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Obesity is caused by a prolonged positive energy balance1,2. Whether reduced energy expenditure stemming from reduced activity levels contributes is debated3,4. Here we show that in both sexes, total energy expenditure (TEE) adjusted for body composition and age declined since the late 1980s, while adjusted activity energy expenditure increased over time. We use the International Atomic Energy Agency Doubly Labelled Water database on energy expenditure of adults in the United States and Europe (n = 4,799) to explore patterns in total (TEE: n = 4,799), basal (BEE: n = 1,432) and physical activity energy expenditure (n = 1,432) over time. In males, adjusted BEE decreased significantly, but in females this did not reach significance. A larger dataset of basal metabolic rate (equivalent to BEE) measurements of 9,912 adults across 163 studies spanning 100 years replicates the decline in BEE in both sexes. We conclude that increasing obesity in the United States/Europe has probably not been fuelled by reduced physical activity leading to lowered TEE. We identify here a decline in adjusted BEE as a previously unrecognized factor.

Anemia control has hitherto been through prophylaxis with weekly iron folic acid (IFA) in Indian women of reproductive age (WRA). Recently, a more precise approach has been proposed, that uses a 'screen and treat with IFA' approach for anemic WRA, combined with continued prophylactic IFA in non-anemic WRA. The efficacy of this approach was assessed in Indian WRA, along with changes in iron status biomarkers.Young WRA (n = 470), aged 17-21 y, were screened for their venous blood hemoglobin (Hb) and treated with IFA for 90 days according to their grade of anemia, or if non-anemic, administered prophylactic IFA, per Indian policy guidelines, and then followed-up for an additional 9-months. Their Hb, plasma ferritin (PF), transferrin receptor, hepcidin and C-reactive protein concentrations were measured at baseline, during treatment and further follow-up. Anemia was diagnosed using Hb (12 g/dL) and iron deficiency (ID) using PF (15 μg/L) cut-offs after adjustment for inflammation. Co-existence of anemia and ID was labelled iron deficiency anemia (IDA).At baseline, in the whole group anemia, ID and IDA prevalence was 69.6%, 68.7% and 62.4%, respectively. At 90 days, IFA treatment or prophylaxis significantly reduced anemia by 40 percentage points (pp), from 69.6% at baseline to 29.8%; ID by 47.3 pp, and IDA by 48 pp. Moreover, significant treatment effects persisted at 365 days of follow-up.The 'screen and treat with IFA' approach is efficacious in reducing the prevalence of anemia in general among WRA, with persistent and significant effects after 9 months of follow-up.CTRI No:2019/02/017806, http://ctri.nic.in/.

BACKGROUND It is thought that there is a high risk of zinc deficiency in India, but there are no representative national estimates. OBJECTIVES We aimed to evaluate the national and state-level prevalence of low serum zinc concentrations (SZCs) in Indian children from the nationally representative Comprehensive National Nutrition Survey. METHODS Prevalence of low SZC, adjusted for C-reactive protein, was estimated among preschool (1-4 y; n = 7874) and school-age children (5-9 y; n = 10,430) and adolescents (10-19 y; n = 10,140), using SZC cutoffs defined by the International Zinc Nutrition Consultative Group. RESULTS Prevalence of low SZC was high among adolescents (31.1%; 95% CI: 29.8%, 32.4%), compared with school-age (15.8%; 95% CI: 15.3%, 16.3%) or preschool children (17.4%; 95% CI: 16.7%, 18.0%). However, stratification of prevalence by fasting status or using an alternative lower SZC cutoff independent of fasting status led to a reduction in prevalence by 3.7% or 7.8% in children

To describe the occurrence, microbiology, and risk factors of catheter- associated urinary tract infections (CA-UTI) in critically ill children.We conducted a review of hospital records for CA-UTI in the pediatric intensive care unit (PICU) over a 7-year period (2014-2020).62 CA-UTI cases (48% boys, median (IQR) age 36 (12,96 month) were identified during the study period with occurrence rate of 7.2/1000 catheter-days. The most common organisms were Escherichia coli (32.4%) and Enterococcus faecalis (30.6%). Using a multivariate logistic regression analysis, the significant associated variables for CA-UTI were duration of catheter drainage (a OR (95% CI) 1.14, (1.03,1.27), P=-0.009), PICU stay (aOR (95% CI) 1.13 (1.05,1.21) (P0.001), and hospital stay (aOR (95% CI): 1.03 (1.01,1.06), P=0.015).CA-UTI is not an uncommon nosocomial infection in PICU. The risk increases with increasing duration of catheter drainage, and hospital or PICU stay.

The association between daily all-cause mortality and short-term fine particulate matter (PM

Background Stunting is determined by using the World Health Organization (WHO) child growth standard which was developed using precise measurements. However, it is unlikely that large scale surveys maintain the same level of rigour and precision when measuring the height of children. The population measure of stunting in children is sensitive to over-dispersion, and the high prevalence of stunting observed in surveys in low and middle-income countries (LMIC) could partly be due to lower measurement precison. Objectives To quantify the incongruence in the dispersion of height-for-age in national surveys of Methods An uncertainty factor was proposed and measured from the observed incongruence in dispersion of the height-for-age of Results The uncertainty factor was estimated for 17 LMICs. This ranged from 0.9 to 2.1 for Peru and Egypt respectively (reference value 1). As an explicit country example, the dispersion of height-for-age in the Indian National Family Health Survey-4 test dataset was 39% higher than the MGRS study, with an uncertainty factor of 1.39. From this, the uncertainty-adjusted Indian national stunting prevalence estimate reduced to 18.7% from the unadjusted estimate of 36.2%. Conclusions This study proposes a robust statistical method to estimate uncertainty in stunting prevalence estimates due to incongruent dispersions of height measured in national surveys for children

Venous plasma metabolomics is a potent and highly sensitive tool for identifying and measuring metabolites of interest in human health and disease. Accurate and reproducible insights from such metabolomic studies require extreme care in removing preanalytical confounders; one of these is the duration of tourniquet application when drawing the venous blood sample. Using an untargeted plasma metabolomics approach, we evaluated the effect of varying durations of tourniquet application on the variability in plasma metabolite concentrations in five healthy female subjects. Tourniquet application introduced appreciable variation in the metabolite abundances: 73% of the identified metabolites had higher temporal variation compared to interindividual variation [Intra-Class Correlation (ICC) > 0.50]. As such, we recommend tourniquet application for minimal duration and to wait for 5 min with the needle in situ after removing the tourniquet, to reduce hemostasis-induced variability and false flags in interpretation.

