01-1·39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79·6 million [67·7-90·8] DALYs or 55·5% [48·2-62·0] of total stroke DALYs), high body-mass index (34·9 million [22·3-48·6] DALYs or 24·3% [15·7-33·2]), high fasting plasma glucose (28·9 million [19·8-41·5] DALYs or 20·2% [13·8-29·1]), ambient particulate matter pollution (28·7 million [23·4-33·4] DALYs or 20·1% [16·6-23·0]), and smoking (25·3 million [22·6-28·2] DALYs or 17·6% [16·4-19·0]). Interpretation: The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries. Funding: Bill & Melinda Gates Foundation.

The Lancet. Neurology · 5441 citationsread the source →

Cognitive decline in older adults in the UK during and after the COVID-19 pandemic: a longitudinal analysis of PROTECT study data.

Background: Although the long-term health effects of COVID-19 are increasingly recognised, the societal restrictions during the COVID-19 pandemic hold the potential for considerable detriment to cognitive and mental health, particularly because major dementia risk factors-such as those related to exercise and dietary habits-were affected during this period. We used longitudinal data from the PROTECT study to evaluate the effect of the pandemic on cognition in older adults in the UK. Methods: For this longitudinal analysis, we used computerised neuropsychology data from individuals aged 50 years and older participating in the PROTECT study in the UK. Data were collected from the same participants before the COVID-19 pandemic (March 1, 2019-Feb 29, 2020) and during its first (March 1, 2020-Feb 28, 2021) and second (March 1, 2021-Feb 28, 2022) years. We compared cognition across the three time periods using a linear mixed-effects model. Subgroup analyses were conducted in people with mild cognitive impairment and in people who reported a history of COVID-19, and an exploratory regression analysis identified factors associated with changes in cognitive trajectory. Findings: Pre-pandemic data were included for 3142 participants, of whom 1696 (54·0%) were women and 1446 (46·0%) were men, with a mean age of 67·5 years (SD 9·6, range 50-96). Significant worsening of executive function and working memory was observed in the first year of the pandemic across the whole cohort (effect size 0·15 [95% CI 0·12-0·17] for executive function and 0·51 [0·49-0·53] for working memory), in people with mild cognitive impairment (0·13 [0·07-0·20] and 0·40 [0·36-0·47]), and in people with a history of COVID-19 (0·24 [0·16-0·31] and 0·46 [0·39-0·53]). Worsening of working memory was sustained across the whole cohort in the second year of the pandemic (0·47; 0·44-0·49). Regression analysis indicated that cognitive decline was significantly associated with reduced exercise (p=0·0049; executive function) and increased alcohol use (p=0·049; working memory) across the whole cohort, as well as depression (p=0·011; working memory) in those with a history of COVID-19 and loneliness (p=0·0038; working memory) in those with mild cognitive impairment. In the second year of the pandemic, reduced exercise continued to affect executive function across the whole cohort, and associations were sustained between worsening working memory and increased alcohol use (p=0·0040), loneliness (p=0·042), and depression (p=0·014) in those with mild cognitive impairment, and reduced exercise (p=0·0029), loneliness (p=0·031) and depression (p=0·036) in those with a history of COVID-19. Interpretation: The COVID-19 pandemic resulted in a significant worsening of cognition in older adults, associated with changes in known dementia risk factors. The sustained decline in cognition highlights the need for public health interventions to mitigate the risk of dementia-particularly in people with mild cognitive impairment, in whom conversion to dementia within 5 years is a substantial risk. Long-term intervention for people with a history of COVID-19 should be considered to support cognitive health. Funding: National Institute for Health and Care Research.

The lancet. Healthy longevity · 43 citationsread the source →

Nowhere to hide: The significant impact of coronavirus disease 2019 (COVID-19) measures on elite and semi-elite South African athletes.

