Cost-effectiveness analysis of the diarrhea alleviation through zinc and oral rehydration therapy (DAZT) program in rural Gujarat India: an application of the net-benefit regression framework.

BACKGROUND: This study evaluates the cost-effectiveness of the DAZT program for scaling up treatment of acute child diarrhea in Gujarat India using a net-benefit regression framework. METHODS: Costs were calculated from societal and caregivers' perspectives and effectiveness was assessed in terms of coverage of zinc and both zinc and Oral Rehydration Salt. Regression models were tested in simple linear regression, with a specified set of covariates, and with a specified set of covariates and interaction terms using linear regression with endogenous treatment effects was used as the reference case. RESULTS: The DAZT program was cost-effective with over 95% certainty above $5.50 and $7.50 per appropriately treated child in the unadjusted and adjusted models respectively, with specifications including interaction terms being cost-effective with 85-97% certainty. DISCUSSION: Findings from this study should be combined with other evidence when considering decisions to scale up programs such as the DAZT program to promote the use of ORS and zinc to treat child diarrhea.

Meta-Analysis With a Continuous Covariate That Is Differentially Categorized Across Studies.

We propose taking advantage of methodology for missing data to estimate relationships and adjust outcomes in a meta-analysis where a continuous covariate is differentially categorized across studies. The proposed method incorporates all available data in an implementation of the expectation-maximization algorithm. We use simulations to demonstrate that the proposed method eliminates bias that would arise by ignoring a covariate and generalizes the meta-analytical approach for incorporating covariates that are not uniformly categorized. The proposed method is illustrated in an application for estimating diarrhea incidence in children aged ≤59 months.

World Health Organization Estimates of the Global and Regional Disease Burden of 22 Foodborne Bacterial, Protozoal, and Viral Diseases, 2010: A Data Synthesis.

BACKGROUND: Foodborne diseases are important worldwide, resulting in considerable morbidity and mortality. To our knowledge, we present the first global and regional estimates of the disease burden of the most important foodborne bacterial, protozoal, and viral diseases. METHODS AND FINDINGS: We synthesized data on the number of foodborne illnesses, sequelae, deaths, and Disability Adjusted Life Years (DALYs), for all diseases with sufficient data to support global and regional estimates, by age and region. The data sources included varied by pathogen and included systematic reviews, cohort studies, surveillance studies and other burden of disease assessments. We sought relevant data circa 2010, and included sources from 1990-2012. The number of studies per pathogen ranged from as few as 5 studies for bacterial intoxications through to 494 studies for diarrheal pathogens. To estimate mortality for Mycobacterium bovis infections and morbidity and mortality for invasive non-typhoidal Salmonella enterica infections, we excluded cases attributed to HIV infection. We excluded stillbirths in our estimates. We estimate that the 22 diseases included in our study resulted in two billion (95% uncertainty interval [UI] 1.5-2.9 billion) cases, over one million (95% UI 0.89-1.4 million) deaths, and 78.7 million (95% UI 65.0-97.7 million) DALYs in 2010. To estimate the burden due to contaminated food, we then applied proportions of infections that were estimated to be foodborne from a global expert elicitation. Waterborne transmission of disease was not included. We estimate that 29% (95% UI 23-36%) of cases caused by diseases in our study, or 582 million (95% UI 401-922 million), were transmitted by contaminated food, resulting in 25.2 million (95% UI 17.5-37.0 million) DALYs. Norovirus was the leading cause of foodborne illness causing 125 million (95% UI 70-251 million) cases, while Campylobacter spp. caused 96 million (95% UI 52-177 million) foodborne illnesses. Of all foodborne diseases, diarrheal and invasive infections due to non-typhoidal S. enterica infections resulted in the highest burden, causing 4.07 million (95% UI 2.49-6.27 million) DALYs. Regionally, DALYs per 100,000 population were highest in the African region followed by the South East Asian region. Considerable burden of foodborne disease is borne by children less than five years of age. Major limitations of our study include data gaps, particularly in middle- and high-mortality countries, and uncertainty around the proportion of diseases that were foodborne. CONCLUSIONS: Foodborne diseases result in a large disease burden, particularly in children. Although it is known that diarrheal diseases are a major burden in children, we have demonstrated for the first time the importance of contaminated food as a cause. There is a need to focus food safety interventions on preventing foodborne diseases, particularly in low- and middle-income settings.

