Systematic review and meta-analysis of the pharmacokinetics of benznidazole in the treatment of Chagas disease

Chagas disease is a neglected parasitic illness affecting approximately 8 million people, predominantly in Latin America. Benznidazole is the drug of choice for treatment, although its availability has been limited. A paucity of knowledge of the pharmacokinetic properties of this drug has contributed to its limited availability in several jurisdictions. The objective of this study was to conduct a systematic literature review and a Bayesian meta-analysis of pharmacokinetic studies to improve estimates of the basic pharmacokinetic properties of benznidazole. A systematic search of the Embase, Medline, LILACS, and SciELO (Scientific Electronic Library Online) databases was conducted. Eligible studies reported patient-level data from single-100-mg-dose pharmacokinetic evaluations of benznidazole in adults or otherwise provided data relevant to the estimation of pharmacokinetic parameters which could be derived from such studies. A Bayesian hierarchical model was used for analysis. Secondary data (i.e., data from studies that did not include patient-level, single-100-mg-dose data) were used for the generation of empirical priors for the Bayesian analysis. The systematic search identified nine studies for inclusion. Nine pharmacokinetic parameters were estimated, including the area under the concentration-time curve (AUC), the maximum concentration of drug in plasma (Cmax), the time to Cmax, the elimination rate constant (kel), the absorption rate constant (Ka), the absorption and elimination half-lives, the apparent oral clearance, and the apparent oral volume of distribution. The results showed consistency across studies. AUC and Cmax were 51.31 mg · h/liter (95% credible interval [CrI], 45.01, 60.28 mg · h/liter) and 2.19 mg/liter (95% CrI, 2.06, 2.33 mg/liter), respectively. Ka and kel were 1.16 h-1 (95% CrI, 0.59, 1.76 h-1) and 0.052 h-1 (95% CrI, 0.045, 0.059 h-1), respectively, with the corresponding absorption and elimination half-lives being 0.60 h (95% CrI, 0.38, 1.11 h) and 13.27 h (95% CrI, 11.79, 15.42 h), respectively. The oral clearance and volume of distribution were 2.04 liters/h (95% CrI, 1.77, 2.32 liters/h) and 39.19 liters (95% CrI, 36.58, 42.17 liters), respectively. A Bayesian meta-analysis was used to improve the estimates of the standard pharmacokinetic parameters of benznidazole. These data can inform clinicians and policy makers as access to this drug increases.Fil: Wiens, Matthew O.. University of British Columbia; CanadáFil: Kanters, Steve. Precision Global Health;Fil: Mills, Edward. Mc Master University; CanadáFil: Peregrina Lucano, Alejandro A.. Universidad de Guadalajara; MéxicoFil: Gold, Silvia. Fundación Mundo Sano; ArgentinaFil: Ayers, Dieter. Precision Global Health;Fil: Ferrero, Luis. Fundación Mundo Sano; ArgentinaFil: Krolewiecki, Alejandro Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentin

Selecting candidate predictor variables for the modelling of post-discharge mortality from sepsis: a protocol development project

Background: Post-discharge mortality is a frequent but poorly recognized contributor to child mortality in resource limited countries. The identification of children at high risk for post-discharge mortality is a critically important first step in addressing this problem.Objectives: The objective of this project was to determine the variables most likely to be associated with post-discharge mortality which are to be included in a prediction modelling study.Methods: A two-round modified Delphi process was completed for the review of a priori selected variables and selection of new variables. Variables were evaluated on relevance according to (1) prediction (2) availability (3) cost and (4) time required for measurement. Participants included experts in a variety of relevant fields.Results: During the first round of the modified Delphi process, 23 experts evaluated 17 variables. Forty further variables were suggested and were reviewed during the second round by 12 experts. During the second round 16 additional variables were evaluated. Thirty unique variables were compiled for use in the prediction modelling study.Conclusion: A systematic approach was utilized to generate an optimal list of candidate predictor variables for the incorporation into a study on prediction of pediatric post-discharge mortality in a resource poor setting.Keywords: Candidate predictor variables, pediatrics, prediction, post-discharge mortality, sepsi

A species-centered approach for uncovering generalities in organism responses to habitat loss and fragmentation

