Ethics of clinical research and practice in India during the Covid-19 pandemic.

Covid-19 has been one of the worst public health calamities faced by humankind in over a century. As of July 23, 2020, there have been 15,633,159 confirmed cases and 635,422 deaths reported, worldwide (1). We are six months into the pandemic, and yet we know little about the disease. The role of medicines is far from optimal, and vaccines are still under trials. Therefore, we have little to defend ourselves against this novel virus.

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Impact of community-based health insurance and economic status on utilization of healthcare services: A household-level cross-sectional survey from rural central India.

Background: . Community-based health insurance (CBHI) is a health-financing mechanism based on voluntary membership, risk pooling, with a non-profit objective and relies on social capital as a driving force. It aims to improve equity in healthcare utilization in the community. We did this study to understand if CBHI schemes reach the poor, improve healthcare utilization and protect them from catastrophic health events. Methods: . Mahatma Gandhi Institute of Medical Sciences (MGIMS), Sevagram, located in Wardha district of Maharashtra, India, runs a variety of CBHI schemes in surrounding villages. Many households (HHs) have opted for these schemes. We conducted a cross-sectional survey of all HHs of 35 villages and collected information about sociodemographics, inpatient healthcare utilization (in previous 5 years), outpatient healthcare utilization (in previous 1 year) and insurance status of the HHs. We derived wealth index based on 33 sociodemographic variables and classified HHs in quintiles of wealth index. We compared the distribution of healthcare utilization variables by insurance status and wealth index and used logistic regression to evaluate if health insurance independently improves healthcare utilization, after adjusting for confounders. Results: . Of a total of 7261 HHs surveyed, 2210 (30.4%) were uninsured, 4153 (57.2%) were insured under MGIMS CBHI schemes, and 898 (12.4%) had family insurance either from MGIMS or other providers. Insured HHs had a higher wealth index compared to uninsured. Mean (SD) hospitalization episodes in an HH were 0.82 (1.75) among uninsured, 1.13 (1.56) in CBHI insured and 1.21 (1.55) in those with family insurance. Within each category, healthcare utilization was lower for poor HHs (lowest quintile of wealth index) and higher for affluent HHs (higher quintiles of wealth index). Among those who were hospitalized, catastrophic health events were less in CBHI insured (7.9%) compared to uninsured (12.3%). After adjusting for socioeconomic status and other confounders, our data suggest that participating in a CBHI scheme increased odds of utilization of inpatient services (OR 1.18; 95% CI 1.04-1.33) and protected from catastrophic health events (OR 0.52; 95% CI 0.43-0.64). Conclusion: . CBHI schemes improve healthcare utilization and protect against catastrophic health expenditure among those who get hospitalized. However, there also exists a socioeconomic gradient both in membership and in utilization of healthcare services favouring those who are more affluent.

Tropical fevers: Management guidelines.

Tropical fevers were defined as infections that are prevalent in, or are unique to tropical and subtropical regions. Some of these occur throughout the year and some especially in rainy and post-rainy season. Concerned about high prevalence and morbidity and mortality caused by these infections, and overlapping clinical presentations, difficulties in arriving at specific diagnoses and need for early empiric treatment, Indian Society of Critical Care Medicine (ISCCM) constituted an expert committee to develop a consensus statement and guidelines for management of these diseases in the emergency and critical care. The committee decided to focus on most common infections on the basis of available epidemiologic data from India and overall experience of the group. These included dengue hemorrhagic fever, rickettsial infections/scrub typhus, malaria (usually falciparum), typhoid, and leptospira bacterial sepsis and common viral infections like influenza. The committee recommends a 'syndromic approach' to diagnosis and treatment of critical tropical infections and has identified five major clinical syndromes: undifferentiated fever, fever with rash / thrombocytopenia, fever with acute respiratory distress syndrome (ARDS), fever with encephalopathy and fever with multi organ dysfunction syndrome. Evidence based algorithms are presented to guide critical care specialists to choose reliable rapid diagnostic modalities and early empiric therapy based on clinical syndromes.

