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Dose-dependent and joint associations between screen time, physical activity, and mental wellbeing in adolescents: an international observational study.

Background: Mental wellbeing in adolescents has declined considerably during past decades, making the identification of modifiable risk factors important. Prolonged screen time and insufficient physical activity appear to operate independently and synergistically to increase the risk of poor mental wellbeing in school-aged children. We aimed to examine the gender-stratified dose-dependent and joint associations of screen time and physical activity with mental wellbeing in adolescents. Methods: We used data from three rounds of Health Behaviour in School-aged Children cross-sectional surveys (2006, 2010, and 2014) from 42 European and North American countries. Survey participants, aged 11 years, 13 years, and 15 years, provided self-reported information by completing an anonymous questionnaire that included items on health indicators and related behaviours. We used the self-reported variables of life satisfaction and psychosomatic complaints as indicators of adolescents' mental wellbeing, combining these with the self-reported discretionary use of screens and engagement in physical activity. We used generalised additive models and multilevel regression modelling to examine the gender-stratified relationships between mental wellbeing and screen time and physical activity. Findings: Our sample included 577 475 adolescents (mean age 13·60 years, SD 1·64), with 296 542 (51·35%) girls and 280 933 (48·64%) boys. The mean reported life satisfaction score (on a scale of 0-10) was 7·70 (95% CI 7·69-7·71) in boys and 7·48 (7·46-7·50) in girls. Psychosomatic complaints were more common among girls (mean 9·26, 95% CI 9·23-9·28) than boys (6·89, 6·87-6·91). Generalised additive model analyses showed slightly non-linear associations of screen time and physical activity with life satisfaction and psychosomatic complaints for girls and boys. Detrimental associations between screen time and mental wellbeing started when screen time exceeded 1 h per day, whereas increases in physical activity levels were beneficially and monotonically associated with wellbeing. Multilevel modelling showed that screen time levels were negatively associated with life satisfaction and positively associated with psychosomatic complaints in a dose-dependent manner. Physical activity levels were positively associated with life satisfaction and negatively associated with psychosomatic complaints in a dose-dependent manner. Joint associations of screen time-physical activity with mental wellbeing showed that, compared with the least active participants with more than 8 h per day of screen time and no physical activity, most of the other screen time-physical activity groups had considerably higher life satisfaction and lower psychosomatic complaints. Interpretation: Higher levels of screen time and lower levels of physical activity were associated with lower life satisfaction and higher psychosomatic complaints among adolescents from high-income countries. Public health strategies to promote adolescents' mental wellbeing should aim to decrease screen time and increase physical activity simultaneously. Funding: None.

The Lancet. Child & adolescent health · cohort or longitudinal · 63 citationsread the source →

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

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

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

Sexual dysfunction related to psychiatric disorders: a systematic review.

Background: Sexual dysfunction is thought to be highly prevalent in patients with psychiatric disorders. Factors such as the use of psychotropic substances (ie, psychopharmaceuticals and drugs), age, or somatic diseases may contribute to sexual problems, but the extent to which psychopathology itself affects sexual functioning is not well understood. Aim: The study sought to provide an overview of the literature on the prevalence of sexual dysfunction in psychotropic-free and somatic disease-free psychiatric patients. Method: A systematic review (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) was conducted by 2 authors (TH and AWMP) independently, with the review process being monitored by a third author. Relevant articles on the relationship between sexual dysfunctions and psychopathology were searched in PubMed, Web of Science, and PsycINFO from inception until June 16, 2022. The study methods were entered in the international register of systematic reviews PROSPERO (2021, CRD42021223410). Outcomes: The main outcome measures were sexual dysfunction and sexual satisfaction. Results: Twenty-four studies were identified, including a total of 1199 patients. These studies focused on depressive disorders (n = 9 studies), anxiety disorders (n = 7), obsessive- compulsive disorder (OCD) (n = 5), schizophrenia (n = 4), and posttraumatic stress disorder (n = 2). No studies on bipolar disorder were found. Reported prevalence rates of sexual dysfunction in psychiatric disorders were 45% to 93% for depressive disorders, 33% to 75% for anxiety disorders, 25% to 81% for OCD, and 25% for schizophrenia. The most affected phase of the sexual response cycle was sexual desire, in both men and women with depressive disorders, posttraumatic stress disorder, and schizophrenia. Patients with OCD and anxiety disorders most frequently reported dysfunction in the orgasm phase, 24% to 44% and 7% to 48%, respectively. Clinical implications: The high prevalence of sexual dysfunction requires more clinical attention by means of psychoeducation, clinical guidance, sexual anamnesis, and additional sexological treatment. Strengths and limitations: This is the first systematic review on sexual dysfunction in psychotropic-free and somatic disease-free psychiatric patients. Limitations include the small number of studies, small sample sizes, the use of multiple questionnaires (some not validated), which may contribute to bias. Conclusion: A limited number of studies identified a high prevalence of sexual dysfunction in patients with a psychiatric disorder, with substantial variation between patient groups in frequency and phase of reported sexual dysfunction.

The journal of sexual medicine · systematic review · 33 citationsread the source →

Evaluation of a Whole-School Change Intervention: Findings from a Two-Year Cluster-Randomized Trial of the Restorative Practices Intervention.

This study fills a gap in research on multi-level school-based approaches to promoting positive youth development and reducing bullying, in particular cyberbullying, among middle school youth. The study evaluates the Restorative Practices Intervention, a novel whole-school intervention designed to build a supportive environment through the use of 11 restorative practices (e.g., communication approaches that aim to build stronger bonds among leadership, staff, and students such as using "I" statements, encouraging students to express their feelings) that had only quasi-experimental evidence prior to this study. Studying multilevel (e.g., individual, peer group, school) approaches like the Restorative Practices Intervention is important because they are hypothesized to address a more complex interaction of risk factors than single level efforts, which are more common. Baseline and two-year post survey data was collected from 2771 students at 13 middle schools evenly split between grades 6 (48 percent) and 7 (52 percent), and primarily ages 11 (38 percent) or 12 (41 percent). Gender was evenly split (51 percent male), and 92 percent of students were white. The intervention did not yield significant changes in the treatment schools. However, student self-reported experience with restorative practices significantly predicted improved school climate and connectedness, peer attachment, and social skills, and reduced cyberbullying victimization. While more work is needed on how interventions can reliably produce restorative experiences, this study suggests that the restorative model can be useful in promoting positive behaviors and addressing bullying.

Journal of youth and adolescence · randomised controlled trial · 34 citationsread the source →

A novel digital intervention for actively reducing severity of paediatric ADHD (STARS-ADHD): a randomised controlled trial.

Background: Attention-deficit hyperactivity disorder (ADHD) is a common paediatric neurodevelopmental disorder with substantial effect on families and society. Alternatives to traditional care, including novel digital therapeutics, have shown promise to remediate cognitive deficits associated with this disorder and may address barriers to standard therapies, such as pharmacological interventions and behavioural therapy. AKL-T01 is an investigational digital therapeutic designed to target attention and cognitive control delivered through a video game-like interface via at-home play for 25 min per day, 5 days per week for 4 weeks. This study aimed to assess whether AKL-T01 improved attentional performance in paediatric patients with ADHD. Methods: The Software Treatment for Actively Reducing Severity of ADHD (STARS-ADHD) was a randomised, double-blind, parallel-group, controlled trial of paediatric patients (aged 8-12 years, without disorder-related medications) with confirmed ADHD and Test of Variables of Attention (TOVA) Attention Performance Index (API) scores of -1·8 and below done by 20 research institutions in the USA. Patients were randomly assigned 1:1 to AKL-T01 or a digital control intervention. The primary outcome was mean change in TOVA API from pre-intervention to post-intervention. Safety, tolerability, and compliance were also assessed. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02674633 and is completed. Findings: Between July 15, 2016, and Nov 30, 2017, 857 patients were evaluated and 348 were randomly assigned to receive AKL-T01 or control. Among patients who received AKL-T01 (n=180 [52%]; mean [SD] age, 9·7 [1·3] years) or control (n=168 [48%]; mean [SD] age, 9·6 [1·3] years), the non-parametric estimate of the population median change from baseline TOVA API was 0·88 (95% CI 0·24-1·49; p=0·0060). The mean (SD) change from baseline on the TOVA API was 0·93 (3·15) in the AKL-T01 group and 0·03 (3·16) in the control group. There were no serious adverse events or discontinuations. Treatment-related adverse events were mild and included frustration (5 [3%] of 180) and headache (3 [2%] of 180). Patient compliance was a mean of 83 (83%) of 100 expected sessions played (SD, 29·2 sessions). Interpretation: Although future research is needed for this digital intervention, this study provides evidence that AKL-T01 might be used to improve objectively measured inattention in paediatric patients with ADHD, while presenting minimal adverse events. Funding: Sponsored by Akili Interactive Labs.

The Lancet. Digital health · randomised controlled trial · 215 citationsread the source →

Prosocial development from childhood to adolescence: a multi-informant perspective with Canadian and Italian longitudinal studies.

Objectives: To longitudinally describe prosocial behaviour development from childhood to adolescence, using multiple informants within Canadian and Italian samples. Method: Participants in Study 1 were 1037 boys from low socioeconomic status (SES) areas in Montreal, Canada, for whom yearly teacher and mother reports were obtained between the ages of 10 and 15. Participants in Study 2 were 472 children (209 girls) from Genzano, Italy, for whom yearly self and teacher reports were obtained between the ages of 10 and 14. Developmental trajectories were estimated from ratings by each informant to identify subgroups of children following distinct courses of prosocial development. Results: In Study 1, three trajectory groups (low/declining 53%, high/declining 16%, high/steep declining 31%) were identified from teacher ratings, while five trajectories (low/stable 7%, low/declining 19%, moderate/stable 41%, high/declining 24%, high/stable 9%) were identified from mother ratings. Small but significant associations were observed between mother and teacher ratings. In Study 2, three trajectory groups (low/stable 9%, moderate/stable 50%, high/stable 42%) were identified from self-ratings, while four trajectory groups (low/stable 8%, moderate/declining 48%, high/declining 37%, increasing 7%) were identified from teacher ratings. Small but significant associations were observed between self- and teacher ratings. Conclusions: The present studies investigated levels of prosocial behaviours from childhood to adolescence, using a multi-informant, cross-cultural perspective. All but one of the developmental trajectories identified were characterised by stable or declining levels of prosocial behaviours. Further research longitudinally investigating prosociality across developmental periods is needed to clarify prosocial behaviour development over time.

Journal of child psychology and psychiatry, and allied disciplines · cohort or longitudinal · 39 citationsread the source →

Allostasis and allostatic load in the context of poverty in early childhood.

This paper examined the relation of early environmental adversity associated with poverty to child resting or basal level of cortisol in a prospective longitudinal sample of 1135 children seen at 7, 15, 24, 35, and 48 months of age. We found main effects for poor housing quality, African American ethnicity, and low positive caregiving behavior in which each was uniquely associated with an overall higher level of cortisol from age 7 to 48 months. We also found that two aspects of the early environment in the context of poverty, adult exits from the home and perceived economic insufficiency, were related to salivary cortisol in a time-dependent manner. The effect for the first of these, exits from the home, was consistent with the principle of allostatic load in which the effects of adversity on stress physiology accumulate over time. The effect for perceived economic insufficiency was one in which insufficiency was associated with higher levels of cortisol in infancy but with a typical but steeper decline in cortisol with age at subsequent time points.

Development and psychopathology · 152 citationsread the source →

The socioeconomic gradient of alcohol use: an analysis of nationally representative survey data from 55 low-income and middle-income countries.

Background: Alcohol is a leading risk factor for over 200 conditions and an important contributor to socioeconomic health inequalities. However, little is known about the associations between individuals' socioeconomic circumstances and alcohol consumption, especially heavy episodic drinking (HED; ≥5 drinks on one occasion) in low-income or middle-income countries. We investigated the association between individual and household level socioeconomic status, and alcohol drinking habits in these settings. Methods: In this pooled analysis of individual-level data, we used available nationally representative surveys-mainly WHO Stepwise Approach to Surveillance surveys-conducted in 55 low-income and middle-income countries between 2005 and 2017 reporting on alcohol use. Surveys from participants aged 15 years or older were included. Logistic regression models controlling for age, country, and survey year stratified by sex and country income groups were used to investigate associations between two indicators of socioeconomic status (individual educational attainment and household wealth) and alcohol use (current drinking and HED amongst current drinkers). Findings: Surveys from 336 287 participants were included in the analysis. Among males, the highest prevalence of both current drinking and HED was found in lower-middle-income countries (L-MICs; current drinking 49·9% [95% CI 48·7-51·2] and HED 63·3% [61·0-65·7]). Among females, the prevalence of current drinking was highest in upper-middle-income countries (U-MIC; 29·5% [26·1-33·2]), and the prevalence of HED was highest in low-income countries (LICs; 36·8% [33·6-40·2]). Clear gradients in the prevalence of current drinking were observed across all country income groups, with a higher prevalence among participants with high socioeconomic status. However, in U-MICs, current drinkers with low socioeconomic status were more likely to engage in HED than participants with high socioeconomic status; the opposite was observed in LICs, and no association between socioeconomic status and HED was found in L-MICs. Interpretation: The findings call for urgent alcohol control policies and interventions in LICs and L-MICs to reduce harmful HED. Moreover, alcohol control policies need to be targeted at socially disadvantaged groups in U-MICs. Funding: Deutsche Forschungsgemeinschaft and the National Center for Advancing Translational Sciences of the US National Institutes of Health.

The Lancet. Global health · 26 citationsread the source →

Association of school absence and exclusion with recorded neurodevelopmental disorders, mental disorders, or self-harm: a nationwide, retrospective, electronic cohort study of children and young people in Wales, UK.

Background: Poor attendance at school, whether due to absenteeism or exclusion, leads to multiple social, educational, and lifelong socioeconomic disadvantages. We aimed to measure the association between a broad range of diagnosed neurodevelopmental and mental disorders and recorded self-harm by the age of 24 years and school attendance and exclusion. Methods: In this nationwide, retrospective, electronic cohort study, we drew a cohort from the Welsh Demographic Service Dataset, which included individuals aged 7-16 years (16 years being the school leaving age in the UK) enrolled in state-funded schools in Wales in the academic years 2012/13-2015/16 (between Sept 1, 2012, and Aug 31, 2016). Using the Adolescent Mental Health Data Platform, we linked attendance and exclusion data to national demographic and primary and secondary health-care datasets. We identified all pupils with a recorded diagnosis of neurodevelopmental disorders (ADHD and autism spectrum disorder [ASD]), learning difficulties, conduct disorder, depression, anxiety, eating disorders, alcohol or drugs misuse, bipolar disorder, schizophrenia, other psychotic disorders, or recorded self-harm (our explanatory variables) before the age of 24 years. Outcomes were school absence and exclusion. Generalised estimating equations with exchangeable correlation structures using binomial distribution with the logit link function were used to calculate odds ratios (OR) for absenteeism and exclusion, adjusting for sex, age, and deprivation. Findings: School attendance, school exclusion, and health-care data were available for 414 637 pupils (201 789 [48·7%] girls and 212 848 [51·3%] boys; mean age 10·5 years [SD 3·8] on Sept 1, 2012; ethnicity data were not available). Individuals with a record of a neurodevelopmental disorder, mental disorder, or self-harm were more likely to be absent or excluded in any school year than were those without a record. Unadjusted ORs for absences ranged from 2·1 (95% CI 2·0-2·2) for those with neurodevelopmental disorders to 6·6 (4·9-8·3) for those with bipolar disorder. Adjusted ORs (aORs) for absences ranged from 2·0 (1·9-2·1) for those with neurodevelopmental disorders to 5·5 (4·2-7·2) for those with bipolar disorder. Unadjusted ORs for exclusion ranged from 1·7 (1·3-2·2) for those with eating disorders to 22·7 (20·8-24·7) for those with a record of drugs misuse. aORs for exclusion ranged from 1·8 (1·5-2·0) for those with learning difficulties to 11·0 (10·0-12·1) for those with a record of drugs misuse. Interpretation: Children and young people up to the age of 24 years with a record of a neurodevelopmental or mental disorder or self-harm before the age of 24 years were more likely to miss school than those without a record. Exclusion or persistent absence are potential indicators of current or future poor mental health that are routinely collected and could be used to target assessment and early intervention. Integrated school-based and health-care strategies to support young peoples' engagement with school life are required. Funding: The Medical Research Council, MQ Mental Health Research, and the Economic and Social Research Council. Translation: For the Welsh translation of the abstract see Supplementary Materials section.

