Keeping the herds healthy and alert: implications of predator control for infectious disease

Predator control programmes are generally implemented in an attempt to increase prey population sizes. However, predator removal could prove harmful to prey populations that are regulated primarily by parasitic infections rather than by predation. We develop models for microparasitic and macroparasitic infection that specify the conditions where predator removal will (a) increase the incidence of parasitic infection, (b) reduce the number of healthy individuals in the prey population and (c) decrease the overall size of the prey population. In general, predator removal is more likely to be harmful when the parasite is highly virulent, macroparasites are highly aggregated in their prey, hosts are long-lived and the predators select infected prey

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure

The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure. Trial registration: NCT01661634. © 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiolog

SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials

Background: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. Methods: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. Findings: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0·87, 95% CI 0·77–0·98; p=0·018) and 14% reduction in cardiovascular death (0·86, 0·76–0·98; p=0·027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0·74, 0·68–0·82; p<0·0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0·75, 0·68–0·84; p<0·0001). The risk of the composite renal endpoint was also reduced (0·62, 0·43–0·90; p=0·013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. Interpretation: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. Funding: Boehringer Ingelheim. © 2020 Elsevier Lt