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Asthma is the most common chronic disease in children globally. The Global Asthma Network (GAN) Phase I study aimed to determine if the worldwide burden of asthma symptoms is changing. This updated cross-sectional study used the same methods as the International study of Asthma and Allergies in Childhood (ISAAC) Phase III. Asthma symptoms were assessed from centres that completed GAN Phase I and ISAAC Phase I (1993–95), ISAAC Phase III (2001–03), or both. We included individuals from two age groups (children aged 6–7 years and adolescents aged 13–14 years) who self-completed written questionnaires at school. We estimated the 10-year rate of change in prevalence of current wheeze, severe asthma symptoms, ever having asthma, exercise wheeze, and night cough (defined by core questions in the questionnaire) for each centre, and we estimated trends across world regions and income levels using mixed-effects linear regression models with region and country income level as confounders. Overall, 119 795 participants from 27 centres in 14 countries were included: 74 361 adolescents (response rate 90%) and 45 434 children (response rate 79%). About one in ten individuals of both age groups had wheeze in the preceding year, of whom almost half had severe symptoms. Most centres showed a change in prevalence of 2 SE or more between ISAAC Phase III to GAN Phase I. Over the 27-year period (1993–2020), adolescents showed a significant decrease in percentage point prevalence per decade in severe asthma symptoms (–0·37, 95% CI –0·69 to –0·04) and an increase in ever having asthma (1·25, 0·67 to 1·83) and night cough (4·25, 3·06 to 5·44), which was also found in children (3·21, 1·80 to 4·62). The prevalence of current wheeze decreased in low-income countries (–1·37, –2·47 to –0·27], in children and –1·67, –2·70 to –0·64, in adolescents) and increased in lower-middle-income countries (1·99, 0·33 to 3·66, in children and 1·69, 0·13 to 3·25, in adolescents), but it was stable in upper-middle-income and high-income countries. Trends in prevalence and severity of asthma symptoms over the past three decades varied by age group, country income, region, and centre. The high worldwide burden of severe asthma symptoms would be mitigated by enabling access to effective therapies for asthma. International Union Against Tuberculosis and Lung Disease, Boehringer Ingelheim New Zealand, AstraZeneca Educational Grant, National Institute for Health Research, UK Medical Research Council, European Research Council, and Instituto de Salud Carlos III.

The promotion of health equity, the absence of avoidable and unfair differences in health outcomes, is a global imperative. Systematic reviews are an important source of evidence for health decision makers but have been found to lack assessments of the intervention effects on health equity. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) is a 27-item checklist intended to improve transparency and reporting of systematic reviews. We developed an equity extension for PRISMA (PRISMA-E 2012) to help systematic reviewers identify, extract, and synthesize evidence on equity in systematic reviews. In this explanation and elaboration article, we provide the rationale for each extension item. These items are additions or modifications to the existing PRISMA statement items, to incorporate a focus on equity. An example of good reporting is provided for each item as well as the original PRISMA item. This explanation and elaboration document is intended to accompany the PRISMA-E 2012 statement and the PRISMA statement to improve understanding of the reporting guideline for users. The PRISMA-E 2012 reporting guideline is intended to improve transparency and completeness of reporting of equity-focused systematic reviews. Improved reporting can lead to better judgment of applicability by policy makers which may result in more appropriate policies and programs and may contribute to reductions in health inequities.

Background. Pneumonia, the leading infectious cause of child mortality globally, mainly afflicts developing countries. This prospective observational study aimed to assess the microorganisms associated with pneumonia in children aged <5 years in developing and emerging countries. Methods. A multicenter, case-control study by the GABRIEL (Global Approach to Biological Research, Infectious diseases and Epidemics in Low-income countries) network was conducted between 2010 and 2014 in Cambodia, China, Haiti, India (2 sites), Madagascar, Mali, Mongolia, and Paraguay. Cases were hospitalized children with radiologically confirmed pneumonia; controls were children from the same setting without any features suggestive of pneumonia. Nasopharyngeal swabs were collected from all subjects; 19 viruses and 5 bacteria were identified by reverse-transcription polymerase chain reaction. Associations between microorganisms and pneumonia were quantified by calculating the adjusted population attributable fraction (aPAF) after multivariate logistic regression analysis adjusted for sex, age, time period, other pathogens, and site. Results. Overall, 888 cases and 870 controls were analyzed; ≥1 microorganism was detected in respiratory samples in 93.0% of cases and 74.4% of controls (P < .001). Streptococcus pneumoniae, Mycoplasma pneumoniae, human metapneumovirus, rhinovirus, respiratory syncytial virus (RSV), parainfluenza virus 1, 3, and 4, and influenza virus A and B were independently associated with pneumonia; aPAF was 42.2% (95% confidence interval [CI], 35.5%–48.2%) for S. pneumoniae, 18.2% (95% CI, 17.4%–19.0%) for RSV, and 11.2% (95% CI, 7.5%–14.7%) for rhinovirus. Conclusions. Streptococcus pneumoniae, RSV, and rhinovirus may be the major microorganisms associated with pneumonia infections in children <5 years of age from developing and emerging countries. Increasing S. pneumoniae vaccination coverage may substantially reduce the burden of pneumonia among children in developing countries.

