Receipt of antimalarials among children aged 6-59 months in Nigeria from 2010 to 2021.

BACKGROUND: Nigeria has the highest malaria burden globally, and anti-malarials have been commonly used to treat malaria without parasitological confirmation. In 2012, Nigeria implemented rapid diagnostic tests (RDTs) to reduce the use of anti-malarials for those without malaria and to increase the use of artemisinin-based combination therapy (ACT) for malaria treatment. This study examined changes in anti-malarial receipt among children aged 6-59 months during a 12-year period of increasing RDT availability. METHODS: A cross-sectional analysis was conducted using the Nigeria Malaria Indicator Survey (NMIS) data from 2010 (before RDT implementation in 2012), 2015, and 2021. The analysis assessed trends in prevalence of malaria by survey RDT result, and fever and anti-malarial/ACT receipt in the 2 weeks prior to the survey. A multivariable logistic regression was used to account for the complex survey design and to examine factors associated with anti-malarial receipt, stratified by survey RDT result, a proxy for recent/current malaria infection. RESULTS: In a nationally-representative, weighted sample of 22,802 children aged 6-59 months, fever prevalence remained stable over time, while confirmed malaria prevalence decreased from 51.2% in 2010 to 44.3% in 2015 and 38.5% in 2021 (trend test p < 0.0001). Anti-malarial use among these children decreased from 19% in 2010 to 10% in 2021 (trend test p < 0.0001), accompanied by an increase in ACT use (2% in 2010 to 8% in 2021; trend test p < 0.0001). Overall, among children who had experienced fever, 30.6% of survey RDT-positive and 36.1% of survey RDT-negative children had received anti-malarials. The proportion of anti-malarials obtained from the private sector increased from 61.8% in 2010 to 80.1% in 2021 for RDT-positive children; most of the anti-malarials received in 2021 were artemisinin-based combinations. Factors associated with anti-malarial receipt for both RDT-positive and RDT-negative children included geographic region, greater household wealth, higher maternal education, and older children. CONCLUSION: From 2010 to 2021 in Nigeria, both malaria prevalence and anti-malarial treatments among children aged 6-59 months decreased, as RDT availability increased. Among children who had fever in the prior 2 weeks, anti-malarial receipt was similar between children with either positive or negative survey RDT results, indicative of persistent challenges in reducing inappropriate anti-malarials uptake.

Selection, optimization, and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse populations.

Polygenic risk scores (PRS) have improved in predictive performance supporting their use in clinical practice. Reduced predictive performance of PRS in diverse populations can exacerbate existing health disparities. The NHGRI-funded eMERGE Network is returning a PRS-based genome-informed risk assessment to 25,000 diverse adults and children. We assessed PRS performance, medical actionability, and potential clinical utility for 23 conditions. Standardized metrics were considered in the selection process with additional consideration given to strength of evidence in African and Hispanic populations. Ten conditions were selected with a range of high-risk thresholds: atrial fibrillation, breast cancer, chronic kidney disease, coronary heart disease, hypercholesterolemia, prostate cancer, asthma, type 1 diabetes, obesity, and type 2 diabetes. We developed a pipeline for clinical PRS implementation, used genetic ancestry to calibrate PRS mean and variance, created a framework for regulatory compliance, and developed a PRS clinical report. eMERGE's experience informs the infrastructure needed to implement PRS-based implementation in diverse clinical settings.

PCSK9 loss-of-function variants and risk of infection and sepsis in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort.

BACKGROUND: Elevated proprotein convertase subtilisin/kexin type 9 (PCSK9) levels have been associated with adverse outcomes in patients hospitalized for sepsis. PCSK9 loss-of-function (LOF) variants area associated with lower low-density lipoprotein cholesterol (LDL-C) levels. Decreased LDL-C is a biomarker of acute and chronic infection and sepsis risk. We examined the association between presence of two genetic PCSK9 LOF variants and risk of infection and sepsis in community-dwelling adults. METHODS: We analyzed data from 10,924 Black participants tested for PCSK9 LOF variants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The primary endpoint was hospitalization for a serious infection. Within serious infection hospitalizations, we defined sepsis as ≥2 system inflammatory response syndrome criteria. Using multivariable Cox and logistic regression, we investigated the association between LOF variants and hospitalization for infection and sepsis events, adjusting for sociodemographics, health behaviors, chronic medical conditions and select biomarkers. RESULTS: Among 10,924 Black participants, PCSK9 LOF variants were present in 244 (2.2%). Serious infection hospitalizations occurred in 779 participants (14 with PCSK9 variants and 765 without). The presence of PCSK9 variants was not associated with infection risk (adjusted HR 0.68; 95% CI: 0.38-1.25). Among participants hospitalized for a serious infection, the presence of PCSK9 variants was not associated with sepsis (adjusted OR 7.31; 95% CI = 0.91-58.7). CONCLUSIONS: PCSK9 LOF variants are not associated with increased risk of hospitalization for a serious infection. Among those hospitalized for a serious infection, PCSK9 LOF variants was not associated with odds of sepsis.

Drug-Gene Interactions of Antihypertensive Medications and Risk of Incident Cardiovascular Disease: A Pharmacogenomics Study from the CHARGE Consortium.

BACKGROUND: Hypertension is a major risk factor for a spectrum of cardiovascular diseases (CVD), including myocardial infarction, sudden death, and stroke. In the US, over 65 million people have high blood pressure and a large proportion of these individuals are prescribed antihypertensive medications. Although large long-term clinical trials conducted in the last several decades have identified a number of effective antihypertensive treatments that reduce the risk of future clinical complications, responses to therapy and protection from cardiovascular events vary among individuals. METHODS: Using a genome-wide association study among 21,267 participants with pharmaceutically treated hypertension, we explored the hypothesis that genetic variants might influence or modify the effectiveness of common antihypertensive therapies on the risk of major cardiovascular outcomes. The classes of drug treatments included angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers, and diuretics. In the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, each study performed array-based genome-wide genotyping, imputed to HapMap Phase II reference panels, and used additive genetic models in proportional hazards or logistic regression models to evaluate drug-gene interactions for each of four therapeutic drug classes. We used meta-analysis to combine study-specific interaction estimates for approximately 2 million single nucleotide polymorphisms (SNPs) in a discovery analysis among 15,375 European Ancestry participants (3,527 CVD cases) with targeted follow-up in a case-only study of 1,751 European Ancestry GenHAT participants as well as among 4,141 African-Americans (1,267 CVD cases). RESULTS: Although drug-SNP interactions were biologically plausible, exposures and outcomes were well measured, and power was sufficient to detect modest interactions, we did not identify any statistically significant interactions from the four antihypertensive therapy meta-analyses (Pinteraction > 5.0×10-8). Similarly, findings were null for meta-analyses restricted to 66 SNPs with significant main effects on coronary artery disease or blood pressure from large published genome-wide association studies (Pinteraction ≥ 0.01). Our results suggest that there are no major pharmacogenetic influences of common SNPs on the relationship between blood pressure medications and the risk of incident CVD.