Search the source libraries

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

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

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

Circumcision versus preputioplasty for balanitis xerotica obliterans: a randomised controlled feasibility trial.

Objectives: To determine: (i) feasibility for a randomised controlled trial (RCT) comparing circumcision to preputioplasty and intralesional triamcinolone (PIT) to treat balanitis xerotica obliterans (BXO) and (ii) patient outcomes to inform future study design. Patients and methods: Approval was obtained from the UK Health Research Authority and local Research Ethics Committee (Reference 16/NW/0364) and the trial protocol registered with ClinicalTrials.gov (NCT02854995). A total of 20 boys (aged 2-16 years) with BXO were randomised to either circumcision or PIT (online parallel group 1:1 allocation, non-blinded). Exclusion criteria were: (i) previous penile surgery and (ii) contraindication for either treatment. Follow-up (including satisfaction questionnaire) was at 6 weeks, 3 and 12 months. Data are presented as median (interquartile range [IQR]), continuous variables were compared by t-test. Results: A total of 54 boys were approached over 18 months: 23 (45%) were recruited and randomised. The commonest reason for non-entry was treatment preference: 12 preferred circumcision, 18 preferred PIT. Four patients withdrew after randomisation, three did not want circumcision and one did not want PIT. The groups were similar in terms of age (median [IQR] 11 [6-12] vs 8 [7-10] years, P = 0.53) and duration of symptoms (median [IQR] 6 [6-15] vs 6 [2-24] months, P = 0.77). There were no protocol breaches, serious adverse events or postoperative meatal stenosis. There was one self-resolving haematoma after PIT and one suture granuloma after circumcision. Two boys went on to have a circumcision after PIT. Overall, satisfaction levels were high for both groups. Conclusion: A definitive RCT of circumcision vs PIT for BXO appears feasible, with 39% of those approached completing the trial. More families preferred PIT. A robust comparison in the form of a multicentred RCT is required.

BJU international · randomised controlled trial · 5 citationsread the source →

Psychosocial work stressors as antecedents of musculoskeletal problems: a systematic review and meta-analysis of stability-adjusted longitudinal studies.

Although the relationship between psychosocial workplace conditions and musculoskeletal problems has been extensively studied, the causal impact of psychosocial workplace factors in the development of musculoskeletal problems remains unclear. The purpose of the present study was to conduct a systematic review of baseline-adjusted prospective longitudinal studies estimating the lagged effect of psychosocial risk factors on musculoskeletal problems in industrialized work settings. A literature review was conducted by searching the MEDLINE, EMBASE, and PsychINFO databases dated until August 2009. The authors classified studies into categories of psychological work stressors and musculoskeletal problems. Available effect sizes were converted to odds ratios (OR). ORs were then pooled for each stressor-problem relationship using a random-effects model. Additionally, the possibility of publication bias was assessed with the Duval and Tweedie nonparametric "trim and fill" procedure. In total, 50 primary studies fulfilled inclusion criteria. Within these studies at least five effect sizes were available for 23 of the 45 possible psychosocial work stress-musculoskeletal problems relationships, leaving 9 psychosocial variables and four musculoskeletal problem areas for analyses. Of these 23 relationships, pooled OR estimates were positive and significant ranging from 1.15 to 1.66 with the largest pooled OR estimating the relationship between highly monotonous work and lower back pain. The lagged effect of low social support on lower limb problems was the only effect size for which the statistical test for bias was significant. Most psychosocial stressors had small but significant lagged effects on the development of musculoskeletal problems. Thus, organizational interventions to minimize these stressors may be promising in reducing one risk factor for the development of employee musculoskeletal problems.

Social science & medicine (1982) · meta-analysis · 164 citationsread the source →

mHealth Intervention for Improving Pain, Quality of Life, and Functional Disability in Patients With Chronic Pain: Systematic Review.

Background: Chronic pain (CP) is 1 of the leading causes of disability worldwide and represents a significant burden on individual, social, and economic aspects. Potential tools, such as mobile health (mHealth) systems, are emerging for the self-management of patients with CP. Objective: A systematic review was conducted to analyze the effects of mHealth interventions on CP management, based on pain intensity, quality of life (QoL), and functional disability assessment, compared to conventional treatment or nonintervention. Methods: PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines were followed to conduct a systematic review of randomized controlled trials (RCTs) published in PubMed, Web of Science, Scopus, and Physiotherapy Evidence Database (PEDro) databases from February to March 2022. No filters were used. The eligibility criteria were RCTs of adults (≥18 years old) with CP, intervened with mHealth systems based on mobile apps for monitoring pain and health-related outcomes, for pain and behavioral self-management, and for performing therapeutic approaches, compared to conventional treatments (physical, occupational, and psychological therapies; usual medical care; and education) or nonintervention, reporting pain intensity, QoL, and functional disability. The methodological quality and risk of bias (RoB) were assessed using the Checklist for Measuring Quality, the Oxford Centre for Evidence-Based Medicine Levels of Evidence, and the Cochrane RoB 2.0 tool. Results: In total, 22 RCTs, involving 2641 patients with different CP conditions listed in the International Classification of Diseases 11th Revision (ICD-11), including chronic low back pain (CLBP), chronic musculoskeletal pain (CMSP), chronic neck pain (CNP), unspecified CP, chronic pelvic pain (CPP), fibromyalgia (FM), interstitial cystitis/bladder pain syndrome (IC/BPS), irritable bowel syndrome (IBS), and osteoarthritis (OA). A total of 23 mHealth systems were used to conduct a variety of CP self-management strategies, among which monitoring pain and symptoms and home-based exercise programs were the most used. Beneficial effects of the use of mHealth systems in reducing pain intensity (CNP, FM, IC/BPS, and OA), QoL (CLBP, CNP, IBS, and OA), and functional disability (CLBP, CMSP, CNP, and OA) were found. Most of the included studies (18/22, 82%) reported medium methodological quality and were considered as highly recommendable; in addition, 7/22 (32%) studies had a low RoB, 10/22 (45%) had some concerns, and 5/22 (23%) had a high RoB. Conclusions: The use of mHealth systems indicated positive effects for pain intensity in CNP, FM, IC/BPS, and OA; for QoL in CLBP, CNP, IBS, and OA; and for functional disability in CLBP, CMSP, CNP, and OA. Thus, mHealth seems to be an alternative to improving pain-related outcomes and QoL and could be part of multimodal strategies for CP self-management. High-quality studies are needed to merge the evidence and recommendations of the use of mHealth systems for CP management. Trial registration: PROSPERO International Prospective Register of Systematic Reviews CRD42022315808; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=315808.

JMIR mHealth and uHealth · systematic review · 79 citationsread the source →

Interventions to improve return to work in depressed people.

Background: Work disability such as sickness absence is common in people with depression. Objectives: To evaluate the effectiveness of interventions aimed at reducing work disability in employees with depressive disorders. Search methods: We searched CENTRAL (The Cochrane Library), MEDLINE, Embase, CINAHL, and PsycINFO until April 4th 2020. Selection criteria: We included randomised controlled trials (RCTs) and cluster-RCTs of work-directed and clinical interventions for depressed people that included days of sickness absence or being off work as an outcome. We also analysed the effects on depression and work functioning. Data collection and analysis: Two review authors independently extracted the data and rated the certainty of the evidence using GRADE. We used standardised mean differences (SMDs) or risk ratios (RR) with 95% confidence intervals (CI) to pool study results in studies we judged to be sufficiently similar.  MAIN RESULTS: In this update, we added 23 new studies. In total, we included 45 studies with 88 study arms, involving 12,109 participants with either a major depressive disorder or a high level of depressive symptoms. Risk of bias The most common types of bias risk were detection bias (27 studies) and attrition bias (22 studies), both for the outcome of sickness absence. Work-directed interventions Work-directed interventions combined with clinical interventions A combination of a work-directed intervention and a clinical intervention probably reduces days of sickness absence within the first year of follow-up (SMD -0.25, 95% CI -0.38 to -0.12; 9 studies; moderate-certainty evidence). This translates back to 0.5 fewer (95% CI -0.7 to -0.2) sick leave days in the past two weeks or 25 fewer days during one year (95% CI -37.5 to -11.8). The intervention does not lead to fewer persons being off work beyond one year follow-up (RR 0.96, 95% CI 0.85 to 1.09; 2 studies, high-certainty evidence). The intervention may reduce depressive symptoms (SMD -0.25, 95% CI -0.49 to -0.01; 8 studies, low-certainty evidence) and probably has a small effect on work functioning (SMD -0.19, 95% CI -0.42 to 0.06; 5 studies, moderate-certainty evidence) within the first year of follow-up.  Stand alone work-directed interventions A specific work-directed intervention alone may increase the number of sickness absence days compared with work-directed care as usual (SMD 0.39, 95% CI 0.04 to 0.74; 2 studies, low-certainty evidence) but probably does not lead to more people being off work within the first year of follow-up (RR 0.93, 95% CI 0.77 to 1.11; 1 study, moderate-certainty evidence) or beyond (RR 1.00, 95% CI 0.82 to 1.22; 2 studies, moderate-certainty evidence). There is probably no effect on depressive symptoms (SMD -0.10, 95% -0.30 CI to 0.10; 4 studies, moderate-certainty evidence) within the first year of follow-up and there may be no effect on depressive symptoms beyond that time (SMD 0.18, 95% CI -0.13 to 0.49; 1 study, low-certainty evidence). The intervention may also not lead to better work functioning (SMD -0.32, 95% CI -0.90 to 0.26; 1 study, low-certainty evidence) within the first year of follow-up.   Psychological interventions A psychological intervention, either face-to-face, or an E-mental health intervention, with or without professional guidance, may reduce the number of sickness absence days, compared with care as usual (SMD -0.15, 95% CI -0.28 to -0.03; 9 studies, low-certainty evidence). It may also reduce depressive symptoms (SMD -0.30, 95% CI -0.45 to -0.15, 8 studies, low-certainty evidence). We are uncertain whether these psychological interventions improve work ability (SMD -0.15 95% CI -0.46 to 0.57; 1 study; very low-certainty evidence). Psychological intervention combined with antidepressant medication Two studies compared the effect of a psychological intervention combined with antidepressants to antidepressants alone. One study combined psychodynamic therapy with tricyclic antidepressant (TCA) medication and another combined telephone-administered cognitive behavioural therapy (CBT) with a selective serotonin reuptake inhibitor (SSRI). We are uncertain if this intervention reduces the number of sickness absence days (SMD -0.38, 95% CI -0.99 to 0.24; 2 studies, very low-certainty evidence) but found that there may be no effect on depressive symptoms (SMD -0.19, 95% CI -0.50 to 0.12; 2 studies, low-certainty evidence). Antidepressant medication only Three studies compared the effectiveness of SSRI to selective norepinephrine reuptake inhibitor (SNRI) medication on reducing sickness absence and yielded highly inconsistent results. Improved care Overall, interventions to improve care did not lead to fewer days of sickness absence, compared to care as usual (SMD -0.05, 95% CI -0.16 to 0.06; 7 studies, moderate-certainty evidence). However, in studies with a low risk of bias, the intervention probably leads to fewer days of sickness absence in the first year of follow-up (SMD -0.20, 95% CI -0.35 to -0.05; 2 studies; moderate-certainty evidence). Improved care probably leads to fewer depressive symptoms (SMD -0.21, 95% CI -0.35 to -0.07; 7 studies, moderate-certainty evidence) but may possibly lead to a decrease in work-functioning (SMD 0.5, 95% CI 0.34 to 0.66; 1 study; moderate-certainty evidence). Exercise Supervised strength exercise may reduce sickness absence, compared to relaxation (SMD -1.11; 95% CI -1.68 to -0.54; one study, low-certainty evidence). However, aerobic exercise probably is not more effective than relaxation or stretching (SMD -0.06; 95% CI -0.36 to 0.24; 2 studies, moderate-certainty evidence). Both studies found no differences between the two conditions in depressive symptoms. Authors' conclusions: A combination of a work-directed intervention and a clinical intervention probably reduces the number of sickness absence days, but at the end of one year or longer follow-up, this does not lead to more people in the intervention group being at work. The intervention may also reduce depressive symptoms and probably increases work functioning more than care as usual. Specific work-directed interventions may not be more effective than usual work-directed care alone. Psychological interventions may reduce the number of sickness absence days, compared with care as usual. Interventions to improve clinical care probably lead to lower sickness absence and lower levels of depression, compared with care as usual. There was no evidence of a difference in effect on sickness absence of one antidepressant medication compared to another. Further research is needed to assess which combination of work-directed and clinical interventions works best.

The Cochrane database of systematic reviews · meta-analysis · 158 citationsread the source →

Computer-based psychological treatments for depression: a systematic review and meta-analysis.

The aim of the paper was to systematically review the literature on computer-based psychological treatments for depression and conduct a meta-analysis of the RCT studies, including examining variables which may effect outcomes. Database and hand searches were made using specific search terms and inclusion criteria. The review included a total of 40 studies (45 published papers), and 19 RCTs (23 published papers) were included in a standard meta-analysis. The review describes the different computer-based treatments for depression, their design, communication types employed: synchronous, asynchronous, and face-to-face (F:F); alongside various types and frequency of support delivered. The evidence supports their effectiveness and highlights participant satisfaction. However, pertinent limitations are noted. Across 19 studies the meta-analysis revealed a moderate post-treatment pooled effect size d=.56 (95% confidence interval [CI] -.71, -.41), Z=7.48, p<.001). Supported interventions yielded better outcomes, along with greater retention. The results reported statistically significant clinical improvement and recovery post-treatment. The review and meta-analysis support the efficacy and effectiveness of computer-based psychological treatments for depression, in diverse settings and with different populations. Further research is needed, in particular to investigate the influence of therapist factors in supported treatments, the reasons for dropout, and the maintenance of gains post-treatment.

Clinical psychology review · meta-analysis · 880 citationsread the source →

Identifying patients hospitalized with heart failure at risk for unfavorable future quality of life.

Background: Communicating prognosis to enable shared decision-making is strongly endorsed by heart failure (HF) guidelines. Patients are concerned with both their quantity and quality of life (QoL). To facilitate the recognition of patients at high risk for unfavorable future QoL or death, we created a simple prognostic tool to estimate this combined outcome. Methods and results: We identified factors associated with 6-month mortality or persistently unfavorable QoL, defined by Kansas City Cardiomyopathy Questionnaire (KCCQ) scores <45 at 1 and 24 weeks after hospital discharge, among 1458 patients from the Efficacy of Vasopressin Antagonism in HF Outcome Study with Tolvaptan (EVEREST). Within 24 weeks of discharge, 478 (32.8%) patients had died and 192 (13.2%) patients had serial KCCQ scores <45. After adjusting for 23 predischarge covariates, independent predictors of the combined end point included low admission KCCQ score, high B-type natriuretic peptide, hyponatremia, tachycardia, hypotension, absence of β-blocker therapy, and history of diabetes mellitus and arrhythmia. A simplified predischarge HF score for subsequent death or unfavorable QoL had moderate discrimination (c-statistic 0.72). Predischarge clinical covariates were substantially different in predicting the QoL end point as compared with traditional death or rehospitalization end points. Conclusions: At the time of hospital discharge, readily available clinical characteristics are associated with HF patients at high risk for persistently unfavorable QoL or death over the next 6 months. Such information can target patients for whom aggressive treatment options (eg, devices or transplantation) and/or end-of-life discussions should be strongly considered before hospital discharge.

Circulation. Cardiovascular quality and outcomes · clinical trial · 111 citationsread the source →

Parent-child relationship of directly measured physical activity.

Background: Studies on parent-child correlations of physical activity have been mixed. Few studies have examined concurrent temporal patterns of physical activity and sedentary behaviors in parents and children using direct measures. The purpose of this study was to examine parent-child activity correlations by gender, day of week, and time of day, using accelerometers - a method for direct assessment of physical activity. Methods: Accelerometers were used to assess physical activity and sedentary time in 45 fathers, 45 mothers and their children (23 boys, 22 girls, mean age 9.9 years) over the course of 4 days (Thursday - Sunday). Participants were instructed to wear accelerometers for 24 hours per day. Data from accelerometers were aggregated into waking hours on weekdays and weekends (6:00 am to midnight) and weekday after-school hours (3:00 - 7:00 pm). Results: Across the 4 days, the mean minutes per day of moderate-to-vigorous physical activity (MVPA) for fathers was 30.0 (s.d. = 17.3), for mothers was 30.1 (s.d. = 20.1) and for children was 145.47 (s.d. = 51.64). Mothers' and fathers' minutes of MVPA and minutes of sedentary time were positively correlated with child physical activity and sedentary time (all ps < .05, with the exception of mothers' and children's sedentary time on weekdays from 6 am to 12 am). Multivariate linear regression analyses resulted in significant effects between parents and children for MVPA across all time segments. For sedentary activity, significant associations were observed only between father and child on the weekend. Sedentary activity of parents and children were not related for other time segments. Models examining the associations of one or two parents with high levels of MVPA or sedentary time indicated a dose response increase in child activity relative to parent. Conclusions: Greater parental MVPA was associated with increased child MVPA. In addition, having two parents with higher levels of MVPA was associated with greater levels of activity in children. Sedentary time in children was not as strongly correlated with that of their parents. Findings lend support to the notion that to increase childhood activity levels it may be fruitful to improve physical activity among parents.

The international journal of behavioral nutrition and physical activity · 149 citationsread the source →

Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects.

Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3-6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58-81%) in the 74 Gy group vs 59% (95% CI 45-70%) in the 64 Gy group. There were 23 failures in the 74 Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38-1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53-77% vs 63%, 95% CI 50-74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50-1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men had persistent > or =Grade 1 bowel or bladder side effects, respectively. Statistically significant increases in acute bladder side effects were seen after treatment in the men receiving 74 Gy (P=0.006), and increases in both acute bowel side effects during treatment (P=0.05) and acute bladder sequelae (P=0.002) were recorded for men in the 1.5 cm margin group. While statistically significant, these differences were of short duration and of doubtful clinical importance. Late bowel side effects (RTOG> or =2) were seen more commonly in the 74 Gy and 1.5 cm margin groups (P=0.02 and P=0.05, respectively) in the first 2 years after randomisation. Similar results were found using the LENT SOM assessments. No significant differences in late bladder side effects were seen between the randomised groups using the RTOG scoring system. Using the LENT SOM instrument, a higher proportion of men treated in the 74 Gy group had Grade > or =3 urinary frequency at 6 and 12 months. Compared to baseline scores, bladder symptoms improved after 6 months or more follow-up in all groups. Sexual function deteriorated after treatment with the number of men reporting some sexual dysfunction (Grade> or =1) increasing from 38% at baseline to 66% at 6 months and 1 year and 81% by year 5. However, no consistent differences were seen between the randomised groups. In conclusion, dose escalation from 64 to 74 Gy using conformal radiotherapy may improve long-term PSA control, but a treatment margin of 1.5 cm is unnecessary and is associated with increased acute bowel and bladder reactions and more late rectal side effects. Data from this randomised pilot study informed the Data Monitoring Committee of the Medical Research Council RT 01 Trial and the two studies will be combined in subsequent meta-analysis.

British journal of cancer · randomised controlled trial · 155 citationsread the source →

Are interventions focused on gender-norms effective in preventing domestic violence against women in low and lower-middle income countries? A systematic review and meta-analysis.

