Thoughts on the future of scientific dissemination

Scientific discourse has traditionally been conducted primarily through the scientific literature and face-to-face scientific meetings. The data supporting that discourse was either not available, or only available by special request to the generators of that data. The internet has changed the way we undertake that discourse, but I would argue only marginally. Data are now available through on-line databases – although not usually data for failed experiments. Traditional publishers have learnt how to use the internet as a dissemination medium, but little else. In short the power of the medium has yet to be realized. Glimmers of change are found in open access publishing made possible when dissemination costs plummet, but where are the killer applications that make use of this full on-line text? On-line databases strive for more automated and manual annotation, while publications accept data as supplemental information, but where are the applications that bring these together? PDFs are often a poor medium to convey scientific ideas and understand data when a video clip could do so much more. Where is the YouTube for scientists? Unread papers bring academic credit, but well read entries on blog sites do not; entries into databases and sites such as wikipedia count for nothing, why? These questions are not without preliminary answers and we will discuss some of the work that we and others are undertaking to address the beginning of a change in how we communicate and learn as scientists

Comparative Analysis of Control Barrier Functions and Artificial Potential Fields for Obstacle Avoidance

Artificial potential fields (APFs) and their variants have been a staple for collision avoidance of mobile robots and manipulators for almost 40 years. Its model-independent nature, ease of implementation, and real-time performance have played a large role in its continued success over the years. Control barrier functions (CBFs), on the other hand, are a more recent development, commonly used to guarantee safety for nonlinear systems in real-time in the form of a filter on a nominal controller. In this paper, we address the connections between APFs and CBFs. At a theoretic level, we prove that APFs are a special case of CBFs: given a APF one obtains a CBFs, while the converse is not true. Additionally, we prove that CBFs obtained from APFs have additional beneficial properties and can be applied to nonlinear systems. Practically, we compare the performance of APFs and CBFs in the context of obstacle avoidance on simple illustrative examples and for a quadrotor, both in simulation and on hardware using onboard sensing. These comparisons demonstrate that CBFs outperform APFs

The Immune Epitope Database and Analysis Resource: From Vision to Blueprint

A planned repository of immune epitope data with associated analysis tools should be a boon to vaccine developmen

The Herschel–ATLAS data release 2, Paper I. Submillimeter and far-infrared images of the South and North Galactic Poles: the largest Herschel survey of the extragalactic sky

We present the largest submillimeter images that have been made of the extragalactic sky. The Herschel Astrophysical Terahertz Large Area Survey (H-ATLAS) is a survey of 660 deg2 with the PACS and SPIRE cameras in five photometric bands: 100, 160, 250, 350, and 500 μm. In this paper we present the images from our two largest fields, which account for ~75% of the survey. The first field is 180.1 deg2 in size, centered on the north Galactic pole (NGP), and the second is 317.6 deg2 in size, centered on the south Galactic pole. The NGP field serendipitously contains the Coma cluster. Over most (~80%) of the images, the pixel noise, including both instrumental noise and confusion noise, is approximately 3.6, and 3.5 mJy pix−1 at 100 and 160 μm, and 11.0, 11.1 and 12.3 mJy beam−1 at 250, 350 and 500 μm, respectively, but reaches lower values in some parts of the images. If a matched filter is applied to optimize point-source detection, our total 1σ map sensitivity is 5.7, 6.0, and 7.3 mJy at 250, 350, and 500 μm, respectively. We describe the results of an investigation of the noise properties of the images. We make the most precise estimate of confusion in SPIRE maps to date, finding values of 3.12 ± 0.07, 4.13 ± 0.02, and 4.45 ± 0.04 mJy beam−1 at 250, 350, and 500 μm in our un-convolved maps. For PACS we find an estimate of the confusion noise in our fast-parallel observations of 4.23 and 4.62 mJy beam−1 at 100 and 160 μm. Finally, we give recipes for using these images to carry out photometry, both for unresolved and extended sources

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

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

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

Structural insights into the binding modes of viral RNA-dependent RNA polymerases using a function-site interaction fingerprint method for RNA virus drug discovery

The COVID-19 pandemic speaks to the need for drugs that are not only effective but also remain so given the mutation rate of COVID-19. To this end, we describe a strategy to design potential drugs that target RNA-dependent RNA polymerase (RDRP), a common conserved component of RNA viruses. We combine an RDRP structure dataset and all RDRP-ligand interaction fingerprints into an RDRP-targeted drug discovery procedure. In so doing we reveal the ligand-binding modes and RDRP structural characteristics. Specifically, four types of binding modes with corresponding binding pockets were determined, suggesting two major potential sub-pockets available for drug discovery. We screened a drug dataset of approximately 8,000 compounds against these binding pockets and presented the top ten small molecules as a starting point in further exploring the prevention of virus replication. In summary, the binding characteristics determined here help rationalize RDRP targeted drug discovery and provide insights into the specific binding mechanisms

A QM/MM Study of Acylphosphatase Reveals the Nucleophilic-Attack and Ensuing Carbonyl-Assisted Catalytic Mechanisms

Acylphosphatase is one of the vital enzymes in many organs/tissues to catalyze an acylphosphate molecule into carboxylate and phosphate. Here we use a combined ab initio QM/MM approach to reveal the catalytic mechanism of the benzoylphosphate-bound acylphosphatase system. Using a multi-dimensional reaction-coordinates-driving scheme, we obtained a detailed catalytic process including one nucleophilic-attack and then an ensuing carbonyl-shuttle catalytic mechanism by calculating two-dimensional potential energy surfaces. We also obtained an experiment-agreeable energy barrier and validated the role of the key amino acid Asn38. Additionally, we qualified the transition state stabilization strategy based on the amino acids-contributed interaction networks revealed in the enzymatic environment. This study provided usefule insights into the underlying catalytic mechanism to contribute to disease-involved research