Estimating the effect of realistic improvements of metformin adherence on COVID-19 mortality using targeted machine learning.

Background: Type 2 diabetes elevates the risk of severe outcomes in COVID-19 patients, with multiple studies reporting higher case fatality rates. Metformin is a widely used medication for glycemic management. We hypothesize that improved adherence to metformin may lower COVID-19 post-infection mortality risk in this group. Utilizing data from the Mexican Social Security Institute (IMSS), we investigate the relationship between metformin adherence and mortality following COVID-19 infection in patients with chronic metformin prescriptions. Methods: This is a retrospective cohort study consisting of 61,180 IMSS beneficiaries who received a positive polymerase chain reaction (PCR) or rapid test for SARS-CoV-2 and had at least two consecutive months of metformin prescriptions prior to the positive test. The hypothetical intervention is improved adherence to metformin, measured by proportion of days covered (PDC), with the comparison being the observed metformin adherence values. The primary outcome is all-cause mortality following COVID-19 infection. We defined the causal parameter using shift intervention, an example of modified treatment policies. We used the targeted learning framework for estimation of the target estimand. Findings: Among COVID-19 positive patients with chronic metformin prescriptions, we found that a 5% and 10% absolute increase in metformin adherence is associated with a respective 0.26% (95% CI: -0.28%, 0.79%) and 1.26% (95% CI: 0.72%, 1.80%) absolute decrease in mortality risk. Interpretation: Subject to the limitations of a real-world data study, our results indicate a causal association between improved metformin adherence and reduced COVID-19 post-infection mortality risk.

Causes and consequences of child growth faltering in low-resource settings.

Growth faltering in children (low length for age or low weight for length) during the first 1,000 days of life (from conception to 2 years of age) influences short-term and long-term health and survival1,2. Interventions such as nutritional supplementation during pregnancy and the postnatal period could help prevent growth faltering, but programmatic action has been insufficient to eliminate the high burden of stunting and wasting in low- and middle-income countries. Identification of age windows and population subgroups on which to focus will benefit future preventive efforts. Here we use a population intervention effects analysis of 33 longitudinal cohorts (83,671 children, 662,763 measurements) and 30 separate exposures to show that improving maternal anthropometry and child condition at birth accounted for population increases in length-for-age z-scores of up to 0.40 and weight-for-length z-scores of up to 0.15 by 24 months of age. Boys had consistently higher risk of all forms of growth faltering than girls. Early postnatal growth faltering predisposed children to subsequent and persistent growth faltering. Children with multiple growth deficits exhibited higher mortality rates from birth to 2 years of age than children without growth deficits (hazard ratios 1.9 to 8.7). The importance of prenatal causes and severe consequences for children who experienced early growth faltering support a focus on pre-conception and pregnancy as a key opportunity for new preventive interventions.

Associations between social determinants of health and interpersonal violence-related injury in Cameroon: a cross-sectional study.

INTRODUCTION: Risk factors for interpersonal violence-related injury (IPVRI) in low-income and middle-income countries (LMICs) remain poorly defined. We describe associations between IPVRI and select social determinants of health (SDH) in Cameroon. METHODS: We conducted a cross-sectional analysis of prospective trauma registry data collected from injured patients >15 years old between October 2017 and January 2020 at four Cameroonian hospitals. Our primary outcome was IPVRI, compared with unintentional injury. Explanatory SDH variables included education level, employment status, household socioeconomic status (SES) and alcohol use. The EconomicClusters model grouped patients into household SES clusters: rural, urban poor, urban middle-class (MC) homeowners, urban MC tenants and urban wealthy. Results were stratified by sex. Categorical variables were compared via Pearson's χ2 statistic. Associations with IPVRI were estimated using adjusted odds ratios (aOR) with 95% confidence intervals (95%CI). RESULTS: Among 7605 patients, 5488 (72.2%) were men. Unemployment was associated with increased odds of IPVRI for men (aOR 2.44 (95% CI 1.95 to 3.06), p<0.001) and women (aOR 2.53 (95% CI 1.35 to 4.72), p=0.004), as was alcohol use (men: aOR 2.33 (95% CI 1.91 to 2.83), p<0.001; women: aOR 3.71 (95% CI 2.41 to 5.72), p<0.001). Male patients from rural (aOR 1.45 (95% CI 1.04 to 2.03), p=0.028) or urban poor (aOR 2.08 (95% CI 1.27 to 3.41), p=0.004) compared with urban wealthy households had increased odds of IPVRI, as did female patients with primary-level/no formal (aOR 1.78 (95% CI 1.10 to 2.87), p=0.019) or secondary-level (aOR 1.54 (95% CI 1.03 to 2.32), p=0.037) compared with tertiary-level education. CONCLUSION: Lower educational attainment, unemployment, lower household SES and alcohol use are risk factors for IPVRI in Cameroon. Future research should explore LMIC-appropriate interventions to address SDH risk factors for IPVRI.

