Association of transient mitochondrial functional impairment with acute heat exposure in children from Muzaffarpur region of Bihar, India.

Over the past several years, the Muzaffarpur district of Bihar (India) has witnessed recurrent outbreaks of acute encephalitis illness of unknown etiology, called acute encephalitis syndrome (AES) among young children, especially during the peak-summer season. Pesticide exposure, viral encephalitis, and litchi toxin intake have all been postulated as potential sources of the ailment. However, no conclusive etiology for AES has been identified in the affected children. During recent rounds of the outbreak, metabolic abnormalities have been documented in these children, and a direct correlation was observed between higher environmental temperature during the peak-summer month and AES caseload. The clinical and metabolic profiles of these children suggested the possible involvement of mitochondrial dysfunction during heat stress as one of the several contributory factors leading to multisystem metabolic derangement. The present study observed that mitochondrial function parameters such as cell death, mitochondrial membrane potential, oxidative stress, and mitochondrial pathway-related gene expression in peripheral blood mononuclear cells (PBMCs) isolated from children were affected in peak-summer when compared to post-summer months. Similar observations of mitochondrial function parameters along with impaired bioenergetic parameters were demonstrated in the heat-exposed model of PBMCs isolated from healthy adult individuals. In conclusion, the results suggested that there is an association of transient mitochondrial dysfunction when exposed to sustained heat during the summer months. One may consider mitochondrial dysfunction as one of the important factors leading to an outbreak of AES among the children from affected regions though this needs to be substantiated with further studies.

Promoting family integrated early child development (during first 1000 days) in urban slums of India (fine child 3-3-1000): Study protocol.

AIMS: This project tests a novel, targeted home visitation programme for child development targeted behaviour change during the first 1,000 days for families in Delhi urban slums. BACKGROUND: The first 1,000 days have highest brain development potential and is dependent on the available nutrition, health, social and cognitive stimulus. Over 1.3 million children are born annually in the slums of India and are at risk of limited development potential. The children in urban slums at multiplicity of adversities at family, society and environmental levels. No tools are available for the community health functionaries to support the families to promote child development. DESIGN: This cohort study targets provision of behaviour change interventions targeted at three groups (pregnant women, infants and children in year 2) to document the impact on child development. METHODS: This implementation project delivers nutrition, health and child stimulation integrated services for the families through existing government community health workers and nurses. These workers shall train the families using audio-visual messages in tablets and demonstration kits for practice through quarterly home visits. Data on health, nutrition and child development shall be collected at baseline, midterm and after one year. The data from these participants shall be compared with data from recently delivered women, children aged 13 months and 25 months without intervention to document the impact. DISCUSSION: The successful implementation of the project has potential for future integration of the child development components into the existing programme at scale. The learning from this project shall be useful for India and other developing countries. IMPACT: The first 1,000 days are critical period in human brain development and cognitive function acquisition potential, which is dependent on the available nutrition, health, social and cognitive stimulus. The development potential in children born and living in the slums, who are exposed to various adversities, can be mitigated through appropriate family-level practices with support from the community health workers and Nurses. This study is documenting the feasibility and impact of home visit linked coaching of families for improving child development status during the first 1,000 days in three sums of Delhi, India.

Neurodevelopmental disorders in children aged 2-9 years: Population-based burden estimates across five regions in India.