End-of-life care attitudes, values, and practices among health care workers.

INTRODUCTION: This study aims to ascertain attitudes of health care workers on end-of-life care (EOLC) issues and to highlight the disparity that exists in countries with different backgrounds. METHODS: It is a cross-sectional questionnaire survey across heterogeneous health care providers in India, Chile, the United Kingdom, and the Netherlands using an indigenously prepared questionnaire considering regional variations, covering different areas of EOLC. RESULTS: Of the 109 participants, 68 (62.4%) felt that cardiopulmonary resuscitation should be done selectively, 25 (22.9%) had come in contact with at least 1 patient who had asked them to hasten death, and 36 (33%) felt that training was insufficient to prepare them for skills in issues of EOLC. CONCLUSION: To avoid cumbersome through well-meant interventions, it is important that the caregiving team is aware of the patient's own wishes with respect to EOLC issues.

Rationale and design of the Primary pREvention strategies at the community level to Promote Adherence of treatments to pREvent cardiovascular diseases trial number (CTRI/2012/09/002981).

INTRODUCTION: Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality in low-income countries including India. There is a need for effective, low-cost methods to prevent CVDs in rural India. One strategy is to identify and implement interventions at high-risk individuals using community health workers (CHWs). There is a paucity of CHW-based CVD intervention trials from low-income countries. METHODS: We designed a multicenter, household-level, cluster-randomized trial with 1:1 allocation to intervention and control arms. The CHWs undertook a door-to-door survey and screened 5,699 households in 28 villages from 3 rural regions in India to identify at-risk households. The households were defined as those with ≥1 individual aged ≥35 years and at moderate or high risk for CVD based on the non-laboratory-based National Health and Nutrition Examination Survey score. All at-risk individuals were invited to attend a physician-led village clinic that provided a CVD risk reduction prescription and education about target risk factor levels for CVD control. All households in which at least 1 member at moderate to high risk for CVD had received a risk reduction prescription were eligible for randomization. Households randomized to the CHW-based intervention will receive 1 household visit by a CHW every 2 months, for 12 months. During these visits, CHWs will measure blood pressure, ascertain and reinforce adherence to prescribed therapies, and modify therapy to meet targets. Households randomized to the control arm do not receive CHW visits. At 12 months after randomization, we will evaluate 2 primary outcomes of systolic blood pressure and adherence to antihypertensive drugs and secondary outcomes of INTERHEART risk score, body mass index, and waist-to-hip ratios. At 18 to 24 months after randomization and 6 to 12 months after the last intervention, we will record these outcomes to evaluate sustainability of intervention. RESULTS: Community health workers screened a total of 5,033 households that included 9,248 individuals and identified 2,571 households with 3,784 at-risk individuals. We randomized 2,438 households (1,219 to intervention and 1,219 to control groups). CONCLUSION: Our large trial of CHWs in rural India will provide important information regarding a promising approach to primary prevention of CVDs.

Trajectories of tuberculosis-specific interferon-gamma release assay responses among medical and nursing students in rural India.

BACKGROUND: Interferon gamma release assays (IGRAs) have been shown to be highly dynamic tests when used in serial testing for TB infection. However, there is little information demonstrating a clear association between TB exposure and IGRA responses over time, particularly in high TB incidence settings. OBJECTIVES: To assess whether QuantiFERON-TB Gold In-Tube (QFT) responses are associated with occupational TB exposures in a cohort of young health care trainees in India. METHODS: All medical and nursing students at Mahatma Gandhi Institute of Medical Sciences were approached. Participants were followed up for 18 months; QFT was performed 4 times, once every 6 months. Various modeling approaches were used to define IFN-gamma trajectories and correlations with TB exposure. RESULTS: Among 270 medical and nursing trainees, high rates of conversions (6.3-20.9%) and reversions (20.0-26.2%) were found depending on the definitions used. Stable converters were more likely to have had TB exposure in hospital pre-study. Recent occupational exposures were not consistently associated with QFT responses over time. CONCLUSION: IFN-gamma responses and rates of change could not be explained by occupational exposure investigated. High conversion and subsequent reversion rates suggest many health care workers (HCWs) would revert in the absence of treatment, either by clearing the infection naturally or due to fluctuations in the underlying immunological response and/or poor assay reproducibility. QFT may not be an ideal diagnostic test for repeated screening of HCWs in a high TB incidence setting.