Background: One in three women experience intimate partner violence worldwide, according to many primary studies. However, systematic review and meta-analysis of intimate partner violence is very limited. Therefore, we set to summarize the findings of existing primary studies to generate evidence for informed decisions to tackle domestic violence against women in low and lower-middle income countries. Methods: Studies were searched from main databases (Medline via PubMed, EMBASE, CINAHL, PopLine and Web of Science), Google scholar and other relevant sources using electronic and manual techniques. Published and unpublished studies written in English and conducted among women aged (15-49 years) from 1994 to 2017 were eligible. Data were extracted independently by two authors, and recorded in Microsoft Excel sheet. Heterogeneity between included studies was assessed using I2, and publication bias was explored using visual inspection of funnel plot. Statistical analysis was carried out to determine the pooled prevalence using Comprehensive Meta-Analysis software. In addition, sub-group analysis was carried out by study-setting and types of intimate partner violence. Results: Fifty two studies were included in the systematic review. Of these, 33 studies were included in the meta-analysis. The pooled prevalence of lifetime intimate partner violence was 55% (95% CI: 52, 59%). Of these, main categories were lifetime physical violence [39% (95% CI: 33, 45%); psychological violence [45% (95% CI: 40, 52%)] and sexual violence [20% (95% CI: 17, 23%)]. Furthermore, the pooled prevalence of current intimate partner violence was 38% (95% CI: 34, 43%). Of these, physical violence [25% (95% CI: 21, 28%)]; psychological violence [30% (95% CI: 24, 36%)] and sexual violence [7.0% (95% CI: 6.6, 7.5%)] were the pooled prevalence for the major types of intimate partner violence. In addition, concurrent intimate partner violence was 13% (95% CI: 12, 15%). Individual, relationship, community and societal level factors were associated with intimate partner violence. Traditional community gender-norm transformation, stakeholders' engagement, women's empowerment, intervention integration and policy/legal framework were highly recommended interventions to prevent intimate partner violence. Conclusion: Lifetime and current intimate partner violence is common and unacceptably high. Therefore, concerned bodies will need to design and implement strategies to transform traditional gender norms, engage stakeholders, empower women and integrate service to prevent violence against women. Protocol registration: PROSPERO: 2017: CRD42017079977 .

Reproductive health · meta-analysis · 43 citationsread the source →

Changing Student Health Professionals' Attitudes toward Disability: A Longitudinal Study.

Purpose: The purpose of this study was to determine whether positive changes in self-reported attitudes toward disability were retained after students had participated in a 12-week voluntary community-based exercise programme for young people with disability. Method: Sixty-eight physiotherapy and exercise physiology students (45 women, 23 men; mean age 21 y) volunteered. Each student was matched with a young person with disability, and the pair exercised together twice a week for 12 weeks at their local gymnasium. The primary outcome measure was self-reported attitude toward disability. Secondary outcomes were self-reported professional skills competency, confidence, future work intentions, and motivations for volunteering. The outcomes were measured at Weeks 0, 13, and 24. The data were analyzed using generalized linear mixed-effects models, ordinal regression, and linear regression. Results: The students' attitudes toward disability were more positive at Weeks 13 and 24 than at baseline, but positive changes were not fully retained by Week 24. Small statistically significant reductions occurred after Week 13. Self-reported skills competencies, confidence, and future intentions of working in disability were higher at Weeks 13 and 24. Students' motivation for volunteering was wanting to support others, wanting to learn, and perceived positive career effects. Conclusions: Positive changes in students' attitudes toward disability were generally retained 3 months after volunteering in a community-based exercise programme.

Physiotherapy Canada. Physiotherapie Canada · 2 citationsread the source →

Intergenerational transmission of child maltreatment in South Australia, 1986-2017: a retrospective cohort study.

Background: The extent of intergenerational transmission of child maltreatment is unclear due to methodological limitations in previous studies. In this study, we aimed to examine factors associated with intergenerational transmission of child maltreatment and quantify its extent in a population sample over a 30-year period in South Australia. Methods: In this retrospective cohort study, we used linked administrative data from the South Australian Birth Registry to identify dyads of mothers and their children both born in South Australia between July 1, 1986, and June 30, 2017. Three child protection system (CPS) outcomes (any CPS involvement, substantiated maltreatment, and time spent in out-of-home care) were computed from data obtained from the South Australian Department for Child Protection. Multivariable Cox regression models were used to estimate hazard ratios (HRs) for child CPS outcomes according to their mother's CPS exposure. Findings: 38 556 unique mother-child dyads were included. 458 (2·0%) of 23 437 children whose mothers had no CPS involvement in childhood had a substantiated report of maltreatment and 127 (0·5%) spent time in out-of-home care. By comparison, 970 (22·1%) of 4382 children whose mothers experienced substantiated maltreatment in childhood had substantiated maltreatment and 469 (10·7%) spent time in out-of-home care. After adjusting for potential confounders, children of mothers with any CPS involvement in childhood had an increased risk of CPS contact compared with children whose mothers had no CPS involvement; this risk was greatest for children of mothers who had both substantiated maltreatment and spent time in out-of-home care (HR 6·25 [95% CI 5·59-6·98] for any CPS involvement, 13·69 [10·08-16·92] for substantiated maltreatment, and 25·78 [18·23-36·45] for any time in out-of-home care). Risks of child CPS outcomes were substantially increased for children of mothers who had a first CPS notification under the age of 1 year or who had any CPS notification at age 13-17 years. Interpretation: Children are at high risk of maltreatment if their mother experienced maltreatment as a child. Assisting survivors of childhood maltreatment, particularly female survivors, provides a crucial intervention opportunity to help prevent further child abuse and neglect. Funding: Australian National Health and Medical Research Council; Channel 7 Children's Research Foundation.

The Lancet. Public health · 31 citationsread the source →

A Behavioral Measure of Costly Helping: Replicating and Extending the Association with Callous Unemotional Traits in Male Adolescents.

Background: Some conduct-disordered youths have high levels of callous unemotional traits and meet the DSM-5's "with limited prosocial emotions" (LPE) specifier. These youths often do aggressive, self-benefitting acts that cost others. We previously developed a task, the AlAn's game, which asks participants to repeatedly decide whether to accept or reject offers in which they will receive money but a planned charity donation will be reduced. In our prior work, more "costly helping" (i.e., rejecting the offered money and protecting the donation) was associated with lower callous unemotional traits. Here we extend that prior work in a larger sample of adolescent male patients with serious conduct problems and controls, and test whether this association is mediated specifically by a Moral Elevation response (i.e., a positive emotional response to another's act of virtue). Methods: The adolescent male participants were: 45 patients (23 with LPE) and 26 controls, who underwent an extensive phenotypic assessment including a measure of Moral Elevation. About 1 week later participants played the AlAn's game. Results: All AlAn's game outcomes demonstrated significant group effects: (1) money taken for self (p = 0.02); (2) money left in the charitable donation (p = 0.03); and, (3) costly helping (p = 0.047). Controls took the least money and did the most costly helping, while patients with LPE took the most money and did the least costly helping. Groups also significantly differed in post-stimulus Moral Elevation scores (p = 0.005). Exploratory analyses supported that the relationship between callous unemotional traits and costly helping on the AlAn's game may be mediated in part by differences in Moral Elevation. Conclusions: The AlAn's game provides a standardized behavioral measure associated with callous unemotional traits. Adolescents with high levels of callous unemotional traits engage in fewer costly helping behaviors, and those differences may be related to blunting of positive emotional responses.

PloS one · 12 citationsread the source →

Internet-guided self-help with or without exposure therapy for phobic and panic disorders.

Background: As many sufferers from phobic and panic (phobia/panic) disorders cannot get to suitable therapists, routine aspects of therapy were delegated to internet-accessed computer-aided self-help with or without exposure instructions. Methods: Phobia/panic referrals were randomised to computer-aided self-help via the internet at home in a 2:1 ratio either by self-exposure cognitive behaviour therapy (CBT) [FearFighter (FF), n = 45] or by minimal CBT without exposure [Managing Anxiety (MA), n = 23]. All had brief backup phone advice from a clinician concerning their computer guidance. Results: On self-ratings and blinded assessor ratings, patients improved equally with each form of self-help over 10 treatment weeks but significantly more on 5 out of 10 measures by week 14 (1-month follow-up) when the self-help included self-exposure instructions than when it did not. In accord with this, standardised effect sizes (Cohen's d) indicated superiority of FF over MA on 5 measures by week 14. Satisfaction with treatment in all patients pooled correlated positively with improvement after treatment and at 1-month follow-up. Conclusions: At the end of treatment, computer-aided CBT self-help at home via the internet plus brief live helpline support was effective with or without exposure instructions, and at 1-month follow-up it was more effective on some measures if exposure instructions had been included. Analysis is needed of how non-exposure CBT produced its shorter-term effect.

Psychotherapy and psychosomatics · randomised controlled trial · 69 citationsread the source →

Outcomes of Donation After Circulatory Death Heart Transplantation in Australia.

Background: Transplantation of hearts retrieved from donation after circulatory death (DCD) donors is an evolving clinical practice. Objectives: The purpose of this study is to provide an update on the authors' Australian clinical program and discuss lessons learned since performing the world's first series of distantly procured DCD heart transplants. Methods: The authors report their experience of 23 DCD heart transplants from 45 DCD donor referrals since 2014. Donor details were collected using electronic donor records (Donate Life, Australia) and all recipient details were collected from clinical notes and electronic databases at St. Vincent's Hospital. Results: Hearts were retrieved from 33 of 45 DCD donors. A total of 12 donors did not progress to circulatory arrest within the pre-specified timeframe. Eight hearts failed to meet viability criteria during normothermic machine perfusion, and 2 hearts were declined due to machine malfunction. A total of 23 hearts were transplanted between July 2014 and April 2018. All recipients had successful implantation, with mechanical circulatory support utilized in 9 cases. One case requiring extracorporeal membrane oxygenation subsequently died on the sixth post-operative day, representing a mortality of 4.4% over 4 years with a total follow-up period of 15,500 days for the entire cohort. All surviving recipients had normal cardiac function on echocardiogram and no evidence of acute rejection on discharge. All surviving patients remain in New York Heart Association functional class I with normal biventricular function. Conclusions: DCD heart transplant outcomes are excellent. Despite a higher requirement for mechanical circulatory support for delayed graft function, primarily in recipients with ventricular assist device support, overall survival and rejection episodes are comparable to outcomes from contemporary brain-dead donors.

Journal of the American College of Cardiology · 209 citationsread the source →

Energy availability and the female athlete triad in elite endurance athletes.

The female athlete triad (Triad), links low energy availability (EA), with menstrual dysfunction (MD), and impaired bone health. The aims of this study were to examine associations between EA/MD and energy metabolism and the prevalence of Triad-associated conditions in endurance athletes. Forty women [26.2 ± 5.5 years, body mass index (BMI) 20.6 ± 2.0 kg/m(2), body fat 20.0 ± 3.0%], exercising 11.4 ± 4.5 h/week, were recruited from national teams and competitive clubs. Protocol included gynecological examination; assessment of bone health; indirect respiratory calorimetry; diet and exercise measured 7 days to assess EA; eating disorder (ED) examination; blood analysis. Subjects with low/reduced EA (< 45 kcal/kg FFM/day), had lower resting metabolic rate (RMR) compared with those with optimal EA [28.4 ± 2.0 kcal/kg fat-free mass (FFM)/day vs 30.5 ± 2.2 kcal/kg FFM/day, P < 0.01], as did subjects with MD compared with eumenorrheic subjects (28.6 ± 2.4 kcal/kg FFM/day vs 30.2 ± 1.8 kcal/kg FFM/day, P < 0.05). 63% had low/reduced EA, 25% ED, 60% MD, 45% impaired bone health, and 23% had all three Triad conditions. 53% had low RMR, 25% hypercholesterolemia, and 38% hypoglycemia. Conclusively, athletes with low/reduced EA and/or MD had lowered RMR. Triad-associated conditions were common in this group of athletes, despite a normal BMI range. The high prevalence of ED, MD, and impaired bone health emphasizes the importance of prevention, early detection, and treatment of energy deficiency.

Scandinavian journal of medicine & science in sports · 157 citationsread the source →

Women's and girls' experiences of menstruation in low- and middle-income countries: A systematic review and qualitative metasynthesis.

Background: Attention to women's and girls' menstrual needs is critical for global health and gender equality. The importance of this neglected experience has been elucidated by a growing body of qualitative research, which we systematically reviewed and synthesised. Methods and findings: We undertook systematic searching to identify qualitative studies of women's and girls' experiences of menstruation in low- and middle-income countries (LMICs). Of 6,892 citations screened, 76 studies reported in 87 citations were included. Studies captured the experiences of over 6,000 participants from 35 countries. This included 45 studies from sub-Saharan Africa (with the greatest number of studies from Kenya [n = 7], Uganda [n = 6], and Ethiopia [n = 5]), 21 from South Asia (including India [n = 12] and Nepal [n = 5]), 8 from East Asia and the Pacific, 5 from Latin America and the Caribbean, 5 from the Middle East and North Africa, and 1 study from Europe and Central Asia. Through synthesis, we identified overarching themes and their relationships to develop a directional model of menstrual experience. This model maps distal and proximal antecedents of menstrual experience through to the impacts of this experience on health and well-being. The sociocultural context, including menstrual stigma and gender norms, influenced experiences by limiting knowledge about menstruation, limiting social support, and shaping internalised and externally enforced behavioural expectations. Resource limitations underlay inadequate physical infrastructure to support menstruation, as well as an economic environment restricting access to affordable menstrual materials. Menstrual experience included multiple themes: menstrual practices, perceptions of practices and environments, confidence, shame and distress, and containment of bleeding and odour. These components of experience were interlinked and contributed to negative impacts on women's and girls' lives. Impacts included harms to physical and psychological health as well as education and social engagement. Our review is limited by the available studies. Study quality was varied, with 18 studies rated as high, 35 medium, and 23 low trustworthiness. Sampling and analysis tended to be untrustworthy in lower-quality studies. Studies focused on the experiences of adolescent girls were most strongly represented, and we achieved early saturation for this group. Reflecting the focus of menstrual health research globally, there was an absence of studies focused on adult women and those from certain geographical areas. Conclusions: Through synthesis of extant qualitative studies of menstrual experience, we highlight consistent challenges and developed an integrated model of menstrual experience. This model hypothesises directional pathways that could be tested by future studies and may serve as a framework for program and policy development by highlighting critical antecedents and pathways through which interventions could improve women's and girls' health and well-being. Review protocol registration: The review protocol registration is PROSPERO: CRD42018089581.

PLoS medicine · meta-analysis · 270 citationsread the source →

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

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

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

Loneliness before and during the COVID-19 pandemic: A systematic review with meta-analysis.

The COVID-19 pandemic and measures aimed at its mitigation, such as physical distancing, have been discussed as risk factors for loneliness, which increases the risk of premature mortality and mental and physical health conditions. To ascertain whether loneliness has increased since the start of the pandemic, this study aimed to narratively and statistically synthesize relevant high-quality primary studies. This systematic review with meta-analysis was registered at PROSPERO (ID CRD42021246771). Searched databases were PubMed, PsycINFO, Cochrane Library/Central Register of Controlled Trials/EMBASE/CINAHL, Web of Science, the World Health Organization (WHO) COVID-19 database, supplemented by Google Scholar and citation searching (cutoff date of the systematic search December 5, 2021). Summary data from prospective research including loneliness assessments before and during the pandemic were extracted. Of 6,850 retrieved records, 34 studies (23 longitudinal, 9 pseudolongitudinal, 2 reporting both designs) on 215,026 participants were included. Risk of bias (RoB) was estimated using the risk of bias in non-randomised studies-of interventions (ROBINS-I) tool. Standardized mean differences (SMD, Hedges' g) for continuous loneliness values and logOR for loneliness prevalence rates were calculated as pooled effect size estimators in random-effects meta-analyses. Pooling studies with longitudinal designs only (overall N = 45,734), loneliness scores (19 studies, SMD = 0.27 [95% confidence interval = 0.14-0.40], Z = 4.02, p < .001, I 2 = 98%) and prevalence rates (8 studies, logOR = 0.33 [0.04-0.62], Z = 2.25, p = .02, I 2 = 96%) increased relative to prepandemic times with small effect sizes. Results were robust with respect to studies' overall RoB, pseudolongitudinal designs, timing of prepandemic assessments, and clinical populations. The heterogeneity of effects indicates a need to further investigate risk and protective factors as the pandemic progresses to inform targeted interventions. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The American psychologist · meta-analysis · 317 citationsread the source →

Interactive telemedicine: effects on professional practice and health care outcomes.

Background: Telemedicine (TM) is the use of telecommunication systems to deliver health care at a distance. It has the potential to improve patient health outcomes, access to health care and reduce healthcare costs. As TM applications continue to evolve it is important to understand the impact TM might have on patients, healthcare professionals and the organisation of care. Objectives: To assess the effectiveness, acceptability and costs of interactive TM as an alternative to, or in addition to, usual care (i.e. face-to-face care, or telephone consultation). Search methods: We searched the Effective Practice and Organisation of Care (EPOC) Group's specialised register, CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers to June 2013, together with reference checking, citation searching, handsearching and contact with study authors to identify additional studies. Selection criteria: We considered randomised controlled trials of interactive TM that involved direct patient-provider interaction and was delivered in addition to, or substituting for, usual care compared with usual care alone, to participants with any clinical condition. We excluded telephone only interventions and wholly automatic self-management TM interventions. Data collection and analysis: For each condition, we pooled outcome data that were sufficiently homogenous using fixed effect meta-analysis. We reported risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) for continuous outcomes. Main results: We included 93 eligible trials (N = 22,047 participants), which evaluated the effectiveness of interactive TM delivered in addition to (32% of studies), as an alternative to (57% of studies), or partly substituted for usual care (11%) as compared to usual care alone. The included studies recruited patients with the following clinical conditions: cardiovascular disease (36), diabetes (21), respiratory conditions (9), mental health or substance abuse conditions (7), conditions requiring a specialist consultation (6), co morbidities (3), urogenital conditions (3), neurological injuries and conditions (2), gastrointestinal conditions (2), neonatal conditions requiring specialist care (2), solid organ transplantation (1), and cancer (1).Telemedicine provided remote monitoring (55 studies), or real-time video-conferencing (38 studies), which was used either alone or in combination. The main TM function varied depending on clinical condition, but fell typically into one of the following six categories, with some overlap: i) monitoring of a chronic condition to detect early signs of deterioration and prompt treatment and advice, (41); ii) provision of treatment or rehabilitation (12), for example the delivery of cognitive behavioural therapy, or incontinence training; iii) education and advice for self-management (23), for example nurses delivering education to patients with diabetes or providing support to parents of very low birth weight infants or to patients with home parenteral nutrition; iv) specialist consultations for diagnosis and treatment decisions (8), v) real-time assessment of clinical status, for example post-operative assessment after minor operation or follow-up after solid organ transplantation (8) vi), screening, for angina (1).The type of data transmitted by the patient, the frequency of data transfer, (e.g. telephone, e-mail, SMS) and frequency of interactions between patient and healthcare provider varied across studies, as did the type of healthcare provider/s and healthcare system involved in delivering the intervention. We found no difference between groups for all-cause mortality for patients with heart failure (16 studies; N = 5239; RR:0.89, 95% CI 0.76 to 1.03, P = 0.12; I(2) = 44%) (moderate to high certainty of evidence) at a median of six months follow-up. Admissions to hospital (11 studies; N = 4529) ranged from a decrease of 64% to an increase of 60% at median eight months follow-up (moderate certainty of evidence). We found some evidence of improved quality of life (five studies; N = 482; MD:-4.39, 95% CI -7.94 to -0.83; P < 0.02; I(2) = 0%) (moderate certainty of evidence) for those allocated to TM as compared with usual care at a median three months follow-up. In studies recruiting participants with diabetes (16 studies; N = 2768) we found lower glycated haemoglobin (HbA1c %) levels in those allocated to TM than in controls (MD -0.31, 95% CI -0.37 to -0.24; P < 0.00001; I(2)= 42%, P = 0.04) (high certainty of evidence) at a median of nine months follow-up. We found some evidence for a decrease in LDL (four studies, N = 1692; MD -12.45, 95% CI -14.23 to -10.68; P < 0.00001; I(2 =) 0%) (moderate certainty of evidence), and blood pressure (four studies, N = 1770: MD: SBP:-4.33, 95% CI -5.30 to -3.35, P < 0.00001; I(2) = 17%; DBP: -2.75 95% CI -3.28 to -2.22, P < 0.00001; I(2) = 45% (moderate certainty evidence), in TM as compared with usual care. Seven studies that recruited participants with different mental health and substance abuse problems, reported no differences in the effect of therapy delivered over video-conferencing, as compared to face-to-face delivery. Findings from the other studies were inconsistent; there was some evidence that monitoring via TM improved blood pressure control in participants with hypertension, and a few studies reported improved symptom scores for those with a respiratory condition. Studies recruiting participants requiring mental health services and those requiring specialist consultation for a dermatological condition reported no differences between groups. Authors' conclusions: The findings in our review indicate that the use of TM in the management of heart failure appears to lead to similar health outcomes as face-to-face or telephone delivery of care; there is evidence that TM can improve the control of blood glucose in those with diabetes. The cost to a health service, and acceptability by patients and healthcare professionals, is not clear due to limited data reported for these outcomes. The effectiveness of TM may depend on a number of different factors, including those related to the study population e.g. the severity of the condition and the disease trajectory of the participants, the function of the intervention e.g., if it is used for monitoring a chronic condition, or to provide access to diagnostic services, as well as the healthcare provider and healthcare system involved in delivering the intervention.

