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Background Around 1 in 7 people in India are impacted by mental illness. The treatment gap for people with mental disorders is as high as 75–95%. Health care systems, especially in rural regions in India, face substantial challenges to address these gaps in care, and innovative strategies are needed. Methods We hypothesise that an intervention involving an anti-stigma campaign and a mobile-technology-based electronic decision support system will result in reduced stigma and improved mental health for adults at high risk of common mental disorders. It will be implemented as a parallel-group cluster randomised, controlled trial in 44 primary health centre clusters servicing 133 villages in rural Andhra Pradesh and Haryana. Adults aged ≥ 18 years will be screened for depression, anxiety and suicide based on Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorders (GAD-7) scores. Two evaluation cohorts will be derived—a high-risk cohort with elevated PHQ-9, GAD-7 or suicide risk and a non-high-risk cohort comprising an equal number of people not at elevated risk based on these scores. Outcome analyses will be conducted blinded to intervention allocation. Expected outcomes The primary study outcome is the difference in mean behaviour scores at 12 months in the combined ‘high-risk’ and ‘non-high-risk’ cohort and the mean difference in PHQ-9 scores at 12 months in the ‘high-risk’ cohort. Secondary outcomes include depression and anxiety remission rates in the high-risk cohort at 6 and 12 months, the proportion of high-risk individuals who have visited a doctor at least once in the previous 12 months, and change from baseline in mean stigma, mental health knowledge and attitude scores in the combined non-high-risk and high-risk cohort. Trial outcomes will be accompanied by detailed economic and process evaluations. Significance The findings are likely to inform policy on a low-cost scalable solution to destigmatise common mental disorders and reduce the treatment gap for under-served populations in low-and middle-income country settings. Trial registration Clinical Trial Registry India CTRI/2018/08/015355. Registered on 16 August 2018.

ObjectivesTo determine whether hydroxychloroquine when used with personal protective equipment reduces the proportion of laboratory-confirmed COVID-19 among healthcare workers in comparison to the use of personal protective equipment alone.DesignMulticentre, parallel-group, open-label randomised trial. Enrolment started on 29 June 2020 and stopped on 4 February 2021. Participants randomised in HydrOxychloroquine Prophylaxis Evaluation were followed for 6 months.Setting9 hospitals across India.ParticipantsHealthcare workers in an environment with exposure to COVID-19 were randomised in a 1:1 ratio to hydroxychloroquine plus use of personal protective equipment or personal protective equipment alone. 886 participants were screened and 416 randomised (213 hydroxychloroquine arm and 203 personal protective equipment).InterventionParticipants in intervention arm received 800 mg of hydroxychloroquine on day of randomisation and then 400 mg once a week for 12 weeks in addition to the use of personal protective equipment. In the control arm, participants continued to use personal protective equipment alone.Main outcomeProportion of laboratory-confirmed COVID-19 in the 6 months after randomisation.ResultsParticipants were young (mean age 32.1 years, SD 9.1 years) with low-comorbid burden. 47.4% were female. In the 6 months after randomisation (primary analysis population=413), 11 participants assigned to the hydroxychloroquine group and 12 participants assigned to the standard practice group met the primary endpoint (5.2% vs 5.9%; OR 0.85, 95% CI 0.35 to 2.07, p=0.72). There was no heterogeneity of treatment effect in any prespecified subgroup. There were no significant differences in the secondary outcomes. The adverse event rates were 9.9% and 6.9% in the hydroxychloroquine and standard practice arms, respectively. There were no serious adverse events in either group.Conclusions and relevanceHydroxychloroquine along with personal protective equipment was not superior to personal protective equipment alone on the proportion of laboratory-confirmed COVID-19. Definitive conclusions are precluded as the trial stopped early for futility, and hence was underpowered.Trial registration numberCTRI/2020/05/025067.

