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Despite remarkable progress in the improvement of child survival between 1990 and 2015, the Millennium Development Goal (MDG) 4 target of a two-thirds reduction of under-5 mortality rate (U5MR) was not achieved globally. In this paper, we updated our annual estimates of child mortality by cause to 2000–15 to reflect on progress toward the MDG 4 and consider implications for the Sustainable Development Goals (SDG) target for child survival. We increased the estimation input data for causes of deaths by 43% among neonates and 23% among 1–59-month-olds, respectively. We used adequate vital registration (VR) data where available, and modelled cause-specific mortality fractions applying multinomial logistic regressions using adequate VR for low U5MR countries and verbal autopsy data for high U5MR countries. We updated the estimation to use Plasmodium falciparum parasite rate in place of malaria index in the modelling of malaria deaths; to use adjusted empirical estimates instead of modelled estimates for China; and to consider the effects of pneumococcal conjugate vaccine and rotavirus vaccine in the estimation. In 2015, among the 5·9 million under-5 deaths, 2·7 million occurred in the neonatal period. The leading under-5 causes were preterm birth complications (1·055 million [95% uncertainty range (UR) 0·935–1·179]), pneumonia (0·921 million [0·812 −1·117]), and intrapartum-related events (0·691 million [0·598 −0·778]). In the two MDG regions with the most under-5 deaths, the leading cause was pneumonia in sub-Saharan Africa and preterm birth complications in southern Asia. Reductions in mortality rates for pneumonia, diarrhoea, neonatal intrapartum-related events, malaria, and measles were responsible for 61% of the total reduction of 35 per 1000 livebirths in U5MR in 2000–15. Stratified by U5MR, pneumonia was the leading cause in countries with very high U5MR. Preterm birth complications and pneumonia were both important in high, medium high, and medium child mortality countries; whereas congenital abnormalities was the most important cause in countries with low and very low U5MR. In the SDG era, countries are advised to prioritise child survival policy and programmes based on their child cause-of-death composition. Continued and enhanced efforts to scale up proven life-saving interventions are needed to achieve the SDG child survival target. Bill & Melinda Gates Foundation, WHO.

Trend data for causes of child death are crucial to inform priorities for improving child survival by and beyond 2015. We report child mortality by cause estimates in 2000–13, and cause-specific mortality scenarios to 2030 and 2035. We estimated the distributions of causes of child mortality separately for neonates and children aged 1–59 months. To generate cause-specific mortality fractions, we included new vital registration and verbal autopsy data. We used vital registration data in countries with adequate registration systems. We applied vital registration-based multicause models for countries with low under-5 mortality but inadequate vital registration, and updated verbal autopsy-based multicause models for high mortality countries. We used updated numbers of child deaths to derive numbers of deaths by causes. We applied two scenarios to derive cause-specific mortality in 2030 and 2035. Of the 6·3 million children who died before age 5 years in 2013, 51·8% (3·257 million) died of infectious causes and 44% (2·761 million) died in the neonatal period. The three leading causes are preterm birth complications (0·965 million [15·4%, uncertainty range (UR) 9·8−24·5]; UR 0·615–1·537 million), pneumonia (0·935 million [14·9%, 13·0–16·8]; 0·817–1·057 million), and intrapartum-related complications (0·662 million [10·5%, 6·7–16·8]; 0·421–1·054 million). Reductions in pneumonia, diarrhoea, and measles collectively were responsible for half of the 3·6 million fewer deaths recorded in 2013 versus 2000. Causes with the slowest progress were congenital, preterm, neonatal sepsis, injury, and other causes. If present trends continue, 4·4 million children younger than 5 years will still die in 2030. Furthermore, sub-Saharan Africa will have 33% of the births and 60% of the deaths in 2030, compared with 25% and 50% in 2013, respectively. Our projection results provide concrete examples of how the distribution of child causes of deaths could look in 15–20 years to inform priority setting in the post-2015 era. More evidence is needed about shifts in timing, causes, and places of under-5 deaths to inform child survival agendas by and beyond 2015, to end preventable child deaths in a generation, and to count and account for every newborn and every child. Bill & Melinda Gates Foundation.

Background Diarrhea is recognized as a leading cause of morbidity and mortality among children under 5 years of age in low- and middle-income countries yet updated estimates of diarrhea incidence by age for these countries are greatly needed. We conducted a systematic literature review to identify cohort studies that sought to quantify diarrhea incidence among any age group of children 0-59 mo of age. Methods We used the Expectation-Maximization algorithm as a part of a two-stage regression model to handle diverse age data and overall incidence rate variation by study to generate country specific incidence rates for low- and middle-income countries for 1990 and 2010. We then calculated regional incidence rates and uncertainty ranges using the bootstrap method, and estimated the total number of episodes for children 0-59 mo of age in 1990 and 2010. Results We estimate that incidence has declined from 3.4 episodes/child year in 1990 to 2.9 episodes/child year in 2010. As was the case previously, incidence rates are highest among infants 6-11 mo of age; 4.5 episodes/child year in 2010. Among these 139 countries there were nearly 1.9 billion episodes of childhood diarrhea in 1990 and nearly 1.7 billion episodes in 2010. Conclusions Although our results indicate that diarrhea incidence rates may be declining slightly, the total burden on the health of each child due to multiple episodes per year is tremendous and additional funds are needed to improve both prevention and treatment practices in low- and middle-income countries.

Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. Updated total numbers of deaths in children aged 0–27 days and 1–59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1–59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916–1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610–0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252–0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977–1·176), diarrhoea (9·9%; 0·751 million, 0·538–1·031), and malaria (7·4%; 0·564 million, 0·432–0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339–0·547], 0·363 million [0·283–0·419], and 0·359 million [0·215–0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010–15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. The Bill & Melinda Gates Foundation.

ContextObstructive sleep apnea (OSA) is associated with diabetes and cardiovascular disease. This association may be related to metabolic changes that transpire during sleep in OSA.ObjectiveTo examine the impact of OSA, elicited by cessation of continuous positive airway pressure (CPAP), on frequently sampled nocturnal metabolic markers including plasma free fatty acids (FFAs), glucose, insulin, triglycerides (TGs), cortisol, and lactate, as well as glucose production, oral glucose tolerance, blood pressure (BP), endothelial function, cholesterol, and high-sensitivity C-reactive protein (hsCRP).Design and SettingRandomized crossover trial of CPAP vs CPAP withdrawal.PatientsThirty-one patients with moderate to severe OSA acclimated to CPAP.InterventionPatients underwent attended polysomnography while sleeping with therapeutic CPAP, or after CPAP withdrawal, in random order. Venous blood was sampled at ∼20-minute intervals on both nights. In 11 patients, we assessed glucose kinetics with an infusion of 6,6-[2H2]glucose.ResultsCPAP withdrawal caused recurrence of OSA associated with hypoxemia, sleep disruption, and heart rate (HR) elevation. CPAP withdrawal dynamically increased nocturnal FFA (P = 0.007), glucose (P = 0.028), and cortisol (P = 0.037), in proportion to respiratory event frequency, HR elevation, or sleep fragmentation. Diabetes predisposed to glucose elevation. CPAP withdrawal also increased systolic BP (P = 0.017) and augmentation index (P = 0.008), but did not affect insulin, TGs, glucose production, oral glucose tolerance, cholesterol, or hsCRP.ConclusionOSA recurrence during CPAP withdrawal increases FFA and glucose during sleep, associated with sympathetic and adrenocortical activation. Recurring exposure to these metabolic changes may foster diabetes and cardiovascular disease.We studied the overnight metabolic profile of patients during sleep, in the presence or absence of sleep apnea. Sleep apnea caused dynamic elevations of plasma FFA and glucose.

Antenatal anxiety is among the risk factors for adverse birth outcomes, which are common in Pakistan. Between 2019 and 2022, we conducted a randomized controlled trial to evaluate the effects of the Happy Mother-Healthy Baby program, designed to reduce anxiety during pregnancy through use of Cognitive Behavior Therapy, on birth outcomes with 796 women in Rwalpindi, Pakistan. We performed intent-to-treat analysis and per protocol analyses. Intention-to-treat analyses showed no difference in the odds of low birthweight (LBW) (Adj. OR = 0.82, 95% CI 0.55–1.28 p = 0.37), preterm birth (PTB) (Adj. OR = 1.20 95% CI 0.83–1.71, p = 0.33) or small-for-gestational age (SGA) birth, (Adj. OR = 0.76, 95% CI 0.56–1.09, p = 0.16). Among completers who received ≥ 5 intervention sessions, the odds of LBW and SGA were 39% and 32% lower (Adj. OR = 0.61, 95% CI 0.43–0.87, p < 0.01; Adj. OR = 0.68, 95% CI 0.53–0.89, p < 0.01). The significant LBW and SGA results among the intervention completers suggest that the program may be effective when a sufficient dose is received. However, confirmation of these findings is needed due to the fact that randomization is not maintained in completer analyses. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03880032, 19/03/2019.

We conducted 4 years of epidemiologic and genomic surveillance of single-dose effectiveness of a killed whole-cell oral cholera vaccine (kOCV) and Vibrio cholerae transmission in the Democratic Republic of the Congo. We enrolled 1,154 patients with diarrhea; 342 of those had culture-confirmed cholera. We performed whole-genome sequencing on clinical and water V. cholerae isolates from 200 patient households, which showed annual bimodal peaks of V. cholerae clade AFR10e infections. A large clonal cholera outbreak occurred 14 months after a kOCV campaign of >1 million doses, likely because of low (9%) vaccine coverage in informal settlements. Clinical and water isolates collected in the same household were closely related, suggesting person-to-person and water-to-person transmission. Single-dose kOCV vaccine effectiveness 24 months after vaccination was 59.8% (95% CI 19.7%-79.9%), suggesting modest single-dose kOCV protection. kOCV campaigns combined with water, sanitation, and hygiene programs should be used to reduce cholera in disease-endemic settings worldwide.