The lancet. Psychiatry · 73 citationsread the source →

Intravenous Doxycycline, Azithromycin, or Both for Severe Scrub Typhus.

Background: The appropriate antibiotic treatment for severe scrub typhus, a neglected but widespread reemerging zoonotic infection, is unclear. Methods: In this multicenter, double-blind, randomized, controlled trial, we compared the efficacy of intravenous doxycycline, azithromycin, or a combination of both in treating severe scrub typhus. Patients who were 15 years of age or older with severe scrub typhus with at least one organ involvement were enrolled. The patients were assigned to receive a 7-day course of intravenous doxycycline, azithromycin, or both (combination therapy). The primary outcome was a composite of death from any cause at day 28, persistent complications at day 7, and persistent fever at day 5. Results: Among 794 patients (median age, 48 years) who were included in the modified intention-to-treat analysis, complications included those that were respiratory (in 62%), hepatic (in 54%), cardiovascular (in 42%), renal (in 30%), and neurologic (in 20%). The use of combination therapy resulted in a lower incidence of the composite primary outcome than the use of doxycycline (33% and 47%, respectively), for a risk difference of -13.3 percentage points (95% confidence interval [CI], -21.6 to -5.1; P = 0.002). The incidence with combination therapy was also lower than that with azithromycin (48%), for a risk difference of -14.8 percentage points (95% CI, -23.1 to -6.5; P<0.001). No significant difference was seen between the azithromycin and doxycycline groups (risk difference, 1.5 percentage points; 95% CI, -7.0 to 10.0; P = 0.73). The results in the per-protocol analysis were similar to those in the primary analysis. Adverse events and 28-day mortality were similar in the three groups. Conclusions: Combination therapy with intravenous doxycycline and azithromycin was a better therapeutic option for the treatment of severe scrub typhus than monotherapy with either drug alone. (Funded by the India Alliance and Wellcome Trust; INTREST Clinical Trials Registry-India number, CTRI/2018/08/015159.).

The New England journal of medicine · randomised controlled trial · 58 citationsread the source →

Identifying patterns of movement behaviours in relation to depressive symptoms during adolescence: A latent profile analysis approach.

Movement behaviour guideline adherence has been associated with lower depressive symptoms during adolescence, yet no studies have used person-centered approaches to examine this relationship. The purpose of the present study was to identify whether unique adolescent movement behaviour profiles exist, evaluate predictors of profile membership, and determine whether profile membership was associated with differences in depressive symptoms cross sectionally and longitudinally. This study involved secondary analysis of the public-use data from Wave 1 and Wave 2 of the National Study of Adolescent Health. Adolescents (N = 6436; 48% male) in grades 7 to 12 (Mage = 16.03 ± 1.75) completed measures to assess moderate-to-vigorous physical activity (MVPA), recreational screen time (ST), and sleep - collectively known as movement behaviours - and depressive symptoms. Latent profile analysis identified four profiles that had similar sleep patterns and were thus characterized by different levels of MVPA and ST: high MVPA/low ST (29%), high MVPA/high ST (4%), low MVPA/low ST (53%), and low MVPA/high ST (14%). Several socio-demographic variables were found to influence profile membership. After adjusting for covariates, findings revealed depressive symptoms were lowest among the high MVPA/low ST profile and this trend was evident one year later. Engaging in high levels of either MVPA or ST alone did not provide additive benefits for depressive symptoms compared to those who engaged in low levels of both MVPA and ST. These findings suggest intervention efforts should take an integrative approach to improve mental health outcomes among adolescents by considering each of the movement behaviours concurrently.

Preventive medicine · 23 citationsread the source →

Shift work and long work hours and their association with chronic health conditions: A systematic review of systematic reviews with meta-analyses.

Background: Previous reviews have demonstrated that shift work and long work hours are associated with increased risk for chronic conditions. However, these reviews did not comprehensively assessed the body of evidence, and some were not conducted in a systematic manner. A better understanding of the health consequences of shift work and long work hours will aid in creating policy and practice recommendations. This review revisits the epidemiologic evidence on the association of shift work and long work hours with chronic conditions with particular emphasis on assessing the quality of the evidence. Methods and findings: We conducted a systematic review of systematic reviews with meta-analyses (SR-MA) that assessed the link between shift work or long work hours and chronic conditions (PROSPERO CRD42019122084). We evaluated the risk of bias of each SR-MA using AMSTAR v2 and assessed the overall evidence for each condition using the GRADE approach. We included 48 reviews covering cancers, cardiovascular diseases, metabolic syndrome and related conditions, pregnancy complications, depression, hypertension, and injuries. On average, only 7 of 16 AMSTAR items were fulfilled. Few SR-MAs had a registered protocol and nearly all failed to conduct a comprehensive search. We found moderate grade evidence linking shift work to breast cancer and long work hours to stroke. We found low grade evidence linking both shift work and long work hours with low to moderate increase in risk for some pregnancy complications and cardiovascular diseases. Low grade evidence also link long work hours and depression. Conclusions: Moderate grade evidence suggest that shift work and long work hours increase the risk of breast cancer and stroke, but the evidence is unclear on other chronic conditions. There is a need for high-quality studies to address this gap. Stakeholders should be made aware of these increased risks, and additional screening and prevention should be considered, particularly for workers susceptible to breast cancer and stroke.

PloS one · meta-analysis · 131 citationsread the source →

Music interventions for acquired brain injury.

Background: Acquired brain injury (ABI) can result in impairments in motor function, language, cognition, and sensory processing, and in emotional disturbances, which can severely reduce a survivor's quality of life. Music interventions have been used in rehabilitation to stimulate brain functions involved in movement, cognition, speech, emotions, and sensory perceptions. An update of the systematic review published in 2010 was needed to gauge the efficacy of music interventions in rehabilitation for people with ABI. Objectives: To assess the effects of music interventions for functional outcomes in people with ABI. We expanded the criteria of our existing review to: 1) examine the efficacy of music interventions in addressing recovery in people with ABI including gait, upper extremity function, communication, mood and emotions, cognitive functioning, social skills, pain, behavioural outcomes, activities of daily living, and adverse events; 2) compare the efficacy of music interventions and standard care with a) standard care alone, b) standard care and placebo treatments, or c) standard care and other therapies; 3) compare the efficacy of different types of music interventions (music therapy delivered by trained music therapists versus music interventions delivered by other professionals). Search methods: We searched the Cochrane Stroke Group Trials Register (January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to June 2015), Embase (1980 to June 2015), CINAHL (1982 to June 2015), PsycINFO (1806 to June 2015), LILACS (1982 to January 2016), and AMED (1985 to June 2015). We handsearched music therapy journals and conference proceedings, searched dissertation and specialist music databases, trials and research registers, reference lists, and contacted relevant experts and music therapy associations to identify unpublished research. We imposed no language restriction. We performed the original search in 2009. Selection criteria: We included all randomised controlled trials and controlled clinical trials that compared music interventions and standard care with standard care alone or combined with other therapies. We examined studies that included people older than 16 years of age who had ABI of a non-degenerative nature and were participating in treatment programmes offered in hospital, outpatient, or community settings. We included studies in any language, published and unpublished. Data collection and analysis: Two review authors independently extracted data and assessed the risk of bias of the included studies. We contacted trial researchers to obtain missing data or for additional information when necessary. Where possible, we presented results for continuous outcomes in meta-analyses using mean differences (MDs) and standardised mean differences (SMDs). We used post-test scores. In cases of significant baseline difference, we used change scores. We conducted a sensitivity analysis to assess the impact of the randomisation method. Main results: We identified 22 new studies for this update. The evidence for this update is based on 29 trials involving 775 participants. A music intervention known as rhythmic auditory stimulation may be beneficial for improving the following gait parameters after stroke. We found a reported increase in gait velocity of 11.34 metres per minute (95% confidence interval (CI) 8.40 to 14.28; 9 trials; 268 participants; P < 0.00001; moderate-quality evidence). Stride length of the affected side may also benefit, with a reported average of 0.12 metres more (95% CI 0.04 to 0.20; 5 trials; 129 participants; P = 0.003; moderate-quality evidence). We found a reported average improvement for general gait of 7.67 units on the Dynamic Gait Index (95% CI 5.67 to 9.67; 2 trials; 48 participants; P < 0.00001). There may also be an improvement in gait cadence, with a reported average increase of 10.77 steps per minute (95% CI 4.36 to 17.18; 7 trials; 223 participants; P = 0.001; low-quality evidence).Music interventions may be beneficial for improving the timing of upper extremity function after stroke as scored by a reduction of 1.08 seconds on the Wolf Motor Function Test (95% CI -1.69 to -0.47; 2 trials; 122 participants; very low-quality evidence).Music interventions may be beneficial for communication outcomes in people with aphasia following stroke. Overall, communication improved by 0.75 standard deviations in the intervention group, a moderate effect (95% CI 0.11 to 1.39; 3 trials; 67 participants; P = 0.02; very low-quality evidence). Naming was reported as improving by 9.79 units on the Aachen Aphasia Test (95% CI 1.37 to 18.21; 2 trials; 35 participants; P = 0.02). Music interventions may have a beneficial effect on speech repetition, reported as an average increase of 8.90 score on the Aachen Aphasia Test (95% CI 3.25 to 14.55; 2 trials; 35 participants; P = 0.002).There may be an improvement in quality of life following stroke using rhythmic auditory stimulation, reported at 0.89 standard deviations improvement on the Stroke Specific Quality of Life Scale, which is considered to be a large effect (95% CI 0.32 to 1.46; 2 trials; 53 participants; P = 0.002; low-quality evidence). We found no strong evidence for effects on memory and attention. Data were insufficient to examine the effect of music interventions on other outcomes. The majority of studies included in this review update presented a high risk of bias, therefore the quality of the evidence is low. Authors' conclusions: Music interventions may be beneficial for gait, the timing of upper extremity function, communication outcomes, and quality of life after stroke. These results are encouraging, but more high-quality randomised controlled trials are needed on all outcomes before recommendations can be made for clinical practice.

The Cochrane database of systematic reviews · meta-analysis · 116 citationsread the source →

Prevalence of post-traumatic stress disorder symptoms in adult critical care survivors: a systematic review and meta-analysis.

Background: As more patients are surviving intensive care, mental health concerns in survivors have become a research priority. Among these, post-traumatic stress disorder (PTSD) can have an important impact on the quality of life of critical care survivors. However, data on its burden are conflicting. Therefore, this systematic review and meta-analysis aimed to evaluate the prevalence of PTSD symptoms in adult critical care patients after intensive care unit (ICU) discharge. Methods: We searched MEDLINE, EMBASE, LILACS, Web of Science, PsycNET, and Scopus databases from inception to September 2018. We included observational studies assessing the prevalence of PTSD symptoms in adult critical care survivors. Two reviewers independently screened studies and extracted data. Studies were meta-analyzed using a random-effects model to estimate PTSD symptom prevalence at different time points, also estimating confidence and prediction intervals. Subgroup and meta-regression analyses were performed to explore heterogeneity. Risk of bias was assessed using the Joanna Briggs Institute tool and the GRADE approach. Results: Of 13,267 studies retrieved, 48 were included in this review. Overall prevalence of PTSD symptoms was 19.83% (95% confidence interval [CI], 16.72-23.13; I2 = 90%, low quality of evidence). Prevalence varied widely across studies, with a wide range of expected prevalence (from 3.70 to 43.73% in 95% of settings). Point prevalence estimates were 15.93% (95% CI, 11.15-21.35; I2 = 90%; 17 studies), 16.80% (95% CI, 13.74-20.09; I2 = 66%; 13 studies), 18.96% (95% CI, 14.28-24.12; I2 = 92%; 13 studies), and 20.21% (95% CI, 13.79-27.44; I2 = 58%; 7 studies) at 3, 6, 12, and > 12 months after discharge, respectively. Conclusion: PTSD symptoms may affect 1 in every 5 adult critical care survivors, with a high expected prevalence 12 months after discharge. ICU survivors should be screened for PTSD symptoms and cared for accordingly, given the potential negative impact of PTSD on quality of life. In addition, action should be taken to further explore the causal relationship between ICU stay and PTSD, as well as to propose early measures to prevent PTSD in this population. Trial registration: PROSPERO, CRD42017075124 , Registered 6 December 2017.

Critical care (London, England) · meta-analysis · 208 citationsread the source →

Health system and community level interventions for improving antenatal care coverage and health outcomes.