BACKGROUND: Neurodevelopmental disorders (NDDs) compromise the development and attainment of full social and economic potential at individual, family, community, and country levels. Paucity of data on NDDs slows down policy and programmatic action in most developing countries despite perceived high burden. METHODS AND FINDINGS: We assessed 3,964 children (with almost equal number of boys and girls distributed in 2-<6 and 6-9 year age categories) identified from five geographically diverse populations in India using cluster sampling technique (probability proportionate to population size). These were from the North-Central, i.e., Palwal (N = 998; all rural, 16.4% non-Hindu, 25.3% from scheduled caste/tribe [SC-ST] [these are considered underserved communities who are eligible for affirmative action]); North, i.e., Kangra (N = 997; 91.6% rural, 3.7% non-Hindu, 25.3% SC-ST); East, i.e., Dhenkanal (N = 981; 89.8% rural, 1.2% non-Hindu, 38.0% SC-ST); South, i.e., Hyderabad (N = 495; all urban, 25.7% non-Hindu, 27.3% SC-ST) and West, i.e., North Goa (N = 493; 68.0% rural, 11.4% non-Hindu, 18.5% SC-ST). All children were assessed for vision impairment (VI), epilepsy (Epi), neuromotor impairments including cerebral palsy (NMI-CP), hearing impairment (HI), speech and language disorders, autism spectrum disorders (ASDs), and intellectual disability (ID). Furthermore, 6-9-year-old children were also assessed for attention deficit hyperactivity disorder (ADHD) and learning disorders (LDs). We standardized sample characteristics as per Census of India 2011 to arrive at district level and all-sites-pooled estimates. Site-specific prevalence of any of seven NDDs in 2-<6 year olds ranged from 2.9% (95% CI 1.6-5.5) to 18.7% (95% CI 14.7-23.6), and for any of nine NDDs in the 6-9-year-old children, from 6.5% (95% CI 4.6-9.1) to 18.5% (95% CI 15.3-22.3). Two or more NDDs were present in 0.4% (95% CI 0.1-1.7) to 4.3% (95% CI 2.2-8.2) in the younger age category and 0.7% (95% CI 0.2-2.0) to 5.3% (95% CI 3.3-8.2) in the older age category. All-site-pooled estimates for NDDs were 9.2% (95% CI 7.5-11.2) and 13.6% (95% CI 11.3-16.2) in children of 2-<6 and 6-9 year age categories, respectively, without significant difference according to gender, rural/urban residence, or religion; almost one-fifth of these children had more than one NDD. The pooled estimates for prevalence increased by up to three percentage points when these were adjusted for national rates of stunting or low birth weight (LBW). HI, ID, speech and language disorders, Epi, and LDs were the common NDDs across sites. Upon risk modelling, noninstitutional delivery, history of perinatal asphyxia, neonatal illness, postnatal neurological/brain infections, stunting, LBW/prematurity, and older age category (6-9 year) were significantly associated with NDDs. The study sample was underrepresentative of stunting and LBW and had a 15.6% refusal. These factors could be contributing to underestimation of the true NDD burden in our population. CONCLUSIONS: The study identifies NDDs in children aged 2-9 years as a significant public health burden for India. HI was higher than and ASD prevalence comparable to the published global literature. Most risk factors of NDDs were modifiable and amenable to public health interventions.

Research priorities in Maternal, Newborn, & Child Health & Nutrition for India: An Indian Council of Medical Research-INCLEN Initiative.

In India, research prioritization in Maternal, Newborn, and Child Health and Nutrition (MNCHN) themes has traditionally involved only a handful of experts mostly from major cities. The Indian Council of Medical Research (ICMR)-INCLEN collaboration undertook a nationwide exercise engaging faculty from 256 institutions to identify top research priorities in the MNCHN themes for 2016-2025. The Child Health and Nutrition Research Initiative method of priority setting was adapted. The context of the exercise was defined by a National Steering Group (NSG) and guided by four Thematic Research Subcommittees. Research ideas were pooled from 498 experts located in different parts of India, iteratively consolidated into research options, scored by 893 experts against five pre-defined criteria (answerability, relevance, equity, investment and innovation) and weighed by a larger reference group. Ranked lists of priorities were generated for each of the four themes at national and three subnational (regional) levels [Empowered Action Group & North-Eastern States, Southern and Western States, & Northern States (including West Bengal)]. Research priorities differed between regions and from overall national priorities. Delivery domain of research which included implementation research constituted about 70 per cent of the top ten research options under all four themes. The results were endorsed in the NSG meeting. There was unanimity that the research priorities should be considered by different governmental and non-governmental agencies for investment with prioritization on implementation research and issues cutting across themes.