The Cochrane database of systematic reviews · meta-analysis · 456 citationsread the source →

Annual Research Review: Umbrella synthesis of meta-analyses on child maltreatment antecedents and interventions: differential susceptibility perspective on risk and resilience.

Child maltreatment in the family context is a prevalent and pervasive phenomenon in many modern societies. The global perpetration of child abuse and neglect stands in stark contrast to its almost universal condemnation as exemplified in the United Nation's Convention on the Rights of the Child. Much work has been devoted to the task of prevention, yet a grand synthesis of the literature is missing. Focusing on two core elements of prevention, that is, antecedents for maltreatment and the effectiveness of (preventative) interventions, we performed an umbrella review of meta-analyses published between January 1, 2014, and December 17, 2018. Meta-analyses were systematically collected, assessed, and integrated following a uniform approach to allow their comparison across domains. From this analysis of thousands of studies including almost 1.5 million participants, the following risk factors were derived: parental experience of maltreatment in his or her own childhood (d = .47), low socioeconomic status of the family (d = .34), dependent and aggressive parental personality (d = .45), intimate partner violence (d = .41), and higher baseline autonomic nervous system activity (d = .24). The effect size for autonomic stress reactivity was not significant (d = -.10). The umbrella review of interventions to prevent or reduce child maltreatment showed modest intervention effectiveness (d = .23 for interventions targeting child abuse potential or families with self-reported maltreatment and d = .27 for officially reported child maltreatment cases). Despite numerous studies on child maltreatment, some large gaps in our knowledge of antecedents exist. Neurobiological antecedents should receive more research investment. Differential susceptibility theory may shed more light on questions aimed at breaking the intergenerational transmission of maltreatment and on the modest (preventive) intervention effects. In combination with family-based interaction-focused interventions, large-scale socioeconomic experiments such as cash transfer trials and experiments with vouchers to move to a lower-poverty area might be tested to prevent or reduce child maltreatment. Prevalence, antecedents, and preventive interventions of prenatal maltreatment deserve continuing scientific, clinical, and policy attention.

Journal of child psychology and psychiatry, and allied disciplines · systematic review · 137 citationsread the source →

Suicide prevention strategies revisited: 10-year systematic review.

Background: Many countries are developing suicide prevention strategies for which up-to-date, high-quality evidence is required. We present updated evidence for the effectiveness of suicide prevention interventions since 2005. Methods: We searched PubMed and the Cochrane Library using multiple terms related to suicide prevention for studies published between Jan 1, 2005, and Dec 31, 2014. We assessed seven interventions: public and physician education, media strategies, screening, restricting access to suicide means, treatments, and internet or hotline support. Data were extracted on primary outcomes of interest, namely suicidal behaviour (suicide, attempt, or ideation), and intermediate or secondary outcomes (treatment-seeking, identification of at-risk individuals, antidepressant prescription or use rates, or referrals). 18 suicide prevention experts from 13 European countries reviewed all articles and rated the strength of evidence using the Oxford criteria. Because the heterogeneity of populations and methodology did not permit formal meta-analysis, we present a narrative analysis. Findings: We identified 1797 studies, including 23 systematic reviews, 12 meta-analyses, 40 randomised controlled trials (RCTs), 67 cohort trials, and 22 ecological or population-based investigations. Evidence for restricting access to lethal means in prevention of suicide has strengthened since 2005, especially with regard to control of analgesics (overall decrease of 43% since 2005) and hot-spots for suicide by jumping (reduction of 86% since 2005, 79% to 91%). School-based awareness programmes have been shown to reduce suicide attempts (odds ratio [OR] 0·45, 95% CI 0·24-0·85; p=0·014) and suicidal ideation (0·5, 0·27-0·92; p=0·025). The anti-suicidal effects of clozapine and lithium have been substantiated, but might be less specific than previously thought. Effective pharmacological and psychological treatments of depression are important in prevention. Insufficient evidence exists to assess the possible benefits for suicide prevention of screening in primary care, in general public education and media guidelines. Other approaches that need further investigation include gatekeeper training, education of physicians, and internet and helpline support. The paucity of RCTs is a major limitation in the evaluation of preventive interventions. Interpretation: In the quest for effective suicide prevention initiatives, no single strategy clearly stands above the others. Combinations of evidence-based strategies at the individual level and the population level should be assessed with robust research designs. Funding: The Expert Platform on Mental Health, Focus on Depression, and the European College of Neuropsychopharmacology.

The lancet. Psychiatry · systematic review · 1070 citationsread the source →

Dietary patterns and successful ageing: a systematic review.

Purpose: Nutrition is a key determinant of chronic disease in later life. A systematic review was conducted of studies examining dietary patterns and quality of life, physical function, cognitive function and mental health among older adults. Methods: Literature searches in MEDLINE complete, Academic Search Complete, CINAHL Complete, Ageline, Global health, PsycINFO, SCOPUS and EMBASE and hand searching from 1980 up to December 2014 yielded 1236 results. Inclusion criteria included dietary pattern assessment via dietary indices or statistical approaches, a sample of community-dwelling adults aged 45 years and over at baseline and a cross-sectional or longitudinal study design. Exclusion criteria included a single 24-h recall of diet, evaluation of single foods or nutrients, clinical or institutionalised samples and intervention studies. Risk of bias was assessed using the six-item Effective Public Health Practice Project's Quality Assessment Tool for Quantitative Studies. Results: There were 34 articles (11 cross-sectional and 23 longitudinal) included with 23 studies examining dietary indices and 13 studies using empirical analysis. Most studies examined mental health (n = 10) or cognitive function (n = 18), with fewer studies examining quality of life (n = 6) and physical function (n = 8). Although dietary pattern and outcome assessment methods varied, most studies reported positive associations between a healthier diet and better health outcomes. Conclusion: Overall, the number of studies using dietary patterns to investigate diet and successful ageing is small, and further investigation in longitudinal studies is needed, particularly for quality-of-life outcomes. This review provides support for the importance of a healthy diet for the ageing population globally.

European journal of nutrition · systematic review · 126 citationsread the source →

Exercise interventions and patient beliefs for people with hip, knee or hip and knee osteoarthritis: a mixed methods review.

Background: Chronic peripheral joint pain due to osteoarthritis (OA) is extremely prevalent and a major cause of physical dysfunction and psychosocial distress. Exercise is recommended to reduce joint pain and improve physical function, but the effect of exercise on psychosocial function (health beliefs, depression, anxiety and quality of life) in this population is unknown. Objectives: To improve our understanding of the complex inter-relationship between pain, psychosocial effects, physical function and exercise. Search methods: Review authors searched 23 clinical, public health, psychology and social care databases and 25 other relevant resources including trials registers up to March 2016. We checked reference lists of included studies for relevant studies. We contacted key experts about unpublished studies. Selection criteria: To be included in the quantitative synthesis, studies had to be randomised controlled trials of land- or water-based exercise programmes compared with a control group consisting of no treatment or non-exercise intervention (such as medication, patient education) that measured either pain or function and at least one psychosocial outcome (self-efficacy, depression, anxiety, quality of life). Participants had to be aged 45 years or older, with a clinical diagnosis of OA (as defined by the study) or self-reported chronic hip or knee (or both) pain (defined as more than six months' duration).To be included in the qualitative synthesis, studies had to have reported people's opinions and experiences of exercise-based programmes (e.g. their views, understanding, experiences and beliefs about the utility of exercise in the management of chronic pain/OA). Data collection and analysis: We used standard methodology recommended by Cochrane for the quantitative analysis. For the qualitative analysis, we extracted verbatim quotes from study participants and synthesised studies of patients' views using framework synthesis. We then conducted an integrative review, synthesising the quantitative and qualitative data together. Main results: Twenty-one trials (2372 participants) met the inclusion criteria for quantitative synthesis. There were large variations in the exercise programme's content, mode of delivery, frequency and duration, participant's symptoms, duration of symptoms, outcomes measured, methodological quality and reporting. Comparator groups were varied and included normal care; education; and attention controls such as home visits, sham gel and wait list controls. Risk of bias was high in one and unclear risk in five studies regarding the randomisation process, high for 11 studies regarding allocation concealment, high for all 21 studies regarding blinding, and high for three studies and unclear for five studies regarding attrition. Studies did not provide information on adverse effects. There was moderate quality evidence that exercise reduced pain by an absolute percent reduction of 6% (95% confidence interval (CI) -9% to -4%, (9 studies, 1058 participants), equivalent to reducing (improving) pain by 1.25 points from 6.5 to 5.3 on a 0 to 20 scale and moderate quality evidence that exercise improved physical function by an absolute percent of 5.6% (95% CI -7.6% to 2.0%; standardised mean difference (SMD) -0.27, 95% CI -0.37 to -0.17, equivalent to reducing (improving) WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) function on a 0 to 100 scale from 49.9 to 44.3) (13 studies, 1599 participants)). Self-efficacy was increased by an absolute percent of 1.66% (95% CI 1.08% to 2.20%), although evidence was low quality (SMD 0.46, 95% CI 0.34 to 0.58, equivalent to improving the ExBeliefs score on a 17 to 85 scale from 64.3 to 65.4), with small benefits for depression from moderate quality evidence indicating an absolute percent reduction of 2.4% (95% CI -0.47% to 0.5%) (SMD -0.16, 95% CI -0.29 to -0.02, equivalent to improving depression measured using HADS (Hospital Anxiety and Depression Scale) on a 0 to 21 scale from 3.5 to 3.0) but no clinically or statistically significant effect on anxiety (SMD -0.11, 95% CI -0.26 to 0.05, 2% absolute improvement, 95% CI -5% to 1% equivalent to improving HADS anxiety on a 0 to 21 scale from 5.8 to 5.4; moderate quality evidence). Five studies measured the effect of exercise on health-related quality of life using the 36-item Short Form (SF-36) with statistically significant benefits for social function, increasing it by an absolute percent of 7.9% (95% CI 4.1% to 11.6%), equivalent to increasing SF-36 social function on a 0 to 100 scale from 73.6 to 81.5, although the evidence was low quality. Evidence was downgraded due to heterogeneity of measures, limitations with blinding and lack of detail regarding interventions. For 20/21 studies, there was a high risk of bias with blinding as participants self-reported and were not blinded to their participation in an exercise intervention. Twelve studies (with 6 to 29 participants) met inclusion criteria for qualitative synthesis. Their methodological rigour and quality was generally good. From the patients' perspectives, ways to improve the delivery of exercise interventions included: provide better information and advice about the safety and value of exercise; provide exercise tailored to individual's preferences, abilities and needs; challenge inappropriate health beliefs and provide better support. An integrative review, which compared the findings from quantitative trials with low risk of bias and the implications derived from the high-quality studies in the qualitative synthesis, confirmed the importance of these implications. Authors' conclusions: Chronic hip and knee pain affects all domains of people's lives. People's beliefs about chronic pain shape their attitudes and behaviours about how to manage their pain. People are confused about the cause of their pain, and bewildered by its variability and randomness. Without adequate information and advice from healthcare professionals, people do not know what they should and should not do, and, as a consequence, avoid activity for fear of causing harm. Participation in exercise programmes may slightly improve physical function, depression and pain. It may slightly improve self-efficacy and social function, although there is probably little or no difference in anxiety. Providing reassurance and clear advice about the value of exercise in controlling symptoms, and opportunities to participate in exercise programmes that people regard as enjoyable and relevant, may encourage greater exercise participation, which brings a range of health benefits to a large population of people.

The Cochrane database of systematic reviews · systematic review · 193 citationsread the source →

Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors.

Background: Persistent infection with high-risk human papillomaviruses (hrHPV) types is causally linked with the development of cervical precancer and cancer. HPV types 16 and 18 cause approximately 70% of cervical cancers worldwide. Objectives: To evaluate the harms and protection of prophylactic human papillomaviruses (HPV) vaccines against cervical precancer and HPV16/18 infection in adolescent girls and women. Search methods: We searched MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase (June 2017) for reports on effects from trials. We searched trial registries and company results' registers to identify unpublished data for mortality and serious adverse events. Selection criteria: Randomised controlled trials comparing efficacy and safety in females offered HPV vaccines with placebo (vaccine adjuvants or another control vaccine). Data collection and analysis: We used Cochrane methodology and GRADE to rate the certainty of evidence for protection against cervical precancer (cervical intraepithelial neoplasia grade 2 and above [CIN2+], CIN grade 3 and above [CIN3+], and adenocarcinoma-in-situ [AIS]), and for harms. We distinguished between the effects of vaccines by participants' baseline HPV DNA status. The outcomes were precancer associated with vaccine HPV types and precancer irrespective of HPV type. Results are presented as risks in control and vaccination groups and risk ratios (RR) with 95% confidence intervals in brackets. Main results: We included 26 trials (73,428 participants). Ten trials, with follow-up of 1.3 to 8 years, addressed protection against CIN/AIS. Vaccine safety was evaluated over a period of 6 months to 7 years in 23 studies. Studies were not large enough or of sufficient duration to evaluate cervical cancer outcomes. All but one of the trials was funded by the vaccine manufacturers. We judged most included trials to be at low risk of bias. Studies involved monovalent (N = 1), bivalent (N = 18), and quadrivalent vaccines (N = 7). Most women were under 26 years of age. Three trials recruited women aged 25 and over. We summarize the effects of vaccines in participants who had at least one immunisation. Efficacy endpoints by initial HPV DNA statushrHPV negativeHPV vaccines reduce CIN2+, CIN3+, AIS associated with HPV16/18 compared with placebo in adolescent girls and women aged 15 to 26. There is high-certainty evidence that vaccines lower CIN2+ from 164 to 2/10,000 (RR 0.01 (0 to 0.05)) and CIN3+ from 70 to 0/10,000 (RR 0.01 (0.00 to 0.10). There is moderate-certainty evidence that vaccines reduce the risk of AIS from 9 to 0/10,000 (RR 0.10 (0.01 to 0.82).HPV vaccines reduce the risk of any CIN2+ from 287 to 106/10,000 (RR 0.37 (0.25 to 0.55), high certainty) and probably reduce any AIS lesions from 10 to 0/10,000 (RR 0.1 (0.01 to 0.76), moderate certainty). The size of reduction in CIN3+ with vaccines differed between bivalent and quadrivalent vaccines (bivalent: RR 0.08 (0.03 to 0.23), high certainty; quadrivalent: RR 0.54 (0.36 to 0.82), moderate certainty). Data in older women were not available for this comparison.HPV16/18 negativeIn those aged 15 to 26 years, vaccines reduce CIN2+ associated with HPV16/18 from 113 to 6 /10,000 (RR 0.05 (0.03 to 0.10). In women 24 years or older the absolute and relative reduction in the risk of these lesions is smaller (from 45 to 14/10,000, (RR 0.30 (0.11 to 0.81), moderate certainty). HPV vaccines reduce the risk of CIN3+ and AIS associated with HPV16/18 in younger women (RR 0.05 (0.02 to 0.14), high certainty and RR 0.09 (0.01 to 0.72), moderate certainty, respectively). No trials in older women have measured these outcomes. Vaccines reduce any CIN2+ from 231 to 95/10,000, (RR 0.41 (0.32 to 0.52)) in younger women. No data are reported for more severe lesions. Regardless of HPV DNA statusIn younger women HPV vaccines reduce the risk of CIN2+ associated with HPV16/18 from 341 to 157/10,000 (RR 0.46 (0.37 to 0.57), high certainty). Similar reductions in risk were observed for CIN3+ associated with HPV16/18 (high certainty). The number of women with AIS associated with HPV16/18 is reduced from 14 to 5/10,000 with HPV vaccines (high certainty).HPV vaccines reduce any CIN2+ from 559 to 391/10,000 (RR 0.70 (0.58 to 0.85, high certainty) and any AIS from 17 to 5/10,000 (RR 0.32 (0.15 to 0.67), high certainty). The reduction in any CIN3+ differed by vaccine type (bivalent vaccine: RR 0.55 (0.43 to 0.71) and quadrivalent vaccine: RR 0.81 (0.69 to 0.96)).In women vaccinated at 24 to 45 years of age, there is moderate-certainty evidence that the risks of CIN2+ associated with HPV16/18 and any CIN2+ are similar between vaccinated and unvaccinated women (RR 0.74 (0.52 to 1.05) and RR 1.04 (0.83 to 1.30) respectively). No data are reported in this age group for CIN3+ or AIS.Adverse effectsThe risk of serious adverse events is similar between control and HPV vaccines in women of all ages (669 versus 656/10,000, RR 0.98 (0.92 to 1.05), high certainty). Mortality was 11/10,000 in control groups compared with 14/10,000 (9 to 22) with HPV vaccine (RR 1.29 [0.85 to 1.98]; low certainty). The number of deaths was low overall but there is a higher number of deaths in older women. No pattern in the cause or timing of death has been established. Pregnancy outcomesAmong those who became pregnant during the studies, we did not find an increased risk of miscarriage (1618 versus 1424/10,000, RR 0.88 (0.68 to 1.14), high certainty) or termination (931 versus 838/10,000 RR 0.90 (0.80 to 1.02), high certainty). The effects on congenital abnormalities and stillbirths are uncertain (RR 1.22 (0.88 to 1.69), moderate certainty and (RR 1.12 (0.68 to 1.83), moderate certainty, respectively). Authors' conclusions: There is high-certainty evidence that HPV vaccines protect against cervical precancer in adolescent girls and young women aged 15 to 26. The effect is higher for lesions associated with HPV16/18 than for lesions irrespective of HPV type. The effect is greater in those who are negative for hrHPV or HPV16/18 DNA at enrolment than those unselected for HPV DNA status. There is moderate-certainty evidence that HPV vaccines reduce CIN2+ in older women who are HPV16/18 negative, but not when they are unselected by HPV DNA status. We did not find an increased risk of serious adverse effects. Although the number of deaths is low overall, there were more deaths among women older than 25 years who received the vaccine. The deaths reported in the studies have been judged not to be related to the vaccine. Increased risk of adverse pregnancy outcomes after HPV vaccination cannot be excluded, although the risk of miscarriage and termination are similar between trial arms. Long-term of follow-up is needed to monitor the impact on cervical cancer, occurrence of rare harms and pregnancy outcomes.