Background: The World Health Organization (WHO) recommends at least four antenatal care (ANC) visits for all pregnant women. Almost half of pregnant women worldwide, and especially in developing countries do not receive this amount of care. Poor attendance of ANC is associated with delivery of low birthweight babies and more neonatal deaths. ANC may include education on nutrition, potential problems with pregnancy or childbirth, child care and prevention or detection of disease during pregnancy. This review focused on community-based interventions and health systems-related interventions. Objectives: To assess the effects of health system and community interventions for improving coverage of antenatal care and other perinatal health outcomes. Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 June 2015) and reference lists of retrieved studies. Selection criteria: We included randomised controlled trials (RCTs), quasi-randomised trials and cluster-randomised trials. Trials of any interventions to improve ANC coverage were eligible for inclusion. Trials were also eligible if they targeted specific and related outcomes, such as maternal or perinatal death, but also reported ANC coverage. Data collection and analysis: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Main results: We included 34 trials involving approximately 400,000 women. Some trials tested community-based interventions to improve uptake of antenatal care (media campaigns, education or financial incentives for pregnant women), while other trials looked at health systems interventions (home visits for pregnant women or equipment for clinics). Most trials took place in low- and middle-income countries, and 29 of the 34 trials used a cluster-randomised design. We assessed 30 of the 34 trials as of low or unclear overall risk of bias. Comparison 1: One intervention versus no interventionWe found marginal improvements in ANC coverage of at least four visits (average odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01 to 1.22; participants = 45,022; studies = 10; Heterogeneity: Tau² = 0.01; I² = 52%; high quality evidence). Sensitivity analysis with a more conservative intra-cluster correlation co-efficient (ICC) gave similar marginal results. Excluding one study at high risk of bias shifted the marginal pooled estimate towards no effect. There was no effect on pregnancy-related deaths (average OR 0.69, 95% CI 0.45 to 1.08; participants = 114,930; studies = 10; Heterogeneity: Tau² = 0.00; I² = 0%; low quality evidence), perinatal mortality (average OR 0.98, 95% CI 0.90 to 1.07; studies = 15; Heterogeneity: Tau² = 0.01; I² = 58%; moderate quality evidence) or low birthweight (average OR 0.94, 95% CI 0.82 to 1.06; studies = five; Heterogeneity: Tau² = 0.00; I² = 5%; high quality evidence). Single interventions led to marginal improvements in the number of women who delivered in health facilities (average OR 1.08, 95% CI 1.02 to 1.15; studies = 10; Heterogeneity: Tau² = 0.00; I² = 0%; high quality evidence), and in the proportion of women who had at least one ANC visit (average OR 1.68, 95% CI 1.02 to 2.79; studies = six; Heterogeneity: Tau² = 0.24; I² = 76%; moderate quality evidence). Results for ANC coverage (at least four and at least one visit) and for perinatal mortality had substantial statistical heterogeneity. Single interventions did not improve the proportion of women receiving tetanus protection (average OR 1.03, 95% CI 0.92 to 1.15; studies = 8; Heterogeneity: Tau² = 0.01; I² = 57%). No study reported onintermittent prophylactic treatment for malaria. Comparison 2: Two or more interventions versus no interventionWe found no improvements in ANC coverage of four or more visits (average OR 1.48, 95% CI 0.99 to 2.21; participants = 7840; studies = six; Heterogeneity: Tau² = 0.10; I² = 48%; low quality evidence) or pregnancy-related deaths (average OR 0.70, 95% CI 0.39 to 1.26; participants = 13,756; studies = three; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence). However, combined interventions led to improvements in ANC coverage of at least one visit (average OR 1.79, 95% CI 1.47 to 2.17; studies = five; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence), perinatal mortality (average OR 0.74, 95% CI 0.57 to 0.95; studies = five; Heterogeneity: Tau² = 0.06; I² = 83%; moderate quality evidence) and low birthweight (average OR 0.61, 95% CI 0.46 to 0.80; studies = two; Heterogeneity: Tau² = 0.00; I² = 0%; moderate quality evidence). Meta-analyses for both ANC coverage four or more visits and perinatal mortality had substantial statistical heterogeneity. Combined interventions improved the proportion of women who had tetanus protection (average OR 1.48, 95% CI 1.18 to 1.87; studies = 3; Heterogeneity: Tau² = 0.01; I² = 33%). No trial in this comparison reported on intermittent prophylactic treatment for malaria. Comparison 3: Two interventions compared head to head. No trials found. Comparison 4: One intervention versus a combination of interventionsThere was no difference in ANC coverage (four or more visits and at least one visit), pregnancy-related deaths, deliveries in a health facility or perinatal mortality. No trials in this comparison reported on low birthweight orintermittent prophylactic treatment of malaria. Authors' conclusions: Implications for practice - Single interventions may improve ANC coverage (at least one visit and four or more visits) and deliveries in health facilities. Combined interventions may improve ANC coverage (at least one visit), reduce perinatal mortality and reduce the occurrence of low birthweight. The effects of the interventions are unrelated to whether they are community or health system interventions. Implications for research - More details should be provided in reporting numbers of events, group totals and the ICCs used to adjust for cluster effects. Outcomes should be reported uniformly so that they are comparable to commonly-used population indicators. We recommend further cluster-RCTs of pregnant women and women in their reproductive years, using combinations of interventions and looking at outcomes that are important to pregnant women, such as maternal and perinatal morbidity and mortality, alongside the explanatory outcomes along the pathway of care: ANC coverage, the services provided during ANC and deliveries in health facilities.

The Cochrane database of systematic reviews · meta-analysis · 117 citationsread the source →

Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age.

Background: Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation for children aged 6 to 59 months. There are new data available from recently published randomised trials since the previous publication of this review in 2010, and this update incorporates this information and reviews the evidence. Objectives: To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years. Search methods: In March 2016 we searched CENTRAL, Ovid MEDLINE, Embase, six other databases, and two trials registers. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies. Selection criteria: Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation. Data collection and analysis: For this update, two reviewers independently assessed studies for inclusion and abstracted data, resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence. Main results: We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence). Authors' conclusions: Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.

The Cochrane database of systematic reviews · meta-analysis · 175 citationsread the source →

How Does the Family Influence Adolescent Eating Habits in Terms of Knowledge, Attitudes and Practices? A Global Systematic Review of Qualitative Studies.

Promoting healthy eating habits can prevent adolescent obesity in which family may play a significant role. This review synthesized findings from qualitative studies to identify family barriers and facilitators of adolescent healthy eating in terms of knowledge, attitudes, and practices (KAP). A literature search of four databases was completed on 31 July 2020; qualitative studies that explored family factors of adolescent (aged 10 to 19 years) eating habits were included. A total of 48 studies were identified, with the majority being from North America and sampled from a single source. Ten themes on how family influences adolescent dietary KAP were found: Knowledge-(1) parental education, (2) parenting style, and (3) family illness experience; Attitudes-(4) family health, (5) cultivation of preference, and (6) family motivation; Practices-(7) home meals and food availability, (8) time and cost, (9) parenting style, and (10) parental practical knowledge and attitudes. This review highlights five parental characteristics underlying food parenting practices which affect adolescents' KAP on healthy eating. Adolescents with working parents and who are living in low-income families are more vulnerable to unhealthy eating. There is a need to explore cultural-specific family influences on adolescents' KAP, especially regarding attitudes and food choices in Asian families.

Nutrients · systematic review · 60 citationsread the source →

Music interventions for improving psychological and physical outcomes in people with cancer.

Background: This is an update of the review published on the Cochrane Library in 2016, Issue 8. Having cancer may result in extensive emotional, physical and social suffering. Music interventions have been used to alleviate symptoms and treatment side effects in people with cancer. This review includes music interventions defined as music therapy offered by trained music therapists, as well as music medicine, which was defined as listening to pre-recorded music offered by medical staff. Objectives: To assess and compare the effects of music therapy and music medicine interventions for psychological and physical outcomes in people with cancer. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 3) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid, CINAHL, PsycINFO, LILACS, Science Citation Index, CancerLit, CAIRSS, Proquest Digital Dissertations, ClinicalTrials.gov, Current Controlled Trials, the RILM Abstracts of Music Literature, http://www.wfmt.info/Musictherapyworld/ and the National Research Register. We searched all databases, except for the last two, from their inception to April 2020; the other two are no longer functional, so we searched them until their termination date. We handsearched music therapy journals, reviewed reference lists and contacted experts. There was no language restriction. Selection criteria: We included all randomized and quasi-randomized controlled trials of music interventions for improving psychological and physical outcomes in adults and pediatric patients with cancer. We excluded patients undergoing biopsy and aspiration for diagnostic purposes. Data collection and analysis: Two review authors independently extracted the data and assessed the risk of bias. Where possible, we presented results in meta-analyses using mean differences and standardized mean differences. We used post-test scores. In cases of significant baseline difference, we used change scores. We conducted separate meta-analyses for studies with adult participants and those with pediatric participants. Primary outcomes of interest included psychological outcomes and physical symptoms and secondary outcomes included physiological responses, physical functioning, anesthetic and analgesic intake, length of hospitalization, social and spiritual support, communication, and quality of life (QoL) . We used GRADE to assess the certainty of the evidence. Main results: We identified 29 new trials for inclusion in this update. In total, the evidence of this review rests on 81 trials with a total of 5576 participants. Of the 81 trials, 74 trials included adult (N = 5306) and seven trials included pediatric (N = 270) oncology patients. We categorized 38 trials as music therapy trials and 43 as music medicine trials. The interventions were compared to standard care. Psychological outcomes The results suggest that music interventions may have a large anxiety-reducing effect in adults with cancer, with a reported average anxiety reduction of 7.73 units (17 studies, 1381 participants; 95% confidence interval (CI) -10.02 to -5.44; very low-certainty evidence) on the Spielberger State Anxiety Inventory scale (range 20 to 80; lower values reflect lower anxiety). Results also suggested a moderately strong, positive impact of music interventions on depression in adults (12 studies, 1021 participants; standardized mean difference (SMD): -0.41, 95% CI -0.67 to -0.15; very low-certainty evidence). We found no support for an effect of music interventions on mood (SMD 0.47, 95% CI -0.02 to 0.97; 5 studies, 236 participants; very low-certainty evidence). Music interventions may increase hope in adults with cancer, with a reported average increase of 3.19 units (95% CI 0.12 to 6.25) on the Herth Hope Index (range 12 to 48; higher scores reflect greater hope), but this finding was based on only two studies (N = 53 participants; very low-certainty evidence). Physical outcomes We found a moderate pain-reducing effect of music interventions (SMD -0.67, 95% CI -1.07 to -0.26; 12 studies, 632 adult participants; very low-certainty evidence). In addition, music interventions had a small treatment effect on fatigue (SMD -0.28, 95% CI -0.46 to -0.10; 10 studies, 498 adult participants; low-certainty evidence). The results suggest a large effect of music interventions on adult participants' QoL, but the results were highly inconsistent across studies, and the pooled effect size was accompanied by a large confidence interval (SMD 0.88, 95% CI -0.31 to 2.08; 7 studies, 573 participants; evidence is very uncertain). Removal of studies that used improper randomization methods resulted in a moderate effect size that was less heterogeneous (SMD 0.47, 95% CI 0.06 to 0.88, P = 0.02, I2 = 56%). A small number of trials included pediatric oncology participants. The findings suggest that music interventions may reduce anxiety but this finding was based on only two studies (SMD -0.94, 95% CI -1.9 to 0.03; very low-certainty evidence). Due to the small number of studies, we could not draw conclusions regarding the effects of music interventions on mood, depression, QoL, fatigue or pain in pediatric participants with cancer. The majority of studies included in this review update presented a high risk of bias, and therefore the overall certainty of the evidence is low. For several outcomes (i.e. anxiety, depression, pain, fatigue, and QoL) the beneficial treatment effects were consistent across studies for music therapy interventions delivered by music therapists. In contrast, music medicine interventions resulted in inconsistent treatment effects across studies for these outcomes. Authors' conclusions: This systematic review indicates that music interventions compared to standard care may have beneficial effects on anxiety, depression, hope, pain, and fatigue in adults with cancer. The results of two trials suggest that music interventions may have a beneficial effect on anxiety in children with cancer. Too few trials with pediatric participants were included to draw conclusions about the treatment benefits of music for other outcomes. For several outcomes, music therapy interventions delivered by a trained music therapist led to consistent results across studies and this was not the case for music medicine interventions. Moreover, evidence of effect was found for music therapy interventions for QoL and fatigue but not for music medicine interventions. Most trials were at high risk of bias and low or very low certainty of evidence; therefore, these results need to be interpreted with caution.

The Cochrane database of systematic reviews · systematic review · 144 citationsread the source →

Intermittent and periodic fasting, longevity and disease.

Intermittent and periodic fasting (IF and PF, respectively) are emerging as safe strategies to affect longevity and healthspan by acting on cellular aging and disease risk factors, while causing no or minor side effects. IF lasting from 12 to 48 hours and repeated every 1 to 7 days and PF lasting 2 to 7 days and repeated once per month or less have the potential to prevent and treat disease, but their effect on cellular aging and the molecular mechanisms involved are only beginning to be unraveled. Here, we describe the different fasting methods and their effect on longevity in organisms ranging from yeast to humans, linking them to the major nutrient-sensing signaling pathways and focusing on the benefits of the fasting and the refeeding periods. We also discuss both the therapeutic potential and side effects of IF and PF with a focus on cancer, autoimmunity, neurodegeneration and metabolic and cardiovascular disease.

Nature aging · 212 citationsread the source →

Alliance in couple and family therapy.

Couple and family therapy (CFT) is challenging because multiple interacting working alliances develop simultaneously and are heavily influenced by preexisting family dynamics. An original meta-analysis of 24 published CFT alliance-retention/outcome studies (k = 17 family and 7 couple studies; N = 1,416 clients) showed a weighted aggregate r = .26, z = 8.13 (p < .005); 95% CI = .33, .20. This small-to-medium effect size is almost identical to that reported for individual adult psychotherapy (Horvath, Del Re, Flückiger, & Symonds, this issue, pp. 9-16). Analysis of the 17 family studies (n = 1,081 clients) showed a similar average weighted effect size (r = .24; z = 6.55, p < .005; 95% CI = .30, .16), whereas the analysis of the 7 couple therapy studies (n = 335 clients) indicated r = .37; z = 6.16, p < .005; 95% CI = .48, .25. Tests of the null hypothesis of homogeneity suggested unexplained variability in the alliance-outcome association in both treatment formats. In this article we also summarize the most widely used alliance measures used in CFT research, provide an extended clinical example, and describe patient contributions to the developing alliance. Although few moderator or mediator studies have been conducted, the literature points to three important alliance-related phenomena in CFT: the frequency of "split" or "unbalanced" alliances, the importance of ensuring safety, and the need to foster a strong within-family sense of purpose about the purpose, goals, and value of conjoint treatment. We conclude with a series of therapeutic practices predicated on the research evidence.

Psychotherapy (Chicago, Ill.) · meta-analysis · 52 citationsread the source →

Symptoms and Distress in Children With Advanced Cancer: Prospective Patient-Reported Outcomes From the PediQUEST Study.

Purpose: Thousands of children are living with advanced cancer; yet patient-reported outcomes (PROs) have rarely been used to describe their experiences. We aimed to describe symptom distress in 104 children age 2 years or older with advanced cancer enrolled onto the Pediatric Quality of Life and Evaluation of Symptoms Technology (PediQUEST) Study (multisite clinical trial evaluating an electronic PRO system). Methods: Symptom data were collected using age- and respondent-adapted versions of the PediQUEST Memorial Symptom Assessment Scale (PQ-MSAS) at most once per week. Clinical and treatment data were obtained from medical records. Individual symptom scores were dichotomized into high/low distress. Determinants of PQ-MSAS scores were explored using linear mixed-effects models. Results: During 9 months of follow-up, PQ-MSAS was administered 920 times: 459 times in teens (99% self-report), 249 times in children ages 7 to 12 years (96% child/parent report), and 212 times in those ages 2 to 6 years (parent reports). Common symptoms included pain (48%), fatigue (46%), drowsiness (39%), and irritability (37%); most scores indicated high distress. Among the 73 PQ-MSAS surveys administered in the last 12 weeks of life, pain was highly prevalent (62%; 58% with high distress). Being female, having a brain tumor, experiencing recent disease progression, and receiving moderate- or high-intensity cancer-directed therapy in the prior 10 days were associated with worse PQ-MSAS scores. In the final 12 weeks of life, receiving mild cancer-directed therapy was associated with improved psychological PQ-MSAS scores. Conclusion: Children with advanced cancer experience high symptom distress. Strategies to promote intensive symptom management are indicated, especially with disease progression or administration of intensive treatments.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology · randomised controlled trial · 212 citationsread the source →

Evaluation of an online self-help version of the REACH forgiveness program: Outcomes and predictors of persistence in a community sample.

Objective: We evaluated outcomes of an online, self-directed REACH forgiveness intervention for community-based adults. Because many participants dropped out before program completion, predictors of program persistence were also examined. Method: Participants (N = 130 adults, 122 female; mean age 48) completed pretreatment assessment and were randomized to immediate treatment (IT) or delayed treatment (DT). Twenty-three IT and 13 DT participants completed the 7-hour REACH forgiveness modules and postintervention assessment; 32 participants completed 3-month follow-up. Results: The IT group reported greater postintervention improvements in overall forgiveness and emotional forgiveness, as well as reductions in avoidance motivations with large effect sizes and, marginally, state empathy; but revenge motivations, decisional forgiveness, and well-being indicators did not change. Most postintervention improvements were maintained at 3-month follow-up. In this online intervention, persistence was predicted by perspective taking, willingness to forgive the offender, and conscientiousness. Three-month follow-up supported maintenance of gains, particularly in overall and emotional forgiveness, and increases in trait forgiveness compared to pretreatment. Conclusion: An online self-directed version of REACH forgiveness applied in a community sample has potential for improving forgiveness-related responses, particularly those involving emotional forgiveness. However, methods to increase program persistence and target suitable recipients need development.

Journal of clinical psychology · randomised controlled trial · 7 citationsread the source →

Randomized, Controlled Trial of an Advance Care Planning Video Decision Support Tool for Patients With Advanced Heart Failure.