Effect of Topical Silver Nanoparticle Formulation on Wound Bacteria Clearance and Healing in Patients With Infected Wounds Compared to Standard Topical Antibiotic Application: A Randomized Open-Label Parallel Clinical Trial.

BACKGROUND: Infected wounds pose a special challenge for management, with an increased risk of wound chronicity, systemic infection, and the emergence of antibiotic resistance. Silver nanoparticles have multimodal effects on bacteria clearance and wound healing. This study aimed to document the efficacy of a topical silver nanoparticle-based cream on bacteria clearance and wound healing in infected wounds compared to Mupirocin. METHODS: This open-label parallel randomized clinical trial allocated 86 participants with infected wounds (culture-positive) into Kadermin, silver nanoparticle-based cream arm (n=43) and Mupirocin arm (n=43) and documented the swab culture on day 5 and wound healing at day 28, along with periodic wound status using the Bates-Jensen Wound Assessment Tool. Patients received oral/systemic antibiotics and other medications for underlying diseases. The intention-to-treat principle was adopted for data analysis using the chi-square and Student t tests to document the differences between groups according to variable characteristics. RESULTS: All participants completed the follow-up. On day 5, wound bacteria clearance was observed in 86% and 65.1% of the participants in the Kadermin and Mupirocin arms, respectively (p=0.023). At day 28, complete wound healing was observed in 81.4% and 37.2% of the participants in the Kadermin and Mupirocin arms, respectively (p≤0.001). No local or systemic adverse event or local reaction was observed in any of the participants. CONCLUSION: Kadermin, the silver nanoparticle-based cream, has better efficacy in achieving faster wound bacteria clearance and healing in infected wounds compared to Mupirocin. This may have relevance for its use as an antibiotic-sparing agent in wound management.

Challenges of biomedical research collaboration in India: Perceptions of Indian and international researchers.

Biomedical research collaborations are to be contextualized in the larger global health agenda which also opens up new information pathways, expands research networks, and brings additional resources. A qualitative inquiry was employed to understand the perceived benefits and challenges of research collaborations by biomedical scientists from India (Global South [GS] country) and the Global North (GN). In-depth interviews were conducted with 47 biomedical scientists from India and 06 from the GN. The data was analyzed using the grounded theory approach. Complementarity of skills and resources, access to funds, improved quality of work, an opportunity to conduct multi-centric studies, development of collaborative networks, better and larger number of publications, mutual learning, opportunity to work with credible researchers, address common interests, leverage interpersonal and trusted relationships and larger societal good were some of the critical factors for eagerness of participants in joint scientific endeavors. However, the challenging aspects of dissent and disagreements were the power imbalance between the collaborators, the development of a trust deficit, and local administrative issues. The challenges reported in the current publication, also echoed in several previous publications can be surmounted and negotiated amicably when the rules of the game, law of the land, sharing of the credits, and interest of the collaborating parties are addressed and agreed up in a fair and just manner before the start of the collaboration. Overall biomedical partnerships are complex collaborations with its challenges, the processes are dynamic and outcomes are emergent. This requires constant and proactive evolution of the preparation, implementation and sustainability of the collaborative efforts be it national or international.

Urinary potassium loss in children with acute liver failure and acute viral hepatitis.