ObjectivesTo examine the potential for bias in the estimate of under-5 mortality due to birth defects recently produced by the WHO and the Maternal and Child Epidemiology Estimation research group.DesignSystematic analysis.MethodsWe examined the estimated number of under-5 deaths due to birth defects, the birth defect specific under-5 mortality rate, and the per cent of under-5 mortality due to birth defects, by geographic region, national income and under-5 mortality rate for three age groups from 2000 to 2019.ResultsThe under-5 deaths per 1000 live births from birth defects fell from 3.4 (95% uncertainty interval (UI) 3.1–3.8) in 2000 to 2.9 (UI 2.6–3.3) in 2019. The per cent of all under-5 mortality attributable to birth defects increased from 4.6% (UI 4.1%–5.1%) in 2000 to 7.6% (UI 6.9%–8.6%) in 2019. There is significant variability in mortality due to birth defects by national income level. In 2019, the under-5 mortality rate due to birth defects was less in high-income countries than in low-income and middle-income countries, 1.3 (UI 1.2–1.3) and 3.0 (UI 2.8–3.4) per 1000 live births, respectively. These mortality rates correspond to 27.7% (UI 26.6%–28.8%) of all under-5 mortality in high-income countries being due to birth defects, and 7.4% (UI 6.7%–8.2%) in low-income and middle-income countries.ConclusionsWhile the under-5 mortality due to birth defects is declining, the per cent of under-5 mortality attributable to birth defects has increased, with significant variability across regions globally. The estimates in low-income and middle-income countries are likely underestimated due to the nature of the WHO estimates, which are based in part on verbal autopsy studies and should be taken as a minimum estimate. Given these limitations, comprehensive and systematic estimates of the mortality burden due to birth defects are needed to estimate the actual burden.

Appropriate healthcare utilization and compliance with the WHO treatment guidelines can significantly reduce diarrhea-related childhood mortality and morbidity, while overuse of antibiotics notably increases antibiotic resistance. We studied care-seeking behavior and antibiotic use for childhood diarrhea by analyzing data from 8294 diarrheal episodes of 1–59-month-old children visiting a tertiary-care hospital in rural Bangladesh. Overall, 55% of the study children received antibiotics, while only 6% had dysentery. Notably, 77% of the antibiotics were obtained from a local pharmacy without a prescription. Antibiotics alone, without zinc or ORS, were used by more children with dysentery than watery diarrhea (15% vs. 9%; p < 0.001). While 85% of the children received ORS, only 7% received zinc and ORS without antibiotics. Children who received antibiotics before seeking care at the hospital had a significantly higher rate of hospitalization than those who did not have antibiotics (20% vs. 13%; p < 0.001). The factors that influenced the caregivers’ decision to seek care from the pharmacy were the desire for early recovery, traditional practices, faith in seeking care at pharmacies, and distance to a healthcare facility. Our findings warrant that reducing unnecessary antibiotic consumption requires increasing public awareness and strengthening laws on the sale of over-the-counter antibiotics.

Estimates for cause-specific mortality for neonates are generally available for all countries for neonates overall (0 to 28 days). However, cause-specific mortality is generally not being estimated at higher age resolution for neonates, despite evidence of heterogeneity in the causes of deaths during this period. We aimed to use the adapted log quadratic model in a setting where verbal autopsy was the primary means of determining cause of death. We examined the timing and causes of death among a cohort of neonates in rural Nepal followed as part of the Nepal Oil Massage Study (NOMS). We adapted methods defined by Wilmoth et al (2012) and Guillot et al. (2022) to estimate age and cause-specific mortality among neonates. We used cross validation to estimate the accuracy of this model, holding out each three month period. We took the average cross validation across hold out as our measure of model performance and compared to a standard approach which did not account for the heterogeneity in cause-specific mortality rate within this age group. There were 957 neonates in the NOMS cohort with known age and cause of death. We estimated an average cross-validation error of 0.9 per 1000 live births for mortality due to prematurity in the first week, and 1.1 for mortality due to birth asphyxia, compared to the standard approach, having error 7.4 and 7.8 per 1000 live births, respectively. Generally mortality rates for less common causes such as congenital malformations and pneumonia were estimated with higher cross-validation error. The stability and precision of these estimates compare favorably with similar estimates developed with higher quality cause-specific mortality surveillance from China, demonstrating that reliably estimating causes of mortality at high resolution is possible for neonates in low resources areas.