Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case-control analysis.

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

Infectious aetiologies of neonatal illness in south Asia classified using WHO definitions: a primary analysis of the ANISA study.

BACKGROUND: Globally, neonatal mortality accounts for almost half of all deaths in children younger than 5 years. Aetiological agents of neonatal infection are difficult to identify because the clinical signs are non-specific. Using data from the Aetiology of Neonatal Infections in south Asia (ANISA) cohort, we aimed to describe the spectrum of infectious aetiologies of acute neonatal illness categorised post-hoc using the 2015 WHO case definitions of critical illness, clinical severe infection, and fast breathing only. METHODS: Eligible infants were aged 0-59 days with possible serious bacterial infection and healthy infants enrolled in the ANISA study in Bangladesh, India, and Pakistan. We applied a partial latent class Bayesian model to estimate the prevalence of 27 pathogens detectable on PCR, pathogens detected by blood culture only, and illness not attributed to any infectious aetiology. Infants with at least one clinical specimen available were included in the analysis. We assessed the prevalence of these aetiologies according to WHO's case definitions of critically ill, clinical severe infection, and infants with late onset, isolated fast breathing. For the clinical severe definition, we compared the prevalence of signs by bacterial versus viral aetiology. FINDINGS: There were 934 infants (992 episodes) in the critically ill category, 3769 (4000 episodes) in the clinical severe infection category, and 738 (771 episodes) in the late-onset isolated fast breathing category. We estimated the proportion of illness attributable to bacterial infection was 32·7% in infants in the critically ill group, 15·6% in the clinical severe infection group, and 8·8% among infants with late-onset isolated fast breathing group. An infectious aetiology was not identified in 58-82% of infants in these categories. Among 4000 episodes of clinical severe infection, those with bacterial versus viral attribution had higher proportions of hypothermia, movement only when stimulated, convulsions, and poor feeding. INTERPRETATION: Our modelled results generally support the revised WHO case definitions, although a revision of the most severe case definition could be considered. Clinical criteria do not clearly differentiate between young infants with and without infectious aetiologies. Our results highlight the need for improved point-of-care diagnostics, and further study into neonatal deaths and episodes with no identified aetiology, to ensure antibiotic stewardship and targeted interventions. FUNDING: The Bill and Melinda Gates Foundation.

Secular Growth Trends in Early Childhood-Evidence from Two Low-Income Birth Cohorts Recruited over a Decade in Vellore, India.

Stunting and extreme poverty are considered significant risk factors impacting child development in low-and-middle-income countries. We used two birth cohorts recruited 8-9 years apart in urban low-income (slum) settings in Vellore, south India and analyzed secular growth trends and their predictors. In the rotavirus cohort recruited between 2002 and 2003, 373 children completed the 3-year follow-up. "The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development" (MAL-ED) cohort recruited between 2010 and 2012 had 215 children completing follow-up. The MAL-ED cohort had better socio-economic status (SES) markers and mothers were better educated compared with the previous cohort. Children in the MAL-ED cohort had less stunting at 1, 2, and 3 years of age. The linear mixed effects model evaluating linear growth during the first 3 years of age showed that low birth weight and being a female child were associated with stunting in both cohorts. There was no association between SES and stunting in the rotavirus cohort, whereas SES was associated with linear growth in the MAL-ED cohort. Future studies could incorporate nutritional and nonnutritional interventions in vulnerable populations to evaluate their effect on birth weight as well as early childhood stunting.

Developmental trends in early childhood and their predictors from an Indian birth cohort.

BACKGROUND: Early childhood developmental pattern analyses not only project future cognition potential, but also identify potential risks for possible intervention. The current study evaluates developmental trends in the first 3 years of life and their predictors in a low and middle income country setting. METHODS: Trends of early childhood development at 6, 15, 24 and 36 months of age and their predictors were explored in a longitudinal community-based birth cohort study in an urban slum in Vellore, South India. Development was assessed using the Bayley Scales of Infant and Toddler Development-III (BSID-III). RESULTS: The birth cohort enrolled 251 children with 94, 91, 91 and 87% follow-up at 6, 15, 24 and 36 months respectively. Child development domains of cognition, language, motor and social skills showed a significant decline in scores between 6 and 36 months of age. Higher socioeconomic position (SEP) and nurturing home environment contributed to increase in cognition scores by 1.9 and 0.9 units respectively. However, stunting caused a decline in cognition scores by 1.7 units. Higher maternal cognition, higher SEP, and caregiver responsivity positively contributed to language change over time, while higher maternal depression contributed negatively. An enriching home environment, growth parameters and blood iron status had positive association with change in motor skills. CONCLUSIONS: A triple intervention plan to enhance home environment and nurturance, early childhood nutrient supplementation, and maternal education and well-being might prevent child developmental decline in high risk settings.

