Steroid therapy and outcome of parapneumonic pleural effusions (STOPPE): Study protocol for a multicenter, double-blinded, placebo-controlled randomized clinical trial

BACKGROUND: Community-acquired pneumonia (CAP) is a major global disease. Parapneumonic effusions often complicate CAP and range from uninfected (simple) to infected (complicated) parapneumonic effusions and empyema (pus). CAP patients who have a pleural effusion at presentation are more likely to require hospitalization, have a longer length of stay and higher mortality than those without an effusion. Conventional management of pleural infection, with antibiotics and chest tube drainage, fails in about 30% of cases. Several randomized controlled trials (RCT) have evaluated the use of corticosteroids in CAP and demonstrated some potential benefits. Importantly, steroid use in pneumonia has an acceptable safety profile with no adverse impact on mortality. A RCT focused on pediatric patients with pneumonia and a parapneumonic effusion demonstrated shorter time to recovery. The effects of corticosteroid use on clinical outcomes in adults with parapneumonic effusions have not been tested. We hypothesize that parapneumonic effusions develop from an exaggerated pleural inflammatory response. Treatment with systemic steroids may dampen the inflammation and lead to improved clinical outcomes. The steroid therapy and outcome of parapneumonic pleural effusions (STOPPE) trial will assess the efficacy and safety of systemic corticosteroid as an adjunct therapy in adult patients with CAP and pleural effusions. METHODS: STOPPE is a pilot multicenter, double-blinded, placebo-controlled RCT that will randomize 80 patients with parapneumonic effusions (2:1) to intravenous dexamethasone or placebo, administered twice daily for 48 hours. This exploratory study will capture a wide range of clinically relevant endpoints which have been used in clinical trials of pneumonia and/or pleural infection; including, but not limited to: time to clinical stability, inflammatory markers, quality of life, length of hospital stay, proportion of patients requiring escalation of care (thoracostomy or thoracoscopy), and mortality. Safety will be assessed by monitoring for the incidence of adverse events during the study. DISCUSSION: STOPPE is the first trial to assess the efficacy and safety profile of systemic corticosteroids in adults with CAP and pleural effusions. This will inform future studies on feasibility and appropriate trial endpoints. TRIAL REGISTRATION: ACTRN1261800094720

The TESS Grand Unified Hot Jupiter Survey. II. Twenty New Giant Planets

NASA's Transiting Exoplanet Survey Satellite (TESS) mission promises to improve our understanding of hot Jupiters by providing an all-sky, magnitude-limited sample of transiting hot Jupiters suitable for population studies. Assembling such a sample requires confirming hundreds of planet candidates with additional follow-up observations. Here, we present twenty hot Jupiters that were detected using TESS data and confirmed to be planets through photometric, spectroscopic, and imaging observations coordinated by the TESS Follow-up Observing Program (TFOP). These twenty planets have orbital periods shorter than 7 days and orbit relatively bright FGK stars ($10.9 < G < 13.0$). Most of the planets are comparable in mass to Jupiter, although there are four planets with masses less than that of Saturn. TOI-3976 b, the longest period planet in our sample ($P = 6.6$ days), may be on a moderately eccentric orbit ($e = 0.18\pm0.06$), while observations of the other targets are consistent with them being on circular orbits. We measured the projected stellar obliquity of TOI-1937A b, a hot Jupiter on a 22.4 hour orbit with the Rossiter-McLaughlin effect, finding the planet's orbit to be well-aligned with the stellar spin axis ($|\lambda| = 4.0\pm3.5^\circ$). We also investigated the possibility that TOI-1937 is a member of the NGC 2516 open cluster, but ultimately found the evidence for cluster membership to be ambiguous. These objects are part of a larger effort to build a complete sample of hot Jupiters to be used for future demographic and detailed characterization work.Comment: 67 pages, 11 tables, 13 figures, 2 figure sets. Resubmitted to ApJS after revision

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

An international survey on the use of intrapleural tissue plasminogen activator/DNase therapy for pleural infection