Background: Conversations about goals of care and cardiopulmonary resuscitation (CPR)/intubation for patients with advanced heart failure can be difficult. This study examined the impact of a video decision support tool and patient checklist on advance care planning for patients with heart failure. Methods: This was a multisite, randomized, controlled trial of a video-assisted intervention and advance care planning checklist versus a verbal description in 246 patients ≥64 years of age with heart failure and an estimated likelihood of death of >50% within 2 years. Intervention participants received a verbal description for goals of care (life-prolonging care, limited care, and comfort care) and CPR/intubation plus a 6-minute video depicting the 3 levels of care, CPR/intubation, and an advance care planning checklist. Control subjects received only the verbal description. The primary analysis compared the proportion of patients preferring comfort care between study arms immediately after the intervention. Secondary outcomes were CPR/intubation preferences and knowledge (6-item test; range, 0-6) after intervention. Results: In the intervention group, 27 (22%) chose life-prolonging care, 31 (25%) chose limited care, 63 (51%) selected comfort care, and 2 (2%) were uncertain. In the control group, 50 (41%) chose life-prolonging care, 27 (22%) selected limited care, 37 (30%) chose comfort care, and 8 (7%) were uncertain (P<0.001). Intervention participants (compared with control subjects) were more likely to forgo CPR (68% versus 35%; P<0.001) and intubation (77% versus 48%; P<0.001) and had higher mean knowledge scores (4.1 versus 3.0; P<0.001). Conclusions: Patients with heart failure who viewed a video were more informed, more likely to select a focus on comfort, and less likely to desire CPR/intubation compared with patients receiving verbal information only. Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01589120.

Circulation · randomised controlled trial · 88 citationsread the source →

Sphincter of Oddi botulinum toxin injection to prevent pancreatic fistula after distal pancreatectomy.

Background: Postoperative pancreatic fistula represents the most important complication after distal pancreatectomy. The aim of this study was to evaluate the use of a preoperative endoscopic injection of botulinum toxin into the sphincter of Oddi to prevent postoperative pancreatic fistula (German Clinical Trials Register number: DRKS00007885). Methods: This was an investigator-initiated, prospective clinical phase I/II trial with an exploratory study design. We included patients who underwent preoperative endoscopic sphincter botulinum toxin injection (100 units of Botox). End points were the feasibility, safety, and postoperative outcomes, including postoperative pancreatic fistula within 30 days after distal pancreatectomy. Botulinum toxin patients were compared with a control collective of patients undergoing distal pancreatectomy without botulinum toxin injection by case-control matching in a 1:1 ratio. Results: Between February 2015 and February 2016, 29 patients were included. All patients underwent successful sphincter of Oddi botulinum toxin injection within a median of 6 (range 0-10) days before operation. One patient had an asymptomatic, self-limiting (48 hours) increase in serum amylase and lipase after injection. Distal pancreatectomy was performed in 24/29 patients; 5 patients were not resectable. Of the patients receiving botulinum toxin, 7 (29%) had increased amylase levels in drainage fluid on postoperative day 3 (the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula grade A) without symptoms or need for reintervention. Importantly, no clinically relevant fistulas (International Study Group of Pancreatic Surgery grades B/C) were observed in botulinum toxin patients compared to 33% postoperative pancreatic fistula grade B/C in case-control patients (P < .004). Conclusion: Preoperative sphincter of Oddi botulinum toxin injection is a novel and safe approach to decrease the incidence of clinically relevant postoperative pancreatic fistula after distal pancreatectomy. The results of the present trial suggest its efficacy in the prevention of clinically relevant postoperative pancreatic fistula and are validated currently in the German Federal Government-sponsored, multicenter, randomized controlled PREBOT trial.

Surgery · randomised controlled trial · 44 citationsread the source →

Improving sleep after stroke: A randomised controlled trial of digital cognitive behavioural therapy for insomnia.

Stroke is frequently accompanied by long-term sleep disruption. We therefore aimed to assess the efficacy of digital cognitive behavioural therapy for insomnia to improve sleep after stroke. A parallel group randomised controlled trial was conducted remotely in participant's homes/online. Randomisation was online with minimisation of between-group differences in age and baseline Sleep Condition Indicator-8 score. In total, 86 community-dwelling stroke survivors consented, of whom 84 completed baseline assessments (39 female, mean 5.5 years post-stroke, mean 59 years old), and were randomised to digital cognitive behavioural therapy or control (sleep hygiene information). Follow-up was at post-intervention (mean 75 days after baseline) and 8 weeks later. The primary outcome was self-reported insomnia symptoms, as per the Sleep Condition Indicator-8 (range 0-32, lower numbers indicate more severe insomnia, reliable change 7 points) at post-intervention. There were significant improvements in Sleep Condition Indicator-8 for digital cognitive behavioural therapy compared with control (intention-to-treat, digital cognitive behavioural therapy n = 48, control n = 36, 5 imputed datasets, effect of group p ≤ 0.02, ηp2  = 0.07-0.12 [medium size effect], pooled mean difference = -3.35). Additionally, secondary outcomes showed shorter self-reported sleep-onset latencies and better mood for the digital cognitive behavioural therapy group, but no significant differences for self-efficacy, quality of life or actigraphy-derived sleep parameters. Cost-effectiveness analysis found that digital cognitive behavioural therapy dominates over control (non-significant cost savings and higher quality-adjusted life years). No related serious adverse events were reported to the researchers. Overall, digital cognitive behavioural therapy for insomnia effectively improves sleep after stroke. Future research is needed to assess earlier stages post-stroke, with a longer follow-up period to determine whether it should be included as part of routine post-stroke care. Clinicaltrials.gov NCT04272892.

Journal of sleep research · randomised controlled trial · 21 citationsread the source →

Efficacy of cognitive behavioural therapy for sleep improvement in patients with persistent delusions and hallucinations (BEST): a prospective, assessor-blind, randomised controlled pilot trial.

Background: Sleep disturbance occurs in most patients with delusions or hallucinations and should be treated as a clinical problem in its own right. However, cognitive behavioural therapy (CBT)-the best evidence-based treatment for insomnia-has not been tested in this patient population. We aimed to pilot procedures for a randomised trial testing CBT for sleep problems in patients with current psychotic experiences, and to provide a preliminary assessment of potential benefit. Methods: We did this prospective, assessor-blind, randomised controlled pilot trial (Better Sleep Trial [BEST]) at two mental health centres in the UK. Patients (aged 18-65 years) with persistent distressing delusions or hallucinations in the context of insomnia and a schizophrenia spectrum diagnosis were randomly assigned (1:1), via a web-based randomisation system with minimisation to balance for sex, insomnia severity, and psychotic experiences, to receive either eight sessions of CBT plus standard care (medication and contact with the local clinical team) or standard care alone. Research assessors were masked to group allocation. Assessment of outcome was done at weeks 0, 12 (post-treatment), and 24 (follow-up). The primary efficacy outcomes were insomnia assessed by the Insomnia Severity Index (ISI) and delusions and hallucinations assessed by the Psychotic Symptoms Rating Scale (PSYRATS) at week 12. We did analysis by intention to treat, with an aim to provide confidence interval estimation of treatment effects. This study is registered with ISRCTN, number 33695128. Findings: Between Dec 14, 2012, and May 22, 2013, and Nov 7, 2013, and Aug 26, 2014, we randomly assigned 50 patients to receive CBT plus standard care (n=24) or standard care alone (n=26). The last assessments were completed on Feb 10, 2015. 48 (96%) patients provided follow-up data. 23 (96%) patients offered CBT took up the intervention. Compared with standard care, CBT led to reductions in insomnia in the large effect size range at week 12 (adjusted mean difference 6.1, 95% CI 3.0-9.2, effect size d=1.9). By week 12, nine (41%) of 22 patients receiving CBT and one (4%) of 25 patients receiving standard care alone no longer had insomnia, with ISI scores lower than the cutoff for insomnia. The treatment effect estimation for CBT covered a range from reducing but also increasing delusions (adjusted mean difference 0.3, 95% CI -2.0 to 2.6) and hallucinations (-1.9, -6.5 to 2.7). Three patients, all in the CBT group, had five adverse events, although none were regarded as related to study treatment. Interpretation: Our findings show that CBT for insomnia might be highly effective for improving sleep in patients with persistent delusions or hallucinations. A larger, suitably powered phase 3 study is now needed to provide a precise estimate of the effects of CBT for sleep problems, both on sleep and psychotic experiences. Funding: Research for Patient Benefit Programme, National Institute for Health Research.

The lancet. Psychiatry · randomised controlled trial · 160 citationsread the source →

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

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

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

A telehealth lifestyle intervention to reduce excess gestational weight gain in pregnant women with overweight or obesity (GLOW): a randomised, parallel-group, controlled trial.

Background: Excess gestational weight gain (GWG) among women with overweight or obesity synergistically increases their already elevated risk of having gestational diabetes, a caesarean delivery, a large for gestational age infant, and post-partum weight retention, and increases their child's risk of obesity. We investigated whether a primarily telehealth lifestyle intervention reduced excess GWG among women with overweight or obesity. Methods: We did a randomised controlled trial in five antenatal clinics of Kaiser Permanente; Oakland, San Leandro, Walnut Creek, Fremont, and Santa Clara, CA, USA. Women at 8-15 weeks' gestation with singletons, pre-pregnancy BMI 25·0-40·0 kg/m2, and aged 18 years or older were randomly assigned (1:1) to receive the telehealth lifestyle intervention or usual antenatal care. Randomisation was adaptively balanced for age, BMI, and race and ethnicity. Data collectors and investigators were masked to group assignments. The core lifestyle intervention consisted of two in-person and 11 telephone sessions on behavioural strategies to improve weight, diet, and physical activity, and stress management to help women meet a trial goal of gaining at the lower limit of the Institute of Medicine (IOM) guidelines range for total GWG: 7 kg for women with overweight and 5 kg for women with obesity. Usual antenatal care included an antenatal visit at 7-10 weeks' gestation, an additional seven antenatal visits, on average, and periodic health education newsletters, including the IOM GWG guidelines and information on healthy eating and physical activity in pregnancy. The primary outcome was weekly rate of GWG expressed as excess GWG, per Institute of Medicine guidelines and mean assessed in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, NCT02130232. Findings: Between March 24, 2014, and Sept 26, 2017, 5329 women were assessed for eligibility and 200 were randomly assigned to the lifestyle intervention group and 198 to the usual care group. Analyses included 199 women in the lifestyle intervention group (one lost to follow-up) and 195 in the usual care group (three lost to follow-up). 96 (48%) women in the lifestyle intervention group and 134 (69%) women in the usual care group exceeded Institute of Medicine guidelines for rate of GWG per week (relative risk 0·70, 95% CI 0·59 to 0·83). Compared with usual care, women in the lifestyle intervention had reduced weekly rate of GWG (mean 0·26 kg per week [SD 0·15] vs 0·32 kg per week [0·13]; mean between-group difference -0·07 kg per week, 95% CI -0·09 to -0·04). No between-group differences in perinatal complications were observed. Interpretation: Our evidence-based programme showed that health-care delivery systems could further adapt to meet the needs of their clinical settings to prevent excess GWG and improve healthy behaviours and markers of insulin resistance among women with overweight or obesity by using telehealth lifestyle interventions. Funding: US National Institutes of Health.

The lancet. Diabetes & endocrinology · randomised controlled trial · 122 citationsread the source →

Health Coaching Reduces HbA1c in Type 2 Diabetic Patients From a Lower-Socioeconomic Status Community: A Randomized Controlled Trial.

Background: Adoptions of health behaviors are crucial for maintaining good health after type 2 diabetes mellitus (T2DM) diagnoses. However, adherence to glucoregulating behaviors like regular exercise and balanced diet can be challenging, especially for people living in lower-socioeconomic status (SES) communities. Providing cost-effective interventions that improve self-management is important for improving quality of life and the sustainability of health care systems. Objective: To evaluate a health coach intervention with and without the use of mobile phones to support health behavior change in patients with type 2 diabetes. Methods: In this noninferiority, pragmatic randomized controlled trial (RCT), patients from two primary care health centers in Toronto, Canada, with type 2 diabetes and a glycated hemoglobin/hemoglobin A1c (HbA1c) level of ≥7.3% (56.3 mmol/mol) were randomized to receive 6 months of health coaching with or without mobile phone monitoring support. We hypothesized that both approaches would result in significant HbA1c reductions, although health coaching with mobile phone monitoring would result in significantly larger effects. Participants were evaluated at baseline, 3 months, and 6 months. The primary outcome was the change in HbA1c from baseline to 6 months (difference between and within groups). Other outcomes included weight, waist circumference, body mass index (BMI), satisfaction with life, depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), positive and negative affect (Positive and Negative Affect Schedule [PANAS]), and quality of life (Short Form Health Survey-12 [SF-12]). Results: A total of 138 patients were randomized and 7 were excluded for a substudy; of the remaining 131, 67 were allocated to the intervention group and 64 to the control group. Primary outcome data were available for 97 participants (74.0%). While both groups reduced their HbA1c levels, there were no significant between-group differences in change of HbA1c at 6 months using intention-to-treat (last observation carried forward [LOCF]) (P=.48) or per-protocol (P=.83) principles. However, the intervention group did achieve an accelerated HbA1c reduction, leading to a significant between-group difference at 3 months (P=.03). This difference was reduced at the 6-month follow-up as the control group continued to improve, achieving a reduction of 0.81% (8.9 mmol/mol) (P=.001) compared with a reduction of 0.84% (9.2 mmol/mol)(P=.001) in the intervention group. Intervention group participants also had significant decreases in weight (P=.006) and waist circumference (P=.01) while controls did not. Both groups reported improvements in mood, satisfaction with life, and quality of life. Conclusions: Health coaching with and without access to mobile technology appeared to improve glucoregulation and mental health in a lower-SES, T2DM population. The accelerated improvement in the mobile phone group suggests the connectivity provided may more quickly improve adoption and adherence to health behaviors within a clinical diabetes management program. Overall, health coaching in primary care appears to lead to significant benefits for patients from lower-SES communities with poorly controlled type 2 diabetes. Trial registration: ClinicalTrials.gov NCT02036892; http://clinicaltrials.gov/ct2/show/NCT02036892 (Archived by WebCite at http://www.webcitation.org/6b3cJYJOD).

Journal of medical Internet research · randomised controlled trial · 150 citationsread the source →

Promoting well-being in refugee children: An exploratory controlled trial of a positive psychology intervention delivered in Greek refugee camps.

Rigorously evaluated interventions that target protective factors and positive resources rather than ameliorating negative outcomes in child refugees are rare. To address this, we developed and evaluated a short, group-based resilience-building intervention called Strengths for the Journey (SFJ), which was designed for war-affected children. We conducted a quasi-randomized pilot study of the SFJ intervention with 72 7- to 14-year-old forcibly displaced children (Mage = 10.76, 64.8% female) in three refugee camps in Lesvos, Greece. Intervention effectiveness was assessed by measuring pre-post changes in well-being, self-esteem, optimism, and depressive symptoms from before (T1) to immediately after the intervention/wait-list task (T2). Four focus group interviews were conducted with 31 of the participants to discuss their views on the effects of the intervention and the continued use of the skills that were learned. Using repeated-measures ANOVAs, we found improvements in well-being, F (1, 46) = 42.99, ηp2 = .48, self-esteem, F (1, 56) = 29.11, ηp2 = .40, optimism, F (1, 53) = 27.16, ηp2 = .34, and depressive symptoms, F (1, 31) = 62.14, ηp2 = .67, in the intervention group compared with the wait-listed group (p < .05). Focus group participants highlighted the importance of SFJ in developing a sense of togetherness and building their strengths. Child refugees in low-resource settings may benefit from brief, first-line interventions that target protective factors such as well-being, hope, self-esteem, and belonging.