Spillover effects on health outcomes in low- and middle-income countries: a systematic review.

Background: Many interventions delivered to improve health may benefit not only direct recipients but also people in close physical or social proximity. Our objective was to review all published literature about the spillover effects of interventions on health outcomes in low-middle income countries and to identify methods used in estimating these effects. Methods: We searched 19 electronic databases for articles published before 2014 and hand-searched titles from 2010 to 2013 in five relevant journals. We adapted the Cochrane Collaboration's quality grading tool for spillover estimation and rated the quality of evidence. Results: A total of 54 studies met inclusion criteria. We found a wide range of terminology used to describe spillovers, a lack of standardization among spillover methods and poor reporting of spillovers in many studies. We identified three primary mechanisms of spillovers: reduced disease transmission, social proximity and substitution of resources within households. We found the strongest evidence for spillovers through reduced disease transmission, particularly vaccines and mass drug administration. In general, the proportion of a population receiving an intervention was associated with improved health. Most studies were of moderate or low quality. We found evidence of publication bias for certain spillover estimates but not for total or direct effects. To facilitate improved reporting and standardization in future studies, we developed a reporting checklist adapted from the CONSORT framework specific to reporting spillover effects. Conclusions: We found the strongest evidence for spillovers from vaccines and mass drug administration to control infectious disease. There was little high quality evidence of spillovers for other interventions.

Estimation of treatment efficacy with complier average causal effects (CACE) in a randomized stepped wedge trial.

Complier average causal effects (CACE) estimate the impact of an intervention among treatment compliers in randomized trials. Methods used to estimate CACE have been outlined for parallel-arm trials (e.g., using an instrumental variables (IV) estimator) but not for other randomized study designs. Here, we propose a method for estimating CACE in randomized stepped wedge trials, where experimental units cross over from control conditions to intervention conditions in a randomized sequence. We illustrate the approach with a cluster-randomized drinking water trial conducted in rural Mexico from 2009 to 2011. Additionally, we evaluated the plausibility of assumptions required to estimate CACE using the IV approach, which are testable in stepped wedge trials but not in parallel-arm trials. We observed small increases in the magnitude of CACE risk differences compared with intention-to-treat estimates for drinking water contamination (risk difference (RD) = -22% (95% confidence interval (CI): -33, -11) vs. RD = -19% (95% CI: -26, -12)) and diarrhea (RD = -0.8% (95% CI: -2.1, 0.4) vs. RD = -0.1% (95% CI: -1.1, 0.9)). Assumptions required for IV analysis were probably violated. Stepped wedge trials allow investigators to estimate CACE with an approach that avoids the stronger assumptions required for CACE estimation in parallel-arm trials. Inclusion of CACE estimates in stepped wedge trials with imperfect compliance could enhance reporting and interpretation of the results of such trials.

Environmental justice implications of arsenic contamination in California's San Joaquin Valley: a cross-sectional, cluster-design examining exposure and compliance in community drinking water systems.