Objectives: To describe the perceptions of South African elite and semi-elite athletes on return to sport (RTS); maintenance of physical conditioning and other activities; sleep; nutrition; mental health; healthcare access; and knowledge of coronavirus disease 2019 (COVID-19). Design: Cross- sectional study. Methods: A Google Forms survey was distributed to athletes from 15 sports in the final phase (last week of April 2020) of the level 5 lockdown period. Descriptive statistics were used to describe player demographic data. Chi-squared tests investigated significance (p<0.05) between observed and expected values and explored sex differences. Post hoc tests with a Bonferroni adjustment were included where applicable. Results: 67% of the 692 respondents were males. The majority (56%) expected RTS after 1-6 months. Most athletes trained alone (61%; p<0.0001), daily (61%; p<0.0001) at moderate intensity (58%; p<0.0001) and for 30-60min (72%). During leisure time athletes preferred sedentary above active behaviour (p<0.0001). Sleep patterns changed significantly (79%; p<0.0001). A significant number of athletes consumed excessive amounts of carbohydrates (76%; p<0.0001; males 73%; females 80%). Many athletes felt depressed (52%), and required motivation to keep active (55%). Most had access to healthcare during lockdown (80%) and knew proceedings when suspecting COVID-19 (92%). Conclusions: COVID-19 had physical, nutritional and psychological consequences that may impact on the safe RTS and general health of athletes. Lost opportunities and uncertain financial and sporting futures may have significant effects on athletes and the sports industry. Government and sporting federations must support athletes and develop and implement guidelines to reduce the risk in a COVID-19 environment.

Journal of science and medicine in sport · 151 citationsread the source →

Degree of Self-Reported Facial Impairment Correlates with Social Impairment in Individuals with Facial Paralysis and Synkinesis.

Importance: Facial paralysis leads to both aesthetic and functional deficits placing patients at risk for sociopsychological sequelae and social impairment. Objective: To examine the effect of facial paralysis and synkinesis on social impairment and quality of life (QOL). Design, Setting, and Participants: This is a cross-sectional study at a tertiary care medical center. Adults with a history of facial palsy were broadly categorized by self-reported degree of facial paralysis and synkinesis. Main Outcomes and Measures: Clinical demographic information, self-reported degrees of facial paralysis and synkinesis, and facial palsy-specific QOL as measured by the Facial Clinimetric Evaluation (FaCE) Scale and the Synkinesis Assessment Questionnaire (SAQ) were collected. FaCE and SAQ scales were evaluated as predictors of social impairment outcomes, as measured by the Brief Fear of Negative Evaluation-II (BFNE-II), the Social Anxiety Questionnaire (SAQ-A30), and Social Avoidance and Distress (SAD) scales, in addition to health utility scores from the Short-Form 6D (SF-6D). Results: Fifty-six participants with facial palsy were included (30% male; average age: 56.4 [standard deviation (SD): 15] years). Sixty-three percent of participants reported history of Bell's palsy; 37% reported other etiologies. Forty-seven percent of participants reported moderate or severe facial impairment and 46% of participants reported involuntary facial movement. Participants with moderate or severe facial impairment exhibited increased BFNE-II (p = 0.03), SAQ-A30 (p = 0.04), and SAD (p < 0.01) scores and lower health valuation on SF-6D (p = 0.04). FaCE scores moderately correlated with lower health valuation (r = 0.39, p < 0.01), and moderately and inversely correlated with SAD (r = -0.33, p = 0.01) and BFNE-II (r = -0.35, p < 0.01) scores. Furthermore, worsening FaCE scores predicted worsening SAQ (p < 0.01), SAD (p = 0.01), BFNE-II (p < 0.01), and SF-6D (p < 0.01) scores. Worse degrees of synkinesis correlated with higher BFNE-II scores (r = 0.38, p < 0.01) and worsening SAQ scores predicted worsening FaCE (p < 0.01) and BFNE-II (p < 0.01) scores. Females demonstrated significantly worse BFNE-II scores (p = 0.04) when compared with men, and female gender significantly predicted worse FaCE scores (p < 0.01). Seventy-one percent of women with self-reported moderate or severe facial impairment met criteria for social anxiety, as did 67% of women with self-reported moderate or severe synkinesis. Conclusions and Relevance: Individuals with self-reported moderate or severe facial impairment exhibit a higher degree of social impairment and poorer health valuation than those with no or mild facial impairment. Facial palsy-specific QOL moderately and inversely correlated with social impairment and moderately correlated with health valuation. Our results indicate that FaCE scores may be used as a predictor of SAD, BFNE-II, and SF-6D scores and that facial palsy QOL and its relationship with social impairment should be considered when treating patients with a history of facial palsy.

Facial plastic surgery & aesthetic medicine · 32 citationsread the source →

Factors associated with mental health outcomes in a Muslim community following the Christchurch terrorist attack.