Research on simplified antibiotic regimens for outpatient treatment of 'Possible Serious Bacterial Infection' (PSBI) and the subsequent World Health Organization (WHO) guidelines provide an opportunity to increase treatment coverage. This multi-country implementation research initiative aimed to learn how to implement the WHO guideline in diverse contexts. These experiences have been individually published; this overview paper provides a summary of results and lessons learned across sites. A common mixed qualitative and quantitative methods protocol for implementation research was used in eleven sites in the Democratic Republic of Congo (Equateur province), Ethiopia (Tigray and Oromia regions), India (Haryana, Himachal Pradesh, Maharashtra, and Uttar Pradesh states), Malawi (Central Region), Nigeria (Kaduna and Oyo states), and Pakistan (Sindh province). Key steps in implementation research were: i) policy dialogue with the national government and key stakeholders, ii) the establishment of a 'Technical Support Unit' with the research team and district level managers, and iii) development of an implementation strategy and its refinement using an iterative process of implementation, programme learning and evaluation. All sites successfully developed and evaluated an implementation strategy to increase coverage of PSBI treatment. During the study period, a total of 6677 young infants from the study catchment area were identified and treated at health facilities in the study area as inpatients or outpatients among 88179 live births identified. The estimated coverage of PSBI treatment was 75.7% (95% CI 74.8% to 78.6%), assuming a 10% incidence of PSBI among all live births. The treatment coverage was variable, ranging from 53.3% in Lucknow, India to 97.3% in Ibadan, Nigeria. The coverage of inpatient treatment ranged from 1.9% in Zaria, Nigeria, to 33.9% in Tigray, Ethiopia. The outpatient treatment coverage ranged from 30.6% in Pune, India, to 93.6% in Zaria, Nigeria. Overall, the case fatality rate (CFR) was 14.6% (95% CI 11.5% to 18.2%) for 0-59-day old infants with critical illness, 1.9% (95% CI 1.5% to 2.4%) for 0-59-day old infants with clinical severe infection and 0.1% for fast breathing in 7-59 days old. Among infants treated as outpatients, CFR was 13.7% (95% CI 8.7% to 20.2%) for 0-59-day old infants with critical illness, 0.9% (95% CI 0.6% to 1.2%) for 0-59-day old infants with clinical severe infection, and 0.1% for infants 7-59 days old with fast breathing. Important lessons on how to conduct each step of implementation research, and the challenges and facilitators for implementation of PSBI management guideline in routine health systems are summarised and discussed. These lessons will be used to introduce and scale-up implementation in relevant Low- and middle-income countries.

Childhood and adolescence require adequate amount of micronutrients for normal growth and development. The primary objective of study was to assess the prevalence of deficiencies of Vitamins (Vitamin A, 25 Hydroxy Vitamin D, Vitamin B12 and Folate) and minerals (Calcium, Zinc, Selenium and Iron), among urban school going children aged 6-11 and 12-16 years in ten cities of India. Secondary objective was to find the association between micronutrient deficiencies with sociodemographic and anthropometric indicators. A multi-center cross-sectional study was conducted across India. Participants in the age groups of 6 to 11 years (group 1) and 12 to 16 years (group 2) were selected from randomly chosen schools from each center. Data on socio economic status, anthropometric measures was collected. Blood samples were collected for biochemical analysis of micronutrients. Point estimates and 95% confidence intervals was used to assess the prevalence of deficiencies. Associations were observed using chi square, student t test and ANOVA test. From April 2019 to February 2020, 2428 participants (1235 in group 1 and 1193 group 2) were recruited from 60 schools across ten cites. The prevalence of calcium and iron deficiency was 59.9% and 49.4% respectively. 25 Hydroxy Vitamin D deficiency was seen in 39.7% and vitamin B12 in 33.4% of subjects. Folate, Selenium and Zinc were deficient in 22.2%, 10.4% and 6.8% of subjects respectively. Vitamin A deficiency least (1.6%). Anemia was prevalent in 17.6% subjects and was more common among females. One or more micronutrient deficiencies are found in almost one half of school going children in urban area. Hence efforts must be made to combat these on priority. CTRI/2019/02/017783.