The Lives Saved Tool (LiST) as a model for diarrhea mortality reduction.

BACKGROUND: Diarrhea is a leading cause of morbidity and mortality among children under five years of age. The Lives Saved Tool (LiST) is a model used to calculate deaths averted or lives saved by past interventions and for the purposes of program planning when costly and time consuming impact studies are not possible. DISCUSSION: LiST models the relationship between coverage of interventions and outputs, such as stunting, diarrhea incidence and diarrhea mortality. Each intervention directly prevents a proportion of diarrhea deaths such that the effect size of the intervention is multiplied by coverage to calculate lives saved. That is, the maximum effect size could be achieved at 100% coverage, but at 50% coverage only 50% of possible deaths are prevented. Diarrhea mortality is one of the most complex causes of death to be modeled. The complexity is driven by the combination of direct prevention and treatment interventions as well as interventions that operate indirectly via the reduction in risk factors, such as stunting and wasting. Published evidence is used to quantify the effect sizes for each direct and indirect relationship. Several studies have compared measured changes in mortality to LiST estimates of mortality change looking at different sets of interventions in different countries. While comparison work has generally found good agreement between the LiST estimates and measured mortality reduction, where data availability is weak, the model is less likely to produce accurate results. LiST can be used as a component of program evaluation, but should be coupled with more complete information on inputs, processes and outputs, not just outcomes and impact. SUMMARY: LiST is an effective tool for modeling diarrhea mortality and can be a useful alternative to large and expensive mortality impact studies. Predicting the impact of interventions or comparing the impact of more than one intervention without having to wait for the results of large and expensive mortality studies is critical to keep programs focused and results oriented for continued reductions in diarrhea and all-cause mortality among children under five years of age.

Measuring coverage in MNCH: current indicators for measuring coverage of diarrhea treatment interventions and opportunities for improvement.

Diarrhea morbidity and mortality remain important child health problems in low- and middle-income countries. The treatment of diarrhea and accurate measurement of treatment coverage are critical if child mortality is going to continue to decline. In this review, we examine diarrhea treatment coverage indicators collected in two large-scale community-based household surveys--the Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS). Current surveys do not distinguish between children with mild diarrhea episodes and those at risk for dehydration. Additional disease severity questions may improve the identification of cases of severe diarrhea but research is needed to identify indicators with the highest sensitivity and specificity. We also review the current treatment indicators in these surveys and highlight three areas for improvement and research. First, specific questions on fluids other than oral rehydration salts (ORS) should be eliminated to refocus the treatment of dehydration on ORS and to prevent confusion between prevention and treatment of dehydration. Second, consistency across surveys and throughout translations is needed for questions about the caregiver behavior of "offering" the sick child fluid and food. Third, breastfeeding should be separated from other fluid and food questions to capture the frequency and duration of nursing sessions offered during the illness. Research is also needed to assess the accuracy of the current zinc indicator to determine if caregivers are correctly recalling zinc treatment for current and recent diarrhea episodes.

Systematic review of probiotics for the treatment of community-acquired acute diarrhea in children.

