Altered autophagic flux in GNE mutant cells of Indian origin: Potential drug target for GNE myopathy.

Autophagy phenomenon in the cell maintains proteostasis balance by eliminating damaged organelles and protein aggregates. Imbalance in autophagic flux may cause accumulation of protein aggregates in various neurodegenerative disorders. Regulation of autophagy by either calcium or chaperone play a key role in the removal of protein aggregates from the cell. The neuromuscular rare genetic disorder, GNE Myopathy, is characterized by accumulation of rimmed vacuoles having protein aggregates of ß-amyloid and tau that may result from altered autophagic flux. In the present study, the autophagic flux was deciphered in HEK cell-based model for GNE Myopathy harbouring GNE mutations of Indian origin. The refolding activity of HSP70 chaperone was found to be reduced in GNE mutant cells compared to wild type controls. The autophagic markers LC3II/I ratio was altered with increased number of autophagosome formation in GNE mutant cells compared to wild type cells. The cytosolic calcium levels were also increased in GNE mutant cells of Indian origin. Interestingly, treatment of GNE mutant cells with HSP70 activator, BGP-15, restored the expression and refolding activity of HSP70 along with autophagosome formation. Treatment with calcium chelator, BAPTA-AM restored the cytoplasmic calcium levels and autophagosome formation but not LC3II/I ratio significantly. Our study provides insights towards GNE mutation specific response for autophagy regulation and opens up a therapeutic advancement area in calcium signalling and HSP70 function for GNE related Myopathy.

Recalibrating the Non-Communicable Diseases risk prediction tools for the rural population of Western India.

BACKGROUND: The aim of the present study was to recalibrate the effectiveness of Indian Diabetes Risk Score (IDRS) and Community-Based Assessment Checklist (CBAC) by opportunistic screening of Diabetes Mellitus (DM) and Hypertension (HT) among the people attending health centres, and estimating the risk of fatal and non-fatal Cardio-Vascular Diseases (CVDs) among them using WHO/ISH charts. METHODS: All the people aged ≥ 30 years attending the health centers were screened for DM and HT. Weight, height, waist circumference, and hip circumferences were measured, and BMI and Waist-Hip Ratio (WHR) were calculated. Risk categorization of all participants was done using IDRS, CBAC, and WHO/ISH risk prediction charts. Individuals diagnosed with DM or HT were started on treatment. The data was recorded using Epicollect5 and was analyzed using SPSS v.23 and MedCalc v.19.8. ROC curves were plotted for DM and HT with the IDRS, CBAC score, and anthropometric parameters. Sensitivity (SN), specificity (SP), Positive Predictive Value (PPV), Negative Predictive Value (NPV), Accuracy and Youden's index were calculated for different cut-offs of IDRS and CBAC scores. RESULTS: A total of 942 participants were included for the screening, out of them, 9.2% (95% CI: 7.45-11.31) were diagnosed with DM for the first time. Hypertension was detected among 25.7% (95% CI: 22.9-28.5) of the participants. A total of 447 (47.3%) participants were found with IDRS score ≥ 60, and 276 (29.3%) with CBAC score > 4. As much as 26.1% were at moderate to higher risk (≥ 10%) of developing CVDs. Area Under the Curve (AUC) for IDRS in predicting DM was 0.64 (0.58-0.70), with 67.1% SN and 55.2% SP (Youden's Index 0.22). While the AUC for CBAC was 0.59 (0.53-0.65). For hypertension both the AUCs were 0.66 (0.62-0.71) and 0.63 (0.59-0.67), respectively. CONCLUSIONS: IDRS was found to have the maximum AUC and sensitivity thereby demonstrating its usefulness as compared to other tools for screening of both diabetes and hypertension. It thus has the potential to expose the hidden NCD iceberg. Hence, we propose IDRS as a useful tool in screening of Diabetes and Hypertension in rural India.

CKD is the Major Cause of Death in Uddanam: A Population-Representative Study Using Smart Verbal Autopsy.