Population zinc (Zn) status assessment is based on serum zinc concentration (SZC) cut-offs defined by the International Zinc Nutrition Consultative Group (IZiNCG). The objective of this study is to derive reference SZC cut-offs in apparently healthy 1-19 year Indian children and adolescents using comprehensive national nutrition survey (CNNS) data, and to measure the prevalence of Zn deficiency.Apparently healthy children (n = 12,473) were selected from the CNNS, by including the highest 2 wealth quintiles, and excluding stunted, thin and obese children, and those with CRP 5 mg/L, anaemia, hypo-albuminemia, diabetes, recent diarrhoea and history of smoking. The 2.5th centile of age-based distributions defined the SZC cut-offs, used to measure the prevalence of Zn deficiency in India, as against the IZiNCG cut-offs.The present study SZC cut-offs were significantly lower, by 10-18 µg/dL, than the IZiNCG cut-offs; more in adolescents. Prevalence of Zn deficiency in the entire CNNS, with these cut-offs, was 2.7 (10 years) to 5.5 (10-19 years) times lower than with the IZiNCG cut-offs. No geographical state, nor any age group, had Zn deficiency as a serious public health problem (≥20%). In contrast, with IZiNCG cut-offs, 9-27 states (depending on age group) had a public health problem.The present study reference SZC cut-offs for Zn deficiency are lower than the IZiNCG cut-offs, and their rigorous selection from a national sample makes them more appropriate for use in India. A re-examination of the global applicability of IZiNCG recommended cut-offs in other LMICs appears appropriate.

To re-estimate the survival benefit from Vitamin A supplementation (VAS) in India using meta-analysis and to correlate mortality and vitamin A deficiency (VAD) in children aged 6 month to 5 year.Pooled risk ratio (fixed effects model) for mortality reduction with VAS was calculated from available Indian studies. Computed mortality rates in 6 months to 5 years children in Indian states were regressed on VAD prevalence estimates of the states.There was no reduction in risk of all-cause mortality with VAS (RR=0.96; 95% CI: 0.89, 1.03). When regressing mortality on VAD in high or low VAD prevalence states, the regression coefficients were discordant.No survival benefit was observed for VAS in India from the available literature. The targeting of VAS programs should be given serious consideration.

BACKGROUND Differential expression of chemokines/chemokine receptors in colorectal cancer (CRC) may enable molecular characterization of patients' tumors for predicting clinical outcome. OBJECTIVE To evaluate the prognostic ability of these molecules in a CRC cohort and the CRC TCGA-dataset. METHODS Chemokine (CXCL-12α, CXCL-12β, IL-17A, CXCL-8, GM-CSF) and chemokine receptor (CXCR-4, CXCR-7) transcripts were analyzed by RT-qPCR in 76 CRC specimens (normal: 27, tumor: 49; clinical cohort). RNA-Seq data was analyzed from the TCGA-dataset (n= 375). Transcript levels were correlated with outcome; analyses: univariate, multivariable, Kaplan-Meier. RESULTS In the clinical cohort, chemokine/chemokine receptor levels were elevated 3-10-fold in CRC specimens (P⩽ 0.004) and were higher in patients who developed metastasis (P= 0.03 - < 0.0001). CXCR-4, CXCR-7, CXCL-12α, CXCL-8, IL-17 and GM-CSF levels predicted metastasis (P⩽ 0.0421) and/or overall survival (OS; P⩽ 0.0373). The CXCR-4+CXCR-7+CXCL-12 marker (CXCR-4/7+CXCL-12 (α/b) signature) stratified patients into risk for metastasis (P= 0.0014; OR, 2.72) and OS (P= 0.0442; OR, 2.7); sensitivity: 86.67%, specificity: 97.06%. In the TCGA-dataset, the CXCR-4/7+CXCL-12 signature predicted metastasis (P= 0.011; OR, 2.72) and OS (P= 0.0006; OR: 4.04). In both datasets, the signature was an independent predictor of clinical outcome. CONCLUSIONS Results of 451 specimens from both cohorts reveal that the CXCR-4/7+CXCL-12 signature potentially predicts outcome in CRC patients and may allow earlier intervention.

This study aimed to define the estimated average requirement and the recommended dietary allowance of iron for Indian children and adolescents.The Estimated average requirement was derived for children aged 1-17y, from the mean bioavailability-adjusted daily physiological iron requirement, which in turn was estimated using a factorial method. This consisted of mean daily iron losses from the body and additional iron required for tissue growth and storage, while also defining the variance of each factor to derive the Recommended dietary allowance.Results: The estimated average requirement of iron for children ranged from 5.6 to 11.0 mg/d in children aged 1-9y. For adolescents aged 10-17y, these ranged from 10.8 to 18.4 mg/d and 15.4 to 18.5 mg/d for adolescent boys and girls, respectively.New estimates of estimated average requirement for iron in Indian children are presented, and same may be used to inform iron supplementation and food fortification policies.

BACKGROUND Anemia prevalence in India remains high despite preventive iron supplementation programs. Consequently, concurrent national policies of iron fortification of staple foods have been initiated. OBJECTIVES This study evaluated the relation between dietary iron intake and anemia (hemoglobin

Anemia in Indian women continues to be highly prevalent, and is thought to be due to low dietary iron content. The high risk of dietary iron deficiency is based on the Indian Council of Medical Research recommendation of 21 mg/d, but there is a need for a secure and transparent determination of the Estimated Average Requirement (EAR) of iron in this population. In nonpregnant, nonlactating women of reproductive age (WRA), the EAR of iron was determined to be 15 mg/d. Applying this value to daily iron intakes among WRA in nationally representative Indian state–based data showed that the median risk of dietary iron deficiency was lower than previously thought (65%; IQR: 48–78%), with considerable heterogeneity between states (range: 25–93%). However, in a validation, this risk matched the risk of iron deficiency as defined by blood biomarkers in a recently completed survey. When the risk of dietary iron deficiency was modelled for an increase in iron intake through food fortification of a single dietary staple, that provided 10 mg/d, the median risk reduced substantially (from 65% to 20%), and it virtually disappeared when supplementary iron intakes through the national iron supplementation program were considered. The risk of exceeding the tolerable upper level (TUL) of intake of iron remains low in the population when receiving fortification of 10 mg/d, but is much higher if they consume greater amounts of iron through supplements (range: 0–54%). This newly and transparently defined Indian EAR of iron should be used to evaluate, with precision, the benefits and risks of iron fortification and supplementation policies.