Introduction Intrapleural tissue plasminogen activator (tPA) combined with human recombinant DNase (DNase) could be an effective alternative to surgery in managing pleural infection, as demonstrated in the Multi-centre Intrapleural Sepsis Trial (MIST)-2. However, the optimal delivery regimen is still unknown. The aim of this survey was to identify the current practice of tPA/DNase use by physicians with published interests in pleural infection, and their opinions on dose de-escalation of tPA/DNase therapy. Methods Potential participants were identified using four search strategies. Only practising physicians who were managing patients with pleural infections and either actively involved in pleural research and publications, or were members of relevant pleural disease guideline panels at the time of survey were included. Results An invitation email with the questionnaire was sent to 102 participants, of whom 49 (48%) responded. Most respondents (90%, n=44) have used tPA/DNase to manage pleural infection, but the dosing and delivery regimens employed varied. Many (86%, 38 out of 44) respondents have used 10 mg tPA, while 73% (n=32), 16% (n=7) and 9% (n=4) have used 5 mg, 2.5 mg and 1 mg doses, respectively. Most respondents instilled tPA/DNase concurrently (61%, n=27) and routinely administered six doses of tPA/DNase (52%, n=23) twice daily (82%, n=36). Respondents would consider using a lower starting dose of tPA (with the possibility of escalation if clinically needed) if a median 80% (interquartile range 50–80%) of patients could be successfully treated at that dose. Conclusion This survey observed a large variation in the current treatment protocol of intrapleural tPA/ DNase therapy worldwide and the need for more data on this subject

Characteristics of D39 <i>S</i>. <i>pneumoniae</i> mutants used across experiments.

<p>Characteristics of D39 <i>S</i>. <i>pneumoniae</i> mutants used across experiments.</p

Correlation of <i>S</i>. <i>pneumoniae</i> (n = 25) growth in pleural fluid with and without cells (n = 11 pairs) expressed as the fold change from baseline inoculum at 24 hours (n = 275 pairs), p<0.001.

<p>Correlation of <i>S</i>. <i>pneumoniae</i> (n = 25) growth in pleural fluid with and without cells (n = 11 pairs) expressed as the fold change from baseline inoculum at 24 hours (n = 275 pairs), p<0.001.</p

Pleural fluid characteristics for individual experiments.

<p>Pleural fluid characteristics for individual experiments.</p

DNase activity after 6 hours incubation with tPA and antimicrobials or tPA and bacteria.

<p>The activity of DNase in the presence of different antimicrobial agents (Panels A & B) or bacteria (Panels C & D) was measured through digestion of 1 μg of pcDNA3 DNA. V+G = Vancomycin and Gentamicin, A = Amoxicillin, C = Cefazolin and F = Fluconazole. The effects of bacteria on DNase activity was assessed at baseline (T = 0) and following 6 hours incubation (T = 6) at 37°C. Samples were incubated with 5 μg/mL tPA and/or 2.5 μg/mL DNase, as applicable.</p

The median growth of <i>S</i>. <i>pneumoniae</i> (n = 25) in human pleural fluid (n = 11) was consistent across all (a) pleural fluid samples (b) pneumococcal isolates and (c) serotypes.

<p>Each dot-point represents data analyzed as (a) the median growth of all <i>S</i>. <i>pneumoniae</i> in each pleural fluid samples (n = 11), (b) individual <i>S</i>. <i>pneumoniae</i> isolates (n = 25) and the median growth of each isolate across pleural fluid samples and (c) <i>S</i>. <i>pneumoniae</i> grouped according to serotype (n = 13); data from the pleural fluid samples (n = 11) is pooled when more than one serotype is available and includes serotypes 1 (n = 2), 6B, 6C, 8 (n = 3), 10A, 11A (n = 2), 12F, 19A (n = 7), 19F, 21, 22F (n = 2), 35B and 3 reference strain. Proliferation was significant at 24hrs across all pneumococci, serotypes and pleural fluids, p<0.001. The box plot represents the median and IQR of the dot plot data; whiskers represent the 95^th percentile. Pleural fluid characteristics are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0188833#pone.0188833.t003" target="_blank">Table 3</a>.</p

List of <i>Streptococcus pneumoniae</i> serotypes and other bacteria used in this study.

<p>List of <i>Streptococcus pneumoniae</i> serotypes and other bacteria used in this study.</p