Clinical presentation, etiology, and survival in adult acute encephalitis syndrome in rural Central India.

BACKGROUND: Acute encephalitis syndrome (AES) is a constellation of symptoms that includes fever and altered mental status. Most cases are attributed to viral encephalitis (VE), occurring either in outbreaks or sporadically. We conducted hospital-based surveillance for sporadic adult-AES in rural Central India in order to describe its incidence, spatial and temporal distribution, clinical profile, etiology and predictors of mortality. METHODS: All consecutive hospital admissions during the study period were screened to identify adult-AES cases and were followed until 30-days of hospitalization. We estimated incidence by administrative sub-division of residence and described the temporal distribution of cases. We performed viral diagnostic studies on cerebrospinal fluid (CSF) samples to determine the etiology of AES. The diagnostic tests included RT-PCR (for enteroviruses, HSV 1 and 2), conventional PCR (for flaviviruses), CSF IgM capture ELISA (for Japanese encephalitis virus, dengue, West Nile virus, Varicella zoster virus, measles, and mumps). We compared demographic and clinical variables across etiologic subtypes and estimated predictors of 30-day mortality. RESULTS: A total of 183 AES cases were identified between January and October 2007, representing 2.38% of all admissions. The incidence of adult AES in the administrative subdivisions closest to the hospital was 16 per 100,000. Of the 183 cases, a non-viral etiology was confirmed in 31 (16.9%) and the remaining 152 were considered as VE suspects. Of the VE suspects, we could confirm a viral etiology in 31 cases: 17 (11.2%) enterovirus; 8 (5.2%) flavivirus; 3 (1.9%) Varicella zoster; 1 (0.6%) herpesvirus; and 2 (1.3%) mixed etiology); the etiology remained unknown in remaining 121 (79.6%) cases. 53 (36%) of the AES patients died; the case fatality proportion was similar in patients with a confirmed and unknown viral etiology (45.1 and 33.6% respectively). A requirement for assisted ventilation significantly increased mortality (HR 2.14 (95% CI 1.0-4.77)), while a high Glasgow coma score (HR 0.76 (95% CI 0.69-0.83)), and longer duration of hospitalization (HR 0.88 (95% CI 0.83-0.94)) were protective. CONCLUSION: This study is the first description of the etiology of adult-AES in India, and provides a framework for future surveillance programs in India.

The crisis in access to essential medicines in India: key issues which call for action.

The government is planning to introduce free generic and essential medicines in public health facilities. Most people in India buy healthcare from the private sector, a compulsion that accounts for a high proportion of healthcare-related expenditure. To reduce the burden of healthcare costs, the government must improve availability and affordability of generic and essential medicines in the market. It can do so because India's large pharmaceutical industry is a major source of generic medicines worldwide. In this article, we discuss three factors that have impeded access to generic and essential medicines: (1) mistaken notions among policymakers, prescribers and patients about branded drugs and generic drugs in India; (2) high prices of medicines due to the progressive dismantling of the system of regulation of medicine prices, and (3) a drug approval and regulatory system that allows medicines (including fixed dose combinations) of doubtful efficacy, rationale, safety and public health relevance to dominate the market at the cost of access to affordable generic and essential medicines. The consequences of ill-health and wasted expenditure on drugs raise issues of public health ethics.Improving access to essential medicines in India is an urgent public health and ethical imperative. This should include improved public provisioning, a system of regulation of drug prices, and an evidence-based drug approval process.

Changing landscape of acute encephalitis syndrome in India: a systematic review.