Women with recent gestational diabetes (GDM) have increased risk of developing type 2 diabetes.To investigate whether a resource-appropriate and context-appropriate lifestyle intervention could prevent glycemic deterioration among women with recent GDM in South Asia.This randomized, participant-unblinded controlled trial investigated a 12-month lifestyle intervention vs usual care at 19 urban hospitals in India, Sri Lanka, and Bangladesh. Participants included women with recent diagnosis of GDM who did not have type 2 diabetes at an oral glucose tolerance test (OGTT) 3 to 18 months postpartum. They were enrolled from November 2017 to January 2020, and follow-up ended in January 2021. Data were analyzed from April to July 2021.A 12-month lifestyle intervention focused on diet and physical activity involving group and individual sessions, as well as remote engagement, adapted to local context and resources. This was compared with usual care.The primary outcome was worsening category of glycemia based on OGTT using American Diabetes Association criteria: (1) normal glucose tolerance to prediabetes (ie, impaired fasting glucose or impaired glucose tolerance) or type 2 diabetes or (2) prediabetes to type 2 diabetes. The primary analysis consisted of a survival analysis of time to change in glycemic status at or prior to the final patient visit, which occurred at varying times after 12 months for each patient. Secondary outcomes included new-onset type 2 diabetes and change in body weight.A total of 1823 women (baseline mean [SD] age, 30.9 [4.9] years and mean [SD] body mass index, 26.6 [4.6]) underwent OGTT at a median (IQR) 6.5 (4.8-8.2) months postpartum. After excluding 160 women (8.8%) with type 2 diabetes, 2 women (0.1%) who met other exclusion criteria, and 49 women (2.7%) who did not consent or were uncontactable, 1612 women were randomized. Subsequently, 11 randomized participants were identified as ineligible and excluded from the primary analysis, leaving 1601 women randomized (800 women randomized to the intervention group and 801 women randomized to usual care). These included 600 women (37.5%) with prediabetes and 1001 women (62.5%) with normoglycemia. Among participants randomized to the intervention, 644 women (80.5%) received all program content, although COVID-19 lockdowns impacted the delivery model (ie, among 644 participants who engaged in all group sessions, 476 women [73.9%] received some or all content through individual engagement, and 315 women [48.9%] received some or all content remotely). After a median (IQR) 14.1 (11.4-20.1) months of follow-up, 1308 participants (81.2%) had primary outcome data. The intervention, compared with usual care, did not reduce worsening glycemic status (204 women [25.5%] vs 217 women [27.1%]; hazard ratio, 0.92; [95% CI, 0.76-1.12]; P = .42) or improve any secondary outcome.This study found that a large proportion of women in South Asian urban settings developed dysglycemia soon after a GDM-affected pregnancy and that a lifestyle intervention, modified owing to the COVID-19 pandemic, did not prevent subsequent glycemic deterioration. These findings suggest that alternate or additional approaches are needed, especially among high-risk individuals.Clinical Trials Registry of India Identifier: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry Identifier: SLCTR/2017/001; and ClinicalTrials.gov Identifier: NCT03305939.

The LIVING trial aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable. This statistical analysis plan provides the details of all the pre-specified analyses including the analysis of all primary and secondary endpoints. This detailed statistical analysis plan (SAP) was written by the statisticians and chief investigators prior to unblinding and database lock.

HOPE is a prospective, multi-centre, parallel group, concealed, unblinded, randomized, controlled trial to determine whether combination of hydroxychloroquine and standard practice, that is, use of recommended personal protective equipment reduces the proportion of laboratory confirmed COVID-19 infections among frontline healthcare workers in hospitals in India as compared to standard practice. This detailed statistical analysis plan was prepared by trial statisticians and approved by the HOPE management committee prior to completion of data collection.

Additional file 2: Table 1. CONSORT 2010 checklist of information to include when reporting a cluster randomised trial. Table 2. Extension of CONSORT for abstracts1,2 to reports of cluster randomised trials.

Background: Healthcare workers (HCWs),particularly from lower-middle income countries (LMIC), are at high risk of acquiring COVID-19. Limited data exist on the effectiveness of hydroxychloroquine as prophylaxis. Our trial evaluated the effectiveness of a 12-week regimen of hydroxychloroquine among HCWs on the risk of laboratory-confirmed COVID-19 in the 6 months after randomization Methods: We conducted a multicentre parallel-group open-label randomized controlled trial in 9 centres across India. HCWs serving in an environment with exposure to COVID-19 were eligible and randomized in a 1:1 ratio to hydroxychloroquine plus standard practice or to standard practice alone (role-appropriate personal protective equipment). In the intervention arm, participants received 2 doses of 400mg hydroxychloroquine at randomization followed by a weekly dose for 12 weeks. The primary outcome was the proportion of laboratory-confirmed COVID-19 in the 6 months after randomization using an intention-to-treat analysis. The trial was registered on Clinical Trials Registry of India(CTRI/2020/05/025067). Findings: From 29th June 2020 to 4th February 2021, 886 participants were screened and 416 were randomized (203-standard practice and 213- hydroxychloroquine plus standard practice). In the 6 months after randomization (primary analysis population=413), 11 participants assigned to the hydroxychloroquine group and 12 participants assigned to the standard practice group met the primary end point[ 5.1% vs 5.9%; OR 0.85, [95% CI 0.35-2.06] p=0.71]. There was no heterogeneity of treatment effect on the primary outcome in any of the pre-specified subgroups. There were no significant differences in any of the secondary outcomes. The adverse event rates were 9.9% and 6.9% in the hydroxychloroquine and standard practice arms respectively. There were no serious adverse events in either group. Interpretation: Hydroxychloroquine along with standard practice was not superior to standard practice alone on the proportion of lab-confirmed COVID-19. However, conclusions are limited by the premature trial cessation. Trial Registration: Clinical Trials Registry of India (CTRI/2020/05/025067). Funding: Wesley Medical Research, Australia Declaration of Interest: OJ reports being a member of the WHO R&D Blueprint Safety Monitoring Team, ACT Acclerator-R&D Digital Health working group and COVID-19 Clinical Research Coalition data sharing working group. Remaining authors have nothing to declare. Ethical Approval: Written informed consent was obtained from all participants. The trial was approved by the Ethics Committee at all participating sites (coordinating centre EC approval number: The George Institute Ethics Committee:08-2020)

Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.