BACKGROUND: Oral rehydration salts (ORS), zinc, and continued feeding are the recommended treatments for community-acquired acute diarrhea among young children. However, probiotics are becoming increasingly popular treatments for diarrhea in some countries. We sought to estimate the effect of probiotics on diarrhea morbidity and mortality in children < 5 years of age. METHODS: We conducted a systematic review of randomized controlled trials to estimate the effect of probiotic microorganisms for the treatment of community-acquired acute diarrhea in children. Data were abstracted into a standardized table and study quality was assessed using the Child Health Epidemiology Reference Group (CHERG) adaption of the GRADE technique. We measured the relative effect of probiotic treatment in addition to recommended rehydration on hospitalizations, duration and severity. We then calculated the average percent difference for all continuous outcomes and performed a meta-analysis for discrete outcomes. RESULTS: We identified 8 studies for inclusion in the final database. No studies reported diarrhea mortality and overall the evidence was low to moderate quality. Probiotics reduced diarrhea duration by 14.0% (95% CI: 3.8-24.2%) and stool frequency on the second day of treatment by 13.1% (95% CI: 0.8 - 25.3%). There was no effect on the risk of diarrhea hospitalizations. CONCLUSION: Probiotics may be efficacious in reducing diarrhea duration and stool frequency during a diarrhea episode. However, only few studies have been conducted in low-income countries and none used zinc (the current recommendation) thus additional research is needed to understand the effect of probiotics as adjunct therapy for diarrhea among children in developing countries.

Breastfeeding for reducing the risk of pneumonia morbidity and mortality in children under two: a systematic literature review and meta-analysis.

BACKGROUND: Suboptimal breastfeeding practices among infants and young children <24 months of age are associated with elevated risk of pneumonia morbidity and mortality. We conducted a systematic review and meta-analysis to quantify the protective effects of breastfeeding exposure against pneumonia incidence, prevalence, hospitalizations and mortality. METHODS: We conducted a systematic literature review of studies assessing the risk of selected pneumonia morbidity and mortality outcomes by varying levels of breastfeeding exposure among infants and young children <24 months of age. We used random effects meta-analyses to generate pooled effect estimates by outcome, age and exposure level. RESULTS: Suboptimal breastfeeding elevated the risk of pneumonia morbidity and mortality outcomes across age groups. In particular, pneumonia mortality was higher among not breastfed compared to exclusively breastfed infants 0-5 months of age (RR: 14.97; 95% CI: 0.67-332.74) and among not breastfed compared to breastfed infants and young children 6-23 months of age (RR: 1.92; 95% CI: 0.79-4.68). CONCLUSIONS: Our results highlight the importance of breastfeeding during the first 23 months of life as a key intervention for reducing pneumonia morbidity and mortality.

Enteric pathogens and reactive arthritis: a systematic review of Campylobacter, salmonella and Shigella-associated reactive arthritis.

Reactive arthritis (ReA) is a spondyloarthropathic disorder characterized by inflammation of the joints and tissues occurring after gastrointestinal or genitourinary infections. Diagnostic criteria for ReA do not exist and, therefore, it is subject to clinical opinion resulting in cases with a wide range of symptoms and definitions. Using standardized diagnostic criteria, we conducted a systematic literature review to establish the global incidence of ReA for each of the three most commonly-associated enteric pathogens: Campylobacter, Salmonella, and Shigella. The weighted mean incidence of reactive arthritis was 9, 12, and 12 cases per 1,000 cases of Campylobacter, Salmonella and Shigella infections respectively. To our knowledge, this is the first systematic review of worldwide data that use well-defined criteria to characterize diarrhoea-associated ReA. This information will aid in determining the burden of disease and act as a planning tool for public-health programmes.

PrEP uptake and early persistence among adolescent girls and young women receiving services via community and hybrid community-clinic models in Namibia.

