Emergency care of sepsis in sub-Saharan Africa: Mortality and non-physician clinician management of sepsis in rural Uganda from 2010 to 2019.

INTRODUCTION: Little data exists from sub-Saharan Africa describing incidence and outcomes of sepsis in emergency units and uncertainty exists surrounding optimal management of sepsis in low-income settings. There exists limited data regarding quality care metrics for non-physician clinicians trained in emergency care. The objective of this study was to describe changes in septic patients over time and evaluate associations between sepsis care and mortality. METHODS: Secondary analysis of a prospective cohort of all consecutive patients seen from 2010-2019 in a rural Ugandan emergency unit staffed by non-physician clinicians was performed using an electronic database based on paper charts. Sepsis was defined as suspected infection with a quick Sequential Organ Failure Assessment score (qSOFA)≥1. Multi-variable logistic regression was used to analyze three-day mortality. RESULTS: Overall, 48,653 patient visits from 2010-2019 yielded 17,490 encounters for patients age≥18 who had suspected infection, including 10,437 with sepsis. The annual proportion of patients with sepsis decreased from 45.0%% to 21.3% and the proportion with malarial sepsis decreased from 17.7% to 2.1% during the study period. Rates of septic patients receiving quality care ("both fluids and anti-infectives") increased over time (21.2% in 2012 to 32.0% in 2019, p<0.001), but mortality did not significantly improve (4.5% in 2012 to 6.4% in 2019, p = 0.50). The increasing quality of non-physician clinician care was not associated with reduced mortality, and treatment with "both fluids and antibiotics" was associated with increased mortality (RR = 1.55, 95%CI 1.10-2.00). CONCLUSION: The largest study of sepsis management and outcomes ever published in both Uganda and sub-Saharan Africa showed sepsis and malarial sepsis decreasing from 2010 to 2019. The increasing quality of non-physician clinician care did not significantly reduce mortality and treatment with "both fluids and antibiotics" increased mortality. With causal associations between antibiotics and mortality deemed implausible, associations between sepsis mortality and interventions likely represent confounding by indication. Defining optimal sepsis care regionally will likely require randomized controlled trials.

Testosterone interacts with the feedback mechanisms engaged by Tyr985 of the leptin receptor and diet-induced obesity.

Inhibitory signaling through Tyr985 of the leptin receptor contributes to the attenuation of anorectic leptin action in obese animals. Leptin receptor (LEPR-B) Tyr985Leu homozygote mutant mice (termed l/l) were previously generated to study Tyr985's contributions to inhibition of LEPR-B signaling; young female l/l mice display a lean, leptin-sensitive phenotype, while young male l/l are not significantly different from wild-type. We report here that testosterone (but not estrogen) determines the sex-specificity of the l/l phenotype. This provides additional insight into the cellular mechanism by which gonadal hormones determine central sensitivity to leptin, and may help elucidate the long-noted sex differences in leptin sensitivity. Additionally, we observed that Tyr985 signaling protects against a diet-dependent switch that exacerbates obesity with high fat feeding, such that the enhanced leptin sensitivity of l/l mice on a normal diet leads to increased adiposity in the face of chronic high-fat diet.