Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death ...in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.
We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a ...second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate
13 (PF-3893787). The pre-clinical profile of 13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and others in future drug discovery projects.
We describe the development of novel benzimidazoles as small molecule histamine H4 receptor (H4R) antagonists and their profiling in rat early toxicity studies. The discovery and optimisation of a second series of pyrimidine based antagonists is then described culminating in the identification of the clinical development candidate
13 (PF-3893787). The pre-clinical profile of
13 (PF-3893787) is presented including the development of a translatable biomarker. Our pragmatic approach to target selection, safety assessment, and testing for efficacy faced numerous challenges and we share a number of lessons which the team learned and which will assist us and others in future drug discovery projects.
This letter describes the discovery and synthesis of a series of octahydropyrrolo3,4-cpyrrole based selective histamine hH4 receptor antagonists. The amidine compound 20 was found to be a potent and ...selective histamine H4 receptor antagonist with moderate clearance and a high volume of distribution.
HIV-uninfected infants of HIV-positive women may experience worse growth and health outcomes than infants of HIV-negative women, but this has not been thoroughly investigated under the World Health ...Organization's most recent recommendations to reduce vertical transmission.
To determine whether HIV-exposed and -uninfected (HEU) infants whose mothers received Option B+ have higher odds of experiencing suboptimal growth trajectories than HIV-unexposed, -uninfected infants, and if this relationship is affected by food insecurity.
Repeated anthropometric measures were taken on 238 infants (HEU = 86) at 1 week and 1, 3, 6, 9, and 12 months after delivery in Gulu, Uganda. Latent class growth mixture modeling was used to develop trajectories for length-for-age z-scores, weight-for-length z-scores, mid-upper arm circumference, sum of skinfolds, and arm fat area. Multinomial logistic models were also built to predict odds of trajectory class membership, controlling for socioeconomic factors.
HEU infants had greater odds of being in the shortest 2 length-for-age z-scores trajectory classes odds ratio (OR) = 3.80 (1.22-11.82), OR = 8.72 (1.80-42.09) and higher odds of being in smallest sum of skinfolds trajectory class OR = 3.85 (1.39-10.59) vs. unexposed infants. Among HEU infants, increasing food insecurity was associated with lower odds of being in the lowest sum of skinfolds class OR = 0.86 (0.76-0.98).
There continues to be differences in growth patterns by HIV-exposure under the new set of World Health Organization guidelines for the prevention of mother-to-child transmission of HIV and the feeding of HEU infants in low-resource settings that are not readily identified through traditional mixed-effects modeling. Food insecurity was not associated with class membership, but differentially affected adiposity by HIV-exposure status.
ObjectiveTo support evidence informed decision-making, we systematically examine the effectiveness and cost-effectiveness of community engagement interventions on routine childhood immunisation ...outcomes in low-income and middle-income countries (LMICs) and identify contextual, design and implementation features associated with effectiveness.DesignMixed-methods systematic review and meta-analysis.Data sources21 databases of academic and grey literature and 12 additional websites were searched in May 2019 and May 2020.Eligibility criteria for selecting studiesWe included experimental and quasi-experimental impact evaluations of community engagement interventions considering outcomes related to routine child immunisation in LMICs. No language, publication type, or date restrictions were imposed.Data extraction and synthesisTwo independent researchers extracted summary data from published reports and appraised quantitative risk of bias using adapted Cochrane tools. Random effects meta-analysis was used to examine effects on the primary outcome, full immunisation coverage.ResultsOur search identified over 43 000 studies and 61 were eligible for analysis. The average pooled effect of community engagement interventions on full immunisation coverage was standardised mean difference 0.14 (95% CI 0.06 to 0.23, I2=94.46). The most common source of risk to the quality of evidence (risk of bias) was outcome reporting bias: most studies used caregiver-reported measures of vaccinations received by a child in the absence or incompleteness of immunisation cards. Reasons consistently cited for intervention success include appropriate intervention design, including building in community engagement features; addressing common contextual barriers of immunisation and leveraging facilitators; and accounting for existing implementation constraints. The median intervention cost per treated child per vaccine dose (excluding the cost of vaccines) to increase absolute immunisation coverage by one percent was US$3.68.ConclusionCommunity engagement interventions are successful in improving outcomes related to routine child immunisation. The findings are robust to exclusion of studies assessed as high risk of bias.
The health of infants that are HIV-exposed and -uninfected (HEU) is a major public health concern as HIV becomes a chronic condition. We investigate the interrelationship between maternal viral ...suppression, maternal weight status, breastfeeding, and infants that are HEU.
The Kabeho study followed 502 HEU infants in Kigali, Rwanda, for 24 months from 2013 to 2014. We use a structural equation modeling approach to investigate the dynamic relationships between viral suppression, maternal weight change, breastfeeding, and infant length-for-age z-score (LAZ) as defined by the WHO.
Older mothers are more likely to be virally suppressed and to breastfeed. Viral suppression and the mother being on antiretroviral treatment for longer were related to lower infant LAZ at three months. A more positive maternal weight change was related to higher infant LAZ at the end of each period. At 12 months, a higher infant LAZ was related to increased probability of continued breastfeeding. At 18 months, continued breastfeeding was related to lower LAZ, and food shortages were related to higher LAZ.
