Economic evaluation of zinc and copper use in treating acute diarrhea in children: A randomized controlled trial

BACKGROUND: The therapeutic effects of zinc and copper in reducing diarrheal morbidity have important cost implications. This health services research study evaluated the cost of treating a child with acute diarrhea in the hospital, the impact of micronutrient supplementation on the mean predicted costs and its cost-effectiveness as compared to using only standard oral rehydration solution (ORS), from the patient's and government's (providers) perspective. METHODS: Children aged 6 months to 59 months with acute diarrhea were randomly assigned to receive either the intervention or control. The intervention was a daily dose of 40 mg of zinc sulfate and 5 mg of copper sulfate powder dissolved in a liter of standard ORS (n = 102). The control was 50 mg of standard ORS powder dissolved in a liter of standard ORS (n = 98). The cost measures were the total mean cost of treating acute diarrhea, which included the direct medical, the direct non-medical and the indirect costs. The effectiveness measures were the probability of diarrhea lasting ≤ 4 days, the disability adjusted life years (DALYs) and mortality. RESULTS: The mean total cost of treating a child with acute diarrhea was US $14 of which the government incurred an expenditure of 66%. The factors that increased the total were the number of stools before admission (p = 0.01), fever (p = 0.01), increasing grade of dehydration (p = 0.00), use of antibiotics (p = 0.00), use of intra-venous fluids (p = 0.00), hours taken to rehydrate a child (p = 0.00), the amount of oral rehydration fluid used (p = 0.00), presence of any complications (p = 0.00) and the hospital stay (p = 0.00). The supplemented group had a 8% lower cost of treating acute diarrhea, their cost per unit health (diarrhea lasting ≤ 4 days) was 24% less and the incremental cost-effectiveness ratio indicated cost savings (in Rupees) with the intervention [-452; 95%CI (-11306, 3410)]. However these differences failed to reach conventional levels of significance. CONCLUSION: An emphasis on the costs and economic benefits of an alternative therapy is an important aspect of health services research. The cost savings and the attractive cost-effectiveness indicates the need to further assess the role of micronutrients such as zinc and copper in the treatment of acute diarrhea in a larger and more varied population

Recommendations for treatment strategies in people with epilepsy during times of shortage of antiseizure medications

In times of severe antiseizure medication (ASM) shortage due to emergency situations (e.g., disasters, conflicts, sudden disruption to international supply chains), management of people with epilepsy with available ASMs can be difficult. A group of experts was brought together by the International League Against Epilepsy (ILAE) to formulate recommendations for such circumstances. Every effort was made to base these recommendations on direct published literature or extrapolations from basic information available about ASMs. Actual published literature in this area is, however, limited, and at times, assumptions were made by the experts to generate these recommendations. During times of shortage of ASMs, switching between different ASMs (e.g., oxcarbazepine and carbamazepine) can occasionally be considered as a mitigation procedure. However, for many ASMs, the option of an overnight switch to another drug does not exist. Switching from brand to generic or between generic products has often been shown to be safe, if required. Finally, when supplies of benzodiazepines or equipment to administer medications intravenously are not available, rectal administration of some ASMs may be an emergency alternative route for treating serial seizures and status epilepticus. Decision-making with regard to treatment and possible options should be driven by what is best for the patient

Implementation and evaluation of the Helping Babies Breathe curriculum in three resource limited settings: does Helping Babies Breathe save lives? A study protocol

Background: Neonatal deaths account for over 40% of all under-5 year deaths; their reduction is increasingly critical for achieving Millennium Development Goal 4. An estimated 3 million newborns die annually during their first month of life; half of these deaths occur during delivery or within 24 hours. Every year, 6 million babies require help to breathe immediately after birth. Resuscitation training to help babies breathe and prevent/manage birth asphyxia is not routine in low-middle income facility settings. Helping Babies Breathe (HBB), a simulation-training program for babies wherever they are born, was developed for use in low-middle income countries. We evaluated whether HBB training of facility birth attendants reduces perinatal mortality in the Eunice Kennedy Shriver National Institute of Child Health and Human Development’s Global Network research sites. Methods/design: We hypothesize that a two-year prospective pre-post study to evaluate the impact of a facility-based training package, including HBB and essential newborn care, will reduce all perinatal mortality (fresh stillbirth or neonatal death prior to 7 days) among the Global Network’s Maternal Neonatal Health Registry births ≥1500 grams in the study clusters served by the facilities. We will also evaluate the effectiveness of the HBB training program changing on facility-based perinatal mortality and resuscitation practices. Seventy-one health facilities serving 52 geographically-defined study clusters in Belgaum and Nagpur, India, and Eldoret, Kenya, and 30,000 women will be included. Primary outcome data will be collected by staff not involved in the HBB intervention. Additional data on resuscitations, resuscitation debriefings, death audits, quality monitoring and improvement will be collected. HBB training will include training of MTs, facility level birth attendants, and quality monitoring and improvement activities. Discussion: Our study will evaluate the effect of a HBB/ENC training and quality monitoring and improvement package on perinatal mortality using a large multicenter design and approach in 71 resource-limited health facilities, leveraging an existing birth registry to provide neonatal outcomes through day 7. The study will provide the evidence base, lessons learned, and best practices that will be essential to guiding future policy and investment in neonatal resuscitation. Trial registration: Trial registration ClinicalTrials.gov Identifier: NCT0168101