Introduction: Uddanam is an agricultural area with a high burden of chronic kidney disease of unknown etiology (CKDu). Despite reports of many deaths due to CKD in the lay press, the exact contribution of CKD to deaths remains uncertain because most deaths occur outside medical care. Methods: We used SmartVA automated verbal autopsy tool to ascertain the cause-specific mortality fractions among a 2419 subject-strong general population cohort of adult subjects in Uddanam between 2018 and 2022. Verbal autopsy interviews were conducted twice with the family members of the deceased. Results: A total of 133 deaths were recorded, giving a crude death rate of 5.5%, 10 times higher than that recorded in national surveys. CKD was responsible for 45% of all deaths, followed by ischemic heart disease (15%) and respiratory disease (6%). Conclusion: This study confirms CKD as the leading cause of mortality in this high CKD burden area and provides crucial data for public health decision-making and resource allocation.

Patterns of multimorbidity among a community-based cohort in rural India.

Background: Multimorbidity estimates are expected to increase in India primarily due to the population aging. However, there is a lack of research estimating the burden of multimorbidity in the Indian context using a validated tool. We estimated the prevalence and determinants of multimorbidity amongst the adult population of the rural Uddanam region, Andhra Pradesh. Methods: This community-based cross-sectional study was conducted as a part of an ongoing research program. Multistage cluster sampling technique was used to select 2419 adult participants from 40 clusters. Multimorbidity was assessed using Multimorbidity Assessment Questionnaire for Primary Care (MAQ-PC) tool, collecting information on 13 chronic diseases. Patient Health Questionnaire (PHQ-12) was used to screen for depression. Multiple logistic regression was conducted to identify the strongest determinants of multimorbidity. Results: Of the 2419 participants, 2289 completed the MAQ-PC tool. Mean age (standard deviation) of participants was 48.1 (13.1) years. The overall prevalence of multimorbidity was 58.5% (95% CI 56.5-60.6); with 30.7%, 15.6%, and 12.2% reporting two, three, and four chronic conditions, respectively. Acid peptic disease-musculoskeletal disease (44%) and acid peptic disease-musculoskeletal disease-hypertension (14.9%) were the most common dyad and triad. Among metabolic diseases, diabetes-hypertension (28.3%) and diabetes-hypertension-chronic kidney disease (7.6%) were the most common dyad and triad, respectively. Advancing age, female gender, and being obese were the strongest determinates of the presence of multimorbidity. Depression was highly prevalent among the study population, and participants with higher PHQ-12 score had 3.7 (2.5-5.4) greater odds of having multimorbidity. Conclusions: Our findings suggest that six of 10 adults in rural India are affected with multimorbidity. We report a higher prevalence of multimorbidity as compared with other studies conducted in India. We also identified vulnerable groups which would guide policy makers in developing holistic care packages for individuals with multimorbidity.

Challenges in implementation of mother milk banks in Rajasthan: A situational analysis.

BACKGROUND: Breastmilk is the baby's "first vaccine". Donated human milk (DHM) is the next best alternative when a mother's milk is not available, as recommended by WHO- UNICEF. DHM as a nutritional source provides similar immune protection and may prove revolutionary in reducing neonatal morbidity and mortality. The study aimed to explore the challenges in the implementation of selected Mother Milk Banks (MMBs) of Rajasthan. MATERIAL AND METHODS: A qualitative in-depth interview of key stakeholders was conducted to know the various facets of the challenges in milk banking practices using the Root Cause Analysis framework. RESULTS: The system challenges identified in the functioning of AMMBs were lack of recurring funds, dedicated lactational counselors, and trained technicians. Databases for demand-supply estimates were also lacking. The community challenges were low acceptance of DHM due to safety concerns, risk of disease transmission, and quality of donated milk. Moreover, the religious stigma and cultural beliefs regarding the transfer of heredity traits and decrease in mother-child affection act as barriers in donating milk. CONCLUSION: For acceptance and availability of DHM, Social Behavior Communication Change (SBCC) interventions must be incorporated early during the antenatal check-up period. Our study highlighted the role of education; motivation by healthcare providers has a major influence on infant feeding choices. In a developing country such as India, where the frameworks concerning the development of mother milk banks are still maturing, our study findings provide baseline information to address the barriers in the implementation of mother milk banks in India.

Health literacy, preventive COVID 19 behaviour and adherence to chronic disease treatment during lockdown among patients registered at primary health facility in urban Jodhpur, Rajasthan.