There is a complex interrelationship between viral suppression, maternal weight change, breastfeeding, and infant LAZ. These relationships demonstrate the link between maternal and infant health in the context of HIV.
Infants who are HIV-exposed and uninfected have suboptimal growth patterns compared to those who are HIV-unexposed and uninfected. However, little is known about how these patterns persist beyond 1 ...year of life.
This study aimed to examine whether infant body composition and growth trajectories differed by HIV exposure during the first 2 years of life among Kenyan infants using advanced growth modeling.
Repeated infant body composition and growth measurements (mean: 6; range: 2–7) were obtained from 6 weeks to 23 months in the Pith Moromo cohort in Western Kenya (n = 295, 50% HIV-exposed and uninfected, 50% male). Body composition trajectory groups were fitted using latent class mixed modeling (LCMM) and associations between HIV exposure and growth trajectories were examined using logistic regression analysis.
All infants exhibited poor growth. However, HIV-exposed infants generally grew suboptimally than unexposed infants. Across all body composition models except for the sum of skinfolds, HIV-exposed infants had a higher likelihood of belonging to the suboptimal growth groups identified by LCMM than the HIV-unexposed infants. Notably, HIV-exposed infants were 3.3 times more likely (95% CI: 1.5–7.4) to belong to the length-for-age z-score growth class that remained at a z-score of < −2, indicating stunted growth. HIV-exposed infants were also 2.6 times more likely (95% CI: 1.2–5.4) to belong to the weight-for-length-for-age z-score growth class that remained between 0 and −1, and were 4.2 times more likely (95% CI: 1.9–9.3) to belong to the weight-for-age z-score growth class that indicated poor weight gain besides stunted linear growth.
In a cohort of Kenyan infants, HIV-exposed infants grew suboptimally compared to HIV-unexposed infants beyond 1 year of age. These growth patterns and longer-term effects should be further investigated to support the ongoing efforts to reduce early-life HIV exposure-related health disparities.
HIV‐exposed and HIV‐uninfected (HEU) infants may be at increased risk of poor health and growth outcomes. We characterized infant growth trajectories in a cohort of HEU infants to identify factors ...associated with healthy growth. HIV‐positive women participating in prevention of mother‐to‐child HIV transmission programmes in Kigali, Rwanda, were followed until their infants were 2 years old. Infant anthropometrics were regularly collected. Latent class analysis was used to categorize infant growth trajectories. Multiple logistic regression was used to estimate the odds of infants belonging to each growth trajectory class. On average, this population of HEU infants had moderate linear growth faltering, but only modest faltering in weight, resulting in mean weight‐for‐length z‐score (WLZ) above the World Health Organization (WHO) median. Mean WLZ was 0.53, and mean length‐for‐age z‐score (LAZ) was −1.14 over the first 2 years of life. We identified four unique WLZ trajectories and seven trajectories in LAZ. Low neonatal weight‐for‐age and a high rate of illness increased the likelihood that infants were in the lightest WLZ class. Shorter mothers were more likely to have infants with linear growth faltering. Female infants who were older at the end of exclusive breastfeeding were more likely to be in the second tallest LAZ class. In conclusion, the current WHO recommendations of Option B+ and extended breastfeeding may induce higher WLZ and lower LAZ early in infancy. However, there is considerable heterogeneity in growth patterns that is obscured by simply analysing average growth trends, necessitating the analysis of growth in subpopulations.
ObjectiveIdentify and describe the available evidence on the effects food systems interventions on food security and nutrition outcomes in low-income and middle-income countries.MethodsAn adapted ...version of the high-level panel of experts food systems framework defined the interventions and outcomes included studies. Included study designs were experimental and quasi-experimental quantitative impact evaluations and systematic reviews. Following standards for evidence gap maps developed by 3ie, a systematic search of 17 academic databases and 31 sector-specific repositories in May 2020 identified articles for inclusion. Trained consultants screened titles/abstracts, then full texts of identified articles. Studies meeting eligibility criteria had meta-data systematically extracted and were descriptively analysed. Systematic reviews were critically appraised.ResultsThe map includes 1838 impact evaluations and 178 systematic reviews. The most common interventions, with over 100 impact evaluations and 20 systematic reviews each, were: provision of supplements, fortification, nutrition classes, direct provision of foods and peer support/counselling. Few studies addressed national-level interventions or women’s empowerment. The most common final outcomes were: anthropometry, micronutrient status, and diet quality and adequacy. Intermediate outcomes were less studied.Most evaluations were conducted in sub-Saharan Africa (33%) or South Asia (20%). Many studies occurred in lower-middle-income countries (43%); few (7%) were in fragile countries. Among studies in a specific age group, infants were most frequently included (19%); 14% of these also considered mothers.Few evaluations considered qualitative or cost analysis; 75% used randomisation as the main identification strategy.DiscussionThe uneven distribution of research means that some interventions have established impacts while other interventions, often affecting large populations, are underevaluated. Areas for future research include the evaluation of national level policies, evaluation of efforts to support women’s empowerment within the food system, and the synthesis of dietary quality. Quasi-experimental approaches should be adopted to evaluate difficult to randomise interventions.
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