INTRODUCTION: Adolescent girls and young women (AGYW) face barriers in accessing clinic-based HIV pre-exposure prophylaxis (PrEP) services and community-based models are a proposed alternative. Evidence from such models, however, is limited. We evaluated PrEP service coverage, uptake, and early persistence among AGYW receiving services through community and hybrid models in Namibia. METHODS: We analyzed routine data for AGYW aged 15-24 who initiated PrEP within HIV prevention programming. PrEP was delivered via three models: community-concierge (fully community-based services with individually-tailored refill locations), community-fixed (community-based initiation and refills delivered by community providers on a set schedule at fixed sites), and hybrid community-clinic (community-based initiation and referral to clinics for refills delivered by clinic providers). We examined proportions of AGYW engaged in services along a programmatic PrEP cascade, overall and by model, and assessed factors associated with PrEP uptake and early persistence (refill within 15-44 days after initiation) using multivariable generalized estimating equations. RESULTS: Over 10-months, 7593 AGYW participated in HIV prevention programming. Of these, 7516 (99.0%) received PrEP education, 6105 (81.2%) received HIV testing services, 6035 (98.9%) tested HIV-negative, and 2225 (36.9%) initiated PrEP. Of the 2047 AGYW expected for PrEP refill during the study period, 254 (12.4%) persisted with PrEP one-month after initiation. Structural and behavioral HIV risk factors including early school dropout, food insecurity, inconsistent condom use, and transactional sex were associated with PrEP uptake. AGYW who delayed starting PrEP were 2.89 times more likely to persist (95% confidence interval (CI): 1.52-5.46) and those receiving services via the community-concierge model were 8.7 times (95% CI: 5.44-13.9) more likely to persist (compared to the hybrid model). CONCLUSION: Community-based models of PrEP service delivery to AGYW can achieve high PrEP education and HIV testing coverage and moderate PrEP uptake. AGYW-centered approaches to delivering PrEP refills can promote higher persistence.

Male partner age, viral load, and HIV infection in adolescent girls and young women: evidence from eight sub-Saharan African countries.

OBJECTIVE: We aimed to elucidate the role of partnerships with older men in the HIV epidemic among adolescent girls and young women (AGYW) aged 15-24 years in sub-Saharan Africa. DESIGN: Analysis of Population-based HIV Impact Assessments in Eswatini, Lesotho, Malawi, Namibia, Tanzania, Uganda, Zambia, and Zimbabwe. METHODS: We examined associations between reported partner age and recent HIV infection among AGYW, incorporating male population-level HIV characteristics by age-band. Recent HIV infection was defined using the LAg avidity assay algorithm. Viremia was defined as a viral load of more than 1000 copies/ml, regardless of serostatus. Logistic regression compared recent infection in AGYW with older male partners to those reporting younger partners. Dyadic analysis examined cohabitating male partner age, HIV status, and viremia to assess associations with AGYW infection. RESULTS: Among 17 813 AGYW, increasing partner age was associated with higher odds of recent infection, peaking for partners aged 35-44 (adjusted odds ratio = 8.94, 95% confidence interval: 2.63-30.37) compared with partners aged 15-24. Population-level viremia was highest in this male age-band. Dyadic analyses of 5432 partnerships confirmed the association between partner age-band and prevalent HIV infection (male spousal age 35-44-adjusted odds ratio = 3.82, 95% confidence interval: 2.17-6.75). Most new infections were in AGYW with partners aged 25-34, as most AGYW had partners in this age-band. CONCLUSION: These results provide evidence that men aged 25-34 drive most AGYW infections, but partners over 9 years older than AGYW in the 35-44 age-band confer greater risk. Population-level infectiousness and male age group should be incorporated into identifying high-risk typologies in AGYW.

Predicting Treatment Interruption Among People Living With HIV in Nigeria: Machine Learning Approach.