BACKGROUND AND OBJECTIVES: Neuropathy is a common complication of kidney disease that lacks proven disease-modifying treatments. Hemodiafiltration improves clearance of uremic toxins and is associated with better nerve function than hemodialysis. We aimed to determine whether hemodiafiltration reduces the progression of neuropathy in people receiving hemodialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study was an open-label, blinded end point assessment, controlled trial that randomized maintenance hemodialysis recipients to hemodiafiltration or high-flux hemodialysis for 48 months or until death or cessation of dialysis at four study centers. The primary outcome was the mean change in the yearly modified total neuropathy score from baseline, with time points weighted equally. RESULTS: A total of 124 participants were randomized and followed for a mean of 41 months. At baseline, neuropathy was present in 91 (73%) participants (modified total neuropathy score greater than or equal to two), and 38 (31%) had moderate to severe neuropathy (modified total neuropathy score 9–28). Convection volume in the hemodiafiltration arm was a median of 24.7 (interquartile range, 22.4–26.5) L. The mean modified total neuropathy score (SEM) worsened by 1.7 (0.4)/28 and 1.2 (0.4)/28 in the hemodiafiltration and hemodialysis groups, respectively, with a mean difference of 0.5 (95% confidence interval, −0.7 to 1.7; P=0.37). There was no difference in survival (hazard ratio, 1.24; 95% confidence interval, 0.61 to 2.51; log rank P=0.55) or any of the prespecified adverse events. There was no difference between groups in the number of participants who suffered an adverse event adjusted by follow-up time (relative risk, 1.05; 95% confidence interval, 0.83 to 1.32; P=0.68). CONCLUSIONS: Neuropathy is still a common complication of kidney disease without disease-altering therapy. Hemodiafiltration did not affect neuropathy progression compared with hemodialysis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE), ACTRN12609000615280

BACKGROUND Although around 10% of Indians experience depression, anxiety, or alcohol use disorders, very few receive adequate mental health care, especially in rural communities. Stigma and limited availability of mental health services contribute to this treatment gap. The Systematic Medical Appraisal Referral and Treatment Mental Health project aimed to address this gap. OBJECTIVE This study aimed to evaluate the effectiveness of an intervention in increasing the use of mental health services and reducing depression and anxiety scores among individuals at high risk of common mental disorders. METHODS A before-after study was conducted from 2014 to 2019 in 12 villages in Andhra Pradesh, India. The intervention comprised a community antistigma campaign, with the training of lay village health workers and primary care doctors to identify and manage individuals with stress, depression, and suicide risk using an electronic clinical decision support system. RESULTS In total, 900 of 22,046 (4.08%) adults screened by health workers had increased stress, depression, or suicide risk and were referred to a primary care doctor. At follow-up, 731 out of 900 (81.2%) reported visiting the doctor for their mental health symptoms, compared with 3.3% (30/900) at baseline (odds ratio 133.3, 95% CI 89.0 to 199.7; PPP CONCLUSIONS The intervention was associated with a marked increase in service uptake and clinically important reductions in depression and anxiety symptom scores. This will be further evaluated in a large-scale cluster randomized controlled trial.

Background Obesity is characterized by inflammation, caused by increase in proinflammatory cytokines, a key factor for the development of insulin resistance. SR141716A, a cannabinoid receptor 1 (CB1) antagonist, shows significant improvement in clinical status of obese/diabetic patients. Therefore, we studied the effect of SR141716A on human adipocyte inflammatory profile and differentiation. Methods Adipocytes were obtained from liposuction. Stromal vascular cells were extracted and differentiated into adipocytes. Media and cells were collected for secretory (ELISA) and expression analysis (qPCR). Triglyceride accumulation was observed using oil red-O staining. Cholesterol was assayed by a fluorometric method. 2-AG and anandamide were quantified using isotope dilution LC-MS. TLR-binding experiments have been conducted in HEK-Blue cells. Results In LPS-treated mature adipocytes, SR141716A was able to decrease the expression and secretion of TNF-a. This molecule has the same effect in LPS-induced IL-6 secretion, while IL-6 expression is not changed. Concerning MCP-1, the basal level is down-regulated by SR141716A, but not the LPS-induced level. This effect is not caused by a binding of the molecule to TLR4 (LPS receptor). Moreover, SR141716A restored adiponectin secretion to normal levels after LPS treatment. Lastly, no effect of SR141716A was detected on human pre-adipocyte differentiation, although the compound enhanced adiponectin gene expression, but not secretion, in differentiated pre-adipocytes. Conclusion We show for the first time that some clinical effects of SR141716A are probably directly related to its anti-inflammatory effect on mature adipocytes. This fact reinforces that adipose tissue is an important target in the development of tools to treat the metabolic syndrome.