Background Chronic pulmonary aspergillosis (CPA) is a severe form of post tuberculosis lung disease (PTBLD). Considering the high burden of TB in India, it can be concluded that the prevalence of CPA is also high. Chest x-ray though most feasible, interpretation is subjective. Therefore, decision on evaluation for CPA cannot be based on x-ray alone. Objective Present study evaluated an x-ray score as a marker for extent of lung damage in patients with PTBLD presenting with hemoptysis and its utility to predict Aspergillus serum IgG levels. Methods We used a modified scoring system developed by Anna Ralph et al. X-ray score cut-offs of >71 and 40, with or without history of massive hemoptysis, were compared with serum IgG levels. Results With a chest x-ray score cut-off of 71, specificity was 88%. With an x-ray score of >71 combined with history of massive hemoptysis; 86% cases were found to be IgG positive. The specificity of this combination was 96%. Conclusion This study concluded that a simple chest x-ray scoring system in addition to the symptom of massive hemoptysis helped in the decision on further evaluation of the subject for CPA, especially in resource constrained settings.

Background In spring 2020, the novel coronavirus prompted a sudden shift in nursing education. This study evaluated students' perceptions of their ability to adjust to these challenges. Methods A cross-sectional survey of students (n = 286) in BSN programs throughout the United States was conducted via email to examine 3 areas of student confidence (academic success, NCLEX-RN success, and patient care delivery) and to determine how these were affected by the abrupt transition to remote learning. Results Variables, including alignment of remote instruction styles with learning styles, ease of transition to distance learning, and educating children at home, were significantly associated with students' confidence in their ability to be successful academically, on NCLEX-RN, and in patient care. Conclusions With potential for ongoing challenges due to the coronavirus, faculty need to identify and support students at greater risk of experiencing difficulties and threats to success, thereby preventing attrition and ensuring preparation of a diverse workforce.

Background The overall goal of this longitudinal study was to determine if the Black population has decreased myocardial function, which has the potential to lead to the early development of congestive heart failure, compared with the White population. Methods and Results A total of 673 subjects were evaluated over a period of 30 years including similar percentages of Black and White participants. Left ventricular systolic function was probed using the midwall fractional shortening (MFS). A longitudinal analysis of the MFS using a mixed effect growth curve model was performed. Black participants had greater body mass index, higher blood pressure readings, and greater left ventricular mass compared with White participants (all P Conclusions Changes in myocardial function mirror the race‐dependent variations in blood pressure, afterload, and cardiac mass, suggesting that myocardial function depression occurs early in childhood in populations at high cardiovascular risk such as Black participants.

BACKGROUND Anemia control programs in India focus mainly on the measurement of hemoglobin in response to iron-folic acid supplementation. However, representative national estimates of iron deficiency (ID) are not available. OBJECTIVES The objective of the present study was to evaluate ID prevalence among children and adolescents (1-19 y) using nationally representative data and to examine the sociodemographic patterning of ID. METHODS Cross-sectional data from the Comprehensive National Nutrition Survey in children (1-4 y: n = 9635; 5-9 y: n = 11,938) and adolescents (10-19 y; n = 11,507) on serum ferritin (SF) and other biomarkers were analyzed to determine inflammation-adjusted ID prevalence [SF (μg/L)

Background Lysine rich foods such as milk and legumes serve as important food additions to the lysine deficient cereal-based diets of vegetarian populations in low- and middle-income countries (LMICs) to alleviate the risk of quality corrected dietary protein inadequacy. Dietary protein quality can be determined by estimating the metabolic availability (MA) of lysine. Objectives The study aimed to estimate the MA of lysine in spray-dried cow milk powder (SMP), heat-treated spray-dried cow milk powder (HSMP), and a habitually consumed cereal-legume based vegetarian meal (VM), using the indicator amino acid oxidation (IAAO) slope-ratio method. Methods The MA of lysine in SMP, HSMP, and VM was estimated in 7 healthy young men aged 19-24 y with BMI of 21.5 ± 0.5 kg/m2 in a repeated measures design. The IAAO response slopes with 2 graded lysine intakes (10.5 and 15.0 mg·kg-1·d-1) from the SMP and VM were compared with the response slope generated with 3 graded crystalline lysine intakes (6.0, 10.5, and 15.0 mg·kg-1·d-1) at the subrequirement level. To produce HSMP, pasteurized cow milk was heat treated and spray dried. The MA of lysine in HSMP was tested at a single level of lysine intake (15 mg·kg-1·d-1). A total of 8 IAAO experiments were conducted on each participant in randomized order. The IAAO slopes were estimated using a linear mixed-effect regression model. Results The MA of lysine in SMP, HSMP, and VM was 91.9%, 69.9%, and 86.6% respectively. Conclusions Heat treatment reduced the MA of lysine by 22% in HSMP compared with SMP in healthy Indian adults. The lysine MA estimates can be used to optimize lysine limited cereal-based diets, with the addition of appropriately processed legumes and milk powder, to meet the protein requirement. This trial was registered at Clinical Trials Registry of India (http://ctri.nic.in) as CTRI/2019/08/020568.

Central vascular thrombosis (CVT) in critically ill neonates carries significant clinical implications. Neonates with congenital heart disease (CHD) awaiting cardiac intervention might be associated with increased risk of thrombosis. Outcome analysis was undertaken. An analysis of 77 neonates with CHD who were admitted to the NICU prior to cardiac intervention between January 2015 and December 2016 was undertaken. Patients requiring extracorporeal life support prior to any cardiac intervention, or receiving prophylactic anticoagulation not related to central vascular catheter (CVC) were excluded. Diagnosis of CVT was provided based on clinical indication and verified with imaging that warranted anticoagulation therapy. Location of CVC and extent of CVT along with treatments, outcomes, and vascular access types and durations were assessed. Logistic regression multivariate analysis was used to assess predictors of outcome. Neonates with CHD were complicated with CVT in 10.4%. Longer duration of CVC was also associated with thrombosis in neonates with CHD (72.7 days vs. 29.3 days, p 0.001). Independent predictors of outcome included lower gestational age and CHD with single-ventricle (SV) anatomy (p 0.05). In neonates with CHD awaiting cardiac intervention risk of CVT is substantial. Duration CVC, lower gestational age and SV anatomy are risk determinants of outcome. Standardized development of customized surveillance protocols tailored to this unique subsets of neonates and adherence to quality guidelines can influence outcome.

