Short-Term Administration of Rifampin in the Prevention or Eradication of Infection Due to Foreign Bodies

Short-term administration of rifampin was evaluated as a means of preventing or eradicating infection due to foreign bodies. Tissue cages were implanted into guinea pigs and subsequently infected with 103 colony-forming units of Staphylococcus aureus Wood 46. Infection developed in all tissue cages. Rifampin was administered thereafter intraperitoneally at a dosage of 7.5 mg/kg every 12 hr for 48 hr, and the tissue-cage fluid was monitored for possible development of infection by quantitative bacteriologic methods for 15 days. In all cases rifampin prevented or eradicated tissue-cage infection if treatment was initiated either 3 hr before or ⩽12 hr after inoculation of microorganisms but was ineffective if initiated >12 hr after inoculation. In cases of failure of treatment, rifampin-resistant variants could be demonstrated. Rifampin seems to prevent or eradicate tissue-cage infection only if given early after bacterial inoculatio

Assessing determinants of programmatic performance of community management of malaria, pneumonia, and diarrhea in children in Africa: protocol and data collection for a mixed methods evaluation of integrated community case management

BACKGROUND: Integrated community case management (iCCM) is a child health program designed to provide integrated community-based care for children with pneumonia, malaria, or diarrhea in hard-to-reach areas of low- and middle-income countries. The foundation of the intervention is service delivery by community health workers (CHWs) who depend on reliable provision of drugs and supplies, consistent supervision, comprehensive training, and community acceptance and participation to perform optimally. The effectiveness of the program may also depend on a number of other elements, including an enabling policy environment, financing mechanisms from the national to the local level, data transmission systems, and appropriate monitoring and evaluation. The extent to which these factors act upon each other to influence the effectiveness and viability of iCCM is both variable and challenging to assess, especially across different implementation contexts. OBJECTIVE: In this paper, we describe a mixed methods systems-based study protocol to assess the programmatic components of iCCM that are associated with intervention effectiveness and report preliminary results of data collection. METHODS: This protocol uses a mixed qualitative and quantitative study design based on a systems thinking approach within four iCCM programs in Malawi, Democratic Republic of the Congo, and Niger State and Abia State in Nigeria. Routine monitoring data are collected to determine intervention effectiveness, namely testing, treatment, and referral outcomes. Surveys with CHWs, supervisors, and caregivers are performed to collect quantitative data on their demographics, activities, and experiences within the program and how these relate to the areas of intervention effectiveness. Focus group discussions are conducted with these stakeholders as well as local traditional leaders to contextualize these data. Key informant interviews are undertaken with national- and district-level program stakeholders and officers knowledgeable in critical program processes. RESULTS: We performed 3836 surveys and 45 focus group discussions of 379 participants with CHWs, supervisors, caregivers, and traditional leaders, as well as 120 key informant interviews with district- and national-level program managers, health officers, and ministry officials. Policy and program documents were additionally collected for review. CONCLUSIONS: We expect that evidence from this study will inform child health programs and practice in low- and middle-income settings as well as future policy development within the iCCM intervention. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/33076

The building blocks of community health systems: a systems framework for the design, implementation and evaluation of iCCM programs and community-based interventions

INTRODUCTION: Almost all sub-Saharan African countries have adopted some form of integrated community case management (iCCM) to reduce child mortality, a strategy targeting common childhood diseases in hard-to-reach communities. These programs are complex, maintain diverse implementation typologies and involve many components that can influence the potential success of a program or its ability to effectively perform at scale. While tools and methods exist to support the design and implementation of iCCM and measure its progress, these may not holistically consider some of its key components, which can include program structure, setting context and the interplay between community, human resources, program inputs and health system processes. METHODS: We propose a Global South-driven, systems-based framework that aims to capture these different elements and expand on the fundamental domains of iCCM program implementation. We conducted a content analysis developing a code frame based on iCCM literature, a review of policy documents and discussions with key informants. The framework development was guided by a combination of health systems conceptual frameworks and iCCM indices. RESULTS: The resulting framework yielded 10 thematic domains comprising 106 categories. These are complemented by a catalogue of critical questions that program designers, implementers and evaluators can ask at various stages of program development to stimulate meaningful discussion and explore the potential implications of implementation in decentralised settings. CONCLUSION: The iCCM Systems Framework proposed here aims to complement existing intervention benchmarks and indicators by expanding the scope and depth of the thematic components that comprise it. Its elements can also be adapted for other complex community interventions. While not exhaustive, the framework is intended to highlight the many forces involved in iCCM to help managers better harmonise the organisation and evaluation of their programs and examine their interactions within the larger health system

A multicountry randomized controlled trial of comprehensive maternal nutrition supplementation initiated before conception: the Women First trial.