BACKGROUND AND AIMS: Potential role of health literacy in determining adherence to COVID-19 preventive behavior, pharmacological, and lifestyle management among diagnosed patients of chronic diseases during nationwide lockdown is inadequately investigated. METHODS: A cross-sectional study was conducted from May-August 2020 among diagnosed patients of chronic diseases residing in a COVID-19 hotspot of urban Jodhpur, Rajasthan, and availing health services from primary care facility. Telephonic interviews of participants were conducted to determine their health literacy using HLS-EU-Q47 questionnaire, adherence to COVID-19 preventive behaviour as per World Health Organization recommendations, and compliance to prescribed pharmacological and physical activity recommendations for chronic disease. RESULTS: All the 605 diagnosed patients of chronic diseases availing services from primary care facility were contacted for the study, yielding response rate of 68% with 412 agreeing to participate. Insufficient health literacy was observed for 65.8% participants. Only about half of participants had scored above median for COVID-19 awareness (55.1%) and preventive behavior (45.1%). Health literacy was observed to be significant predictor of COVID-19 awareness [aOR: 3.53 (95% CI: 1.81-6.88)]; COVID-19 preventive behavior [aOR: 2.06, 95%CI; 1.14-3.69] and compliance to pharmacological management [aOR: 3.05; 95% CI: 1.47-6.35] but not for physical activity. CONCLUSION: COVID-19 awareness, preventive behavior, and compliance to pharmacological management is associated with health literacy among patients of chronic disease availing services from primary health facility. Focusing on health literacy could thus be an essential strategic intervention yielding long term benefits.

Tobacco, alcohol use and other risk factors for developing symptomatic COVID-19 vs asymptomatic SARS-CoV-2 infection: a case-control study from western Rajasthan, India.

BACKGROUND: Understanding risk factors of symptomatic coronavirus disease 2019 (COVID-19) vis-à-vis asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severe disease and death is important. METHODS: An unmatched case-control study was conducted through telephonic interviews among individuals who tested positive for SARS-CoV-2 in Jodhpur, India from 23 March to 20 July 2020. Contact history, comorbidities and tobacco and alcohol use were elicited using standard tools. RESULTS: Among 911 SARS-CoV-2-infected individuals, 47.5% were symptomatic, 14.1% had severe COVID-19 and 41 (4.5%) died. Older age, working outside the home, cardiac and respiratory comorbidity and alcohol use were found to increase the risk of symptomatic disease as compared with asymptomatic infection. Current tobacco smoking (odds ratio [OR] 0.46 [95% confidence interval {CI} 0.26 to 0.78]) but not smokeless tobacco use (OR 0.81 [95% CI 0.55 to 1.19]) appeared to reduce the risk of symptomatic disease. Age ≥60 y and renal comorbidity were significantly associated with severe COVID-19. Age ≥60 y and respiratory and cardiac comorbidity were found to predispose to mortality. CONCLUSIONS: The apparent reduced risk of symptomatic COVID-19 among tobacco smokers could be due to residual confounding owing to unknown factors, while acknowledging the limitation of recall bias. Cross-protection afforded by frequent upper respiratory tract infection among tobacco smokers could explain why a similar association was not found for smokeless tobacco use, thereby being more plausible than the 'nicotinic hypothesis'. Those with comorbidities and age ≥60 y should be prioritized for hospital admission.

Multisectoral approach to achieve canine rabies controlled zone using Intervention Mapping: Preliminary results.