Fluorescent carbon dot has emerged as promising alternative of conventionally known quantum dot or molecular probe as potential intracellular imaging probe. In particular,10 nm size, tunable and bright fluorescence of carbon dot deserve the application potential as intracellular imaging probe. However, synthesis of carbon dot with narrow particle size distribution, preparation of high-quality red/near-infrared emitting carbon dot and appropriate design of functional carbon dot for subcellular targeting are most critical issues. This advanced review focus on the application potential of fluorescent carbon dot as intracellular imaging probe. At first, we briefly discuss different types of fluorescent carbon dots and origin of their fluorescence. Next, we focus on surface chemistry and functionalization which are relevant to intracellular probe development. Finally we have summarized various types of intracellular nanoprobes that are developed from fluorescence carbon dot. This article is categorized under: Diagnostic Toolsin vitro Nanoparticle-Based Sensing.

A published pilot study showed the feasibility of integrating ethics into physiology in a single medical college. However, questions were raised about feasibility of scale-up and acceptance across different colleges. To assess feasibility of integrating ethics into Physiology, first year MBBS students of three medical colleges (n=449, College A=149; 59M, 90F; College B=150; 78M, 72F; College C=150; 48M, 102F) were exposed to the integrated ethics programme. Triggers related to theory or practicals were included. Faculty volunteers conducted the sessions with feedback from observers and students. Students across three colleges felt that the programme was relevant (92%-98%), effectively integrated (86%-98%) [significantly greater number of College A students: (p=0.003)], seldom interfered with physiology teaching (59%-66%). Greater number of students from College C followed by College B and A opined to continue the integrated programme for future years (p=0.004). A scale-up study of integration of ethics programme across different colleges was perceived to be feasible by students and observers.

ObjectivesSevere pulmonary hypertension (PH) causing right heart failure can occur due to thiamine deficiency in exclusively breastfeeding infants. This study describes the clinical profile and management of thiamine-responsive acute pulmonary hypertension.MethodsA prospective observational study of infants presenting with severe PH without any other significant heart or lung disease. History of symptoms, clinical examination, echocardiography and basic investigations were performed. Dietary patterns of mothers were recorded. Thiamine was administered and serial echocardiography was performed.ResultsA total of 250 infants had severe PH and 231 infants responded to thiamine. The mean age was 3.2±1.2 months. Fast breathing, poor feeding, vomiting and aphonia were the main symptoms. Tachypnoea, tachycardia and hepatomegaly were found on examination. Echocardiogram revealed grossly dilated right heart with severe PH. Intravenous thiamine was administered to all the babies based on clinical suspicion. Clinical improvement with complete resolution of PH was noticed within 24–48 hours. Babies were followed up to a maximum of 60 months with no recurrence of PH. All the mothers consumed polished rice and followed postpartum food restriction.ConclusionThiamine deficiency is still prevalent in selected parts of India. It can cause life-threatening PH in exclusively breastfeeding infants of mothers who are on a restricted diet predominantly consisting of polished rice. It can contribute to infant mortality. Thiamine administration based on clinical suspicion leads to remarkable recovery. High degree of awareness and thiamine supplementation in relevant geographical areas is required to tackle this fatal disease.

The present study reports short-term impact of poor air quality on cardiovascular and respiratory morbidity rate in Delhi. The data on monthly count of patients visiting Out Patient Department (OPD) and hospital admission due to respiratory and cardiovascular illnesses from hospitals along with daily air quality data from air quality monitoring stations of Central Pollution Control Board (CPCB), Government of India, across Delhi were collected for the period 2008 to 2012. A semi-parametric Quasi-Poisson regression model was used to examine the association of high pollution episodes with relative risk of hospital OPD visit and hospital admission due to respiratory and cardiovascular diseases. This study has confirmed the substantial adverse health effects due to air pollution across criterion air pollutants. The study reports the short-term effects of air pollution on morbidity from a time-series study first time in India. The study findings illustrate the evidence of adverse health impact of air pollution from India to the global pool and can influence the policy makers to implement better air quality management system for Indian cities.OPD: Out Patient Department; IPD: Inpatient Department; RD: Respiratory Disease; CVD: Cardiovascular Disease; COPD: Chronic Obstructive Pulmonary Disease; CPCB: Central Pollution Control Board; NAAQMP: National Ambient Air Quality Monitoring Programme; NAAQS: National Ambient Air Quality Standards; RR; Relative Risk; IMD: Indian Meteorological Department; PM

Researchers in genomics are increasingly interested in epigenetic factors such as DNA methylation, because they play an important role in regulating gene expression without changes in the DNA sequence. There have been significant advances in developing statistical methods to detect differentially methylated regions (DMRs) associated with binary disease status. Most of these methods are being developed for detecting differential methylation rates between cases and controls. We consider multiple severity levels of disease, and develop a Bayesian statistical method to detect the region with increasing (or decreasing) methylation rates as the disease severity increases. Patients are classified into more than two groups, based on the disease severity (e.g., stages of cancer), and DMRs are detected by using moving windows along the genome. Within each window, the Bayes factor is calculated to test the hypothesis of monotonic increase in methylation rates corresponding to severity of the disease versus no difference. A mixed-effect model is used to incorporate the correlation of methylation rates of nearby CpG sites in the region. Results from extensive simulation indicate that our proposed method is statistically valid and reasonably powerful. We demonstrate our approach on a bisulfite sequencing dataset from a chronic lymphocytic leukemia (CLL) study.

Purpose: Poor prognosis of patients with muscle-invasive bladder cancer that often metastasizes drives the need for discovery of molecular determinants of bladder cancer progression. Chondroitin sulfate proteoglycans, including CD44, regulate cancer progression; however, the identity of a chondroitinase (Chase) that cleaves chondroitin sulfate from proteoglycans is unknown. HYAL-4 is an understudied gene suspected to encode a Chase, with no known biological function. We evaluated HYAL-4 expression and its role in bladder cancer. Experimental Design: In clinical specimens, HYAL-4 wild-type (Wt) and V1 expression was evaluated by RT-qPCR, IHC, and/or immunoblotting; a novel assay measured Chase activity. Wt and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for stem cell phenotype, invasive signature and tumorigenesis, and metastasis in four xenograft models, including orthotopic bladder. Results: HYAL-4 expression, specifically a novel splice variant (V1), was elevated in bladder tumors; Wt expression was barely detectable. V1 encoded a truncated 349 amino acid protein that was secreted. In bladder cancer tissues, V1 levels associated with metastasis and cancer-specific survival with high efficacy and encoded Chase activity. V1 cleaved chondroitin-6-sulfate from CD44, increasing CD44 secretion. V1 induced stem cell phenotype, motility/invasion, and an invasive signature. CD44 knockdown abrogated these phenotypes. V1-expressing urothelial cells developed angiogenic, muscle-invasive tumors. V1-expressing bladder cancer cells formed tumors at low density and formed metastatic bladder tumors when implanted orthotopically. Conclusions: Our study discovered the first naturally-occurring eukaryotic/human Chase and connected it to disease pathology, specifically cancer. V1-Chase is a driver of malignant bladder cancer and potential predictor of outcome in patients with bladder cancer.

