Modelling bacterial speciation

A central problem in understanding bacterial speciation is how clusters of closely related strains emerge and persist in the face of recombination. We use a neutral Fisher–Wright model in which genotypes, defined by the alleles at 140 house-keeping loci, change in each generation by mutation or recombination, and examine conditions in which an initially uniform population gives rise to resolved clusters. Where recombination occurs at equal frequency between all members of the population, we observe a transition between clonal structure and sexual structure as the rate of recombination increases. In the clonal situation, clearly resolved clusters are regularly formed, break up or go extinct. In the sexual situation, the formation of distinct clusters is prevented by the cohesive force of recombination. Where the rate of recombination is a declining log-linear function of the genetic distance between the donor and recipient strain, distinct clusters emerge even with high rates of recombination. These clusters arise in the absence of selection, and have many of the properties of species, with high recombination rates and thus sexual cohesion within clusters and low rates between clusters. Distance-scaled recombination can thus lead to a population splitting into distinct genotypic clusters, a process that mimics sympatric speciation. However, empirical estimates of the relationship between sequence divergence and recombination rate indicate that the decline in recombination is an insufficiently steep function of genetic distance to generate species in nature under neutral drift, and thus that other mechanisms should be invoked to explain speciation in the presence of recombination

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

One Health drivers of antibacterial resistance: quantifying the relative impacts of human, animal and environmental use and transmission

Objectives: Antibacterial resistance (ABR) is a major global health security threat, with a disproportionate burden on lower-and middle-income countries (LMICs). It is not understood how ‘One Health’, where human health is co-dependent on animal health and the environment, might impact the burden of ABR in LMICs. Thailand’s 2017 “National Strategic Plan on Antimicrobial Resistance” (NSP-AMR) aims to reduce AMR morbidity by 50% through 20% reductions in human and 30% in animal antibacterial use (ABU). There is a need to understand the implications of such a plan within a One Health perspective. Methods: A model of ABU, gut colonisation with extended-spectrum beta-lactamase (ESBL)-producing bacteria and transmission was calibrated using estimates of the prevalence of ESBL-producing bacteria in Thailand. This model was used to project the reduction in human ABR over 20 years (2020–2040) for each One Health driver, including individual transmission rates between humans, animals and the environment, and to estimate the longterm impact of the NSP-AMR intervention. Results: The model predicts that human ABU was the most important factor in reducing the colonisation of humans with resistant bacteria (maximum 65.7–99.7% reduction). The NSP-AMR is projected to reduce human colonisation by 6.0–18.8%, with more ambitious targets (30% reductions in human ABU) increasing this to 8.5–24.9%. Conclusions: Our model provides a simple framework to explain the mechanisms underpinning ABR, suggesting that future interventions targeting the simultaneous reduction of transmission and ABU would help to control ABR more effectively in Thailand

Influenza and RSV make a modest contribution to invasive pneumococcal disease incidence in the UK

OBJECTIVES: The common seasonality of incidence of invasive pneumococcal disease (IPD) and viral respiratory infections has long been recognized, however, the extent to which this affects the association between the pathogens is unknown. We have analysed weekly surveillance data of IPD, influenza and respiratory syncytial virus (RSV), using ambient temperature and hours of sunshine as measures of seasonality. METHODS: Reported cases of influenza, IPD and RSV, were collected in England and Wales, from week 1 (January) 1996 to week 23 (June) 2009. The associations between IPD and respiratory viral infections were analysed using several statistical methods, including correlation coefficients and both additive and multiplicative regression models. RESULTS: 6–7.5% of cases of IPD are attributable to influenza and 3–4% attributable to RSV. Correlation coefficients reported considerably stronger associations between IPD and the viral infections compared to regression models. CONCLUSIONS: A small but potentially important percentage of IPD may be attributable to influenza and RSV when adjusted for seasonality by temperature. Jointly these viral infections may lead to over 10% of IPD cases. Therefore, prevention of viral respiratory infections may offer some additional benefit in reducing invasive pneumococcal infections