EARLY PERSISTENT LYMPHOPENIA AND RISK OF DEATH IN CRITICALLY ILL PATIENTS WITH AND WITHOUT SEPSIS.

ABSTRACT: Purpose: To examine the relationship of early persistent lymphopenia with hospital survival in critically ill patients with and without sepsis to assess whether it can be considered a treatable trait. Methods: Retrospective database analysis of patients with nonelective admission to intensive care units (ICUs) during January 2015 to December 2018. Patients were classified as having sepsis if the Acute Physiology and Chronic Health Evaluation III admission diagnostic code included sepsis or coded for an infection combined with a Sequential Organ Failure Assessment score of ≥2. We defined early persistent lymphopenia at two thresholds (absolute lymphocyte count [ALC] <1.0 and <0.75 × 10 9 /L) based on two qualifying values recorded during the first 4 days in ICU. The main outcome measure was time to in-hospital death. Results: Of 8,507 eligible patients, 7,605 (89.4%) had two ALCs recorded during their first 4 days in ICU; of these, 1,482 (19.5%) had sepsis. Persistent lymphopenia (ALC <1.0) was present in 728 of 1,482 (49.1%) and 2,302 of 6,123 (37.6%) patients with and without sepsis, respectively. For ALC <0.75, the results were 487 of 1,482 (32.9%) and 1,125 of 6,123 (18.4%), respectively. Of 3,030 patients with persistent lymphopenia (ALC <1.0), 562 (18.5%) died compared with 439 of 4,575 (9.6%) without persistent lymphopenia. Persistent lymphopenia was an independent risk factor for in-hospital death in all patients. The hazard ratios for death at ALC <1.0 were 1.89 (95% confidence interval, 1.32-2.71; P = 0.0005) and 1.17 (95% confidence interval, 1.02-1.35; P = 0.0246) in patients with and without sepsis respectively. Conclusions: Early persistent lymphopenia is common in critically ill patients and associated with increased risk of death in patients with and without sepsis. Although the association is stronger in patients with sepsis, lymphopenia is a candidate to be considered a treatable trait; drugs that reverse lymphopenia should be trialed in critically ill patients.

Effect of COVID-19 containment measures on access to snakebite care in India.

INTRODUCTION: The extensive spread of COVID-19 meant action to address the pandemic took precedence over routine service delivery, thus impacting access to care for many health conditions, including the effects of snakebite. METHOD: We prospectively collected facility-level data from several health facilities in India, including number of snakebite admissions and snakebite envenoming admissions on modality of transport to reach the health facility. To analyse the effect of a health facility being in cluster-containment zone, we used negative binomial regression analysis. RESULTS: Our findings suggest that that health facilities located within a COVID containment zone saw a significant decrease in total snakebite admissions (incidence rate ratio 0.64 (0.43-0.94), standard error 0.13, p≤0.02)) and envenoming snakebite admissions (incidence rate ratio 0.43 (0.23-0.81), standard error 0.14, p≤0.01) compared to when health facilities were not within a COVID containment zone. There was no statistically significant difference in non-envenoming admissions and modalities of transport used to reach health facilities. CONCLUSION: This article provides the first quantitative estimate of the impact of COVID-19 containment measures on access to snakebite care. More research is needed to understand how containment measures altered care-seeking pathways and the nature of snake-human-environment conflict. Primary healthcare systems need to be safeguarded for snakebite care to mitigate effects of cluster-containment measures.

An intervention to reduce stigma and improve management of depression, risk of suicide/self-harm and other significant emotional or medically unexplained complaints among adolescents living in urban slums: protocol for the ARTEMIS project.

BACKGROUND: There are around 250 million adolescents in India. Adolescents are vulnerable to common mental disorders with depression and self-harm accounting for a major share of the burden of death and disability in this age group. Around 20% of children and adolescents are diagnosed with/ or live with a disabling mental illness. A national survey has found that suicide is the third leading cause of death among adolescents in India. The authors hypothesise that an intervention involving an anti-stigma campaign co-created by adolescents themselves, and a mobile technology-based electronic decision support system will help reduce stigma, depression, and suicide risk and improve mental health for high-risk adolescents living in urban slums in India. METHODS: The intervention will be implemented as a cluster randomised control trial in 30 slum clusters in each of the cities of Vijayawada and New Delhi in India. Adolescents aged 10 to 19 years will be screened for depression and suicide ideation using the Patient Health Questionnaire (PHQ-9). Two evaluation cohorts will be derived-a high-risk cohort with an elevated PHQ-9 score ≥ 10 and/or a positive response (score ≥ 2) to the suicide risk question on the PHQ-9, and a non-high-risk cohort comprising an equal number of adolescents not at elevated risk based on these scores. DISCUSSION: The key elements that ARTEMIS will focus on are increasing awareness among adolescents and the slum community on these mental health conditions as well as strengthening the skills of existing primary healthcare workers and promoting task sharing. The findings from this study will provide evidence to governments about strategies with potential for addressing the gaps in providing care for adolescents living in urban slums and experiencing depression, other significant emotional or medically unexplained complaints or increased suicide risk/self-harm and should have relevance not only for India but also for other low- and middle-income countries. TRIAL STATUS: Protocol version - V7, 20 Dec 2021 Recruitment start date: tentatively after 15th July 2022 Recruitment end date: tentatively 14th July 2023 (1 year after the trial start date) TRIAL REGISTRATION: The trial has been registered in the Clinical Trial Registry India, which is included in the WHO list of Registries ( https://www.who.int/clinical-trials-registry-platform/network/primary-registries ) Reference No. CTRI/2022/02/040307 . Registered on 18 February 2022. The tentative start date of participant recruitment for the trial will begin after 15th July 2022.