Characteristics associated with the transition to partial breastfeeding prior to 6 months of age: Data from seven sites in a birth cohort study.

The WHO recommends exclusive breastfeeding for the first 6 months of life. However, the transition of the infants' diet to partial breastfeeding with the addition of animal milks and/or solids typically occurs earlier than this. Here, we explored factors associated with the timing of an early transition to partial breastfeeding across seven sites of a birth cohort study in which twice weekly information on infant feeding practices was collected. Infant (size, sex, illness and temperament), maternal (age, education, parity and depressive symptoms), breastfeeding initiation practices (time of initiation, colostrum and pre-lacteal feeding) and household factors (food security, crowding, assets, income and resources) were considered. Three consecutive caregiver reports of feeding animal milks and/or solids (over a 10-day period) were characterized as a transition to partial breastfeeding, and Cox proportional hazard models with time (in days) to partial breastfeeding were used to evaluate associations with both fixed and time-varying characteristics. Overall, 1470 infants were included in this analysis. Median age of transition to partial breastfeeding ranged from 59 days (South Africa and Tanzania) to 178 days (Bangladesh). Overall, higher weight-for-length z-scores were associated with later transitions to partial breastfeeding, as were food insecurity, and infant cough in the past 30 days. Maternal depressive symptoms (evaluated amongst 1227 infants from six sites) were associated with an earlier transition to partial breastfeeding. Relative thinness or heaviness within each site was related to breastfeeding transitions, as opposed to absolute z-scores. Further research is needed to understand relationships between local perceptions of infant body size and decisions about breastfeeding.

Association between head circumference at two years and second and fifth year cognition.

BACKGROUND: Head circumference (HC) measurement is routinely not performed in early childhood and there is conflicting information about its utility in literature. The current study analyses the association between HC at two years of age and cognition at two and five years of age. METHODS: A community based birth-cohort recruited between 2010 and 2012 was followed up till five years of age in an urban slum in Vellore, India. Children were recruited at birth after informed parental consent by consecutive sampling using eligibility criteria of healthy new-born, singleton pregnancy and family's availability in the study area during follow-up. HC measured at two years of age was used as the exposure variable to calculate association with cognition at both two and five years of age. Cognitive domain of Bayley scale of infant development was used at two years of age and Wechsler Preschool Primary Scales of Intelligence at five years. RESULTS: Of the 251 enrolled children, 138 (55%) were girls and 71 (30%) belonged to lower socioeconomic status. At 2 years, 8.81% of children had HC < - 3SD. Compared to children with HC z-scores ≥ - 2 SD, those with measurements < - 3 SD had a lower cognition scores by - 2.21 [95% CI: - 3.87 - -0.56] at 2 years. Also, children with HC < - 3 SD at two years scored significantly lower scores in cognitive domains of verbal, - 7.35 [95% CI: - 11.78 - -2.92] and performance, - 7.07 [95% CI: - 11.77 - -2.36] intelligence at five years. CONCLUSIONS: This study showed that smaller HC at 2 years of age was negatively associated with cognition at both 2 and 5 years of age. Early childhood HC measurements can be utilised as a cheaper screening tool to identify children at risk in LMIC settings. Further studies can confirm these findings in diverse settings.

Home environment: Short-term trends and predictors in early childhood from an Indian community birth cohort.

