Analysis of Cholera Risk in India: Insights from 2017-18 Serosurvey Data Integrated with Epidemiologic data and Societal Determinants from 2015-2019.

BACKGROUND: Indian subcontinent being an important region in the fight to eliminate cholera needs better cholera surveillance. Current methods miss most infections, skewing disease burden estimates. Triangulating serosurvey data, clinical cases, and risk factors could reveal India's true cholera risk. METHODS: We synthesized data from a nationally representative serosurvey, outbreak reports and risk factors like water, sanitation and the Multidimensional Poverty Index, to create a composite vulnerability index for assessing state-wise cholera risk in India. We tested 7,882 stored sera samples collected during 2017-18 from individuals aged 9-45 years, for vibriocidal antibodies to Vibrio cholerae O1 using a cut-off titre ≥320 defining as elevated titre. We also extracted data from the 2015-19 Integrated Disease Surveillance Programme and published cholera reports. RESULTS: Overall, 11.7% (CI: 10.4-13.3%) of the sampled population had an elevated titre of cholera vibriocidal antibodies (≥320). The Southern region experienced the highest incidence (16.8%, CI: 12.1-22.8), followed by the West (13.2%, CI: 10.0-17.3) and North (10.7%, CI: 9.3-12.3). Proportion of samples with an elevated vibriocidal titre (≥320) was significantly higher among individuals aged 18-45 years (13.0% CI: 11.2-15.1) compared to children 9-17 years (8.6%, CI 7.3-10.0, p<0.05); we found no differences between sex or urbanicity. Between 2015-2019, the Integrated Disease Surveillance Program (IDSP) reported 29,400 cases of cholera across the country. Using the composite vulnerability index, we found Karnataka, Madhya Pradesh, and West Bengal were the most vulnerable states in India in terms of risk of cholera. CONCLUSION: The present study showed that cholera infection is present in all five regions across India. The states with high cholera vulnerability could be prioritized for targeted prevention interventions.

COVID-19 mortality in 1984 Bhopal gas tragedy survivors: implications for chemically exposed populations.

Leakage of methyl isocyanate from the Union Carbide plant in Bhopal, India, killed thousands and left deleterious trans-generational effects. Gas-exposed populations experience higher rates of lung and metabolic diseases, and immune dysregulation, all associated with adverse outcomes in coronavirus disease 2019 (COVID-19). We used publicly available, official data from government sources to estimate COVID-19-associated crude mortality in populations with and without a history of gas exposure. Overall, there were 1240 deaths among patients hospitalized with known COVID-19 in Bhopal, of which 453 (36.53%) were in gas-exposed individuals, 726 (58.55%) were in gas-unexposed individuals and the exposure status of 61 (4.92%) individuals could not be determined. There were 351 and 375 deaths in gas-unexposed people in the first (April 2020-February 2021) and second (March 2021-July 2021) waves, respectively; in the gas-exposed population, there were 300 and 153 deaths in the two respective waves. The overall annualized crude mortality of COVID-19 was 3.84 (95% CI 3.41 to 4.33) times higher in the gas-exposed population at 83.6 (95% CI 76.1 to 91.7) per 100 000 compared with the gas-unexposed population, at 21.8 (95% CI 20.2 to 23.4) per 100,000. When stratified by age, compared with unexposed people, the gas-exposed individuals experienced 1.88 (95% CI 1.61 to 2.21) and 1.24 (95% CI 1.02 to 1.50) times the mortality rates in the age groups of 35-65 and >65 y, respectively. These findings indicate that gas-exposed individuals are likely to have a higher risk of severe COVID-19 and death and need to be specifically targeted and recognized for preventive and promotive efforts.

Using antioppressive teaching principles to transform a graduate global health course at Johns Hopkins University.

Education systems and pedagogical practices in global public health are facing substantive calls for change during the current and ongoing 'decolonising global health' movement. Incorporating antioppressive principles into learning communities is one promising approach to decolonising global health education. We sought to transform a four-credit graduate-level global health course at the Johns Hopkins Bloomberg School of Public Health using antioppressive principles. One member of the teaching team attended a year-long training designed to support changes in pedagogical philosophy, syllabus development, course design, course implementation, assignments, grading, and student engagement. We incorporated regular student self-reflections designed to capture student experiences and elicit constant feedback to inform real-time changes responsive to student needs. Our efforts at remediating the emerging limitations of one course in graduate global health education provide an example of overhauling graduate education to remain relevant in a rapidly changing global order.