BACKGROUND: Antiretroviral therapy (ART) has transformed HIV from a fatal illness to a chronic disease. Given the high rate of treatment interruptions, HIV programs use a range of approaches to support individuals in adhering to ART and in re-engaging those who interrupt treatment. These interventions can often be time-consuming and costly, and thus providing for all may not be sustainable. OBJECTIVE: This study aims to describe our experiences developing a machine learning (ML) model to predict interruption in treatment (IIT) at 30 days among people living with HIV newly enrolled on ART in Nigeria and our integration of the model into the routine information system. In addition, we collected health workers' perceptions and use of the model's outputs for case management. METHODS: Routine program data collected from January 2005 through February 2021 was used to train and test an ML model (boosting tree and Extreme Gradient Boosting) to predict future IIT. Data were randomly sampled using an 80/20 split into training and test data sets, respectively. Model performance was estimated using sensitivity, specificity, and positive and negative predictive values. Variables considered to be highly associated with treatment interruption were preselected by a group of HIV prevention researchers, program experts, and biostatisticians for inclusion in the model. Individuals were defined as having IIT if they were provided a 30-day supply of antiretrovirals but did not return for a refill within 28 days of their scheduled follow-up visit date. Outputs from the ML model were shared weekly with health care workers at selected facilities. RESULTS: After data cleaning, complete data for 136,747 clients were used for the analysis. The percentage of IIT cases decreased from 58.6% (36,663/61,864) before 2017 to 14.2% (3690/28,046) from October 2019 through February 2021. Overall IIT was higher among clients who were sicker at enrollment. Other factors that were significantly associated with IIT included pregnancy and breastfeeding status and facility characteristics (location, service level, and service type). Several models were initially developed; the selected model had a sensitivity of 81%, specificity of 88%, positive predictive value of 83%, and negative predictive value of 87%, and was successfully integrated into the national electronic medical records database. During field-testing, the majority of users reported that an IIT prediction tool could lead to proactive steps for preventing IIT and improving patient outcomes. CONCLUSIONS: High-performing ML models to identify patients with HIV at risk of IIT can be developed using routinely collected service delivery data and integrated into routine health management information systems. Machine learning can improve the targeting of interventions through differentiated models of care before patients interrupt treatment, resulting in increased cost-effectiveness and improved patient outcomes.

Systematic review of diarrhea duration and severity in children and adults in low- and middle-income countries.

BACKGROUND: Diarrhea is a leading cause of morbidity and mortality globally; yet the overall burden of diarrhea in terms of duration and severity has not been quantified. As improvements in treatment lead to decreases in diarrhea mortality, it is important to understand the substantial impact of diarrhea morbidity on disability among children and adults worldwide. METHODS: We conducted a systematic review to generate estimates of duration and severity outcomes for individuals 0-59 mos, 5-15 yrs, and ≥ 16 yrs, and for 3 severity indexes: mild, moderate, and severe. RESULTS: We estimate that among children under-five, 64.8% of diarrheal episodes are mild, 34.7% are moderate, and 0.5% are severe. On average, mild episodes last 4.3 days, and severe episodes last 8.4 days and cause dehydration in 84.6% of cases. We estimate that among older children and adults, 95% of episodes are mild; 4.95% are moderate; and 0.05% are severe. Among individuals ≥ 16 yrs, severe episodes typically last 2.6 days and cause dehydration in 92.8% of cases. CONCLUSIONS: Moderate and severe episodes constitute a substantial portion of the total envelope of diarrhea among children under-five (35.2%; about 588 million episodes). Among older children and adults, moderate and severe episodes account for a much smaller proportion of the total envelope of diarrhea (5%), but the absolute number of such episodes is noteworthy (about 21.5 million episodes among individuals ≥ 16 yrs). Hence, the global burden of diarrhea consists of significant morbidity, extending beyond episodes progressing to death.

Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review.

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.

Updating the assumptions on the impact of household water, sanitation and hygiene interventions on diarrhea morbidity in young children.

Background: The Lives Saved Tool (LiST) is a publicly available and widely used model used to estimate the impact of scaling up interventions on maternal and child health. A strength of the model is that it is continuously updated with country-specific information about intervention coverage, risk factors and causes of death. This paper reports an updated review and meta-analysis on the efficacy of water, sanitation and hygiene (WASH) interventions in reducing diarrhea morbidity among children under the age of five years. Methods: We updated previous LiST systematic reviews for improved WASH interventions according to standard LiST criteria. We sought to identify more recent WASH studies to update LiST efficacy estimates for each WASH intervention on diarrhea morbidity. In addition, we conducted a search to identify studies that reported an effect size for combined improved WASH interventions. For interventions where we found new studies, we conducted a weighted meta-analysis to produce an updated effect size estimate. Results: We did not find new studies demonstrating an effect of improved water source alone on diarrhea morbidity among children under 5 years of age. For improved sanitation, we conducted an updated meta-analysis among 4 studies and found no difference between intervention and control arms (weighted mean difference (WMD) = -5% (95% confidence interval (CI) = -11% to 2%). We identified four trials that assessed the effect of combined interventions targeting improved water, sanitation and hygiene. The weighted mean difference also showed no effect on diarrhea morbidity among children under 5 years of age (WMD = -6%, 95% CI = -15% to 4%). Our updated results for handwashing promotion estimate the effects to results in a 17% reduction in childhood diarrhea morbidity (95% CI = 7% to 27%). Conclusions: Despite widespread acceptance that WASH interventions can improve diarrhea morbidity, the evidence supporting this specifically for children under 5 years of age remains weak. Children interact with the environment in ways that differ from adults and these constant exposures may limit the effect that these WASH interventions can have on diarrhea morbidity.