OBJECTIVES: The aim of the present study was to determine urinary potassium (K⁺) loss (as measured by fractional excretion of K⁺ [FEK] and transtubular K⁺ gradient [TTKG]) in children with acute liver failure (ALF) and acute viral hepatitis (AVH) at the time of presentation to the hospital and day 45 of follow-up. METHODS: Twenty-five patients with ALF and 84 patients with AVH were worked up for clinical features, liver function tests, and hepatitis viral infections and monitored for outcome. All of the patients with ALF were hospitalized. FEK and TTKG were estimated on the day patients were first seen in the hospital or hospitalized and later on day 45 of follow-up. RESULTS: Sixty percent (15/25) of patients with ALF were hypokalemic (serum K⁺ <3.5 mEq/L) as compared with only 12% (10/84) in the AVH group (P = 0.000) at the time of presentation in the hospital. Inappropriate kaliuresis was present in 80% to 100% of hypokalemic children compared with 0% to 30% of normokalemic individuals at the time of first contact in either the ALF or AVH group. Inappropriate urinary K⁺ loss and serum K⁺ levels in the hypokalemic individuals improved as the hepatic functions recovered by day 45 of follow-up (P = 0.014-0.000). No significant change in kaliuresis was observed among normokalemic subjects between first contact and later on day 45 of follow-up (P = 0.991-0.228). Despite different physiologic mechanisms, appropriateness of kaliuresis measured by FEK and TTKG showed results in the same direction. CONCLUSIONS: Hypokalemia and inappropriate kaliuresis observed during the acute phase of ALF and AVH reversed with clinical and biochemical recovery. In the absence of major gastrointestinal losses and renal abnormalities, there is need to investigate the contributory role of factors like hyperaldosteronism and food intake, which may have therapeutic implications.

Acute Encephalopathy in Children From Muzaffarpur, Bihar, India, and the Potential Role of Ambient Heat Stress-Induced Mitochondrial Dysfunction.

BACKGROUND: Periodic outbreaks of acute encephalopathy in children have been reported from Muzaffarpur, Bihar, India. No infectious cause has been identified for this. This study presents the clinical and metabolic profile of children hospitalized with acute encephalopathy and the potential role of ambient heat stress. METHODS: This cross-sectional study included children (<15 years) with acute encephalopathy admitted from April 4, 2019, to July 4, 2019. The clinical and laboratory investigations included infections, metabolic abnormalities, and muscle tissue analysis. The children who had metabolic derangements but no infectious cause were labeled as acute metabolic encephalopathy. The descriptive analysis summarized the clinical, laboratory, and histopathology findings, and their association with the ambient heat parameters was explored. RESULTS: Out of the 450 children hospitalized (median age, four years), 94 (20.9%) died. Children had early morning onset (89%), seizures (99%), fever (82%), hypoglycemia at admission (64%), raised aminotransferases (60%), and high blood urea (66%). Blood lactate (50%), lactate dehydrogenase (84%), pyruvate (100%), ammonia (32%), and creatinine phosphokinase (69%) were raised. Viral marker tests were negative. The patients had abnormal metabolic markers like decreased blood-free carnitine, elevated blood acylcarnitines, and elevated urinary lactate, oxalate, maleate, adipate, and fatty acid metabolites. Blood carnitine and acylcarnitine levels normalized in 75% of the patients treated with carnitine and coenzyme-Q. Muscle tissues showed megamitochondria on electron microscopy and reduced respiratory enzyme complex-I activity. A significant correlation between the number of admissions and ambient heat indices was observed. CONCLUSIONS: The findings suggest secondary mitochondrial dysfunction as a possible mechanism for acute encephalopathy in children from Muzaffarpur, Bihar, and ambient heat stress as a possible risk factor.

A Longer Quarantine Period May Be Needed for Effective Control of COVID-19 Transmission: Experience From Odisha, India.

Background The novel coronavirus disease (COVID-19) has become pandemic. For effective disease control, quarantine of the infected and exposed cases for an optimal period is critical. Currently, infected individuals are quarantined for 14 days. We tried to check if the quarantine period practiced is optimal in the Indian context. Methods This cross-sectional study was conducted in Odisha, India. We compiled and analyzed the information of 152 laboratory-confirmed SARS-CoV-2 positive cases. Descriptive analysis was conducted. Results Out of the 152 cases, 80% were males, 9.8% were symptomatic, 66.4% had travel history, and 53.9% had contact with COVID-19 cases. The incubation period ranged from 1-50 days with a median of 19.5 days (IQR: 17-27 days). The median periods were similar according to gender, history of contact, and presence of symptoms. Interestingly, 84.7% of the cases had an incubation period of more than 14 days. To cover 95% and 90% of the individuals, the quarantine period may have to be extended to 38 days and 35 days, respectively. Conclusion A longer observed incubation period (minimum 28 days) suggests the extension of the quarantine period for adults beyond the presently practiced 14 days. Considering the fast-spreading outbreak, an extended quarantine period for 28 days or active periodic follow-up could be more effective.