STUDY DESIGN: This was a single-centre, retrospective, descriptive, hospital-based study in persons with spinal cord injuries (SCI) patients. OBJECTIVES: To study the incidence and characteristics of heterotopic ossification (HO) after SCI. SETTING: The in-patient services of the Department of Physical Medicine and Rehabilitation of a tertiary care institute in India between January 2001 and December 2017. METHODS: Medical records of all consecutive patients with diagnosis of SCI in the age group of 15–60 years were reviewed for presence of HO (diagnosed by clinical signs, laboratory investigations (ALP, ESR and X-rays)) and characteristics of HO. R-Ver 3.4.2 was used for analysis and correlations. Results were considered significant at P

BACKGROUND Indian babies are hypothesized to be born thin but fat. This has not been confirmed with precise measurements at birth. If it is true, it could track into later life and confer risk of noncommunicable diseases (NCDs). OBJECTIVES Primarily, to accurately measure percentage of body fat (%BF) and body cell mass (BCM) in Indian babies with normal birth weight, compare them across different gestational ages and sex, and test the hypothesis of the thin but fat phenotype in Indian babies. Secondarily, to examine the relation between body weight and body fat in Indian babies. METHODS Term newborns (n = 156) weighing ≥2500 g, from middle socioeconomic status mothers were recruited in Bengaluru, India, and their anthropometry, %BF (air displacement plethysmography), and BCM (whole-body potassium counter) were measured. Maternal demography and anthropometry were recorded. The mean %BF and its dispersion were compared with earlier studies. The relation between newborn %BF and body weight was explored by regression analysis. RESULTS Mean birth weight was 3.0 ± 0.3 kg, with mean %BF 9.8 ± 3.5%, which was comparable to pooled estimates of %BF from published studies (9.8%; 95% CI: 9.7, 10.0; P > 0.05). Appropriate-for-gestational age (AGA) babies had higher %BF (1.8%) compared to small-for-gestational age (SGA) babies (P

Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome.We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications.Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p0.0001) and overall survival (p=0.01 to0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively).Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.

Background & objectives: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disorder, characterized by the fluid filled cysts in the kidneys leading to end stage renal failure in later years of life. Hypertension is one of the major factors independently contributing to the chronic kidney disease (CKD) progression. The renin-angiotensin aldosterone system (RAAS) genes have been extensively studied as hypertension candidate genes. The aim of the present study was to investigate the role of angiotensin converting enzyme tagging - single nucleotide polymorphisms (ACE tag-SNPs) in progression of CKD in patients with ADPKD. m0 ethods: In the present study six ACE tagSNPs (angiotensin converting enzyme tag single nucleotide polymorphisms) and insertion/deletion (I/D) in 102 ADPKD patients and 106 control subjects were investigated. The tagSNPs were genotyped using FRET-based KASPar method and ACE ID by polymerase chain reaction (PCR) and electrophoresis. Genotypes and haplotypes were compared between ADPKD patients and controls. Univariate and multivariate logistic regression analyses were performed to assess the effect of genotypes and hypertension on CKD advancement. Mantel-Haenszel (M-H) stratified analysis was performed to study the relationship between different CKD stages and hypertension and their interaction. Results: All loci were polymorphic and except rs4293 SNP the remaining loci followed Hardy-Weinberg equilibrium. Distribution of ACE genotypes and haplotypes in controls and ADPKD patients was not significant. A significant linkage disequilibrium (LD) was observed between SNPs forming two LD blocks. The univariate analysis revealed that the age, hypertension, family history of diabetes and ACE rs4362 contributed to the advancement of CKD. Interpretation & conclusions: The results suggest that the ACE genotypes are effect modifiers of the relationship between hypertension and CKD advancement among the ADPKD patients.

Climate extremes are often associated with increased human mortality and such association varies considerably with space and time. We therefore, aimed to systematically investigate the effects of temperature extremes, daily means and diurnal temperature variations (DTV) on mortality in the city of Varanasi, India during 2009-2016. Time series data on daily mortality, air quality (SO2, NO2, O3 and PM10) and weather variables were obtained from the routinely collected secondary sources. A semiparametric quasi-Poisson regression model estimated the effects of temperature extremes on daily all-cause mortality adjusting nonlinear confounding effects of time trend, relative humidity and air pollution; stratified by seasons. An effect modification by age, gender and place of death as semi-economic indicator were also explored. Daily mean temperature was strongly associated with excess mortality, both during summer (5.61% with 95% CI: 4.69-6.53% per unit increase in mean temperature) and winter (1.53% with 95% CI: 0.88-2.18% per unit decrease in mean temperature). Daily mortality was found to be increased by 12.02% (with 95% CI: 4.21-19.84%) due to heat wave. The DTV has exhibited downward trend over the years and showed a negative association with all-cause mortality. Significant association of mortality and different metric of temperature extreme along with decreasing trend in DTV clearly indicate the potential impact of climate change on human health in the city of Varanasi. The finding may well be useful to prioritize the government policies to curb the factors that causes the climate change and for developing early warning system.