BACKGROUND: Early childhood home environment is intricately linked to child development and later cognitive and academic skills. There is limited literature evaluating home environmental trends and predictors in the low- and middle-income country settings. AIMS: Determine the trends of early childhood home environment changes between 6 and 36 months of age, and the factors associated with these changes. STUDY DESIGN: Longitudinal community-based birth cohort follow-up study in a semi-urban slum in Vellore, South India. SUBJECTS: Consecutive sampling of a birth cohort between March 2010 and February 2012. OUTCOME MEASURES: Home environment was objectively assessed using the 'Home Observation for the Measurement of the Environment' (HOME) scale. Predictors of change in the home environment over time also were analyzed. Multivariable linear regression models and linear mixed effect models were used to identify the factors associated with HOME score at individual time points and over-a-time period, respectively. RESULTS: The birth cohort enrolled 251 children with a follow-up of 235, 228 and 218 children at 6, 24 and 36 months, respectively. The socio-economic status (SES) was the single biggest predictor for the HOME score at each time point, with increasing strength over time. Maternal education predicted home environment at 24 months, while maternal depression was negatively associated at 6 and 24 months of age. SES and maternal factors contributed to the overall change in the HOME score. Maternal factors predicted relational home environmental change over time. CONCLUSION: SES and maternal factors consistently predicted early childhood home environment at 6, 24 and 36 months of age and its change over time. It is important to support maternal education and wellbeing along with socio-economic measures to optimize early childhood environment.

Predictors of recovery in children aged 6-59 months with uncomplicated severe acute malnutrition: a multicentre study.

OBJECTIVE: To identify predictors of recovery in children with uncomplicated severe acute malnutrition (SAM). DESIGN: This is a secondary data analysis from an individual randomised controlled trial, where children with uncomplicated SAM were randomised to three feeding regimens, namely ready-to-use therapeutic food (RUTF) sourced from Compact India, locally prepared RUTF or augmented home-prepared foods, under two age strata (6-17 months and 18-59 months) for 16 weeks or until recovery. Three sets of predictors that could influence recovery, namely child, family and nutritional predictors, were analysed. SETTING: Rural and urban slum areas of three states of India, namely Rajasthan, Delhi and Tamil Nadu. PARTICIPANTS: In total, 906 children (age: 6-59 months) were analysed to estimate the adjusted hazard ratio (AHR) using the Cox proportional hazard ratio model to identify various predictors. RESULTS: Being a female child (AHR: 1·269 (1·016, 1·584)), better employment status of the child's father (AHR: 1·53 (1·197, 1·95)) and residence in a rental house (AHR: 1·485 (1·137, 1·94)) increased the chances of recovery. No hospitalisation (AHR: 1·778 (1·055, 2·997)), no fever, (AHR: 2·748 (2·161, 3·494)) and ≤ 2 episodes of diarrhoea (AHR: 1·579 (1·035, 2·412)) during the treatment phase; availability of community-based peer support to mothers for feeding (AHR: 1·61 (1·237, 2·097)) and a better weight-for-height Z-score (WHZ) at enrolment (AHR: 1·811 (1·297, 2·529)) predicted higher chances of recovery from SAM. CONCLUSION: The probability of recovery increases in children with better WHZ and with the initiation of treatment for acute illnesses to avoid hospitalisation, availability of peer support and better employment status of the father.

Risk factors for severe acute malnutrition among children aged 6-59 months: A community-based case-control study from Vellore, Southern India.

BACKGROUND: Malnutrition plays an important role in the economic burden of society as well as the country. This study aimed to identify the various risk factors and determinants of severe acute malnutrition (SAM) as defined by WHO growth reference standards in children aged 6 months to 59 months living in Vellore. METHODS: A community-based case-control study matched for age (±2months), gender and location was done among the children of the age group 6- 59 months residing in both rural and urban Vellore. Children of age group 6-59 months with SAM according to WHO definition, i.e., weight for height of less than -3SD with or without nutritional oedema were classified as cases. Children with weight-for-height z-score more than -1 SD and MUAC ≥13.5cms were classified as controls. With 2 controls per case, the required sample size was 54 cases and 108 controls. A questionnaire used to identify the risk factors including dietary intake. Uni-variate and multivariate analysis was done to generate an odds ratio and 95% confidence interval for the risk factors. RESULTS: Majority of the cases 64.8% and 50% of the controls belonged to low SES. After adjusting all confounders, Severe Acute Malnutrition was significantly associated with birth weight <2.499kg [AOR- 8.95 (95% CI: 2.98-26.85)], not exclusively breastfed for 6 months [AOR 4.67 (95% CI: 1.72-12.65)], inadequate calorie intake [AOR 8.09 (95% CI: 3.15-20.82)] and mother being underweight [AOR 6.87 (95% CI: 1.92-24.55)]. CONCLUSION: Programs should be implemented to reduce the poor nutritional status of young girls and women in the reproductive age group. The importance of exclusive breastfeeding for the first six months, the time of weaning and appropriate feeding practice for the child should be emphasized to postnatal mothers during their hospital visits.