BackgroundCommunity-acquired pneumonia (CAP) is one of the leading causes of death in children under five. In developing countries, delayed treatment seeking has been associated with mortality and morbidity. There are only a few studies in India evaluating care-seeking behavior, particularly in children with CAP.MethodsThe present study was a hospital-based prospective semi-qualitative study. The study was conducted on parents or caregivers of consecutively hospitalized children under five (two to 59 months) with WHO-defined severe CAP along with radiological abnormalities consistent with CAP. Categorization of CAP and interpretation of chest X-rays (CXR) were done as per WHO criteria. Complicated CAP was categorized as severe pneumonia and had additional characteristics, including pleural effusion/empyema/pneumothorax requiring intercostal drainage, acute respiratory distress syndrome, or septic shock.ResultsAfter the screening of 420 consecutively hospitalized children under five with WHO-defined severe CAP along with radiological abnormalities consistent with it, 350 children were recruited in the present study. Among the recruited children, 58.6% experienced delayed care seeking, and among delayed care seekers, 94.6% presented with complications or developed complications during their hospital stay. The median delay in medical attention was three days. It also found that mothers with education levels below a high school had delayed care-seeking behavior. Mothers noticed the illness first in the majority of subjects (190, 54.3%), followed by fathers (78, 22.3%). Visiting traditional healers (46, 22.4%) and opting for home-bound remedies (44, 21.5%) were among the most common reasons for delayed care seeking. Fast breathing was the most concerning symptom among the parents and caregivers of the hospitalized children due to severe CAP followed by retractions, cough, and drowsiness. Retractions, drowsiness, and inability to feed were significantly recognized as alarming symptoms by the parents and caregivers in children with complicated CAP. Delayed care-seeking behavior was more prevalent in families from rural areas than in urban areas. If decision takers were in close relation with the sick child, chances of delayed care were less and vice versa. In urban areas, mothers can make decisions in significantly higher numbers than in rural areas, while grandmothers were more involved in decision-making in rural areas.ConclusionThe delayed care-seeking behavior was significantly higher in children with complicated CAP. Delayed care-seeking behavior was more prevalent in families from rural areas than in urban areas. The most common reasons for delayed care-seeking behavior were home remedies and visiting traditional healers. Caregivers need to be more aware of the danger signs of CAP and the consequences of treatment delay.

Control of pneumonia and diarrhea mortality in India requires understanding of their etiologies. We combined time series analysis of seasonality, climate region, and clinical syndromes from 243,000 verbal autopsies in the nationally representative Million Death Study. Pneumonia mortality at 1 month-14 years was greatest in January (Rate ratio (RR) 1.66, 99% CI 1.51–1.82; versus the April minimum). Higher RRs at 1–11 months suggested respiratory syncytial virus (RSV) etiology. India’s humid subtropical region experienced a unique summer pneumonia mortality. Diarrhea mortality peaked in July (RR 1.66, 1.48–1.85) and January (RR 1.37, 1.23–1.48), while deaths with fever and bloody diarrhea (indicating enteroinvasive bacterial etiology) showed little seasonality. Combining mortality at ages 1–59 months with prevalence surveys, we estimate 40,600 pneumonia deaths from Streptococcus pneumoniae , 20,700 from RSV, 12,600 from influenza, and 7200 from Haemophilus influenzae type b and 24,700 diarrheal deaths from rotavirus occurred in 2015. Careful mortality studies can elucidate etiologies and inform vaccine introduction.

In north India, vitamin A deficiency (retinol <0·70 μmol/L) is common in pre-school children and 2–3% die at ages 1·0–6·0 years. We aimed to assess whether periodic vitamin A supplementation could reduce this mortality. Participants in this cluster-randomised trial were pre-school children in the defined catchment areas of 8338 state-staffed village child-care centres (under-5 population 1 million) in 72 administrative blocks. Groups of four neighbouring blocks (clusters) were cluster-randomly allocated in Oxford, UK, between 6-monthly vitamin A (retinol capsule of 200 000 IU retinyl acetate in oil, to be cut and dripped into the child's mouth every 6 months), albendazole (400 mg tablet every 6 months), both, or neither (open control). Analyses of retinol effects are by block (36 vs 36 clusters). The study spanned 5 calendar years, with 11 6-monthly mass-treatment days for all children then aged 6–72 months. Annually, one centre per block was randomly selected and visited by a study team 1–5 months after any trial vitamin A to sample blood (for retinol assay, technically reliable only after mid-study), examine eyes, and interview caregivers. Separately, all 8338 centres were visited every 6 months to monitor pre-school deaths (100 000 visits, 25 000 deaths at ages 1·0–6·0 years [the primary outcome]). This trial is registered at ClinicalTrials.gov, NCT00222547. Estimated compliance with 6-monthly retinol supplements was 86%. Among 2581 versus 2584 children surveyed during the second half of the study, mean plasma retinol was one-sixth higher (0·72 [SE 0·01] vs 0·62 [0·01] μmol/L, increase 0·10 [SE 0·01] μmol/L) and the prevalence of severe deficiency was halved (retinol <0·35 μmol/L 6%vs 13%, decrease 7% [SE 1%]), as was that of Bitot's spots (1·4%vs 3·5%, decrease 2·1% [SE 0·7%]). Comparing the 36 retinol-allocated versus 36 control blocks in analyses of the primary outcome, deaths per child-care centre at ages 1·0–6·0 years during the 5-year study were 3·01 retinol versus 3·15 control (absolute reduction 0·14 [SE 0·11], mortality ratio 0·96, 95% CI 0·89–1·03, p=0·22), suggesting absolute risks of death between ages 1·0 and 6·0 years of approximately 2·5% retinol versus 2·6% control. No specific cause of death was significantly affected. DEVTA contradicts the expectation from other trials that vitamin A supplementation would reduce child mortality by 20–30%, but cannot rule out some more modest effect. Meta-analysis of DEVTA plus eight previous randomised trials of supplementation (in various different populations) yielded a weighted average mortality reduction of 11% (95% CI 5–16, p=0·00015), reliably contradicting the hypothesis of no effect. UK Medical Research Council, USAID, World Bank (vitamin A donated by Roche).