BACKGROUND: Few studies of environmental justice examine inequities in drinking water contamination. Those studies that have done so usually analyze either disparities in exposure/harm or inequitable implementation of environmental policies. The US EPA's 2001 Revised Arsenic Rule, which tightened the drinking water standard for arsenic from 50 µg/L to 10 µg/L, offers an opportunity to analyze both aspects of environmental justice. METHODS: We hypothesized that Community Water Systems (CWSs) serving a higher proportion of minority residents or residents of lower socioeconomic status (SES) have higher drinking water arsenic levels and higher odds of non-compliance with the revised standard. Using water quality sampling data for arsenic and maximum contaminant level (MCL) violation data for 464 CWSs actively operating from 2005-2007 in California's San Joaquin Valley we ran bivariate tests and linear regression models. RESULTS: Higher home ownership rate was associated with lower arsenic levels (ß-coefficient= -0.27 µg As/L, 95% (CI), -0.5, -0.05). This relationship was stronger in smaller systems (ß-coefficient = -0.43, CI, -0.84, -0.03). CWSs with higher rates of homeownership had lower odds of receiving an MCL violation (OR, 0.33; 95% CI, 0.16, 0.67); those serving higher percentages of minorities had higher odds (OR, 2.6; 95% CI, 1.2, 5.4) of an MCL violation. CONCLUSIONS: We found that higher arsenic levels and higher odds of receiving an MCL violation were most common in CWSs serving predominantly socio-economically disadvantaged communities. Our findings suggest that communities with greater proportions of low SES residents not only face disproportionate arsenic exposures, but unequal MCL compliance challenges.

Inequalities in body mass index and smoking behavior in 70 countries: evidence for a social transition in chronic disease risk.

Despite the growing burden of chronic disease globally, few studies have examined the socioeconomic patterning of risk across countries. The authors examined differences in the social patterning of body mass index (BMI) and current smoking by urbanicity among 70 countries from the 2002-2003 World Health Surveys. Age-adjusted, gender-stratified ordinary least squares and logistic regression analyses were conducted in each country to assess the relation between education and BMI or smoking. Meta-analytic techniques were used to assess heterogeneity between countries in the education-risk factor relations. Meta-regression was used to determine whether the heterogeneity could be explained by country-level urbanicity. In the least urban countries, persons with higher education had a higher BMI, while the opposite pattern was seen in the most urban countries, with this pattern being especially pronounced among women. In contrast, smoking was consistently concentrated among persons of lower education among all men and among women in the least urban countries. For women in the most urban countries, higher education was associated with higher odds of smoking, although there was substantial variability in this relation. These results highlight a global trend toward an increasing burden of chronic disease risk among persons of lower socioeconomic position as countries become more urban.

Toxicogenomic profiling of chemically exposed humans in risk assessment.

Gene-environment interactions contribute to complex disease development. The environmental contribution, in particular low-level and prevalent environmental exposures, may constitute much of the risk and contribute substantially to disease. Systematic risk evaluation of the majority of human chemical exposures, has not been conducted and is a goal of regulatory agencies in the U.S. and worldwide. With the recent recognition that toxicological approaches more predictive of effects in humans are required for risk assessment, in vitro human cell line data as well as animal data are being used to identify toxicity mechanisms that can be translated into biomarkers relevant to human exposure studies. In this review, we discuss how data from toxicogenomic studies of exposed human populations can inform risk assessment, by generating biomarkers of exposure, early effect, and/or susceptibility, elucidating mechanisms of action underlying exposure-related disease, and detecting response at low doses. Good experimental design incorporating precise, individual exposure measurements, phenotypic anchors (pre-disease or traditional toxicological markers), and a range of relevant exposure levels, is necessary. Further, toxicogenomic studies need to be designed with sufficient power to detect true effects of the exposure. As more studies are performed and incorporated into databases such as the Comparative Toxicogenomics Database (CTD) and Chemical Effects in Biological Systems (CEBS), data can be mined for classification of newly tested chemicals (hazard identification), and, for investigating the dose-response, and inter-relationship among genes, environment and disease in a systems biology approach (risk characterization).