Background: Household air pollution (HAP) resulting from the use of solid cooking fuels is a leading contributor to the burden of disease in India. Advanced combustion cookstoves that reduce emissions from biomass fuels have been considered potential interventions to reduce this burden. Relatively little effort has been directed, however, to assessing the concentration and exposure changes associated with the introduction of such devices in households. Objectives: The aim of this study was to describe HAP exposure patterns in pregnant women receiving a forced-draft advanced combustion cookstove (Philips model HD 4012) in the SOMAARTH Demographic Development & Environmental Surveillance Site (DDESS) Palwal District, Haryana, India. The monitoring was performed as part of a feasibility study to inform a potential large-scale HAP intervention (Newborn Stove trial) directed at pregnant women and newborns. Methods: This was a paired comparison exercise study with measurements of 24-hour personal exposures and kitchen area concentrations of carbon monoxide (CO) and particulate matter less than 2.5 μm in aerodynamic diameter (PM2.5), before and after the cookstove intervention. Women (N = 65) were recruited from 4 villages of SOMAARTH DDESS. Measurements were performed between December 2011 and March 2013. Ambient measurements of PM2.5 were also performed throughout the study period. Findings: Measurements showed modest improvements in 24-hour average concentrations and exposures for PM2.5 and CO (ranging from 16% to 57%) with the use of the new stoves. Only those for CO showed statistically significant reductions. Conclusion: Results from the present study did not support the widespread use of this type of stove in this population as a means to reliably provide health-relevant reductions in HAP exposures for pregnant women compared with open biomass cookstoves. The feasibility assessment identified multiple factors related to user requirements and scale of adoption within communities that affect the field efficacy of advanced combustion cookstoves as well as their potential performance in HAP intervention studies.

Non-inferiority trials are becoming increasingly popular for comparative effectiveness research. However, inclusion of the placebo arm, whenever possible, gives rise to a three-arm trial which has lesser burdensome assumptions than a standard two-arm non-inferiority trial. Most of the past developments in a three-arm trial consider defining a pre-specified fraction of unknown effect size of reference drug, that is, without directly specifying a fixed non-inferiority margin. However, in some recent developments, a more direct approach is being considered with pre-specified fixed margin albeit in the frequentist setup. Bayesian paradigm provides a natural path to integrate historical and current trials' information via sequential learning. In this paper, we propose a Bayesian approach for simultaneous testing of non-inferiority and assay sensitivity in a three-arm trial with normal responses. For the experimental arm, in absence of historical information, non-informative priors are assumed under two situations, namely when (i) variance is known and (ii) variance is unknown. A Bayesian decision criteria is derived and compared with the frequentist method using simulation studies. Finally, several published clinical trial examples are reanalyzed to demonstrate the benefit of the proposed procedure. Copyright © 2015 John Wiley & Sons, Ltd.

Background: Household air pollution from solid fuel burning is a leading contributor to disease burden globally. Fine particulate matter (PM2.5) is thought to be responsible for many of these health impacts. A co-pollutant, carbon monoxide (CO) has been widely used as a surrogate measure of PM2.5 in studies of household air pollution. Objective: The goal was to evaluate the validity of exposure to CO as a surrogate of exposure to PM2.5 in studies of household air pollution and the consistency of the PM2.5–CO relationship across different study settings and conditions. Methods: We conducted a systematic review of studies with exposure and/or cooking area PM2.5 and CO measurements and assembled 2,048 PM2.5 and CO measurements from a subset of studies (18 cooking area studies and 9 personal exposure studies) retained in the systematic review. We conducted pooled multivariate analyses of PM2.5–CO associations, evaluating fuels, urbanicity, season, study, and CO methods as covariates and effect modifiers. Results: We retained 61 of 70 studies for review, representing 27 countries. Reported PM2.5–CO correlations (r) were lower for personal exposure (range: 0.22–0.97; median=0.57) than for cooking areas (range: 0.10–0.96; median=0.71). In the pooled analyses of personal exposure and cooking area concentrations, the variation in ln(CO) explained 13% and 48% of the variation in ln(PM2.5), respectively. Conclusions: Our results suggest that exposure to CO is not a consistently valid surrogate measure of exposure to PM2.5. Studies measuring CO exposure as a surrogate measure of PM exposure should conduct local validation studies for different stove/fuel types and seasons. https://doi.org/10.1289/EHP767

Exposure to PMWe examined whether PMWe recruited 1285 pregnant women in the first trimester of pregnancy from primary health care centers and urban health posts and followed them until birth to collect antenatal care data and birthweight. We estimated pregnancy period PMA 10-μg/mThe study provides some of the first quantitative effects estimates for linking rural-urban PM

Household air pollution from use of solid fuels is a major contributor to the national burden of disease in India. Currently available models of advanced combustion biomass cook-stoves (ACS) report significantly higher efficiencies and lower emissions in the laboratory when compared to traditional cook-stoves, but relatively little is known about household level exposure reductions, achieved under routine conditions of use. We report results from initial field assessments of six commercial ACS models from the states of Tamil Nadu and Uttar Pradesh in India. We monitored 72 households (divided into six arms to each receive an ACS model) for 24-h kitchen area concentrations of PM2.5 and CO before and (1-6 months) after installation of the new stove together with detailed information on fixed and time-varying household characteristics. Detailed surveys collected information on user perceptions regarding acceptability for routine use. While the median percent reductions in 24-h PM2.5 and CO concentrations ranged from 2 to 71% and 10-66%, respectively, concentrations consistently exceeded WHO air quality guideline values across all models raising questions regarding the health relevance of such reductions. Most models were perceived to be sub-optimally designed for routine use often resulting in inappropriate and inadequate levels of use. Household concentration reductions also run the risk of being compromised by high ambient backgrounds from community level solid-fuel use and contributions from surrounding fossil fuel sources. Results indicate that achieving health relevant exposure reductions in solid-fuel using households will require integration of emissions reductions with ease of use and adoption at community scale, in cook-stove technologies. Imminent efforts are also needed to accelerate the progress towards cleaner fuels.

Background: Understanding the potential links between extreme weather events and human health in India is important in the context of vulnerability and adaptation to climate change. Research exploring such linkages in India is sparse. Objectives: We evaluated the association between extreme precipitation and gastrointestinal (GI) illness-related hospital admissions in Chennai, India, from 2004 to 2007. Methods: Daily hospital admissions were extracted from two government hospitals in Chennai, India, and meteorological data were retrieved from the Chennai International Airport. We evaluated the association between extreme precipitation (≥ 90th percentile) and hospital admissions using generalized additive models. Both single-day and distributed lag models were explored over a 15-day period, controlling for apparent temperature, day of week, and long-term time trends. We used a stratified analysis to explore the association across age and season. Results: Extreme precipitation was consistently associated with GI-related hospital admissions. The cumulative summary of risk ratios estimated for a 15-day period corresponding to an extreme event (relative to no precipitation) was 1.60 (95% CI: 1.29, 1.98) among all ages, 2.72 (95% CI: 1.25, 5.92) among the young (≤ 5 years of age), and 1.62 (95% CI: 0.97, 2.70) among the old (≥ 65 years of age). The association was stronger during the pre-monsoon season (March–May), with a cumulative risk ratio of 6.50 (95% CI: 2.22, 19.04) for all ages combined compared with other seasons. Conclusions: Hospital admissions related to GI illness were positively associated with extreme precipitation in Chennai, India, with positive cumulative risk ratios for a 15-day period following an extreme event in all age groups. Projected changes in precipitation and extreme weather events suggest that climate change will have important implications for human health in India, where health disparities already exist. Citation: Bush KF, O’Neill MS, Li S, Mukherjee B, Hu H, Ghosh S, Balakrishnan K. 2014. Associations between extreme precipitation and gastrointestinal-related hospital admissions in Chennai, India. Environ Health Perspect 122:249–254; http://dx.doi.org/10.1289/ehp.1306807