BACKGROUND: Seasonal outbreaks of acute encephalitis syndrome (AES) occur with striking regularity in India and lead to substantial mortality. Several viruses, endemic in many parts of India, account for AES. Although Japanese encephalitis virus (JEV) is a key aetiological agent for AES in India, and has attracted countrywide attention, many recent studies suggest that enteroviruses and rhabdoviruses might account for outbreaks of AES. We did a systematic review of published studies to understand the changing landscape of AES in India. DATA SOURCES: Electronic databases (PubMed, Web of Science and BIOSIS) from the start of the database to 2010. We also hand-searched journals and screened reference lists of original articles, reviews and book chapters to identify additional studies. STUDY SELECTION: We included studies only on humans and from three time-periods: pre-1975, 1975-1999 and 2000-2010. DATA EXTRACTION: Independent, duplicate data extraction and quality assessment were conducted. Data extracted included study characteristics, type of study and aetiological agent identified. DATA SYNTHESIS: Of the 749 unique published articles screened, 57 studies met the inclusion criteria (35 outbreak investigations and 22 surveillance studies). RESULTS: While most studies from 1975 to 1999 identified JEV as the main cause of AES, many studies published after 2000 identified Chandipura and enteroviruses as the most common agents, in both outbreaks and surveillance studies. Overall, a positive yield with respect to identification of aetiological agents was higher in outbreak investigations as compared to surveillance studies. CONCLUSION: The landscape of AES in India has changed in the previous decade, and both outbreak investigations and surveillance studies have increasingly reported non-JEV aetiologies. Because of these findings, there is a need to explore additional strategies to prevent AES beyond vector control and JEV vaccination.

Accuracy of a multispecies rapid diagnostic test kit for detection of malarial parasite at the point of care in a low endemicity region.

Although highly accurate rapid diagnostic tests (RDT) for Plasmodium falciparum [based on identification of histidine-rich protein-2 (PfHRP2)] have been developed, the accuracy of non-falciparum tests is relatively poor. Recently, a Plasmodium vivax-specific RDT [based on identification of species-specific lactate dehydrogenase (PvLDH)] became available, which along with PfHRP2 may improve malaria diagnosis by identifying the species correctly. A cross-sectional hospital-based study was designed to evaluate the diagnostic accuracy of FalciVax, a commercially available PfHRP2- and PvLDH-based RDT (index test), using malaria microscopy as a reference standard. All consecutive inpatients who presented with fever underwent both the index test and the reference standard. The study sample included 657 patients and the overall sensitivity and specificity of the RDT for diagnosis of any malarial species were 92.9% and 98.4%, respectively. The diagnostic accuracy estimates for correct species identification were lower (sensitivity 91.8%, specificity 96.8%). The accuracy of the PvLDH test to detect P. vivax was low (sensitivity 76.6%, specificity 98.1%).

Profile of adults seeking voluntary HIV testing and counseling in rural Central India: results from a hospital-based study.

Rural India has an undetected load of HIV-positive individuals. Few rural adults present for HIV testing and counseling due to stigma, discrimination, and fear of social ostracization. In this rural hospital clinic-based study, we document profiles of rural adults seeking voluntary testing and counseling, and analyze correlates of HIV seropositivity. This cross-sectional study was conducted in 450 participants presenting to the outpatient clinics of Mahatma Gandhi Institute of Medical Sciences, Sevagram, Central India. After informed consent, pre- and post-test counseling, HIV testing, and face-to-face interviews were conducted. Data were collected using a structured questionnaire. The median age of the 450 study participants was 34 years (range 18-88 years); the majority (74%) was married. The overall proportion of HIV seropositivity was 32% [95% CI 28%, 37%]. The proportions of HIV seropositivity in married women, married men, and single men were 41%, 37%, 18%, respectively. No single woman was found seropositive in the study. Very few married women were aware of their husbands' HIV status. In a multivariate analysis, correlates of HIV seropositivity in men were: age 30-39 years, being married, having sex with multiple partners, use of alcohol before sex, and testing positive for HIV in the past. In married women, the only predictor of seropositivity was being married. Although limited by the non-random nature of the sampling method, this pilot study is unique in that it is the first from this rural region of Central India. It provides baseline data on marginalized, largely unstudied populations that may aid in designing probabilistic community-based surveys in this neglected population.