Data quality monitoring and performance metrics of a prospective, population-based observational study of maternal and newborn health in low resource settings

BACKGROUND: To describe quantitative data quality monitoring and performance metrics adopted by the Global Network´s (GN) Maternal Newborn Health Registry (MNHR), a maternal and perinatal population-based registry (MPPBR) based in low and middle income countries (LMICs). METHODS: Ongoing prospective, population-based data on all pregnancy outcomes within defined geographical locations participating in the GN have been collected since 2008. Data quality metrics were defined and are implemented at the cluster, site and the central level to ensure data quality. Quantitative performance metrics are described for data collected between 2010 and 2013. RESULTS: Delivery outcome rates over 95% illustrate that all sites are successful in following patients from pregnancy through delivery. Examples of specific performance metric reports illustrate how both the metrics and reporting process are used to identify cluster-level and site-level quality issues and illustrate how those metrics track over time. Other summary reports (e.g. the increasing proportion of measured birth weight compared to estimated and missing birth weight) illustrate how a site has improved quality over time. CONCLUSION: High quality MPPBRs such as the MNHR provide key information on pregnancy outcomes to local and international health officials where civil registration systems are lacking. The MNHR has measures in place to monitor data collection procedures and improve the quality of data collected. Sites have increasingly achieved acceptable values of performance metrics over time, indicating improvements in data quality, but the quality control program must continue to evolve to optimize the use of the MNHR to assess the impact of community interventions in research protocols in pregnancy and perinatal health.Fil: Goudar, Shivaprasad S.. KLE University. Jawaharlal Nehru Medical College; IndiaFil: Stolka, Kristen B.. Research Triangle Institute International; Estados UnidosFil: Koso Thomas, Marion. Eunice Kennedy Shriver National Institute of Child Health and Human Development; Estados UnidosFil: Honnungar, Narayan V.. KLE University. Jawaharlal Nehru Medical College; IndiaFil: Mastiholi, Shivanand C.. KLE University. Jawaharlal Nehru Medical College; IndiaFil: Ramadurg, Umesh Y.. S. Nijalingappa Medical College; IndiaFil: Dhaded, Sangappa M.. KLE University. Jawaharlal Nehru Medical College; IndiaFil: Pasha, Omrana. Aga Khan University; PakistánFil: Patel, Archana. Indira Gandhi Government Medical College and Lata Medical Research Foundation; IndiaFil: Esamai, Fabian. University School of Medicine; KeniaFil: Chomba, Elwyn. University of Zambia; ZambiaFil: Garces, Ana. Universidad de San Carlos; GuatemalaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Efectividad Clínica y Sanitaria; ArgentinaFil: Carlo, Waldemar A.. University of Alabama at Birmingahm; Estados UnidosFil: Goldenberg, Robert L.. Columbia University; Estados UnidosFil: Hibberd, Patricia L.. Massachusetts General Hospital for Children; Estados UnidosFil: Liechty, Edward A.. Indiana University; Estados UnidosFil: Krebs, Nancy F.. University of Colorado School of Medicine; Estados UnidosFil: Hambidge, Michael K.. University of Colorado School of Medicine; Estados UnidosFil: Moore, Janet L.. Research Triangle Institute International; Estados UnidosFil: Wallace, Dennis D.. Research Triangle Institute International; Estados UnidosFil: Derman, Richard J. Christiana Care Health Services; Estados UnidosFil: Bhalachandra, Kodkany S.. KLE University. Jawaharlal Nehru Medical College; IndiaFil: Bose, Carl L.. University of North Carolina; Estados Unido