BACKGROUND: Annually, in India, millions of dog bite cases occur; most of them are inflicted by a stray dog. There are over 25 million dogs in the country. The rate of stray dog vaccination is suboptimal in India. This study aims to develop an intervention strategy, using Intervention Mapping framework, tailored for the target community to achieve canine rabies controlled zone. METHODOLOGY: This is an exploratory, cross-sectional study conducted at a tertiary care Medical Institute at Jodhpur, Rajasthan, India, from 2018-2019. The semi-structured, In-Depth Discussion was conducted with a multidisciplinary planning group comprising of members from veterinary, health, and administrative sectors. The In-Depth Discussion focused on knowledge regarding complete stray dog vaccination schedule, self-efficacy (to prevent dog bites), challenges, and barriers faced by residents to achieve canine rabies controlled zone. Further, discussion with veterinary stakeholders focused on challenges faced for rigorous implementation of stray dog vaccination and sterilization. RESULTS: In-Depth Discussion revealed the following challenges: Lack of participation by the study population for canine vaccination, incomplete knowledge about annual canine vaccination schedule, lack of understanding of dog gestures, lack of infrastructure and resources at veterinary hospitals. The majority of the dogs in the study area were stray dogs that were partially or non-vaccinated and non-sterilized. An intersectoral collaboration was achieved between the community members, veterinary stakeholders both private and Non-Governmental organisations, and heath sector. Following which 35 (76.0%) stray dogs were vaccinated, and 17 (35.4%) were sterilized with community support. Burden of dog bite cases also decreased. The stray dog density map was prepared, and community engagement activity on dog gestures was conducted. CONCLUSION: The present study demonstrates the feasibility of achieving canine rabies controlled zone. When implemented in a phase-wise manner across all Medical and Residential complex, this strategy would ensure achieving canine rabies controlled zone through multi-stakeholder engagement.

Burden of internet addiction, social anxiety and social phobia among University students, India.

BACKGROUND: Social anxiety disorder (SAD) is a common mental health disorder affecting adolescents often associated with comorbidities like depression, suicide ideation and substance abuse. The objective of this study was to estimate the prevalence of social anxiety in adolescents and to explore its correlation with internet usage. METHODS: An exploratory cross-sectional study was conducted among 307 undergraduate students to screen for social anxiety and social phobia using a validated instrument, social interaction anxiety scale (SIAS). Young's internet addiction scale was used for measuring internet addiction. Respondents were categorised according to the scores obtained and later compared with their internet addiction behaviours. RESULTS: Internet addiction was seen in 93.8% of respondents. The prevalence of SAD was estimated to be 15.3%. Internet addiction was positively correlated with social anxiety score (Pearson correlation = 0.994, P < 0.001). CONCLUSION: More than 90% of participants had internet addiction, the majority had mild-moderate internet addiction. Social anxiety was present in more than one-third of the participants. SAD was found to be associated with internet addiction.

Steering the predictors to improve the knowledge and utilization of partograph by skilled birth attendants: An intervention study.

CONTEXT: It was hypothesized that knowledge of skilled birth attendants (SBAs) about partograph and its utilization can be improved by modifying their predictors through training workshops. AIM: To upgrade the knowledge regarding partograph and its utilization by SBAs by modifying their predictors through training workshops. SETTINGS AND DESIGN: This was an intervention study, which was conducted in a rural area of the Jodhpur district of Rajasthan state. SUBJECTS AND METHODS: The SBAs were interviewed through pre and postintervention with the help of a prevalidated semi-structured interview schedule. As a part of an intervention, a series of half-day training workshops were conducted in the intervention block. Data were analyzed using SPSS version 23. STATISTICAL ANALYSIS USED: Descriptive statistics, univariate (Chi-square, t-test), and multivariate (logistic regression) analysis. RESULTS: A total of 213 SBAs (105 from intervention and 108 from control block) were included in the study. SBAs who had received training related to the partograph were having significantly higher odds of knowing (AOR = 22.6[10.7-47.9]) as well as utilization (AOR = 22.5[7.05-72.1]) of partographs as compared to their counterparts. Knowledge was also a significant predictor of the utilization of partograph. Intervention could significantly improve the knowledge of SBAs about partograph as well as its utilization in the intervention block. CONCLUSION: Significant impact of the intervention on knowledge about partograph and its utilization was evidenced in the present study. There is a need to conduct training and refresher courses for healthcare workers on partograph use.

Transmission Dynamics of the COVID-19 Epidemic at the District Level in India: Prospective Observational Study.

