A Specialized Polythioamide‐Binding Protein Confers Antibiotic Self‐Resistance in Anaerobic Bacteria

Understanding antibiotic resistance mechanisms is central to the development of anti‐infective therapies and genomics‐based drug discovery. Yet, many knowledge gaps remain regarding the resistance strategies employed against novel types of antibiotics from less‐explored producers such as anaerobic bacteria, among them the Clostridia. Through the use of genome editing and functional assays, we found that CtaZ confers self‐resistance against the copper chelator and gyrase inhibitor closthioamide (CTA) in Ruminiclostridium cellulolyticum . Bioinformatics, biochemical analyses, and X‐ray crystallography revealed CtaZ as a founding member of a new group of GyrI‐like proteins. CtaZ is unique in binding a polythioamide scaffold in a ligand‐optimized hydrophobic pocket, thereby confining CTA. By genome mining using CtaZ as a handle, we discovered previously overlooked homologs encoded by diverse members of the phylum Firmicutes, including many pathogens. In addition to characterizing both a new role for a GyrI‐like domain in self‐resistance and unprecedented thioamide binding, this work aids in uncovering related drug‐resistance mechanisms

The ethics and safety of medical student global health electives

Abstract Objectives: To explore and characterize the ethical and safety challenges of global health experiences as they affect medical students in order to better prepare trainees to face them. Methods: Semi-structured interviews were conducted with 23 Canadian medical trainees who had participated in global health experiences during medical school. Convenience and snowball sampling were utilized. Using Moustakas's transcendental phenomenological approach, participant descriptions of ethical dilemmas and patient/trainee safety problems were analyzed. This generated an aggregate that illustrates the essential meanings of global health experience ethical and safety issues faced. Results: We interviewed 23 participants who had completed 38 electives (71%, n=27, during pre-clinical years) spending a mean 6.9 weeks abroad, and having visited 23 countries. Sixty percent (n=23) had pre-departure training while 36% (n=14) had post-experience debriefing. Three macrolevel themes were identified: resource disparities and provision of care; navigating clinical ethical dilemmas; and threats to trainee safety. Conclusions: Medical schools have a responsibility to ensure ethical and safe global health experiences. However, our findings suggest that medical students are often poorly prepared for the ethical and safety dilemmas they encounter during these electives. Medical students require intensive pre-departure training that will prepare them emotionally to deal with these dilemmas. Such training should include discussions of how to comply with clinical limitations

Health and Historical Levels of Freedom

Background: The link between political freedom and health is unclear. We aimed to determine the association byexploring the relationship of historical and cumulative freedom levels with important health outcomes. Methods: We obtained countrywide health indicators for life expectancy, infant mortality, maternal mortality ratio, %low birth weight babies, Gini coefficient (a measure of wealth inequality) and various markers of freedom based onpolitical rights and civil liberties. We applied multivariable logistic regression to examine the association betweenhealth indicators and within-country years of freedom as determined by Freedom House rankings. Results: The total proportion of free years from 1972-2005, the duration of current freedom level, and the Ginicoefficient show independent positive associations with health indicators, which remain after the adjustment fornational wealth, total government expenditure, and spending on health. Countries identified as having high totalproportion of free years demonstrated significantly better health outcomes than countries with low levels of freedom(life expectancy, Odds Ratio [OR] 7.2, 95% Confidence Interval [CI], 2.3-22.6, infant mortality OR 19.6, 95% CI, 5.6-67.7,maternal mortality ratio, OR 24.3, 95% CI, 6.2-94.9, and % low birth weight babies OR 3.8, 95% CI, 1.4-10.8). This was alsothe case for infant mortality (OR 3.4, 95% CI, 1.0-8.4), maternal mortality ratio (OR 4.0, 95% CI, 1.2-12.8), and % low birthweight babies (OR 2.6, 95% CI, 1.0-6.6) among countries considered as having medium levels of freedom. Interpretation: We found strong associations between country-level freedom and important health outcomes. Thecumulative level of freedom over time shows stronger associations with all health indicators than the duration ofcurrent freedom level

Health and historical levels of freedom

<p>Abstract</p> <p>Background</p> <p>The link between political freedom and health is unclear. We aimed to determine the association by exploring the relationship of historical and cumulative freedom levels with important health outcomes.</p> <p>Methods</p> <p>We obtained countrywide health indicators for life expectancy, infant mortality, maternal mortality ratio, % low birth weight babies, Gini coefficient (a measure of wealth inequality) and various markers of freedom based on political rights and civil liberties. We applied multivariable logistic regression to examine the association between health indicators and within-country years of freedom as determined by Freedom House rankings.</p> <p>Results</p> <p>The total proportion of free years from 1972-2005, the duration of current freedom level, and the Gini coefficient show independent positive associations with health indicators, which remain after the adjustment for national wealth, total government expenditure, and spending on health. Countries identified as having high total proportion of free years demonstrated significantly better health outcomes than countries with low levels of freedom (life expectancy, Odds Ratio [OR] 7.2, 95% Confidence Interval [CI], 2.3-22.6, infant mortality OR 19.6, 95% CI, 5.6-67.7, maternal mortality ratio, OR 24.3, 95% CI, 6.2-94.9, and % low birth weight babies OR 3.8, 95% CI, 1.4-10.8). This was also the case for infant mortality (OR 3.4, 95% CI, 1.0-8.4), maternal mortality ratio (OR 4.0, 95% CI, 1.2-12.8), and % low birth weight babies (OR 2.6, 95% CI, 1.0-6.6) among countries considered as having medium levels of freedom.</p> <p>Interpretation</p> <p>We found strong associations between country-level freedom and important health outcomes. The cumulative level of freedom over time shows stronger associations with all health indicators than the duration of current freedom level.</p

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

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

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Gene function hypotheses for the Campylobacter jejuni glycome generated by a logic-based approach.

Increasingly, experimental data on biological systems are obtained from several sources and computational approaches are required to integrate this information and derive models for the function of the system. Here, we demonstrate the power of a logic-based machine learning approach to propose hypotheses for gene function integrating information from two diverse experimental approaches. Specifically, we use inductive logic programming that automatically proposes hypotheses explaining the empirical data with respect to logically encoded background knowledge. We study the capsular polysaccharide biosynthetic pathway of the major human gastrointestinal pathogen Campylobacter jejuni. We consider several key steps in the formation of capsular polysaccharide consisting of 15 genes of which 8 have assigned function, and we explore the extent to which functions can be hypothesised for the remaining 7. Two sources of experimental data provide the information for learning-the results of knockout experiments on the genes involved in capsule formation and the absence/presence of capsule genes in a multitude of strains of different serotypes. The machine learning uses the pathway structure as background knowledge. We propose assignments of specific genes to five previously unassigned reaction steps. For four of these steps, there was an unambiguous optimal assignment of gene to reaction, and to the fifth, there were three candidate genes. Several of these assignments were consistent with additional experimental results. We therefore show that the logic-based methodology provides a robust strategy to integrate results from different experimental approaches and propose hypotheses for the behaviour of a biological system