Environmental impacts of mass drug administration programs: exposures, risks, and mitigation of antimicrobial resistance.

Mass drug administration (MDA) of antimicrobials has shown promise in the reduction and potential elimination of a variety of neglected tropical diseases (NTDs). However, with antimicrobial resistance (AMR) becoming a global crisis, the risks posed by widespread antimicrobial use need to be evaluated. As the role of the environment in AMR emergence and dissemination has become increasingly recognized, it is likewise crucial to establish the role of MDA in environmental AMR pollution, along with the potential impacts of such pollution. This review presents the current state of knowledge on the antimicrobial compounds, resistant organisms, and antimicrobial resistance genes in MDA trials, routes of these determinants into the environment, and their persistence and ecological impacts, particularly in low and middle-income countries where these trials are most common. From the few studies directly evaluating AMR outcomes in azithromycin MDA trials, it is becoming apparent that MDA efforts can increase carriage and excretion of resistant pathogens in a lasting way. However, research on these outcomes for other antimicrobials used in MDA trials is sorely needed. Furthermore, while paths of AMR determinants from human waste to the environment and their persistence thereafter are supported by the literature, quantitative information on the scope and likelihood of this is largely absent. We recommend some mitigative approaches that would be valuable to consider in future MDA efforts. This review stands to be a valuable resource for researchers and policymakers seeking to evaluate the impacts of MDA.

Safety and immunogenicity of the Rotavac and Rotasiil rotavirus vaccines administered in an interchangeable dosing schedule among healthy Indian infants: a multicentre, open-label, randomised, controlled, phase 4, non-inferiority trial.

BACKGROUND: Rotavirus is the leading cause of severe dehydrating gastroenteritis among children younger than 5 years in low-income and middle-income countries. Two vaccines-Rotavac and Rotasiil-are used in routine immunisation in India. The safety and immunogenicity of these vaccines administered in a mixed regimen is not documented. We therefore aimed to compare the safety and seroresponse of recipients of a mixed regimen versus a single regimen. METHODS: We did a multicentre, open-label, randomised, controlled, phase 4, non-inferiority trial at two sites in India. We recruited healthy infants aged 6-8 weeks. Infants with systemic disorders, weight-for-height Z scores of less than minus three SDs, or a history of persistent diarrhoea were excluded. Eligible infants were randomly allocated to six groups in equal numbers to receive either the single vaccine regimen (ie, Rotavac-Rotavac-Rotavac [group 1] or Rotasiil-Rotasiil-Rotasiil [group 2]) or the mixed vaccine regimen (ie, Rotavac-Rotasiil-Rotavac [group 3], Rotasiil-Rotavac-Rotasiil [group 4], Rotavac-Rotasiil-Rotasiil [group 5], or Rotasiil-Rotavac-Rotavac [group 6]). Randomisation was done using an online software by site in blocks of at least 12. The primary outcome was seroresponse to rotavirus vaccine, measured using rotavirus-specific serum IgA antibodies 4 weeks after the third dose. The seroresponse rates were compared between recipients of the four mixed vaccine regimens (consisting of various combinations of Rotavac and Rotasiil) with recipients of the single vaccine regimens (consisting of Rotavac or Rotasiil only for all three doses). The non-inferiority margin was set at 10%. Safety follow-ups were done for the duration of study participation. This trial was registered with the Clinical Trials Registry India, number CTRI/2018/08/015317. FINDINGS: Between March 25, 2019, and Jan 15, 2020, a total of 1979 eligible infants were randomly assigned to receive a single vaccine regimen (n=659; 329 in group 1 and 330 in group 2) or a mixed vaccine regimen (n=1320; 329 each in groups 3 and 4, and 331 each in groups 5 and 6). All eligible participants received the first dose, 1925 (97·3%) of 1979 received the second dose, and 1894 (95·7%) received all three doses of vaccine. 1852 (93·6%) of 1979 participants completed the follow-up. The immunogenicity analysis consisted of 1839 infants (1238 [67·3%] in the mixed vaccine regimen and 601 [32·7%] in the single vaccine regimen; 13 samples were insufficient in quantity) who completed vaccination and provided post-vaccination sera. The seroresponse rate in the mixed vaccine regimen group (33·5% [95% CI 30·9-36·2]) was non-inferior compared with the single vaccine regimen group (29·6% [26·1-33·4]); the seroresponse rate difference was 3·9% (95% CI -0·7 to 8·3). The proportion of participants with any type of solicited adverse events was 90·9% (95% CI 88·4-93·0) in the single vaccine regimen group and 91·1% (89·5-92·6) in the mixed vaccine regimen group. No vaccine-related serious adverse events or intussusception were reported during the study. INTERPRETATION: Rotavac and Rotasiil can be safely used in an interchangeable manner for routine immunisation since the seroresponse was non-inferior in the mixed vaccine regimen compared with the single vaccine regimen. These results allow for flexibility in administering the vaccines, helping to overcome vaccine shortages and supply chain issues, and targeting migrant populations easily. FUNDING: Ministry of Health and Family Welfare, Government of India. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Factors associated with mortality among moderate and severe patients with COVID-19 in India: a secondary analysis of a randomised controlled trial.