Background: On 15 March 2019, a white supremacist terrorist attacked two mosques in Christchurch, New Zealand. Fifty-one people were killed and another 40 sustained non-fatal gunshot injuries. Aims: To examine the mental health of the Muslim community, and individual and exposure-related factors associated with mental health outcomes. Method: This is the baseline analysis of a longitudinal study of adults from the Muslim community interviewed 11-32 months after the shootings. It included a diagnostic interview (MINI), measures of sociodemographic factors, prior mental health, prior traumatic events, exposure in the attacks, discrimination, life stressors, social support and religious coping. Logistic regression models examined associations with mental health outcomes. Results: The sample comprised 189 participants (mean age 41 (s.d. = 13); 60% female), and included: bereaved, 17% (n = 32); injured survivors 12% (n = 22); non-injured survivors, 19% (n = 36); family members of survivors, 35% (n = 67); and community members without the above exposures, 39% (n = 74). Overall, 61% had at least one mental disorder since the attacks. Those bereaved (P < 0.01, odds ratio 4.28, 95% CI 1.75-10.49) and survivors, whether injured (P < 0.001, odds ratio 18.08, 95% CI 4.70-69.60) or not (P < 0.01, odds ratio 5.26, 95% CI 1.99-13.89), had greater odds of post-traumatic stress disorder. Those bereaved (P < 0.001, odds ratio 5.79, 95% CI 2.49-13.46) or injured (P = 0.04, odds ratio 4.43, 95% CI 1.07-18.28) had greater odds of depression. Conclusions: Despite unique features of this attack on a Muslim population, findings accord with previous studies. They suggest generalisability of psychopathology after terror attacks, and that being bereaved or directly experiencing such events is associated with adverse mental health outcomes. Trial registration number: The study is registered on the Australian NZ Clinical Trials Registry (ACTRN12620000909921).

BJPsych open · 3 citationsread the source →

Cognitive ability at kindergarten entry and socioeconomic status.

Objective: To examine how gradients in socioeconomic status (SES) impact US children's reading and math ability at kindergarten entry and determine the contributions of family background, health, home learning, parenting, and early education factors to those gradients. Methods: Analysis of 6600 children with cognitive assessments at kindergarten entry from the US Early Childhood Longitudinal Birth Cohort Study. A composite SES measure based on parent's occupation, education, and income was divided into quintiles. Wald F tests assessed bivariate associations between SES and child's cognitive ability and candidate explanatory variables. A decomposition methodology examined mediators of early cognitive gradients. Results: Average reading percentile rankings increased from 34 to 67 across SES quintiles and math from 33 to 70. Children in lower SES quintiles had younger mothers, less frequent parent reading, less home computer use (27%-84%), and fewer books at home (26-114). Parent's supportive interactions, expectations for their child to earn a college degree (57%-96%), and child's preschool attendance (64%-89%) increased across quintiles. Candidate explanatory factors explained just over half the gradients, with family background factors explaining 8% to 13%, health factors 4% to 6%, home learning environment 18%, parenting style/beliefs 14% to 15%, and early education 6% to 7% of the gaps between the lowest versus highest quintiles in reading and math. Conclusions: Steep social gradients in cognitive outcomes at kindergarten are due to many factors. Findings suggest policies targeting levels of socioeconomic inequality and a range of early childhood interventions are needed to address these disparities.

Pediatrics · 65 citationsread the source →

Prevalence of job-related distress and satisfaction in a nationwide cardiology setting: The IANUS - itAliaN cardiologists' Undetected distress Study.

Introduction and objectives: Cardiologists' work distress has been seldom studied. The ItAliaN cardiologists' Undetected distress Study survey was designed to assess prevalence of work distress and satisfaction, and to gain insight into associations among these constructs and socio-demographics and job description. Methods: We invited members of our national cardiological society (Associazione Nazionale Medici Cardiologi Ospedalieri) to participate in an anonymous, self-report, exclusively web-based survey, posted on the Associazione Nazionale Medici Cardiologi Ospedalieri website. ItAliaN cardiologists' Undetected distress Study included socio-demographics, job description and a 15-item questionnaire on job-related distress and work satisfaction. Results: Of 7393 invited cardiologists, 1064 completed the survey. Organizational problems and worries about medico-legal controversies were reported by 71% and 49% of participants, respectively; over one-third reported loss of enthusiasm, helplessness, work-life imbalance and lack of control over work. Conversely, 86% felt competent at work, 67% rewarded by the moral/human meaning of their work and 52% satisfied with their professional fulfilment. Factor analysis revealed a meaningful underlying structure including four factors: job strain, positive meaning, emotional fatigue and relational difficulties. Relational difficulties were more frequent in cardiologists working in primary-level than in secondary and tertiary care hospitals (P = 0.017 and P = 0.013, respectively). Interventional cardiologists reported higher positive meaning than those in the clinical inpatients area and outpatient diagnostic settings (P = 0.007 and P = 0.025, respectively) and lower emotional fatigue than subjects in the clinical inpatients area (P = 0.0005). Conclusion: Cardiologists' work distress should be interpreted integrating job-related negative aspects with a reappraisal of protective personal and relational resources, which should be fostered to promote physicians' wellbeing at the individual, collective and organizational levels.