Motivation: Researchers in genomics are increasingly interested in epigenetic factors such as DNA methylation because they play an important role in regulating gene expression without changes in the sequence of DNA. Abnormal DNA methylation is associated with many human diseases. Results: We propose two different approaches to test for differentially methylated regions (DMRs) associated with complex traits, while accounting for correlations among CpG sites in the DMRs. The first approach is a nonparametric method using a kernel distance statistic and the second one is a likelihood-based method using a binomial spatial scan statistic. The kernel distance method uses the kernel function, while the binomial scan statistic approach uses a mixed-effects model to incorporate correlations among CpG sites. Extensive simulations show that both approaches have excellent control of type I error, and both have reasonable statistical power. The binomial scan statistic approach appears to have higher power, while the kernel distance method is computationally faster. The proposed methods are demonstrated using data from a chronic lymphocytic leukemia (CLL) study.

Exposure to ambient air pollution is a major risk factor for global disease. Assessment of the impacts of air pollution on population health and evaluation of trends relative to other major risk factors requires regularly updated, accurate, spatially resolved exposure estimates. We combined satellite-based estimates, chemical transport model simulations, and ground measurements from 79 different countries to produce global estimates of annual average fine particle (PM2.5) and ozone concentrations at 0.1° × 0.1° spatial resolution for five-year intervals from 1990 to 2010 and the year 2013. These estimates were applied to assess population-weighted mean concentrations for 1990-2013 for each of 188 countries. In 2013, 87% of the world's population lived in areas exceeding the World Health Organization Air Quality Guideline of 10 μg/m(3) PM2.5 (annual average). Between 1990 and 2013, global population-weighted PM2.5 increased by 20.4% driven by trends in South Asia, Southeast Asia, and China. Decreases in population-weighted mean concentrations of PM2.5 were evident in most high income countries. Population-weighted mean concentrations of ozone increased globally by 8.9% from 1990-2013 with increases in most countries-except for modest decreases in North America, parts of Europe, and several countries in Southeast Asia.

Background Previous global burden of disease (GBD) estimates for household air pollution (HAP) from solid cookfuel use were based on categorical indicators of exposure. Recent progress in GBD methodologies that use integrated–exposure–response (IER) curves for combustion particles required the development of models to quantitatively estimate average HAP levels experienced by large populations. Such models can also serve to inform public health intervention efforts. Thus, we developed a model to estimate national household concentrations of PM2.5 from solid cookfuel use in India, together with estimates for 29 states. Methods We monitored 24-hr household concentrations of PM2.5, in 617 rural households from 4 states in India on a cross-sectional basis between November 2004 and March 2005. We then, developed log-linear regression models that predict household concentrations as a function of multiple, independent household level variables available in national household surveys and generated national / state estimates using The Indian National Family and Health Survey (NFHS 2005). Results The measured mean 24-hr concentration of PM2.5 in solid cookfuel using households ranged from 163 μg/m3 (95% CI: 143,183; median 106; IQR: 191) in the living area to 609 μg/m3 (95% CI: 547,671; median: 472; IQR: 734) in the kitchen area. Fuel type, kitchen type, ventilation, geographical location and cooking duration were found to be significant predictors of PM2.5 concentrations in the household model. k-fold cross validation showed a fair degree of correlation (r = 0.56) between modeled and measured values. Extrapolation of the household results by state to all solid cookfuel-using households in India, covered by NFHS 2005, resulted in a modeled estimate of 450 μg/m3 (95% CI: 318,640) and 113 μg/m3 (95% CI: 102,127) , for national average 24-hr PM2.5 concentrations in the kitchen and living areas respectively. Conclusions The model affords substantial improvement over commonly used exposure indicators such as “percent solid cookfuel use” in HAP disease burden assessments, by providing some of the first estimates of national average HAP levels experienced in India. Model estimates also add considerable strength of evidence for framing and implementation of intervention efforts at the state and national levels.

BACKGROUND: Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. METHODS: We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. FINDINGS: In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2-7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5-7·0]), and alcohol use (5·5% [5·0-5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8-9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6-8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4-6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2-10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0·9% (0·4-1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. INTERPRETATION: Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children. FUNDING: Bill and Melinda Gates Foundation.