Inter- and intra-individual variation in brain structural-cognition relationships in aging

The sources of inter- and intra-individual variability in age-related cognitive decline remain poorly understood. We examined the association between 20-year trajectories of cognitive decline and multimodal brain structure and morphology in older age. We used the Whitehall II Study, an extensively characterised cohort with 3T brain magnetic resonance images acquired at older age (mean age = 69.52 ± 4.9) and 5 repeated cognitive performance assessments between mid-life (mean age = 53.2 ±4.9 years) and late-life (mean age = 67.7 ± 4.9). Using non-negative matrix factorization, we identified 10 brain components integrating cortical thickness, surface area, fractional anisotropy, and mean and radial diffusivities. We observed two latent variables describing distinct brain-cognition associations. The first describes variations in 5 structural components associated with low mid-life performance across multiple cognitive domains, decline in reasoning, but maintenance of fluency abilities. The second describes variations in 6 structural components associated with low mid-life performance in fluency and memory, but retention of multiple abilities. Expression of latent variables predicts future cognition 3.2 years later (mean age = 70.87 ± 4.9). This data-driven approach highlights brain-cognition relationships wherein individuals degrees of cognitive decline and maintenance across diverse cognitive functions are both positively and negatively associated with markers of cortical structure

Trends and determinants of stillbirth in developing countries: results from the Global Network\u27s Population-Based Birth Registry.

BACKGROUND: Stillbirth rates remain high, especially in low and middle-income countries, where rates are 25 per 1000, ten-fold higher than in high-income countries. The United Nations\u27 Every Newborn Action Plan has set a goal of 12 stillbirths per 1000 births by 2030 for all countries. METHODS: From a population-based pregnancy outcome registry, including data from 2010 to 2016 from two sites each in Africa (Zambia and Kenya) and India (Nagpur and Belagavi), as well as sites in Pakistan and Guatemala, we evaluated the stillbirth rates and rates of annual decline as well as risk factors for 427,111 births of which 12,181 were stillbirths. RESULTS: The mean stillbirth rates for the sites were 21.3 per 1000 births for Africa, 25.3 per 1000 births for India, 56.9 per 1000 births for Pakistan and 19.9 per 1000 births for Guatemala. From 2010 to 2016, across all sites, the mean stillbirth rate declined from 31.7 per 1000 births to 26.4 per 1000 births for an average annual decline of 3.0%. Risk factors for stillbirth were similar across the sites and included maternal age \u3c 20 years and age \u3e 35 years. Compared to parity 1-2, zero parity and parity \u3e 3 were both associated with increased stillbirth risk and compared to women with any prenatal care, women with no prenatal care had significantly increased risk of stillbirth in all sites. CONCLUSIONS: At the current rates of decline, stillbirth rates in these sites will not reach the Every Newborn Action Plan goal of 12 per 1000 births by 2030. More attention to the risk factors and treating the causes of stillbirths will be required to reach the Every Newborn Action Plan goal of stillbirth reduction. TRIAL REGISTRATION: NCT01073475

A pre-post study of a multi-country scale up of resuscitation training of facility birth attendants: does Helping Babies Breathe training save lives?

Background: Whether facility-based implementation of Helping Babies Breathe (HBB) reduces neonatal mortality at a population level in low and middle income countries (LMIC) has not been studied. Therefore, we evaluated HBB implementation in this context where our study team has ongoing prospective outcome data on all pregnancies regardless of place of delivery. Methods: We compared outcomes of birth cohorts in three sites in India and Kenya pre-post implementation of a facility-based intervention, using a prospective, population-based registry in 52 geographic clusters. Our hypothesis was that HBB implementation would result in a 20 % decrease in the perinatal mortality rate (PMR) among births ≥1500 g. Results: We enrolled 70,704 births during two 12-month study periods. Births within each site did not differ prepost intervention, except for an increased proportion ofbirths; however, a post-hoc analysis stratified by birthweight documented improvement insurvival. Conclusions: Rapid scale up of HBB training of facility birth attendants in three diverse sites in India and Kenya was not associated with consistent improvements in mortality among all neonates ≥1500 g; however, differential improvements inpopulation, data collection, and ongoing quality monitoring activities. Trial registration: The study was registered at ClinicalTrials.gov: NCT0168101

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks\u27 gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks\u27 gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (\u3c34 \u3eweeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development