Bottlenecks and Solutions During Implementation of the DREAMS Program for Adolescent Girls and Young Women in Namibia.

BACKGROUND: We synthesize implementation bottlenecks experienced while implementing the DREAMS (Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe) program, an HIV prevention intervention for adolescent girls and young women (AGYW), in Namibia from 2017 to 2019. Bottlenecks were organized into the following 4 AGYW program components. PROGRAM ACCESS: Enrollment was slowed by the time-intensive nature of screening and other baseline data collection requirements, delays in acquiring parental consent, and limited time for after-school activities. Solutions included obtaining advance consent and providing 1-stop service delivery and transportation assistance. HEALTH EDUCATION: We experienced difficulty identifying safe spaces for AGYW to meet. A lack of tailored curricula also impeded activities. Governments, stakeholders, and partners can plan ahead to help DREAMS identify appropriate safe spaces. Curricula should be identified and adapted before implementation. HEALTH SERVICES: Uneven availability of government-provided commodities (e.g., condoms, preexposure prophylaxis [PrEP], family planning products) and lack of AGYW-centered PrEP delivery approaches impacted services. Better forecasting of commodity needs and government commitment to supply chain strengthening will help ensure adequate program stock. SOCIAL SERVICES: The availability of only centralized care following gender-based violence (GBV) and the limited number of government social workers to manage GBV cases constrained service provision. Triaging GBV cases-i.e., referring high-risk cases to government social workers and providing DREAMS-specific social services for other cases-can ensure proper caseload management. CONCLUSION: These bottlenecks highlight practical implementation issues and higher-level considerations for AGYW-centered HIV prevention programs. The critical need for multilayered programming for HIV/GBV prevention in AGYW cannot be addressed simply with additional funds but requires multilevel collaboration and forecasting. The urgency to achieve results must be balanced with the need for adequate implementation preparedness.

Scaling up diarrhea prevention and treatment interventions: a Lives Saved Tool analysis.

BACKGROUND: Diarrhea remains a leading cause of mortality among young children in low- and middle-income countries. Although the evidence for individual diarrhea prevention and treatment interventions is solid, the effect a comprehensive scale-up effort would have on diarrhea mortality has not been estimated. METHODS AND FINDINGS: We use the Lives Saved Tool (LiST) to estimate the potential lives saved if two scale-up scenarios for key diarrhea interventions (oral rehydration salts [ORS], zinc, antibiotics for dysentery, rotavirus vaccine, vitamin A supplementation, basic water, sanitation, hygiene, and breastfeeding) were implemented in the 68 high child mortality countries. We also conduct a simple costing exercise to estimate cost per capita and total costs for each scale-up scenario. Under the ambitious (feasible improvement in coverage of all interventions) and universal (assumes near 100% coverage of all interventions) scale-up scenarios, we demonstrate that diarrhea mortality can be reduced by 78% and 92%, respectively. With universal coverage nearly 5 million diarrheal deaths could be averted during the 5-year scale-up period for an additional cost of US$12.5 billion invested across 68 priority countries for individual-level prevention and treatment interventions, and an additional US$84.8 billion would be required for the addition of all water and sanitation interventions. CONCLUSION: Using currently available interventions, we demonstrate that with improved coverage, diarrheal deaths can be drastically reduced. If delivery strategy bottlenecks can be overcome and the international community can collectively deliver on the key strategies outlined in these scenarios, we will be one step closer to achieving success for the United Nations' Millennium Development Goal 4 (MDG4) by 2015.