Development and psychopathology · randomised controlled trial · 24 citationsread the source →

An online breathing and wellbeing programme (ENO Breathe) for people with persistent symptoms following COVID-19: a parallel-group, single-blind, randomised controlled trial.

Background: There are few evidence-based interventions for long COVID; however, holistic approaches supporting recovery are advocated. We assessed whether an online breathing and wellbeing programme improves health related quality-of-life (HRQoL) in people with persisting breathlessness following COVID-19. Methods: We conducted a parallel-group, single-blind, randomised controlled trial in patients who had been referred from one of 51 UK-based collaborating long COVID clinics. Eligible participants were aged 18 years or older; were recovering from COVID-19 with ongoing breathlessness, with or without anxiety, at least 4 weeks after symptom onset; had internet access with an appropriate device; and were deemed clinically suitable for participation by one of the collaborating COVID-19 clinics. Following clinical assessment, potential participants were given a unique online portal code. Participants were randomly assigned (1:1) to either immediate participation in the English National Opera (ENO) Breathe programme or to usual care. Randomisation was done by the research team using computer-generated block randomisation lists, with block size 10. The researcher responsible for randomisation was masked to responses. Participants in the ENO Breathe group participated in a 6-week online breathing and wellbeing programme, developed for people with long COVID experiencing breathlessness, focusing on breathing retraining using singing techniques. Those in the deferred group received usual care until they exited the trial. The primary outcome, assessed in the intention-to-treat population, was change in HRQoL, assessed using the RAND 36-item short form survey instrument mental health composite (MHC) and physical health composite (PHC) scores. Secondary outcome measures were the chronic obstructive pulmonary disease assessment test score, visual analogue scales (VAS) for breathlessness, and scores on the dyspnoea-12, the generalised anxiety disorder 7-item scale, and the short form-6D. A thematic analysis exploring participant experience was also conducted using qualitative data from focus groups, survey responses, and email correspondence. This trial is registered with ClinicalTrials.gov, NCT04830033. Findings: Between April 22 and May 25, 2021, 158 participants were recruited and randomly assigned. Of these, eight (5%) individuals were excluded and 150 participants were allocated to a treatment group (74 in the ENO Breathe group and 76 in the usual care group). Compared with usual care, ENO Breathe was associated with an improvement in MHC score (regression coefficient 2·42 [95% CI 0·03 to 4·80]; p=0·047), but not PHC score (0·60 [-1·33 to 2·52]; p=0·54). VAS for breathlessness (running) favoured ENO Breathe participation (-10·48 [-17·23 to -3·73]; p=0·0026). No other statistically significant between-group differences in secondary outcomes were observed. One minor self-limiting adverse event was reported by a participant in the ENO Breathe group who felt dizzy using a computer for extended periods. Thematic analysis of ENO Breathe participant experience identified three key themes: (1) improvements in symptoms; (2) feeling that the programme was complementary to standard care; and (3) the particular suitability of singing and music to address their needs. Interpretation: Our findings suggest that an online breathing and wellbeing programme can improve the mental component of HRQoL and elements of breathlessness in people with persisting symptoms after COVID-19. Mind-body and music-based approaches, including practical, enjoyable, symptom-management techniques might have a role supporting recovery. Funding: Imperial College London.

The Lancet. Respiratory medicine · randomised controlled trial · 74 citationsread the source →

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

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

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

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

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

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

Neighborhood disadvantage and adult alcohol outcomes: differential risk by race and gender.

Objective: We examined whether relationships of neighborhood disadvantage with drinker status, heavy drinking, alcohol-related consequences, and dependence differed by race and/or gender. We hypothesized that neighborhood disadvantage would be negatively associated with drinker status but positively associated with heavy and problem drinking, with more pronounced relationships among African American and Hispanic men than other groups. Method: Data consisted of nationally representative, randomly selected, cross-sectional samples of White, African American, and Hispanic adults (N = 13,864, of which 52% were female; with 7,493 drinkers, of which 48% were female) from the 2000 and 2005 National Alcohol Surveys merged with 2000 Census data. Analyses included logistic and linear regression using weights to adjust for sampling and nonresponse. Results: Hypotheses were partly supported. Bivariate relationships were in the expected direction. Multivariate main effect models showed that neighborhood disadvantage was significantly associated with increased abstinence and marginally associated with increased negative consequences experienced by drinkers, but race/ethnicity and gender modified these associations. Disadvantage was significantly associated with increased abstinence for all groups except African American and Hispanic men. Among drinkers, disadvantage was significantly negatively associated with heavy drinking by Whites but significantly positively associated with heavy drinking by African Americans. Disadvantage also was associated with elevated alcohol-related consequences for White women and African American men. Conclusions: The findings have implications for the development of targeted interventions to reduce the unequal impacts of neighborhood disadvantage on alcohol outcomes. Future research should examine the contribution of multiple types of disadvantage to heavy drinking and alcohol problems.

Journal of studies on alcohol and drugs · 90 citationsread the source →

Preventing a first episode of psychosis: meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups.

Over the last decade many studies were conducted to assess the feasibility of early detection of people at risk of developing psychosis and intervention to prevent or delay a first psychotic episode. Most of these studies were small and underpowered. A meta-analysis can demonstrate the effectiveness of the efforts to prevent or postpone a first episode of psychosis. A search conducted according the PRISMA guideline identified 10 studies reporting 12-month follow-up data on transition to psychosis, and 5 studies with follow-ups varying from 24 to 48 months. Both random and fixed effects meta-analyses were conducted. The quality of the studies varied from poor to excellent. Overall the risk reduction at 12 months was 54% (RR=0.463; 95% CI=0.33-0.64) with a Number Needed to Treat (NNT) of 9 (95% CI=6-15). Although the interventions differed, there was only mild heterogeneity and publication bias was small. All sub-analyses demonstrated effectiveness. Also 24 to 48-month follow-ups were associated with a risk reduction of 37% (RR=.635; 95% CI=0.44-0.92) and a NNT of 12 (95% CI=7-59). Sensitivity analysis excluding the methodologically weakest study showed that the findings were robust. Early detection and intervention in people at ultra-high risk of developing psychosis can be successful to prevent or delay a first psychosis. Antipsychotic medication showed efficacy, but more trials are needed. Omega-3 fatty acid needs replication. Integrated psychological interventions need replication with more methodologically sound studies. The findings regarding CBT appear robust, but the 95% confidence interval is still wide.

Schizophrenia research · meta-analysis · 246 citationsread the source →

Association of behaviour change techniques with effectiveness of dietary interventions among adults of retirement age: a systematic review and meta-analysis of randomised controlled trials.

Background: There is a need for development of more effective interventions to achieve healthy eating, enhance healthy ageing, and to reduce the risk of age-related diseases. The aim of this study was to identify the behaviour change techniques (BCTs) used in complex dietary behaviour change interventions and to explore the association between BCTs utilised and intervention effectiveness. Methods: We undertook a secondary analysis of data from a previous systematic review with meta-analysis of the effectiveness of dietary interventions among people of retirement age. BCTs were identified using the reliable CALO-RE taxonomy in studies reporting fruit and vegetable (F and V) consumption as outcomes. The mean difference in F and V intake between active and control arms was compared between studies in which the BCTs were identified versus those not using the BCTs. Random-effects meta-regression models were used to assess the association of interventions BCTs with F and V intakes. Results: Twenty-eight of the 40 BCTs listed in the CALO-RE taxonomy were identified in the 22 papers reviewed. Studies using the techniques 'barrier identification/problem solving' (93 g, 95% confidence interval (CI) 48 to 137 greater F and V intake), 'plan social support/social change' (78 g, 95%CI 24 to 132 greater F and V intake), 'goal setting (outcome)' (55 g 95%CI 7 to 103 greater F and V intake), 'use of follow-up prompts' (66 g, 95%CI 10 to 123 greater F and V intake) and 'provide feedback on performance' (39 g, 95%CI -2 to 81 greater F and V intake) were associated with greater effects of interventions on F and V consumption compared with studies not using these BCTs. The number of BCTs per study ranged from 2 to 16 (median = 6). Meta-regression showed that one additional BCT led to 8.3 g (95%CI 0.006 to 16.6 g) increase in F and V intake. Conclusions: Overall, this study has identified BCTs associated with effectiveness suggesting that these might be active ingredients of dietary interventions which will be effective in increasing F and V intake in older adults. For interventions targeting those in the peri-retirement age group, 'barrier identification/problem solving' and 'plan for social support/social change' may be particularly useful in increasing the effectiveness of dietary interventions.

BMC medicine · meta-analysis · 78 citationsread the source →

Depression and anxiety in long-term cancer survivors compared with spouses and healthy controls: a systematic review and meta-analysis.

Background: Cancer survival has improved in the past 20 years, affecting the long-term risk of mood disorders. We assessed whether depression and anxiety are more common in long-term survivors of cancer compared with their spouses and with healthy controls. Methods: We systematically searched Medline, PsycINFO, Embase, Science Direct, Ingenta Select, Ovid, and Wiley Interscience for reports about the prevalence of mood disorders in patients diagnosed with cancer at least 2 years previously. We also searched the records of the International Psycho-oncology Society and for reports that cited relevant references. Three investigators independently extracted primary data. We did a random-effects meta-analysis of the prevalences of depression and anxiety in cancer patients compared with spouses and healthy controls. Findings: Our search returned 144 results, 43 were included in the main analysis: for comparisons with healthy controls, 16 assessed depression and ten assessed anxiety; of the comparisons with spouses, 12 assessed depression and five assessed anxiety. The prevalence of depression was 11·6% (95% CI 7·7-16·2) in the pooled sample of 51 381 cancer survivors and 10·2% (8·0-12·6) in 217 630 healthy controls (pooled relative risk [RR] 1·11, 95% CI 0·96-1·27; p=0·17). The prevalence of anxiety was 17·9% (95% CI 12·8-23·6) in 48 964 cancer survivors and 13·9% (9·8-18·5) in 226 467 healthy controls (RR 1·27, 95% CI 1·08-1·50; p=0·0039). Neither the prevalence of depression (26·7% vs 26·3%; RR 1·01, 95% CI 0·86-1·20; p=0·88) nor the prevalence of anxiety (28·0% vs 40·1%; RR 0·71, 95% CI 0·44-1·14; p=0·16) differed significantly between cancer patients and their spouses. Interpretation: Our findings suggest that anxiety, rather than depression, is most likely to be a problem in long-term cancer survivors and spouses compared with healthy controls. Efforts should be made to improve recognition and treatment of anxiety in long-term cancer survivors and their spouses. Funding: None.

The Lancet. Oncology · meta-analysis · 536 citationsread the source →

Screening to prevent spontaneous preterm birth: systematic reviews of accuracy and effectiveness literature with economic modelling.

Objectives: To identify combinations of tests and treatments to predict and prevent spontaneous preterm birth. Data sources: Searches were run on the following databases up to September 2005 inclusive: MEDLINE, EMBASE, DARE, the Cochrane Library (CENTRAL and Cochrane Pregnancy and Childbirth Group trials register) and MEDION. We also contacted experts including the Cochrane Pregnancy and Childbirth Group and checked reference lists of review articles and papers that were eligible for inclusion. Review methods: Two series of systematic reviews were performed: (1) accuracy of tests for the prediction of spontaneous preterm birth in asymptomatic women in early pregnancy and in women symptomatic with threatened preterm labour in later pregnancy; (2) effectiveness of interventions with potential to reduce cases of spontaneous preterm birth in asymptomatic women in early pregnancy and to reduce spontaneous preterm birth or improve neonatal outcome in women with a viable pregnancy symptomatic of threatened preterm labour. For the health economic evaluation, a model-based analysis incorporated the combined effect of tests and treatments and their cost-effectiveness. Results: Of the 22 tests reviewed for accuracy, the quality of studies and accuracy of tests was generally poor. Only a few tests had LR+ > 5. In asymptomatic women these were ultrasonographic cervical length measurement and cervicovaginal prolactin and fetal fibronectin screening for predicting spontaneous preterm birth before 34 weeks. In this group, tests with LR- < 0.2 were detection of uterine contraction by home uterine monitoring and amniotic fluid C-reactive protein (CRP) measurement. In symptomatic women with threatened preterm labour, tests with LR+ > 5 were absence of fetal breathing movements, cervical length and funnelling, amniotic fluid interleukin-6 (IL-6), serum CRP for predicting birth within 2-7 days of testing, and matrix metalloprotease-9, amniotic fluid IL-6, cervicovaginal fetal fibronectin and cervicovaginal human chorionic gonadotrophin (hCG) for predicting birth before 34 or 37 weeks. In this group, tests with LR- < 0.2 included measurement of cervicovaginal IL-8, cervicovaginal hCG, cervical length measurement, absence of fetal breathing movement, amniotic fluid IL-6 and serum CRP, for predicting birth within 2-7 days of testing, and cervicovaginal fetal fibronectin and amniotic fluid IL-6 for predicting birth before 34 or 37 weeks. The overall quality of the trials included in the 40 interventional topics reviewed for effectiveness was also poor. Antibiotic treatment was generally not beneficial but when used to treat bacterial vaginosis in women with intermediate flora it significantly reduced the incidence of spontaneous preterm birth. Smoking cessation programmes, progesterone, periodontal therapy and fish oil appeared promising as preventative interventions in asymptomatic women. Non-steroidal anti-inflammatory agents were the most effective tocolytic agent for reducing spontaneous preterm birth and prolonging pregnancy in symptomatic women. Antenatal corticosteroids had a beneficial effect on the incidence of respiratory distress syndrome and the risk of intraventricular haemorrhage (28-34 weeks), but the effects of repeat courses were unclear. For asymptomatic women, costs ranged from 1.08 pounds for vitamin C to 1219 pounds for cervical cerclage, whereas costs for symptomatic women were more significant and varied little, ranging from 1645 pounds for nitric oxide donors to 2555 pounds for terbutaline; this was because the cost of hospitalisation was included. The best estimate of additional average cost associated with a case of spontaneous preterm birth was approximately 15,688 pounds for up to 34 weeks and 12,104 pounds for up to 37 weeks. Among symptomatic women there was insufficient evidence to draw firm conclusions for preventing birth at 34 weeks. Hydration given to women testing positive for amniotic fluid IL-6 was the most cost-effective test-treatment combination. Indomethacin given to all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among symptomatic women. For a symptomatic woman, the most cost-effective test-treatment combination for postponing delivery by at least 48 h was the cervical length (15 mm) measurement test with treatment with indomethacin for all those testing positive. This combination was also the most cost-effective option for postponing delivery by at least 7 days. Antibiotic treatment for asymptomatic bacteriuria of all women without any initial testing was the most cost-effective option for preventing birth before 37 weeks among asymptomatic women but this does not take into account the potential side effects of antibiotics or issues such as increased resistance. Conclusions: For primary prevention, an effective, affordable and safe intervention applied to all mothers without preceding testing is likely to be the most cost-effective approach in asymptomatic women in early pregnancy. For secondary prevention among women at risk of preterm labour in later pregnancy, a management strategy based on the results of testing is likely to be more cost-effective. Implementation of a treat-all strategy with simple interventions, such as fish oils, would be premature for asymptomatic women. Universal provision of high-quality ultrasound machines in labour wards is more strongly indicated for predicting spontaneous preterm birth among symptomatic women than direct management, although staffing issues and the feasibility and acceptability to mothers and health providers of such strategies need to be explored. Further research should include investigations of low-cost and effective tests and treatments to reduce and delay spontaneous preterm birth and reduce the risk of perinatal mortality arising from preterm birth.

Health technology assessment (Winchester, England) · meta-analysis · 129 citationsread the source →

Job strain as a risk factor for coronary heart disease: a collaborative meta-analysis of individual participant data.