This report describes the results of a time-series analysis of the effect of short-term exposure to particulate matter with an aerodynamic diameteror = 10 pm (PM10) on mortality in metropolitan Chennai, India (formerly Madras). This was one of three sites in India chosen by HEI as part of its Public Health and Air Pollution in Asia (PAPA) initiative. The study involved integration and analysis of retrospective data for the years 2002 through 2004. The data were obtained from relevant government agencies in charge of routine data collection. Data on meteorologic confounders (including temperature, relative humidity, and dew point) were available on all days of the study period. Data on mortality were also available on all days, but information on cause-of-death (including accidental deaths) could not be reliably ascertained. Hence, only all-cause daily mortality was used as the major outcome for the time-series analyses. Data on PM10, nitrogen dioxide (NO2), and sulfur dioxide (SO2) were limited to a much smaller number of days, but spanned the full study period. Data limitations resulting from low sensitivity of gaseous pollutant measurements led to using only PM10 in the main analysis. Of the eight operational ambient air quality monitor (AQM) stations in the city, seven met the selection criteria set forth in the common protocol developed for the three PAPA studies in India. In addition, all raw data used in the analysis were subjected to additional quality assurance (QA) and quality control (QC) criteria to ensure the validity of the measurements. Two salient features of the PM10 data set in Chennai were a high percentage of missing readings and a low correlation among daily data recorded by the AQMs. The latter resulted partly because each AQM had a small footprint (approximate area over which the air pollutant measurements recorded in the AQM are considered valid), and partly because of differences in source profiles among the 10 zones within the city. The zones were defined by the Chennai Corporation based on population density. Alternative exposure series were developed to control for these data features. We first developed exposure series based on data from single AQMs and multiple AQMs. Because neither was found to satisfactorily represent population exposures, we subsequently developed an exposure series that disaggregated pollutant data to individual zones within the city boundary. The zonal series, despite some uncertainties, was found to best represent population exposures among other available choices. The core model was thus a zonal model developed using disaggregated mortality and pollutant data from individual zones. We used quasi-Poisson generalized additive models (GAMs) with smooth functions of time, temperature, and relative humidity modeled using penalized splines. The degrees of freedom (df) for these confounders were selected to maximize the precision with which the relative risk for PM10 was estimated. This is a deviation from the traditional approaches to degrees of freedom selection, which usually aim to optimize overall model fit. Our approach led to the use of 8 df/year for time, 6 df/year for temperature, and 5 df/year for relative humidity. The core model estimated a 0.44% (95% confidence interval [CI] = 0.17 to 0.71) increase in daily all-cause mortality per 10-pg/m3 increase in daily average PM10 concentrations. Extensive sensitivity analyses compared models constructed using alternative exposure series and contributions of model parameters to the core model with regard to confounder degrees of freedom, alternative lags for exposure and meteorologic confounders, inclusion of outliers, seasonality, inclusion of multiple pollutants, and stratification by sex and age. The sensitivity analyses showed that our estimates were robust to a range of specifications and were also comparable to estimates reported in previous time-series studies: PAPA, the National Morbidity, Mortality, and Air Pollution Study (NMMAPS), Air Pollution and Health: A European Approach (APHEA), and Air Pollution and Health: A European and North American Approach (APHENA). While the approaches developed in previous studies served as the basis for our model development, the present study has new refinements that have allowed us to address specific data limitations (such as missing measurements and small footprints of air pollution monitors). The methods developed in the study may allow better use of routine data for time-series analysis in a broad range of settings where similar exposure and data-related issues prevail. We hope that the estimates derived in this study, although somewhat tentative, will facilitate local environmental management initiatives and spur future studies.

Environmental and occupational risk factors contribute to nearly 40% of the national burden of disease in India, with air pollution in the indoor and outdoor environment ranking amongst leading risk factors. It is now recognized that the health burden from air pollution exposures that primarily occur in the rural indoors, from pollutants released during the incomplete combustion of solid fuels in households, may rival or even exceed the burden attributable to urban outdoor exposures. Few environmental epidemiological efforts have been devoted to this setting, however. We provide an overview of important available information on exposures and health effects related to household solid fuel use in India, with a view to inform health research priorities for household air pollution and facilitate being able to address air pollution within an integrated rural-urban framework in the future.Keywords: Household air pollution; solid fuels; exposure assessment; India(Published: 4 October 2011)Citation: Global Health Action 2011, 4: 5638 - DOI: 10.3402/gha.v4i0.5638

Introduction In rapidly developing countries such as India, the ubiquity of air pollution sources in urban and rural communities often results in ambient and household exposures significantly in excess of health-based air quality guidelines. Few efforts, however, have been directed at establishing quantitative exposure–response relationships in such settings. We describe study protocols for The Tamil Nadu Air Pollution and Health Effects (TAPHE) study, which aims to examine the association between fine particulate matter (PM 2.5 ) exposures and select maternal, child and adult health outcomes in integrated rural–urban cohorts. Methods and analyses The TAPHE study is organised into five component studies with participants drawn from a pregnant mother–child cohort and an adult cohort (n=1200 participants in each cohort). Exposures are assessed through serial measurements of 24–48 h PM 2.5 area concentrations in household microenvironments together with ambient measurements and time-activity recalls, allowing exposure reconstructions. Generalised additive models will be developed to examine the association between PM 2.5 exposures, maternal (birth weight), child (acute respiratory infections) and adult (chronic respiratory symptoms and lung function) health outcomes while adjusting for multiple covariates. In addition, exposure models are being developed to predict PM 2.5 exposures in relation to household and community level variables as well as to explore inter-relationships between household concentrations of PM 2.5 and air toxics. Finally, a bio-repository of peripheral and cord blood samples is being created to explore the role of gene–environment interactions in follow-up studies. Ethics and dissemination The study protocols have been approved by the Institutional Ethics Committee of Sri Ramachandra University, the host institution for the investigators in this study. Study results will be widely disseminated through peer-reviewed publications and scientific presentations. In addition, policy-relevant recommendations are also being planned to inform ongoing national air quality action plans concerning ambient and household air pollution.

Background: Chronic obstructive pulmonary disease (COPD) is the 13th leading cause of burden of disease worldwide and is expected to become 5th by 2020. Biomass fuel combustion significantly contributes to COPD, although smoking is recognized as the most important risk factor. Rural women in developing countries bear the largest share of this burden resulting from chronic exposures to biomass fuel smoke. Although there is considerable strength of evidence for the association between COPD and biomass smoke exposure, limited information is available on the background prevalence of COPD in these populations. Objective: This study was conducted to estimate the prevalence of COPD and its associated factors among non-smoking rural women in Tiruvallur district of Tamilnadu in Southern India. Design: This cross-sectional study was conducted among 900 non-smoking women aged above 30 years, from 45 rural villages of Tiruvallur district of Tamilnadu in Southern India in the period between January and May 2007. COPD assessments were done using a combination of clinical examination and spirometry. Logistic regression analysis was performed to examine the association between COPD and use of biomass for cooking. R software was used for statistical analysis. Results: The overall prevalence of COPD in this study was found to be 2.44% (95% CI: 1.43-3.45). COPD prevalence was higher in biomass fuel users than the clean fuel users 2.5 vs. 2%, (OR: 1.24; 95% CI: 0.36-6.64) and it was two times higher (3%) in women who spend >2 hours/day in the kitchen involved in cooking. Use of solid fuel was associated with higher risk for COPD, although no statistically significant results were obtained in this study. Conclusion: The estimates generated in this study will contribute significantly to the growing database of available information on COPD prevalence in rural women. Moreover, with concomitant indoor air pollution measurements, it may be possible to increase the resolution of the association between biomass use and COPD prevalence and refine available attributable burden of disease estimates. Keywords: chronic obstructive pulmonary disease; prevalence; biomass fuel users; rural women; disease burden (Published: 3 November 2011) Citation: Global Health Action 2011, 4 : 7226 - DOI: 10.3402/gha.v4i0.7226