OBJECTIVE: Large data on the clinical characteristics and outcome of COVID-19 in the Indian population are scarce. We analysed the factors associated with mortality in a cohort of moderately and severely ill patients with COVID-19 enrolled in a randomised trial on convalescent plasma. DESIGN: Secondary analysis of data from a Phase II, Open Label, Randomized Controlled Trial to Assess the Safety and Efficacy of Convalescent Plasma to Limit COVID-19 Associated Complications in Moderate Disease. SETTING: 39 public and private hospitals across India during the study period from 22 April to 14 July 2020. PARTICIPANTS: Of the 464 patients recruited, two were lost to follow-up, nine withdrew consent and two patients did not receive the intervention after randomisation. The cohort of 451 participants with known outcome at 28 days was analysed. PRIMARY OUTCOME MEASURE: Factors associated with all-cause mortality at 28 days after enrolment. RESULTS: The mean (SD) age was 51±12.4 years; 76.7% were males. Admission Sequential Organ Failure Assessment score was 2.4±1.1. Non-invasive ventilation, invasive ventilation and vasopressor therapy were required in 98.9%, 8.4% and 4.0%, respectively. The 28-day mortality was 14.4%. Median time from symptom onset to hospital admission was similar in survivors (4 days; IQR 3-7) and non-survivors (4 days; IQR 3-6). Patients with two or more comorbidities had 2.25 (95% CI 1.18 to 4.29, p=0.014) times risk of death. When compared with survivors, admission interleukin-6 levels were higher (p<0.001) in non-survivors and increased further on day 3. On multivariable Fine and Gray model, severity of illness (subdistribution HR 1.22, 95% CI 1.11 to 1.35, p<0.001), PaO2/FiO2 ratio <100 (3.47, 1.64-7.37, p=0.001), neutrophil lymphocyte ratio >10 (9.97, 3.65-27.13, p<0.001), D-dimer >1.0 mg/L (2.50, 1.14-5.48, p=0.022), ferritin ≥500 ng/mL (2.67, 1.44-4.96, p=0.002) and lactate dehydrogenase ≥450 IU/L (2.96, 1.60-5.45, p=0.001) were significantly associated with death. CONCLUSION: In this cohort of moderately and severely ill patients with COVID-19, severity of illness, underlying comorbidities and elevated levels of inflammatory markers were significantly associated with death. TRIAL REGISTRATION NUMBER: CTRI/2020/04/024775.

Research priorities for control of zoonoses in South Africa.