Progress and barriers for the control of diarrhoeal disease.

Discovery of intestinal sodium-glucose transport was the basis for development of oral rehydration solution, and was hailed as potentially the most important medical advance of the 20th century. Before widespread use of oral rehydration solution, treatment for diarrhoea was restricted to intravenous fluid replacement, for which patients had to go to a health-care facility to access appropriate equipment. These facilities were usually neither available nor reasonable to use in the resource-poor settings most affected by diarrhoea. Use of oral rehydration solution has stagnated, despite being effective, inexpensive, and widely available. Thus, diarrhoea continues to be a leading cause of child death with consistent mortality rates during the past 5 years. New methods for prevention, management, and treatment of diarrhoea-including an improved oral rehydration formulation, zinc supplementation, and rotavirus vaccines-make now the time to revitalise efforts to reduce diarrhoea mortality worldwide.

Rotavirus vaccine and diarrhea mortality: quantifying regional variation in effect size.

BACKGROUND: Diarrhea mortality remains a leading cause of child death and rotavirus vaccine an effective tool for preventing severe rotavirus diarrhea. New data suggest vaccine efficacy may vary by region. METHODS: We reviewed published vaccine efficacy trials to estimate a regional-specific effect of vaccine efficacy on severe rotavirus diarrhea and hospitalizations. We assessed the quality of evidence using a standard protocol and conducted meta-analyses where more than 1 data point was available. RESULTS: Rotavirus vaccine prevented severe rotavirus episodes in all regions; 81% of episodes in Latin America, 42.7% of episodes in high-mortality Asia, 50% of episodes in sub-Saharan Africa, 88% of episodes low-mortality Asia and North Africa, and 91% of episodes in developed countries. The effect sizes observed for preventing severe rotavirus diarrhea will be used in LiST as the effect size for rotavirus vaccine on rotavirus-specific diarrhea mortality. CONCLUSIONS: Vaccine trials have not measured the effect of vaccine on diarrhea mortality. The overall quality of the evidence and consistency observed across studies suggests that estimating mortality based on a severe morbidity reduction is highly plausible.

Breastfeeding and the risk for diarrhea morbidity and mortality.

BACKGROUND: Lack of exclusive breastfeeding among infants 0-5 months of age and no breastfeeding among children 6-23 months of age are associated with increased diarrhea morbidity and mortality in developing countries. We estimate the protective effects conferred by varying levels of breastfeeding exposure against diarrhea incidence, diarrhea prevalence, diarrhea mortality, all-cause mortality, and hospitalization for diarrhea illness. METHODS: We systematically reviewed all literature published from 1980 to 2009 assessing levels of suboptimal breastfeeding as a risk factor for selected diarrhea morbidity and mortality outcomes. We conducted random effects meta-analyses to generate pooled relative risks by outcome and age category. RESULTS: We found a large body of evidence for the protective effects of breastfeeding against diarrhea incidence, prevalence, hospitalizations, diarrhea mortality, and all-cause mortality. The results of random effects meta-analyses of eighteen included studies indicated varying degrees of protection across levels of breastfeeding exposure with the greatest protection conferred by exclusive breastfeeding among infants 0-5 months of age and by any breastfeeding among infants and young children 6-23 months of age. Specifically, not breastfeeding resulted in an excess risk of diarrhea mortality in comparison to exclusive breastfeeding among infants 0-5 months of age (RR: 10.52) and to any breastfeeding among children aged 6-23 months (RR: 2.18). CONCLUSIONS: Our findings support the current WHO recommendation for exclusive breastfeeding during the first 6 months of life as a key child survival intervention. Our findings also highlight the importance of breastfeeding to protect against diarrhea-specific morbidity and mortality throughout the first 2 years of life.