Hydroxychloroquine plus personal protective equipment versus personal protective equipment alone for the prevention of laboratory-confirmed COVID-19 infections among healthcare workers: a multicentre, parallel-group randomised controlled trial from India.

OBJECTIVES: To 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. DESIGN: Multicentre, 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. SETTING: 9 hospitals across India. PARTICIPANTS: Healthcare 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). INTERVENTION: Participants 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 OUTCOME: Proportion of laboratory-confirmed COVID-19 in the 6 months after randomisation. RESULTS: Participants 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 RELEVANCE: Hydroxychloroquine 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 NUMBER: CTRI/2020/05/025067.

Effects of a Lifestyle Intervention to Prevent Deterioration in Glycemic Status Among South Asian Women With Recent Gestational Diabetes: A Randomized Clinical Trial.

Importance: Women with recent gestational diabetes (GDM) have increased risk of developing type 2 diabetes. Objective: To investigate whether a resource-appropriate and context-appropriate lifestyle intervention could prevent glycemic deterioration among women with recent GDM in South Asia. Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: Clinical Trials Registry of India Identifier: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry Identifier: SLCTR/2017/001; and ClinicalTrials.gov Identifier: NCT03305939.

Effect of Hemodiafiltration on the Progression of Neuropathy with Kidney Failure: A Randomized Controlled Trial.

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.

An integrated community and primary healthcare worker intervention to reduce stigma and improve management of common mental disorders in rural India: protocol for the SMART Mental Health programme.

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.

Psychological impact of COVID-19 on ophthalmologists-in-training and practising ophthalmologists in India.

Purpose: To evaluate the psychological impact of the COVID 19 crisis on ophthalmologists-in-training and practising ophthalmologists during lockdown in India. Methods: An online survey was completed by ophthalmologists and ophthalmology trainees during the lockdown. The information collected included demographics (age, gender), domicile (state, union territory), current professional status (in training or practising), type of practice (solo, group, institutional, governmental, non-governmental), marital status (married, single), impact of COVID-19 on their training or practice, and impact on income and ability to meet living expenses. Psychological distress was assessed using the Patient Health Questionnaire-9 (PHQ-9). Results: In all, 2,355 ophthalmologists responded. Mean age was 42.5 (range, 25-82 years; SD, 12.05) years. Of these, 1,332 (56.7%) were males; 475 (20.2%) were still not in practice; 366 (15.5%) were single; 1,244 (52.8%) felt that COVID-19 would impact on their training or professional work; and 869 (37%) had difficulty in meeting their living expenses. The mean PHQ-9 score was 3.98 (range, 0-27; SD, 4.65). In terms of psychological impact, 768 (32.6%) had some degree of depression; mild in 504 (21.4%), moderate in 163 (6.9%), and severe in 101 (4.3%). Multivariable analysis showed that depression was significantly higher at younger age. The odds of depression decreased by 3% with 1 year increase in age. It was higher in non-practicing ophthalmologists, especially those who were considerably worried about their training or professional growth, and those with difficulty in meeting living expenses. Conclusion: A strikingly high proportion of ophthalmologists are psychologically affected and may require personalized mental health care.

The Systematic Medical Appraisal Referral and Treatment Mental Health Project: Quasi-Experimental Study to Evaluate a Technology-Enabled Mental Health Services Delivery Model Implemented in Rural India.

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; P<.001). Mean depression and anxiety scores were significantly lower postintervention compared with baseline from 13.4 to 3.1 (P<.001) and from 12.9 to 1.9 (P<.001), respectively. 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.

Effect of the Cannabinoid Receptor-1 antagonist SR141716A on human adipocyte inflammatory profile and differentiation.

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.