BACKGROUND: Zoonoses pose major threats to the health of humans, domestic animals and wildlife, as seen in the COVID-19 pandemic. Zoonoses are the commonest source of emerging human infections and inter-species transmission is facilitated by anthropogenic factors such as encroachment and destruction of wilderness areas, wildlife trafficking and climate change. South Africa was selected for a 'One Health' study to identify research priorities for control of zoonoses due to its complex disease burden and an overstretched health system. METHODS: A multidisciplinary group of 18 experts identified priority zoonotic diseases, knowledge gaps and proposed research priorities for the next 5 y. Each priority was scored using predefined criteria by another group of five experts and then weighted by a reference group (n=28) and the 18 experts. RESULTS: Seventeen diseases were mentioned with the top five being rabies (14/18), TB (13/18), brucellosis (11/18), Rift Valley fever (9/11) and cysticercosis (6/18). In total, 97 specific research priorities were listed, with the majority on basic epidemiological research (n=57), such as measuring the burden of various zoonoses (n=24), followed by 20 on development of new interventions. The highest research priority score was for improving existing interventions (0.77/1.0), followed by health policy and systems research (0.72/1.0). CONCLUSION: Future zoonotic research should improve understanding of zoonotic burden and risk factors and new interventions in public health. People with limited rural services, immunocompromised, in informal settlements and high-risk occupations, should be the highest research priority.

One Health, "Disease X" & the challenge of "Unknown" Unknowns.

The emergence of SARS-CoV-2 and its rapid spread globally emphasizes the ever-present threat of emerging and re-emerging infectious diseases. In this review, the pathogen pyramid framework was utilized to identify the "unknown unknowns" associated with the emergence and rapid transmission of novel infectious disease agents. Given that the evolutionary origin of most of the emerging infectious disease agents can be traced to an animal source, we argue the need to integrate the "One Health" approach as a part of surveillance activities. The need for focusing on undertaking global and regional mapping activities to identify novel pathogens is discussed, given that there are an estimated 1.67 million unknown viruses, of which around 631,000 to 827,000 unknown viruses have the capacity to infect human beings. The emerging risks due to the ever-expanding interface between human, animals, both domestic and wildlife, and the environment are highlighted, these are largely driven by the need for safe habitation, growing food, developing infrastructure to support the increasing human population and desire for economic growth. The One Health approach provides a holistic way to address these cross-sectoral issues, by bridging institutional gaps, enumerating priority risk areas and pathogens, and highlighting putative risk factors for subsequent spillover events involving emerging and re-emerging infectious disease pathogens at the human-animal-environment interface.

SARS-CoV-2 re-infection: development of an epidemiological definition from India.

The current investigation was conducted with the objective to develop an epidemiological case definition of possible severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) re-infection and assess its magnitude in India. The epidemiological case definition for SARS-CoV-2 re-infection was developed from literature review of data on viral kinetics. For achieving second objective, the individuals who satisfied the developed case definition for SARS-CoV-2 re-infection were contacted telephonically. Taking available evidence into consideration, re-infection with SARS-CoV-2 in our study was defined as any individual who tested positive for SARS-CoV-2 on two separate occasions by either molecular tests or rapid antigen test at an interval of at least 102 days with one negative molecular test in between. In this archive based, telephonic survey, 58 out of 1300 individuals (4.5%) fulfilled the above-mentioned definition; 38 individuals could be contacted with healthcare workers (HCWs) accounting for 31.6% of the cases. A large proportion of participants was asymptomatic and had higher Ct value during the first episode. While SARS-CoV-2 re-infection is still a rare phenomenon, there is a need for epidemiological definition of re-infection for establishing surveillance systems and this study contributes to such a goal.Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) re-infection is an emerging concern and there is a need to define it. Therefore, working epidemiological case definition for re-infection was developed and its magnitude was explored via archive-based, telephonic survey. Re-infection with SARS-CoV-2 was defined as two positive tests at an interval of at least 102 days with one interim negative test. Thirty-eight of the 58 eligible patients could be contacted with 12 (31.6%) being HCWs. Majority of the participants were asymptomatic and had higher Ct value during their first episode. To conclude, a working epidemiological case definition of SARS-CoV-2 re-infection is important to strengthen surveillance. The present investigation contributes to this goal and records reinfection in 4.5% of SARS-CoV-2 infected individuals in India.

Assessment of effectiveness of Japanese encephalitis vaccination in West Bengal, India using sample positivity rate as an alternate measure.