The Cochrane database of systematic reviews · systematic review · 290 citationsread the source →

Heart Rate Variability and Cognitive Bias Feedback Interventions to Prevent Post-deployment PTSD: Results from a Randomized Controlled Trial.

Introduction: There is a long history of pre-deployment PTSD prevention efforts in the military and effective pre-deployment strategies to prevent post-deployment PTSD are still needed. Materials and methods: This randomized controlled trial included three arms: heart rate variability biofeedback (HRVB), cognitive bias modification for interpretation (CBM-I), and control. The hypothesis was that pre-deployment resilience training would result in lower post-deployment PTSD symptoms compared with control. Army National Guard soldiers (n = 342) were enrolled in the Warriors Achieving Resilience (WAR) study and analyzed. The outcome was PTSD symptom severity using the PTSD Checklist - Military version (PCL) measured at pre-deployment, 3- and 12-month post-deployment. Due to the repeated measures for each participant and cluster randomization at the company level, generalized linear mixed models were used for the analysis. This study was approved by the Army Human Research Protection Office, Central Arkansas Veterans Healthcare System Institutional Review Board (IRB), and Southeast Louisiana Veterans Health Care System IRB. Results: Overall, there was no significant intervention effect. However, there were significant intervention effects for subgroups of soldiers. For example, at 3-months post-deployment, the HRVB arm had significantly lower PCL scores than the control arm for soldiers with no previous combat zone exposure who were age 30 and older and for soldiers with previous combat zone exposure who were 45 and older (unadjusted effect size -0.97 and -1.03, respectively). A significant difference between the CBM-I and control arms was found for soldiers without previous combat zone exposure between ages 23 and 42 (unadjusted effect size -0.41). Similarly, at 12-months post-deployment, the HRVB arm had significantly lower PCL scores in older soldiers. Conclusion: Pre-deployment resilience training was acceptable and feasible and resulted in lower post-deployment PTSD symptom scores in subgroups of older soldiers compared with controls. Strengths of the study included cluster randomization at the company level, use of iPod device to deliver the resilience intervention throughout the deployment cycle, and minimal disruption of pre-deployment training by using self-paced resilience training. Weaknesses included self-report app use, study personnel not able to contact soldiers during deployment, and in general a low level of PTSD symptom severity throughout the study. In future studies, it would important for the study team and/or military personnel implementing the resilience training to be in frequent contact with participants to ensure proper use of the resilience training apps.

Military medicine · randomised controlled trial · 23 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 →

Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.

Background: Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence. Methods: We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794. Findings: Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]). Interpretation: We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis. Funding: The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.

The lancet. Gastroenterology & hepatology · randomised controlled trial · 103 citationsread the source →

Evaluation of Drinking Risk Levels as Outcomes in Alcohol Pharmacotherapy Trials: A Secondary Analysis of 3 Randomized Clinical Trials.

Importance: The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. Objective: To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. Design, setting, and participants: Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. Main outcomes and measures: Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). Results: Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.214 [95% CI, 0.053 -0.375]; varenicline, 0.273 [95% CI, -0.006 to 0.553]; topiramate, 0.230 [95% CI, 0.024-0.435]) and WHO 1-level reduction (naltrexone, Cohen h = 0.116 [95% CI, -0.046 to 0.277]; varenicline, 0.338 [95% CI, 0.058-0.617]; topiramate, 0.014 [95% CI, -0.192 to 0.219]) were comparable with those obtained using abstinence (naltrexone, Cohen h = 0.142 [95% CI, -0.020 to 0.303]; varenicline, 0.146 [95% CI, -0.133 to 0.426]; topiramate, 0.369 [95% CI, 0.163-0.574]) and no heavy drinking days (naltrexone, Cohen h = 0.140 [95% CI, -0.021 to 0.302]; varenicline, 0.232 [95% CI, -0.048 to 0.511]; topiramate, 0.207 [95% CI, 0.002-0.413]). Conclusions and relevance: WHO drinking risk level reductions appear to be worthwhile indicators of treatment outcome in AUD pharmacotherapy trials. These outcomes may align with drinking reduction goals of many patients and capture clinically meaningful improvements experienced by more patients than either abstinence or no heavy drinking days. Trial registration: ClinicalTrials.gov identifiers: NCT00006206; NCT01146613; NCT00210925.

JAMA psychiatry · randomised controlled trial · 98 citationsread the source →

Safety, tolerability, and immunogenicity of a 21-valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, US-based trial.

Background: A pneumococcal conjugate vaccine (PCV) specifically focused on serotypes associated with adult residual disease burden is urgently needed. We aimed to assess V116, an investigational 21-valent PCV, that contains pneumococcal polysaccharides (PnPs), which account for 74-94% of invasive pneumococcal disease in adults aged 65 years or older. Methods: We did a phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, non-inferiority and superiority trial. The phase 1 study was done at two clinical sites in the USA, and the phase 2 study was done in 18 clinical sites in the USA. Eligible participants were healthy adults with or without chronic medical conditions assessed as stable, aged 18-49 years in the phase 1 trial and aged 50 years or older in the phase 2 trial. Participants were excluded if they had a history of invasive pneumococcal disease or other culture-positive pneumococcal disease within the past 3 years, known hypersensitivity to a vaccine component, known or suspected impairment of immunological function, were pregnant or were breastfeeding, or had previously received any pneumococcal vaccine. Participants had to abstain from sexual activity or use protocol approved contraception. All participants were centrally randomly assigned to a vaccine group using an interactive response technology system. Participants and investigators were masked to group assignment. In phase 1, participants were randomly assigned (1:1:1) to receive a single dose of V116-1 (2 μg per pneumococcal polysaccharide [PnP] per 0·5 mL) or V116-2 (4 μg per PnP per 1·0 mL) or the 23-valent unconjugated PnP vaccine, PPSV23 (25 μg per PnP per 0·5 mL). In phase 2, participants were randomly assigned (1:1) to receive one dose of V116 (4 μg per PnP per 1·0 mL) or PPSV23 (25 μg per PnP per 0·5 mL), stratified by age. Safety analyses included all randomly assigned participants who received study vaccine; immunogenicity analyses were per protocol. For both phases, the primary safety outcome was the proportion of participants with solicited injection-site adverse events and solicited systemic adverse events up to day 5 after vaccination and the proportion of participants with vaccine-related serious adverse events to 6 months after vaccination. In phase 2, primary immunogenicity outcomes were to test non-inferiority of V116 compared with PPSV23 as measured by serotype-specific opsonophagocytic antibody geometric mean titres (OPA-GMT) ratios for the serotypes common to the two vaccines at 30 days after vaccination (using a 0·33 margin) and to test superiority of V116 compared with PPSV23 as measured by serotype-specific OPA-GMT ratios for the serotypes unique to V116 at 30 days after vaccination (using a 1·0 margin). This trial is registered with Clinicaltrials.gov, NCT04168190. Findings: Between Dec 6 and 26, 2019, 92 volunteers were screened and 90 (98%) enrolled for phase 1 (59 [66%] women; 31 [34%] men); 30 participants were assigned to each group and received study vaccine. 30 (100%) participants in the V116-1 group, 29 (97%) in the V116-2 group, and 30 (100%) participants in the PPSV23 group were included in the per-protocol immunogenicity evaluation. From Sept 23, 2020, to Jan 12, 2021, 527 volunteers were screened, and 510 (97%) participants were enrolled in the phase 2 trial. 508 participants (>99%; 254 [100%] of 254 participants randomly assigned to the V116 group and 254 [99%] of 256 randomly assigned to PPSV23 group) received study vaccine (281 [55%] women; 227 [45%] men). 252 (99%) of 254 of participants in the V116 group and 254 (99%) of 256 participants in the PPSV23 group were included in the primary immunogenicity analyses. There were no vaccine-related serious adverse events or vaccine-related deaths in either study phase. In both phases, the most common solicited injection site adverse event was injection site pain (phase 1 22 [73%] participants in V116-1 group, 23 [77%] participants in V116-2 group, and 17 [57%] participants in the PPSV23 group; phase 2 118 [46%] of 254 participants in the V116 group and 96 [38%] of 254 in the PPSV23 group]. The most common solicited systemic adverse events in phase 1 was fatigue (eight [27%] participants in the V116-1 group, eight [27%] participants in the V116-2 group, and five [17%] participants in PPSV23 group) and myalgia (eight [27%] participants in the V116-1 group, nine (30%) participants in the V116-2 group, and four (13%) participants in the PPSV23 group]. In phase 2, the most frequently reported solicited systemic adverse event was fatigue (49 [19%] participants in V116 group, and 31 [12%] participants in PPSV23 group). In both phases, most of the solicited adverse events in all vaccine groups were mild and of short duration (≤3 days). V116 met non-inferiority criteria compared with PPSV23 for the 12 shared serotypes and met superiority criteria compared to PPSV23 for the nine unique serotypes. Interpretation: V116 was well tolerated with a safety profile generally similar to PPSV23; consistent with licensed pneumococcal conjugate vaccines. Functional OPA antibodies were induced to all V116 vaccine serotypes. The vaccine was non-inferior to PPSV23 for the 12 serotypes common to both vaccines and superior to PPSV23 for the nine unique serotypes in V116. Our findings support the development of V116 for prevention of pneumococcal disease in adults. Funding: Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA.

The Lancet. Infectious diseases · randomised controlled trial · 73 citationsread the source →

Underlying mechanisms and efficacy of a suicide-focused psychological intervention for psychosis, the Cognitive Approaches to Combatting Suicidality (CARMS): a multicentre, assessor-masked, randomised controlled trial in the UK.

Background: There is a need for theoretically grounded and testable suicide-focused psychological therapies, especially in people with severe mental health problems, specifically non-affective psychosis. We aimed to test both the underlying mechanisms and efficacy of a suicide-focused therapy, cognitive behavioural suicide prevention for psychosis (CBSPp). Methods: We did a multicentre, assessor-masked, randomised controlled trial conducted at four UK National Health Service (NHS) sites. Participants were eligible for enrolment if they were 18 years or older; met ICD-10 criteria for non-affective psychosis (F20-F29); had self-reported suicidal experiences in the 3 months before recruitment; were under the care of an NHS mental health services team; were not receiving a psychological therapy as part of a similar trial; had sufficient competency in the English language not to need an interpreter to participate; and were able to give informed consent. After screening for eligibility and completion of baseline assessments, participants were randomly allocated in a 1:1 ratio to either the treatment as usual group (control) or CBSPp therapy plus standard treatment group (treatment), with stratification by use of antidepressant medication and NHS site. Randomisation took place using an online Sealed Envelope randomisation procedure conducted and overseen by the Manchester Academic Health Sciences Centre Clinical Trials Unit (MCTU). This system was accessed only by specially allocated staff (eg, the CARMS Trial Manager or the MCTU Trial manager). When the system randomly allocated a participant, an unmasked email confirmation was sent to the unmasked coprincipal investigator and the CARMS Trial Manager (also unmasked). Assessors, the trial statistician, and one coprincipal investigator were masked to allocation group. Participants were informed of their randomised allocation group by an unmasked CARMS staff member. Experts-by-experience were involved in all stages of the research. For those in the treatment group, approximately 24 one-to-one therapy sessions were offered, usually weekly, for around 50 min per session. Assessments were conducted at baseline, month 6, and month 12. The primary outcome was suicide ideation severity measured by the 25-item Adult Suicide Ideation Questionnaire (ASIQ), assessed at month 6 relative to baseline. Outcome analyses used mixed models in the intention-to-treat population. Planned mediation indirect linear regression models examined appraisals of poor social support, emotional difficulties, interpersonal problem-solving difficulties, defeat, entrapment, and hopelessness as mediators at 6 months with allocation condition (treatment vs control) as the predictor variable and suicidal ideation severity (ASIQ) at 6 months as the outcome variable, whilst controlling for baseline levels of the mediator and outcome variables. The trial was registered before recruitment at ClinicalTrials.gov (NCT03114917) and ISRCTN (ISRCTN17776666) and is complete. Findings: We recruited participants from four NHS sites from June 21, 2017, to Nov 25, 2020, with the final 12-month assessment completed on Jan 10, 2022. 479 participants were screened for eligibility, and of these 329 (69%) provided consent and were enrolled. After 69 participants were lost to follow-up, 292 participants were randomly allocated to the treatment and control groups (149 [51%] and 143 [49%], respectively). At baseline, 161 (55%) participants were male and 130 (45%) were female; one participant (<1%) in the treatment group was missing gender data. Mean age was 35·1 years (SD 13·2; range 18-69), and 247 (85%) were White or Caucasian. Severity of suicidal ideation was not statistically different between the treatment (n=136) and the control groups (n=116) at 6 months (p=0·07; Cohen's d -0·20 [95% CI -0·42 to 0·02]). A significant indirect mediation effect (-2·85, -7·00 to -0·23) showed that therapy strengthened social support appraisals which, in turn, reduced suicidal ideation severity at 6 months more in the treatment group than in the control group. Suicide attempts were the most frequent severe adverse event (132 attempts in 26 participants in the treatment group vs 91 attempts in 30 participants in the control group). There were four deaths in the CARMS study, none of which were by suicide or considered related to treatment. Interpretation: CBSPp had no effect on suicidal ideation at 6 months, but it did have a significant indirect effect via improving appraisals of social support. It is important to explore how suicide-focused therapies can be developed and implemented in mental health services so that they maximally enhance appraisals of social support and social connection in ways that endure. Funding: Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health and Care Research partnership (reference number: 13/161/25).

The lancet. Psychiatry · randomised controlled trial · 4 citationsread the source →

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

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

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

Evaluation of agomelatine for the treatment of sleep problems in adults with autism spectrum disorder and co-morbid intellectual disability.

Purpose: Intellectual disability (ID) and autism spectrum disorder (ASD) are common, co-occurring developmental disorders and are frequently associated with sleep problems. This study aimed to assess the effectiveness and tolerability of agomelatine as a pharmacotherapy for sleep problems in ASD adults with ID. Method: A randomised, crossover, triple-blind, placebo-controlled clinical trial, with two three-month periods of treatment starting with either agomelatine or placebo and a washout period of two weeks. Ambulatory circadian monitoring (24 hours/7 days) evaluated total sleep time (TST) as the primary outcome variable. Results: Participants (N=23; 35±12 years old; 83% male) had a median of three (interquartile range (IQR) 1-4) co-morbidities and were taking a median of five (IQR 2-7) prescribed drugs. Before agomelatine or placebo treatment, all subjects presented with insomnia symptoms, including sleep latency (100% abnormal, 55±23 minutes) or TST (55% abnormal, 449±177 minutes), and 66% had circadian rhythm sleep-wake abnormalities with rhythm phase advancements according to the M5 sleep phase marker values. During the three-month agomelatine treatment, night TST significantly increased by a mean of 83 minutes (16% abnormal, 532±121 minutes), together with a phase correction (M5 1:45±2:28 hours vs. 3:15±2:20 hours), improving sleep stability in wrist temperature rhythm (0.43±0.29 vs. 0.52±0.18 AU). Adverse events were mild and transient. Conclusions: Agomelatine was effective and well tolerated for treating insomnia and circadian rhythm sleep problems present in adults with ASD and ID.

Journal of psychopharmacology (Oxford, England) · randomised controlled trial · 15 citationsread the source →

Novel community health worker strategy for HIV service engagement in a hyperendemic community in Rakai, Uganda: A pragmatic, cluster-randomized trial.

Background: Effective implementation strategies are needed to increase engagement in HIV services in hyperendemic settings. We conducted a pragmatic cluster-randomized trial in a high-risk, highly mobile fishing community (HIV prevalence: approximately 38%) in Rakai, Uganda, to assess the impact of a community health worker-delivered, theory-based (situated Information, Motivation, and Behavior Skills), motivational interviewing-informed, and mobile phone application-supported counseling strategy called "Health Scouts" to promote engagement in HIV treatment and prevention services. Methods and findings: The study community was divided into 40 contiguous, randomly allocated clusters (20 intervention clusters, n = 1,054 participants at baseline; 20 control clusters, n = 1,094 participants at baseline). From September 2015 to December 2018, the Health Scouts were deployed in intervention clusters. Community-wide, cross-sectional surveys of consenting 15 to 49-year-old residents were conducted at approximately 15 months (mid-study) and at approximately 39 months (end-study) assessing the primary programmatic outcomes of self-reported linkage to HIV care, antiretroviral therapy (ART) use, and male circumcision, and the primary biologic outcome of HIV viral suppression (<400 copies/mL). Secondary outcomes included HIV testing coverage, HIV incidence, and consistent condom use. The primary intent-to-treat analysis used log-linear binomial regression with generalized estimating equation to estimate prevalence risk ratios (PRR) in the intervention versus control arm. A total of 2,533 (45% female, mean age: 31 years) and 1,903 (46% female; mean age 32 years) residents completed the mid-study and end-study surveys, respectively. At mid-study, there were no differences in outcomes between arms. At end-study, self-reported receipt of the Health Scouts intervention was 38% in the intervention arm and 23% in the control arm, suggesting moderate intervention uptake in the intervention arm and substantial contamination in the control arm. At end-study, intention-to-treat analysis found higher HIV care coverage (PRR: 1.06, 95% CI: 1.01 to 1.10, p = 0.011) and ART coverage (PRR: 1.05, 95% CI: 1.01 to 1.10, p = 0.028) among HIV-positive participants in the intervention compared with the control arm. Male circumcision coverage among all men (PRR: 1.05, 95% CI: 0.96 to 1.14, p = 0.31) and HIV viral suppression among HIV-positive participants (PRR: 1.04, 95% CI: 0.98 to 1.12, p = 0.20) were higher in the intervention arm, but differences were not statistically significant. No differences were seen in secondary outcomes. Study limitations include reliance on self-report for programmatic outcomes and substantial contamination which may have diluted estimates of effect. Conclusions: A novel community health worker intervention improved HIV care and ART coverage in an HIV hyperendemic setting but did not clearly improve male circumcision coverage or HIV viral suppression. This community-based, implementation strategy may be a useful component in some settings for HIV epidemic control. Trial registration: ClinicalTrials.gov NCT02556957.