How coping can hide larger systems problems: the routine immunisation supply chain in Bihar, India.

INTRODUCTION: Coping occurs when health system personnel must make additional, often undocumented efforts to compensate for existing system and management deficiencies. While such efforts may be done with good intentions, few studies evaluate the broader impact of coping. METHODS: We developed a computational simulation model of Bihar, India's routine immunisation supply chain where coping (ie, making additional vaccine shipments above stated policy) occurs. We simulated the impact of coping by allowing extra trips to occur as needed up to one time per day and then limiting coping to two times per week and three times per month before completely eliminating coping. RESULTS: Coping as needed resulted in 3754 extra vaccine shipments over stated policy resulting in 56% total vaccine availability and INR 2.52 logistics cost per dose administered. Limiting vaccine shipments to two times per week reduced shipments by 1224 trips, resulting in a 7% vaccine availability decrease to 49% and an 8% logistics cost per dose administered increase to INR 2.73. Limiting shipments to three times per month reduced vaccine shipments by 2635 trips, which decreased vaccine availability by 19% to 37% and increased logistics costs per dose administered by 34% to INR 3.38. Completely eliminating coping further reduced shipments by 1119 trips, decreasing total vaccine availability an additional 24% to 13% and increasing logistics cost per dose administered by 169% to INR 9.08. CONCLUSION: Our results show how coping can hide major system design deficiencies and how restricting coping can improve problem diagnosis and potentially lead to enhanced system design.

Establishing a Demographic, Development and Environmental Geospatial Surveillance Platform in India: Planning and Implementation.

BACKGROUND: Inadequate administrative health data, suboptimal public health infrastructure, rapid and unplanned urbanization, environmental degradation, and poor penetration of information technology make the tracking of health and well-being of populations and their social determinants in the developing countries challenging. Technology-integrated comprehensive surveillance platforms have the potential to overcome these gaps. OBJECTIVE: This paper provides methodological insights into establishing a geographic information system (GIS)-integrated, comprehensive surveillance platform in rural North India, a resource-constrained setting. METHODS: The International Clinical Epidemiology Network Trust International established a comprehensive SOMAARTH Demographic, Development, and Environmental Surveillance Site (DDESS) in rural Palwal, a district in Haryana, North India. The surveillance platform evolved by adopting four major steps: (1) site preparation, (2) data construction, (3) data quality assurance, and (4) data update and maintenance system. Arc GIS 10.3 and QGIS 2.14 software were employed for geospatial data construction. Surveillance data architecture was built upon the geospatial land parcel datasets. Dedicated software (SOMAARTH-1) was developed for handling high volume of longitudinal datasets. The built infrastructure data pertaining to land use, water bodies, roads, railways, community trails, landmarks, water, sanitation and food environment, weather and air quality, and demographic characteristics were constructed in a relational manner. RESULTS: The comprehensive surveillance platform encompassed a population of 0.2 million individuals residing in 51 villages over a land mass of 251.7 sq km having 32,662 households and 19,260 nonresidential features (cattle shed, shops, health, education, banking, religious institutions, etc). All land parcels were assigned georeferenced location identification numbers to enable space and time monitoring. Subdivision of villages into sectors helped identify socially homogenous community clusters (418/676, 61.8%, sectors). Water and hygiene parameters of the whole area were mapped on the GIS platform and quantified. Risk of physical exposure to harmful environment (poor water and sanitation indicators) was significantly associated with the caste of individual household (P=.001), and the path was mediated through the socioeconomic status and density of waste spots (liquid and solid) of the sector in which these households were located. Ground-truthing for ascertaining the land parcel level accuracies, community involvement in mapping exercise, and identification of small habitations not recorded in the administrative data were key learnings. CONCLUSIONS: The SOMAARTH DDESS experience allowed us to document and explore dynamic relationships, associations, and pathways across multiple levels of the system (ie, individual, household, neighborhood, and village) through a geospatial interface. This could be used for characterization and monitoring of a wide range of proximal and distal determinants of health.