Background: Reported benefits of maternal nutrition supplements commenced during pregnancy in low-resource populations have typically been quite limited. Objectives: This study tested the effects on newborn size, especially length, of commencing nutrition supplements for women in low-resource populations ≥3 mo before conception (Arm 1), compared with the same supplement commenced late in the first trimester of pregnancy (Arm 2) or not at all (control Arm 3). Methods: Women First was a 3-arm individualized randomized controlled trial (RCT). The intervention was a lipid-based micronutrient supplement; a protein-energy supplement was also provided if maternal body mass index (kg/m2) was(DRC), Guatemala, India, and Pakistan. The primary outcome was length-for-age z score (LAZ), with all anthropometry obtainedDRC, outcomes were determined for all 4 sites from WHO newborn standards (non-gestational-age-adjusted, NGAA) as well as INTERGROWTH-21st fetal standards (3 sites, gestational age-adjusted, GAA). Results: A total of 7387 nonpregnant women were randomly assigned, yielding 2451 births with NGAA primary outcomes and 1465 with GAA outcomes. Mean LAZ and other outcomes did not differ between Arm 1 and Arm 2 using either NGAA or GAA. Mean LAZ (NGAA) for Arm 1 was greater than for Arm 3 (effect size: +0.19; 95% CI: 0.08, 0.30, P = 0.0008). For GAA outcomes, rates of stunting and small-for-gestational-age were lower in Arm 1 than in Arm 3 (RR: 0.69; 95% CI: 0.49, 0.98, P = 0.0361 and RR: 0.78; 95% CI: 0.70, 0.88, P \u3c 0.001, respectively). Rates of preterm birth did not differ among arms. Conclusions: In low-resource populations, benefits on fetal growth-related birth outcomes were derived from nutrition supplements commenced before conception or late in the first trimester. This trial was registered at clinicaltrials.gov as NCT01883193

The World Health Organization Fetal Growth Charts: A Multinational Longitudinal Study Of Ultrasound Biometric Measurements And Estimated Fetal Weight

Background Perinatal mortality and morbidity continue to be major global health challenges strongly associated with prematurity and reduced fetal growth, an issue of further interest given the mounting evidence that fetal growth in general is linked to degrees of risk of common non-communicable diseases in adulthood. Against this background, WHO made it a high priority to provide the present fetal growth charts for estimated fetal weight (EFW) and common ultrasound biometric measurements intended for worldwide use. Methods and Findings We conducted a multinational prospective observational longitudinal study of fetal growth in low-risk singleton pregnancies of women of high or middle socioeconomic status and without known environmental constraints on fetal growth. Centers in ten countries (Argentina, Brazil, Democratic Republic of the Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand) recruited participants who had reliable information on last menstrual period and gestational age confirmed by crown-rump length measured at 8-13 wk of gestation. Participants had anthropometric and nutritional assessments and seven scheduled ultrasound examinations during pregnancy. Fifty-two participants withdrew consent, and 1,387 participated in the study. At study entry, median maternal age was 28 y (interquartile range [IQR] 25-31), median height was 162 cm (IQR 157-168), median weight was 61 kg (IQR 55-68), 58% of the women were nulliparous, and median daily caloric intake was 1,840 cal (IQR 1,487-2,222). The median pregnancy duration was 39 wk (IQR 38-40) although there were significant differences between countries, the largest difference being 12 d (95% CI 8-16). The median birthweight was 3,300 g (IQR 2,980-3,615). There were differences in birthweight between countries, e. g., India had significantly smaller neonates than the other countries, even after adjusting for gestational age. Thirty-one women had a miscarriage, and three fetuses had intrauterine death. The 8,203 sets of ultrasound measurements were scrutinized for outliers and leverage points, and those measurements taken at 14 to 40 wk were selected for analysis. A total of 7,924 sets of ultrasound measurements were analyzed by quantile regression to establish longitudinal reference intervals for fetal head circumference, biparietal diameter, humerus length, abdominal circumference, femur length and its ratio with head circumference and with biparietal diameter, and EFW. There was asymmetric distribution of growth of EFW: a slightly wider distribution among the lower percentiles during early weeks shifted to a notably expanded distribution of the higher percentiles in late pregnancy. Male fetuses were larger than female fetuses as measured by EFW, but the disparity was smaller in the lower quantiles of the distribution (3.5%) and larger in the upper quantiles (4.5%). Maternal age and maternal height were associated with a positive effect on EFW, particularly in the lower tail of the distribution, of the order of 2% to 3% for each additional 10 y of age of the mother and 1% to 2% for each additional 10 cm of height. Maternal weight was associated with a small positive effect on EFW, especially in the higher tail of the distribution, of the order of 1.0% to 1.5% for each additional 10 kg of bodyweight of the mother. Parous women had heavier fetuses than nulliparous women, with the disparity being greater in the lower quantiles of the distribution, of the order of 1% to 1.5%, and diminishing in the upper quantiles. There were also significant differences in growth of EFW between countries. In spite of the multinational nature of the study, sample size is a limiting factor for generalization of the charts. Conclusions This study provides WHO fetal growth charts for EFW and common ultrasound biometric measurements, and shows variation between different parts of the world.141UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organizatio