BACKGROUND & OBJECTIVES: Japanese encephalitis (JE), is a vaccine preventable mosquito borne arboviral disease. The State Health Department of West Bengal, India started a vaccination programme using live attenuated, single dose JE vaccine (SA-14-14-2) in children aged 1-below15 years since 2006 in five districts. The objectives were to compare Sample Positivity Rates (SPR) of Acute Encephalitis Syndrome (AES) cases for JE between vaccinated & unvaccinated districts and observe trend of SPR & Cumulative Incidence in vaccinated districts for three years. METHODS: The study was based on the analysis of surveillance data from all tested AES cases including confirmed JE (IgM ELISA) from all JE testing facilities existent in the state during the study period (2011-13). Calculation of Cumulative Incidence, Odds Ratio (OR) with 95% CI, Preventive Fraction and Chi Square for trend (for SPR) was done. Trend of incidence was assessed by linear regression. RESULTS: In three years, 5 vaccinated districts contributed 945 AES and 88 JE cases (SPR - 9.3%) compared to 1807 and 254 (SPR - 14.1%) JE cases in 14 unvaccinated districts. Effectiveness of vaccination was evident by gradual decline of Odds Ratio in favour of vaccinated districts. Vaccination effectiveness of 68% overall and 80% [OR = 0.20 (0.10 - 0.41)] in below 15 years were observed. Trend of SPR was found significantly declining in most of the vaccinated districts. INTERPRETATION & CONCLUSION: Significant reduction in sample positivity rate over three years in most of the vaccinated districts indicated that the vaccination programme had been gradually effective.

Water, Sanitation, and Hygiene Practices in Urban Slums of Eastern India.

BACKGROUND: The Sustainable Development Goals identified universal access to water and sanitation facilities as key components for improving health. We assessed water, sanitation, and hygiene (WASH) practices and associated determinants among residents of urban slums in Kolkata, India. METHODS: Information on WASH practices was collected in 2 surveys (2018 and 2019) from participants of a prospective enteric fever surveillance conducted in 2 municipal wards of Kolkata. A composite WASH practice score was computed and a hierarchical stepwise multiple linear regression model constructed to identify key determinants of improved WASH score. RESULTS: Over 90% of households had access to piped water; 6% reported access to continuous supply. Adult women (61% in 2018; 45% in 2019) spent 20 minutes daily to fetch water. Access to improved latrines was almost universal, although 80% used shared facilities. Unhealthy disposal of children's stools was reported in both rounds. Food hygiene practices were high, with most (>90%) washing uncooked items before eating; frequent consumption of street food items was reported. CONCLUSIONS: The study area reported high WASH coverage. Unhygienic behavioral patterns predisposing to food- or water-borne diseases were also noted. Awareness building and sustainable community mobilization for food hygiene needs to be emphasized to ensure community well-being.

Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial).

OBJECTIVE: To investigate the effectiveness of using convalescent plasma to treat moderate coronavirus disease 2019 (covid-19) in adults in India. DESIGN: Open label, parallel arm, phase II, multicentre, randomised controlled trial. SETTING: 39 public and private hospitals across India. PARTICIPANTS: 464 adults (≥18 years) admitted to hospital (screened 22 April to 14 July 2020) with confirmed moderate covid-19 (partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2) ratio between 200 mm Hg and 300 mm Hg or a respiratory rate of more than 24/min with oxygen saturation 93% or less on room air): 235 were assigned to convalescent plasma with best standard of care (intervention arm) and 229 to best standard of care only (control arm). INTERVENTIONS: Participants in the intervention arm received two doses of 200 mL convalescent plasma, transfused 24 hours apart. The presence and levels of neutralising antibodies were not measured a priori; stored samples were assayed at the end of the study. MAIN OUTCOME MEASURE: Composite of progression to severe disease (PaO2/FiO2 <100 mm Hg) or all cause mortality at 28 days post-enrolment. RESULTS: Progression to severe disease or all cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the intervention arm and 41 (18%) in the control arm (risk difference 0.008 (95% confidence interval -0.062 to 0.078); risk ratio 1.04, 95% confidence interval 0.71 to 1.54). CONCLUSION: Convalescent plasma was not associated with a reduction in progression to severe covid-19 or all cause mortality. This trial has high generalisability and approximates convalescent plasma use in real life settings with limited laboratory capacity. A priori measurement of neutralising antibody titres in donors and participants might further clarify the role of convalescent plasma in the management of covid-19. TRIAL REGISTRATION: Clinical Trial Registry of India CTRI/2020/04/024775.