Background: Published work assessing psychosocial stress (job strain) as a risk factor for coronary heart disease is inconsistent and subject to publication bias and reverse causation bias. We analysed the relation between job strain and coronary heart disease with a meta-analysis of published and unpublished studies. Methods: We used individual records from 13 European cohort studies (1985-2006) of men and women without coronary heart disease who were employed at time of baseline assessment. We measured job strain with questions from validated job-content and demand-control questionnaires. We extracted data in two stages such that acquisition and harmonisation of job strain measure and covariables occurred before linkage to records for coronary heart disease. We defined incident coronary heart disease as the first non-fatal myocardial infarction or coronary death. Findings: 30,214 (15%) of 197,473 participants reported job strain. In 1·49 million person-years at risk (mean follow-up 7·5 years [SD 1·7]), we recorded 2358 events of incident coronary heart disease. After adjustment for sex and age, the hazard ratio for job strain versus no job strain was 1·23 (95% CI 1·10-1·37). This effect estimate was higher in published (1·43, 1·15-1·77) than unpublished (1·16, 1·02-1·32) studies. Hazard ratios were likewise raised in analyses addressing reverse causality by exclusion of events of coronary heart disease that occurred in the first 3 years (1·31, 1·15-1·48) and 5 years (1·30, 1·13-1·50) of follow-up. We noted an association between job strain and coronary heart disease for sex, age groups, socioeconomic strata, and region, and after adjustments for socioeconomic status, and lifestyle and conventional risk factors. The population attributable risk for job strain was 3·4%. Interpretation: Our findings suggest that prevention of workplace stress might decrease disease incidence; however, this strategy would have a much smaller effect than would tackling of standard risk factors, such as smoking. Funding: Finnish Work Environment Fund, the Academy of Finland, the Swedish Research Council for Working Life and Social Research, the German Social Accident Insurance, the Danish National Research Centre for the Working Environment, the BUPA Foundation, the Ministry of Social Affairs and Employment, the Medical Research Council, the Wellcome Trust, and the US National Institutes of Health.

Lancet (London, England) · meta-analysis · 578 citationsread the source →

The Social Epidemiology of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

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

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

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

The Lancet. Neurology · 5441 citationsread the source →

SARS-CoV-2 in Spanish Intensive Care Units: Early experience with 15-day survival in Vitoria.

Purpose: Community transmission of SARS-CoV-2 was detected in Spain in February 2020, with 216% intensive care unit (ICU) capacity expanded in Vitoria by March 18th, 2020. Methods: We identified patients from the two public hospitals in Vitoria who were admitted to ICU with confirmed infection by SARS-CoV-2. Data reported here were available in April 6th, 2020. Mortality was assessed in those who completed 15-days of ICU stay. Results: We identified 48 patients (27 males) with confirmed SARS-CoV-2. Median [interquartile range (IQR)] age of patients was 63 [51-75] years. Symptoms began a median of 7 [5-12] days before ICU admission. The most common comorbidities identified were obesity (48%), arterial hypertension (44%) and chronic lung disease (37%). All patients were admitted by hypoxemic respiratory failure and none received non-invasive mechanical ventilation. Forty-five (94%) underwent intubation, 3 (6%) high flow nasal therapy (HFNT), 1 (2%) extracorporeal membrane oxygenation (ECMO) and 22 (46%) required prone position. After 15 days, 14/45 (31%) intubated patients died (13% within one week), 10/45 (22%) were extubated, and 21/45 (47%) underwent mechanical ventilation. Six patients had documented super-infection. Procalcitonin plasma above 0.5μg/L was associated with 16% vs. 19% (p=0.78) risk of death after 7 days. Conclusion: This early experience with SARS-CoV-2 in Spain suggests that a strategy of right oxygenation avoiding non-invasive mechanical ventilation was life-saving. Seven-day mortality in SARS-CoV-2 requiring intubation was lower than 15%, with 80% of patients still requiring mechanical ventilation. After 15 days of ICU admission, half of patients remained intubated, whereas one third died.

Anaesthesia, critical care & pain medicine · cohort or longitudinal · 156 citationsread the source →

Safety of Tirofiban in acute Ischemic Stroke: the SaTIS trial.

Background and purpose: Tirofiban is a highly selective, fast-acting nonpeptide glycoprotein IIb/IIIa platelet receptor antagonist with a short half-life time. Glycoprotein IIb/IIIa antagonists are effective for the treatment of acute coronary syndromes proven in large clinical trials. Safety and efficacy in patients with ischemic stroke are uncertain. This was addressed in the Safety of Tirofiban in acute Ischemic Stroke (SaTIS) trial. Methods: Two hundred sixty patients with acute ischemic stroke were randomized in a placebo-controlled, prospective, open-label treatment, blinded outcome reading multicenter trial. Subjects with a National Institutes of Health Stroke Scale between 4 and 18 received intravenously either tirofiban or placebo within 3 to 22 hours after symptom onset for 48 hours. The primary end point was the rate of cerebral bleeding as measured in follow-up CT scans 2 to 7 days after inclusion. The secondary end point was clinical efficacy within 1 week (National Institutes of Health Stroke Scale, modified Rankin Scale) and after 5 months (Barthel Index, modified Rankin Scale). Results: The rate of cerebral hemorrhagic transformation (I/II) and parenchymal hemorrhage (I/II) did not differ between both groups (tirofiban 36 of 120; placebo 33 of 124: OR, 1.18; 95% CI, 0.66 to 2.06). Mortality after 5 months was significantly lower in patients treated with tirofiban (3 of 130 [2.3%] versus 11 of 126 [8.7%]; OR, 4.05; 95% CI, 1.1 to 14.9). No difference in neurological/functional outcome was found after 1 week and after 5 months. Conclusions: We conclude that tirofiban might be safe in acute moderate ischemic stroke even when administered within a large time window after symptom onset and might save lives in the late outcome. Clinical Trial Registration- URL: www.strokecenter.org/trials/. Trial name: SaTIS. Enrollment began before July 1, 2005.

Stroke · randomised controlled trial · 134 citationsread the source →

Marital adjustment, satisfaction and dissolution among hematopoietic stem cell transplant patients and spouses: a prospective, five-year longitudinal investigation.

Objective: To examine the trajectory of marital adjustment, satisfaction and dissolution among 121 hematopoietic stem cell transplant (HSCT) couples-as a function of role (patient or spouse) and gender. Methods: Prospective, longitudinal design. Participants completed the Dyadic Adjustment Scale at six time points: pre-transplant (4-7 days after beginning medical workup prior to starting transplant), 6 months post-transplant, and 1, 2, 3 and 5 years post-transplant. They also reported on marital status over time. Results: Participants ranged in age from 23-68 (52% female patients and 48% female spouses). Ninety-eight patients received an allogeneic transplant; 23 received an autologous transplant. Marital dissolution was uncommon (four divorces since the transplant among 55 participating 5-year survivors, 7%). Dyadic satisfaction was stable over time for both male and female patients and male spouses, but not for female spouses who reported reductions in satisfaction at all time points relative to baseline. Conclusion: Couples were by and large resilient. However, caregiver-specific gender differences indicate an increased risk for relationship maladjustment and dissatisfaction among female spouses and ultimately, female spouse/male patient couples.

Psycho-oncology · randomised controlled trial · 46 citationsread the source →

Effects of nurse home visitation on cigarette smoking, pregnancy outcomes and breastfeeding: a randomized controlled trial.

Objective: antenatal smoking is more prevalent among young women with low socio-economic status. The aim of our study is to assess whether the VoorZorg programme, compared to usual care, is effective in reducing cigarette smoking among young high risk pregnant women. Furthermore, the effect of VoorZorg on pregnancy outcomes and on breast feeding will be described. Design: a randomised controlled trial of VoorZorg, a nurse home visitation intervention, was undertaken over a 2½ year period from 2007 to 2009. Data were collected between 16 and 28 weeks gestation, 32 weeks gestation and at two months post partum on cigarette smoking status plus six months post partum for breastfeeding prevalence. Neonatal birth weight and gestation at birth were also collected. Setting: participants living in 20 municipalities in the Netherlands. Participants: 460 pregnant women were recruited by different professionals. Inclusion criteria were age <26 years, ≤28 weeks pregnancy with the first child, low educational level and some knowledge of the Dutch language. Interventions: women in the intervention group received, in addition to usual care, the VoorZorg programme which consisted of 40-60 home visits by specialised nurses from pregnancy until two years after birth. Findings: the percentage of smokers was significantly lower in the intervention group (40%) compared to the control group (48%) during pregnancy (p=0.03) and at two months post birth (49% and 62%; p=0.02). During pregnancy the number of daily cigarettes smoked was reduced in both groups. After birth, the intervention group smoked 50% less cigarettes compared to the control group (C: 8±10; I: 4±7 (mean±standard deviation (SD)), p=0.01). Furthermore, women in the intervention group did not smoke near the baby (C: 2±5; I: 0±0 (mean±SD) p=0.03). Birth weight and gestational age were similar in both groups (C: 3147g, 40 weeks; I: 3144g, 39 weeks (p=0.94, p=0.17)). Significantly more women in the intervention group were still breast feeding their baby at six months post -birth (C: 6%; I: 13%, p=0.04). Key conclusions: VoorZorg seemed to be effective in reducing cigarette smoking and in increasing breastfeeding duration. No effect was found on pregnancy outcomes.

Midwifery · randomised controlled trial · 57 citationsread the source →

Integrating tobacco cessation into mental health care for posttraumatic stress disorder: a randomized controlled trial.

Context: Most smokers with mental illness do not receive tobacco cessation treatment. Objective: To determine whether integrating smoking cessation treatment into mental health care for veterans with posttraumatic stress disorder (PTSD) improves long-term smoking abstinence rates. Design, setting, and patients: A randomized controlled trial of 943 smokers with military-related PTSD who were recruited from outpatient PTSD clinics at 10 Veterans Affairs medical centers and followed up for 18 to 48 months between November 2004 and July 2009. Intervention: Smoking cessation treatment integrated within mental health care for PTSD delivered by mental health clinicians (integrated care [IC]) vs referral to Veterans Affairs smoking cessation clinics (SCC). Patients received smoking cessation treatment within 3 months of study enrollment. Main outcome measures: Smoking outcomes included 12-month bioverified prolonged abstinence (primary outcome) and 7- and 30-day point prevalence abstinence assessed at 3-month intervals. Amount of smoking cessation medications and counseling sessions delivered were tested as mediators of outcome. Posttraumatic stress disorder and depression were repeatedly assessed using the PTSD Checklist and Patient Health Questionnaire 9, respectively, to determine if IC participation or quitting smoking worsened psychiatric status. Results: Integrated care was better than SCC on prolonged abstinence (8.9% vs 4.5%; adjusted odds ratio, 2.26; 95% confidence interval [CI], 1.30-3.91; P = .004). Differences between IC vs SCC were largest at 6 months for 7-day point prevalence abstinence (78/472 [16.5%] vs 34/471 [7.2%], P < .001) and remained significant at 18 months (86/472 [18.2%] vs 51/471 [10.8%], P < .001). Number of counseling sessions received and days of cessation medication used explained 39.1% of the treatment effect. Between baseline and 18 months, psychiatric status did not differ between treatment conditions. Posttraumatic stress disorder symptoms for quitters and nonquitters improved. Nonquitters worsened slightly on the Patient Health Questionnaire 9 relative to quitters (differences ranged between 0.4 and 2.1, P = .03), whose scores did not change over time. Conclusion: Among smokers with military-related PTSD, integrating smoking cessation treatment into mental health care compared with referral to specialized cessation treatment resulted in greater prolonged abstinence. Trial registration: clinicaltrials.gov Identifier: NCT00118534.

JAMA · randomised controlled trial · 166 citationsread the source →

Is it possible to improve residents breaking bad news skills? A randomised study assessing the efficacy of a communication skills training program.

Background: This study aims to assess the efficacy of a 40-h training programme designed to teach residents the communication skills needed to break the bad news. Methods: Residents were randomly assigned to the training programme or to a waiting list. A simulated patient breaking bad news (BBN) consultation was audiotaped at baseline and after training in the training group and 8 months after baseline in the waiting-list group. Transcripts were analysed by tagging the used communication skills with a content analysis software (LaComm) and by tagging the phases of bad news delivery: pre-delivery, delivery and post-delivery. Training effects were tested with generalised estimating equation (GEE) and multivariate analysis of variance (MANOVA). Results: The trained residents (n=50) used effective communication skills more often than the untrained residents (n=48): more open questions (relative rate (RR)=5.79; P<0.001), open directive questions (RR=1.71; P=0.003) and empathy (RR=4.50; P=0.017) and less information transmission (RR=0.72; P=0.001). The pre-delivery phase was longer for the trained (1 min 53 s at baseline and 3 min 55 s after training) compared with the untrained residents (2 min 7 s at baseline and 1 min 46 s at second assessment time; P<0.001). Conclusion: This study shows the efficacy of training programme designed to improve residents' BBN skills. The way residents break bad news may thus be improved.

British journal of cancer · randomised controlled trial · 77 citationsread the source →

Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial.

Background: Influenza is an important cause of morbidity and mortality worldwide. Treatment options are scarce, and new drugs with novel mechanisms of action are needed. We aimed to assess the efficacy and safety of nitazoxanide, a thiazolide anti-infective, for treatment of acute uncomplicated influenza. Methods: We did a double-blind, randomised, placebo-controlled, phase 2b/3 trial in 74 primary care clinics in the USA between Dec 27, 2010, and April 30, 2011. We enrolled participants aged 12-65 years with fever, at least one respiratory symptom, and one constitutional symptom of influenza within 48 h of symptom onset. We randomly assigned participants to receive either nitazoxanide 600 mg, nitazoxanide 300 mg, or placebo twice daily for 5 days, (ratio 1:1:1) and followed them up for 28 days. Randomisation lists were computer generated and done in blocks of three. Sponsor, investigators, study monitors, patients, and laboratory personnel were all masked to treatment allocation in the study. The primary endpoint was the time from first dose to alleviation of symptoms. The primary analysis was by intention-to-treat for participants with influenza infection confirmed by RT-PCR or culture at baseline. This trial is registered with ClinicalTrials.gov, number NCT01227421. Findings: Of 650 participants screened, 624 (96%) were enrolled. Of these, 212 were randomly assigned to receive placebo twice a day, 201 to receive nitazoxanide 300 mg twice a day, and 211 to receive nitazoxanide 600 mg a day. The median duration of symptoms for participants receiving placebo was 116·7 h (95% CI 108·1-122·1) compared with 95·5 h (84·0-108·0; p=0·0084) for those receiving 600 mg nitazoxanide and 109·1 h (96·1-129·5, p=0·52) for those receiving 300 mg nitazoxanide. Adverse events were similar between the three groups, the most common being headache reported by 24 (11%) of 212 patients enrolled in placebo group, 12 (6%) of 201 patients in the low-dose group, and 17 (8%) of 211 patients in the high-dose group, or diarrhoea, reported by seven (3%) patients in the placebo group, four (2%) patients enrolled in the low-dose group, and 17 (8%) patients in the high-dose group. Interpretation: Treatment with nitazoxanide 600 mg twice daily for 5 days was associated with a reduction of the duration of symptoms in participants with acute uncomplicated influenza. Further studies are warranted to confirm these findings and to assess efficacy of the drug alone or in combination with existing drugs in seriously ill patients and those at risk of influenza complications. Funding: Romark Laboratories LC.

The Lancet. Infectious diseases · randomised controlled trial · 189 citationsread the source →

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

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

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

Sustained care intervention and postdischarge smoking cessation among hospitalized adults: a randomized clinical trial.