Key factors predicting suspected severe malaria case management and health outcomes: an operational study in the Democratic Republic of the Congo

BACKGROUND: Evidence suggests that pre-referral Rectal Artesunate (RAS) can be a life-saving intervention for severe malaria in remote settings in Africa. Recognition of danger signs indicative of severe malaria is critical for prompt and appropriate case management. METHODS: This was an observational study conducted in three Health Zones of the Democratic Republic of the Congo to determine the distribution of dangers signs for severe malaria and assess their impact on RAS use, referral completion, injectable treatment and ACT provision, and health outcomes including death. An individual-level analysis was carried out, using multilevel-mixed effects logistic regression models. Severely ill febrile children < 5 years seeking care from community-based healthcare providers were recruited into a patient surveillance system based on the presence of key danger signs. Clinical and case management data were collected comprehensively over a 28 days period. Treatment seeking was elicited and health outcomes assessed during 28 days home visits. RESULTS: Overall, 66.4% of patients had iCCM general danger signs. Age of 2-5 years and iCCM general danger signs predicted RAS use (aOR = 2.77, 95% CI 2.04-3.77). RAS administration positively affected referral completion (aOR = 0.63, 95% CI 0.44-0.92). After RAS rollout, 161 children died (case fatality ratio: 7.1%, 95% CI 6.1-8.2). RAS improved the health status of the children on Day 28 (aOR = 0.64, 95% CI 0.45-0.92) and there was a non-significant trend that mortality was higher in children not receiving RAS (aOR = 1.50, 95% CI 0.86-2.60). Full severe malaria treatment at the RHF including injectable anti-malarial and a course of ACT was highly protective against death (aOR = 0.26, 95% CI 0.09-0.79). CONCLUSIONS: The main findings point towards the fact that danger signs are reasonably well recognized by health provider at the primary care level, and that RAS could influence positively health outcomes of such severe disease episodes and death. Its effectiveness is hampered by the insufficient quality of care at RHF, especially the provision of a full course of ACT following parenteral treatment. These are simple but important findings that requires urgent action by the health system planners and implementers

Reduced perinatal mortality following enhanced training of birth attendants in the Democratic Republic of Congo: a time-dependent effect

<p>Abstract</p> <p>Background</p> <p>In many developing countries, the majority of births are attended by traditional birth attendants, who lack formal training in neonatal resuscitation and other essential care required by the newly born infant. In these countries, the major causes of neonatal mortality are birth asphyxia, infection, and low-birth-weight/prematurity. Death from these causes is potentially modifiable using low-cost interventions, including neonatal resuscitation training. The purpose of this study was to evaluate the effect on perinatal mortality of training birth attendants in a rural area of the Democratic Republic of Congo (DRC) using two established programs.</p> <p>Methods</p> <p>This study, a secondary analysis of DRC-specific data collected during a multi-country study, was conducted in two phases. The effect of training using the WHO Essential Newborn Care (ENC) program was evaluated using an active baseline design, followed by a cluster randomized trial of training using an adaptation of a neonatal resuscitation program (NRP). The perinatal mortality rates before ENC, after ENC training, and after randomization to additional NRP training or continued care were compared. In addition, the influence of time following resuscitation training was investigated by examining change in perinatal mortality during sequential three-month increments following ENC training.</p> <p>Results</p> <p>More than two-thirds of deliveries were attended by traditional birth attendants and occurred in homes; these proportions decreased after ENC training. There was no apparent decline in perinatal mortality when the outcome of all deliveries prior to ENC training was compared to those after ENC but before NRP training. However, there was a gradual but significant decline in perinatal mortality during the year following ENC training (RR 0.73; 95% CI: 0.56-0.96), which was independently associated with time following training. The decline was attributable to a decline in early neonatal mortality. NRP training had no demonstrable effect on early neonatal mortality.</p> <p>Conclusion</p> <p>Training DRC birth attendants using the ENC program reduces perinatal mortality. However, a period of utilization and re-enforcement of training may be necessary before a decline in mortality occurs. ENC training has the potential to be a low cost, high impact intervention in developing countries.</p> <p>Trial registration</p> <p>This trial has been registered at <url>http://www.clinicaltrials.gov</url> (identifier <a href="http://www.clinicaltrials.gov/ct2/show/NCT00136708">NCT00136708</a>).</p