Journal of cardiovascular medicine (Hagerstown, Md.) · 5 citationsread the source →

Evaluation of Brain Alterations and Behavior in Children With Low Levels of Prenatal Alcohol Exposure.

Importance: High levels of prenatal alcohol exposure (PAE) are associated with widespread behavioral and cognitive problems as well as structural alterations of the brain. However, it remains unclear whether low levels of PAE affect brain structure and function, and prior studies generally have not had well-matched control populations (eg, for sociodemographic variables). Objective: To compare structural brain alterations and behavioral changes in children with lower levels of PAE with those of well-matched controls with no PAE. Design, setting, and participants: In this cross-sectional study, participants were selected from the Adolescent Brain Cognitive Development study. Children with PAE were compared with controls matched for age, sex, family income, maternal educational level, and caregiver status. Neither group had prenatal exposure to other adverse substances (eg, tobacco, cannabis, illicit drugs). Data were collected from September 1, 2016, to November 15, 2018, and analyzed from October 14, 2020, to February 14, 2022. Exposures: Diffusion tensor imaging, resting-state functional magnetic resonance imaging (MRI), and Child Behavior Checklist (CBCL) administration. Main outcomes and measures: Fractional anisotropy (FA); mean, axial, and radial diffusivity from diffusion tensor imaging; brain functional signal variations from functional MRI; and several scores, including internalizing and externalizing behavior problems, from the CBCL. Spearman correlation coefficients between diffusion tensor imaging and functional MRI measures and the CBCL scores were calculated. Results: A total of 270 children were included in the analysis (mean [SD] age, 9.86 [0.46] years; 141 female [52.2%] and 129 male [47.8%]), consisting of 135 children with PAE (mean [SD] age, 9.85 [0.65] years; 73 female [54.1%] and 62 male [45.9%]) (mean exposure, 1 drink/wk) and 135 unexposed controls (mean [SD] age, 9.87 [0.04] years; 68 female [50.4%] and 67 male [49.6%]). Children with PAE had lower mean (SD) FA in white matter of the left postcentral (0.35 [0.05] vs 0.36 [0.04]; mean difference, -0.02 [95% CI, -0.03 to -0.01]), left inferior parietal (0.31 [0.07] vs 0.33 [0.06]; mean difference, -0.03 [95% CI, -0.04 to -0.01]), left planum temporale (0.26 [0.04] vs 0.28 [0.03]; mean difference, -0.02 [95% CI, -0.03 to -0.01]), left inferior occipital (0.30 [0.07] vs 0.32 [0.05]; mean difference, -0.03 [95% CI, -0.04 to -0.01]), and right middle occipital (0.30 [0.04] vs 0.31 [0.04]; mean difference, -0.01 [95% CI, -0.02 to -0.01]) areas compared with controls, and higher FA in the gray matter of the putamen (0.22 [0.03] vs 0.21 [0.02]; mean difference, 0.01 [95% CI, 0.005-0.02]). Externalizing behavior scores were higher (worse) in children with PAE than in controls (mean [SD], 45.2 [9.0] vs 42.8 [9.0]; mean difference, 2.39 [95% CI, 0.30-4.47]). Several of these regions had significant group-behavior interactions, such that the higher FA was associated with less problematic behaviors in controls (ρ range, -0.24 to -0.08) but no associations were present in the PAE group (ρ range, 0.02-0.16). Conclusions and relevance: In this cross-sectional study, children with low levels of PAE had lower FA and more behavioral problems compared with a well-matched control group. These results suggest that PAE, even in small amounts, has a measurable effect on brain structure in children.

JAMA network open · 29 citationsread the source →

Prevalence and burden of headache in children and adolescents in Austria - a nationwide study in a representative sample of pupils aged 10-18 years.