Importance: Health care systems need effective models to manage chronic diseases like tobacco dependence across transitions in care. Hospitalizations provide opportunities for smokers to quit, but research suggests that hospital-delivered interventions are effective only if treatment continues after discharge. Objective: To determine whether an intervention to sustain tobacco treatment after hospital discharge increases smoking cessation rates compared with standard care. Design, setting, and participants: A randomized clinical trial compared sustained care (a postdischarge tobacco cessation intervention) with standard care among 397 hospitalized daily smokers (mean age, 53 years; 48% were males; 81% were non-Hispanic whites) who wanted to quit smoking after discharge and received a tobacco dependence intervention in the hospital; 92% of eligible patients and 44% of screened patients enrolled. The study was conducted from August 2010 through November 2012 at Massachusetts General Hospital. Interventions: Sustained care participants received automated interactive voice response telephone calls and their choice of free smoking cessation medication (any type approved by the US Food and Drug Administration) for up to 90 days. The automated telephone calls promoted cessation, provided medication management, and triaged smokers for additional counseling. Standard care participants received recommendations for postdischarge pharmacotherapy and counseling. Main outcomes and measures: The primary outcome was biochemically confirmed past 7-day tobacco abstinence at 6-month follow-up after discharge from the hospital; secondary outcomes included self-reported tobacco abstinence. Results: Smokers randomly assigned to sustained care (n = 198) used more counseling and more pharmacotherapy at each follow-up assessment than those assigned to standard care (n = 199). Biochemically validated 7-day tobacco abstinence at 6 months was higher with sustained care (26%) than with standard care (15%) (relative risk [RR], 1.71 [95% CI, 1.14-2.56], P = .009; number needed to treat, 9.4 [95% CI, 5.4-35.5]). Using multiple imputation for missing outcomes, the RR for 7-day tobacco abstinence was 1.55 (95% CI, 1.03-2.21; P = .04). Sustained care also resulted in higher self-reported continuous abstinence rates for 6 months after discharge (27% vs 16% for standard care; RR, 1.70 [95% CI, 1.15-2.51]; P = .007). Conclusions and relevance: Among hospitalized adult smokers who wanted to quit smoking, a postdischarge intervention providing automated telephone calls and free medication resulted in higher rates of smoking cessation at 6 months compared with a standard recommendation to use counseling and medication after discharge. These findings, if replicated, suggest an approach to help achieve sustained smoking cessation after a hospital stay. Trial registration: clinicaltrials.gov Identifier: NCT01177176.

JAMA · randomised controlled trial · 110 citationsread the source →

REMCARE: reminiscence groups for people with dementia and their family caregivers - effectiveness and cost-effectiveness pragmatic multicentre randomised trial.

Objectives: The aim of the REMiniscence groups for people with dementia and their family CAREgivers (REMCARE) study was to assess the effectiveness and cost-effectiveness of joint reminiscence groups for people with dementia and their family caregivers as compared with usual care. Design: A multicentre, pragmatic randomised controlled trial with two parallel arms - an intervention group and a usual-care control group - was carried out. A restricted dynamic method of randomisation was used with an overall allocation ratio of 1 : 1, restricted to ensure intervention groups of a viable size. Assessments, blind to treatment allocation, were carried out at baseline, 3 months and 10 months (primary end point). Setting: Most participants were recruited through NHS Memory Clinics and Community Mental Health Teams for older people. Assessments were usually carried out in the person's home, and treatment groups were held in a variety of community settings. Participants: A total of 488 individuals (mean age 77.5 years) with mild to moderate dementia (meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria), who were initially living in the community, and who had a relative or other caregiver maintaining regular contact, who could act as an informant and was willing and able to participate in the intervention, were recruited to the study. Most carers were spouses (71%). A total of 350 dyads completed the study. Interventions: The intervention consisted of joint reminiscence groups held weekly for 12 consecutive weeks, followed by monthly maintenance sessions for a further 7 months. The sessions followed a treatment manual, and were led by two trained facilitators in each centre, supported by a number of volunteers. Up to 12 dyads were invited to attend each group. Main outcome measures: The primary outcome measures were self-reported quality of life for the person with dementia and psychological distress for the carer [General Health Questionnaire-28 item version (GHQ-28)]. Secondary outcome measures included autobiographical memory and activities of daily living for the person with dementia, carer stress for the carer and mood, relationship quality and service use and costs for both parties. Results: The intention-to-treat analysis identified no differences in outcome between the intervention and control conditions on primary or secondary outcomes [self-reported quality of life in Alzheimer's disease: mean difference 0.07, standard error (SE) 0.65; F = 0.48; p = 0.53]. Carers of people with dementia allocated to the reminiscence intervention reported a significant increase in anxiety on a subscale of the GHQ-28 at the 10-month end point (mean difference 1.25, SE 0.5; F = 8.28; p = 0.04). Compliance analyses suggested some benefits for people with dementia who attended more reminiscence sessions; however, carers attending more groups showed increased caregiving stress. Use of health- and social-care services was modest, with no significant difference in service use between conditions. Owing to negligible difference in quality-adjusted life-year gains (derived from European Quality of Life-5 Dimensions) between the conditions the planned full economic analysis was curtailed. Conclusions: This trial does not provide support for the effectiveness or cost-effectiveness of joint reminiscence groups for people with dementia and their carers. Although there may be some beneficial effects for people with dementia who attend sessions as planned, this must be viewed in the context of raised anxiety and stress in their carers. The reasons for these discrepant outcomes need to be explored further, and may necessitate reappraisal of the movement towards joint interventions. Trial registration: Current Controlled Trials ISRCTN42430123. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 48. See the HTA programme website for further project information.

Health technology assessment (Winchester, England) · randomised controlled trial · 97 citationsread the source →

The epidemiology of trauma and post-traumatic stress disorder in a representative cohort of young people in England and Wales.

Background: Despite the emphasis placed on childhood trauma in psychiatry, comparatively little is known about the epidemiology of trauma and trauma-related psychopathology in young people. We therefore aimed to evaluate the prevalence, clinical features, and risk factors associated with trauma exposure and post-traumatic stress disorder (PTSD) in young people. Methods: We carried out a comprehensive epidemiological study based on participants from the Environmental Risk Longitudinal Twin Study, a population-representative birth-cohort of 2232 children born in England and Wales in 1994-95. At the follow-up home visit at age 18 years, participants were assessed with structured interviews for trauma exposure, PTSD, other psychopathology, risk events, functional impairment, and service use. Risk factors for PTSD were measured prospectively over four previous assessments between age 5 and 12 years. The key outcomes were the prevalence, clinical features, and risk factors associated with trauma exposure and PTSD. We also derived and tested the internal validity of a PTSD risk calculator. Findings: We found that 642 (31·1%) of 2064 participants reported trauma exposure and 160 (7·8%) of 2063 experienced PTSD by age 18 years. Trauma-exposed participants had high rates of psychopathology (187 [29·2%] of 641 for major depressive episode, 146 [22·9%] of 638 for conduct disorder, and 102 [15·9%] of 641 for alcohol dependence), risk events (160 [25·0%] of 641 for self-harm, 53 [8·3%] of 640 for suicide attempt, and 42 [6·6%] of 640 for violent offence), and functional impairment. Participants with lifetime PTSD had even higher rates of psychopathology (87 [54·7%] of 159 for major depressive episode, 43 [27·0%] of 159 for conduct disorder, and 41 [25·6%] of 160 for alcohol dependence), risk events (78 [48·8%] of 160 for self-harm, 32 [20·1%] of 159 for suicide attempt, and 19 [11·9%] of 159 for violent offence), and functional impairment. However, only 33 (20·6%) of 160 participants with PTSD received help from mental health professionals. The PTSD risk calculator had an internally validated area under the receiver operating characteristic curve of 0·74, indicating adequate discrimination of trauma-exposed participants with and without PTSD, and internally validated calibration-in-the-large of -0·10 and calibration slope of 0·90, indicating adequate calibration. Interpretation: Trauma exposure and PTSD are associated with complex psychiatric presentations, high risk, and significant impairment in young people. Improved screening, reduced barriers to care provision, and comprehensive clinical assessment are needed to ensure that trauma-exposed young people and those with PTSD receive appropriate treatment. Funding: The Medical Research Council, the National Institute of Child Health and Development, the Jacobs Foundation, the Nuffield Foundation, the National Society for Prevention of Cruelty to Children, the Economic and Social Research Council, the National Institute for Health Research, MQ, and Canadian Institutes for Advanced Research.

The lancet. Psychiatry · cohort or longitudinal · 287 citationsread the source →

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

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

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

Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment.

Objective: To report our initial experience with a novel device, designed to provide portable, noninvasive, transcutaneous stimulation of the vagus nerve, both acutely and preventively, as a treatment for cluster headache. Methods: Patients with cluster headache (11 chronic, 8 episodic), from 2 centers, including 7 who were refractory to drug treatment, had sufficient data available for analysis in this open-label observational cohort study. The device, known as the gammaCore, was used acutely to treat individual attacks as well as to provide prevention. Patient-estimated efficacy data were collected by systematic inquiry during follow-up appointments up to a period of 52 weeks of continuous use. Results: Fifteen patients reported an overall improvement in their condition, with 4 reporting no change, providing a mean overall estimated improvement of 48%. Of all attacks treated, 47% were aborted within an average of 11 ± 1 minutes of commencing stimulation. Ten patients reduced their acute use of high-flow oxygen by 55% with 9 reducing triptan use by 48%. Prophylactic use of the device resulted in a substantial reduction in estimated mean attack frequency from 4.5/24 hours to 2.6/24 hours (p < 0.0005) posttreatment. Conclusion: These data suggest that noninvasive vagus nerve stimulation may be practical and effective as an acute and preventive treatment in chronic cluster headache. Further evaluation of this treatment using randomized sham-controlled trials is thus warranted. Classification of evidence: This study provides Class IV evidence that for patients with cluster headache, transcutaneous stimulation of the vagus nerve aborts acute attacks and reduces the frequency of attacks.

Neurology · cohort or longitudinal · 108 citationsread the source →

Pharmacokinetics of once-daily darunavir-ritonavir and atazanavir-ritonavir over 72 hours following drug cessation.

The object of this study was to investigate the pharmacokinetics of darunavir-ritonavir and atazanavir-ritonavir once-daily dosing over 72 h (h) following drug intake cessation. Volunteers received darunavir-ritonavir at 800 and 100 mg, respectively, once daily for 10 days, followed by a 7-day washout period, and atazanavir-ritonavir at 300 and 100 mg, respectively, once daily for 10 days. Full pharmacokinetic profiles were assessed for each phase for the 72 h following day 10. Pharmacokinetic parameters were determined over 24 h and to the last measurable concentration by noncompartmental methods. Seventeen subjects completed the study. The geometric mean (GM) terminal elimination half-life to 72 h of darunavir was 6.48 h, which was lower than the 0- to 24-h half-life (10.70 h). The terminal elimination half-life of atazanavir was 6.74 h, which was lower than the 0- to 24-h half-life (13.72 h). All subjects but one had darunavir concentrations higher than the target of 550 ng/ml for protease-resistant HIV isolates (equivalent to 10 times the protein-binding-corrected 50% inhibitory concentration [IC(50)] for wild-type virus) at 24 h postdose, and 14 out of 17 had concentrations higher than the target at 30 h postdose (GM of 1,088 and 851 ng/ml). All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/ml (equivalent to 10 times the protein-binding-corrected IC(50) for wild-type virus) at 24 and 30 h postdose (GM of 693 and 392 ng/ml). Two of 17 and 5 of 17 subjects were above target at 48 h postdose while on darunavir-ritonavir and atazanavir-ritonavir. Ritonavir half-life to 72 h was 6.84 h with darunavir and 6.07 with atazanavir. This study investigated the pharmacokinetic forgiveness of two boosted protease inhibitors. Although the rates of decline of darunavir and atazanavir slightly increased as ritonavir concentrations declined, most individuals had concentrations 6 h after the end of the ideal dosing interval of 24 h which were above the cutoff used to define therapeutic concentrations.

Antimicrobial agents and chemotherapy · clinical trial · 31 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 →

A review and content analysis of engagement, functionality, aesthetics, information quality, and change techniques in the most popular commercial apps for weight management.

Background: There are thousands of apps promoting dietary improvement, increased physical activity (PA) and weight management. Despite a growing number of reviews in this area, popular apps have not been comprehensively analysed in terms of features related to engagement, functionality, aesthetics, information quality, and content, including the types of change techniques employed. Methods: The databases containing information about all Health and Fitness apps on GP and iTunes (7,954 and 25,491 apps) were downloaded in April 2015. Database filters were applied to select the most popular apps available in both stores. Two researchers screened the descriptions selecting only weight management apps. Features, app quality and content were independently assessed using the Mobile App Rating Scale (MARS) and previously-defined categories of techniques relevant to behaviour change. Inter-coder reliabilities were calculated, and correlations between features explored. Results: Of the 23 popular apps included in the review 16 were free (70%), 15 (65%) addressed weight control, diet and PA combined; 19 (83%) allowed behavioural tracking. On 5-point MARS scales, apps were of average quality (Md = 3.2, IQR = 1.4); "functionality" (Md = 4.0, IQR = 1.1) was the highest and "information quality" (Md = 2.0, IQR = 1.1) was the lowest domain. On average, 10 techniques were identified per app (range: 1-17) and of the 34 categories applied, goal setting and self-monitoring techniques were most frequently identified. App quality was positively correlated with number of techniques included (rho = .58, p < .01) and number of "technical" features (rho = .48, p < .05), which was also associated with the number of techniques included (rho = .61, p < .01). Apps that provided tracking used significantly more techniques than those that did not. Apps with automated tracking scored significantly higher in engagement, aesthetics, and overall MARS scores. Those that used change techniques previously associated with effectiveness (i.e., goal setting, self-monitoring and feedback) also had better "information quality". Conclusions: Popular apps assessed have overall moderate quality and include behavioural tracking features and a range of change techniques associated with behaviour change. These apps may influence behaviour, although more attention to information quality and evidence-based content are warranted to improve their quality.

The international journal of behavioral nutrition and physical activity · review · 228 citationsread the source →

What do people do before going to bed? A study of bedtime procrastination using time use surveys.

Study objectives: Bedtime procrastination (BP) is defined as going to bed later than intended despite absence of external reasons. This study investigated sleep and psychological factors associated with BP in young adults, and further compared how high and low BP groups spend their time over 24 h and also 3 h prior to bedtime using time use surveys. Methods: Young adults (N = 106) from the community were classified as either high (n = 54) or low (n = 52) BP group based on the Bedtime Procrastination Scale. All participants were asked to complete questionnaires on insomnia, depression, anxiety, stress, and chronotype, in addition to keeping a 7-day sleep diary and completing time use surveys over 48 h. Results: Participants were 61.3% female, mean age 22.7 (±2.89) years old. Individuals in the high BP group reported significantly more depression, anxiety, and insomnia, went to bed later, woke up later, and had more eveningness tendencies compared to the low BP group. Results from the time use surveys revealed that the high BP group spent significantly more time engaging in leisure and social activity with the majority of time spent using media over 24 h compared to the low BP group. Finally, the high BP group spent on average approximately 451% (or 61 min) more time per day on their smartphone 3 h prior to bedtime compared to the low BP group. Conclusions: Our results suggest that BP is negatively associated with sleep and mood, and should be considered a serious health-interfering behavior.