Population pharmacokinetics of artesunate and dihydroartemisinin in pregnant and non-pregnant women with malaria

<p>Abstract</p> <p>Background</p> <p>The World Health Organization endorses the use of artemisinin-based combination therapy for treatment of acute uncomplicated falciparum malaria in the second and third trimesters of pregnancy. However, the effects of pregnancy on the pharmacokinetics of artemisinin derivatives, such as artesunate (AS), are poorly understood. In this analysis, the population pharmacokinetics of oral AS, and its active metabolite dihydroartemisinin (DHA), were studied in pregnant and non-pregnant women at the Kingasani Maternity Clinic in the DRC.</p> <p>Methods</p> <p>Data were obtained from 26 pregnant women in the second (22 - 26 weeks) or the third (32 - 36 weeks) trimester of pregnancy and from 25 non-pregnant female controls. All subjects received 200 mg AS. Plasma AS and DHA were measured using a validated LC-MS method. Estimates for pharmacokinetic and variability parameters were obtained through nonlinear mixed effects modelling.</p> <p>Results</p> <p>A simultaneous parent-metabolite model was developed consisting of mixed zero-order, lagged first-order absorption of AS, a one-compartment model for AS, and a one-compartment model for DHA. Complete conversion of AS to DHA was assumed. The model displayed satisfactory goodness-of-fit, stability, and predictive ability. Apparent clearance (CL/F) and volume of distribution (V/F) estimates, with 95% bootstrap confidence intervals, were as follows: 195 L (139-285 L) for AS V/F, 895 L/h (788-1045 L/h) for AS CL/F, 91.4 L (78.5-109 L) for DHA V/F, and 64.0 L/h (55.1-75.2 L/h) for DHA CL/F. The effect of pregnancy on DHA CL/F was determined to be significant, with a pregnancy-associated increase in DHA CL/F of 42.3% (19.7 - 72.3%).</p> <p>Conclusions</p> <p>In this analysis, pharmacokinetic modelling suggests that pregnant women have accelerated DHA clearance compared to non-pregnant women receiving orally administered AS. These findings, in conjunction with a previous non-compartmental analysis of the modelled data, provide further evidence that higher AS doses would be required to maintain similar DHA levels in pregnant women as achieved in non-pregnant controls.</p

Challenge of Reducing Perinatal Mortality in Rural Congo: Findings of a Prospective, Population-based Study

Each year, an estimated six million perinatal deaths occur worldwide, and 98% of these deaths occur in lowand middle-income countries. These estimates are based on surveys in both urban and rural areas, and they may underrepresent the problem in rural areas. This study was conducted to quantify perinatal mortality, to identify the associated risk factors, and to determine the most common causes of early neonatal death in a rural area of the Democratic Republic of the Congo (DRC). Data were collected on 1,892 births. Risk factors associated with perinatal deaths were identified using multivariate analysis with logistic regression models. Causes of early neonatal deaths were determined by physician-review of information describing death. The perinatal mortality rate was 61 per 1,000 births; the stillbirth rate was 30 per 1,000 births; and the early neonatal death rate was 32 per 1,000 livebirths. Clinically-relevant factors independently associated with perinatal death included: low birthweight [odds ratio (OR)=13.51, 95% confidence interval (CI) 7.82-23.35], breech presentation (OR)=12.41; 95% CI 4.62-33.33), lack of prenatal care (OR=2.70, 95% CI 1.81-4.02), and parity greater than 4 (OR=1.93 95% CI 1.11-3.37). Over one-half of early neonatal deaths (n=37) occurred during the first two postnatal days, and the most common causes were low birthweight/prematurity (47%), asphyxia (34%), and infection (8%). The high perinatal mortality rate in rural communities in the DRC, approximately one-half of which is attributable to early neonatal death, may be modifiable. Specifically, deaths due to breech presentation, the second most common risk factor, may be reduced by making available emergency obstetric care. Most neonatal deaths occur soon after birth, and nearly three-quarters are caused by low birthweight/prematurity or asphyxia. Neonatal mortality might be reduced by targeting interventions to improve neonatal resuscitation and care of larger preterm infants

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