SB-224289 Antagonizes the Antifungal Mechanism of the Marine Depsipeptide Papuamide A

In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS) synthase (Cho1p) was developed based on antagonism of the toxin papuamide A (Pap-A). Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type Candida albicans, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the CHO1 gene (cho1ΔΔ) do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A) as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A), but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins

Increasing access to integrated ESKD care as part of Universal Health Coverage

The global nephrology community recognizes the need for a cohesive strategy to address the growing problem of end-stage kidney disease (ESKD). In March 2018, the International Society of Nephrology hosted a summit on integrated ESKD care, including 92 individuals from around the globe with diverse expertise and professional backgrounds. The attendees were from 41 countries, including 16 participants from 11 low- and lower-middle–income countries. The purpose was to develop a strategic plan to improve worldwide access to integrated ESKD care, by identifying and prioritizing key activities across 8 themes: (i) estimates of ESKD burden and treatment coverage, (ii) advocacy, (iii) education and training/workforce, (iv) financing/funding models, (v) ethics, (vi) dialysis, (vii) transplantation, and (viii) conservative care. Action plans with prioritized lists of goals, activities, and key deliverables, and an overarching performance framework were developed for each theme. Examples of these key deliverables include improved data availability, integration of core registry measures and analysis to inform development of health care policy; a framework for advocacy; improved and continued stakeholder engagement; improved workforce training; equitable, efficient, and cost-effective funding models; greater understanding and greater application of ethical principles in practice and policy; definition and application of standards for safe and sustainable dialysis treatment and a set of measurable quality parameters; and integration of dialysis, transplantation, and comprehensive conservative care as ESKD treatment options within the context of overall health priorities. Intended users of the action plans include clinicians, patients and their families, scientists, industry partners, government decision makers, and advocacy organizations. Implementation of this integrated and comprehensive plan is intended to improve quality and access to care and thereby reduce serious health-related suffering of adults and children affected by ESKD worldwide

Equalization of four cardiovascular risk algorithms after systematic recalibration: individual-participant meta-analysis of 86 prospective studies

Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied. Methods & Results: Using individual-participant data on 360737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE overpredicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged \u3e_40years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms. Conclusions: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

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

SB-224289 Antagonizes the Antifungal Mechanism of the Marine Depsipeptide Papuamide A

<div><p>In order to expand the repertoire of antifungal compounds a novel, high-throughput phenotypic drug screen targeting fungal phosphatidylserine (PS) synthase (Cho1p) was developed based on antagonism of the toxin papuamide A (Pap-A). Pap-A is a cyclic depsipeptide that binds to PS in the membrane of wild-type <i>Candida albicans</i>, and permeabilizes its plasma membrane, ultimately causing cell death. Organisms with a homozygous deletion of the <i>CHO1</i> gene (<i>cho1ΔΔ</i>) do not produce PS and are able to survive in the presence of Pap-A. Using this phenotype (i.e. resistance to Pap-A) as an indicator of Cho1p inhibition, we screened over 5,600 small molecules for Pap-A resistance and identified SB-224289 as a positive hit. SB-224289, previously reported as a selective human 5-HT_1B receptor antagonist, also confers resistance to the similar toxin theopapuamide (TPap-A), but not to other cytotoxic depsipeptides tested. Structurally similar molecules and truncated variants of SB-224289 do not confer resistance to Pap-A, suggesting that the toxin-blocking ability of SB-224289 is very specific. Further biochemical characterization revealed that SB-224289 does not inhibit Cho1p, indicating that Pap-A resistance is conferred by another undetermined mechanism. Although the mode of resistance is unclear, interaction between SB-224289 and Pap-A or TPap-A suggests this screening assay could be adapted for discovering other compounds which could antagonize the effects of other environmentally- or medically-relevant depsipeptide toxins.</p></div

Screen of FDA-approved bioactive compounds for those that confer Pap-A resistance.

<p>5,760 compounds were screened for their effects on the growth of wild-type <i>C</i>. <i>albicans</i> (open black circles) in the presence of 4 μg/ml Pap-A. Cell growth was measured by transformation of the dye Alamar Blue over approximately 3 hours at 37°C. The <i>cho1ΔΔ</i> positive control cells growth in the presence of Pap-A with no compounds from the library are represented by green circles. Compounds that allowed wild-type cells to display >90% (above the blue line) of the growth of <i>cho1ΔΔ</i> control were designated with filled-in blue circles. Around 95% of the tested compounds showed growth levels closer to the negative control, wells which contained no cells or drugs (open red circles). The horizontal lines show the 99th quantile (purple) where 99% of the compounds exhibited growth and the 95th quantile (yellow) 95% of the compounds lie. The vertical lines divide the compounds by the 384-well plate in which they were screened which correlate to plate numbers along the bottom. A full description of the screening method is found in Materials and Methods.</p

Resistance to Pap-A correlates with decreases in PS.

<p>The <i>cho1ΔΔ</i> mutant is resistant to all concentrations of papuamide A (Pap-A) indicating a total lack of PS. The <i>cho1ΔΔ</i>::<i>CHO1</i> reintegrant strain is more resistant to Pap-A than the wild-type (WT), but less resistant than the <i>cho1ΔΔ</i> mutant.</p