Based on World Health Organization guidelines, Government of India recommended management of possible serious bacterial infection (PSBI) in young infants up to two months of age on an outpatient basis where referral is not feasible. We implemented the guideline in program setting to increase access to treatment with high treatment success and low resultant mortality. Implementation research was conducted in four rural blocks of Lucknow district in Uttar Pradesh, India. It included policy dialogues with the central and state government and district level officials. A Technical Support Unit was established. Thereafter, capacity building across all cadres of health workers in the implementation area was done for strengthening of home based newborn care (HBNC) program, skills enhancement for identification and management of PSBI, logistics management to ensure availability of necessary supplies, monitoring and evaluation as well as providing feedback. Data was collected by the research team. From June 2017 to February 2019 there were 24,448 live births in a population of 856106. We identified 1302 infants, aged 0-59 days, with any sign of PSBI leading to a coverage of 53% (1302/2445), assuming an incidence of 10%. However, in the establishment phase the coverage was 33%, while it was 85% in the implementation phase. Accredited social health activists (ASHAs) identified 81.2% (1058/1302) cases while rest were identified by families. ASHAs increased home visits within first 7 days of life in home based newborn care program from 74.3% (2781/3738) to 89.0% (3128/3513) and detection of cases of PSBI from 1.6% (45/2781) to 8.7% (275/3128) in the first and last quarter of the project, respectively. Of these 18.7% (244/1302) refused referral to government health system and 6.7% (88/1302) were treated in a hospital. Among cases of PSBI, there were 13.3% (173/1302) cases of fast breathing in young infant aged 7-59 days in whom referral was not needed. Of these 147 were treated by oral amoxicillin and 95.2% (140/147) were cured. Among those who needed referral, simplified treatment was given when referral was refused. There were 2.9% (37/1302) cases of fast breathing at ages of 0-6 days of which 34 were treated by simplified treatment with100% (34/34) cured;66.5% (866/1302) were cases of clinical severe infection of which 685 treated by simplified treatment with94.2% (645/685)cured and 09 died;17.3% (226/1302) cases of critical illness of which 93 were treated by simplified treatment, as a last resort, 72% (67/93) cured and 16 died. Among 255 cases who either did not seek formal treatment or sought it at private facilities, 96 died. Simplified treatment for PSBI is feasible in public program settings in northern India with good cure rates. It required system strengthening and supportive supervision.

Over the last few years, a significant progress has been made in understanding the role of a disintegrin and metalloproteinase 33 (ADAM33) in asthma. The previous observations for the association with asthma have been replicated in over 33 different population samples worldwide. We and others have performed association analysis and meta-analysis and provided further evidence that several polymorphisms in the ADAM33 are risk factors for asthma, especially in the Asian population. Further, several studies have suggested that alterations in epigenetic marks alter the patterns of DNA methylation of ADAM33 and result in potentially adverse biological effects. Finally, while the biological activities of ADAM33 are as yet unknown, ADAM33 may play a possible role in airway remodeling because of its high expression in epithelium, myo/fibroblasts, and airway smooth muscle cells (ASMCs) and its role in promoting angiogenesis and stimulating cell proliferation and differentiation. Thus, ADAM33 represents a promising target for asthma. However, further investigations are clearly needed to discover functional ADAM33 gene polymorphisms and the role of genetic/epigenetic factors in conferring genetic susceptibility to environmental exposure induced asthma as well as biological function in asthma. This, in turn, will unlock the possibility of ADAM33 as a target for asthma therapy.