Background: Headache disorders are highly prevalent worldwide, but not so well investigated in children and adolescents as in adults: few studies have included representative nationwide samples. No data exist for Austria until now. In a representative sample of children and adolescents in Austria, we estimated the prevalence and attributable burden of headache disorders, including the new diagnostic category of "undifferentiated headache" (UdH) defined as mild headache lasting less than 1 hour. Methods: Within the context of a broader national mental health survey, children and adolescents aged 10-18 years were recruited from purposively selected schools. Mediated self-completed questionnaires included sociodemographic enquiry (gender, age, socioeconomic status, family constellation, residence [urban or rural] and migration background). Prevalence and attributable burden of all headache, UdH, migraine (definite plus probable), tension-type headache (TTH: definite plus probable) and headache on ≥15 days/month (H15+) were assessed using the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire for children and adolescents. Health-related quality of life (HrQoL) was assessed using the KIDSCREEN questionnaire. Results: Of 7643 selected pupils, 3386 (44.3%) completed the questionnaires. The 1-year prevalence of headache was 75.7%, increasing with age and higher in girls (82.1%) than in boys (67.7%; p < 0.001). UdH, migraine, TTH and H15+ were reported by 26.1%, 24.2%, 21.6% and 3.0% of participants. Attributable burden was high, with 42% of those with headache experiencing restrictions in daily activities. Medication use (50% overall) was highest in H15+ (67%) and still considerable in UdH (29%). HrQoL was reduced for all headache types except UdH. Participants in single parent or patchwork families had a higher probability of migraine (respectively, OR 1.5, p < 0.001; OR 1.5, p < 0.01). Participants with a migration background had a lower probability of TTH (OR 0.7, p < 0.01). Conclusions: Headache disorders are both very common and highly burdensome in children and adolescents in Austria. This study contributes to the global atlas of headache disorders in these age groups, and corroborates and adds knowledge of the new yet common and important diagnostic category of UdH. The findings call for action in national and international health policies, and for further epidemiological research.

The journal of headache and pain · 90 citationsread the source →

Usability, Acceptability, Feasibility, and Effectiveness of a Gamified Mobile Health Intervention (Triumf) for Pediatric Patients: Qualitative Study.

Background: Mental disorders are notably prevalent in children with chronic illnesses, whereas a lack of access to psychological support might lead to potential mental health problems or disruptions in treatment. Digitally delivered psychological interventions have shown promising results as a supportive treatment measure for improving health outcomes during chronic illness. Objective: This study aimed to evaluate the usability, acceptability, and feasibility of providing psychological and treatment support in a clinical setting via a mobile game environment. In addition, the study aimed to evaluate the preliminary effectiveness of the mobile health game. Methods: Patients aged 7 to 14 years with less than a year from their diagnosis were eligible to participate in the study. In total, 15 patients were invited to participate by their doctor. A total of 9 patients (age range: 7-12 years; mean age 9.1 years) completed the 60-day-long study in which the Triumf mobile health game was delivered as a digital intervention. In an engaging game environment, patients were offered psychological and treatment support, cognitive challenges, and disease-specific information. The fully digital intervention was followed by a qualitative interview conducted by a trained psychologist. The results of the interview were analyzed in conjunction with patient specific in-game qualitative data. Ethical approval was obtained to conduct the study. Results: Patients positively perceived the game, resulting in high usability and acceptability evaluations. Participants unanimously described the game as easy to use and engaging in terms of gamified activities, while also providing beneficial and trustworthy information. Furthermore, the overall positive evaluation was emphasized by an observed tendency to carry on gaming post study culmination (67%, 10/15). Psychological support and mini games were the most often used components of the game, simultaneously the participants also highlighted the education module as one of the most preferred. On average, the patients sought and received psychological support or education on 66.6 occasions during the 60-day intervention. Participants spent the most time collecting items from the city environment (on average 15.6 days, SD 8.1), indicative of exploratory behavior, based on the quantitative in-game collected data. During the intervention period, we observed a statistically significant decrease in general health problems (P=.003) and saw a trend toward a decrease in depression and anxiety symptoms. Conclusions: This study demonstrated that a game environment could be a promising medium for delivering comprehensive supportive care to pediatric patients with cancer alongside standard treatment, with potential application across a variety of chronic conditions. Importantly, the results indicate that the study protocol was feasible with modifications to randomized controlled trials, and the game could be considered applicable in a clinical context. By giving an empirical evaluation of delivering psychological support via the game environment, our work stands to inform future mobile health interventions.

JMIR serious games · 26 citationsread the source →

Palliative care experience and perceived gaps in training among transplant hepatology fellows: A national survey.

Despite the likely benefits of palliative care (PC) for patients with cirrhosis, physician experiences and perspectives about best practices are variable. We aimed to assess PC experience and gaps in training among transplant hepatology fellows. We conducted a national survey of all transplant hepatology fellows enrolled in accredited fellowship programs during the 2020-2021 academic year. We assessed the frequency of PC provision and comfort with physical and psychological symptom management, psychosocial care, communication skills, advance care planning, and end-of-life care. A total of 45 of 56 (79%) of transplant hepatology fellows responded to the survey; 50% (n = 22) were female. Most trained at centers performing over 100 transplants per year (67%, n = 29) distributed evenly across geographic regions. Most fellows (69%, n = 31) had a PC or hospice care rotation during residency, and 42% (n = 19) of fellows received education in PC during transplant hepatology fellowship. Fellows reported feeling moderately to very comfortable with communication skills such as breaking bad news (93%, n = 41) and leading family meetings (75%, n = 33), but nearly one-third (30%, n = 13) reported feeling not very or not at all comfortable assessing and managing anxiety and depression (30%, n = 13) and spiritual distress (34%, n = 15). Nearly one-quarter (22%, n = 10) had never discussed or documented advance care plans during fellowship. Fellows wished to receive future instruction on the assessment and management of physical symptoms (68%, n = 30) and anxiety and depression (64%, n = 28). Conclusion: Our survey highlights gaps in PC experience and education during transplant hepatology fellowship, lack of comfort in managing psychological distress and advance care planning, and desire to improve skills, particularly in symptom management. Future studies should investigate how to enhance transplant hepatology competencies in these PC domains and whether this impacts clinical care, advance care planning, or patient experience.

Hepatology communications · 13 citationsread the source →

Roles of cyberbullying, sleep, and physical activity in mediating the effects of social media use on mental health and wellbeing among young people in England: a secondary analysis of longitudinal data.

Background: There is growing concern about the potential associations between social media use and mental health and wellbeing in young people. We explored associations between the frequency of social media use and later mental health and wellbeing in adolescents, and how these effects might be mediated. Methods: We did secondary analyses of publicly available data from the Our Futures study, a nationally representative, longitudinal study of 12 866 young people from age 13 years to 16 years in England. The exposure considered was the frequency of social media use (from weekly or less to very frequent [multiple times daily]) at wave 1 (participants aged 13-14 years) through wave 3 of the study (participants aged 15-16 years). Outcomes were mental health at wave 2 (with high 12-item General Health Questionnaire [GHQ12] scores [≥3] indicating psychological distress), and wellbeing at wave 3 (life satisfaction, feeling life is worthwhile, happiness, and anxiety, rated from 1 to 10 by participants). Analyses were adjusted for a minimal sufficient confounding structure, and were done separately for boys and girls. Cyberbullying, sleep adequacy, and physical activity were assessed as potential mediators of the effects. Findings: Very frequent use of social media increased from wave 1 to wave 3: from 34·4% (95% CI 32·4-36·4) to 61·9% (60·3-63·6) in boys, and 51·4% (49·5-53·3) to 75·4% (73·8-76·9) in girls. Very frequent social media use in wave 1 predicted a high GHQ12 score at wave 2 among girls (adjusted odds ratio [OR] 1·31 [95% CI 1·06-1·63], p=0·014; N=4429) and boys (1·67 [1·24-2·26], p=0·0009; N=4379). Persistent very frequent social media use across waves 1 and 2 predicted lower wellbeing among girls only (adjusted ORs 0·86 [0·74-0·99], N=3753, p=0·039 for life satisfaction; 0·80 [0·70-0·92], N=3831, p=0·0013 for happiness; 1·28 [1·11-1·48], N=3745, p=0·0007 for anxiety). Adjustment for cyberbullying, sleep, and physical activity attenuated the associations of social media use with GHQ12 high score (proportion mediated 58·2%), life satisfaction (80·1%), happiness (47·7%), and anxiety (32·4%) in girls, such that these associations (except for anxiety) were no longer significant; however, the association with GHQ12 high score among boys remained significant, being mediated only 12·1% by these factors. Interpretation: Mental health harms related to very frequent social media use in girls might be due to a combination of exposure to cyberbullying or displacement of sleep or physical activity, whereas other mechanisms appear to be operative in boys. Interventions to promote mental health should include efforts to prevent or increase resilience to cyberbullying and ensure adequate sleep and physical activity in young people. Funding: None.

The Lancet. Child & adolescent health · 131 citationsread the source →

Toyoko Kids: A case series on the psychosocial backgrounds of eight runaway girls transported to emergency care in Tokyo.

Aim: Runaway behavior, defined as leaving home without parental permission and not returning, is associated with adverse educational, physical, and mental health outcomes. In Japan, since around 2018, a group of runaway adolescents known as "Toyoko Kids" has emerged in Tokyo's Kabukicho area, reportedly engaging in substance use, violence, and prostitution. This study aimed to examine the psychosocial characteristics of Toyoko Kids who were transported to emergency care due to impaired consciousness from drug overdose or alcohol intoxication. Methods: We conducted a retrospective chart review of eight female adolescents under 18 years old, transported from Kabukicho to Keio University Hospital between June 2022 and August 2023. Inclusion criteria included having run away for at least two nights (or one night for those under 15) and being transported by a third party. A multidisciplinary team assessed psychosocial risks using a Bio-Psycho-Social model. Data on consciousness level, pregnancy, substance use, self-harm, psychiatric history, family structure, school attendance, abuse, and child welfare involvement were analyzed and compared with national statistics. Results: All subjects were female, aged 12-16. The most common reason for transport was impaired consciousness due to overdose, primarily involving over-the-counter medications. Self-harm was confirmed in 86% and abuse in 67% of cases. Although several had prior psychiatric or welfare intervention, support was often temporary and insufficient. Most came from single-parent households, and over half had a history of school absenteeism. Conclusions: This study identified severe psychosocial vulnerabilities among Toyoko Kids. Findings highlight gaps in mental health and child protection systems.

Pediatrics international : official journal of the Japan Pediatric Society · 1 citationsread the source →

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

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

Frontiers in Psychology · 12 citationsread the source →

The adult galactosemic phenotype.

Background: Classic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression. Methods: Thirty-three adults (mean age = 32.6 ± 11.7 years; range = 18-59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures. Results: The sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55-122). All subjects followed a dairy-free diet and 75-80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression. Conclusions: Taken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

Journal of inherited metabolic disease · 134 citationsread the source →

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

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

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

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 →

The structure of risk factors and outcomes for family caregivers: implications for assessment and treatment.

Purpose: We examined the associations among risk factors (e.g., behavioral problems, family conflict) and outcomes (e.g., overload, depression) commonly used in the research literature in order to inform the design of caregiver assessment and interventions. Methods: A sample of 67 caregivers caring for a family member in the middle stages of dementia were assessed on 15 risk factors and six outcome measures. Results: Risk factors were at best only moderately correlated with one another, suggesting their relative independence. Outcome measures showed somewhat higher correlations with one another, but participants varied in terms of the number and type of outcomes that were elevated. Multivariate results showed that risk factors differed in their contribution to models, predicting various outcomes. Implications: Caregivers possess unique combinations of risk factors and outcomes that suggest the need for individualized or tailored interventions. Designing an effective caregiver assessment and corresponding targeted intervention requires careful planning and selection of appropriate risk factors and outcomes.

Aging & mental health · 53 citationsread the source →

Prevalence of mental illness among homeless men in the community--approach to a full census in a southern German university town.

Aim: Within the framework of a study of homeless men in the university town of Tubingen in southern Germany, the prevalence of psychiatric disorders and the existing help-seeking behavior, among other things, were to be recorded. Method: A total of 151 men belonging to the target group were identified; 91 of them participated in the study. Besides the psychiatric diagnosis, the registered data included psychopathology, cognitive capacity, social functioning and satisfaction with life, as well as social history and case history. Results: Of the probands, 73% were suffering from at least one ongoing psychiatric disorder (diagnosed according to ICD-10 and DSM-IV), primarily alcohol dependence (74%) and drug dependence (34 %), 26% were suffering from an anxiety disorder, 15% from an affective disorder, and 11 % from a disorder of the schizophrenic spectrum. Comorbidity was diagnosed in 67%. Targeted help-seeking behavior concerning the psychiatric or addictive symptoms was extremely rare. Emergency contacts existed with hospitals and general practitioners. Discussion: This study represents the first attempt within Germany and Europe at a full census of homeless men. In international terms, the target region-a small town on the fringes of a conurbation-is a special case. However, compared with studies of help-seeking populations in large cities, virtually no differences were recorded with respect to the prevalence of psychiatric disorders or to help-seeking behavior concerning psychiatric problems and addictions. On the other hand, a substantial number of those concerned evade a resource-intensive, outreach-based study like the present one. Because of German data protection legislation, data on these subjects remain sparse. Concepts aimed at improving the health care system for this target group were found to be dependent in no small measure on the success of the initial contact.

Social psychiatry and psychiatric epidemiology · 20 citationsread the source →

The prevalence of post-traumatic stress disorder (PTSD) in US combat soldiers: a head-to-head comparison of DSM-5 versus DSM-IV-TR symptom criteria with the PTSD checklist.

Background: The definition of post-traumatic stress disorder (PTSD) underwent substantial changes in the 2013 edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). How this will affect estimates of prevalence, whether clinical utility has been improved, and how many individuals who meet symptom criteria according to the previous definition will not meet new criteria is unknown. Updated screening instruments, including the PTSD checklist (PCL), have not been compared with previously validated methods through head-to-head comparisons. Methods: We compared the new 20-item PCL, mapped to DSM-5 (PCL-5), with the original validated 17-item specific stressor version (PCL-S) in 1822 US infantry soldiers, including 946 soldiers who had been deployed to Iraq or Afghanistan. Surveys were administered in November, 2013. Soldiers alternately received either of two surveys that were identical except for the order of the two PCL versions (911 per group). Standardised scales measured major depression, generalised anxiety, alcohol misuse, and functional impairment. Results: In analysis of all soldiers, 224 (13%) screened positive for PTSD by DSM-IV-TR criteria and 216 (12%) screened positive by DSM-5 criteria (κ 0·67). In soldiers exposed to combat, 177 (19%) screened positive by DSM-IV-TR and 165 (18%) screened positive by DSM-5 criteria (0·66). However, of 221 soldiers with complete data who met DSM-IV-TR criteria, 67 (30%) did not meet DSM-5 criteria, and 59 additional soldiers met only DSM-5 criteria. PCL-5 scores from 15-38 performed similarly to PCL-S scores of 30-50; a PCL-5 score of 38 gave optimum agreement with a PCL-S of 50. The two definitions showed nearly identical association with other psychiatric disorders and functional impairment. Conclusions: Our findings showed the PCL-5 to be equivalent to the validated PCL-S. However, the new PTSD symptom criteria do not seem to have greater clinical utility, and a high percentage of soldiers who met criteria by one definition did not meet the other criteria. Clinicians need to consider how to manage discordant outcomes, particularly for service members and veterans with PTSD who no longer meet criteria under DSM-5. Funding: US Army Military Operational Medicine Research Program (MOMRP), Fort Detrick, MD.

The lancet. Psychiatry · 230 citationsread the source →

Health-seeking behaviour of male foreign migrant workers living in a dormitory in Singapore.

Background: Foreign workers' migrant status may hinder their utilisation of health services. This study describes the health-seeking behaviour and beliefs of a group of male migrant workers in Singapore and the barriers limiting their access to primary healthcare. Methods: A cross-sectional study of 525 male migrant workers, ≥ 21 years old and of Indian, Bangladeshi or Myanmar nationality, was conducted at a dormitory via self-administered questionnaires covering demographics, prevalence of medical conditions and health-seeking behaviours through hypothetical scenarios and personal experience. Results: 71% (95%CI: 67 to 75%) of participants did not have or were not aware if they had healthcare insurance. 53% (95%CI: 48 to 57%) reported ever having had an illness episode while in Singapore, of whom 87% (95%CI: 82 to 91%) saw a doctor. The number of rest days was significantly associated with higher probability of having consulted a doctor for their last illness episode (p = 0.026), and higher basic monthly salary was associated with seeing a doctor within 3 days of illness (p = 0.002). Of those who saw a doctor, 84% (95%CI: 79 to 89%) responded that they did so because they felt medical care would help them to work better. While 55% (95%CI: 36 to 73%) said they did not see a doctor because the illness was not serious, those with lower salaries were significantly more likely to cite inadequate finances (55% of those earning < S$500/month). In hypothetical injury or illness scenarios, most responded that they would see the doctor, but a sizeable proportion (15% 95%CI: 12 to 18%) said they would continue to work even in a work-related injury scenario that caused severe pain and functional impairment. Those with lower salaries were significantly more likely to believe they would have to pay for their own healthcare or be uncertain about who would pay. Conclusions: The majority of foreign workers in this study sought healthcare when they fell ill. However, knowledge about health-related insurance was poor and a sizeable minority, in particular those earning < S$500 per month, may face significant issues in accessing care.

BMC health services research · 38 citationsread the source →