PLoS medicine · randomised controlled trial · 20 citationsread the source →

Effect of Prefrontal Cortex Stimulation on Regulation of Amygdala Response to Threat in Individuals With Trait Anxiety: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) is under clinical investigation as a treatment for major depressive disorder. However, the mechanisms of action are unclear, and there is a lack of neuroimaging evidence, particularly among individuals with affective dysfunction. Furthermore, there is no direct causal evidence among humans that the prefrontal-amygdala circuit functions as described in animal models (ie, that increasing activity in prefrontal cortical control regions inhibits amygdala response to threat). Objective: To determine whether stimulation of the prefrontal cortex reduces amygdala threat reactivity in individuals with trait anxiety. Design, setting, and participants: This community-based randomized clinical trial used a double-blind, within-participants design (2 imaging sessions per participant). Eighteen women with high trait anxiety (age range, 18-42 years) who scored greater than 45 on the trait measure of State-Trait Anxiety Inventory were randomized to receive active or sham tDCS of the DLPFC during the first session and the other intervention during the next session. Each intervention was followed immediately by a functional imaging scan during which participants performed an attentional task requiring them to ignore threatening face distractors. Data were collected from May 7 to October 6, 2015. Main outcomes and measures: Amygdala threat response, measured with functional magnetic resonance imaging. Results: Data from 16 female participants (mean age, 23 years; range, 18-42 years), with 8 in each group, were analyzed. Compared with sham stimulation, active DLPFC stimulation significantly reduced bilateral amygdala threat reactivity (z = 3.30, P = .04) and simultaneously increased activity in cortical regions associated with attentional control (z = 3.28, P < .001). In confirmatory behavioral analyses, there was a mean improvement in task accuracy of 12.2% (95% CI, 0.30%-24.0%; mean [SD] difference in number of correct answers, 2.2 [4.5]; t15 = 1.94, P = .04) after active DLPFC stimulation. Conclusions and relevance: These results reveal a causal role for prefrontal regulation of amygdala function in attentional capture by threat in individuals with high trait anxiety. The finding that prefrontal stimulation acutely increases attentional control signals and reduces amygdala threat reactivity may indicate a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders. Trial registration: isrctn.org Identifier: ISRCTN78638425.

JAMA psychiatry · randomised controlled trial · 102 citationsread the source →

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

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

JAMA · randomised controlled trial · 177 citationsread the source →

The Social Epidemiology of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

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

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

Psychological morbidity and quality of life of ethnic minority patients with cancer: a systematic review and meta-analysis.

Background: Ethnic minority is associated with higher cancer incidence and poorer survival than is being in the majority group. We did a systematic review and meta-analysis to assess whether psychological morbidity and health-related quality of life (HRQoL) were affected by minority status. Methods: We searched Medline, AMED, PsycINFO, Embase, CENTRAL, CINAHL, PubMed, Sociological Abstracts, and Web of Science for English-language articles published between Jan 1, 1995, and October, 2009. Articles were eligible if they reported original data on anxiety, depression, distress (for psychological morbidity), or HRQoL in minority and majority cancer patients or survivors. Minority status was defined as being an immigrant or having an ethnic, linguistic, or religious background different to the majority of the population in the country where the research was done. We excluded African Americans and indigenous groups. Eligible articles were rated for quality of reporting, external validity, internal validity, sample size, and power. Each quality criterion was rated independently by two reviewers until inter-rater reliability was achieved. In a meta-analysis we compared mean scores adjusted for socioeconomic status and other sociodemographic and clinical variables, where available. Effect sizes greater than 0·5 and 95% CI that included 0·5 or -0·5 were deemed clinically important, with negative values indicating worse outcomes in minority patients. We assessed publication bias by estimating the number of potential unpublished studies and the number of non-signficant studies with p=0·05 required to produce a non-significant overall result. Findings: We identified 21 eligible articles that included 18 datasets collected in the USA and one in each of Canada, Romania, and the UK. Ethnic minority groups were Hispanic, Asian or Pacific Islander, or Hungarian (one dataset). Overall, we found minority versus majority groups to have significantly worse distress (mean difference -0·37, 95% CI -0·46 to -0·28; p<0·0001), depression (-0·23, -0·36 to -0·11; p=0·0003), and overall HRQoL (-0·33, -0·58 to -0·07; p=0·013). Further analyses found disparities to be specific to Hispanic patients in the USA, in whom poorer outcomes were consistent with potentially clinically important differences for distress (effect size -0·37, 95% CI -0·54 to -0·20; p<0·0001), social HRQoL (-0·45, -0·87 to -0·03; p=0·035), and overall HRQoL (-0·49, -0·78 to -0.20; p=0·0008). Results were significantly heterogeneous for overall HRQoL and all domains. Tests for interaction, for adjusted versus unadjusted and comparisons of high-quality, medium-quality, and low-quality articles, were generally non-significant, which suggests no bias. We found no evidence of any substantive publication bias. Interpretation: Hispanic cancer patients in the USA, but not other ethnic minority groups, report significantly worse distress, depression, social HRQoL, and overall HRQoL than do majority patients, of which all but depression might be clinically important. Heterogeneous results might, however, have limited the interpretation. Data for other minority groups and for anxiety are scarce. More studies are needed from outside the USA. Future reports should more clearly describe their minority group samples and analyses should control for clinical and sociodemographic variables known to predict outcomes. Understanding of why outcomes are poor in US Hispanic patients is needed to inform the targeting of interventions. Funding: Prince of Wales Hospital, Sydney, Australia.

The Lancet. Oncology · meta-analysis · 152 citationsread the source →

Do couple-based interventions make a difference for couples affected by cancer? A systematic review.

Background: With the growing recognition that patients and partners react to a cancer diagnosis as an interdependent system and increasing evidence that psychosocial interventions can be beneficial to both patients and partners, there has been a recent increase in the attention given to interventions that target couples. The aim of this systematic review was to identify existing couple-based interventions for patients with cancer and their partners and explore the efficacy of these interventions (including whether there is added value to target the couple versus individuals), the content and delivery of couple-based interventions, and to identify the key elements of couple-based interventions that promote improvement in adjustment to cancer diagnosis. Method: A systematic review of the cancer literature was performed to identify experimental and quasi-experimental couple-based interventions published between 1990 and 2011. To be considered for this review, studies had to test the efficacy of a psychosocial intervention for couples affected by cancer. Studies were excluded if they were published in a language other than English or French, focused on pharmacological, exercise, or dietary components combined with psychosocial components, or did not assess the impact of the intervention on psychological distress (e.g., depression, anxiety) or quality of life. Data were extracted using a standardised data collection form, and were analysed independently by three reviewers. Results: Of the 709 articles screened, 23 were included in this review. Couple-based interventions were most efficacious in improving couple communication, psychological distress, and relationship functioning. Interventions had a limited impact on physical distress and social adjustment. Most interventions focused on improving communication and increasing understanding of the cancer diagnosis within couples. Interventions were most often delivered by masters-level nurses or clinical psychologists. Although most were delivered in person, few were telephone-based. No difference in efficacy was noted based on mode of delivery. Factors associated with uptake and completion included symptom severity, available time and willingness to travel. Conclusion: Given effect sizes of couple-based interventions are similar to those reported in recent meta-analyses of patient-only and caregiver-only interventions (~d=.35-.45), it appears couple-based interventions for patients with cancer and their partners may be at least as efficacious as patient-only and caregiver-only interventions. Despite evidence that couple-based interventions enhance psycho-social adjustment for both patients and partners, these interventions have not yet been widely adopted. Although more work is needed to facilitate translation to routine practice, evidence reviewed is promising in reducing distress and improving coping and adjustment to a cancer diagnosis or to cancer symptoms.

BMC cancer · systematic review · 124 citationsread the source →

8-year follow-up of patients treated for borderline personality disorder: mentalization-based treatment versus treatment as usual.

Objective: This study evaluated the effect of mentalization-based treatment by partial hospitalization compared to treatment as usual for borderline personality disorder 8 years after entry into a randomized, controlled trial and 5 years after all mentalization-based treatment was complete. Method: Interviewing was by research psychologists blind to original group allocation and structured review of medical notes of 41 patients from the original trial. Multivariate analysis of variance, chi-square, univariate analysis of variance, and nonparametric Mann-Whitney statistics were used to contrast the two groups depending on the distribution of the data. Results: Five years after discharge from mentalization-based treatment, the mentalization-based treatment by partial hospitalization group continued to show clinical and statistical superiority to treatment as usual on suicidality (23% versus 74%), diagnostic status (13% versus 87%), service use (2 years versus 3.5 years of psychiatric outpatient treatment), use of medication (0.02 versus 1.90 years taking three or more medications), global function above 60 (45% versus 10%), and vocational status (employed or in education 3.2 years versus 1.2 years). Conclusions: Patients with 18 months of mentalization-based treatment by partial hospitalization followed by 18 months of maintenance mentalizing group therapy remain better than those receiving treatment as usual, but their general social function remains impaired.

The American journal of psychiatry · randomised controlled trial · 333 citationsread the source →

Effect of topical honey application along with intralesional injection of glucantime in the treatment of cutaneous leishmaniasis.

Background: Leishmaniasis is an endemic disease in Iran. Although many treatments have been suggested for this disease, there hasn't been an effective and safe treatment yet. Regarding the healing effect of honey in the chronic ulcers and its reported therapeutic effect in cutaneous leishmaniasis, we performed a study to better evaluate the efficacy of honey in cutaneous leishmaniasis and its final scar. Methods: In a prospective clinical trial, 100 patients with confirmed cutaneous leishmaniasis were selected and randomized into 2 groups. Group A were treated with topical honey twice daily along with intralesional injection of glucantime once weekly until complete healing of the ulcer or for maximum of 6 weeks. Group B were treated with intralesional injection of glucantime alone until complete healing of the ulcer or for a maximum of 6 weeks, too. The patients were followed for 4 months. The collected data were analyzed statistically using statistical tests including Chi-square, Mann Whitney and Kaplan-Mayer tests. Results: In this study, 45 patients that had cutaneous leishmaniasis were treated with intralesional glucantime alone and 45 patients were treated with topical honey and glucantime. Ten patients left out the study. In the glucantime alone treated group, 32 patients (71.1%) had complete cure whereas in the group treated with both glucantime & topical honey, 23 patients (51.1%) achieved complete cure. This difference was significant statistically (p = 0.04). Conclusion: Further studies to better clarify the efficacy of honey in cutaneous leishmaniasis is needed. We suggest that in another study, the efficacy of honey with standardized level of antibacterial activity is evaluated against cutaneous leishmaniasis.

BMC complementary and alternative medicine · randomised controlled trial · 28 citationsread the source →

Association of Social Isolation With Disability Burden and 1-Year Mortality Among Older Adults With Critical Illness.

Importance: Disability and mortality are common among older adults with critical illness. Older adults who are socially isolated may be more vulnerable to adverse outcomes for various reasons, including fewer supports to access services needed for optimal recovery; however, whether social isolation is associated with post-intensive care unit (ICU) disability and mortality is not known. Objectives: To evaluate whether social isolation is associated with disability and with 1-year mortality after critical illness. Design, setting, and participants: This observational cohort study included community-dwelling older adults who participated in the National Health and Aging Trends Study (NHATS) from May 2011 through November 2018. Hospitalization data were collected through 2017 and interview data through 2018. Data analysis was conducted from February 2020 through February 2021. The mortality sample included 997 ICU admissions of 1 day or longer, which represented 5 705 675 survey-weighted ICU hospitalizations. Of these, 648 ICU stays, representing 3 821 611 ICU hospitalizations, were eligible for the primary outcome of post-ICU disability. Exposures: Social isolation from the NHATS survey response in the year most closely preceding ICU admission, which was assessed using a validated measure of social connectedness with partners, families, and friends as well as participation in valued life activities (range 0-6; higher scores indicate more isolation). Main outcomes and measures: The primary outcome was the count of disability assessed during the first interview following hospital discharge. The secondary outcome was time to death within 1 year of hospital admission. Results: A total of 997 participants were in the mortality cohort (511 women [51%]; 45 Hispanic [5%], 682 non-Hispanic White [69%], and 228 non-Hispanic Black individuals [23%]) and 648 in the disability cohort (331 women [51%]; 29 Hispanic [5%], 457 non-Hispanic White [71%], and 134 non-Hispanic Black individuals [21%]). The median (interquartile range [IQR]) age was 81 (75.5-86.0) years (range, 66-102 years), the median (IQR) preadmission disability count was 0 (0-1), and the median (IQR) social isolation score was 3 (2-4). After adjustment for demographic characteristics and illness severity, each 1-point increase in the social isolation score (from 0-6) was associated with a 7% greater disability count (adjusted rate ratio, 1.07; 95% CI, 1.01-1.15) and a 14% increase in 1-year mortality risk (adjusted hazard ratio, 1.14; 95% CI, 1.03-1.25). Conclusions and relevance: In this cohort study, social isolation before an ICU hospitalization was associated with greater disability burden and higher mortality in the year following critical illness. The study findings suggest a need to develop social isolation screening and intervention frameworks for older adults with critical illness.

JAMA internal medicine · cohort or longitudinal · 71 citationsread the source →

Barriers to Physical Activity in Children With Autism Spectrum Disorders: Relationship to Physical Activity and Screen Time.

Background: Individual, social, and community barriers to physical activity (PA) experienced by children with autism spectrum disorder (ASD) make PA participation more difficult and may contribute to increased screen time. Methods: We compared the prevalence of parent-reported barriers to PA among 58 typically developing (TD) children and 53 children with an ASD, 3 to 11 years, and assessed the association between barriers and PA participation and screen time among children with ASD. Results: Parents of children with ASD reported significantly more barriers than parents of TD children. Based on parent-report, 60% of children with ASD required too much supervision compared with no TD children (P < .001). Parents of children with ASD were more likely to report that adults lack skills needed to include their child (58%), that their child has few friends (45%), and that other children exclude their child (23%). The number of parent-reported barriers to PA was inversely correlated with the hours spent in PA per year (r = -0.27, P = .05) and positively related to total screen time (r = .32, P < .03). Conclusions: These findings underscore the need for community-based PA programs designed to meet the special requirements of this population and policies that compel schools and other government-supported organizations for inclusion and/or targeted programming.

Journal of physical activity & health · 110 citationsread the source →

Attachment style, relationship quality, and psychological distress in patients with psychogenic non-epileptic seizures versus epilepsy.

Objectives: Psychopathology levels are elevated in patients with psychogenic non-epileptic seizures (PNES) and those with epilepsy. However, patients with PNES report higher rates of trauma and neglect, poorer health-related quality of life (HRQoL), and an increased prevalence of insecure attachment. We examined to what extent attachment style and relationship quality with their main informal carer impact on levels of HRQoL, depression, and anxiety in patients with PNES versus those with epilepsy. Method: Consecutive patients with PNES (N=23) and epilepsy (N=72) completed questionnaires about attachment style, quality of their relationship with their main informal carer, seizure severity, HRQoL, depression, and anxiety. Results: Patients with PNES reported higher levels of anxiety and depression and lower HRQoL than those with epilepsy. PNES: No significant correlations were found with HRQoL but depression correlated positively with attachment avoidance, attachment anxiety, and relationship conflict. Anxiety correlated positively with attachment avoidance, attachment anxiety, and relationship conflict, and negatively with relationship depth and support. Epilepsy: HRQoL correlated negatively with seizure severity, depression, anxiety, attachment avoidance, and attachment anxiety. Depression correlated positively with attachment avoidance, attachment anxiety, and relationship conflict. Anxiety correlated positively with seizure severity, attachment avoidance, and attachment anxiety. Correlations between measures of relationship quality and anxiety were stronger in patients with PNES versus those with epilepsy (zs=2.66 to 2.97, ps<0.004). Attachment style and relationship quality explained larger amounts of variance in depression (45%) and anxiety (60%) in the patients with PNES than those with epilepsy (16% and 13%). Significance: Levels of anxiety and depression were higher in patients with PNES than those with epilepsy. Interpersonal problems were much more closely associated with anxiety and depression in patients with PNES than those with epilepsy. The findings support the use of therapeutic interventions for PNES focusing on attachment and relationship issues.

Epilepsy & behavior : E&B · cohort or longitudinal · 44 citationsread the source →

Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder.

Background: Anecdotal reports suggest that psychedelic agents may relieve symptoms of obsessive-compulsive disorder (OCD). This modified double-blind study investigated the safety, tolerability, and clinical effects of psilocybin, a potent 5-HT(1A) and 5-HT(2A/2C) agonist, in patients with OCD. Method: Nine subjects with DSM-IV-defined OCD and no other current major psychiatric disorder participated in up to 4 single-dose exposures to psilocybin in doses ranging from sub-hallucinogenic to frankly hallucinogenic. Low (100 microg/kg), medium (200 microg/kg), and high (300 microg/kg) doses were assigned in that order, and a very low dose (25 microg/kg) was inserted randomly and in double-blind fashion at any time after the first dose. Testing days were separated by at least 1 week. Each session was conducted over an 8-hour period in a controlled environment in an outpatient clinic; subjects were then transferred to a psychiatric inpatient unit for overnight observation. The Yale-Brown Obsessive Compulsive Scale (YBOCS) and a visual analog scale measuring overall obsessive-compulsive symptom severity were administered at 0, 4, 8, and 24 hours post-ingestion. The Hallucinogen Rating Scale was administered at 8 hours, and vital signs were recorded at 0, 1, 4, 8, and 24 hours after ingestion. The study was conducted from November 2001 to November 2004. Results: Nine subjects were administered a total of 29 psilocybin doses. One subject experienced transient hypertension without relation to anxiety or somatic symptoms, but no other significant adverse effects were observed. Marked decreases in OCD symptoms of variable degrees were observed in all subjects during 1 or more of the testing sessions (23%-100% decrease in YBOCS score). Repeated-measures analysis of variance for all YBOCS values revealed a significant main effect of time on Wilks lambda (F = 9.86, df = 3,3; p = .046), but no significant effect of dose (F = 2.25, df = 3,3; p = .261) or interaction of time and dose (F = 0.923, df = 9,45; p = .515). Improvement generally lasted past the 24-hour timepoint. Conclusions: In a controlled clinical environment, psilocybin was safely used in subjects with OCD and was associated with acute reductions in core OCD symptoms in several subjects.

The Journal of clinical psychiatry · clinical trial · 441 citationsread the source →

Adult health outcomes of childhood bullying victimization: evidence from a five-decade longitudinal British birth cohort.

Objective: The authors examined midlife outcomes of childhood bullying victimization. Method: Data were from the British National Child Development Study, a 50-year prospective cohort of births in 1 week in 1958. The authors conducted ordinal logistic and linear regressions on data from 7,771 participants whose parents reported bullying exposure at ages 7 and 11 years, and who participated in follow-up assessments between ages 23 and 50 years. Outcomes included suicidality and diagnoses of depression, anxiety disorders, and alcohol dependence at age 45; psychological distress and general health at ages 23 and 50; and cognitive functioning, socioeconomic status, social relationships, and well-being at age 50. Results: Participants who were bullied in childhood had increased levels of psychological distress at ages 23 and 50. Victims of frequent bullying had higher rates of depression (odds ratio=1.95, 95% CI=1.27-2.99), anxiety disorders (odds ratio=1.65, 95% CI=1.25-2.18), and suicidality (odds ratio=2.21, 95% CI=1.47-3.31) than their nonvictimized peers. The effects were similar to those of being placed in public or substitute care and an index of multiple childhood adversities, and the effects remained significant after controlling for known correlates of bullying victimization. Childhood bullying victimization was associated with a lack of social relationships, economic hardship, and poor perceived quality of life at age 50. Conclusions: Children who are bullied-and especially those who are frequently bullied-continue to be at risk for a wide range of poor social, health, and economic outcomes nearly four decades after exposure. Interventions need to reduce bullying exposure in childhood and minimize long-term effects on victims' well-being; such interventions should cast light on causal processes.

The American journal of psychiatry · 361 citationsread the source →

Improving newborn preventive services at the birth hospitalization: a collaborative, hospital-based quality-improvement project.