Body iron and lead status in early childhood and its effects on development and cognition: a longitudinal study from urban Vellore.

OBJECTIVE: Early childhood factors can have persisting effects on development and cognition in children. We propose to explore the trends of Fe deficiency and Pb toxicity in early childhood and their association with child development at 2 years of age and cognition at 5 years. DESIGN: Longitudinal birth cohort study. SETTING: Urban slum, Vellore, India. PARTICIPANTS: Children enrolled at birth were followed up regularly in the first 2 years with developmental and cognitive assessments at 2 and 5 years of age, respectively. RESULTS: The birth cohort enrolled 251 children with 228 children followed up at 2 years and 212 at 5 years of age. Fe deficiency (ID) was highest at 15 months of age and improved subsequently at 24 months. Blood Pb levels (BLL) remained high at all age groups with an increasing trend with age; 97 % at 36 months having high BLL. Persistent high mean BLL at 15 and 24 months had negative association with both cognition and expressive language raw scores of 24 months, while high mean BLL at 15, 24 and 36 months had no significant association with any of the domains of cognition at 5 years of age. Early childhood cumulative body Fe status at 7, 15 and 24 months did not show any association with child development at 2 years, but was associated with verbal, performance and processing speed components of cognition at 5 years. CONCLUSIONS: Optimising body Fe status and limiting Pb exposure in early childhood can augment child development and school entry cognition.

Intestinal permeability and inflammation mediate the association between nutrient density of complementary foods and biochemical measures of micronutrient status in young children: results from the MAL-ED study.

BACKGROUND: Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation. OBJECTIVE: We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status. METHODS: Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network. RESULTS: A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations. CONCLUSIONS: EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

Exclusive breastfeeding practices in an urban settlement of Vellore, southern India: findings from the MAL-ED birth cohort.

Background: Exclusive breastfeeding is recommended in the first six months of life. Observing breastfeeding practices and further the introduction of complementary food using a birth cohort can provide a better understanding with reference to the child's growth and nutrition. We aim to describe the exclusive breastfeeding practices in the Indian MAL-ED birth cohort. Methods: The Indian MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort comprises of eight contiguous urban slums in Vellore. Of the 251 children enrolled in the cohort at birth, a 24 month follow-up was completed for 228 children and data collection was from March 2010 through February 2012. Trained field research assistants collected data on exclusive breastfeeding and complementary feeding practices from birth using a structured questionnaire through a biweekly surveillance. Survival and Cox proportional hazard regression analyses were used to estimate the duration of exclusive breastfeeding and factors influencing the same. Results: Breastfeeding was initiated within the first hour of birth in 148 (59%) infants. Colostrum was given in 225 (89.6%) infants whilst 32 (12.7%) infants received prelacteal feeds. Exclusive breastfeeding up to four months was observed in 55 (22.1%, 95% Confidence Interval [CI] 17.1%, 27.5%) infants with only three (1.1%, 95% CI 0.2%, 3.5%) of the cohort mothers continuing to exclusively breastfeed up to six months. Cox proportional hazard regression analysis revealed no gender differences to being exclusive breastfed (Adjusted Hazard Ratio [AHR] 0.97; 95% CI 0.74, 1.27). Children from families of low socioeconomic status had a lower risk of early cessation of exclusive breastfeeding compared to children from middle or higher socioeconomic status (AHR 0.52; 95% CI 0.38, 0.71). Conclusions: Early initiation of exclusive breastfeeding is important and improving rates suggest continuation of efforts in this direction energetically. Continuation of exclusive breastfeeding practice is significantly low in these urban slums with introduction of animal milk and complementary foods even before six months of age. This highlights the urgent need to evaluate pragmatic interventions to raise awareness on the importance of exclusive breastfeeding and its practice.

Low head circumference during early childhood and its predictors in a semi-urban settlement of Vellore, Southern India.