Sleep · 65 citationsread the source →

Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology

Despite over 50 yr of experience with steroid replacement therapy, the management of congenital adrenal hyperplasia (CAH) remains difficult, and clinical practice varies substantially throughout the world. To consider the evidence for best practice, to formulate management guidelines, and to consider innovative therapies, The Lawson Wilkins Pediatric Endocrine Society (LWPES) and The European Society for Pediatric Endocrinology (ESPE) convened a meeting in Gloucester, MA, March 14–17, 2002. The 40 participating physicians, psychologists, scientists, and surgeons from 12 countries on 4 continents agreed with the following consensus statement; this statement is concerned exclusively with CAH caused by 21-hydroxylase deficiency and does not address the other, rarer forms of CAH. The newborn female with CAH and ambiguous external genitalia requires urgent expert medical attention. The ambiguity is highly distressing to the family; therefore, immediate comprehensive evaluation is needed by referral to, or a visit by, a pediatric endocrinologist. An important goal is to ensure that the parents develop a positive relationship with their child. A well-organized multidisciplinary team (including specialists in pediatric endocrinology, psychosocial services, pediatric surgery/urology, and genetics) is essential for the diagnosis and management of the infant with ambiguous genitalia. It is important that the coordinator of the team has experience in the long-term care of the patient with CAH and provides a consistent message to the parents. Every newborn with ambiguous genitalia, a suspected diagnosis of CAH, or an abnormal result in a newborn screen for 17-hydroxyprogesterone (17OHP) should be evaluated by a pediatric endocrinologist. The evaluation of an infant with ambiguous genitalia includes a complete history, a physical examination, a reliable ultrasound investigation of the internal genitalia and adrenals, karyotype or fluorescence in situ hybridization for sex chromosome material, and a rapid, reliable plasma or serum measurement of 17OHP. Premature newborns may need serial measurements of 17OHP to differentiate false positive results from affected infants with CAH. Neonatal mass screening for 21-hydroxylase deficiency identifies both male and female affected infants, prevents incorrect sex assignment, and decreases mortality and morbidity (1–4). Therefore, newborn screening for CAH is beneficial and is recommended. Newborn screening is sufficiently specific and sensitive to detect almost all infants with classical CAH and some infants with nonclassical CAH (NCCAH). Sampling of blood spots should be performed, ideally between 48 and 72 h of age, and sent to the screening laboratory without delay. At present, direct binding assays for blood-spot 17OHP are the only practical method for screening. Each screening laboratory needs to establish validated cut-off levels related to gestational age and birth-weight, because 17OHP levels decline with increasing gestational age. Only laboratories with excellent internal and external quality control, demonstrated accuracy, and a rapid turn-around time on a large number of samples should be used. The laboratory should report immediately any abnormal result to the physician responsible for the patient. A reliable CAH screening program requires both clinical evaluation and laboratory investigation for diagnostic confirmation. A positive screening result needs to be confirmed either by a validated 17OHP measurement of a second serum/plasma sample, a urine sample for a steroid profile, or analysis of the CYP21 gene. Newborn screening, using 17OHP, may detect other forms of CAH. In uncertain cases, additional specific tests are required. Measurements of androstenedione, aldosterone, cortisol, and testosterone by direct immunoassays are of limited value for diagnosis in the newborn. Molecular genetic analysis is not essential for the diagnosis but may be helpful to confirm the basis of the defect, to aid in genetic counseling, and to establish the diagnosis in uncertain cases. Ten mutations account for 90–95% of the affected alleles, but molecular genetic analysis is complicated by multiple copies of the genes and the possibility of multiple mutations on one allele (5, 6). The clinical features may not correlate with the genetic mutation in a small percentage of cases. Parental DNA samples are essential to segregate alleles. Salt wasters may not be apparent in the first days, or even weeks, after birth by electrolyte measurements. Salt wasters may be differentiated from simple virilizers by serial serum/plasma and/or urine electrolytes, plasma renin activity (PRA) or direct renin, and the results of CYP21 molecular analysis. Prenatal treatment has been advocated for fetuses at risk for classic CAH but is not appropriate for nonclassic CAH. The appropriateness, ethics, and outcomes of the prenatal treatment of CAH with dexamethasone remain controversial (7, 8). However, based on more than 200 fetuses treated to term and more than 1000 partially treated fetuses, it is clear that very early institution of treatment ameliorates the genital virilization in all affected females and completely eliminates it in more than 85% (7, 9). Variations in outcome may be attributable to starting treatment late, interruption of treatment, and individual differences in dexamethasone metabolism and androgen sensitivity. No consistent untoward effects have been reported, and birth weight is not reduced. However, few treated fetuses have reached adulthood, and long-term prospective studies have not been done. Thus, all agree that the results to date are very good, but long-term safety has not yet been proven in patients treated to term or in the 7 of 8 fetuses in whom treatment is stopped because they are male or unaffected. Treated mothers experience greater weight gain, edema, and striae than untreated mothers, but present data do not show increased risk of hypertension or gestational diabetes (9). Feto/maternal glucocorticoid physiology and pharmacology are poorly understood. Available data indicate that human fetal cortisol levels are low, approximately 20 nm or 0.7 μg/dl (10); the administered dose of dexamethasone may result in fetal concentrations of glucocorticoid that greatly exceed normal levels. However, the data on serum cortisol values in the fetus are scanty, and fetal serum dexamethasone values have not been reported. Several recent reports have raised concerns about the use of short-term, very-high-dose glucocorticoids in late pregnancy or in premature infants (11). Animal studies have reported numerous complications from long-term, high-dose treatment of pregnant rodents and primates. Treatment of pregnant rats with 20 μg/kg·d dexamethasone was associated with decreased birth weight and adult hypertension, whereas similar treatment of pregnant sheep caused no apparent complications. However, the relevance of any of these studies to human physiology is not known. Components of a prenatal treatment program include prepregnancy genetic counseling and genotyping of the proband and parents, followed by diagnosis on fetal DNA obtained by chorionic villous biopsy. Fetal sex should be determined by Y chromosome PCR or karyotype. Allele-specific PCR should identify at least 90% of affected alleles. This number can be increased to nearly 100% with microsatellite analysis; Southern blotting; and, occasionally, DNA sequencing (5, 6). Competent core laboratories should study large numbers of samples. Inclusion criteria for prenatal treatment include: 1) a previously affected sibling or first-degree relative with known mutations causing classic CAH, proven by DNA analysis; 2) reasonable expectation that the father is the same as the proband’s; 3) availability of rapid, high-quality genetic analysis; 4) therapy started less than 9 wk after the last menstrual period; 5) no plans for therapeutic abortion; and 6) reasonable expectation of patient compliance. The optimal dosage and timing is 20 μg/kg maternal body weight·d, in three divided doses, starting as soon as pregnancy is confirmed, and no later than 9 wk after the last menstrual period. Treatment is continued to term in the affected female fetus and discontinued in all other fetuses. Maternal blood pressure (BP), weight, glycosuria, HbA1C plasma cortisol, dehydroepiandrosterone sulfate, and androstenedione should be measured initially and then every 2 months, adding plasma or urinary estriol after 15–20 wk of gestation. There is substantial difference of opinion concerning whether prenatal treatment of CAH is a research endeavor. However, all are agreed that this requires a team consisting of a pediatric endocrinologist, an expert in high-risk obstetrics, a genetic counselor, and a reliable molecular genetics laboratory. It is not the “standard of care” for obstetricians in the community. The treatment of 7 out of 8 fetuses who cannot be helped by prenatal treatment creates an ethical dilemma for which there is no clear answer, and parents should be aware of this. We believe that this specialized and demanding therapy should be undertaken by designated teams using nationally or multinationally approved protocols, subject to institutional review boards or ethics committees in recognized centers. Written informed consent must be obtained after the balanced review of the risks and benefits of treatment. Families and clinicians should be obliged to undertake prospective follow-up of prenatally treated children whether they have CAH or not. The data should be entered into a central database audited by an independent safety committee. Study protocols should consider all psychological/behavioral and somatic effects of excess prenatal glucocorticoids and androgens that have been observed in animal experiments or in human studies. Long-term follow-up into late adolescence is mandatory. Relevant control populations should be identified. These studies should also include the partially treated fetuses. Funding agencies, such as the National Institutes of Health or the European Commission, should be encouraged to support such long-term studies. The decision about surgery should be made by the parents, together with the clinical team, after complete disclosure of all relevant clinical information and all available options have been discussed and after informed consent has been obtained. The goals of surgery are: 1) genital appearance compatible with gender; 2) unobstructed urinary emptying without incontinence or infections; and 3) good adult sexual and reproductive function. Once a decision has been made to raise a newborn as female, surgery for those with virilized genitalia caused by CAH is recommended when the patient has a high proximal junction between the vagina and urethra (12, 13). Surgery on infants with ambiguous genitalia requires a high degree of expertise and should only be performed in centers with significant experience. Based on recent clinical experience, the recommended time for surgery is at age 2–6 months; although, at present, this is not universal practice. It is important to note that surgery at this stage is technically easier than at later stages. When the degree of virilization is less (minimal clitoromegaly and the junction between the vagina and urethra near the perineum), surgery may not be necessary. In such cases, the decision to operate should be based on appropriate contrast studies of the urinary tract and examination under anesthesia, with cystoscopy. Surgery to reduce clitoral size requires careful consideration. Total removal of the clitoris should never be performed. If clitoral reduction is elected, it is crucial to preserve the neurovascular bundle, the glans, and the preputial skin related to the glans (14, 15). The early operation should be a one-stage complete repair using the newest techniques of vaginoplasty, clitoral, and labial surgery (12–14, 16) and should be carried out at a center with experience of at least 3–4 cases/yr. Revision vaginoplasty is often required at adolescence, and the timing should be decided with the patient and family. Patients who wish to consider further procedures should be treated by a surgeon experienced in the current techniques. Surgery between the age of 12 months and adolescence is not recommended in the absence of complications causing medical problems. Vaginal dilatations are contraindicated at this stage, although this procedure is often useful in adolescence and in adulthood. Repeated genital examinations should be minimized. Genital photography should be discouraged and only be done with parental consent and, except in infancy, performed only under anesthesia. At each designated center, one surgical team should be responsible for all surgery involving ambiguous genitalia. There should be close cooperation between centers to broaden experience, to audit results, and to allow adequate evaluation of outcomes. We acknowledge that there are concerns about early surgery. However, surgical techniques have improved. We urge caution in judging outcome from outdated procedures. Systematic studies are needed to evaluate ultimate function for all girls undergoing surgery. It is recognized that 46,XX children with significant virilization may present at a later age. Consideration for sex reassignment must be undertaken only after thorough psychological evaluation of patient and family. Surgery appropriate to gender assignment should be undertaken after a period of endocrine treatment. Females with CAH show behavioral masculinization, most pronounced in gender role behavior, less so in sexual orientation, and rarely in gender identity (17–19). Even in females with psychosexual problems, general psychological adjustment seems to be similar to that of females without CAH. Currently, there is insufficient evidence to support rearing a 46,XX infant at Prader stage 5 as male. Whereas studies of women whose surgery was performed 20–30 yr ago indicate a range of psychosexual difficulties, there is reason for optimism that outcome will be better with current surgical and medical treatment. We recognize a need for greater availability of professional psychological services and support groups for patients and families. Decisions concerning sex assignment and associated genital surgery must consider the culture in which a child and her/his family are embedded. As the pace of societal change, including the flexibility of gender role, increases, more frequent review of management policies and long-term outcomes is important. Recognizing that treatment does not mimic physiologic secretion, the goal is to replace deficient steroids while minimizing adrenal sex hormone and glucocorticoid excess, preventing virilization, optimizing growth, and protecting potential fertility. Outcome is not always ideal. Consensus is based on clinical experience. During infancy, initial reduction of markedly elevated adrenal sex hormones may require up to 25 mg hydrocortisone (HC)/m2·d, but typical dosing is 10–15 mg/m2·d divided three times daily. HC oral suspension is not recommended (20); divided or of HC should be in requires to cortisol for HC is the of first doses, infancy, may and other Therefore, complete adrenal should be data to or Whereas HC is and glucocorticoids may be an at or near the of and need to be daily. may be because this is the The dose should be approximately one the dose of The dosage of dexamethasone is daily. of these more glucocorticoids should include in to weight, and other clinical and laboratory These steroids have with In children with age, such as in with CAH, of therapy may central treatment with a classic CAH patients should be treated with at diagnosis in the newborn period. in early range from whereas typical are on the therapy will reduce and levels and the dosage of glucocorticoid required. The need for should be based on and are often needed in infancy, at in The method of diagnosis a with However, a of 17OHP may also as a reliable screening Treatment is only recommended for patients those with an age with a with the family menstrual and the may be based on physical and of or steroid measurements may include serum/plasma electrolytes, serum 17OHP, androstenedione, and/or and or direct renin, every months and every months The time from the last glucocorticoid dose should be the of the adrenal should be into Patients adequate replacement therapy may have hormone levels the normal measurements include urinary or blood and laboratory data will indicate a need for dose physical growth, and indicate or Patients with CAH should medical and information concerning therapy for should have an of HC or glucocorticoid levels of cortisol patients should be increased of glucocorticoids when or when to oral after and surgery. in may also require steroid and such as does not require increased dosing should be times the glucocorticoid dose for patients to oral and patients and those to oral steroids require or concentrations should be and and replacement may be required. or patients may or When an may be followed by of for and dosage are as for children than yr of age, 25 mg followed by for children yr of age, 50 mg followed by and for and mg followed by CAH and should be by and and made available to other pediatric endocrine of useful as family include: and The practice of frequent genital examinations in females should be Therefore, there is clinical or laboratory evidence of control or one to the and size of the genital examinations should not be performed. In females or the of the use of or of sexual genital examination with to the of the may need to be performed. the patient and/or family should be of the for the examinations and support of the patient both classic and and family should be a of the comprehensive care and management of these and/or patients should be the of and counseling at the time of the initial sexual gender role, and related to with a should be the pediatric or for infants, and with CAH. In late adolescence or even early adulthood, care is to an internal in the same institution or clinical We that a team should also as a a and a with specific expertise and in the treatment of such should be that with treatment is important to normal and reduce the risk of a mass by may not be of clinical physical examinations and, as and of both to in the of such removal of a glucocorticoid may be in or The of the genital repair in and adult women needs to be and should be about and other sexual as as is useful with should be an increased risk of However, the risk is not available and may on the and degree of with The risk of women with CAH or an affected fetus is women with CAH should be and in a center and experienced to such that do not the such as HC and should be used. should be when in prenatal should be to maternal serum testosterone concentrations near the range of normal for pregnancy When surgery has been performed, to to the genital When is performed, of HC have to be increased and after A should be present to care of the newborn and to diagnostic procedures when an affected child is to the results of prenatal by is in adrenal androgens and the of It should be only in therapy is in of HC and is with institution of at the of The patient must be throughout for of adrenal The procedure should only be carried out long-term follow-up is and in the of approved clinical studies. The use of in CAH is on but of with Based on the of an in male sexual it was that the effects of elevated androgens on adult be by using an to androgen and/or an to of androgen to studies in CAH show control of and at glucocorticoid dosage Long-term safety data are not and reproductive effects are not known. function has to be Patients with CAH from of and of the adrenal as deficiency This may a role in to therapeutic are under genetic diagnosis for CAH is but further research is required to therapy is not in with this CAH patients on glucocorticoid treatment have levels. in adult patients with have beneficial effects of replacement but the relevance in CAH is have the potential for activity of glucocorticoids At present, there are no specific that are of or and clinical experience with is Therefore, the use of these cannot be at A of patients with CAH with an of Thus, an is by patients with CAH, and the adult is substantially less than However, some CAH patients to normal adult A small of CAH patients have been treated with for 2 either or in with a This and but adult data are not yet These are to all of the management of this in from diagnosis adulthood. The multidisciplinary of management is with the that such expert teams need appropriate and There remain important in about this and these have been therapeutic are as require evaluation into practice. In the should on early optimal medical and surgical treatment, and to compliance. The for support of the consensus meeting in The following convened in Gloucester, March 14–17, and to this The and The also the of and congenital adrenal European Society for Pediatric Lawson Wilkins Pediatric Endocrine nonclassical plasma renin

The Journal of Clinical Endocrinology & Metabolism · review · 331 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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