Objective: The goal was to test the effectiveness of a statewide, collaborative, hospital-based quality-improvement project targeting preventive services delivered to healthy newborns during the birth hospitalization. Methods: All Vermont hospitals with obstetric services participated. The quality-improvement collaborative (intervention) was based on the Breakthrough Series Collaborative model. Targeted preventive services included hepatitis B immunization; assessment of breastfeeding; assessment of risk of hyperbilirubinemia; performance of metabolic and hearing screens; assessment of and counseling on tobacco smoke exposure, infant sleep position, car safety seat fit, and exposure to domestic violence; and planning for outpatient follow-up care. The effect of the intervention was assessed at the end of an 18-month period. Preintervention and postintervention chart audits were conducted by using a random sample of 30 newborn medical charts per audit for each participating hospital. Results: Documented rates of assessment improved for breastfeeding adequacy (49% vs 81%), risk for hyperbilirubinemia (14% vs 23%), infant sleep position (13% vs 56%), and car safety seat fit (42% vs 71%). Documented rates of counseling improved for tobacco smoke exposure (23% vs 53%) and car safety seat fit (38% vs 75%). Performance of hearing screens also improved (74% vs 97%). No significant changes were noted in performance of hepatitis B immunization (45% vs 30%) or metabolic screens (98% vs 98%), assessment of tobacco smoke exposure (53% vs 67%), counseling on sleep position (46% vs 68%), assessment of exposure to domestic violence (27% vs 36%), or planning for outpatient follow-up care (80% vs 71%). All hospitals demonstrated preintervention versus postintervention improvement of > or = 20% in > or = 1 newborn preventive service. Conclusions: A statewide, hospital-based quality-improvement project targeting hospital staff members and community physicians was effective in improving documented newborn preventive services during the birth hospitalization.

Pediatrics · cohort or longitudinal · 30 citationsread the source →

Normal variation of magnetic resonance T1 relaxation times in the human population at 1.5 T using ShMOLLI.

Background: Quantitative T1-mapping is rapidly becoming a clinical tool in cardiovascular magnetic resonance (CMR) to objectively distinguish normal from diseased myocardium. The usefulness of any quantitative technique to identify disease lies in its ability to detect significant differences from an established range of normal values. We aimed to assess the variability of myocardial T1 relaxation times in the normal human population estimated with recently proposed Shortened Modified Look-Locker Inversion recovery (ShMOLLI) T1 mapping technique. Methods: A large cohort of healthy volunteers (n = 342, 50% females, age 11-69 years) from 3 clinical centres across two countries underwent CMR at 1.5T. Each examination provided a single average myocardial ShMOLLI T1 estimate using manually drawn myocardial contours on typically 3 short axis slices (average 3.4 ± 1.4), taking care not to include any blood pool in the myocardial contours. We established the normal reference range of myocardial and blood T1 values, and assessed the effect of potential confounding factors, including artefacts, partial volume, repeated measurements, age, gender, body size, hematocrit and heart rate. Results: Native myocardial ShMOLLI T1 was 962 ± 25 ms. We identify the partial volume as primary source of potential error in the analysis of respective T1 maps and use 1 pixel erosion to represent "midwall myocardial" T1, resulting in a 0.9% decrease to 953 ± 23 ms. Midwall myocardial ShMOLLI T1 was reproducible with an intra-individual, intra- and inter-scanner variability of ≤2%. The principle biological parameter influencing myocardial ShMOLLI T1 was the female gender, with female T1 longer by 24 ms up to the age of 45 years, after which there was no significant difference from males. After correction for age and gender dependencies, heart rate was the only other physiologic factor with a small effect on myocardial ShMOLLI T1 (6ms/10bpm). Left and right ventricular blood ShMOLLI T1 correlated strongly with each other and also with myocardial T1 with the slope of 0.1 that is justifiable by the resting partition of blood volume in myocardial tissue. Overall, the effect of all variables on myocardial ShMOLLI T1 was within 2% of relative changes from the average. Conclusion: Native T1-mapping using ShMOLLI generates reproducible and consistent results in normal individuals within 2% of relative changes from the average, well below the effects of most acute forms of myocardial disease. The main potential confounder is the partial volume effect arising from over-inclusion of neighbouring tissue at the manual stages of image analysis. In the study of cardiac conditions such as diffuse fibrosis or small focal changes, the use of "myocardial midwall" T1, age and gender matching, and compensation for heart rate differences may all help to improve the method sensitivity in detecting subtle changes. As the accuracy of current T1 measurement methods remains to be established, this study does not claim to report an accurate measure of T1, but that ShMOLLI is a stable and reproducible method for T1-mapping.

Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance · cohort or longitudinal · 208 citationsread the source →

Cost-effectiveness of adherence-enhancing interventions: a quality assessment of the evidence.

Objective: To determine whether the current cost-effectiveness evidence on adherence-enhancing interventions (AEIs) was of sufficient quality to aid in decision-making regarding medication adherence policies. Data sources: A computerized search of Embase, MEDLINE, Cinahl, Econlit, NHSEED, Psychlit, EPIC, and Cochrane databases (1980-April 2004) was performed. English-language human subject articles were identified using the key words compliance, adherence, concordance, patient assistance, therapeutic alliance, costs, economics, efficiency, resource use/utilization, cost-of-illness, cost-effectiveness, cost-minimization, cost-utility, and cost-benefit. Study selection and data extraction: Studies that appeared to assess the cost-effectiveness of medication AEIs were included. Methodologic rigor was assessed using 15 minimum quality criteria. Data synthesis: We found 45 comparative studies in 43 publications. Asthma (14 studies) and psychiatric illness (12 studies) were most commonly investigated. In 33 studies, interventions were educational, 18 had multiple components, and 23 did not appear to be linked to proven reasons for nonadherence. Reporting of adherence and outcome results was often unclear. Cost data were poorer quality than outcome data, using average or estimated costs and omitting some cost elements. Nine studies carried out incremental economic analysis. No study met all quality criteria. Conclusions: We were not able to make definitive conclusions about the cost-effectiveness of AEIs due to the heterogeneity of the studies found and incomplete reporting of results. Important policy decisions need to be made about nonadherence; however, they are currently being made in a vacuum of adequate information. AEIs must be based on reasons for nonadherence and be evaluated using accepted clinical and economic quality criteria.

The Annals of pharmacotherapy · review · 52 citationsread the source →

Heart rate variability

IN FOCUSHeart rate variabilityHarald M. StaussHarald M. StaussDepartment of Exercise Science, University of Iowa, Iowa City, Iowa 52242Published Online:01 Nov 2003https://doi.org/10.1152/ajpregu.00452.2003MoreSectionsPDF (59 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the rhythm of the heart has not only fascinated cardiologists but also inspired poets and musicians. Indeed, the periodic beat of the heart was used to define the speed of music. In music notation, the traditional Italian term "moderato" originally referred to one beat of the measure per walking pace (76-80 paces/min) or heartbeat (∼72 beats/min). The use of the heartbeat to define the speed of music may imply that the periodicity of the beat of the heart is very constant. However, this is not necessarily the case. In fact, loss of heart rate variability can indicate severe cardiovascular diseases and reliably predict poor outcome of such conditions (18, 22, 27, 47a). This In Focus article reviews sources of heart rate variability, its role as a prognostic marker for cardiovascular diseases, and its application in estimation of cardiac autonomic nervous system activity. All of these topics have been addressed intensely in articles published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology during the last two years. In healthy subjects, the sinoatrial node located at the posterior wall of the right atrium initiates each beat of the heart. Due to the unstable membrane potential of the myocytes located in this region, action potentials are generated periodically at a fairly constant frequency. This relatively constant frequency generated by the autorhythmicity of the sinoatrial node is modulated by many factors that add variability to the heart rate signal at different frequencies. According to the Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology (47a) these frequencies are classified into 1) ultra-low frequencies (ULF; >5-h cycle length) that include the circadian rhythm (6, 9, 34, 54); 2) very low frequencies (VLF; >25-s cycle length) that are supposed to be affected by temperature regulation (1, 7, 34, 52, 54) and humoral systems (9, 36); 3) low frequencies (LF; >6-s cycle length in humans) that are sensitive to changes in cardiac sympathetic (and presumably parasympathetic) nerve activity (27, 30); and 4) high frequencies (HF; 2.5- to 6.0-s cycle length in humans) that are synchronized to the respiratory rhythm (5) and are primarily modulated by cardiac parasympathetic innervation (38).The most prominent oscillation in the ULF band of the heart rate spectrum is the circadian rhythm. The autonomic nervous system contributes significantly to circadian heart rate variability. Using long-term recordings in conscious rabbits, Barrett et al. (6) demonstrated a strong circadian rhythm in heart rate, mean arterial blood pressure, renal blood flow, and renal sympathetic nerve activity. The importance of this study is that it clearly demonstrates that sympathetic nerve discharges exhibit a strong circadian rhythmicity. The paraventricular nucleus of the hypothalamus (PVN) appears to play a central role in mediating the circadian rhythm of autonomic nervous system activity. First, GABAergic and glutamatergic neurons project from the suprachiasmatic nuclei of the hypothalamus (SCN) to spinal-projecting neurons of the PVN (12). The SCN is the major central oscillator that triggers the day/night cycle. It receives photic input from the retina (47) and drives many neuroendocrine, metabolic, autonomic, and behavioral circadian rhythms (14, 16, 21, 31, 35, 44, 46, 50). In addition, microinjections of the inhibitory neurotransmitter GABA into the PVN of anesthetized rats elicit dose-dependent decreases in renal sympathetic nerve activity, whereas bicuculline (a GABA antagonist) increases renal sympathetic nerve activity (56). Second, from the PVN, neurons project to the nucleus of the solitary tract (that integrates inputs from the baroreceptors), the nucleus ambiguus (origin of preganglionic parasympathetic neurons to the heart), the rostroventrolateral medulla (location of sympathetic premotor neurons), and the intermediolateral cell column of the thoracolumbar spinal cord (location of preganglionic sympathetic neurons). Thus PVN neurons can modulate autonomic nervous system activity by sending inputs to major sites of autonomic nervous system regulation. As an example, a pivotal role of the PVN for sympathoexcitation during parturition was recently demonstrated in sheep. The increase in sympathetic nerve activity that accompanies birth in maternal animals was prevented by stereotactic lesioning of the PVN (43). Taken together, a major component of the circadian heart rate variability is elicited by diurnal fluctuations in autonomic nervous system activity, generated by corresponding fluctuations of neuronal activity within the PVN, which depend on circadian inputs originating from the SCN.It has been suggested that thermoregulation affects VLF heart rate variability (10, 26). Cooling the heart causes bradycardia, a mechanism used in heart surgeries. Conversely, fever is known to increase heart rate. Raising body core temperature from 36.0 to 36.6°C caused an increase in heart rate by almost 40 beats/min in male subjects (1), whereas acutely reducing ambient temperature from thermoneutral conditions (35°C) to 29, 23, and 17°C, reduced heart rate from 400 to 250 beats/min in 8-day-old rats (7). In addition, lowering temperature in the isolated working rat heart from 37 to 31°C reduced heart rate from 332 to 215 beats/min and markedly increased heart rate variability (28), indicating that parts of the temperature effects on heart rate and heart rate variability are independent from the autonomic nervous system. In contrast to the tachycardia that accompanies acute elevations in temperature, chronically raising ambient temperature in adult rodents from a standard housing temperature of 21-23°C to thermoneutral conditions (29-30°C) reduced heart rate by roughly 50 beats/min in rats (34) and by 200-300 beats/min in mice (54). The authors of these articles (34, 54) suggested that standard housing temperatures are associated with cold stress that causes parallel activation of brown adipose tissue, cardiac, and vasomotor sympathetic drives that elicits nonshivering thermogenesis and tonically elevates heart rate and arterial blood pressure. These and other studies indicate that both direct effects of temperature on pacemaker activity of the sinus node (28) and indirect effects mediated via the autonomic nervous system (11, 25, 51, 55) mediate temperature effects on heart rate and heart rate variability. Thus fluctuation in temperature is an important source of heart rate variability that should not be underestimated. In a more recent study, this was taken into account by core body temperature correction of heart rate variability (3).Endocrine factors affecting heart rate variability include thyroxine, reproductive hormones, the renin-angiotensin system, steroids, and others. Chronic subcutaneous infusion of angiotensin II in rats markedly increased blood pressure and heart rate variability, expressed as standard deviation (9). In contrast, chronic corticosterone treatment is likely to reduce baroreflex-mediated heart rate variability, because baroreceptor-heart rate (39) and baroreceptor-renal sympathetic nerve activity reflex sensitivity (41) were blunted in chronically corticosterone-treated rats. Furthermore, an interaction between angiotensin II and glucocorticoids was recently described. Intracerebro-ventricular microinjections of angiotensin II AT1 receptor antagonists caused marked decreases in mean blood pressure and heart rate in rats chronically treated with corticosterone but not in control animals (40). This interaction is likely to take place in the central nervous system, because peripheral angiotensin II AT1 receptor blockade did not alter the effects of betamethasone treatment on blood pressure, heart rate, and baroreceptor-heart rate reflex sensitivity in newborn lambs (42).Adenosine is a substance less known to affect heart rate variability. It is produced locally in the heart (53) and binds to A1-adenosinergic receptors, which are among the earliest expressed G protein-coupled receptors in the heart (36). The A1-adenosinergic agonist N6-cyclopentyladenosine dose dependently reduced heart rate in murine embryos, whereas 1,3-dipropyl-8-cyclopentylxanthine, an A1-adenosinergic antagonist, increased heart rate (36). Adenosine also exerts central nervous system effects in various brain areas (15, 20). Microinjections of adenosine into the nucleus of the solitary tract of awake rats caused dose-dependent changes in heart rate: low doses (0.01 nmol) produced a bradycardic response, whereas high doses (2.5-5.0 nmol) elicited a tachycardic response (15). Thus adenosine may indeed be involved in the regulation of heart rate and modulate heart rate variability via local cardiac and central nervous system effects. It has been proposed that the intrinsic cardiac nervous system plays an active role in regulating cardiac function (4, 37, 45, 57). This nervous system consists of sympathetic and parasympathetic neurons and interconnecting local circuits (37). Neurons in the canine right atrial ganglionated plexus (RAGP) spontaneously generate activity even after chronic cardiac autonomic denervation (45). Right atrial neurons in patients undergoing coronary artery bypass surgery generated spontaneous activity that was unrelated to the cardiac cycle but sensitive to changes in systemic arterial pressure, indicating that these neurons receive pressure-sensitive sensory inputs (4). In addition, it has been suggested that substance P acts as a neuromodulator and neurotransmitter in intracardiac ganglia of the guinea pig, modulates the response to vagal inputs, and triggers action potentials at the site of parasympathetic ganglia independent of acetylcholine (57). Furthermore, the right atrial (RAGP) and the posterior atrial ganglionated plexus (PAGP) appear to have different functions. Ablation of the PAGP reduced vagally mediated bradycardia by 26%, whereas RAGP ablation completely abolished this response. Inhibition of sympathetically mediated tachycardia by vagal stimulation was attenuated by ablation of either plexus (37). Thus parasympathetic efferent neurons are primarily located in the RAGP, whereas prejunctional parasympathetic-sympathetic interactions also involve neurons within the PAGP (37). The spontaneous activity of neurons in the intrinsic cardiac nervous system, even after cardiac denervation (45), suggests an active role of this system in regulating heart rate. However, the impact of the intrinsic cardiac nervous system on heart rate variability remains to be elucidated. The importance of the autonomic nervous system for heart rate variability in humans becomes apparent in patients following cardiac transplantation, in whom heart rate variability is markedly reduced (49). Although reinnervation is possible after months and years, initially transplanted hearts can be considered to be denervated. Thus the reduced heart rate variability in cardiac transplanted patients (49) underlines the importance of an intact autonomic innervation for spontaneously occurring heart rate variability. A major component of the chronotropic effect of the autonomic nervous system is linked to cAMP. Intracellular cAMP increases the inward current of Na+ (funny current, If), which determines the rate of the slow diastolic depolarization that precedes each action potential. The activity of adenylate cyclase and thus intracellular cAMP levels are increased by stimulation of sympathetic β1-adrenergic receptors and decreased (via a Gi protein) by stimulation of parasympathetic muscarinic receptors. Thus cardiac sympathetic innervation increases the rate of the slow diastolic depolarization and accelerates heart rate, while cardiac parasympathetic innervation elicits opposite effects. Interestingly, parasympathetic-mediated changes in heart rate occur much faster than sympathetic-mediated effects on heart rate (27, 30, 47a). As a result, cardiac sympathetic nervous system activity can only affect LF components of heart rate variability, whereas the parasympathetic nervous system can also modulate HF components. A hitherto unsolved question in this context is if the rapid heart rate response to parasympathetic stimulation compared with the slow effect of sympathetic inputs is due to 1) different kinetics of β1-adrenergic vs. muscarinic receptors, 2) different kinetics of adenylate cyclase vs. phosphodiesterase, the enzyme that cleaves cAMP, or 3) fast parasympathetic-mediated opening of KACh channels (via muscarinic receptors and a GK protein). Support for the latter possibility comes from experiments in the rabbit sinoatrial node that demonstrated that activation of KACh channels contributes to the initial slowing of heart rate as a result of vagal stimulation (8).On the basis of the different frequency response characteristics of sympathetic and parasympathetic modulation of heart rate, frequency analysis of heart rate variability is often used as a tool to determine "autonomic balance" or sympathetic and parasympathetic nervous system activity (27, 47a). As an example, the wavelet transform was recently used to determine cardiac autonomic responses to reperfusion in patients with thrombolysis after coronary thrombosis. Depending on the location of the infarct, marked alterations in LF or HF spectral power of heart rate or in the LF/HF ratio was observed in all successful reperfusions (48).The HF component corresponds to the frequency of respiration and is driven by the vagus as indicated by the strong respiratory pattern of cardiac vagal motoneurons in the nucleus ambiguus (38). The LF component has been ascribed to sympathetic modulation of cardiac pacemaker activity, because a variety of studies demonstrated that acute interventions that increase sympathetic nervous system activity, such as orthostatic perturbations (17, 19, 33), mental stress (32), or handgrip exercise (13, 24) increases LF spectral power of heart rate (27, 30). In addition to acute perturbations of cardiac sympathetic nerve activity, feedback oscillations generated by the baroreceptor reflex also appear to contribute to LF spectral power of heart rate as it was demonstrated that sinoaortic denervation markedly reduces the LF component (27, 30). Despite the strong modulation of heart rate by the autonomic nervous system, the LF and HF spectral components of heart rate variability may not always be very reliable markers for cardiac sympathetic and parasympathetic "tone" (30). In a recent study, muscle sympathetic nerve activity was recorded together with heart rate variability during application of lower body negative pressure that is known to increase muscle sympathetic nerve activity (17, 33). At higher levels of lower body negative pressure (-15 mmHg), both muscle sympathetic nerve activity and relative LF spectral power of heart rate increased significantly, whereas HF spectral power decreased (17). These findings suggest that LF spectral power reflects cardiac sympathetic "tone." However, no correlation within subjects was found between changes in LF/HF ratio and muscle sympathetic nerve activity (17). Thus heart rate variability does not reliably reflect the sympathetic response to orthostatic stress. Respiration-related fluctuation of heart rate (respiratory sinus arrhythmia) is probably the most often investigated component of heart rate variability, as it is believed that this component reflects respiration-driven vagal modulation of sinus arrhythmia (27). In a recent study, Rentero et al. (38) recorded the electrical activity from cardiac vagal motoneurons in the nucleus ambiguus. Firing of these neurons was modulated by the central respiratory cycle. This and other studies support the view that respiratory sinus arrhythmia is generated by central coupling of the respiratory oscillator with autonomic centers in the brain stem. However, a mechanical cardiopulmonary coupling as a source of respiration-related heart rate variability has also been suggested (5). The Bainbridge reflex causes a tachycardia in response to hypervolemia. This reflex is initiated by atrial mechanoreceptors and uses efferent sympathetic and parasympathetic pathways to modulate heart rate in response to changes in central venous pressure (23). Thus respiratory changes in central blood volume cause corresponding respiratory fluctuations in cardiac autonomic nervous system activity via the Bainbridge reflex. Only the parasympathetic component of the efferent pathway of the reflex can contribute to respiratory sinus arrhythmia, because sympathetic actions on heart rate are too damped to follow the respiratory frequency. The gain and phase of the transfer function between respiratory changes in lung volume and R-R intervals of the ECG were calculated in human subjects during graded changes in central blood volume (5). At the respiratory frequency, the phase was -180 degree, indicating that an inspiratory increase in central blood volume was associated with a decrease in R-R interval (increase in heart rate). Furthermore, the gain of the transfer function at the respiratory frequency steadily increased with increasing central volumes (except at the highest volume). Both of these findings confirm the presence of the Bainbridge reflex in humans (5). Thus, in addition to the central coupling of respiratory oscillators with cardiovascular centers, the Bainbridge reflex may contribute to respiration-related heart rate variability by mechanical cardiopulmonary coupling. There is general agreement that low heart rate variability is an unfavorable prognostic marker for cardiovascular diseases, such as diabetic autonomic neuropathy, hypertension, myocardial infarction, and heart failure (18, 22, 27, 29, 47a). Heart rate variability (variance of R-R intervals) was reduced in patients with mild hypertension (29) compared with normal values (1,134 ± 202 vs. 3,466 ± 1,018 ms2) provided by the Task Force (47a). In the rat model of myocardial infarction-induced congestive heart failure, Francis and colleagues (18) reported loss of spontaneous heart rate variability 6 wk after coronary artery ligation. Interestingly, reduced heart rate variability was also observed in a rat model of depression that is based on chronic (4 wk) mild stress application (22). Because depression is an independent risk factor for coronary artery disease, this finding may realistically model a human disease process. The reduction in heart rate variability was abolished by β-adrenergic receptor blockade, indicating that the reduced heart rate variability in this model of depression is related to elevated cardiac sympathetic tone (22).In summary, heart rate variability is generated by multiple factors not exclusively limited to the autonomic nervous system. Specific frequency components of heart rate variability mirror acute perturbations of the autonomic nervous system but do not always reflect autonomic nervous system activity. Simple statistics of heart rate variability, such as the standard deviation of R-R intervals in the ECG, can reliably predict the prognosis of cardiovascular diseases.I thank Dr. R. McAllen for critically reviewing the manuscript. References 1 Aoki K, Stephens DP, and Johnson JM. Diurnal variation in cutaneous vasodilator and vasoconstrictor systems during heat stress. Am J Physiol Regul Integr Comp Physiol 281: R591-R595, 2001.Link | ISI | Google Scholar3 Aoyagi N, Ohashi K, and Yamamoto Y. Frequency characteristics of long-term heart rate variability during constant-routine protocol. Am J Physiol Regul Integr Comp Physiol 285: R171-R176, 2003.Link | ISI | Google Scholar4 Arora RC, Hirsch GM, Johnson Hirsch K, Hancock Friesen C, and Armour JA. Function of human intrinsic cardiac neurons in situ. Am J Physiol Regul Integr Comp Physiol 280: R1736-R1740, 2001.Link | ISI | Google Scholar5 Barbieri R, Triedman JK, and Saul JP. Heart rate control and mechanical cardiopulmonary coupling to assess central volume: a systems analysis. Am J Physiol Regul Integr Comp Physiol 283: R1210-R1220, 2002.Link | ISI | Google Scholar6 Barrett CJ, Navakatikyan MA, and Malpas SC. Long-term control of renal blood flow: what is the role of the renal nerves? Am J Physiol Regul Integr Comp Physiol 280: R1534-R1545, 2001.Link | ISI | Google Scholar7 Blumberg MS, Knoot TG, and Kirby RF. Neural and hormonal control of arterial pressure during cold exposure in un-anesthetized week-old rats. Am J Physiol Regul Integr Comp Physiol 281: R1514-R1521, 2001.Link | ISI | Google Scholar8 Boyett MR, Kodama I, Honjo H, Arai A, Suzuki R, and Toyama J. Ionic basis of the chronotropic effect of acetylcholine on the rabbit sinoatrial node. Cardiovasc Res 29: 867-878, 1995.Crossref | PubMed | ISI | Google Scholar9 Braga and of on fluctuations and changes in blood pressure. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and elicited of heart rate variability. J Physiol | ISI | Google and modulation of sympathetic nerve activity to muscle in Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and and GABA mediate suprachiasmatic nucleus inputs to spinal-projecting paraventricular Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and is not associated with of the exercise reflex in Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google C, and Y. The effect of on the circadian control of human core body temperature is Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and of adenosine receptors in the does not affect the in awake rats. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google JK, A, and circadian and during two Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and sympathetic nerve and heart rate spectral effects of lower body negative pressure. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google Francis Johnson and of heart failure after myocardial in the Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google A, and of lower body pressure on muscle sympathetic nerve activity response to Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and Adenosine initial depression of in the rat in Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google R, and and circadian phase in a diurnal the Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and Johnson alterations and autonomic in an model of Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google MA, and The interaction of the Bainbridge and in the conscious Res | ISI | Google A, and handgrip exercise arterial control of sympathetic in Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and nerve regulation to is in rats. Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and in heart rate variability. J Physiol | ISI | Google and function and cardiovascular interactions and Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and interval variability in isolated working rat hearts at various conditions and Res | PubMed | Google A, A, and and autonomic of in patients with mild Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google Malpas SC. Neural on cardiovascular and Am J Physiol Heart Physiol 2002.Link | ISI | Google and thermoregulation in and rats in a Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and effects on reflex responses to mental stress in Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and reflex during orthostatic in Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and and responses to and are in rats. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and and in a by cycle. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and of humoral heart rate regulation in the Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google Armour and within the intrinsic cardiac nervous system contribute to chronotropic regulation. Am J Physiol Regul Integr Comp Physiol 285: 2003.Link | ISI | Google Rentero N, A, and McAllen of cardiac vagal motoneurons in rat nucleus ambiguus. Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and modulate control of heart rate in conscious rats. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and central actions of angiotensin to increase arterial pressure. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and modulate control of renal sympathetic nerve activity. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and modulation of cardiovascular and autonomic function in role of Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and Inhibition of sympathetic responses at birth in by of the paraventricular Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and JP. pattern of during acute and chronic in conscious adult rats. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google Armour and of chronic cardiac on of canine intracardiac neurons in Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and levels and circadian rhythm of activity in the a model of Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and nerve response of suprachiasmatic nucleus and Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google

