Investigating the Diversity of Wolbachia across the Spiny Ants (Polyrhachis)

Among insects, Wolbachia is an exceedingly common bacterial endosymbiont with a range of consequences of infection. Despite the frequency of Wolbachia infection, very little is known about this bacteria\u27s diversity and role within hosts, especially within ant hosts. In this study, we analyze the occurrence and diversity of Wolbachia across the spiny ants (Polyrhachis), a large and geographically diverse genus. Polyrhachis samples from throughout the host genus\u27 phylogenetic and biogeographical range were first screened for single infections of Wolbachia using the wsp gene and Sanger sequencing. The multilocus sequence typing (MLST) scheme was then used on these singly infected samples to identify the Wolbachia strains. A Wolbachia phylogeny was inferred from the Polyrhachis samples analyzed in this study as well as other Formicidae MLST profiles from the MLST online database. We hypothesized that three key host factors were impacting Wolbachia diversity within the Polyrhachis genus: biogeography, phylogeny, and species level. The results suggest that the phylogeny and biogeography of Polyrhachis hosts have no impact on Wolbachia diversity; however, species level may have some limited influence. Additionally, Wolbachia strains appear to group according to being either Old World or New World strains. Among the taxa able to form complete MLST allelic profiles, all twenty are seemingly new strains

Pulmonary hypertension: intensification and personalization of combination Rx (PHoenix): a phase IV randomized trial for the evaluation of dose‐response and clinical efficacy of riociguat and selexipag using implanted technologies

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type‐5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate‐cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital‐based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory‐approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline‐recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory‐approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra‐patient efficacy of the two treatment approaches

Mammal responses to global changes in human activity vary by trophic group and landscape

Wildlife must adapt to human presence to survive in the Anthropocene, so it is critical to understand species responses to humans in different contexts. We used camera trapping as a lens to view mammal responses to changes in human activity during the COVID-19 pandemic. Across 163 species sampled in 102 projects around the world, changes in the amount and timing of animal activity varied widely. Under higher human activity, mammals were less active in undeveloped areas but unexpectedly more active in developed areas while exhibiting greater nocturnality. Carnivores were most sensitive, showing the strongest decreases in activity and greatest increases in nocturnality. Wildlife managers must consider how habituation and uneven sensitivity across species may cause fundamental differences in human–wildlife interactions along gradients of human influence.Peer reviewe

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

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

Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies.

Publication status: PublishedApproved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches