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A 12-week double-blind, placebo-controlled study of bupropion sr added to high-dose dual nicotine replacement therapy for smoking cessation or reduction in schizophrenia.

The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy (NRT) and weekly group cognitive behavioral therapy (CBT) for smoking reduction or cessation in schizophrenia. Fifty-one adult smokers with schizophrenia were randomly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch, nicotine polacrilex gum, and CBT. The treatment goal was smoking cessation. The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50% to 100% smoking reduction at week 12. Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide (CO) and psychiatric symptoms. Subjects on bupropion + NRT had a greater rate of 50% to 100% smoking reduction at weeks 12 (60% vs. 31%; P = 0.036) and 24, a lower expired air CO in the treatment and follow-up periods, (F = 13.8; P < 0.001) and a greater continuous abstinence rate at week 8, before NRT taper, (52% vs. 19%; P = 0.014). However, relapse rates in subjects on bupropion + dual NRT were 31% during NRT taper (weeks 8-12) and 77% at the 12-month follow-up. Abstinence rates did not differ by treatment group at weeks 12 (36% vs. 19%), 24 (20% vs. 8%), or 52 (12% vs. 8%). Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment, study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention.

Journal of clinical psychopharmacology · randomised controlled trial · 112 citationsread the source →

Combined pharmacotherapy and behavioural interventions for smoking cessation.

Background: Both behavioural support (including brief advice and counselling) and pharmacotherapies (including nicotine replacement therapy (NRT), varenicline and bupropion) are effective in helping people to stop smoking. Combining both treatment approaches is recommended where possible, but the size of the treatment effect with different combinations and in different settings and populations is unclear. Objectives: To assess the effect of combining behavioural support and medication to aid smoking cessation, compared to a minimal intervention or usual care, and to identify whether there are different effects depending on characteristics of the treatment setting, intervention, population treated, or take-up of treatment. Search methods: We searched the Cochrane Tobacco Addiction Group Specialised Register in July 2015 for records with any mention of pharmacotherapy, including any type of NRT, bupropion, nortriptyline or varenicline. Selection criteria: Randomized or quasi-randomized controlled trials evaluating combinations of pharmacotherapy and behavioural support for smoking cessation, compared to a control receiving usual care or brief advice or less intensive behavioural support. We excluded trials recruiting only pregnant women, trials recruiting only adolescents, and trials with less than six months follow-up. Data collection and analysis: Search results were prescreened by one author and inclusion or exclusion of potentially relevant trials was agreed by two authors. Data was extracted by one author and checked by another. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. We calculated the risk ratio (RR) and 95% confidence interval (CI) for each study. Where appropriate, we performed meta-analysis using a Mantel-Haenszel fixed-effect model. Main results: Fifty-three studies with a total of more than 25,000 participants met the inclusion criteria. A large proportion of studies recruited people in healthcare settings or with specific health needs. Most studies provided NRT. Behavioural support was typically provided by specialists in cessation counselling, who offered between four and eight contact sessions. The planned maximum duration of contact was typically more than 30 minutes but less than 300 minutes. Overall, studies were at low or unclear risk of bias, and findings were not sensitive to the exclusion of any of the six studies rated at high risk of bias in one domain. One large study (the Lung Health Study) contributed heterogeneity due to a substantially larger treatment effect than seen in other studies (RR 3.88, 95% CI 3.35 to 4.50). Since this study used a particularly intensive intervention which included extended availability of nicotine gum, multiple group sessions and long term maintenance and recycling contacts, the results may not be comparable with the interventions used in other studies, and hence it was not pooled in other analyses. Based on the remaining 52 studies (19,488 participants) there was high quality evidence (using GRADE) for a benefit of combined pharmacotherapy and behavioural treatment compared to usual care, brief advice or less intensive behavioural support (RR 1.83, 95% CI 1.68 to 1.98) with moderate statistical heterogeneity (I² = 36%).The pooled estimate for 43 trials that recruited participants in healthcare settings (RR 1.97, 95% CI 1.79 to 2.18) was higher than for eight trials with community-based recruitment (RR 1.53, 95% CI 1.33 to 1.76). Compared to the first version of the review, previous weak evidence of differences in other subgroup analyses has disappeared. We did not detect differences between subgroups defined by motivation to quit, treatment provider, number or duration of support sessions, or take-up of treatment. Authors' conclusions: Interventions that combine pharmacotherapy and behavioural support increase smoking cessation success compared to a minimal intervention or usual care. Updating this review with an additional 12 studies (5,000 participants) did not materially change the effect estimate. Although trials differed in the details of their populations and interventions, we did not detect any factors that modified treatment effects apart from the recruitment setting. We did not find evidence from indirect comparisons that offering more intensive behavioural support was associated with larger treatment effects.

The Cochrane database of systematic reviews · meta-analysis · 337 citationsread the source →

Randomised, controlled, open-label pragmatic trial evaluating changes in functional exercise capacity after primary care PUlmonary REhabilitation in patients with long COVID: protocol of the PuRe-COVID trial in Belgium.

Introduction: Long COVID is a prevalent condition with many multisystemic symptoms, such as fatigue, dyspnoea, muscle weakness, anxiety, depression and sleep difficulties, impacting daily life and (social and physical) functioning. Pulmonary rehabilitation (PR) may improve physical status and symptoms of patients with long COVID, yet the evidence is limited. Therefore, this trial aims to study the effect of primary care PR on exercise capacity, symptoms, physical activity and sleep in patients with long COVID. Methods and analysis: PuRe-COVID is a prospective, pragmatic, open-label, randomised controlled trial. A sample of 134 adult patients with long COVID will be randomised to a 12 week PR programme in primary care, supervised by a physiotherapist or to a control group, following no PR. A 3 month and 6 month follow-up period is foreseen. The primary endpoint will be the change in exercise capacity measured by 6-minute walk distance (6MWD) at 12 weeks, hypothesising a more significant improvement in the PR group. Other parameters, such as pulmonary function tests (including maximal inspiratory pressure/maximal expiratory pressure), patient-reported outcomes (COPD Assessment Test, modified Medical Research Council Dyspnoea Scale, Checklist Individual Strength, post-COVID-19 Functional Status, Nijmegen questionnaire, Hospital Anxiety and Depression Scale, Work Productivity and Activity Impairment Questionnaire and EuroQol-5D-5L), physical activity measured by an activity tracker, hand grip strength and sleep efficiency, are secondary and exploratory outcomes. The recruitment started on 19 April 2022, and 52 patients were included as of 14 December 2022. Ethics and dissemination: Ethical approval was obtained in Belgium from the relevant institutional review boards on 21 February 2022 (Antwerp University Hospital, approval number 2022-3067) and on 1 April 2022 (Ziekenhuis Oost-Limburg in Genk, approval number Z-2022-01). Findings from this randomised controlled trial will be disseminated in peer-reviewed publications and presentations at international scientific meetings. Trial registration number: NCT05244044.

BMJ open · clinical trial · 6 citationsread the source →

The Healthy Activity Program (HAP), a lay counsellor-delivered brief psychological treatment for severe depression, in primary care in India: a randomised controlled trial.

Background: Although structured psychological treatments are recommended as first-line interventions for depression, only a small fraction of people globally receive these treatments because of poor access in routine primary care. We assessed the effectiveness and cost-effectiveness of a brief psychological treatment (Healthy Activity Program [HAP]) for delivery by lay counsellors to patients with moderately severe to severe depression in primary health-care settings. Methods: In this randomised controlled trial, we recruited participants aged 18-65 years scoring more than 14 on the Patient Health Questionnaire 9 (PHQ-9) indicating moderately severe to severe depression from ten primary health centres in Goa, India. Pregnant women or patients who needed urgent medical attention or were unable to communicate clearly were not eligible. Participants were randomly allocated (1:1) to enhanced usual care (EUC) alone or EUC combined with HAP in randomly sized blocks (block size four to six [two to four for men]), stratified by primary health centre and sex, and allocation was concealed with use of sequential numbered opaque envelopes. Physicians providing EUC were masked. Primary outcomes were depression symptom severity on the Beck Depression Inventory version II and remission from depression (PHQ-9 score of <10) at 3 months in the intention-to-treat population, assessed by masked field researchers. Secondary outcomes were disability, days unable to work, behavioural activation, suicidal thoughts or attempts, intimate partner violence, and resource use and costs of illness. We assessed serious adverse events in the per-protocol population. This trial is registered with the ISRCTN registry, number ISRCTN95149997. Findings: Between Oct 28, 2013, and July 29, 2015, we enrolled and randomly allocated 495 participants (247 [50%] to the EUC plus HAP group [two of whom were subsequently excluded because of protocol violations] and 248 [50%] to the EUC alone group), of whom 466 (95%) completed the 3 month primary outcome assessment (230 [49%] in the EUC plus HAP group and 236 [51%] in the EUC alone group). Participants in the EUC plus HAP group had significantly lower symptom severity (Beck Depression Inventory version II in EUC plus HAP group 19·99 [SD 15·70] vs 27·52 [13·26] in EUC alone group; adjusted mean difference -7·57 [95% CI -10·27 to -4·86]; p<0·0001) and higher remission (147 [64%] of 230 had a PHQ-9 score of <10 in the HAP plus EUC group vs 91 [39%] of 236 in the EUC alone group; adjusted prevalence ratio 1·61 [1·34-1·93]) than did those in the EUC alone group. EUC plus HAP showed better results than did EUC alone for the secondary outcomes of disability (adjusted mean difference -2·73 [-4·39 to -1·06]; p=0·001), days out of work (-2·29 [-3·84 to -0·73]; p=0·004), intimate partner physical violence in women (0·53 [0·29-0·96]; p=0·04), behavioural activation (2·17 [1·34-3·00]; p<0·0001), and suicidal thoughts or attempts (0·61 [0·45-0·83]; p=0·001). The incremental cost per quality-adjusted life-year gained was $9333 (95% CI 3862-28 169; 2015 international dollars), with an 87% chance of being cost-effective in the study setting. Serious adverse events were infrequent and similar between groups (nine [4%] in the EUC plus HAP group vs ten [4%] in the EUC alone group; p=1·00). Interpretation: HAP delivered by lay counsellors plus EUC was better than EUC alone was for patients with moderately severe to severe depression in routine primary care in Goa, India. HAP was readily accepted by this previously untreated population and was cost-effective in this setting. HAP could be a key strategy to reduce the treatment gap for depressive disorders, the leading mental health disorder worldwide. Funding: Wellcome Trust.

Lancet (London, England) · randomised controlled trial · 295 citationsread the source →

Charitable donations and the theory of planned behaviour: A systematic review and meta-analysis.

Given the predominance of the theory of planned behaviour (TPB) to represent the psychological determinants underlying people's charitable decisions, the present study synthesised the model's key relationships, using meta-analysis, and tested the predictive utility of the model for charitable giving encompassing donations of blood, organs, time, and money. Given its relevance to altruistic decisions, the impact of moral norm was assessed also. A systematic literature review identified 117 samples (from 104 studies) examining donation intentions and/or prospective behaviour using TPB measures. The sample-weighted average effects for all associations were moderate-to-strong with perceived behavioural control (PBC) most strongly associated with intention (r+ = 0.562), followed by moral norm (r+ = 0.537), attitude (r+ = 0.507), and subjective norm (r+ = 0.472). Intention (r+ = 0.424) showed stronger associations with prospective behaviour than PBC (r+ = 0.301). The standard TPB predictors explained 44% of variance in intention (52% including moral norm). Intention and PBC explained 19% of variance in behaviour. A number of TPB associations showed differences when analysed for moderator variables such as length of follow-up for prospective behaviour and type of target behaviour. Stronger associations were found for the (subjective and moral) norm-intention associations among some of the different types of giving behaviours, especially for donating organs and time. Overall, the large proportion of variance explained by the TPB predictors especially for intention highlights those cognitions associated with people's plans to give, informative for charities reliant on people's propensity to give.

PloS one · meta-analysis · 6 citationsread the source →

Secular trends in self reported sexual activity and satisfaction in Swedish 70 year olds: cross sectional survey of four populations, 1971-2001.

Objective: To study secular trends in self reported sexual behaviour among 70 year olds. Design: Cross sectional survey. Settings Four samples representative of the general population in Gothenburg, Sweden. Participants: 1506 adults (946 women, 560 men) examined in 1971-2, 1976-7, 1992-3, and 2000-1. Main outcome measures: Sexual intercourse, attitudes to sexuality in later life, sexual dysfunctions, and marital satisfaction. Results: From 1971 to 2000 the proportion of 70 year olds reporting sexual intercourse increased among all groups: married men from 52% to 68% (P=0.002), married women from 38% to 56% (P=0.001), unmarried men from 30% to 54% (P=0.016), and unmarried women from 0.8% to 12% (P<0.001). Men and women from later birth cohorts reported higher satisfaction with sexuality, fewer sexual dysfunctions, and more positive attitudes to sexuality in later life than those from earlier birth cohorts. A larger proportion of men (57% v 40%, P<0.001) and women (52% v 35%, P<0.001) reported very happy relationships in 2000-1 compared with those in 1971-2. Sexual debut before age 20 increased in both sexes: in men from 52% to 77% (P<0.001) and in women from 19% to 64% (P<0.001). Conclusion: Self reported quantity and quality of sexual experiences among Swedish 70 year olds has improved over a 30 year period.

BMJ (Clinical research ed.) · cohort or longitudinal · 123 citationsread the source →

Uncertainty in Transition of African American Caregivers.

The purpose of this study was to gain an understanding of the ambiguities and uncertainties experienced by a diverse group of African-American caregivers. The study applied Schlossberg's transition theory (TT) and Mishel's revised uncertainty theory to narratives of self-identified African-American caregivers who provided care at least 5 h a week. The men (6) and women (8) were mostly unmarried, mostly caring for a parent or grandparent. The caregivers' average age was 52 (SD = 19; ages ranged from 24 to 82 years); and the care recipients' average age was 84 (SD = 9). Six care recipients had dementia and the remainder had multiple disease diagnoses. Narratives were obtained by in-depth interviews or focus group discussions. These were audio-recorded, transcribed verbatim professionally and analyzed independently by trained coders. Schlossberg's TT contextualized whereas Mishel's RUIT illuminated the characteristics of the transition, its associated uncertainty, and their relationship to the development of caregiver stress. Situational factors such as difficulties with illness symptoms of the care recipient, conflict between previous experience and current expectations and the adjustments to the new caregiving role, burdened younger caregivers more than older caregivers. Self-factors related to lack of knowledge about the illness and feelings of lack of control. Social support was predominantly provided by family members, and its absence resulted in conflict among siblings and caregiver stress. The most common coping strategies include religiosity, expectations of reciprocity, and coming to terms with the uncertainty. Understanding the feelings, perceptions and needs of caregivers in transition is tantamount to providing nursing care.

Issues in mental health nursing · 4 citationsread the source →

The effects of psychological meaning-centered therapies on quality of life and psychological stress: A metaanalysis.

ABSTRACTObjective:Many psychotherapists speak with clients about meaning in life. Meaning is an neutral evidence-based term for a subjective sense of purpose, values, understanding, self-worth, action-directed goals, and self-regulation. Since little is known about its effectiveness, our study aimed to determine the effects of meaning-centered therapies (MCTs) on improving quality of life and reducing psychological stress. Method: Independent researchers selected and scored articles in multiple languages in multiple search engines. Weighted pooled mean effects were calculated following a random-effects model. Sensitivity analyses included moderators, study and sample characteristics, risk of bias, randomization, types of MCT, control condition, and outcome instruments. Results: Some 52,220 citations included 60 trials (total sample N = 3,713), of which 26 were randomized controlled trials (N = 1,975), 15 nonrandomized controlled trials (N = 709), and 19 nonrandomized noncontrolled trials with pre/post measurements (N = 1,029). Overall analyses showed large improvements from baseline to immediate posttreatment and follow-up on quality of life (Hedges' g = 1.13, SE = 0.12; g = 0.99, SE = 0.20) and psychological stress (g = 1.21, SE = 0.10; g = 0.67, SE = 0.20). As effects varied between studies, further analyses focused only on controlled trials: MCT had large effect sizes compared to control groups, both immediate and at follow-up, on quality of life (g = 1.02, SE = 0.06; g = 1.06, SE = 0.12) and psychological stress (g = 0.94, SE = 0.07, p < 0.01; g = 0.84, SE = 0.10). Immediate effects were larger for general quality of life (g = 1.37, SE = 0.12) than for meaning in life (g = 1.18, SE = 0.08), hope and optimism (g = 0.80, SE = 0.13), self-efficacy (g = 0.89, SE = 0.14), and social well-being (g = 0.81, SE = 13). The homogeneity of these results was validated by the lack of significance of moderators and alternative ways of selecting studies. Metaregression analyses showed that increases in meaning in life predicted decreases in psychological stress (β = -0.56, p < 0.001). Significance of results: MCT strongly improves quality of life and reduces psychological stress. MCT should be made more widely available, particularly to individuals in transitional moments in life or with a chronic or life-threatening physical illness as they explicitly report meaning-centered concerns.

Palliative & supportive care · meta-analysis · 72 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 →

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 May 2019 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 81 studies (69,094 participants), five of which are new to this update. We judged 22 studies to be at high risk of bias, 53 to be at unclear risk of bias, and six studies to be at low risk of bias. Fifty studies included abstainers, and 30 studies helped people to quit and then tested treatments to prevent relapse. Twenty-eight studies focused on special populations who were abstinent because of pregnancy (19 studies), hospital admission (six 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 the 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 (5 studies, n = 1385, RR 1.10, 95% CI 0.82 to 1.47, I2 = 58%), and studies in assisted abstainers (11 studies, n = 5523, RR 0.98, 95% CI 0.87 to 1.11, I2 = 52%; 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 · 37 citationsread the source →

Psychological interventions for antisocial personality disorder.

Background: Antisocial personality disorder (AsPD) is associated with poor mental health, criminality, substance use and relationship difficulties. This review updates Gibbon 2010 (previous version of the review). Objectives: To evaluate the potential benefits and adverse effects of psychological interventions for adults with AsPD. Search methods: We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also searched reference lists and contacted study authors to identify studies. Selection criteria: Randomised controlled trials of adults, where participants with an AsPD or dissocial personality disorder diagnosis comprised at least 75% of the sample randomly allocated to receive a psychological intervention, treatment-as-usual (TAU), waiting list or no treatment. The primary outcomes were aggression, reconviction, global state/functioning, social functioning and adverse events. Data collection and analysis: We used standard methodological procedures expected by Cochrane. Main results: This review includes 19 studies (eight new to this update), comparing a psychological intervention against TAU (also called 'standard Maintenance'(SM) in some studies). Eight of the 18 psychological interventions reported data on our primary outcomes. Four studies focussed exclusively on participants with AsPD, and 15 on subgroups of participants with AsPD. Data were available from only 10 studies involving 605 participants. Eight studies were conducted in the UK and North America, and one each in Iran, Denmark and the Netherlands. Study duration ranged from 4 to 156 weeks (median = 26 weeks). Most participants (75%) were male; the mean age was 35.5 years. Eleven studies (58%) were funded by research councils. Risk of bias was high for 13% of criteria, unclear for 54% and low for 33%. Cognitive behaviour therapy (CBT) + TAU versus TAU One study (52 participants) found no evidence of a difference between CBT + TAU and TAU for physical aggression (odds ratio (OR) 0.92, 95% CI 0.28 to 3.07; low-certainty evidence) for outpatients at 12 months post-intervention. One study (39 participants) found no evidence of a difference between CBT + TAU and TAU for social functioning (mean difference (MD) -1.60 points, 95% CI -5.21 to 2.01; very low-certainty evidence), measured by the Social Functioning Questionnaire (SFQ; range = 0-24), for outpatients at 12 months post-intervention. Impulsive lifestyle counselling (ILC) + TAU versus TAU One study (118 participants) found no evidence of a difference between ILC + TAU and TAU for trait aggression (assessed with Buss-Perry Aggression Questionnaire-Short Form) for outpatients at nine months (MD 0.07, CI -0.35 to 0.49; very low-certainty evidence). One study (142 participants) found no evidence of a difference between ILC + TAU and TAU alone for the adverse event of death (OR 0.40, 95% CI 0.04 to 4.54; very low-certainty evidence) or incarceration (OR 0.70, 95% CI 0.27 to 1.86; very low-certainty evidence) for outpatients between three and nine months follow-up. Contingency management (CM) + SM versus SM One study (83 participants) found evidence that, compared to SM alone, CM + SM may improve social functioning measured by family/social scores on the Addiction Severity Index (ASI; range = 0 (no problems) to 1 (severe problems); MD -0.08, 95% CI -0.14 to -0.02; low-certainty evidence) for outpatients at six months. 'Driving whilst intoxicated' programme (DWI) + incarceration versus incarceration One study (52 participants) found no evidence of a difference between DWI + incarceration and incarceration alone on reconviction rates (hazard ratio 0.56, CI -0.19 to 1.31; very low-certainty evidence) for prisoner participants at 24 months. Schema therapy (ST) versus TAU One study (30 participants in a secure psychiatric hospital, 87% had AsPD diagnosis) found no evidence of a difference between ST and TAU for the number of participants who were reconvicted (OR 2.81, 95% CI 0.11 to 74.56, P = 0.54) at three years. The same study found that ST may be more likely to improve social functioning (assessed by the mean number of days until patients gain unsupervised leave (MD -137.33, 95% CI -271.31 to -3.35) compared to TAU, and no evidence of a difference between the groups for overall adverse events, classified as the number of people experiencing a global negative outcome over a three-year period (OR 0.42, 95% CI 0.08 to 2.19). The certainty of the evidence for all outcomes was very low. Social problem-solving (SPS) + psychoeducation (PE) versus TAU One study (17 participants) found no evidence of a difference between SPS + PE and TAU for participants' level of social functioning (MD -1.60 points, 95% CI -5.43 to 2.23; very low-certainty evidence) assessed with the SFQ at six months post-intervention. Dialectical behaviour therapy versus TAU One study (skewed data, 14 participants) provided very low-certainty, narrative evidence that DBT may reduce the number of self-harm days for outpatients at two months post-intervention compared to TAU. Psychosocial risk management (PSRM; 'Resettle') versus TAU One study (skewed data, 35 participants) found no evidence of a difference between PSRM and TAU for a number of officially recorded offences at one year after release from prison. It also found no evidence of difference between the PSRM and TAU for the adverse event of death during the study period (OR 0.89, 95% CI 0.05 to 14.83, P = 0.94, 72 participants (90% had AsPD), 1 study, very low-certainty evidence). Authors' conclusions: There is very limited evidence available on psychological interventions for adults with AsPD. Few interventions addressed the primary outcomes of this review and, of the eight that did, only three (CM + SM, ST and DBT) showed evidence that the intervention may be more effective than the control condition. No intervention reported compelling evidence of change in antisocial behaviour. Overall, the certainty of the evidence was low or very low, meaning that we have little confidence in the effect estimates reported. The conclusions of this update have not changed from those of the original review, despite the addition of eight new studies. This highlights the ongoing need for further methodologically rigorous studies to yield further data to guide the development and application of psychological interventions for AsPD and may suggest that a new approach is required.

The Cochrane database of systematic reviews · meta-analysis · 32 citationsread the source →

Health impacts of parental migration on left-behind children and adolescents: a systematic review and meta-analysis.

Background: Globally, a growing number of children and adolescents are left behind when parents migrate. We investigated the effect of parental migration on the health of left behind-children and adolescents in low-income and middle-income countries (LMICs). Methods: For this systematic review and meta-analysis we searched MEDLINE, Embase, CINAHL, the Cochrane Library, Web of Science, PsychINFO, Global Index Medicus, Scopus, and Popline from inception to April 27, 2017, without language restrictions, for observational studies investigating the effects of parental migration on nutrition, mental health, unintentional injuries, infectious disease, substance use, unprotected sex, early pregnancy, and abuse in left-behind children (aged 0-19 years) in LMICs. We excluded studies in which less than 50% of participants were aged 0-19 years, the mean or median age of participants was more than 19 years, fewer than 50% of parents had migrated for more than 6 months, or the mean or median duration of migration was less than 6 months. We screened studies using systematic review software and extracted summary estimates from published reports independently. The main outcomes were risk and prevalence of health outcomes, including nutrition (stunting, wasting, underweight, overweight and obesity, low birthweight, and anaemia), mental health (depressive disorder, anxiety disorder, conduct disorders, self-harm, and suicide), unintentional injuries, substance use, abuse, and infectious disease. We calculated pooled risk ratios (RRs) and standardised mean differences (SMDs) using random-effects models. This study is registered with PROSPERO, number CRD42017064871. Findings: Our search identified 10 284 records, of which 111 studies were included for analysis, including a total of 264 967 children (n=106 167 left-behind children and adolescents; n=158 800 children and adolescents of non-migrant parents). 91 studies were done in China and focused on effects of internal labour migration. Compared with children of non-migrants, left-behind children had increased risk of depression and higher depression scores (RR 1·52 [95% CI 1·27-1·82]; SMD 0·16 [0·10-0·21]), anxiety (RR 1·85 [1·36-2·53]; SMD 0·18 [0·11-0·26]), suicidal ideation (RR 1·70 [1·28-2·26]), conduct disorder (SMD 0·16 [0·04-0·28]), substance use (RR 1·24 [1·00-1·52]), wasting (RR 1·13 [1·02-1·24]) and stunting (RR 1·12 [1·00-1·26]). No differences were identified between left-behind children and children of non-migrants for other nutrition outcomes, unintentional injury, abuse, or diarrhoea. No studies reported outcomes for other infectious diseases, self-harm, unprotected sex, or early pregnancy. Study quality varied across the included studies, with 43% of studies at high or unclear risk of bias across five or more domains. Interpretation: Parental migration is detrimental to the health of left-behind children and adolescents, with no evidence of any benefit. Policy makers and health-care professionals need to take action to improve the health of these young people. Funding: Wellcome Trust.

Lancet (London, England) · meta-analysis · 330 citationsread the source →

Robot-based hand motor therapy after stroke.

Robots can improve motor status after stroke with certain advantages, but there has been less emphasis to date on robotic developments for the hand. The goal of this study was to determine whether a hand-wrist robot would improve motor function, and to evaluate the specificity of therapy effects on brain reorganization. Subjects with chronic stroke producing moderate right arm/hand weakness received 3 weeks therapy that emphasized intense active movement repetition as well as attention, speed, force, precision and timing, and included virtual reality games. Subjects initiated hand movements. If necessary, the robot completed movements, a feature available at all visits for seven of the subjects and at the latter half of visits for six of the subjects. Significant behavioural gains were found at end of treatment, for example, in Action Research Arm Test (34 +/- 20 to 38 +/- 19, P< 0.0005) and arm motor Fugl-Meyer score (45 +/- 10 to 52 +/- 10, P < 0.0001). Results suggest greater gains for subjects receiving robotic assistance in all sessions as compared to those receiving robotic assistance in half of sessions. The grasp task practiced during robotic therapy, when performed during functional MRI, showed increased sensorimotor cortex activation across the period of therapy, while a non-practiced task, supination/pronation, did not. A robot-based therapy showed improvements in hand motor function after chronic stroke. Reorganization of motor maps during the current therapy was task-specific, a finding useful when considering generalization of rehabilitation therapy.

Brain : a journal of neurology · randomised controlled trial · 278 citationsread the source →

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

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

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

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

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

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

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 →

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial.

Background: New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. Methods: EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). Findings: From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). Interpretation: In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. Funding: Karuna Therapeutics.

Lancet (London, England) · randomised controlled trial · 144 citationsread the source →

Effectiveness of a brief lay counsellor-delivered, problem-solving intervention for adolescent mental health problems in urban, low-income schools in India: a randomised controlled trial.

Background: Mental health problems are a leading cause of disability in adolescents worldwide. Problem solving is a well-tested mental health intervention in many populations. We aimed to investigate the effectiveness of a brief, transdiagnostic problem-solving intervention for common adolescent mental health problems when delivered by non-specialist school counsellors in New Delhi, India. Methods: This randomised trial was done in six government-run schools (three all-boys schools, two all-girls schools, and one co-educational school) that serve low-income communities. We recruited participants from grades 9 to 12 (ages 12-20 years) by selecting students with persistently elevated mental health symptoms accompanied by distress or functional impairment. Clinical eligibility criteria were assessed by research assistants using the Hindi-language version of the Strengths and Difficulties Questionnaire (SDQ), with reference to locally validated borderline cutoff scores of 19 or greater for boys and 20 or greater for girls on the SDQ Total Difficulties scale, an abnormal score of 2 or more on the SDQ Impact scale, and persistence of more than 1 month on the SDQ Chronicity index. Participants were randomly allocated (1:1) to problem solving delivered through a brief (2-3 week) counsellor-led intervention with supporting printed materials (intervention group), or problem solving delivered via printed booklets alone (control group). Primary outcomes were adolescent-reported mental health symptoms (SDQ Total Difficulties scale) and idiographic psychosocial problems (Youth Top Problems [YTP]) at 6 weeks. Primary analyses were done on an intention-to-treat basis at the 6-week endpoint. The trial is registered with ClinicalTrials.gov, NCT03630471. Findings: Participants were enrolled between Aug 20, and Dec 4, 2018. 283 eligible adolescents were referred to the trial, and 251 (89%) of these were enrolled (mean age 15·61 years; 174 [69%] boys). 125 participants were allocated to each group (after accounting for one participant in the intervention group who withdrew consent after randomisation). Primary outcome data were available for 245 (98%) participants. At 6 weeks, the mean YTP scores were 3·52 (SD 2·66) in the intervention group and 4·60 (2·75) in the control group (adjusted mean difference -1·01, 95% CI -1·63 to -0·38; adjusted effect size 0·36, 95% CI 0·11 to 0·61; p=0·0015). The mean SDQ Total Difficulties scores were 17·48 (5·45) in the intervention group and 18·33 (5·45) in the control group (-0·86, -2·14 to 0·41; 0·16, -0·09 to 0·41; p=0·18). We observed no adverse events. Interpretation: A brief lay counsellor-delivered problem-solving intervention combined with printed booklets seemed to have a modest effect on psychosocial outcomes among adolescents with diverse mental health problems compared with problem-solving booklets alone. This counsellor-delivered intervention might be a suitable first-line intervention in a stepped care approach, which is being evaluated in ongoing studies. Funding: Wellcome Trust.

The Lancet. Child & adolescent health · randomised controlled trial · 69 citationsread the source →

Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-on Treatment for Bipolar Depression: A Randomized Clinical Trial.

Importance: More effective, tolerable interventions for bipolar depression treatment are needed. Transcranial direct current stimulation (tDCS) is a novel therapeutic modality with few severe adverse events that showed promising results for unipolar depression. Objective: To determine the efficacy and safety of tDCS as an add-on treatment for bipolar depression. Design, setting, and participants: A randomized, sham-controlled, double-blind trial (the Bipolar Depression Electrical Treatment Trial [BETTER]) was conducted from July 1, 2014, to March 30, 2016, at an outpatient, single-center academic setting. Participants included 59 adults with type I or II bipolar disorder in a major depressive episode and receiving a stable pharmacologic regimen with 17-item Hamilton Depression Rating Scale (HDRS-17) scores higher than 17. Data were analyzed in the intention-to-treat sample. Interventions: Ten daily 30-minute, 2-mA, anodal-left and cathodal-right prefrontal sessions of active or sham tDCS on weekdays and then 1 session every fortnight until week 6. Main outcomes and measures: Change in HDRS-17 scores at week 6. Results: Fifty-nine patients (40 [68%] women), with a mean (SD) age of 45.9 (12) years participated; 36 (61%) with bipolar I and 23 (39%) with bipolar II disorder were randomized and 52 finished the trial. In the intention-to-treat analysis, patients in the active tDCS condition showed significantly superior improvement compared with those receiving sham (βint = -1.68; number needed to treat, 5.8; 95% CI, 3.3-25.8; P = .01). Cumulative response rates were higher in the active vs sham groups (67.6% vs 30.4%; number needed to treat, 2.69; 95% CI, 1.84-4.99; P = .01), but not remission rates (37.4% vs 19.1%; number needed to treat, 5.46; 95% CI, 3.38-14.2; P = .18). Adverse events, including treatment-emergent affective switches, were similar between groups, except for localized skin redness that was higher in the active group (54% vs 19%; P = .01). Conclusions and relevance: In this trial, tDCS was an effective, safe, and tolerable add-on intervention for this small bipolar depression sample. Further trials should examine tDCS efficacy in a larger sample. Trial registration: clinicaltrials.gov Identifier: NCT02152878.

JAMA psychiatry · randomised controlled trial · 103 citationsread the source →

Interventions for treating femoral shaft fractures in children and adolescents.

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

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

Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols.

Purpose: To determine the survival of infants and young children with non-metastatic medulloblastoma using intensive myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHCR). Methods: Twenty-one children less than 3 years old at diagnosis with non-metastatic medulloblastoma were enrolled on two identical serial studies, "Head Start" I and "Head Start" II. After surgery, patients received five cycles of induction chemotherapy consisting of vincristine, cisplatin, cyclophosphamide and etoposide. Following induction, all patients underwent myeloablative chemotherapy using carboplatin, thiotepa and etoposide with AuHCR. Irradiation was used only at relapse. Results: The 5-year event-free (EFS) and overall survival (OS) rates (+/-SE) for all patients, patients with gross total resection, and patients with residual tumor were 52 +/- 11% and 70 +/- 10%, 64 +/- 13% and 79 +/- 11%, and 29 +/- 17% and 57 +/- 19%, respectively. The 5-year EFS and OS ( +/- SE) for patients with desmoplastic and classical medulloblastoma were 67 +/- 16% and 78 +/- 14%, and 42 +/- 14 and 67 +/- 14%, respectively. There were four treatment related deaths. The majority of survivors (71%) avoided irradiation completely. Mean intellectual functioning and quality of life (QoL) for children surviving without irradiation was within average range for a majority of survivors tested. Conclusion: This strategy of brief intensive chemotherapy for young children with non-metastatic medulloblastoma eliminated the need for craniospinal irradiation 52% of the patients, and may preserve QoL and intellectual functioning. The excellent survival rates are somewhat dampened by high toxic mortality.

Pediatric blood & cancer · randomised controlled trial · 155 citationsread the source →

Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: a randomized clinical trial.

Importance: It is estimated that more than half of those with serious mental illness smoke tobacco regularly. Standard courses of pharmacotherapeutic cessation aids improve short-term abstinence, but most who attain abstinence relapse rapidly after discontinuation of pharmacotherapy. Objective: To determine whether smokers diagnosed with schizophrenia and bipolar disease have higher rates of prolonged tobacco abstinence with maintenance pharmacotherapy than with standard treatment. Design, setting, and participants: Randomized, double-blind, placebo-controlled, parallel-group, relapse-prevention clinical trial conducted in 10 community mental-health centers. Of 247 smokers with schizophrenia or bipolar disease recruited from March 2008-April 2012, 203 received 12-weeks' open-label varenicline and cognitive behavioral therapy and 87 met abstinence criteria to enter the relapse prevention intervention. Interventions: Participants who had 2 weeks or more of continuous abstinence at week 12 of open treatment were randomly assigned to receive cognitive behavioral therapy and double-blind varenicline (1 mg, 2 per day) or placebo from weeks 12 to 52. Participants then discontinued study treatment and were followed up to week 76. Main outcomes and measures: Seven-day rate of continuous abstinence at study week 52, the end of the relapse-prevention phase, confirmed by exhaled carbon monoxide. Secondary outcomes were continuous abstinence rates for weeks 12 through 64 based on biochemically verified abstinence and weeks 12 through 76, based on self-reported smoking behavior. Results: Sixty-one participants completed the relapse-prevention phase; 26 discontinued participation (7 varenicline, 19 placebo) and were considered to have relapsed for the analyses; 18 of these had relapsed prior to dropout. At week 52, point-prevalence abstinence rates were 60% in the varenicline group (24 of 40) vs 19% (9 of 47) in the placebo group (odds ratio [OR], 6.2; 95% CI, 2.2-19.2; P < .001). From weeks 12 through 64, 45% (18 of 40) among those in the varenicline group vs 15% (7 of 47) in the placebo group were continuously abstinent (OR, 4.6; 95% CI, 1.5-15.7; P = .004), and from weeks 12 through 76, 30% (12 of 40) in the varenicline group vs 11% (5 of 47) in the placebo group were continuously abstinent (OR, 3.4; 95% CI, 1.02-13.6; P = .03). There were no significant treatment effects on psychiatric symptom ratings or psychiatric adverse events. Conclusions and relevance: Among smokers with serious mental illness who attained initial abstinence with standard treatment, maintenance pharmacotherapy with varenicline and cognitive behavioral therapy improved prolonged tobacco abstinence rates compared with cognitive behavioral therapy alone after 1 year of treatment and at 6 months after treatment discontinuation. Trial registration: clinicaltrials.gov Identifier: NCT00621777.

JAMA · randomised controlled trial · 157 citationsread the source →

Association between financial strain, social network and five-year recovery from first episode psychosis.

Despite much effort to positively affect long-term outcome in psychosis and schizophrenia many patients are still facing a poor outcome with persistent psychotic symptoms and decline in social functioning. The aim of this study was to examine the relationship between financial strain and social network and five-year outcome of first episode psychosis (FEP). FEP patients were divided into recovered (n = 52) and non-recovered (n = 19). Each person was matched according to age and gender with four persons (n = 284) from a longitudinal population-based study. All persons had answered an extensive questionnaire including social network, quantitative and qualitative, financial strain and mental health. Linear regression analysis showed that both financial strain and social network were associated, and had a unique contribution, to outcome. The results indicate that FEP patients might benefit from interventions that reduce financial strain thus facilitating daily life and cultural and social activities.

Social psychiatry and psychiatric epidemiology · 30 citationsread the source →

Outreach for chlamydia and gonorrhoea screening: a systematic review of strategies and outcomes.

Background: High Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) prevalence have been reported in populations that do not regularly access health centres for sexually transmissible infections (STI) testing. We reviewed current outreach strategies used to increase access to STI testing and their outcomes. Methods: We systematically reviewed the literature for English language studies published between 1 January 2005 and 28 January 2011 describing CT and/or NG screening programs in non-clinical outreach settings. Results: We identified 25 programs, with the majority occurring in either Australia (32%) or the United States (32%). The most common target groups were young people aged 15-29 years (52%), men who have sex with men (24%) and sex workers (8%). The median CT positivity was 7.7% (Inter Quartile Range [IQR]: 3.0%-11.1%, n=19 programs), and median NG positivity was 2.6% (IQR: 0.0%-8.0%, n=10). The median participation rate was 53% (IQR: 23.9%-81.3%), and a median of 79.6% (IQR: 55.1%-89.4%) of participants were tested, with a median of 100 tests conducted per program (IQR: 65-331, range: 11-1808). Across all settings the participation rate was highest among target groups gathering in community service venues (community centres, parenting centres, homeless shelters) (median=81.4%, n=4), and social venues (sporting venues or bars) (80.4%, n=1). Lower participation rates were found in street/public community areas (median=23.9%, n=3) and sex on premises venues (10.4% and 24.3%, n=2). Conclusions: The review indicated that although CT and NG outreach programs reached a relatively small number of people the yield of infections is high. Settings which appear to be more effective at encouraging participation appear to be those within an existing venue, rather than in public areas.

BMC public health · systematic review · 32 citationsread the source →

Process evaluation in occupational stress management programs: a systematic review.

Objective: To conduct a systematic review of workplace stress management intervention studies that have incorporated process evaluation. Data Source. Electronic databases such as PsycINFO and MEDline were searched. STUDY INCLUSION CRITERIA: The inclusion criteria included interventions published in the English language that were focused on either individual- or organizational-level stress management interventions at the workplace, with an outcome evaluation. Data extraction: Each article was coded on key process-relevant variables, including context, recruitment, reach, dose delivered, dose received, fidelity, implementation, and participant's attitudes toward the intervention. Studies that reported on at least one of these process variables were also coded on the following study characteristics: participants, setting, evaluation design, intervention content, intervention format, and study outcomes. Data synthesis: Statistical Package for the Social Science was used to analyze the data with descriptive statistics. Results: Of the 84 studies identified that met the study inclusion criteria, 52 (61.9%) reported findings on at least one of the key relevant process-relevant variables. Variables most frequently included were recruitment (30%), intervention dose received (22%), participants' attitudes toward intervention (19%), and program reach (13%). Fewer than half of the studies presented any findings linking process evaluation and outcome evaluation. Conclusions: The incomplete reporting of information relevant to process evaluation makes it difficult to identify reliable determinants of effective intervention implementation or outcomes.

American journal of health promotion : AJHP · systematic review · 79 citationsread the source →

Brief Behavioral Therapy and Bupropion for Sleep and Fatigue in Young Adults With Crohn's Disease: An Exploratory Open Trial Study.

Background/aims: Sleep disturbances and fatigue are common symptoms amongst patients with Crohn's disease (CD). The aim of this study was to test the feasibility and effects of a pragmatic, stepped-care intervention for the treatment of poor sleep quality and fatigue in adolescents and young adults with CD. Methods: This study is a two-phase open trial exploring interventions for sleep and fatigue. After the initial comprehensive assessment which included quantitative measures and an interview to evaluate sleep and physical and mental health, the 12-week intervention consisted of two sequential steps: 1) a brief behavioral therapy for sleep in inflammatory bowel disease (IBD) (BBTS-I; 4 weeks) and 2) adding the psychotropic medication, bupropion sustained release (BUP-SR; 8 weeks), for the subset of subjects continuing to experience fatigue. Results: 232 CD patients (median age=24, median sex=female) were approached over 18 months, of whom 112 screened positive on the Pittsburgh Sleep Quality Index (PSQI) and multi-dimensional fatigue inventory (MFI), with 68 CD patients completing the more comprehensive baseline assessment. Of the 68 patients, 52 participated in Phase I of the BBTS-I intervention. Following 4-weeks of the BBTS-I, there were significant improvements in sleep quality (p < .001) and fatigue (p < .001). As part of Phase II, of the 52 patients who met fatigue threshold criteria, 33 patients participated in the BUP-SR+BBTS-I arm while 19 participated in the BBTS-I only intervention group. After 8 weeks of Phase II, both intervention groups saw significant further improvement in sleep, fatigue, anxiety and depressive symptoms, but without significant differences between the two intervention groups. Conclusions: A stepped-care approach shows that we can improve sleep disturbance with BBTS-I in CD patients, but fatigue only partially improves. For a subset of patients who chose to add BUP-SR to their behavioral therapy, fatigue improves further but not to a statistically significant effect compared to behavioral therapy alone.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association · clinical trial · 25 citationsread the source →

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

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

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

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 →

Brief antenatal cognitive behaviour therapy group intervention for the prevention of postnatal depression and anxiety: a randomised controlled trial.

Background: The majority of randomised controlled trials examining the effectiveness of antenatal group interventions at preventing postnatal depression in "at risk" women have used a "psychoeducational" intervention. The aim of the present study is to evaluate the effectiveness of an antenatal cognitive behavioural group intervention in a primary care setting for pregnant women identified with mild to moderate symptoms in pregnancy and/or at risk of developing depression or anxiety in the perinatal period. Method: Subjects were randomised to a CBT group intervention or control condition (information booklet) and administered the EPDS and STAI at pre (Time 1) and post intervention (Time 2), and at 2 months (Time 3) and 4 months postpartum (Time 4). MINIs were administered at Times 1, 3 and 4. Results: Of the 774 women approached, 277 accepted and were suitable; thus 191 were randomised to the CBT intervention and 86 to the control condition. The subsequent 52% drop-out left 89 women "completing" the CBT groups and 43 in the control group; these two groups were well matched on demographic variables. Intention to treat analyses revealed relatively low mean baseline EPDS scores (means 6.88 -8.16) with no reduction in EPDS scores in either group from Time 1 to Time 4. MINI depression criteria were fulfilled by 19% of all participants at Time 1 but there was no reduction in depression in either group; in contrast those with MINI anxiety diagnoses reduced from 28% in late pregnancy to 16% at four months postpartum in the CBT group with similar reductions in the control group. Analyses on the 132 "completers" showed significant symptomatic improvement over time for both the CBT group and control condition. Depression scores in the most symptomatic women (EPDS>12; N=19) decreased steadily by over 50% over the total time course but there were no differences in improvement between the CBT and control groups. Limitations: A number of methodological factors may have obscured our results including a tendency to natural remission in mildly symptomatic subjects and the possibility that our control condition was therapeutic in itself. Conclusion: While a modest reduction in depression scores was noted in study "completers", both the CBT group intervention control condition were equally beneficial. The reasons for this finding include the low symptom level at baseline; the potential effectiveness of the control condition; and the brevity of the intervention.

Journal of affective disorders · randomised controlled trial · 122 citationsread the source →

Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.

Context: The alpha4beta2 nicotinic acetylcholine receptors (nAChRs) are linked to the reinforcing effects of nicotine and maintaining smoking behavior. Varenicline, a novel alpha4beta2 nAChR partial agonist, may be beneficial for smoking cessation. Objective: To assess efficacy and safety of varenicline for smoking cessation compared with sustained-release bupropion (bupropion SR) and placebo. Design, setting, and participants: Randomized, double-blind, parallel-group, placebo- and active-treatment-controlled, phase 3 clinical trial conducted at 19 US centers from June 19, 2003, to April 22, 2005. Participants were 1025 generally healthy smokers (> or =10 cigarettes/d) with fewer than 3 months of smoking abstinence in the past year, 18 to 75 years old, recruited via advertising. Intervention: Participants were randomly assigned in a 1:1:1 ratio to receive brief counseling and varenicline titrated to 1 mg twice per day (n = 352), bupropion SR titrated to 150 mg twice per day (n = 329), or placebo (n = 344) orally for 12 weeks, with 40 weeks of nondrug follow-up. Main outcome measures: Primary outcome was the exhaled carbon monoxide-confirmed 4-week rate of continuous abstinence from smoking for weeks 9 through 12. A secondary outcome was the continuous abstinence rate for weeks 9 through 24 and weeks 9 through 52. Results: For weeks 9 through 12, the 4-week continuous abstinence rates were 44.0% for varenicline vs 17.7% for placebo (odds ratio [OR], 3.85; 95% confidence interval [CI], 2.70-5.50; P<.001) and vs 29.5% for bupropion SR (OR, 1.93; 95% CI, 1.40-2.68; P<.001). Bupropion SR was also significantly more efficacious than placebo (OR, 2.00; 95% CI, 1.38-2.89; P<.001). For weeks 9 through 52, the continuous abstinence rates were 21.9% for varenicline vs 8.4% for placebo (OR, 3.09; 95% CI, 1.95-4.91; P<.001) and vs 16.1% for bupropion SR (OR, 1.46; 95% CI, 0.99-2.17; P = .057). Varenicline reduced craving and withdrawal and, for those who smoked while receiving study drug, smoking satisfaction. No sex differences in efficacy for varenicline were observed. Varenicline was safe and generally well tolerated, with study drug discontinuation rates similar to those for placebo. The most common adverse events for participants receiving active-drug treatment were nausea (98 participants receiving varenicline [28.1%]) and insomnia (72 receiving bupropion SR [21.9%]). Conclusion: Varenicline was significantly more efficacious than placebo for smoking cessation at all time points and significantly more efficacious than bupropion SR at the end of 12 weeks of drug treatment and at 24 weeks. Trial registration: clinicaltrials.gov Identifier: NCT00141206.

JAMA · randomised controlled trial · 934 citationsread the source →

Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial.

Importance: Although vitamin E and memantine have been shown to have beneficial effects in moderately severe Alzheimer disease (AD), evidence is limited in mild to moderate AD. Objective: To determine if vitamin E (alpha tocopherol), memantine, or both slow progression of mild to moderate AD in patients taking an acetylcholinesterase inhibitor. Design, setting, and participants: Double-blind, placebo-controlled, parallel-group, randomized clinical trial involving 613 patients with mild to moderate AD initiated in August 2007 and concluded in September 2012 at 14 Veterans Affairs medical centers. Interventions: Participants received either 2000 IU/d of alpha tocopherol (n = 152), 20 mg/d of memantine (n = 155), the combination (n = 154), or placebo (n = 152). Main outcomes and measures: Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score (range, 0-78). Secondary outcomes included cognitive, neuropsychiatric, functional, and caregiver measures. Results: Data from 561 participants were analyzed (alpha tocopherol = 140, memantine = 142, combination = 139, placebo = 140), with 52 excluded because of a lack of any follow-up data. Over the mean (SD) follow-up of 2.27 (1.22) years, ADCS-ADL Inventory scores declined by 3.15 units (95% CI, 0.92 to 5.39; adjusted P = .03) less in the alpha tocopherol group compared with the placebo group. In the memantine group, these scores declined 1.98 units less (95% CI, -0.24 to 4.20; adjusted P = .40) than the placebo group's decline. This change in the alpha tocopherol group translates into a delay in clinical progression of 19% per year compared with placebo or a delay of approximately 6.2 months over the follow-up period. Caregiver time increased least in the alpha tocopherol group. All-cause mortality and safety analyses showed a difference only on the serious adverse event of "infections or infestations," with greater frequencies in the memantine (31 events in 23 participants) and combination groups (44 events in 31 participants) compared with placebo (13 events in 11 participants). Conclusions and relevance: Among patients with mild to moderate AD, 2000 IU/d of alpha tocopherol compared with placebo resulted in slower functional decline. There were no significant differences in the groups receiving memantine alone or memantine plus alpha tocopherol. These findings suggest benefit of alpha tocopherol in mild to moderate AD by slowing functional decline and decreasing caregiver burden. Trial registration: clinicaltrials.gov Identifier: NCT00235716.

JAMA · randomised controlled trial · 380 citationsread the source →

HIV combination prevention and declining orphanhood among adolescents, Rakai, Uganda, 2001-18: an observational community cohort study.

Background: Orphanhood increased markedly in the 1980s and 1990s in sub-Saharan Africa because of HIV-related mortality. Little is known about the contribution of HIV interventions, such as antiretroviral therapy (ART) and male medical circumcision, to more recent trends in orphanhood. In this study, we examined trends over time in maternal-only, paternal-only, and double orphanhood among adolescents before and after ART and male medical circumcision became widely available in the Rakai region of south-central Uganda. We sought to understand the association between adolescent orphanhood and HIV combination prevention (community-level ART use and prevalence of male medical circumcision). We hypothesised that increasing combination prevention, including greater use of ART and higher prevalence of male medical circumcision, would be associated with a lower probability of orphanhood. Methods: We examined the prevalence of orphanhood among adolescents aged 15-19 years, before and after roll-out of ART in mid-2004 and male medical circumcision in 2007, using data from 28 continuously followed communities within the Rakai Community Cohort Study. We used multinomial logistic regression with clustered SEs to estimate adjusted relative risk ratios (RRs) for maternal-only, paternal-only, and double orphanhood compared with non-orphanhood over 11 survey rounds between 2001 and 2018. Controlling for community HIV prevalence, household socioeconomic status, and adolescent age, we examined the association between community prevalence of ART use among people living with HIV and prevalence of male circumcision, including traditional circumcision. The primary outcome was orphanhood among adolescents aged 15-19 years. Findings: Orphanhood declined from 52% (920 of 1768 participants) in 2001-02 to 23% (592 of 2609 participants) by 2016-18 (p<0·0001), while double orphanhood declined from 20% (346 of 1768 participants) to 3% (86 of 2609 participants) (p<0·0001). Community prevalence of ART use among people living with HIV increased from 11% (105 of 945 participants) in 2005-06 to 78% (1163 of 1485 participants) in 2016-18. Male circumcision rates rose from 19% (147 of 790 participants) in 2005-06 to 65% (3535 of 5433 participants) in 2016-18. In the multinomial logistic regression model, a 10% increase in community prevalence of ART use was associated with a decrease in maternal orphanhood (adjusted relative RR 0·90, 95% CI 0·85-0·95) and double orphanhood (0·80, 0·75-0·85). In the post-ART era, a 10% increase in the community prevalence of male circumcision was associated with a decrease in paternal orphanhood (2005-18, adjusted relative RR 0·92, 0·87-0·97) and double orphanhood (0·91, 0·85-0·98). Interpretation: Widespread availability and uptake of HIV combination prevention was associated with marked reductions in orphanhood among adolescents. Reductions in orphanhood promise improved health and social outcomes for young people. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Allergy and Infectious Diseases, the National Institute of Mental Health, and the Division of Intramural Research of the National Institute for Allergy and Infectious Diseases.

The lancet. HIV · cohort or longitudinal · 5 citationsread the source →

Association between Spirituality, Religiosity, Spiritual Pain, Symptom Distress, and Quality of Life among Latin American Patients with Advanced Cancer: A Multicenter Study.

Objectives: The purpose of this multicenter study was to characterize the association between spirituality, religiosity, spiritual pain, symptom distress, coping, and quality of life (QOL) among Latin American advanced cancer patients. Methods: Three hundred twenty-five advanced cancer patients from palliative care clinics in Chile, Guatemala, and the United States completed validated assessments: Faith, Importance and Influence, Community, and Address (FICA) (spirituality/religiosity), Edmonton Symptom Assessment Scale-Financial/Spiritual (ESAS-FS), including spiritual pain, Penn State Worry Questionnaire-Abbreviated (PSWQ-A), Center for Epidemiologic Studies Depression Scale (CES-D), Brief-coping strategies (COPE) and Brief religious coping (RCOPE) and RCOPE, respectively, and Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being, Expanded version (FACIT-Sp-Ex). Results: Median age: 58 years (range: 19-85); 60% female; and 62% Catholic and 30% Christian, but not Catholic. Three hundred fifteen patients (97%) considered themselves spiritual and 89% religious, with median intensities of 7 (interquartile range [IQR]: 5-10) and 7 (5-9), respectively (0-10 scale, 10 = "very much"). Median importance of spirituality/religiosity was 10 (IQR: 8-10). The frequency and associations between spirituality/religiosity and various items were as follows: helps to cope with illness (98%; r = 0.66303; p < 0.0001), positive effect on physical symptoms (81%; r = 0.42067; p < 0.0001), and emotional symptoms (84%; r = 0.16577; p < 0.0001). One hundred ninety-five patients (60%) reported that their spiritual/religious needs had not been supported by the medical team. Spiritual pain was reported in 162/311 patients (52%), with median intensity of 6 (IQR: 5-8). Spiritual pain was associated with pain (p = 0.0225), depression (p < 0.0001), anxiety (p < 0.0001), worry (p < 0.001), behavioral disengagement (p = 0.0148), FACIT-Sp-Ex score (p = 0.0002), and negative RCOPE (p < 0.0001). Significance of Results: Spirituality and religiosity are frequent, intense, and rarely addressed among Latin American patients. Spirituality/religiosity was associated with positive COPE and higher QOL. Spiritual pain was also frequent and associated with physical and psychosocial distress. These patients need increased spiritual/religious support.

Journal of palliative medicine · cohort or longitudinal · 58 citationsread the source →

Psychosocial interventions for psychostimulant misuse.

Background: Psychostimulant misuse is a continuously growing medical and social burden. There is no evidence proving the efficacy of pharmacotherapy. Psychosocial interventions could be a valid approach to help patients in reducing or ceasing drug consumption. Objectives: To assess the effects of psychosocial interventions for psychostimulant misuse in adults. Search methods: We searched the Cochrane Drugs and Alcohol Group Specialised Register (via CRSLive); Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; CINAHL; Web of Science and PsycINFO, from inception to November 2015. We also searched for ongoing and unpublished studies via ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).All searches included non-English language literature. We handsearched references of topic-related systematic reviews and the included studies. Selection criteria: We included randomised controlled trials comparing any psychosocial intervention with no intervention, treatment as usual (TAU) or a different intervention in adults with psychostimulant misuse or dependence. Data collection and analysis: We used the standard methodological procedures expected by Cochrane. Main results: We included a total of 52 trials (6923 participants).The psychosocial interventions considered in the studies were: cognitive behavioural therapy (19 studies), contingency management (25 studies), motivational interviewing (5 studies), interpersonal therapy (3 studies), psychodynamic therapy (1 study), 12-step facilitation (4 studies).We judged most of the studies to be at unclear risk of selection bias; blinding of personnel and participants was not possible for the type of intervention, so all the studies were at high risk of performance bias with regard to subjective outcomes; the majority of studies did not specify whether the outcome assessors were blind. We did not consider it likely that the objective outcomes were influenced by lack of blinding. The comparisons made were: any psychosocial intervention versus no intervention (32 studies), any psychosocial intervention versus TAU (6 studies), and one psychosocial intervention versus an alternative psychosocial intervention (13 studies). Five of included studies did not provide any useful data for inclusion in statistical synthesis. We found that, when compared to no intervention, any psychosocial treatment: reduced the dropout rate (risk ratio (RR): 0.83, 95% confidence interval (CI) 0.76 to -0.91, 24 studies, 3393 participants, moderate quality evidence); increased continuous abstinence at the end of treatment (RR: 2.14, 95% CI 1.27 to -3.59, 8 studies, 1241 participants, low quality evidence); did not significantly increase continuous abstinence at the longest follow-up (RR: 2.12, 95% CI 0.77 to -5.86, 4 studies, 324 participants, low quality evidence); significantly increased the longest period of abstinence: (standardised mean difference (SMD): 0.48, 95% CI 0.34 to 0.63, 10 studies, 1354 participants, high quality evidence). However, it should be noted that the in the vast majority of the studies in this comparison the specific psychosocial treatment assessed in the experimental arm was given in add on to treatment as usual or to another specific psychosocial or pharmacological treatment which was received by both groups. So, many of the control groups in this comparison were not really untreated. Receiving some amount of treatment is not the same as not receiving any intervention, so we could argue that the overall effect of the experimental psychosocial treatment could be smaller if given in add on to TAU or to another intervention than if given to participants not receiving any intervention; this could translate to a smaller magnitude of the effect of the psychosocial intervention when it is given in add on. When compared to TAU, any psychosocial treatment reduced dropout rate (RR: 0.72, 95% CI 0.59 to 0.89, 6 studies, 516 participants, moderate quality evidence), did not increase continuous abstinence at the end of treatment (RR: 1.27, 95% CI 0.94 to 1.72, 2 studies, 224 participants, low quality evidence), did not increase longest period of abstinence (MD -3.15 days, 95% CI -10.35 to 4.05, 1 study, 110 participants, low quality evidence). No studies in this comparison assessed the outcome of continuous abstinence at longest follow-up. There were few studies comparing two or more psychosocial interventions, with small sample sizes and considerable heterogeneity in terms of the types of interventions assessed. None reported significant results. None of the studies reported harms related to psychosocial interventions. Authors' conclusions: The addition of any psychosocial treatment to treatment as usual (usually characterised by group counselling or case management) probably reduces the dropout rate and increases the longest period of abstinence. It may increase the number of people achieving continuous abstinence at the end of treatment, although this might not be maintained at longest follow-up. The most studied and the most promising psychosocial approach to be added to treatment as usual is probably contingency management. However, the other approaches were only analysed in a few small studies, so we cannot rule out the possibility that the results were not significant because of imprecision. When compared to TAU, any psychosocial treatment may improve adherence, but it may not improve abstinence at the end of treatment or the longest period of abstinence. The majority of the studies took place in the United States, and this could limit the generalisability of the findings, because the effects of psychosocial treatments could be strongly influenced by the social context and ethnicity. The results of our review do not answer the most relevant clinical question, demonstrating which is the most effective type of psychosocial approach. Further studies should directly compare contingency management with the other psychosocial approaches.

The Cochrane database of systematic reviews · review · 54 citationsread the source →

Emergency IVF for embryo freezing to preserve female fertility: a French multicentre cohort study.

Study question: What are the outcomes of French emergency IVF procedures involving embryo freezing for fertility preservation before gonadotoxic treatment? Summary answer: Pregnancy rates after emergency IVF, cryopreservation of embryos, storage, thawing and embryo transfer (embryo transfer), in the specific context of the preservation of female fertility, seem to be similar to those reported for infertile couples undergoing ART. Study design, size, duration: A French retrospective multicentre cohort study initiated by the GRECOT network-the French Study Group for Ovarian and Testicular Cryopreservation. We sent an e-mail survey to the 97 French centres performing the assisted reproduction technique in 2011, asking whether the centre performed emergency IVF and requesting information about the patients' characteristics, indications, IVF cycles and laboratory and follow-up data. The response rate was 53.6% (52/97). Participants/materials, setting, methods: Fourteen French centres reported that they performed emergency IVF (56 cycles in total) before gonadotoxic treatment, between 1999 and July 2011, in 52 patients. Main results and the role of chance: The patients had a mean age of 28.9 ± 4.3 years, and a median length of relationship of 3 years (1 month-15 years). Emergency IVF was indicated for haematological cancer (42%), brain tumour (23%), sarcoma (3.8%), mesothelioma (n = 1) and bowel cancer (n = 1). Gynaecological problems accounted for 17% of indications. In 7.7% of cases, emergency IVF was performed for autoimmune diseases. Among the 52 patients concerned, 28% (n = 14) had undergone previous courses of chemotherapy before beginning controlled ovarian stimulation (COS). The initiation of gonadotoxic treatment had to be delayed in 34% of the patients (n = 19). In total, 56 cycles were initiated. The mean duration of stimulation was 11.2 ± 2.5 days, with a mean peak estradiol concentration on the day on which ovulation was triggered of 1640 ± 1028 pg/ml. Three cycles were cancelled due to ovarian hyperstimulation syndrome (n = 1), poor response (n = 1) and treatment error (n = 1). A mean of 8.2 ± 4.8 oocytes were retrieved, with 6.1 ± 4.2 mature oocytes and 4.4 ± 3.3 pronuclear-stage embryos per cycle. The mean number of embryos frozen per cycle was 4.2 ± 3.1. During follow-up, three patients died from the consequences of their disease. For the 49 surviving patients, 22.5% of the couples concerned (n = 11) requested embryo replacement. A total of 33 embryos were thawed with a post-thawing survival rate of 76%. Embryo replacement was finally performed for 10 couples with a total of 25 embryos transferred, leading to one biochemical pregnancy, one miscarriage and three live births. Clinical pregnancy rate and live birth per couple who wanted a pregnancy after cancer were, respectively, 36% (95% CI = 10.9-69.2%) and 27% (95% CI = 6.0-61%). Limitations, reasons for caution: The overall response rate for clinics was 53.6%. Therefore, it is not only that patients may not have been included, but also that those that were included were biased towards the University sector with a response rate of 83% (25/30) for a small number of patients. Wider implications of the findings: According to literature, malignant disease is a risk factor for a poor response to COS. However, patients having emergency IVF before gonadotoxic treatment have a reasonable chance of pregnancy after embryo replacement. Embryo freezing is a valuable approach that should be included among the strategies used to preserve fertility. Study funding/competing interest(s): No external funding was sought for this study. None of the authors has any conflict of interest to declare.

Human reproduction (Oxford, England) · cohort or longitudinal · 32 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 →

A Critical Review: Moral Injury in Nurses in the Aftermath of a Patient Safety Incident.

Background: To date, there has been no published work towards understanding or classifying patient safety incidents (PSIs) or their aftermath as potential morally injurious experiences (pMIEs). A morally injurious experience is one that violates deeply held moral values and beliefs, and can put an individual at risk for burnout, post-traumatic stress disorder, and other trauma-related problems. This can also set the stage for moral injury, which can occur when there has been a betrayal of what is right by someone in a position of legitimate authority, or by one's self, in a high-stakes situation. Objective: The objective of this review of nurse second victim literature is to describe symptoms of moral injury empirically observed in nurses in the aftermath of a PSI. Methods: A critical review using a SALSA (search, appraisal, synthesis, analysis) method commenced with a search of electronic data base-indexed original evidence between 1980 and December 2018, focusing on registered nurses involved with a PSI. Results: The nurse empirical literature reviewed included qualitative (n = 10), quantitative (n = 7), and mixed-methods (n = 4) studies (total n = 21). Core moral injury symptoms included guilt (67%), shame (71%), spiritual-existential crisis (9%), and loss of trust (52%). Secondary symptoms of moral injury included depression (33%), anxiety (57%), anger (71%), self-harm, (19%), and social problems (48%). Implications: Moral injury better describes what historically has been called the nurse second victim phenomenon. Through identification of pMIEs and symptoms of moral injury, nurses and organizations can be empowered to advance training and intervention programs addressing pMIEs that affect nurses' safety and retention in the aftermath of a PSI. Clinical relevance: By describing the experiences associated with a PSI as potentially morally injurious, we set the stage to describe the potential consequences associated with the aftermath of the PSI. Furthermore, this language avoids victimizing those involved by more accurately reflecting the pMIEs of the aftermath.

Journal of nursing scholarship : an official publication of Sigma Theta Tau International Honor Society of Nursing · review · 52 citationsread the source →

The Silent Crisis: Loneliness in Older Adults-A Critical Review of Impacts, Strategies and Path Forward.

Background: Loneliness, distinct from social isolation, is a subjective sense of social disconnection exacerbating a public health crisis among older adults. Affecting ~33% of community-dwelling individuals aged 50-80 years post-COVID-19, it rivals smoking in mortality risk and drives cognitive, cardiovascular, and mental health declines. This review synthesises evidence to inform clinical strategies. Methods: A critical review of per-reviewed meta-analyses, RCTs, and prospective cohorts literature (2019-2025) was conducted for adults aged 50 years and above. Studies were selected using validated loneliness or social isolation measures, with quality appraised via AMSTAR-2, Cochrane RoB 2, and Newcastle-Ottawa Scale; 34 studies met eligibility criteria from an initial yield of 1,847 records. Results: Prevalence of loneliness stands at 29% isolation by 2024, highest among those with poor health (53%-75%), unemployment (52%), solitary living, and ages 50-64. Loneliness elevates all-cause mortality (32%), dementia (50%-59%), cardiovascular events (29%-32%), depression (40%), and anxiety (35%). Mechanisms include increased inflammation (↑CRP, IL-6), HPA dysregulation, immune compromise, hippocampal atrophy, and behavioural lapses. Interventions like CBT/reminiscence therapy, multicomponent programs, animal therapy, exercise, and digital platforms have been shown to reduce loneliness, though primary care implementation lags due to screening/referral barriers. Tools such as the UCLA Loneliness Scale enable feasible assessment. Conclusions: Loneliness as a geriatric syndrome demands mandated screening, provider education, and reimbursement reforms. Coordinated healthcare-community efforts could avert substantial morbidity/mortality, addressing gaps in long-term outcomes and cost-effectiveness research.

Scandinavian journal of caring sciences · reviewread the source →

Long-term outcome of cognitive behaviour therapy clinical trials in central Scotland.

Objectives: To establish the long-term outcome of participants in clinical trials of cognitive behaviour therapy (CBT) for anxiety disorders and psychosis, examining the effectiveness and cost-effectiveness associated with receiving CBT in comparison with alternative treatments. Design: An attempt was made to contact and interview all of the participants in eight randomised, controlled, clinical trials of CBT for anxiety disorders and two randomised, controlled, clinical trials of CBT for schizophrenia conducted between 1985 and 2001. Case note reviews of healthcare resources used in the 2 years prior to entering the trials and the 2 years prior to follow-up interview were undertaken. Setting: Mixed rural and urban settings in five localities in central Scotland. Anxiety disorder trials were conducted mainly in primary care and included three with generalised anxiety disorder, four with panic disorder and one with post-traumatic stress disorder (PTSD). The psychosis studies (one on relapse prevention and one with chronic disorder) were conducted in secondary care. Participants: Of the 1071 entrants to the 10 studies, 489 agreed to participate (46% of original entrants, 52% of those available to contact). Interventions: Follow-up interviews took place between 1999 and 2003, 2-14 years after the original treatment. Interviews for Trials 1-8 were conducted by a research psychologist blind to original treatment condition. Interviews for Trials 9 and 10 were conducted by community psychiatric nurses also blind to treatment condition. Case note reviews were completed following the interview. Main outcome measures: For Trials 1-8 the main interview-based outcome measures were: Anxiety Disorders Interview Schedule-DSM-IV for diagnosis and co-morbidity, Clinical Global Severity (0-8) and the Hamilton Anxiety Rating Scale. The main patient-rated measures were: Brief Symptom Inventory, SF-36 II, Clinical Global Improvement (1-7), and the Positive and Negative Affect Scale. For Trials 9 and 10 the primary outcome measure was the interview-based Positive and Negative Syndrome Scale (PANSS). Results: For the anxiety disorder studies (Trials 1-8), over half of the participants (52%) had at least one diagnosis at long-term follow-up, with significant levels of co-morbidity and health status scores comparable to the lowest 10% of the general population. Only 36% reported receiving no interim treatment for anxiety over the follow-up period with 19% receiving almost constant treatment. Patients with PTSD did particularly poorly. There was a 40% real increase in healthcare costs over the two time periods, mainly due to an increase in prescribing. A close relationship was found between poor mental and physical health for those with a chronic anxiety disorder. Treatment with CBT was associated with a better long-term outcome than non-CBT in terms of overall symptom severity but not with regard to diagnostic status. The positive effects of CBT found in the original trials were eroded over longer time periods. No evidence was found for an association between more intensive therapy and more enduring effects of CBT. Long-term outcome was found to be most strongly predicted by the complexity and severity of presenting problems at the time of referral, by completion of treatment irrespective of modality and by the amount of interim treatment during the follow-up period. The quality of the therapeutic alliance, measured in two of the studies, was not related to long-term outcome but was related to short-term outcome. The cost-effectiveness analysis showed no advantages of CBT over non-CBT. The cost of providing CBT in the original trials was only a very small proportion (6.4%) of the overall costs of healthcare for this population, which are high for both physical and mental health problems. In the psychosis studies (Trials 9 and 10), outcome was generally poor with only 10% achieving a 25% reduction in total PANSS scores from pretreatment to long-term follow-up, also cost-effectiveness analysis showed no advantages of CBT over non-CBT, although healthcare costs fell over the two time periods mainly owing to a reduction in inpatient costs. Conclusions: Psychological therapy services need to recognise that anxiety disorders tend to follow a chronic course and that good outcomes with CBT over the short term are no guarantee of good outcomes over the longer term. Clinicians who go beyond standard treatment protocols of about 10 sessions over a 6-month period are unlikely to bring about greater improvement. Poor outcomes over the long term are related to greater complexity and severity of presenting problems at the time of referral, failure to complete treatment irrespective of modality and the amount of interim treatment during the follow-up period. The relative gains of CBT are greater in anxiety disorders than in psychosis. Longitudinal research designs over extended periods of time (2-5 years), with large numbers of participants (500+), are required to investigate the relative importance of patient characteristics, therapeutic alliance and therapist expertise in determining the cost-effectiveness of CBT in the longer term.

Health technology assessment (Winchester, England) · review · 62 citationsread the source →

Inflammation and Schizophrenia

An association between inflammatory abnormalities and schizophrenia has been found repeatedly. The purposes of this special feature are to clarify the key findings on inflammation in schizophrenia, identify major gaps in the literature, and suggest priorities for research in this area. Inflammation is one of the body’s first lines of defense in response to injury or infection, and increased inflammation is found in many diseases. Acute inflammation is a nonspecific response characterized by warmth, pain, and swelling. Leukocytes migrate to the area of injury and become activated, the blood supply to the area increases, and blood vessels become more permeable, allowing cells and molecules to leave blood vessels and enter the injured tissue. The inflammatory response also involves the complement system, a group of proteins that, when activated, combine to form a complex molecular structure that kills cells, usually bacteria and parasites. Cytokines are key molecules that regulate inflammation; they also have important roles in the immune system. They are produced by a wide variety of immune cells and cells outside of the immune system. The term cytokine derives from their ability to influence the movement of inflammatory cells, but they also have other functions. Chronic inflammation is usually a lower grade response, lacks the grossly visible signs of acute inflammation, and may be systemic rather than localized. Chronic inflammation plays a role in the pathophysiology of many chronic diseases, including cardiovascular and cerebrovascular disease, diabetes, Alzheimer’s disease, and some cancers. The characteristics of chronic inflammation differ somewhat in the brain from what occurs in other tissues. An important component of neuroinflammation is the microglial activation. The brain contains relatively few of the inflammatory cells that are found outside the brain. Microglia, which are related to the peripheral inflammatory cells, serve some of the protective functions such cells play in the rest of the body. Microglia are involved in other brain functions, including the pruning and maintenance of synapses, trafficking of neurotransmitters, and devouring—phagocytosis—of cell fragments and damaged cells. Activated microglia produce inflammatory cytokines and the phagocytose cells or proteins that provoke the inflammatory response. Microglial activation and subsequent proinflammatory cytokine production may disrupt the blood-brain barrier (BBB). An intact BBB usually tightly controls the entry of cytokines and leukocytes into brain tissue. Damage to the BBB impairs its ability to control which inflammatory cells and molecules enter the brain; other substances leak into brain tissue, and the brain is unable to function normally. A discussion of prenatal inflammation as a risk factor for schizophrenia is beyond the scope of the present special feature, and the reader is referred to previous reviews of human1,2 and animal studies.3–6 Numerous studies have found that people with schizophrenia have increased blood concentrations of inflammatory cytokines.7 Two important themes emerge from these studies. First, inflammatory abnormalities are present in subjects with first-episode, drug-naive psychosis (FEP) compared with controls, suggesting an association that may be independent of the effects of antipsychotic medications. Second, the concentrations of some inflammatory molecules may vary with the clinical status of patients: ie, there appear to be separate groups of state and trait markers. The state-related markers include interleukin (IL) 1-beta, IL-6, and transforming growth factor-beta. People with schizophrenia have higher concentrations of these cytokines than controls during an exacerbation of symptoms, but there is no difference during periods of clinical stability. IL-12, interferon-gamma, and tumor necrosis factor-alpha (TNF-alpha) appear to be trait markers. Concentrations of these cytokines are higher in patients with FEP than in controls, and in patients with chronic illness, during both periods of symptomatic worsening, than in controls. C-reactive protein (CRP), another proinflammatory molecule, also appears to be a state marker,8 and specific lymphocyte populations may also segregate into state and trait markers.9 Additional evidence for potential state-related markers in schizophrenia has been reviewed elsewhere.10 Two studies suggest that inflammatory molecules may predict subsequent relapse.11,12 Other studies have found abnormal levels of inflammatory parameters in the central nervous system (CNS) in schizophrenia, including cerebrospinal fluid (CSF) cytokine11 and leukocyte levels,13,14 CNS microglia and lymphocytes,15–19 CSF and CNS oxidative stress,20,21 and anti-N-methyl-D-aspartate receptor autoantibodies.22 There is also evidence suggesting that infections may be associated with illness relapse.23 Within schizophrenia, blood cytokine abnormalities have been associated with poorer cognitive function and measures of regional brain volume24–26 and negative symptoms.27–30 There are several randomized clinical trials of the nonsteroidal anti-inflammatory drugs (NSAIDs) celecoxib and aspirin as adjuncts to antipsychotics.31 Interpretation of this evidence is complex, as these studies have not consistently distinguished relapsed from clinically stable patients. Furthermore, if inflammation plays a role in psychotic relapse, the efficacy of anti-inflammatory treatments may “disappear” in a lengthy trial because the treatment would not have any effect once patients have returned to their clinical baseline. However, an adjunctive agent that accelerates a patient’s antipsychotic response would be valuable. Agents other than NSAIDs that have anti-inflammatory properties, used in adjunct to antipsychotics, have been found to be superior to placebo. There have been two trials of minocycline,32,33 a second-generation tetracycline with anti-inflammatory and antimicrobial effects, that were superior to placebo. The efficacy of minocycline may have “disappeared” over the course of one trial,33 raising the possibility of an effect restricted to relapsed patient and not in those at a stable baseline. Adenosine is a purine nucleoside that modulates many physiological processes and has anti-inflammatory effects. A meta-analysis found that adjunctive treatment with adenosine-modulating drugs is superior to the effects of placebo.34 These drugs were associated with significant symptomatic improvement in inpatients, but not in outpatients, supporting the concept that state/trait differences may be an important predictor of antipsychotic response to adjunctive agents. Oxidative stress refers to an increase in free radicals, highly reactive molecules generated from metabolism and environmental exposures that can damage cell membranes. Inflammation and oxidative stress strongly influence each other.35 Antioxidant drugs decrease oxidative stress. One trial found that adjunctive treatment with the antioxidant N-acetylcysteine significantly reduced psychopathology in schizophrenia.36 A trial of fish oil, which also has significant anti-inflammatory effects, was conducted in adolescents and young adults with subthreshold psychotic symptoms,37 ie, “prodromal” patients. Patients receiving fish oil were significantly less likely to progress to a psychotic disorder than subjects receiving a placebo. Interestingly, fish oil was prescribed for 12 weeks, but the protective benefits with regards to transition to psychosis remained significant for 40 weeks after cessation of treatment. Inflammation may be a common mediator of diverse prenatal risk factors for schizophrenia, including preterm labor; preeclampsia (pregnancy-induced hypertension); neonatal birth asphyxia; and maternal gestational diabetes, stress, and depression.2 Maternal serum concentrations of the cytokines IL-838 and TNF-alpha39 during pregnancy were associated with an increased risk of schizophrenia in the offspring. Animal studies suggest that inflammation during critical periods of neurodevelopment may permanently alter the “set-point” of the inflammatory system, with increased inflammation in adult offspring.40–45 Meta-analyses have confirmed the presence of other abnormalities in schizophrenia that are associated with inflammation: increased autoantibodies,22 oxidative stress,46 CRP,8 and circulating lymphocytes.9 Antibodies are crucial “weapons” the immune system uses against foreign proteins. Autoantibodies, antibodies against a person’s own proteins, are associated with cytokine abnormalities.47 Lymphocytes, a group of white blood cells that combat infections, produce antibodies, and are an important source of cytokines, are increased in schizophrenia.9 Some subsets of lymphocytes may be state markers for acute psychosis, whereas others may be trait markers.9 CRP is a protein synthesized by the liver in response to inflammation, particularly IL-6 and other cytokines. Inflammation and oxidative stress may contribute to the decreased blood and CNS membrane levels of polyunsaturated fatty acids observed in schizophrenia.48 There are other disorders outside of schizophrenia in which peripheral inflammation appears to impact brain function. Inflammation is a risk factor for Alzheimer’s disease and mild cognitive impairment,49 rheumatoid arthritis is a risk factor for dementia,50 and “sickness behavior” is induced by peripheral cytokines.51,52 Depression is also associated with increased inflammation.53 The effects in depressed patients of an antibody against the cytokine TNF-alpha54 support the concept that brain function is impacted by peripheral cytokines. There are other mechanisms by which peripheral inflammation might cause or reflect brain dysfunction in schizophrenia. Cytokines may directly modulate dopaminergic neurotransmission55–57 or indirectly modulate glutamatergic neurotransmission through tryptophan metabolism.58–61 There is also some movement of peripheral leukocytes into the brain parenchyma, and the interaction of cytokines with the vagus nerve influences brain function.62 Blood cytokines induce cytokine production in the cells that form the BBB, and cytokines may move into the brain via the circumventricular organs, which lack a BBB.62 Inflammation may also disrupt the BBB, resulting in abnormal trafficking of cells and inflammatory molecules between blood and brain. Some have suggested that the increase in blood concentrations of the protein S100-beta in schizophrenia63 is consistent with abnormal function of the BBB in people with schizophrenia, resulting in abnormal trafficking of cells and inflammatory molecules between blood and brain. However, circulating S100-beta has sources other than the brain.64,65 Several potentially confounding variables are important to consider in studies of inflammation. Antipsychotics increase the risk of weight gain and diabetes, which are associated with inflammation. However, there is evidence from meta-analyses of abnormal inflammatory parameters in FEP,8,9,22,46 suggesting that the association between schizophrenia and inflammation is not solely due to antipsychotics. Antipsychotic-naïve relatives of people with schizophrenia also have increased inflammation compared with controls.66–68 Other potentially confounding variables include body mass index, age, gender, smoking, alcohol and illicit drug use, and whether patients are fasting at the time of sampling.69 The proportion of studies that either matched patients and controls, or statistically controlled for many of these potential confounders, has been low.8,9,22,46 Inflammation is comorbid with other physiological abnormalities, including hypertension, impaired glucose tolerance (fasting blood glucose [FBG] 100–126mg/dl), diabetes (FBG > 126, or a random blood glucose >200mg/dl), and increased oxidative stress. The associations with these other conditions also support the plausibility of increased inflammation in schizophrenia. However, the comorbidity of these physiological measures in schizophrenia complicates the interpretation of adjunctive treatment trials: what is the best therapeutic target? Another complicating issue is the relationship of inflammation to neurotropic viruses. One study found that treatment of patients with antibodies to herpes simplex 1 virus with a herpes-specific antiviral drug improved cognition with impressive effect sizes, suggesting the presence of an ongoing problem related to the virus.70 The association of other infectious agents with schizophrenia also raises the question of what relationship might exist between inflammation and either chronic infections or the expression of genes derived from an infectious agent and integrated into human DNA. The background presented above can be used to guide future research. Attempts to replicate current findings in well-matched patients and controls would be helpful. Cytokine levels in subjects with prodromal psychosis have not been investigated. We would hypothesize that these subjects should have abnormal trait markers compared with controls; within prodromal subjects, those who develop clinical psychosis should have abnormal state markers compared with high-risk subjects who do not. The effects of fish oil in preventing conversion to psychosis in high-risk subjects should be investigated in relationship to its effects on inflammation. The therapeutic anti-inflammatory agents that have been studied to date, such as aspirin, celecoxib, and fish oil, have multiple actions. Specific antibodies against individual cytokines are used in the treatment of rheumatoid arthritis and have been studied in depression.54 A change in symptoms or cognition in response to these antibodies would directly implicate inflammation in the pathophysiology of schizophrenia. More longitudinal studies with serial measurement of inflammatory parameters across the clinical course of illness are needed. It would be useful to test the hypothesis that patients with treatment-resistant schizophrenia have a different inflammatory profile than other patients with schizophrenia.7 Although it seems likely that there is increased inflammation in the brain when there are cytokine increases in the peripheral blood, the response might not be exactly the same in these two compartments. For instance, the inflammatory cytokines with altered levels in the brain might not be the same as those that change in the blood. More studies of markers of inflammation in the CNS—including CSF, postmortem analyses, and imaging studies—are needed. Two strategies may increase the signal-to-noise ratio for adjunctive trials of anti-inflammatory agents. First, inflammation may play a role in some patients with schizophrenia but not others. Patients with evidence of inflammation in the peripheral blood may be more likely to respond to an anti-inflammatory treatment strategy than those without inflammation and should be the ones included in treatment studies. Second, acutely ill and stable patients should be studied in separate trials and considered separately in meta-analyses. Furthermore, baseline-to-end-point analyses may not appropriate for studies of relapsed patients because there may be faster improvement with the use of adjunctive anti-inflammatories but not a greater total improvement by the end of the study. Studies of inflammation in schizophrenia should assess possible relationships of inflammatory cells and molecules to symptoms and cognition. To date, few studies have considered these measures.8,9,22,46 The comorbidity of inflammation, oxidative stress, hypertension, and abnormal glucose concentrations raise the issue what is the most appropriate treatment target in schizophrenia. As a first step in understanding this issue, it would be helpful to investigate relationships between inflammation, oxidative stress, hypertension, and glucose intolerance on the one hand, and clinical variables on the other. Several studies found that first-degree relatives of people with schizophrenia have increased inflammation and oxidative stress.66–68 It would advance the field to test the hypothesis that relatives have abnormal concentrations of the trait markers for schizophrenia but not of the state markers associated with relapse. Inflammatory molecules do not work in isolation but have complex interactions among themselves and with other systems. Most previous studies have measured only a small number of molecules. Concurrent measurement of cytokines, leukocytes, oxidative stress, and related parameters would increase the ability to make broader inferences regarding inflammation. Furthermore, if groups or clusters of covarying molecules—ie, molecules that change simultaneously—could be defined within schizophrenia, investigation of these groups is likely to yield better signal-to-noise ratios than individual molecules and should have more biological validity. Does increased inflammation due to infections or physical trauma increase the risk of relapse? If so, do preventive measures (eg, antibiotic prophylaxis for recurrent urinary tract infections)23 decrease that risk? What is the relationship between inflammation and the presence of antibodies to herpes viruses, toxoplasmosis, etc? Although the evidence on inflammation in schizophrenia is provocative, the number of studies in some areas is small, and increased methodological rigor is needed. Nonetheless, the evidence from FEP and first-degree relatives of patients with schizophrenia supports the idea that increased inflammation is truly associated with schizophrenia. This research raises the possibility that further study of inflammation will lead to greater understanding of the etiology and pathophysiology of schizophrenia. Dr B.K. is a member of Advisory Boards for Genentech and Roche. In the past 3 years, Dr B.J.M has received grant support from the National Institute of Mental Health (K23MH098014), the Georgia Regents University (GRU) Intramural Scientist Training Program, the GRU Brain & Behavior and Immunotherapy Discovery Institutes, the University of Oulu (Finland), the Thule Institute of the University of Oulu, and Oy H. Lundbeck Ab; research support from the National Institutes of Health Clinical Loan Repayment Program; consultancy fees for surveys from Medefied Europe and Plaza Research, on behalf of Genetech/Roche; speaker fees for grand rounds lectures from the Maryland Psychiatric Research Center and the Texas A&M University and Scott and White Hospital Department of Psychiatry; and payment for a survey from e-Rewards Medical Market Research.

Schizophrenia Bulletin · review · 315 citationsread the source →

Heart rate variability

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

Introduction Early in the epidemic, the public perception of AIDS as a highly fatal acute illness with a rapid downward trajectory was crystallized. Nevertheless, as early as 1991 in the nursing and medical sociology literature, a few investigators were already discussing HIV/AIDS as a chronic illness (for example [1,2]). Shortly thereafter, a number of psychosocial investigations of small groups of long-term AIDS survivors appeared in the literature, although these cases were still seen as infrequent exceptions (see [3] for a review). It was not until the advent of protease inhibitors in 1996, which ushered in the era of highly active antiretroviral therapy (HAART), that the view of AIDS as a chronic illness became widely accepted. These medications were touted in the mass media as ‘miraculous’ because they reduced the risk of opportunistic infections and extended survival by suppressing viral replication and increasing CD4 cell counts. Their availability was said to have “reinserted the word ‘hope’ into the discussion about AIDS for the first time in a decade of treatment trials” [4] (p. 161), and to have offered infected individuals the opportunity for a “second life” [5]. Among those at advanced stages of the disease, recoveries have often been so dramatic that the phenomenon has been dubbed the ‘Lazarus Syndrome’, referring to the seeming rising from the dead made possible by these new medications [6]. While in the United States recent treatment advances have had a profound impact on the illness trajectory and thus life expectancy of many infected individuals [7], AIDS-related mortality continues to rise unabated in parts of the world where access to the new therapies is limited. The prohibitively high prices of antiretrovirals coupled with inadequate and inefficient health delivery systems have allowed AIDS to reach catastrophic levels in many developing countries [8]. Even in the United States, however, not all infected persons have access to or choose to adopt the new treatments. Some physicians are less likely to offer HAART to patients they assume to be at risk for poor adherence, such as those with a history of drug use, the homeless, and the mentally ill [9–11], although the evidence supporting their actions remains inconclusive [12, 13]. Other research indicates that women, African-Americans, and those with low levels of education are less likely to have ever used the new therapies [14–17]. These findings have been attributed not only to a lack of access to these medications among these socio-economically disadvantaged groups, but also to their own reluctance to use them due to such factors as fear of medication side-effects and distrust of physicians. Similar issues were identified as barriers to antiretroviral use and medication adherence before HAART became available [18,19]. Chronic illness and AIDS Chronic illnesses are typically incurable, and thus the goals of medical care are usually containment, slowing disease progression and symptom management rather than cure. Beyond this, chronic diseases tend to share a variety of characteristics [20–23]. Frequently, they have an uncertain course or disease trajectory often characterized by alternating periods of remission and recurrence, or stable periods interrupted by episodic exacerbations of symptoms. Most require adherence to a treatment regimen, although these differ significantly across diseases in complexity and efficacy. Chronic disease also typically requires considerable self-care (including self-monitoring of symptoms) on the patient's part, since most of the day-to-day management of the illness takes place outside formal health institutions or facilities. As illness is a form of deviance and thus an undesirable state, chronic conditions also carry some degree of stigma. However, this varies greatly across diseases and depends on a variety of factors, such as whether the individual is perceived as being responsible for having acquired the illness, whether the illness is contagious and whether there is visible disfigurement. In addition, changes in roles and relationships are common. Illness almost always necessitates some degree of dependency, at least at the more advanced stages of a disease. Roles and responsibilities in relationships and families typically must be re-negotiated in light of the patient's limitations or disabilities. Finally, chronic diseases often bring about identity changes as the patient attempts to integrate the illness into his/her life and self-perception over the long haul. Psychological distress is a prevalent concomitant of living with chronic conditions, because of the uncertainty inherent in many of these illness characteristics. Each of these aspects of chronic disease posses an adaptive task or challenge (e.g., tolerating uncertainty, managing stigma, adhering to treatment) that is stressful for the individual to confront. How well the chronically ill individual will adapt to one's disease will depend in large part on his/her ability to master, or at least successfully manage, these tasks. Today, AIDS meets the criteria for a chronic illness [24]. While available treatments can render a viral load undetectable, they cannot fully eradicate it from the body and, left untreated, the viral load will rebound. Consequently, there is still no cure for the disease. Furthermore, while the natural history of the disease has been delineated, the course of HIV disease progression varies considerably among individuals [25]. Current multi-drug regimens remain complex, often requiring that many pills be taken on a rigid schedule while following strict dietary guidelines. Yet, similar to many other chronic illnesses, the regimens for HIV infection are not equally effective for all patients [26]. It is also well recognized that HIV/AIDS has a profound impact on intimate and social relationships. The fact that the disease can be transmitted through sexual behaviors renders intimate relationships fraught with anxiety and ambivalence. Moreover, infected adults often feel that others are unwilling to enter into long-term relationships with them for fear of having to assume care-giving responsibilities when the disease progresses. Additionally, self-care is a component of living with HIV. Many patients engage in self-initiated strategies (e.g., diet, relaxation exercises, stress avoidance) aimed at managing illness or treatment-related symptoms, boosting their immune system, or alleviating stress. In the present paper, we discuss several of the principal characteristics of chronic illnesses, reviewing in each case the relevant available literature. In each section, we attempt to highlight continuities and discontinuities between the pre-HAART and the HAART eras. In addition, we discuss prevention in the context of AIDS as a chronic illness. We conclude with some suggestions for future research in the field of HIV/AIDS and chronic illness. Emotional distress From the outset of the AIDS epidemic, there has been considerable documentation of the adverse psychological consequences of knowing one is infected. When AIDS was viewed as a highly fatal illness with an inexorable downhill course, much of this work focused on assessing depression (depressive symptomatology or clinical depression) and suicidal ideation or acts. While the findings of studies sometimes differed, the preponderance of evidence from the pre-HAART era suggested that depression was prevalent and that suicidal ideation and risk were elevated [27–30]. Infected individuals seemed particularly emotionally vulnerable shortly after diagnosis, when HIV-related symptoms first appeared, in the later stages of the disease, and after suffering multiple AIDS-related losses in their social network. It is a widely held, although largely unexamined, assumption that the experience of living with HIV infection in the HAART era is significantly less distressing compared with the past because of the prospects for extended survival and enhanced quality of life offered by the new treatments. Only recently, however, has this issue begun to be empirically investigated. Rabkin et al. [31] followed a sample of gay and bisexual men with symptomatic illness over a period that included the time before and after the availability of protease inhibitors. On all measures of psychological distress employed, the sample as a whole showed a statistically significant, although clinically modest, decline over time (when CD4 cell count, HIV symptoms, physical limitations, and social support were included as co-variates). However, when they further compared subjects whose status on medical markers had improved and had not improved, no significant differences in decline in hopelessness or improvement in quality of life were observed. In another study [32], changes in depressive symptomatology were investigated among 456 HIV-infected individuals (433 men) receiving antiretroviral treatment who were asked to complete a self-administered questionnaire annually. All study participants had completed at least one survey before and one after using protease inhibitors. The investigators found that, between assessment points, the percentage of individuals with a score indicative of probable clinical depression declined from 52 to 46%. While this change was not statistically significant, there were improvements in the total score of the Center for Epidemiological Studies—Depression scale, as well as on the depressive mood, positive affect and somatic symptom subscales. Similarly, in another study [33], changes in depressive symptomatology among 125 HIV-infected adults (most homosexual/bisexual males) assessed at 6-month intervals over a 2-year period were examined. The investigators found a pattern of declining scores on the Beck Depression Inventory over time, especially after the third assessment (12 months after baseline), when 51% of study participants were receiving HAART. There was, however, substantial drop-out before the 6-month assessment, and the number of cases included at each assessment point varied. It thus seems that the evidence on whether living with HIV infection is less psychologically distressing since the availability of HAART remains inconclusive. If ultimately it is shown to be so, this could have implications for needed mental health services. Catalan et al. [34], for example, suggest that as AIDS becomes a more manageable disease there will be a diminished need for acute mental health services (e.g., psychiatric hospitalization, crisis intervention), and a greater need for interventions assisting individuals in adjusting long-term to chronic-illness-related psychosocial stressors. While this may be true among gay and bisexual men and drug users who can recall infected individuals’ bleaker prospects in the pre-HAART era, the need for acute psychiatric services may grow among more recently impacted populations, such as infected adults living in rural America, adolescents, and heterosexual women without a history of drug use. Members of these populations often do not recognize that they were at risk for infection, making diagnosis a more psychologically disruptive event. Uncertainty Individuals living with HIV/AIDS have always confronted uncertainty. Early in the epidemic, this uncertainty revolved around issues such as when one had become infected, where one was in the disease trajectory, how long one was likely to survive, and whether any effective treatments for slowing or halting progression of one's disease would be developed. With the advent of zidovudine and other drugs of the pre-HAART era, uncertainty centered on issues such as whether to get tested, when to initiate treatment, and whether one would have a positive response to treatment. With the availability of HAART, new uncertainties have emerged [35] while old ones persist. For example, many infected individuals who realize extended survival as a result of new treatment regimens may confront emerging opportunistic infections that, in the past, patients did not live long enough to experience. Also, because these medications are new, there is uncertainty about their long-term safety. There is also a lack of clarity about how functional a restored immune system is likely to be [36,37]. The meaning of an improved CD4 cell count, a fundamental disease marker, is also ambiguous. For instance, is an individual who was diagnosed earlier as having AIDS solely on the basis of a CD4 cell count below 200 and who now has a count above that threshold still considered as having AIDS [35]? Those with advanced disease who had expected to die, but have now experienced a ‘reprieve’ on protease inhibitors, may feel insecure about their new-found well-being. While no longer imminently facing death, and possibly they recognize that they could experience a at any time, and The of many is by the fact that they have been to significant in their Finally, as in the pre-HAART era, and uncertainty to the of the time to initiate medication use Those who have not HAART recognize that not or can the Furthermore, those who have experienced recognize that they may be over an extended period of time adherence to the [26]. another of uncertainty is the risk of developing drug with Roles and relationships health has allowed infected individuals to the assumption of new social roles or the to old ones (e.g., For example, the in that zidovudine treatment could significantly of the from an infected to allowed infected women to more With the advent of HAART, more may now as a significant in viral load further the risk of survival and improved health due to HAART may also earlier about not being to or long enough to a However, the adverse of on their health to be of HIV-infected women the and of in the HAART Many infected individuals from HAART are also to work to their to become more to feel more and to however, uncertainty the impact of the stress of work their their after a long period of and their ability to their their health decline Many also about and in the Moreover, not all those using the new treatments feel to but may feel to do so the public perception of the new therapies as infected persons may that others view them as The of extended survival has also many infected individuals to the they have made their relationships Those a many of the confronted before HAART, the anxiety of one's HIV one's and Moreover, in an era of viral the of and may a considerable in relationships. The of living longer and may those who have in relationships because of about health and to the of these relationships Furthermore, the of of and sexual relationships may be anxiety when infected individuals do not feel for these changes The diagnosis of a chronic illness typically necessitates identity work Infected individuals differ in how they integrate their illness in their one are those who their life around their illness. These individuals may work or for AIDS are in or social on of infected and largely their social to other infected the other are those who have to and their illness while as much as possible with their to the illness from a in their In the era, many living with HIV/AIDS now have the opportunity to as living with a chronic illness rather than from a disease. Furthermore, new treatments have patients to feel and to their for longer periods of time, thus the and of the illness and the of the patient However, patients may feel their medication regimens are a of their patient From the outset of the epidemic, infected individuals have been and by have been to and social among physicians and in the United States to care for HIV-infected individuals has been well since early in the reluctance to care for these patients between 1991 and in HIV-related in the United States some but also some of stigma, support for (e.g., had significantly in almost of the that those with AIDS were responsible for the illness. Furthermore, significant they would be or having their with a with AIDS or having an with AIDS or at a where the had AIDS substantial also in that HIV could be transmitted through with AIDS on the a with them and using public all likely to be with to and HIV-infected has also that AIDS is on the it may be and at infected groups and of infected individuals may be greater in developing countries where there has been public education about the disease study of HIV-infected women in rural their that the to them at the time of delivery because of their infected that the medical were infected patients to the were also by study and so was their fear that their would or them Many infected individuals and the and feel and however, the and the and to public patients to remain for longer periods of time, the new treatments have made it possible for them to their illness longer and to as Their social identity as is thus and the many infected individuals experience with their distressing consequences are Yet, they may the psychological of having to a identity and possibly needed adherence The by of the of protease inhibitors was by the that adherence to these and regimens was often a task has been attributed to the to medication fear of the high that medication use will to of illness, and the of For these many individuals treatment or have been unwilling to use protease inhibitors from their physicians to do so While the of the recently regimens for treatment are being the impact of these of treatment on adherence remains to be While the of intervals may adherence because patients can to these treatment they also may adherence by patients to initiate their own who are to adherence to treatment regimens may engage in and have a of Those adhering to but not the dramatic health that early media with the ‘miraculous’ new medications may experience a of anxiety and fear and have also that, before HAART, all infected individuals a from the illness. However, now that some from treatment while others do of and has been by one of as becomes more that can be by and individual but also the to and (p. Finally, because many will not from HAART, those who do may experience a of similar to that in gay men who and to AIDS earlier in the care an part of the management of most chronic Many individuals living with HIV/AIDS engage in a variety of self-care to their immune system, to disease to stress and to symptoms. may be as as that their in a that for periods of so as to manage, for instance, remains a although we have an study infected individuals’ self-initiated for managing symptoms that they to the illness or to antiretroviral The research has focused on the use of and the of the new treatment use by HIV-infected persons has not diminished in the HAART era and and and or are used by infected adults in an to their immune system, to symptoms or medication and to stress. However, as most research has been on gay men with high levels of these findings may not be to other more disadvantaged populations, such as and In own we have found that infected adults often to when they cannot the side-effects of antiretrovirals or they Furthermore, most as than treatments. to these therapies is also by since the of many of are not by health in the era of HAART There is a that the of the new HAART and the availability of may to an in for a variety of the that AIDS is a chronic illness may significantly the of infection that has the of risk with considerably extended for may be a task for especially they feel well and become in relationships. some that having an viral load the of the to a on the impact of the new therapies on infected and although that the new treatments are about the of and sometimes also behaviors In a study of women and of heterosexual were asked about their and sexual behaviors the of viral and the new treatments. While many study that they were not as about being HIV positive because of the improved and they viewed AIDS as a less illness in the protease inhibitors era, they also that viral load and the new therapies (including have not them from Other however, evidence that the new treatments are in of sexual especially among gay and bisexual In one investigators found that, among active gay and bisexual those having sexual were more likely to the that having a who protease inhibitors or whose viral load is is less Additionally, a study of and heterosexual found that gay and bisexual men were more likely to sexual with or status in the HAART era while the sexual of heterosexual Finally, in a study of men and women who were and in more since the new therapies became available for future research for future research are suggested by the present that in survival and quality of life made possible by HAART can only be by those to these we must the treatment are the characteristics and of infected individuals who choose to remain antiretroviral to to their disease through or some other form or The phenomenon of long-term survivors be a one as treatments to the life expectancy of infected How is the of of later impacted by this illness. How HIV/AIDS or In the United States, HIV/AIDS has been a health in rural however, the of research on the disease has been on where health and social are more available and infected individuals may be more research whether the of living with HIV/AIDS in rural the rapid into rural among adolescents, heterosexual women, and future prevention and studies need to these more recently of risk behaviors and interventions behaviors were from work with gay and often these and interventions are in and long-term adherence to among the more recently populations be investigated. The of the epidemic, extended and new of AIDS as a manageable chronic illness may the of new prevention of the consequences that the new of AIDS as a manageable disease will have on and active of HIV-infected individuals is also As the treatment advances the and the health of will the fear and with the disease and, will social of those infected The issue of also be examined. HIV-infected individuals feel less about their illness, and are they more to their HIV status to in light of recent treatment advances and their consequences for those living with the As the present there are many continuities as well as discontinuities in the experience of living with HIV/AIDS over the past There is to feel by the that has been made since the of the in the diagnosis, treatment and clinical management of this disease. however, are still many of the psychosocial as in the pre-HAART era, in While we AIDS as a chronic illness, we to and we have about to with the illness, since many of the issues remain as the

AIDS · review · 178 citationsread the source →

The effect of older sibling, postnatal maternal stress, and household factors on language development in two- to four-year-old children.

Previous literature has shown that family structure affects language development. Here, factors relating to older siblings (their presence in the house, sex, and age gap), mothers (maternal stress), and household size and residential crowding were assessed to systematically examine the different roles of these factors. Data from mother-child dyads in a Singaporean birth cohort, (677-855 dyads; 52% males; 58% to 61% Chinese, 20% to 24% Malay, 17% to 19% Indian) collected when children were 24, 48, and 54 months old, were analyzed. There was a negative effect of having an older sibling, moderated by the siblings' age gap, but not by the older sibling's sex, nor household size or residential crowding. Maternal stress affected language outcomes in some analyses but not others. Implications for understanding the possible effects of family structure on language development are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Developmental psychology · 12 citationsread the source →

The pleasure of art as a matter of fact

You have accessMoreSectionsView PDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail Cite this article Nadal Marcos and Skov Martin 2018The pleasure of art as a matter of factProc. R. Soc. B.2852017225220172252http://doi.org/10.1098/rspb.2017.2252SectionYou have accessCommentThe pleasure of art as a matter of fact Marcos Nadal Marcos Nadal http://orcid.org/0000-0002-9341-4688 Department of Psychology, University of the Balearic Islands, Palma de Mallorca 07122, Spain [email protected] Google Scholar Find this author on PubMed Search for more papers by this author and Martin Skov Martin Skov Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Copenhagen 2650, Denmark Center for Decision Neuroscience, Copenhagen Business School, Copenhagen 2000, Denmark Google Scholar Find this author on PubMed Search for more papers by this author Marcos Nadal Marcos Nadal http://orcid.org/0000-0002-9341-4688 Department of Psychology, University of the Balearic Islands, Palma de Mallorca 07122, Spain [email protected] Google Scholar Find this author on PubMed and Martin Skov Martin Skov Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Copenhagen 2650, Denmark Center for Decision Neuroscience, Copenhagen Business School, Copenhagen 2000, Denmark Google Scholar Find this author on PubMed Published:21 March 2018https://doi.org/10.1098/rspb.2017.2252All other forms of perception divide a man, because they are exclusively based either on the sensuous or on the intellectual part of his being; only the perception of the Beautiful makes something whole of him, because both his natures must accord with it.— Schiller, 1793–1795, Letters on the Aesthetic Education of Man, p. 138, Letter 27Can art make us better people? Better members of society? In her recent article, 'Pleasure junkies all around! Why it matters and why "the arts" might be the answer: a biopsychological perspective', Christensen [1] claims that engaging with art can promote healthy choices, choices that balance short-term pleasure goals with long-term general well-being. She suggests that many modern life conveniences, such as social media, computer games or online shopping, have the potential to turn us into 'pleasure junkies' because they maximize short-term pleasures. But art, Christensen argues, is a safe choice and a means to remedy this unhealthy addiction to pleasure. Christensen's argument is grounded on three claims about the sort of pleasure we get from art. First, in contrast to low-level pleasure, which Christensen conceives as 'a mere perceptual stimulation leading to a rewarding sensation (food, sex, etc.)' ([1], p. 2), pleasure from art is presented as a kind of higher-order pleasure that engages 'broader neural networks implied in the attribution of meaning' (p. 2), presumably leading to 'long-term maintenance of healthy bodily function' (p. 2). Second, 'the arts do not induce states of craving without fulfilment—as do activities with reinforcement schedules which are prone to create habits and addictions such as intermittent variable ratio or interval reinforcement schedules (e.g. social media, gambling, football, extreme sports, drugs' (p. 4). Third, 'the arts do not search for a perceptual "Bliss point" […]. They do not just repeat over and over again a sensory stimulus that excites the senses and induces craving for more of a "pleasurable itch" (e.g. sugar, sexualized body displays, certain musical lyrics, tones; i.e. a perceptual "bliss point")' (p. 4).The claim, in a nutshell, is that the pleasure induced by art is different to the pleasure induced by food, sex, sports or drugs, because it is related to the balanced activation of brain systems related to short-term pleasure and long-term wellbeing goals, because it does not induce craving, and because it is not aimed at a perceptual 'bliss point'. This distinct sort of pleasure, according to Christensen, makes it possible for the arts to thwart the pernicious effects that the unhealthy urges and cravings licensed by 'today's mainstream acceptance of pleasure-seeking behaviour' (p. 5) have on individuals' lives and on societies. Such sweeping statements about art, food, sex, sports and society as a whole merit close examination. Christensen's primary claim that the pleasure induced by art is of a special kind, different to the pleasure induced by other activities is not supported by current understanding of what pleasure is. It is, moreover, contradicted by abundant empirical evidence. This evidence shows that pleasures, whatever their source, owe to activity in the same mesocorticolimbic circuit [2] and are encoded as a common neural currency [3]. As Kent Berridge and Morten Kringelbach put it: 'the brain mechanisms involved in fundamental pleasures (food and sexual pleasures) overlap with those for higher-order pleasures (e.g. monetary, artistic, musical, altruistic and transcendent pleasures) […] From sensory pleasures and drugs of abuse […] to monetary, aesthetic and musical delights, all pleasures seem to involve the same hedonic brain systems' ([4], p. 481). Thus, there is no evidence for specific brain regions or neural circuits related to the pleasure from art. Rather, the appreciation of art relies on brain mechanisms that evolved to appraise the value of biologically relevant objects in relation to internal homeostatic states [5]: 'Emotional reactions to music, further, activate the same cortical, subcortical and autonomic circuits, which are considered as the essential survival circuits of biological organisms in general' ([6], p. 6). In sum, the evidence shows that pleasure elicited by music and other art forms is no different in genesis and function to the pleasure induced by food, drugs and sex [7,8]. This is a matter of fact, not opinion. What supports Christensen's argument if not empirical evidence? In our view, her argument for the distinctness of art-induced pleasure seems based upon an oversimplified and devaluing conception of the pleasures of sex, food and sports, and a very narrow notion of art and its function. Christensen presents food, sex and sports as meaningless low-level sources of pleasure, and the arts as privileged vehicles for meaningful experiences. It is the personal and meaningful engagement with art—Christensen suggests—that fosters a balanced activation of brain systems related to short-term pleasure and long-term well-being goals. However, rarely—if ever—are food, sex and sports meaningless rewarding sensations. Contrary to Christensen's definition on page 2 of her article, pleasure—even sensory pleasure—is not simply reward, and never simply a sensation [4]. Indulging in food, sex or sports are meaningful and personally significant experiences that are not a matter of mere physical sensation. The experience of pleasure from food and sex is shaped by context, knowledge, expectations, anticipations, attitudes and beliefs that bring meaning to them [9–11]. Sex can be meaningful because it signifies physical connection with one's loved one, because it is cheating on someone, or deemed a sin. Likewise, eating is not about obtaining low-level pleasure. What we eat, the way we eat, what we believe about what we eat, where and whom we eat with, imbue eating with individual and social meaning, and shape the actual pleasure of eating [12]. On the other hand, encounters with art are not necessarily meaningful [13,14]. Actually, there is nothing intrinsically meaningful about engaging with art. Many laypeople lack the knowledge schemata required to engage meaningfully with abstract, cubist or contemporary art [15,16]. There are plenty of artworks people do not find meaningful or pleasant. Meaning making is not a special feature of art; it is a general feature of our species's cognition [17,18]. We can endow virtually any aspect of reality with meaning: sex, food, sports, a urinal, the shape of a cloud, an averted glance, someone's absence. Christensen's argument also rests on a historically and culturally narrow conception of art and its function. Art is presented as a circumscribed category of activities that elicit a unique sort of pleasant experiences: — The arts are set of activities of a special kind that share certain defining features distinguishing them from other activities: 'the arts push boundaries, surprise, reveal and excite both artist and spectator' ([1], p. 4).— Art encounters are positive, leading to 'pleasurable chills' and pleasurable experiences of understanding: 'The moment of meaning-assignation, also called "mastering" or "understanding" an artwork, is therefore a pleasurable experience' ([1], p. 4).— The pleasure elicited by art is special, because it does not involve craving for intense peaks: 'The arts do not search for a perceptual "bliss point" […] They do not just repeat over and over a sensory stimulus that excites the senses and induces craving for more of a "pleasurable itch"' ([1], p. 4).This characterization of the arts substantially overlaps with the notion of 'fine arts'. The core features of this characterization were instituted in the eighteenth century, after European intellectuals grouped certain activities into a distinct and autonomous collection, labelled 'fine arts'. To make sense of and promote this grouping, it became imperative to identify a common essence setting art apart from other activities [19,20,21]. One of the most popular proposals was that only art could produce a special sort of pleasure, sophisticated and polite [19,21]—a conception stemming not from any understanding of physiology, but from mere speculation. This limited historical and cultural scope renders this conception of the arts unfit for behavioural or neuroscientific research [19]. The category 'the arts' should not be mistaken for a natural kind. It is a historical convention, and has no direct biological correspondence. Moreover, this conception of art that Christensen espouses does not apply to art as practised in non-Western societies [19,22]. It does not even apply to Western art before the eighteenth century or after the nineteenth century [19,20,21]. First, art does not necessarily evoke pleasurable experiences. There are abundant artworks intended to arouse negative emotions [19,23], and to portray physical and moral ugliness [24]. Understanding art is not necessarily a pleasant experience: it can be an angering, disgusting or upsetting one [25]. Second, many artworks actually exploit repetition, bliss points and craving [26]. Repetition is a fundamental design feature of music and other performance arts [27]: In Relation in Space (1976) Marina Abramovic and Ulay ran into each other repeatedly for an hour; Ravel's Bolero is a 17 min-long instance of melodic and rhythmic repetitiveness. Anticipation and craving for bliss points are also essential to music [28]. In fact, the enjoyment of music is linked to intense feelings of anticipation and expectation caused by dopamine activity in the caudate nucleus (also involved in the rewarding aspect of food) [29,30], and peak pleasure states (bliss points) [31], caused by the release of dopamine and opioids in the brain's reward system (also involved in cocaine induced euphoria) [29,30]. Given the available evidence, therefore, there is no reason to believe that the pleasure from art is special or unique [32].In sum, Christensen's claim for the distinctiveness of pleasure from art is contradicted by empirical evidence, and her argument for the beneficial effects of art rests upon disputed foundations. Art's capacity to promote healthier choices and make us better people that can contribute to a better society remains as unconfirmed today as it was when Schiller speculated on art's power to harmonize human's conflicting sensuous and formal impulses. Christensen's argument is problematic even if intended to highlight hypothetical possibilities. Arguments about hypothetical possibilities should still rely on valid premises, and scientific hypotheses should be grounded on evidence, or at least in line with it. Otherwise, they are merely unfounded speculations. Scientific aesthetics is only just finding its footing and its place within cognitive neuroscience [33,34]. If evidence is ignored or rejected because it does not fit preconceived notions about art and its function, scientific aesthetics will become only an arena to promote and legitimize personally appealing notions of art by applying a scientific gloss over them. A proper scientific study of art needs to be grounded on empirical evidence and strong arguments that follow from solid premises [35,36]. 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Kalpokas I (2019) Making the Theory Political A Political Theory of Post-Truth, 10.1007/978-3-319-97713-3_4, (87-121), . Kalpokas I (2019) Affective Encounters of the Algorithmic Kind: Post-Truth and Posthuman Pleasure, Social Media + Society, 10.1177/2056305119845678, 5:2, (205630511984567), Online publication date: 1-Apr-2019. Skov M (2019) Aesthetic Appreciation: The View From Neuroimaging, Empirical Studies of the Arts, 10.1177/0276237419839257, 37:2, Online publication date: H, I and (2020) A for We Aesthetic in Human Neuroscience, A and in A New for Arts, This March Article in 2018 The Author(s)Published by the Royal Society. All rights Citations and are available with

Proceedings of the Royal Society B Biological Sciences · editorial or comment · 24 citationsread the source →

Online activity of mosques and Muslims in the Netherlands: A study of Facebook, Instagram, YouTube and Twitter.

Research on Muslim minorities in western societies has mainly focused on offline behavior, such as mosque attendance, whereas little is known about their presence in the online world. This study explores the online visibility and activities of all (478) mosques in the Netherlands. We collected data on personal websites and four social media platforms (Facebook, Twitter, Instagram and YouTube). The majority of mosques have a website (52%) and an account on Facebook (61%). Less often used are Twitter (17%), Instagram (17%) and YouTube (19%). On social media platforms, mosques strongly differ in their activity and number of followers. We find evidence to suggest that Salafist mosques, which tend to have a strict ideology, are more active on Twitter and YouTube, and also attract a larger share of followers on Facebook than non-Salafist mosques. Our more fine-grained analysis on Twitter shows that Salafist mosques in the Netherlands cluster together. Followers of Salafist mosques make up a community of users who are mainly connected to each other ("bonding ties"), and much less so to other users ("bridging ties"). We conclude with a discussion of opportunities for studying the online presence and activities of mosques and Muslims in western societies.

PloS one · 1 citationsread the source →

Empowerment in adolescents and young adults with cancer: Relationship with health-related quality of life.

Background: The difficulties adolescents and young adults (AYAs) encounter during a cancer experience may result in a reduction in or absence of empowerment. The aims of the current study were to assess levels of empowerment and associated (demographic, clinical, or psychological) factors and examine the association between empowerment and health-related quality of life (HRQOL) among AYA patients with cancer. Methods: Patients aged 18 to 35 years at time of cancer diagnosis and who were seen by 1 of the members of the specialized multidisciplinary AYA team of the Radboud University Medical Center were invited to complete questionnaires regarding empowerment; HRQOL; and sociodemographic, clinical, and psychological characteristics (autonomy, coping, unmet social support needs, and psychological distress). Results: A total of 83 AYA patients completed the questionnaires. The mean age of the participants at the time of diagnosis was 27.5 years. The vast majority had been treated with chemotherapy (86%), had a more advanced stage of disease, and had completed treatment at the time of participation (74%). The mean empowerment level was 154.1 (standard deviation, 17.8) with a range of 114 to 200. Multivariate analysis demonstrated that the autonomy subscales of self-awareness (β = .35), capacity for managing new situations (β = .19), and social support (β = .35) were found to be positively associated with empowerment. Coping difficulties (β = -.19) were found to be negatively associated with empowerment. Empowerment was independently associated with physical (β = .31), psychological (β = .50), social (β = .39), religious (β = .33), and total HRQOL (β = .52; all P<.01). Conclusions: Low levels of empowerment were associated with low levels of autonomy and social support, female sex, and coping difficulties among AYA patients with cancer. Recognizing these patients as candidates for empowerment interventions ultimately could help to improve HRQOL in late adolescence and young adulthood. Cancer 2017;123:4039-47. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cancer · 42 citationsread the source →

Primal world beliefs.

Beck's insight-that beliefs about one's self, future, and environment shape behavior-transformed depression treatment. Yet environment beliefs remain relatively understudied. We introduce a set of environment beliefs-primal world beliefs or primals-that concern the world's overall character (e.g., the world is interesting, the world is dangerous). To create a measure, we systematically identified candidate primals (e.g., analyzing tweets, historical texts, etc.); conducted exploratory factor analysis (N = 930) and two confirmatory factor analyses (N = 524; N = 529); examined sequence effects (N = 219) and concurrent validity (N = 122); and conducted test-retests over 2 weeks (n = 122), 9 months (n = 134), and 19 months (n = 398). The resulting 99-item Primals Inventory (PI-99) measures 26 primals with three overarching beliefs-Safe, Enticing, and Alive (mean α = .93)-that typically explain ∼55% of the common variance. These beliefs were normally distributed; stable (2 weeks, 9 months, and 19 month test-retest results averaged .88, .75, and .77, respectively); strongly correlated with many personality and wellbeing variables (e.g., Safe and optimism, r = .61; Enticing and depression, r = -.52; Alive and meaning, r = .54); and explained more variance in life satisfaction, transcendent experience, trust, and gratitude than the BIG 5 (3%, 3%, 6%, and 12% more variance, respectively). In sum, the PI-99 showed strong psychometric characteristics, primals plausibly shape many personality and wellbeing variables, and a broad research effort examining these relationships is warranted. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Psychological assessment · 48 citationsread the source →

Adverse childhood experiences, associated stressors and comorbidities in children and youth with fetal alcohol spectrum disorder across the justice and child protection settings in Western Australia.

Background: Individuals with Fetal Alcohol Spectrum Disorder (FASD) are at risk of having adverse childhood experiences (ACEs), especially those with child protection and/or justice system involvement. The complex relationship between FASD and psychosocial vulnerabilities in the affected individual is an important clinical risk factor for comorbidity. This study (1) explored the ACEs and associated stressors in individuals with FASD; (2) investigated the association between ACEs and negative outcomes, i.e., justice/child protection system involvement; and (3) examined the relationship between ACEs and comorbid conditions such as mood and neurodevelopmental disorders. Methods: Data were collected retrospectively via file review from diagnostic clinics in Western Australia. Life adversity was coded using a standardised ACEs questionnaire. A total of 211 participants (72% males) with FASD with a mean age of 11 years (range = 2-21) were included in the final sample. 70% of the total sample had been involved with the child protection system and 40% had trouble with the law. Results: Exposure to drinking/substance misuse at home (70%) and domestic violence (52%) were the two most common ACEs across the total sample. In the entire cohort, 39% had four or more ACEs, indicating higher risks of poor health outcomes. Additional stressors recorded were disengagement from school (43%), transiency (19%), victims of bullying (12%), traumatic brain injury (9%) and homelessness (5%). ACEs such as drinking/substance misuse at home, emotional neglect and physical neglect were positively associated with child protection system involvement. Additionally, exposure to domestic violence was positively correlated with justice system involvement. Higher rates of life adversity in this clinical population were associated with an increased number of comorbidities. Specifically, those with FASD who had comorbidities such as attachment disorder, substance use disorder, and PTSD also reported higher ACEs scores. Conclusion: ACEs were common in this clinical population. Increased ACEs in this sample were associated with increased comorbidities and involvement with the child protection and/or justice system. This highlights that prevention, intervention and early diagnosis of FASD are important for at risk children to reduce the negative effects of ACEs.

BMC pediatrics · 17 citationsread the source →

Migration and risk of HIV acquisition in Rakai, Uganda: a population-based cohort study.

Background: In sub-Saharan Africa, migrants typically have higher HIV prevalence than non-migrants; however, whether HIV acquisition typically precedes or follows migration is unknown. We aimed to investigate the risk of HIV after migration in Rakai District, Uganda. Methods: In a prospective population-based cohort of HIV-negative participants aged 15-49 years in Rakai, Uganda, between April 6, 1999, and Jan 30, 2015, we assessed the association between migration and HIV acquisition. Individuals were classified as recent in-migrants (≤2 years in community), non-recent in-migrants (>2 years in community), or permanent residents with no migration history. The primary outcome was incident HIV infection. We used Poisson regression to estimate incidence rate ratios (IRRs) of HIV associated with residence status with adjustment for demographics, sexual behaviours, and time. Data were also stratified and analysed within three periods (1999-2004, 2005-11, and 2011-15) in relation to the introduction of combination HIV prevention (CHP; pre-CHP, early CHP, and late CHP). Findings: Among 26 995 HIV-negative people who participated in the Rakai Community Cohort Study survey, 15 187 (56%) contributed one or more follow-up visits (89 292 person-years of follow-up) and were included in our final analysis. 4451 (29%) were ever in-migrants and 10 736 (71%) were permanent residents. 841 incident HIV events occurred, including 243 (29%) among in-migrants. HIV incidence per 100 person-years was significantly increased among recent in-migrants compared with permanent residents, for both women (1·92, 95% CI 1·52-2·43 vs 0·93, 0·84-1·04; IRR adjusted for demographics 1·75, 95% CI 1·33-2·33) and men (1·52, 0·99-2·33 vs 0·84, 0·74-0·94; 1·74, 1·12-2·71), but not among non-recent in-migrants (IRR adjusted for demographics 0·94, 95% CI 0·74-1·19 for women and 1·28, 0·94-1·74 for men). Between the pre-CHP and late-CHP periods, HIV incidence declined among permanent resident men (p<0·0001) and women (p=0·002) and non-recent in-migrant men (p=0·031), but was unchanged among non-recent in-migrant women (p=0·13) and recent in-migrants (men p=0·76; women p=0·84) INTERPRETATION: The first 2 years after migration are associated with increased risk of HIV acquisition. Prevention programmes focused on migrants are needed to reduce HIV incidence in sub-Saharan Africa. Funding: National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, the National Institute for Allergy and Infectious Diseases Division of Intramural Research, National Institutes of Health; the Centers for Disease Control and Prevention; the Bill & Melinda Gates Foundation; and the Johns Hopkins University Center for AIDS Research.

The lancet. HIV · 83 citationsread the source →

Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK.

Background: A rise in the incidence of some autoimmune disorders has been described. However, contemporary estimates of the overall incidence of autoimmune diseases and trends over time are scarce and inconsistent. We aimed to investigate the incidence and prevalence of 19 of the most common autoimmune diseases in the UK, assess trends over time, and by sex, age, socioeconomic status, season, and region, and we examine rates of co-occurrence among autoimmune diseases. Methods: In this UK population-based study, we used linked primary and secondary electronic health records from the Clinical Practice Research Datalink (CPRD), a cohort that is representative of the UK population in terms of age and sex and ethnicity. Eligible participants were men and women (no age restriction) with acceptable records, approved for Hospital Episodes Statistics and Office of National Statistics linkage, and registered with their general practice for at least 12 months during the study period. We calculated age and sex standardised incidence and prevalence of 19 autoimmune disorders from 2000 to 2019 and used negative binomial regression models to investigate temporal trends and variation by age, sex, socioeconomic status, season of onset, and geographical region in England. To characterise co-occurrence of autoimmune diseases, we calculated incidence rate ratios (IRRs), comparing incidence rates of comorbid autoimmune disease among individuals with a first (index) autoimmune disease with incidence rates in the general population, using negative binomial regression models, adjusted for age and sex. Findings: Among the 22 009 375 individuals included in the study, 978 872 had a new diagnosis of at least one autoimmune disease between Jan 1, 2000, and June 30, 2019 (mean age 54·0 years [SD 21·4]). 625 879 (63·9%) of these diagnosed individuals were female and 352 993 (36·1%) were male. Over the study period, age and sex standardised incidence rates of any autoimmune diseases increased (IRR 2017-19 vs 2000-02 1·04 [95% CI 1·00-1·09]). The largest increases were seen in coeliac disease (2·19 [2·05-2·35]), Sjogren's syndrome (2·09 [1·84-2·37]), and Graves' disease (2·07 [1·92-2·22]); pernicious anaemia (0·79 [0·72-0·86]) and Hashimoto's thyroiditis (0·81 [0·75-0·86]) significantly decreased in incidence. Together, the 19 autoimmune disorders examined affected 10·2% of the population over the study period (1 912 200 [13·1%] women and 668 264 [7·4%] men). A socioeconomic gradient was evident across several diseases, including pernicious anaemia (most vs least deprived area IRR 1·72 [1·64-1·81]), rheumatoid arthritis (1·52 [1·45-1·59]), Graves' disease (1·36 [1·30-1·43]), and systemic lupus erythematosus (1·35 [1·25-1·46]). Seasonal variations were observed for childhood-onset type 1 diabetes (more commonly diagnosed in winter) and vitiligo (more commonly diagnosed in summer), and regional variations were observed for a range of conditions. Autoimmune disorders were commonly associated with each other, particularly Sjögren's syndrome, systemic lupus erythematosus, and systemic sclerosis. Individuals with childhood-onset type 1 diabetes also had significantly higher rates of Addison's disease (IRR 26·5 [95% CI 17·3-40·7]), coeliac disease (28·4 [25·2-32·0]), and thyroid disease (Hashimoto's thyroiditis 13·3 [11·8-14·9] and Graves' disease 6·7 [5·1-8·5]), and multiple sclerosis had a particularly low rate of co-occurrence with other autoimmune diseases. Interpretation: Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases. The socioeconomic, seasonal, and regional disparities observed among several autoimmune disorders in our study suggest environmental factors in disease pathogenesis. The inter-relations between autoimmune diseases are commensurate with shared pathogenetic mechanisms or predisposing factors, particularly among connective tissue diseases and among endocrine diseases. Funding: Research Foundation Flanders.

Lancet (London, England) · 508 citationsread the source →

Association between socioeconomic status and fertility among adolescents aged 15 to 19: an analysis of the 2013/2014 Zambia Demographic Health Survey (ZDHS).

Background: Adolescents face significant barriers to access and utilization of sexual and reproductive health services in many low-income settings, which in turn may be associated with adverse consequences such as early pregnancy, sexually transmitted infections, unsafe abortion and mortality. There is evidence suggesting that limited access to sexual and reproductive health information and services among adolescents contributes to these outcomes. We aimed to find out the factors that affect the fertility of adolescents aged 15 to 19 years in Zambia and to identify possible drivers of adolescents' fertility. Methods: Secondary analysis of the ZDHS 2013/14 data was carried out to find out the factors that affect the fertility rate of adolescents aged 15 to 19 years using multivariate logistic regression (n = 3666). Results: Overall, 23.1% of adolescents had given birth at least once in the 5 years leading to the survey (n = 3666, 99.4% response), and 49.8% were rural-based while 50.2% were urban-based. The median number of schooling was 8 years (IQR 6-10). About 52% of the adolescents were in the poorer, poor and medium wealth quintiles while the other 48% were in the rich and richer quintiles. Factors found to affect fertility include residence, wealth status, educational attainment, marriage and abortion. An urban-based adolescent with a lower socioeconomic status was 2.4 times more likely to give birth compared to rural-based poorer adolescents (aOR = 2.4, 95% CI: 1.5, 3.7, p < 0.001). Although odds of giving birth were much higher among rural-based married adolescents (aOR = 8.0, 95% CI: 5.4, 11.9, p < 0.001) compared to urban married adolescents (aOR = 5.5, 95% CI: 8.3, 16.0, p < 0.001), and these relationships both statistically significant, higher educational attainment (aOR = 0.7, 95% CI: 0.6, 0.8 p < 0.001) and abortion (aOR = 0.3, 95% CI: 0.1, 0.8, p = 0.020) reduced these odds, particularly for rural-based adolescents. Conclusion: Despite response aimed at reducing adolescent fertility, low wealth status, low educational attainment and early marriage remain significant drivers of adolescent fertility in Zambia. There is a need to address sexual and reproductive health needs of urban-based adolescents with a lower socioeconomic status.

Reproductive health · 17 citationsread the source →

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017.

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of "leaving no one behind", it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990-2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0-100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4-67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6-14·0) to a high of 84·9 (83·1-86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains-curative interventions in the case of NCDs-towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions-or inaction-today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030. Funding: Bill & Melinda Gates Foundation.

Lancet (London, England) · 333 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 use of biofeedback for children with fecal incontinence secondary to retentive constipation: Experience of a French Pediatric Center.

Background: Fecal incontinence (FI) secondary to chronic retentive constipation is a frequent demand in pediatric gastroenterology clinics. The management of constipation in children includes laxatives (polyethylene glycol, PEG), enhanced toilet training, and dietary advice. Biofeedback is a possible treatment for children above the age of 7 years with resistant FI. Aim: To analyze any changes in volume to trigger defecation (VTD) and envy score over the course of biofeedback sessions according to clinical response. Methods: In this retrospective study, we reviewed the medical records of 23 children diagnosed with FI according to the Rome IV criteria and treated with biofeedback. For each biofeedback session, a mean VTD by subject was measured. At the end, therapy was considered a success if soiling disappeared and a failure if any persisted. The need to defecate expressed by the child was described as an envy score. A 0-10 visual analog scale was used to express the intensity of this sensation. Follow-up involved calling the parents 12 months after the biofeedback sessions had ended to assess symptoms remotely. Results: The study included 19 boys and 4 girls with a median age of 10 years. Patients' ages ranged between 7 and 17 years. None of them had any associated neurological disorders. All children had FI for >1 year. The median number of soiling episodes per week was 7. The average number of biofeedback sessions was 3 (range 1-5). At the end of the rehabilitation sessions, 12 children (52%) were in the "success" group. In the latter, median VTD decreased from 97 ml to 70 ml between the first and last session. In the "failure" group, VTD decreased from 120 ml to 100 ml. The between-group difference in the median VTD at the first session was not statistically significant. The last observation carried forward (LOCF) VTD was significantly lower in the "success" group compared to the "failure" group (70 ml versus 100 ml, p = 0.03). Median envy scores decreased during the biofeedback sessions with no statistical difference between the groups at the last session. Follow-up of children in the "success" group one year after the last biofeedback session revealed that 10 patients had no relapse (83%) and 2 were lost to follow-up. Conclusions: Biofeedback might be an effective tool for the management of FI resistant to medical treatment in children.

Clinics and research in hepatology and gastroenterology · 6 citationsread the source →

Donor quality of life after living donor liver transplantation: a review of the literature.

Living donor liver transplantation (LDLT) provides a source for transplant in the setting of the deceased donor organ shortage. Seeing as living donors do not derive any medical benefit from the procedure, fully understanding the impact of donation on donor health-related quality of life (HRQOL) is essential. A systematic search of the MEDLINE database was performed from 2008-2020, using relevant Medical Subject Headings. Articles were evaluated for study design, cohort size and follow-up time and excluded if they contained significant methodological flaws. A total of 43 articles were included: 20 (47%) were cross-sectional and 23 (53%) were longitudinal. The mean number of donors per study was 142 (range:8-578) with follow-up ranging from 12-132 months. Forty-two unique HRQOL metrics were implemented across the 43 studies, the majority of which were questionnaires. Of the 31 studies that used the Medical Outcomes Study Short Form 36 questionnaire, 9.1% of donors reported physical QOL did not return to pre-LDLT levels for at least 2 years after donation. Mental QOL remained stable or improved after LDLT, with mean mental composite scores increasing from 50 to 52 at 3 months post-LDLT in one study. The predicted probability of poor sexual desire decreased at 1-year post-LDLT (male: 0.08, female: 0.26) relative to pre-LDLT (male: 0.44, female: 0.76; P<0.001) and three months post-LDLT (male: 0.35, female 0.69; P=0.001). Forty percent of donors found LDLT to be financially burdensome at 3 months and 19% at 2 years post-LDLT. Female gender and obesity were consistent predictors of worse HRQOL. Laparoscopy-assisted donor hepatectomy was associated with shorter hospitalizations than open donor hepatectomy (10.3 vs. 18.3 days, P=0.02). No studies used the National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) measures of HRQOL. Our review demonstrates that LDLT can have a long-lasting negative impact on physical QOL in 9.1% of donors and can cause both sexual dysfunction and significant financial strain. Future studies should consider using standardized and extensively validated patient reported outcomes measures, such as PROMIS, in order to directly compare outcomes across studies and gain further insight into the impact of LDLT on D-HRQOL.

Digestive medicine research · 11 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 →

Interventions for treating femoral shaft fractures in children and adolescents.

Background: Fractures of the femoral shaft in children are relatively uncommon but serious injuries that disrupt the lives of children and their carers and can result in significant long-term disability. Treatment involves either surgical fixation, such as intramedullary nailing or external fixation, or conservative treatment involving prolonged immobilisation, often in hospital. Objectives: To assess the effects (benefits and harms) of interventions for treating femoral shaft fractures in children and adolescents. Search methods: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (accessed 16 August 2013), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2013 Issue 7), MEDLINE (1946 to August Week 1 2013), EMBASE (1980 to 2012 week 9), CINAHL (16 August 2013), clinical trials registries, conference proceedings and reference lists; and contacted trial authors and experts in the field. Selection criteria: Randomised and quasi-randomised controlled trials comparing conservative and surgical interventions for diaphyseal fractures of the femur in children under 18 years of age. Our primary outcomes were functional outcome measures, unacceptable malunion, and serious adverse events. Data collection and analysis: Two authors independently screened and selected trials, assessed risk of bias and extracted data. We assessed the overall quality of the evidence for each outcome for each comparison using the GRADE approach. We pooled data using a fixed-effect model. Main results: We included 10 trials (six randomised and four quasi-randomised) involving a total of 527 children (531 fractures). All trials were at some risk of bias, including performance bias as care provider blinding was not practical, but to a differing extent. Just one trial was at low risk of selection bias. Reflecting both the risk of bias and the imprecision of findings, we judged the quality of evidence to be 'low' for most outcomes, meaning that we are unsure about the estimates of effect. Most trials failed to report on self-assessed function or when children resumed their usual activities. The trials evaluated 10 different comparisons, belonging to three main categories. Surgical versus conservative treatment. Four trials presenting data for 264 children aged 4 to 12 years made this comparison. Low quality evidence (one trial, 101 children) showed children had very similar function assessed using the RAND health status score at two years after surgery (external fixation) compared with conservative treatment (spica cast): mean 69 versus 68. The other three trials did not report on function. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up 3 to 24 months) that surgery reduced the risk of malunion (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.15 to 0.59, 4 trials). Assuming an illustrative baseline risk of 115 malunions per 1000 in children treated conservatively, these data equate to 81 fewer (95% CI 47 to 97 fewer) malunions per 1000 in surgically-treated children. Conversely, low quality evidence indicated that there were more serious adverse events such as infections after surgery (RR 2.39, 95% CI 1.10 to 5.17, 4 trials). Assuming an illustrative baseline risk of 40 serious adverse events per 1000 for conservative treatment, these data equate to 56 more (95% CI 4 to 167 more) serious adverse events per 1000 children treated surgically. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with intramedullary nailing than with traction followed by a cast, and that surgery reduced the time taken off from school. Comparisons of different methods of conservative treatment. The three trials in this category made three different comparisons. We are very unsure if unacceptable malunion rates differ between immediate hip spica versus skeletal traction followed by spica in children aged 3 to 10 years followed up for six to eight weeks (RR 4.0, 95% CI 0.5 to 32.9; one trial, 42 children; very low quality evidence). Malunion rates at 5 to 10 years may not differ between traction followed by functional orthosis versus traction followed by spica cast in children aged 5 to 13 years (RR 0.98, 95% CI 0.46 to 2.12; one trial, 43 children; low quality evidence). We are very unsure (very low quality evidence) if either function or serious adverse events (zero events reported) differ between single-leg versus double-leg spica casts (one trial, 52 young children aged two to seven years). Low quality evidence on the same comparison indicates that single-leg casts are less awkward to manage by parents, more comfortable for the child and may require less time off work by the caregiver. Comparisons of different methods of surgical treatment. The three trials in this category made three different comparisons. Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using elastic stable intramedullary nailing or external fixation (one trial, 19 children). The same applies to the rates of serious adverse events and time to resume full weight-bearing in children treated with dynamic versus static external fixation (one trial, 52 children). Very low quality evidence (one trial, 47 children) means that we do not know if malunion, serious adverse events and time to resume weight-bearing actually differ between intramedullary nailing versus submuscular plating. However, there could be more difficulties in plate removal subsequently. Authors' conclusions: There is insufficient evidence to determine if long-term function differs between surgical and conservative treatment. Surgery results in lower rates of malunion in children aged 4 to 12 years, but may increase the risk of serious adverse events. Elastic stable intramedullary nailing may reduce recovery time. There is insufficient evidence from comparisons of different methods of conservative treatment or of different methods of surgical treatment to draw conclusions on the relative effects of the treatments compared in the included trials. Plain language summary: Different methods of treating fractures of the shaft of the thigh bone in children and adolescents Although uncommon, fractures of the femoral shaft (thigh bone) in children may require prolonged treatment in hospital and sometimes surgery. This can cause significant discomfort and can disrupt the lives of the children and their familles. This review compared different methods of treating these fractures. Surgical treatment comprises different methods of fixing the broken bones, such as internally-placed nails, or pins incorporated into an external frame (external fixation). Non-surgical or conservative treatment usually involves different types of plaster casts with or without traction (where a pulling force is applied to the leg). We searched for studies in the medical literature until August 2013. The review includes 10 randomised or quasi-randomised controlled trials that recruited 527 children. Four trials compared different surgical versus non-surgical treatments; three compared different methods of non-surgical treatment and three compared different methods of surgical treatment. Generally we are unsure about the results of these trials because some were at risk of bias, some results were contradictory and usually there was too little evidence to rule out chance findings. Most trials failed to report on self-assessed function or when children resumed their usual activities. Comparing surgical versus non-surgical treatment. Low quality evidence (one trial, 101 children) showed children had similar function at two years after having surgery, involving external fixation, compared with those treated with a plaster cast. The other three trials did not report this outcome. There was moderate quality evidence (four trials, 264 children, aged 4 to 12 years, followed up for 3 to 24 months) that surgery reduced the risk of malunion (the leg is deformed) compared with non-surgical treatment. However, low quality evidence (four trials) indicated that there were more serious adverse events such as infections after surgery. There was low quality evidence (one trial, 101 children) of similar satisfaction levels in children and parents with surgery involving external fixation and plaster cast only. However, there was low quality evidence (one trial, 46 children) that more parents were satisfied with surgery involving an internal nail than with traction followed by a cast and that surgery reduced the time taken off from school. Comparing various non-surgical treatments. Very low quality evidence means that we are very unsure if the rates of malunion differ or not between children treated with immediate plaster casts versus with traction followed by plaster cast (one trial, 42 children), or between children treated with traction followed by either a functional orthosis (a brace or cast that allows some movement) or a cast (one trial, 43 children). We are very unsure if either function or serious adverse events differ between young children (aged two to seven years) immobilised in single-leg versus double-leg casts (one trial, 52 children). However, single-leg casts appear to be easier to manage by parents and more comfortable for the child. Comparing various surgical treatments Very low quality evidence means that we are very unsure if the rates of malunion, serious adverse events, time to return to school or parental satisfaction actually differ in children whose fractures were fixed using internal nails or external fixation (one trial, 19 children). (ABSTRACT TRUNCATED)