Improving the estimation of tuberculosis infection prevalence using T-cell-based assay and mixture models.

BACKGROUND: The prevalence of latent tuberculosis infection (LTBI) is traditionally estimated using the tuberculin skin test (TST). Highly specific blood-based interferon-gamma release assays (IGRAs) are now available and could enhance the estimation of LTBI prevalence in combination with model-based methods. DESIGN: We compared conventional and model-based methods for estimating LTBI prevalence among 719 Indian health care workers who underwent both TST and QuantiFERON-TB Gold In-Tube (QFT-G). In addition to using standard cut-off points on TST and QFT-G, Bayesian mixture model analyses were performed with: 1) continuous TST data and 2) categorical data using both TST and QFT-G results in a latent class analysis (LCA), accounting for prior information on sensitivity and specificity. RESULTS: Estimates of LTBI prevalence varied from 33.8% to 60.7%, depending on the method used. The mixture model based on TST alone estimated the prevalence at 36.5% (95%CI 28.5-47.0). When results from both tests were combined using LCA, the prevalence was 45.4% (95%CI 39.5-51.1). The LCA provided additional results on the sensitivity, specificity and predictive values of joint results. CONCLUSION: The availability of novel, specific IGRAs and development of methods such as mixture analyses allow a more realistic and informative approach to prevalence estimation.

Novel tests for diagnosing tuberculous pleural effusion: what works and what does not?

Tuberculous pleuritis is a common manifestation of extrapulmonary tuberculosis and is the most common cause of pleural effusion in many countries. Conventional diagnostic tests, such as microscopic examination of the pleural fluid, biochemical tests, culture of pleural fluid, sputum or pleural tissue, and histopathological examination of pleural tissue, have known limitations. Due to these limitations, newer and more rapid diagnostic tests have been evaluated. In this review, the authors provide an overview of the performance of new diagnostic tests, including markers of specific and nonspecific immune response, nucleic acid amplification and detection, and predictive models based on combinations of markers. Directions for future development and evaluation of novel assays and biomarkers for pleural tuberculosis are also suggested.

Evaluation of diagnostic accuracy, feasibility and client preference for rapid oral fluid-based diagnosis of HIV infection in rural India.

BACKGROUND: Oral fluid-based rapid tests are promising for improving HIV diagnosis and screening. However, recent reports from the United States of false-positive results with the oral OraQuick ADVANCE HIV1/2 test have raised concerns about their performance in routine practice. We report a field evaluation of the diagnostic accuracy, client preference, and feasibility for the oral fluid-based OraQuick Rapid HIV1/2 test in a rural hospital in India. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional, hospital-based study was conducted in 450 consenting participants with suspected HIV infection in rural India. The objectives were to evaluate performance, client preference and feasibility of the OraQuick Rapid HIV-1/2 tests. Two Oraquick Rapid HIV1/2 tests (oral fluid and finger stick) were administered in parallel with confirmatory ELISA/Western Blot (reference standard). Pre- and post-test counseling and face to face interviews were conducted to determine client preference. Of the 450 participants, 146 were deemed to be HIV sero-positive using the reference standard (seropositivity rate of 32% (95% confidence interval [CI] 28%, 37%)). The OraQuick test on oral fluid specimens had better performance with a sensitivity of 100% (95% CI 98, 100) and a specificity of 100% (95% CI 99, 100), as compared to the OraQuick test on finger stick specimens with a sensitivity of 100% (95% CI 98, 100), and a specificity of 99.7% (95% CI 98.4, 99.9). The OraQuick oral fluid-based test was preferred by 87% of the participants for first time testing and 60% of the participants for repeat testing. CONCLUSION/SIGNIFICANCE: In a rural Indian hospital setting, the OraQuick Rapid- HIV1/2 test was found to be highly accurate. The oral fluid-based test performed marginally better than the finger stick test. The oral OraQuick test was highly preferred by participants. In the context of global efforts to scale-up HIV testing, our data suggest that oral fluid-based rapid HIV testing may work well in rural, resource-limited settings.