BACKGROUND: On March 9, 2020, the first COVID-19 case was reported in Jodhpur, Rajasthan, in the northwestern part of India. Understanding the epidemiology of COVID-19 at a local level is becoming increasingly important to guide measures to control the pandemic. OBJECTIVE: The aim of this study was to estimate the serial interval and basic reproduction number (R0) to understand the transmission dynamics of the COVID-19 outbreak at a district level. We used standard mathematical modeling approaches to assess the utility of these factors in determining the effectiveness of COVID-19 responses and projecting the size of the epidemic. METHODS: Contact tracing of individuals infected with SARS-CoV-2 was performed to obtain the serial intervals. The median and 95th percentile values of the SARS-CoV-2 serial interval were obtained from the best fits with the weibull, log-normal, log-logistic, gamma, and generalized gamma distributions. Aggregate and instantaneous R0 values were derived with different methods using the EarlyR and EpiEstim packages in R software. RESULTS: The median and 95th percentile values of the serial interval were 5.23 days (95% CI 4.72-5.79) and 13.20 days (95% CI 10.90-18.18), respectively. R0 during the first 30 days of the outbreak was 1.62 (95% CI 1.07-2.17), which subsequently decreased to 1.15 (95% CI 1.09-1.21). The peak instantaneous R0 values obtained using a Poisson process developed by Jombert et al were 6.53 (95% CI 2.12-13.38) and 3.43 (95% CI 1.71-5.74) for sliding time windows of 7 and 14 days, respectively. The peak R0 values obtained using the method by Wallinga and Teunis were 2.96 (95% CI 2.52-3.36) and 2.92 (95% CI 2.65-3.22) for sliding time windows of 7 and 14 days, respectively. R0 values of 1.21 (95% CI 1.09-1.34) and 1.12 (95% CI 1.03-1.21) for the 7- and 14-day sliding time windows, respectively, were obtained on July 6, 2020, using method by Jombert et al. Using the method by Wallinga and Teunis, values of 0.32 (95% CI 0.27-0.36) and 0.61 (95% CI 0.58-0.63) were obtained for the 7- and 14-day sliding time windows, respectively. The projection of cases over the next month was 2131 (95% CI 1799-2462). Reductions of transmission by 25% and 50% corresponding to reasonable and aggressive control measures could lead to 58.7% and 84.0% reductions in epidemic size, respectively. CONCLUSIONS: The projected transmission reductions indicate that strengthening control measures could lead to proportionate reductions of the size of the COVID-19 epidemic. Time-dependent instantaneous R0 estimation based on the process by Jombart et al was found to be better suited for guiding COVID-19 response at the district level than overall R0 or instantaneous R0 estimation by the Wallinga and Teunis method. A data-driven approach at the local level is proposed to be useful in guiding public health strategy and surge capacity planning.

Knowledge and Parity: Perspectives of Usage of Emergency Contraceptive Pills among Women of a Rural Area of Delhi.

CONTEXT: Correct use of emergency contraceptive pills (ECPs) may prevent up to 95% of unwanted pregnancies which may significantly decrease unsafe abortions and maternal mortality. AIMS: Assessment of knowledge and use of ECPs among women and to explore factors associated with them. MATERIALS AND METHODS: This was a facility-based cross-sectional study. Data were collected using a prestructured, pretested questionnaire from 381 reproductive age women (15-49 years) selected by systematic random sampling. Statistical Package for the Social Sciences version 16 and Epi info (version 7.0.) were used for all statistical analyses. Descriptive analysis was performed, and results were expressed in terms of frequencies and percentages. The Chi-square and Fisher's exact test were used as tests of significance in univariate analysis. Determinants of use of ECPs were identified using logistic regression. RESULTS: Of 381 women interviewed, awareness level of ECPs (ever heard about ECPs) was found to be 34% (n = 128). Ever use of emergency contraception was reported by 38 (9.7%). Age (odds ratio [OR] = 3.02, 95% confidence interval [CI] [1.88-4.87]), education (OR = 0.086, 95% CI [0.047-0.158]), husband's education (OR = 0.11, 95% CI [0.067-0.187]), socioeconomic status (OR = 6.14, 95% CI [3.28-11.51]), and family status (OR = 2.6, 95% CI [1.59-4.24]) were found to be significantly associated with the use of emergency contraceptives. CONCLUSIONS: The study identified that most respondents lack adequate knowledge about ECPs, and ever use of ECPs was very low. Factors that were associated with the use of ECPs were age, literacy, socioeconomic status, and knowledge about the method. Creating a sustainable awareness on ECPs and their use may serve them with power to control their parity.