Evidence-based child health : a Cochrane review journal · 16 citationsread the source →

Emerging Adulthood and College‐aged Youth: An Overlooked Age for Weight‐related Behavior Change

Obesity is a major public health concern, and effective population-wide intervention strategies aimed at reducing obesity are needed. Although a growing body of literature has explored modifiable determinants of excess weight gain in adults and, to a lesser extent, in children, other important ages have been understudied. Though once considered to be an age of optimal health and well-being, the transition from adolescence to young adulthood is gaining recognition as an important time for health promotion and disease prevention. Not only is the presence of obesity and unhealthy lifestyle characteristics at this life stage associated with increased chronic disease risk, but this also may be a critical time during which young people establish independence and adopt lasting health behavior patterns. The objectives of this article are to: (i) describe emerging adulthood as a developmentally unique life stage, (ii) highlight epidemiologic evidence documenting adverse changes in diet, physical activity, and weight during this stage, (iii) discuss the influence of food and beverage marketing targeting emerging adults, and (iv) illustrate the need for health promotion and intervention efforts that could target young adults through settings such as postsecondary institutions. Over the past 50 years, major population-level demographic shifts including increases in postsecondary education and delays in marriage and childbearing have occurred. These shifts have opened the door for a period of “emerging adulthood,” typically defined as 18–25 years of age (1). This period is marked by important transitions such as leaving home and increasing autonomy in decision-making; however at the same time, adult responsibilities such as financial independence and residential and employment stability are still in flux. This period of emerging adulthood may be an important, yet overlooked, age for establishing long-term health behavior patterns. Several factors differentiate emerging adulthood from other life stages and have specific relevance to the formation of health behavior patterns, including identity development and shifting interpersonal influences. One defining characteristic of this life stage is the development of a self identity. Emerging adulthood is a time for the exploration of new ideologies and behaviors which allow individuals to express their individuality. Given previous research showing that identity (e.g., incorporating healthy lifestyle characteristics in the concept of one's self) is an important indicator of lasting health behavior change, emerging adulthood may be a particularly important time for establishing and intervening on long-term health behavior patterns (2,3). In addition, other psychosocial attributes associated with beneficial health behaviors (e.g., self-efficacy) develop or become established during this period of emerging adulthood (4), providing support for the unique importance of this life stage in long-term behavioral patterning. Emerging adulthood may also be a time for changing support systems and shifting interpersonal influences. Although the influence of parents and family is well established in the literature on childhood and, to a lesser extent, adolescent diet and physical activity patterns, little research has examined these issues among young adults. Young adults spend more leisure time alone compared to other age group (except retirees ≥55 years) (5) and are often assumed to be more disconnected from their family. However, some research suggests that closer relationships with parents (6,7) and siblings (8) may evolve as youth transition into college and adulthood (9,10). As youth become more independent, family and social network influences begin to shift and may serve different roles, as compared to that which they served in childhood and adolescence. Much additional research is needed to understand the evolving social influences in the emerging adult years and the extent to which this may influence health behavior patterns. Given the overall paucity of research in this area, more work is needed to understand better how the unique characteristics of emerging adulthood may contribute to establishing long-term behavioral patterns and the possible vulnerability of this life stage to various influences. The transition from adolescence to adulthood and the determinants of eating and physical activity is understudied. However, national trend data suggest that this is a risky period for the development of obesity, as well as unhealthy diet and physical activity practices. Weight gain. Research from national surveys and longitudinal cohorts has identified the transition between adolescence and adulthood as a period of increased risk for excess weight gain. Nationally representative cross-sectional survey data from the Behavioral Risk Factor Surveillance System indicated that from 1991 to 1998, the greatest magnitude of increase in obesity prevalence was among 18–29-year olds (increasing from 7.1 to 12.1%) (11). The prevalence of obesity among young adults more than doubled in the past 30 years. The most recent National Health and Nutrition Examination Survey (NHANES) data indicate that the prevalence has continued to increase since 1999 (ref. 12). Currently, 28.5% of 20–39-year olds are obese and 57.1% are overweight or obese (12). Nationally representative longitudinal cohort data from the National Longitudinal Study of Adolescent Health (Add Health) (13), assessing 9,795 adolescents (baseline age: 13–20 years in 1996), found that the 5-year incidence of obesity was nearly 13% (follow-up age: 19–26 years in 2001), whereas only 1.6% shifted from being obese to nonobese. In comparison to NHANES (1971–1974), the Add Health cohort showed substantial secular changes in the BMI distribution over time, particularly among individuals aged 19–26 years (13). In addition, findings from the CARDIA (Coronary Artery Risk Development in Young Adults) (14,15) longitudinal cohort illustrate both 5- and 10-year increases in weight among individuals 18–30 years of age at baseline (1985). Five-year weight gain was greater for men aged 18–24 years compared to men aged 25–30 years (14). Furthermore, the largest 10-year weight gains were seen among those in their early- to mid-twenties, as compared to those in their thirties (15). Physical activity. Although longitudinal data are limited, there is evidence of dramatic changes in lifestyle characteristics during this period. Cohort data from Add Health indicate that although most adolescents fail to meet national guidelines for physical activity (33.6%), even fewer meet these guidelines as young adults (12.7%) (16). In addition, findings from Project EAT (Eating Among Teens), a 5-year longitudinal cohort study of Minnesota adolescents, confirm such adverse changes in activity patterns during the transition from high school to young adulthood (17). Findings showed longitudinal changes in moderate to vigorous physical activity, particularly among girls (decreasing from 5.1 to 3.5 h/week aged from 16 to 20 years), and leisure time computer use, particularly among boys (increasing from 10.4 to 14.2 h/week aged from 16 to 20 years). Overall, many changes in physical activity patterns began during the transition from junior to senior high school and continued during the transition from high school to post-high school. One notable exception is moderate to vigorous physical activity among boys, which only began to decline during the transition after high school. Furthermore, a recent analysis of the National Health Interview survey data (18) indicated that age-related declines in physical activity are particularly pronounced between 15 and 18 years of age and continue through age 21. Physical activity has been shown to decline even further with specific life events typically following emerging adulthood (such as moving into a live-in relationship, getting married, and becoming a parent), but generally do not appear to continue to decline with age after mid-adulthood (30–64 years) (18). Thus health-promotion efforts to increase activity during emerging adulthood may be particularly important. Dietary intake. Research also suggests that declines in overall-diet quality may accompany these unfavorable shifts in activity patterns during the transition to adulthood (19,20). For example, fast food consumption has been associated with weight gain over time, and findings from national survey data indicate that fast food restaurant use is highest in young adulthood: 52% of 20–39 years reported eating fast food on one or both days of the Continuing Survey of Food Intakes by Individuals (1994–1996, 1998) (21). These data also indicate that soft drink intake is highest among 19–39-year olds compared to other age groups (22). In addition, NHANES data illustrate that a majority of young adults (aged 20–29 years) consume <1 serving/day of fruit (males 63%, females 59%) and vegetables (including potatoes, males 19%, females 20%) (23). Unfortunately, however, the collapsing of ages 19–39 years does not allow for an examination of the emerging adult period. Longitudinal findings from Project EAT also indicate adverse changes in dietary intake. For example, total fruit and vegetable intake decreased significantly (by >½ serving/day) during the 5-year transition period after high school (24). Add Health data indicate that fast food consumption markedly increased and consumption of breakfast decreased across a 5-year transition between adolescence and adulthood (25). The Bogalusa Heart Study (19), a longitudinal study of a biracial cohort following children >15 years into young adulthood, also showed a substantial decline in diet quality as individuals progressed through this transition. Findings indicate that individuals consumed less fruits/fruit juice and milk (19) and more sweetened beverages, salty snacks, and beef as young adults (19–28 years) than as children. Several studies have reported that despite changes in diet quality, there is substantial tracking in dietary intake between adolescence and young adulthood, as well as into later adulthood (20,26,27). Weight status also shows a high degree of tracking over time (28). Thus setting a “trajectory” for beneficial health behavior patterns and dietary intake during this time may be an important step toward initiating lasting healthy behaviors. Furthermore, a growing number of individuals are now becoming obese during adolescence and are exposed to a wide array of precursors to poor-diet quality and inactivity before the emerging adult years. For example, secular trends suggest declining rates of family meals and home food preparation (29), potentially leaving young adults without the skills to prepare foods and plan healthful meals on their own. Thus, challenges lie in reversing the effects of adverse adolescent exposures during the emerging adult years and promoting healthful long-term behavior patterns in all segments of the population. Dietary intake is influenced by a variety of factors, including individual, interpersonal, institutional, and macro-system influences. Although many of these influences are thought to be shared by a wide range of age groups, food and beverage marketing may be a particularly potent macro-level influence for emerging adults. The food, beverage and restaurant industries are estimated to have spent >$11 billion on advertising in 2004 alone (30). Young adults aged 18–24 years are a highly desirable market, particularly among fast food and soft drink companies. Marketing campaigns geared toward young adults, particularly males, have brought increased sales to fast food restaurant chains in the past decade (31,32,33,34). These campaigns have been specifically designed to increase product recognition, sales and brand loyalty among this group and have been widely promoted in young adult media markets. A number of these successful campaigns have targeted issues such as fast food late night dining and value pricing (32,35). For example, in launching its late night “Fourthmeal” campaign (with “Fourthmeal” marketed as “the meal between dinner and breakfast”), Taco Bell cites industry research in its press release indicating that nearly 50% of males aged 18–29 years are eating out after 7 pm (32). Industry research also suggests that young males spend well above market averages in these visits, averaging over $7.00 (ref. 36). To our knowledge, similar peer-reviewed evidence in the scientific literature is not available to confirm these trends. A number of these successful industry-driven campaigns have received recognition from the marketing and advertising community, for example, receiving EFFIE Awards (prestigious annual advertising awards) for their work in effectively targeting young adults. Honored campaigns include: • Hardee's. In 2001, industry research found that among its target markets Hardee's was “the most avoided restaurant in the fast food category” (31). Launching a major initiative targeting frequent fast food consumers, the company conducted “a segmentation analysis … to create a landscape from which we selected a more meaningful target for Hardee's. We called this target ‘Young Hungry Guys.’ This group is defined as young burger eaters (men 16–34) who want a more adult-like place to eat the burgers they love. This group seeks out big burgers as their food of choice, has the most growth potential for Hardee's and represent the heaviest usage in the fast food category” (31). With this, the Thickburger was introduced (providing ∼850–1,400 calories/burger). As a result, the company grew from the lowest to the highest ranked leading quick-service restaurant among young male fast food consumers (31). • Burger King. In February 2004 after significantly declining sales, Burger King refocused its efforts on its heaviest users, identified as males aged 16–34 years (34). To do so, they introduced the large-sized Angus Steak Burger. Describing its creative strategy, the marketing team states that “since the beginning of time, men have been eating large amounts of meat cooked over fires. For thousands of years, society has been wired to associate this kind of indulgence with power, pleasure and status. The problem is our culture is on an anti-indulgence craze the likes of which we have never seen before. Our strategy was to give our target permission to indulge in a great tasting burger and not apologize for it. And nothing gives them permission better than the affordable, deeply satisfying fire-grilled Angus Steak Burger…” (34). After increasing its market share among young men, this single-menu item subsequently accounted for 10% of sales dollars for Burger King. • Jack in the Box. After from the of a Jack in the that its was to create with the of the fast food young men, ages These were the fast food most began a marketing campaign on to to this including the campaign a of a media targeting males 18–24 years, Jack in the sales more than doubled from over billion in drink have also emerging adults as an important market For example, has major marketing campaigns targeting men, with the and In to promoting and advertising their through soft drink have to the of beverage by new targeting this age such as and (e.g., Thus, in we have little in the of public health to health among young adults, food and beverage marketing particularly from the fast food and soft drink have been targeting this age group over the past decade to establish brand loyalty and a of aged years are postsecondary In the development of health-promotion such may be well for emerging adult behaviors. However, that this life stage has been an of particularly in of obesity evidence is available to specific behaviors of college we have the which is from is a of research behaviors among other of such as those or obesity and weight Obesity is a major health among from the Health National Health an of indicated that the prevalence of overweight was including of these individuals who are obese Among the there has been recognition of the weight gain associated with college however, little research has explored this and its Several studies have shown that college is by substantial weight gain. the of gain an of with the of overweight or obese as as by the of the In females who home to to college have been shown to be to as to gain or more above their weight compared to females who not home indicating an important influence of some in the college on Furthermore, previous research suggests that this weight gain is specifically to important changes in body increased decreased Although some weight college has been estimated that gain weight during their years research following across years of that this weight gain is over time, with females on gaining and males gaining from to senior Although some growth may be to continued gains in particularly among males, many college youth may be on a of weight gain. 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In to diet and activity, there are other risk factors that are in emerging adults which may be to data indicate that of college consumed at one during the past intake has been with decreased and increased dietary intake in Although research that is associated with a range of adverse dietary patterns, and unhealthy weight among college youth additional work is needed to understand better the by which these behaviors are little research is available to understand the of other use (e.g., which of college youth in the past on meal and weight gain. 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As adopt new health behavior patterns, often from home for the time, college life may the stage for establishing important behavioral patterns that chronic disease postsecondary are settings for diet and physical may share residential factors (e.g., have to (e.g., less than of college and are to a Although postsecondary an even of groups (e.g., groups of work to has the prevalence of behaviors on these and the of these Although some of the factors (e.g., may not be to both and settings shared eating on and and in the for the need in this area, have not to work with these to and and physical activity In obesity and healthy weight are to and To be such strategies be and to the of the target Although there is a paucity of epidemiologic research to understand the most potent modifiable determinants of excess weight gain during the emerging adult years, we are to use the little evidence that is available to important for research in this Given the of influence on health as by the widely important for epidemiologic and intervention research a range of from macro-level to In some from research in other settings (e.g., and may be highly in postsecondary institutions. For example, once research is available to postsecondary food strategies to healthy food pricing and be to intervention strategies in these However, although have scientific in recent years, important factors specific to this age group not be Emerging adults and college youth many new to healthy lifestyle characteristics (e.g., high challenges in time and targeting and strategies in these may be highly effective in obesity particularly in with research also to be and and by which we may be to target emerging adults who are not postsecondary institutions. Although research in other of health promotion suggests that emerging adults who are not postsecondary may represent particularly youth research to has examined health behaviors among this work in this is by the through we these Although and postsecondary may a to develop health-promotion strategies targeting large groups of there is a continued need to develop through which also be that we do not the research is also needed to the for health which may also for many individuals during the emerging adult years, particularly as begin to ideologies of autonomy are on with those of on responsibilities and to This growing of and may in that an important influence diet and physical behaviors. 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Obesity · 1316 citationsread the source →

Spirituality, religiosity, and spiritual pain among caregivers of patients with advanced cancer.

Background: Caregivers of patients with advanced cancer often face physical, social, and emotional distress as well as spiritual pain. Limited research has focused on the spiritual aspects of caregivers' suffering in the palliative care setting. Methods: We interviewed 43 caregivers of patients with advanced cancer in our palliative care outpatient clinic. We determined demographic characteristics, religious affiliation, and relationship to the patient. Levels of spirituality, religiosity, and spiritual pain were self-reported using numeric rating scales (0 = lowest; 10 = highest). The participants completed various validated questionnaires to assess sleep disturbances, psychosocial distress, coping skills, and quality of life (QOL). Results: The median age was 52 years (range, 21-83); 29 (67%) were women, 34 (78%) were white, 7 (17%) were African American, and 2 (5%) were Hispanic; 39 (91%) were Christian, 1 (2%) was Jewish, and 1 (2%) was agnostic; 37 (86%) were married; 18 (42%) were working full time; and 25 (58%) were spouses. All considered themselves spiritual, and 98% considered themselves religious, with median scores of 8 (interquartile range, 6-10) and 8 (interquartile range, 4-9), respectively. All the caregivers reported that spirituality and religiosity helped them cope with their loved one's illness, and many reported that spirituality and religiosity had a positive impact on their loved one's physical (58%) and emotional (76%) symptoms. Spiritual pain was reported by 23 (58%), with a median score of 5 (interquartile range, 2-8). Caregivers with spiritual pain had higher levels of anxiety (median 10 vs 4; P = .002), depression (6 vs 2; P = .006), and denial (3 vs 2; P = .01); more behavioral disengagement (3 vs 2; P = 0.011) more dysfunctional coping strategies (19 vs 16; P < .001) and worse QOL (70 vs 51; P < .001) than those who did not have spiritual pain. Conclusions: The majority of caregivers of patients with advanced cancer considered themselves spiritual and religious. Despite this, there is high prevalence of spiritual pain in this population. Caregivers with spiritual pain experienced worse psychological distress and worse QOL. These findings support the importance of spiritual assessment of and spiritual support for caregivers in this setting.

The American journal of hospice & palliative care · 65 citationsread the source →

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

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

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