Theoretical models predict strong influences of habitat loss and fragmentation on species distributions and demography, but empirical studies have shown relatively inconsistent support across species and systems. We argue that species' responses to landscape-scale habitat loss and fragmentation are likely to appear less idiosyncratic if it is recognized that species perceive the same landscapes in different ways. We present a new quantitative approach that uses species distribution models (SDMs) to measure landscapes (e.g. patch size, isolation, matrix amount) from the perspective of individual species. First, we briefly summarize the few efforts to date demonstrating that once differences in habitat distributions are controlled, consistencies in species' responses to landscape structure emerge. Second, we present a detailed example providing step-by-step methods for application of a species-centered approach using freely available land-cover data and recent statistical modeling approaches. Third, we discuss pitfalls in current applications of the approach and recommend avenues for future developments. We conclude that the species-centered approach offers considerable promise as a means to test whether sensitivity to habitat loss and fragmentation is mediated by phylogenetic, ecological, and life-history traits. Cross-species generalities in responses to habitat loss and fragmentation will be challenging to uncover unless landscape mosaics are defined using models that reflect differing species-specific distributions, functional connectivity, and domains of scale. The emergence of such generalities would not only enhance scientific understanding of biotic processes driving fragmentation effects, but would allow managers to estimate species sensitivities in new regions.this study was supported by US National Science Foundation grants (NSF-ARC-0941748 and DEB-1050954

Changing trends in β-hemolytic streptococcal bacteremia in Manitoba, Canada:2007-2012

OBJECTIVES: European surveillance studies have reported an increasing incidence of β-hemolytic group G streptococcal bacteremia, but no studies have evaluated trends in β-hemolytic streptococcal bacteremia in North America. METHODS: We reviewed bacteremic episodes and positive throat swab cultures from two tertiary care centers in Manitoba, Canada, from January 2007 to December 2012. RESULTS: During the study period, 19 864 bacteremic episodes, and 9948 positive throat swabs were identified. There were 1025 (5.16%) bacteremic episodes attributable to β-hemolytic streptococci: 425 (2.03%), 339 (1.71%), 62 (0.31%), and 199 (0.95%) to β-hemolytic groups A, B, C, and G streptococci, respectively. From 2007 to 2012, there were significant increases in the proportion of bacteremia attributable to β-hemolytic streptococci in general (6.32% vs. 4.02%; p<0.0001; linear trend test, p<0.0001), and to groups G (1.49% vs. 0.43%; p<0.0001; linear trend test, p<0.0001) and C (0.58% vs. 0.13%; p=0.0068; linear trend test, p=0.0105) β-hemolytic streptococci in particular. Bacteremia attributable to groups A and B β-hemolytic streptococci and Streptococcus pneumoniae were unchanged. There were no changes in the distribution of β-hemolytic streptococcal groups among throat swabs. CONCLUSIONS: Bacteremia attributable to β-hemolytic groups G and C streptococci increased in Manitoba, Canada. Further study of the factors underlying these changes is required

Prognostic algorithms for post-discharge readmission and mortality among mother-infant dyads: an observational study protocol

IntroductionIn low-income country settings, the first six weeks after birth remain a critical period of vulnerability for both mother and newborn. Despite recommendations for routine follow-up after delivery and facility discharge, few mothers and newborns receive guideline recommended care during this period. Prediction modelling of post-delivery outcomes has the potential to improve outcomes for both mother and newborn by identifying high-risk dyads, improving risk communication, and informing a patient-centered approach to postnatal care interventions. This study aims to derive post-discharge risk prediction algorithms that identify mother-newborn dyads who are at risk of re-admission or death in the first six weeks after delivery at a health facility.MethodsThis prospective observational study will enroll 7,000 mother-newborn dyads from two regional referral hospitals in southwestern and eastern Uganda. Women and adolescent girls aged 12 and above delivering singletons and twins at the study hospitals will be eligible to participate. Candidate predictor variables will be collected prospectively by research nurses. Outcomes will be captured six weeks following delivery through a follow-up phone call, or an in-person visit if not reachable by phone. Two separate sets of prediction models will be built, one set of models for newborn outcomes and one set for maternal outcomes. Derivation of models will be based on optimization of the area under the receiver operator curve (AUROC) and specificity using an elastic net regression modelling approach. Internal validation will be conducted using 10-fold cross-validation. Our focus will be on the development of parsimonious models (5–10 predictor variables) with high sensitivity (&gt;80%). AUROC, sensitivity, and specificity will be reported for each model, along with positive and negative predictive values.DiscussionThe current recommendations for routine postnatal care are largely absent of benefit to most mothers and newborns due to poor adherence. Data-driven improvements to postnatal care can facilitate a more patient-centered approach to such care. Increasing digitization of facility care across low-income settings can further facilitate the integration of prediction algorithms as decision support tools for routine care, leading to improved quality and efficiency. Such strategies are urgently required to improve newborn and maternal postnatal outcomes. Clinical trial registrationhttps://clinicaltrials.gov/, identifier (NCT05730387)