Impact of exposure to cooking fuels on stillbirths, perinatal, very early and late neonatal mortality - a multicenter prospective cohort study in rural communities in India, Pakistan, Kenya, Zambia and Guatemala

BACKGROUND: Consequences of exposure to household air pollution (HAP) from biomass fuels used for cooking on neonatal deaths and stillbirths is poorly understood. In a large multi-country observational study, we examined whether exposure to HAP was associated with perinatal mortality (stillbirths from gestation week 20 and deaths through day 7 of life) as well as when the deaths occurred (macerated, non-macerated stillbirths, very early neonatal mortality (day 0-2) and later neonatal mortality (day 3-28). Questions addressing household fuel use were asked at pregnancy, delivery, and neonatal follow-up visits in a prospective cohort study of pregnant women in rural communities in five low and lower middle income countries participating in the Global Network for Women and Children's Health's Maternal and Newborn Health Registry. The study was conducted between May 2011 and October 2012. Polluting fuels included kerosene, charcoal, coal, wood, straw, crop waste and dung. Clean fuels included electricity, liquefied petroleum gas (LPG), natural gas and biogas. RESULTS: We studied the outcomes of 65,912 singleton pregnancies, 18 % from households using clean fuels (59 % LPG) and 82 % from households using polluting fuels (86 % wood). Compared to households cooking with clean fuels, there was an increased risk of perinatal mortality among households using polluting fuels (adjusted relative risk (aRR) 1.44, 95 % confidence interval (CI) 1.30-1.61). Exposure to HAP increased the risk of having a macerated stillbirth (adjusted odds ratio (aOR) 1.66, 95%CI 1.23-2.25), non-macerated stillbirth (aOR 1.43, 95 % CI 1.15-1.85) and very early neonatal mortality (aOR 1.82, 95 % CI 1.47-2.22). CONCLUSIONS: Perinatal mortality was associated with exposure to HAP from week 20 of pregnancy through at least day 2 of life. Since pregnancy losses before labor and delivery are difficult to track, the effect of exposure to polluting fuels on global perinatal mortality may have previously been underestimated. TRIAL REGISTRATION: ClinicalTrials.gov NCT01073475

The Tudor-domain protein TDRD7, mutated in congenital cataract, controls the heat shock protein HSPB1 (HSP27) and lens fiber cell morphology

Mutations of the RNA granule component TDRD7 (OMIM: 611258) cause pediatric cataract. We applied an integrated approach to uncover the molecular pathology of cataract in Tdrd7−/− mice. Early postnatal Tdrd7−/− animals precipitously develop cataract suggesting a global-level breakdown/misregulation of key cellular processes. High-throughput RNA sequencing integrated with iSyTE-bioinformatics analysis identified the molecular chaperone and cytoskeletal modulator, HSPB1, among high-priority downregulated candidates in Tdrd7−/− lens. A protein fluorescence two-dimensional difference in-gel electrophoresis (2D-DIGE)-coupled mass spectrometry screen also identified HSPB1 downregulation, offering independent support for its importance to Tdrd7−/− cataractogenesis. Lens fiber cells normally undergo nuclear degradation for transparency, posing a challenge: how is their cell morphology, also critical for transparency, controlled post-nuclear degradation? HSPB1 functions in cytoskeletal maintenance, and its reduction in Tdrd7−/− lens precedes cataract, suggesting cytoskeletal defects may contribute to Tdrd7−/− cataract. In agreement, scanning electron microscopy (SEM) revealed abnormal fiber cell morphology in Tdrd7−/− lenses. Further, abnormal phalloidin and wheat germ agglutinin (WGA) staining of Tdrd7−/− fiber cells, particularly those exhibiting nuclear degradation, reveals distinct regulatory mechanisms control F-actin cytoskeletal and/or membrane maintenance in post-organelle degradation maturation stage fiber cells. Indeed, RNA immunoprecipitation identified Hspb1 mRNA in wild-type lens lysate TDRD7-pulldowns, and single-molecule RNA imaging showed co-localization of TDRD7 protein with cytoplasmic Hspb1 mRNA in differentiating fiber cells, suggesting that TDRD7–ribonucleoprotein complexes may be involved in optimal buildup of key factors. Finally, Hspb1 knockdown in Xenopus causes eye/lens defects. Together, these data uncover TDRD7’s novel upstream role in elevation of stress-responsive chaperones for cytoskeletal maintenance in post-nuclear degradation lens fiber cells, perturbation of which causes early-onset cataracts