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

Inflammation and Schizophrenia

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

Schizophrenia Bulletin · review · 315 citationsread the source →

The link between infertility-related distress and psychological distress in couples awaiting fertility treatment: a dyadic approach.

While there is broad evidence to suggest that individual stress increases, and that high couple relationship quality reduces the risk for psychological distress, our understanding of these associations in couples dealing with infertility remains limited. In this cross-sectional study, we used dyadic data-analysis (Actor-Partner Interdependence Model; APIM) to examine the effects of infertility-related distress (experienced as an individual risk factor) and couple relationship quality (experienced as a couple-based resource), on psychological distress in a sample of 116 infertile couples. 59% of women and 23% of men reported clinical levels of psychological distress, 71% of women and 45% of men reported infertility-related distress, and 3% of participants reported low couple relationship quality. Infertility-related distress predicted psychological distress at the individual level ('actor effects') while men's infertility-related distress predicted women's psychological distress (partner effect'). Women without medically assisted reproduction (MAR) treatment exposure reported significantly higher couple relationship quality than women with MAR exposure, and men without treatment exposure reported significantly lower infertility-related distress than men with exposure. The level of psychological distress depended on whether both or neither of the partners, or only one partner reported infertility-related distress. Couple relationship quality was not associated with distress, which may imply that dyadic dimensions other than overall satisfaction could be relevant in supporting couples facing infertility.

Human fertility (Cambridge, England) · 12 citationsread the source →

The associations of socioeconomic status, social activities, and loneliness with depressive symptoms in adults aged 50 years and older across 24 countries: findings from five prospective cohort studies.

Background: Depression is the leading cause of mortality among mental health disorders. Evidence about the associations of socioeconomic status, social activities, and loneliness with depression is scarce. We aimed to identify whether social activities and loneliness mediate the association between socioeconomic status and depression, and the extent of interactive or joint relationships between social activities, loneliness, and socioeconomic status on depression. Methods: In this population-based, cross-national cohort study we used data from five nationally representative surveys across 24 countries between Feb 15, 2008, and Feb 27, 2019: the Health and Retirement Study (HRS); the English Longitudinal Study of Ageing (ELSA); the Survey of Health, Ageing and Retirement in Europe (SHARE); the China Health and Retirement Longitudinal Study (CHARLS); and the Mexican Health and Ageing Study (MHAS). We included participants who were aged 50 years and older with reported information on socioeconomic status, social activities, and loneliness at baseline, and who had been assessed at least twice. We excluded participants with depressive symptoms at baseline; those with missing data on depressive symptoms and covariates; and those lost to follow-up. We defined socioeconomic status as high and low using latent class analysis based on family income, education, and employment status. Depression was assessed using the Center for Epidemiological Studies Depression Scale (CES-D) or EURO-D. We applied Cox proportional hazard models to estimate the association of socioeconomic status with depression. We used random-effects models to obtain pooled results. Joint and interactive effects of socioeconomic status, social activities, and loneliness on depression were explored, and the mediating roles of social activities and loneliness in the association between socioeconomic status and depression were explored using causal mediation analysis. Findings: A total of 69 160 participants were included in our study and, during a median follow-up of 5 years, a total of 20 237 participants developed depression with a pooled incidence of 7·2 (95% CI 4·4-10·0) per 100 person-years. Compared with participants with high socioeconomic status, those with low socioeconomic status had a higher risk of depression (pooled hazard ratio [HR] 1·34; 95% CI 1·23-1·44). The proportion of the associations between socioeconomic status and depression mediated by social activities and loneliness were 6·12% (1·14-28·45) and 5·54% (0·71-27·62), respectively. We only observed a significant multiplicative interaction of socioeconomic status and loneliness with depression (pooled HR 0·84; 0·79-0·90). Compared with participants with high socioeconomic status and who were socially active and not lonely, those with low socioeconomic status and who were socially inactive and lonely had a higher risk of depression (pooled HR 2·45; 2·08-2·82). Interpretation: Social inactivity and loneliness positively mediated a small proportion of the association between socioeconomic status and depression, indicating that other approaches in addition to interventions targeting social isolation and loneliness are required to mitigate the risk of depression in older adults. Additionally, the joint effects of socioeconomic status, social activities, and loneliness highlight the benefits of simultaneous and integrated interventions to reduce the global burden of depression. Funding: National Natural Science Foundation of China.

The lancet. Healthy longevity · 98 citationsread the source →

Ethnoracial and social trends in breast cancer staging at diagnosis in Brazil, 2001-14: a case only analysis.

Background: Policies for early detection of breast cancer, including clinical breast examinations and mammographic screening, were introduced in Brazil in 2004, but their effect on disease stage at diagnosis is unclear. We aimed to assess whether these policies have led to a decrease in the prevalence of late-stage breast cancer at diagnosis. Methods: In this case only analysis, using an anonymised nationwide hospital based-cancer registry network, we identified women aged 18-89 years who had been diagnosed with an invasive breast cancer in Brazil during 2001-14. We extracted individual patient-level data on patient demographics, tumour variables, and health-care provider variables for the centre where the patient was diagnosed. Our objectives were to estimate the prevalence of late-stage breast cancer (TNM stage III or IV) at diagnosis overall, across age groups, and by ethnoracial and social strata (ie, self-reported ethnoracial group, as white, black, brown, Asian, or Indigenous, and educational level, marital status, and region of residence) across the study period, and compare these estimates with international data from high-income countries (Norway and the USA). We used logistic regression to estimate odds ratios (ORs) for late-stage versus early-stage (TNM stage I or II) breast cancer at diagnosis in relation to relevant exposures, either minimally adjusted (for age, year of diagnosis, and region of residence) or fully adjusted (for all patient, tumour, and health-care provider variables). Findings: We identified 247 719 women who were diagnosed with invasive breast cancer between Jan 1, 2001, and Dec 31, 2014, with a mean age at diagnosis of 55·4 years (SD 13·3), of whom 36·2% (n=89 550) identified as white, 29·8% (n=73 826) as black or brown, and 0·7% (n=1639) as Asian or Indigenous. Prevalence of late-stage breast cancer at diagnosis remained high throughout 2001-14, at approximately 40%, was inversely associated with educational level (p value for linear trend <0·0001), and was higher for women who identified as black (minimally adjusted OR 1·61, 95% CI 1·53-1·70; fully adjusted OR 1·45, 95% CI 1·38-1·54) and brown (minimally adjusted OR 1·26, 95% CI 1·22-1·30; fully adjusted OR 1·18, 1·14-1·23) than those who identified as white. The predicted prevalence of late-stage cancer at diagnosis was highest for women who were black or brown with little or no formal education (48·8%, 95% CI 48·2-49·5) and lowest for women who were white with university education (29·4%, 28·2-30·6), but both these prevalences were higher than that of all women diagnosed with breast cancer in Norway before the introduction of mammography screening (ie, 16·3%, 95% CI 15·4%-17·2% in 1970-74). Similar ethnoracial and social patterns emerged in analyses restricted to the age group targeted by screening (50-69 years). Interpretation: The persistently high prevalence of late-stage breast cancer at diagnosis across all ethnoracial and social strata in Brazil, although more substantially among the most disadvantaged populations, implies that early detection policies might have had little effect on breast cancer mortality so far, and highlights the need to focus primarily on timely diagnosis of symptomatic breast cancer rather than on screening for asymptomatic disease. Funding: Newton Fund, Research Councils UK, and Conselho Nacional das Fundações Estaduais de Amparo à Pesquisa.

The Lancet. Global health · 56 citationsread the source →

Modeling Multisystem Physiological Dysregulation.

Objectives: The purposes of this study were to compare the relative fit of two alternative factor models of allostatic load (AL) and physiological systems, and to test factor invariance across age and sex. Methods: Data were from the Midlife in the United States II Biomarker Project, a large (n = 1255) multisite study of adults aged 34 to 84 years (56.8% women). Specifically, 23 biomarkers were included, representing seven physiological systems: metabolic lipids, metabolic glucose, blood pressure, parasympathetic nervous system, sympathetic nervous system, hypothalamic-pituitary-adrenal axis, and inflammation. For factor invariance tests, age was categorized into three groups (≤45, 45-60, and >60 years). Results: A bifactor model where biomarkers simultaneously load onto a common AL factor and seven unique system-specific factors provided the best fit to the biomarker data (comparative fit index = 0.967, root mean square error of approximation = 0.043, standardized root mean square residual = 0.028). Results from the bifactor model were consistent with invariance across age groups and sex. Conclusions: These results support the theory that represents and operationalizes AL as multisystem physiological dysregulation and operationalizing AL as the shared variance across biomarkers. Results also demonstrate that in addition to the variance in biomarkers accounted for by AL, individual physiological systems account for unique variance in system-specific biomarkers. A bifactor model allows researchers greater precision to examine both AL and the unique effects of specific systems.

Psychosomatic medicine · 89 citationsread the source →

Feasibility and pilot study of a brief self-compassion intervention addressing body image distress in breast cancer survivors.

Background: The majority of breast cancer survivors (BCSs) experience body image concerns following treatment. Body Image distress (BID) is associated with psychological distress and diminished quality of life. A web-based self-compassion focused writing activity (My Changed Body - MyCB) reduces BID in BCSs, yet limited research exists on participant characteristics associated with such intervention adherence. Self-compassion-based meditations are also efficacious in reducing BID in non-BCS populations. This parallel, double-blind pilot randomised controlled trial aimed to assess the feasibility and acceptability of MyCB, with and without an additional meditation component, on BID and related psychological outcomes in BCSs. The trial was registered with the Australian and New Zealand Clinical Trials Registry (#ACTRN12619001693112). Methods: BCSs were randomly allocated to MyCB (n = 39), MyCB + Meditation (MyCB + M) (n = 17) or an expressive writing (EW) active control arm (n = 23). The primary outcome was BID. Secondary outcomes were body appreciation, affect (positive and negative), psychological distress (depression, anxiety and stress) and self-compassion (state and trait). Assessments were completed online at baseline, post-intervention and 1-month. Results: Adherence to the MyCB writing (45%) and meditation (50%) was modest, and acceptability was high for both MyCB and MyCB + M. Intent to treat linear mixed model analyses indicated: Post-intervention - state self-compassion and positive affect increased for MyCB compared to EW; 1-month: BID scores decreased across all conditions; trait self-compassion increased and anxiety decreased for MyCB + M compared to MyCB and EW. Conclusion: These findings provide preliminary evidence for the efficacy and potential clinical use of the MyCB brief web-based self-compassion intervention alone and with the addition of meditation, to increase self-compassion and psychological wellbeing in BCSs.

Health psychology and behavioral medicine · 30 citationsread the source →

Infusing Technology Into Perinatal Home Visitation in the United States for Women Experiencing Intimate Partner Violence: Exploring the Interpretive Flexibility of an mHealth Intervention.

Background: Intimate partner violence (IPV) is common during pregnancy and the postpartum. Perinatal home visitation provides favorable conditions in which to identify and support women affected by IPV. However, the use of mHealth for delivering IPV interventions in perinatal home visiting has not been explored. Objective: Our objective was to conduct a nested qualitative interpretive study to explore perinatal home visitors' and women's perceptions and experiences of the Domestic Violence Enhanced Home Visitation Program (DOVE) using mHealth technology (ie, a computer tablet) or a home visitor-administered, paper-based method. Methods: We used purposive sampling, using maximum variation, to select women enrolled in a US-based randomized controlled trial of the DOVE intervention for semistructured interviews. Selection criteria were discussed with the trial research team and 32 women were invited to participate. We invited 45 home visitors at the 8 study sites to participate in an interview, along with the 2 DOVE program designers. Nonparticipant observations of home visits with trial participants who chose not to participate in semistructured interviews were undertaken. Results: We conducted 51 interviews with 26 women, 23 home visiting staff at rural and urban sites, and the 2 DOVE program designers. We conducted 4 nonparticipant observations. Among 18 IPV-positive women, 7 used the computer tablet and 11 used the home visitor method. Among 8 IPV-negative women, 7 used the home visitor method. The computer tablet was viewed as a safe and confidential way for abused women to disclose their experiences without fear of being judged. The meanings that the DOVE technology held for home visitors and women led to its construction as either an impersonal artifact that was an impediment to discussion of IPV or a conduit through which interpersonal connection could be deepened, thereby facilitating discussion about IPV. Women's and home visitors' comfort with either method of screening was positively influenced by factors such as having established trust and rapport, as well as good interpersonal communication. The technology helped reduce the anticipated stigma associated with disclosing abuse. The didactic intervention video was a limiting feature, as the content could not be tailored to accommodate the fluidity of women's circumstances. Conclusions: Users and developers of technology-based IPV interventions need to consider the context in which they are being embedded and the importance of the patient-provider relationship in promoting behavior change in order to realize the full benefits. An mHealth approach can and should be used as a tool for initiating discussion about IPV, assisting women in enhancing their safety and exploring help-seeking options. However, training for home visitors is required to ensure that a computer tablet is used to complement and enhance the therapeutic relationship. Clinicaltrial: Clinicaltrials.gov NCT01688427; https://clinicaltrials.gov/ct2/show/NCT01688427 (Archived by WebCite at http://www.webcitation.org/6limSWdZP).