Determinants of childhood obesity: need for a trans-sectoral convergent approach.

The emerging burden of non communicable diseases is likely to erode the "Demographic-Dividend" of India and compromise the national growth and development. Increasing rates of childhood obesity globally and in India is a cause for serious public health concern. It is becoming increasingly apparent that obesity is result of complex interplay between multiple genes, environmental factors and human behavior. Clear comprehension of this interaction and pathway is still not clear, making the prevention and management of obesity especially challenging. Globalization and rapid economic growth has led to dramatic changes in the life style of the population including food intake, physical activity, market, environmental factors and social structures. A growing economy, urbanization and motorized transport have increased physical inactivity. A systematic multi-sectoral approach with population health as the center of discourse and attention is the only key to tackle this problem.

Alpha 1 antitrypsin deficiency in children with chronic liver disease in North India.

OBJECTIVE: We attempted to determine the role of alpha-1-antitrypsin (AAT) deficient variants as an etiologic factor for chronic liver disease in North Indian children. DESIGN: This study investigated 1700 children (682 retrospectively and 1018 prospectively) (840 CLD, 410 neonatal cholestasis and 450 without liver disease) for AAT deficiency. SETTING: Tertiary referral center, All India Institute of Medical Sciences, New Delhi. PATIENTS: Of 1250 liver disease patients, 98 (7.8%) were suspected to be AAT deficient on the basis of screening tests (low serum AAT levels and/or absent/faint alpha-1-globulin band on serum agarose electrophoresis and/or diastase resistant PAS positive granules on liver biopsy). MAIN OUTCOME MEASURES: AAT deficient Z or S allele in suspected patients. RESULTS: Z or S allele was not observed on phenotyping (1700 subjects), or with PCR-RFLP, SSCP and sequencing done in 50 of 98 suspected AAT deficient patients. A novel mutation G-to-A at position 333 in exon V was found in two siblings having positive immunohistochemistry for AAT on liver biopsy, both of whom had significant liver disease with portal hypertension. CONCLUSION: In conclusion, AAT deficiency as an etiologic factor for chronic liver disease in childhood appeared to be uncommon in North India.

Non-alcoholic fatty liver disease and childhood obesity.

Obesity has emerged as a significant global health problem in the pediatric population. Pediatric liver disease is a serious complication of childhood obesity. Non-alcoholic steatohepatitis (NASH) is an entity in the spectrum of non-alcoholic fatty liver disease (NAFLD) ranges from fat in the liver--simple steatosis, NASH/ steatohepatitis--fat with in.ammation and/or fibrosis to advanced fibrosis and cirrhosis when fat may no longer be present. NASH is associated with obesity, diabetes, insulin resistance (IR), and hypertriglyceridemia. Children get NAFLD, and the incidence of this pediatric liver disease is rising as childhood obesity becomes increasingly prevalent. Although much remains to be learned about pediatric NAFLD, it is already evident that children with NASH risk progressive liver damage, including cirrhosis. Liver biopsy is required for definitive diagnosis, and other causes of fatty liver in childhood must be excluded. Gradual weight loss through increased regular exercise and a low-fat, low-refined carbohydrate diet appears to be effective. Drug treatments are being developed. The important message is that childhood obesity poses important health problems, including but not limited to potentially severe chronic liver disease. Early diagnosis of children who are only overweight is a worthy goal so that strategies to limit obesity can be instituted as early as possible. Identification of genetic risks is important, but management will invariably require changes in environmental factors. In addition to individual treatment, a multifaceted, societal initiative is required for solving the childhood obesity epidemic.