A Tale Of 160 Scientists, Three Applications, a Workshop, and a Cloud

The NASA Exoplanet Science Institute (NExScI) hosts the annual Sagan Workshops, thematic meetings aimed at introducing researchers to the latest tools and methodologies in exoplanet research. The theme of the Summer 2012 workshop, held from July 23 to July 27 at Caltech, was to explore the use of exoplanet light curves to study planetary system architectures and atmospheres. A major part of the workshop was to use hands-on sessions to instruct attendees in the use of three open source tools for the analysis of light curves, especially from the Kepler mission. Each hands-on session involved the 160 attendees using their laptops to follow step-by-step tutorials given by experts. One of the applications, PyKE, is a suite of Python tools designed to reduce and analyze Kepler light curves; these tools can be invoked from the Unix command line or a GUI in PyRAF. The Transit Analysis Package (TAP) uses Markov Chain Monte Carlo (MCMC) techniques to fit light curves under the Interactive Data Language (IDL) environment, and Transit Timing Variations (TTV) uses IDL tools and Java-based GUIs to confirm and detect exoplanets from timing variations in light curve fitting. Rather than attempt to run these diverse applications on the inevitable wide range of environments on attendees laptops, they were run instead on the Amazon Elastic Cloud 2 (EC2). The cloud offers features ideal for this type of short term need: computing and storage services are made available on demand for as long as needed, and a processing environment can be customized and replicated as needed. The cloud environment included an NFS file server virtual machine (VM), 20 client VMs for use by attendees, and a VM to enable ftp downloads of the attendees' results. The file server was configured with a 1 TB Elastic Block Storage (EBS) volume (network-attached storage mounted as a device) containing the application software and attendees home directories. The clients were configured to mount the applications and home directories from the server via NFS. All VMs were built with CentOS version 5.8. Attendees connected their laptops to one of the client VMs using the Virtual Network Computing (VNC) protocol, which enabled them to interact with a remote desktop GUI during the hands-on sessions. We will describe the mechanisms for handling security, failovers, and licensing of commercial software. In particular, IDL licenses were managed through a server at Caltech, connected to the IDL instances running on Amazon EC2 via a Secure Shell (ssh) tunnel. The system operated flawlessly during the workshop

Sugammadex and urinary retention after hysterectomy: A propensity-matched cohort study

Postoperative urinary retention (POUR) is a well-known complication after gynecologic surgery. Our objective was to investigate whether the choice of pharmacologic agent for reversing neuromuscular blockade at the end of a hysterectomy is a risk factor for POUR. Among adult patients undergoing hysterectomy with general anesthesia from 2012 to 2017, those who received aminosteroid nondepolarizing neuromuscular agents followed by pharmacologic reversal were identified, and electronic health records were reviewed. The cohort was dichotomized into two groups by reversal agent: 1) sugammadex and 2) neostigmine with glycopyrrolate. The primary outcome, POUR, was defined as unplanned postoperative bladder recatheterization. A propensity-adjusted analysis was performed to investigate the association between POUR and reversal agent by using inverse probability of treatment weighting to adjust for potential confounders. We identified 1,974 patients, of whom 1,586 (80.3%) received neostigmine-glycopyrrolate and 388 (19.7%) received sugammadex for reversal of neuromuscular blockade. The frequency of POUR was 24.8% (393/1,586) after reversal with neostigmine-glycopyrrolate and 18.3% (71/388) with sugammadex. Results from the propensity-adjusted analysis showed that sugammadex was associated with a lower POUR risk than neostigmine-glycopyrrolate (odds ratio 0.53, 95% confidence interval [CI] 0.37 - 0.76, P < 0.001). A post hoc analysis of sugammadex recipients who received glycopyrrolate for another indication showed a higher POUR risk than among those who did not receive glycopyrrolate (odds ratio 1.86, 95% CI 1.07 - 3.22, P = 0.03). Use of sugammadex to reverse aminosteroid neuromuscular blocking agents is associated with decreased risk of POUR after hysterectomy. A potential mechanism is the omission of glycopyrrolate, which is coadministered with neostigmine to mitigate unwanted cholinergic effects

Observing the Evolution of the Universe

How did the universe evolve? The fine angular scale (l>1000) temperature and polarization anisotropies in the CMB are a Rosetta stone for understanding the evolution of the universe. Through detailed measurements one may address everything from the physics of the birth of the universe to the history of star formation and the process by which galaxies formed. One may in addition track the evolution of the dark energy and discover the net neutrino mass. We are at the dawn of a new era in which hundreds of square degrees of sky can be mapped with arcminute resolution and sensitivities measured in microKelvin. Acquiring these data requires the use of special purpose telescopes such as the Atacama Cosmology Telescope (ACT), located in Chile, and the South Pole Telescope (SPT). These new telescopes are outfitted with a new generation of custom mm-wave kilo-pixel arrays. Additional instruments are in the planning stages.Comment: Science White Paper submitted to the US Astro2010 Decadal Survey. Full list of 177 author available at http://cmbpol.uchicago.ed

A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening.

The unparalleled global effort to combat the continuing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic over the last year has resulted in promising prophylactic measures. However, a need still exists for cheap, effective therapeutics, and targeting multiple points in the viral life cycle could help tackle the current, as well as future, coronaviruses. Here, we leverage our recently developed, ultra-large-scale in silico screening platform, VirtualFlow, to search for inhibitors that target SARS-CoV-2. In this unprecedented structure-based virtual campaign, we screened roughly 1 billion molecules against each of 40 different target sites on 17 different potential viral and host targets. In addition to targeting the active sites of viral enzymes, we also targeted critical auxiliary sites such as functionally important protein-protein interactions

Development of risk maps to minimize uranium exposures in the Navajo Churchrock mining district

© 2009 deLemos et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

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

A community effort in SARS-CoV-2 drug discovery.

peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric

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