BACKGROUND: Stunting in developing countries continues to be a major public health problem. Measuring head circumference (HC) during clinical anthropometric assessment can help predict stunting. The aim of this study was to assess burden and determine the predictors of low HC (<- 2 SD) at birth and during first 2 years of life in a semi- urban settlement of Vellore. METHODS: The study uses baseline data and serial HC measurements from the birth cohort of MAL-ED study, where 228 children from Vellore completed follow-up between March 2010 to February 2014. Analysis of baseline, maternal and paternal characteristics, micro-nutrient status and cognition with HC measurements was performed using STATA version 13.0 software. RESULTS: The mean HC (±SD) at 1st, 12th and 24th month were 33.37 (1.29) cm, 42.76 (1.23) cm and 44.9 (1.22) cm respectively. A third of the infants (75/228) had HC less than - 2 SD at first month of life, and on follow-up, 50% of the cohort had HC ≤ -2 SD both at 12th and 24th month. Low HC measurements at all three time-points were observed for 21.6% (46/222) infants. Low HC was significantly associated with stunting in 37.3% (OR = 10.8), 57.3% (OR = 3.1) and 44.4% (OR = 2.6) children at 1st, 12th and 24th month respectively. Bivariate analysis of low HC (<- 2 SD) at 12th month showed a statistically significant association with lower socioeconomic status, low paternal and maternal HC and low maternal IQ. Multivariable logistic regression analysis showed maternal (AOR = 0.759, 95% CI = 0.604 to 0.954) and paternal (AOR = 0.734, 95% CI = 0.581 to 0.930) HC to be significantly associated with HC attained by the infant at the end of 12 months. CONCLUSIONS: One-third of the children in our cohort had low head circumference (HC) at birth, with one-fifth recording low HC at all time-points until 2 years of age. Low HC was significantly associated with stunting. Paternal and maternal HC predicted HC in children. HC measurement, often less used, can be a simple tool that can be additionally used by clinicians as well as parents/caregivers to monitor child growth.

Admissions to a sick new born care unit in a secondary care hospital: Profile and outcomes.

BACKGROUND: To reduce neonatal mortality in North Bihar, evidence is required about the impact of sick newborn care units (SNCUs) in secondary level hospitals on mortality at the end of the neonatal period. OBJECTIVES: The objective of the study is to assess the profile of neonates admitted to an SNCU and the outcome at the completion of neonatal period. METHODS: A cohort of neonates admitted from March to June 2014 to an SNCU was assessed through family interviews and hospital records. Demographic details (age, sex, and socioeconomic status) and clinical details (antenatal care, birthplace, weight, diagnosis, and family history) were documented. Follow-up was done at discharge or death or referral and the completion of neonatal period. The primary outcome was survival at the completion of neonatal period. Secondary outcomes were case fatality rate at discharge and weight gain. RESULTS: Of 210 neonates assessed, 87.6% (95% confidence interval [CI] 82.4-91.4) survived till the end of the neonatal period. The case fatality rate at the time of discharge was 0.9% (95% CI 0.3-3.4). Majority of the diagnoses were infections, hyperbilirubinemia, and infant of diabetic mother. Mean weight gain at the end of neonatal period (n = 157) was 706 g (P = 0.00). Sex ratio at admission was 567 girls to 1000 boys (95% CI 428/1000-751/1000). No neonate from lower socioeconomic families was admitted. CONCLUSIONS: SNCUs in remote areas can bring down neonatal mortality in North Bihar. Unequal access of SNCUs services to girls and lower socioeconomic groups highlighted the existing barriers which require attention.

Optimization of dosing regimens of isoniazid and rifampicin in children with tuberculosis in India.

AIMS: Pharmacokinetic studies in the past have shown inadequate antituberculosis drug levels in children with the currently available dosing regimens. This study attempted to investigate the pharmacokinetics of isoniazid and rifampicin, when used in children, and to optimize their dosing regimens. METHODS: Data were collected from 41 children, aged 2-16 years, who were being treated with antituberculosis drugs for at least 2 months. Concentration measurements were done for 6 h and analysed using a nonlinear, mixed-effects model. RESULTS: Isoniazid pharmacokinetics were described by a one-compartment disposition model with a transit absorption model (fixed, n = 5). A mixture model was used to identify the slow and fast acetylator subgroups. Rifampicin was described by a one-compartment disposition model with a transit absorption model (fixed, n = 9). Body weight was added to the clearance and volume of distribution of both the drugs using an allometric function. Simulations with the isoniazid model showed that 84.9% of the population achieved therapeutic peak serum concentration with the planned fixed-dose combination regimen. Simulations with the rifampicin model showed that only about 28.8% of the simulated population achieve the therapeutic peak serum concentration with the fixed-dose combination regimen. A novel regimen for rifampicin, with an average dose of 35 mg kg-1 , was found to provide adequate drug exposure in most children. CONCLUSIONS: The exposure to isoniazid is adequate with present regimens. For rifampicin, a novel dosing regimen was developed to ensure adequate drug concentrations in children. However, further studies are required to assess the dose-effect relationship of higher doses of rifampicin.

Unintentional injuries among children aged 1-5 years: understanding the burden, risk factors and severity in urban slums of southern India.

BACKGROUND: Globally, 5.82 million deaths occurred among children under the age of five years in 2015 and injury specific mortality rate was 73 per 100,000 population. In India, injury specific mortality rate is around 2.1 per 1000 live births contributing to 4% of the total under 5 mortality rate. This study aims to estimate the burden and understand factors associated with unintentional injuries among children aged 1-5 years residing in urban slums of Vellore, southern India. We also attempted to assess the hazards posed by the living environment of these children and study their association with unintentional injury patterns. METHODS: This cross-sectional study was conducted in eight urban slums of Vellore, southern India and primary caregivers of children aged 1-5 years were interviewed with a questionnaire to obtain the details of injuries sustained in the past three months. Environmental hazard risk assessment was conducted at places frequented by these children and their scores calculated. Baseline prevalence and incidence rates of unintentional injuries were estimated. Multivariate logistic regression and poisson regression analysis were performed to examine factors associated with unintentional injuries and repeated injuries respectively. Association between environmental hazard risk and unintentional injuries was estimated. RESULTS: Prevalence of unintentional injuries was 39.1% (95% CI 35.4-42.9%) and incidence rate was 16.5 (95% CI 14.7-18.3) per 100 child months (N = 662). Bivariate analysis revealed that children of working mothers (OR 1.48; 1.01-2.18) and children from overcrowded families (OR 1.78; 1.22-2.60) had increased odds of sustaining unintentional injuries. Multivariate regression analysis revealed that children from overcrowded families had increased odds of sustaining unintentional injuries (AOR 1.66, 95% CI 1.14-2.41). Boys (IRR 1.33, 95% CI 1.07-1.66) and children from overcrowded families (IRR 1.50; 1.14-1.98) were at increased risk of having repeated injuries. There is an increase in incidence rate of injuries with an increased environmental hazard risk, although not statistically significant. CONCLUSIONS: The burden of unintentional injuries was very high among study children when compared to studies in other urban slums in India. Environment plays an important role in the epidemiology of unintentional injuries; providing safe play environment and adequate supervision of children is important to reduce its burden.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Costing of three feeding regimens for home-based management of children with uncomplicated severe acute malnutrition from a randomised trial in India.

TRIAL DESIGN: Three feeding regimens-centrally produced ready-to-use therapeutic food, locally produced ready-to-use therapeutic food, and augmented, energy-dense, home-prepared food-were provided in a community setting for children with severe acute malnutrition (SAM) in the age group of 6-59 months in an individually randomised multicentre trial that enrolled 906 children. Foods, counselling, feeding support and treatment for mild illnesses were provided until recovery or 16 weeks. METHODS: Costs were estimated for 371 children enrolled in Delhi in a semiurban location after active survey and identification, enrolment, diagnosis and treatment for mild illnesses, and finally treatment with one of the three regimens, both under the research and government setting. Direct costs were estimated for human resources using a price times quantity approach, based on their salaries and average time taken for each activity. The cost per week per child for food, medicines and other consumables was estimated based on the total expenditure over the period and children covered. Indirect costs for programme management including training, transport, non-consumables, infrastructure and equipment were estimated per week per child based on total expenditures for research study and making suitable adjustments for estimations under government setting. RESULTS: No significant difference in costs was found across the three regimens per covered or per treated child. The average cost per treated child in the government setting was estimated at US$56 (<3500 rupees). CONCLUSION: Home-based management of SAM with a locally produced ready-to-use therapeutic food is feasible, acceptable, affordable and very cost-effective in terms of the disability-adjusted life years saved and gross national income per capita of the country. The treatment of SAM at home needs serious attention and integration into the existing health system, along with actions to prevent SAM. TRIAL REGISTRATION NUMBER: NCT01705769; Pre-results.