Community health workers trained to conduct verbal autopsies provide better mortality measures than existing surveillance: Results from a cross-sectional study in rural western Uganda

Background: In much of sub-Saharan Africa, health facilities serve as the primary source of routine vital statistics. These passive surveillance systems, however, are plagued by infrequent and unreliable reporting and do not capture events that occur outside of the formal health sector. Verbal autopsies (VA) have been utilized to estimate the burden and causes of mortality where civil registration and vital statistics systems are weak, but VAs have not been widely employed in national surveillance systems. In response, we trained lay community health workers (CHW) in a rural sub-county of western Uganda to conduct VA interviews in order to assess the feasibility of leveraging CHW to measure the burden of disease in resource limited settings. Methods and findings: Trained CHWs conducted a cross-sectional survey of the 36 villages comprising the Bugoye sub-county to identify all deaths occurring in the prior year. The sub county has an estimated population of 50,249, approximately one-quarter of whom are children under 5 years of age (25.3%). When an eligible death was reported, CHWs administered a WHO 2014 VA questionnaire, the results of which were analyzed using the InterVA-4 tool. To compare the findings of the CHW survey to existing surveillance systems, study staff reviewed inpatient registers from neighboring referral health facilities in an attempt to match recorded deaths to those identified by the survey. Overall, CHWs conducted high quality VA interviews on direct observation, identifying 230 deaths that occurred within the sub-county, including 77 (33.5%) among children under five years of age. More than half of the deaths (123 of 230, 53.5%) were reported to have occurred outside a health facility and thus would not be captured by passive surveillance. More than two-thirds (73 of 107, 68.2%) of facility deaths took place in one of three nearby hospitals, yet only 35 (47.9%) were identified on our review of inpatient registers. Consistent with previous VA studies, the leading causes of death among children under five years of age were malaria (19.5%), prematurity (19.5%), and neonatal pneumonia (15.6%). while among adults, HIV/AIDS-related deaths illness (13.6%), pulmonary tuberculosis (11.4%) and malaria (8.6%) were the leading causes of death. No child deaths identified from inpatient registers listed HIV/AIDS as a cause of death despite 8 deaths (10.4%) attributed to HIV/AIDS as determined by VA. Conclusions: Lay CHWs are able to conduct high quality VA interviews to capture critical information that can be analyzed using standard methodologies to provide a more complete estimate of the burden and causes of mortality. Similar approaches can be scaled to improve the measurement of vital statistics in order to facilitate appropriate public health interventions in rural areas of sub-Saharan Africa

Effects of dairy intake on weight maintenance

Background: To compare the effects of low versus recommended levels of dairy intake on weight maintenance and body composition subsequent to weight loss. Design and Methods: Two site (University of Kansas-KU; University of Tennessee-UT), 9 month, randomized trial. Weight loss was baseline to 3 months, weight maintenance was 4 to 9 months. Participants were maintained randomly assigned to low dairy ( 3 servings/d) diets for the maintenance phase. Three hundred thirty eight men and women, age: 40.3 ± 7.0 years and BMI: 34.5 ± 3.1, were randomized; Change in weight and body composition (total fat, trunk fat) from 4 to 9 months were the primary outcomes. Blood chemistry, blood pressure, resting metabolism, and respiratory quotient were secondary outcomes. Energy intake, calcium intake, dairy intake, and physical activity were measured as process evaluation. Results: During weight maintenance, there were no overall significant differences for weight or body composition between the low and recommended dairy groups. A significant site interaction occurred with the low dairy group at KU maintaining weight and body composition and the low dairy group at UT increasing weight and body fat. The recommended dairy group exhibited reductions in plasma 1,25-(OH)2-D while no change was observed in the low dairy group. No other differences were found for blood chemistry, blood pressure or physical activity between low and recommended dairy groups. The recommended dairy group showed significantly greater energy intake and lower respiratory quotient compared to the low dairy group. Conclusion: Weight maintenance was similar for low and recommended dairy groups. The recommended dairy group exhibited evidence of greater fat oxidation and was able to consume greater energy without greater weight gain compared to the low dairy group. Recommended levels of dairy products may be used during weight maintenance without contributing to weight gain compared to diets low in dairy products. Trial Registration: ClinicalTrials.gov NCT0068642