Journal of medical Internet research · 39 citationsread the source →

Increased Cardiac Sympathetic Activity and Oxidative Stress in Habitual Electronic Cigarette Users: Implications for Cardiovascular Risk.

Importance: Electronic cigarettes (e-cigarettes) have gained unprecedented popularity, but virtually nothing is known about their cardiovascular risks. Objective: To test the hypothesis that an imbalance of cardiac autonomic tone and increased systemic oxidative stress and inflammation are detectable in otherwise healthy humans who habitually use e-cigarettes. Design, setting, and participants: Cross-sectional case-control study of habitual e-cigarette users and nonuser control individuals from 2015 to 2016 at the University of California, Los Angeles. Otherwise healthy habitual e-cigarette users between the ages of 21 and 45 years meeting study criteria, including no current tobacco cigarette smoking and no known health problems or prescription medications, were eligible for enrollment. Healthy volunteers meeting these inclusion criteria who were not e-cigarette users were eligible to be enrolled as control individuals. A total of 42 participants meeting these criteria were enrolled in the study including 23 self-identified habitual e-cigarette users and 19 self-identified non-tobacco cigarette, non-e-cigarette user control participants. Main outcomes and measures: Heart rate variability components were analyzed for the high-frequency component (0.15-0.4 Hz), an indicator of vagal activity, the low-frequency component (0.04-0.15 Hz), a mixture of both vagal and sympathetic activity, and the ratio of the low frequency to high frequency, reflecting the cardiac sympathovagal balance. Three parameters of oxidative stress were measured in plasma: (1) low-density lipoprotein oxidizability, (2) high-density lipoprotein antioxidant/anti-inflammatory capacity, and (3) paraoxonase-1 activity. Results: Of the 42 participants, 35% were women, 35% were white, and the mean age was 27.6 years. The high-frequency component was significantly decreased in the e-cigarette users compared with nonuser control participants (mean [SEM], 46.5 [3.7] nu vs 57.8 [3.6] nu; P = .04). The low-frequency component (mean [SEM], 52.7 [4.0] nu vs 39.9 [3.8] nu; P = .03) and the low frequency to high frequency ratio (mean [SEM], 1.37 [0.19] vs 0.85 [0.18]; P = .05) were significantly increased in the e-cigarette users compared with nonuser control participants, consistent with sympathetic predominance. Low-density lipoprotein oxidizability, indicative of the susceptibility of apolipoprotein B-containing lipoproteins to oxidation, was significantly increased in e-cigarette users compared with nonuser control individuals (mean [SEM], 3801.0 [415.7] U vs 2413.3 [325.0] U; P = .01) consistent with increased oxidative stress, but differences in high-density antioxidant/anti-inflammatory capacity and paraoxonase-1 activity were not significant. Conclusions and relevance: In this study, habitual e-cigarette use was associated with a shift in cardiac autonomic balance toward sympathetic predominance and increased oxidative stress, both associated with increased cardiovascular risk.

JAMA cardiology · 206 citationsread the source →

Comparison of 45-min nap versus no-nap during simulated night shift work on endothelial function: a randomized crossover feasibility trial.

Background: Night shift workers face increased risk of cardiovascular disease (CVD) compared to non-shift workers. Evidence supports on-shift napping and regular non-invasive monitoring of endothelial function for risk mitigation, yet neither strategy is widely used. Methods: We evaluated the feasibility of non-invasive assessment of peripheral arterial tone (PAT) to assess the effect of napping during simulated night shift work on endothelial function. We used a single-site, randomized crossover trial of simulated night shift work with a 45-min nap condition versus a control, no-nap condition (ClinicalTrials.gov NCT05436951). Results: The primary outcome was the number of participants with ≥ 70% of endothelial function assessments. Secondary outcomes included mean reactive hyperemia index (RHI), BP, and cognitive performance with the brief psychomotor vigilance task (PVT-B). Of the 10 consented, 9 completed both conditions. All participants exceeded feasibility benchmarks. Mean RHI did not differ by nap condition, and the delta from pre- to post measure did not differ (difference in delta =  - 0.26, 95% CI - 1.09, 0.58). Hourly PVT-B assessments from 19:00 to 07:00 h did not differ by nap condition. Compared to pre-nap measures, cognitive performance on the PVT-B was poorest at + 0 min post-nap. Conclusion: Our findings can inform larger studies evaluating the effects of night shift work and napping on endothelial function. Trial registrations: ClinicalTrials.gov (NCT05436951, registered on June 23, 2022).

Pilot and feasibility studies · 1 citationsread the source →

Charting the Future of Cancer Health Disparities Research: A Position Statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute

The academic field of cancer health disparities was stimulated by the U.S. civil rights movement. Concerns about civil rights led to concerns about equality in health care. The first publications to make the observation that black Americans have higher rates of death as a result of certain cancers compared with white Americans were published by the early 1970s (1, 2). The discipline concerned with these differences was first called “minority health research” and later “special populations health” or “special populations research.” The National Cancer Institute (NCI) defines cancer health disparities as adverse differences in cancer incidence, cancer prevalence, cancer mortality, cancer survivorship, and burden of cancer or related health conditions that exist among specific population groups in the United States (3). However, with greater and renewed acknowledgment of health disparities as rooted within the context of historical and contextual inequities in the United States, many health disparities are considered health inequities (4).The National Cancer Act of 1971 created the Surveillance, Epidemiology, and End Results (SEER) program within the NCI. This program began collecting incidence, mortality, and survival data by race in the early 1970s from a number of population-based registries around the United States. The SEER program improved documentation of differences in outcomes and analyzed them through its black–white studies (5). These studies especially demonstrated differences in treatment patterns, with a higher proportion of blacks receiving inappropriate cancer care compared with whites. The discipline grew from a focus on black–white differences to encompass differences in outcomes for a number of racial and ethnic groups, as well as for cohorts defined by age, sex, socioeconomic status (SES), and other social determinants of health. There is now even greater appreciation for disparities among communities, whether rural versus urban or even by state or region. The definition of health outcomes also broadened beyond death rates. The field of health disparities was once simply a description of population differences and a call for cultural competence among health care providers. Today, the field is transdisciplinary, integrating basic science, clinical science, policy, epidemiology, and the social sciences. It involves people trained in diverse nonmedical fields, such as education, economics, sociology, religion, geography, and anthropology. The field is also dynamic. It changes as better and more granular statistics, greater understanding of causes of health disparities, and new challenges to mitigate these underlying causes have emerged. As an example, in the 1970s, the breast cancer death rate for black and white American women was the same. Today, the death rate is substantially higher for blacks compared with whites (6). Policy changes have also created opportunities and challenges. The Affordable Care Act has allowed for Medicaid expansion in each state. Expansion has been adopted by 32 states and the District of Columbia. This will create a new challenge, because poor residents of some states have expanded access to care and residents of other states do not. It is essential that any future policy changes should be carefully designed to increase, rather than decrease, equitable access to care throughout the cancer continuum. Population categorizations also are being redefined. The Asian category includes Korean Americans and Pakistani Americans. The Pacific Islander category, often merged with the Asian category, includes native Hawaiians and Samoans. These populations are incredibly heterogeneous and have dramatically different cancer statistics. In 2015, representatives from four leading cancer organizations, the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology (ASCO), and the NCI, began to meet to discuss the state of health disparities in the United States. These discussions involved the state of cancer health disparities research and what could be done to move it forward. The discussions were purposely not meant as a comprehensive review of cancer health disparities research. Rather, the meeting and the resulting document aimed to identify issues in health disparities research and make specific recommendations to improve the way disparities research is conducted and disseminated. This statement presents a unified strategy among four of the leading cancer organizations in the United States to promote cooperation among investigators in all areas of the cancer health disparities research community, to ensure that cancer research benefits all populations and patients regardless of race, ethnicity, age, gender identity, sexual orientation, SES, or the communities in which they live. Disparities in outcomes across the cancer continuum have been identified in numerous medically underserved populations, including racial and ethnic minorities and patients of lower SES. In addition to individual social status, social contextual and community factors, such as neighborhood safety, social cohesion, availability of healthy foods, and residential segregation, play an important role in health of both individuals and populations. All of these factors can intersect to generate larger disparities (7, 8).To understand and fully address cancer health disparities, complete, consistent, and accurate collection of patient, community, and structural factors that put people at risk for disparate outcomes is essential. Unfortunately, cancer health disparities research has often been fraught with missing, inaccurate, or overly simplified patient-level data, and most research has failed to consider the community-level factors described above (9–11).For the most part, the manner in which data are collected and integrated in disparities research is suboptimal. The literature is characterized by variable methodology for collection of the factors that put patients and communities at risk for disparate care and outcomes. For example, although race and ethnicity are distinct constructs, they are often conflated such that a person is identified as Hispanic without identification of his or her race. Many studies that investigate cancer care or outcomes according to socioeconomic position have only area-level data on socioeconomic position, whereas others use only composite measures. While valuable in many cases in identifying disparities, such measures fall short in providing the richness of data needed to understand an individual's socioeconomic position. Health literacy and numeracy are rarely assessed in practice and are not available in administrative and research databases. Finally, methods for uniform data collection of information on sexual orientation and gender identity are in their infancy, despite calls for such data collection from the Institute of Medicine, among others (12).Disparities in cancer incidence are pronounced and longstanding. Drivers of these disparities are multifactorial and multilevel, and they include sociodemographic factors, access to health care, risk factor profiles and lifestyle/health habits, cultural perceptions, biologic differences, and genetic predisposition. Disparities in cancers for which single etiologic factors account for a substantial proportion of disease (e.g., human papillomavirus and cervical cancer, or Helicobacter pylori and stomach cancer) can be reasonably understood and explained, but disparities for many of the common etiologically heterogeneous cancers, such as breast, prostate, and colorectal cancers, remain much less well understood. Multilevel approaches are needed to advance knowledge relevant to addressing disparities in cancer incidence rates. One approach is to design and implement observational studies focused on a population in which disparities exist to advance knowledge about etiology and to inform novel prevention strategies. A successful example of such an effort is the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a multicenter consortium that has combined data and biospecimens from 7,500 African American patients with breast cancer and 17,000 healthy controls, representing the largest study of breast cancer in African American women in the United States (14). It has yielded a number of insights on multilevel risk factors specific to the major molecular subtypes of breast cancer among African American women (15–17).There is also a need for studies focused on identifying the genetic contributors to cancer health disparities. Recent work has focused on the prioritization of candidate variants relevant to prostate cancer risk within the context of genetic ancestry (based on ancestry informative markers) across those with European, African, Japanese, or Latino ancestry (18). Furthermore, the African Ancestry Prostate Cancer Genome-Wide Association Studies (GWAS) Consortium has reported on susceptibility loci for aggressive prostate cancer specific to men of African ancestry (19).Although some cancer risk factors are well established, the biologic mechanisms through which their impact on cancer risk varies across different populations remain incompletely understood. For example, variations in diet are hypothesized to be the primary driver of the dramatic variations in colorectal cancer incidence rates observed across populations. Recent research has evaluated the impact that different diets have on microbiota composition and function, which in turn affects the production of metabolites that either promote mucosal health or are proinflammatory/neoplastic in the gut. A study that compared Americans with African ancestry (who have a relatively high incidence of colorectal cancer) with rural South Africans (who have a comparatively very low colorectal cancer incidence rate) demonstrated that a typical U.S. diet with high meat and fat intake increases mucosal proliferation rates (a marker of cancer risk) when fed to both populations, whereas typical high-fiber South African diets were associated with low proliferation rates when fed to both groups. This demonstrates that diet can have a profound and fairly immediate impact on the gut microbiome that can either promote or suppress tumors (20).Cancer outcome disparities are well documented for racial and ethnic minorities, and presentation at more advanced stages of cancer explains much of this difference. However, even when controlling for the stage of cancer at diagnosis, the survival disparities persist. What is most concerning is that rather than improving over time, for cancers such as colon cancer, the stage-specific disparities are actually worsening (21). The reason for this growing disparity is not completely clear but involves socioeconomic issues such as education status and the level of insurance and access to medical care. Even in studies that normalize socioeconomic issues (with the limitations cited in the Defining Measures section), disparities that disproportionally affect U.S. minority populations can still be demonstrated for several cancers and may highlight the not-so-well-understood interplay between genetic predisposition and environmental exposure, such as lifestyle and diet, that modifies cancer risk (22, 23). Ultimately, growing postdiagnosis survival disparities are caused by the interplay of system, social, biologic, and environmental factors. Documenting and addressing each of these and their interactions are key to eliminating these disparities. The role of system-level and social determinants in explaining cancer health disparities is best demonstrated by recognizing that disparities vary widely across the United States; some states show almost no disparities, whereas others show striking ones (24). We also know that disparities in treatment of cancer differ and that when treatment differences are accounted for, either through the use of standardized therapies on a clinical trial or through multivariable modeling, cancer-specific survival disparities often disappear. We also have clear examples of successful system-level reform (21, 25, 26). We know, therefore, this is a solvable problem. The key step toward improving care and reducing cancer health disparities requires accurate measurement of meaningful variables, fed back in real time to key stakeholders in the system, followed by meaningful action and continued monitoring to ensure that the action was successful. Determining meaningful measurement across the cancer spectrum may vary by sociocultural factors and require patient and stakeholder input. These system-based practices formed the core of a recent Institute of Medicine report, “Systems Practices for the Care of Socially At-Risk Populations” (27). Systems can be thought of at a macro level, such as state, county, or city governments, all the way down to the individual practice or physician level. Implementation science can inform the best approaches to ensure delivery of high-quality cancer care. Cancers can start as a result of chronic inflammation, and inflammation can modify the behavior of cancer. Biomarkers, such as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that can be detected from inflammation-laden cancers, are associated with worse patient outcome and increased metastasis and appear to be more common among African Americans. Microsatellite-unstable (MSI) cancers, which have an overall good prognosis, may be half as common among African Americans compared with whites (28). Both EMAST and MSI have implications for (1) chemotherapeutic response and (2) immunotherapeutic response. In terms of race, these aspects have not been studied. Furthermore, there is much evidence that the microbiome can influence (1) inflammation, (2) response to chemotherapy, and (3) cancer or precancerous lesion formation; also, the microbiome itself can be determined by diet and other factors. These aspects have not been examined with race in mind. Additionally, driver genes may be different within the same type of cancer from patients with different genetic backgrounds, which have implications for correct, definitive therapeutic approaches (29).Most studies that use human specimens to study aspects of cancer and race or ethnicity come from limited individual collections with sparse clinical–epidemiologic information, with rare exception. The exceptions tend to be NCI-funded projects, such as the North Carolina Colon Cancer Study, in which peer review and thoughtful input about how the collection was made with controls, surveys, and linked information to make the collection more meaningful, comprehensive in information, potentially useful for other future studies, and possessed of longevity. However, these types of collections or biorepositories, which include tumor and nontumor specimens, have not been created from diverse samples representative of the U.S. Census population. Current models of health care delivery are highly focused on the use of technology and innovation to improve patient outcomes across disease processes, as demonstrated by the focus on precision medicine in cancer treatment (32–36). Although oncology attempts to embrace this approach, the impact of innovative treatments has been hampered by poor translation of innovation into health care systems and patients from diverse community settings (37, 38). As precision medicine in cancer is accelerated as part of the Beau Biden Cancer Moonshot and other initiatives, the importance of community engagement to ensure that all patients benefit from these advances cannot be overlooked. Cancer health disparities must be taken into consideration in the design, execution, and evaluation of all such programs. Community-engaged research (CER) has been documented as an effective, beneficial method for engaging communities and formulating research that has relevance and impact for both researchers and affected communities (39–42). Involving relevant community stakeholders in research at the planning stages allows for a deeper understanding of community needs, allows researchers to have an iterative method for evaluating research questions in an active realistic milieu, and simultaneously creates a valuable vehicle for active dissemination of the research findings into the communities they are intended to serve. CER offers the potential to improve processes and outcomes in several areas, including care delivery, continuity of care, managing comorbidities, and supportive care (42).Unfortunately, there is a dearth of support for oncology health professionals who choose to work in CER, given its necessity for infrastructure and relationship building, the complex personal interactions with communities and community organizations, and the need to establish long-term benefits to the community after the research project is completed. Importantly, CER requires not only a broad range of expertise across multiple disciplines, but also investigators skilled in a team science approach (43). The benefit of this type of team science has been touted across disciplines; however, its implementation has been limited (44).A lack of workforce diversity has been identified as a barrier to improving access to care for underserved minority groups as well as to advancing research on health disparities (45, 46). Organizations, including ASCO and the American Society of Hematology, have sought to increase workforce diversity in oncology through awards and mentoring programs that expose minorities to in oncology at the medical and In the to Cancer Health Disparities and the American Association for Cancer several programs aimed at the of researchers in cancer and cancer health disparities research. of these types are needed to an oncology workforce that the diversity of the patients it CER not often with most and will require on of the research in both and such an it will remain to create a between CER and the that in cancer are the most important and available to evidence for care and of patients with cancer and individuals at risk for cancer that advanced new approaches from clinical care and diverse oncology the of clinical is to evidence that is both and future must include research questions that consider the multifactorial and multilevel that populations with the cancer This to advance disparities research within the cancer clinical within a new of for in cancer clinical and common for providing trial information have been to for rural patients and patients with lower SES, limited low health and The high and of chronic and of risk factors for chronic such as and must inform to these populations fully in cancer As an example, African Americans a burden of the that from studies, and it is to which could be reasonably as or could be or within the study In addition to those from cancer prevention and treatment also has that populations often are later in the and do not support and rates are key that influence the outcome of clinical cancer studies, those in which minorities have higher disease such as breast, prostate, and cancers In and treatment and rates lower rates exist for those patients who from to and Many such as and to the However, community engagement is to address the and challenges that the clinical CER has been demonstrated to promote building, and the and dissemination of information needed for and long-term As an example, the evaluated the of community health to promote and in and rural populations and that community health can be trained to as research and can be for of and cancer clinical trial and require an of often to be collected at multiple time thought should be given to how best to the of and the study (e.g., and needed to support collection and of specimens from and that to field of cancer health disparities has into a complex science and an field of cancer research. Unfortunately, the to this research has not been and the infrastructure needed to it to the level, can be is The of this which has been by from these four organizations, is to the of advances in this is that this statement will be by both and organizations to inform specific made to improve cancer health disparities eliminating identified disparities in cancer incidence, of care, and recommendations for action have a new in cancer health disparities that has the potential to benefit from across and the in cancer incidence and disparities that affects minorities and the medically it is that in this of cancer research when are being there will be opportunities to this new knowledge to all populations, and cancer health disparities for and future has in a or role for and and as a of the for has research from and has other from the has in a or role for and has research his from and and has and from and has from has in a or role for the and and has research from or other in and has from and has and from for both and an immediate or other in and and has research her from potential of were by the other and and of and of for all aspects of the the of and the for their of this to and

Cancer Research · 84 citationsread the source →