Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection. The alteplase dose assessment for Pleural infection Therapy project

Rationale: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here. Objectives: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. Methods: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. Results: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22–58] to 16% [8–31] of hemithorax; P < 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247–2,984] over 72 h of therapy; P <  0.05) and a reduction in blood C-reactive protein (P < 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. Conclusions: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pl

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

Health problems of cyclists in the city – pilot study

Air pollution is one of the main environmental problems. Health consequences of smog exposure apply in particular to people who spend a lot of time outdoors, including cyclists. The aim of the work was to evaluate the occurrence of symptoms associated with air pollution among the Wroclaw cyclists. The study was conducted via an internet questionnaire. The survey group consisted of 599 respondents - Wrocław cyclists. While cycling or short after cycling, 83.14% of cyclists reported symptoms connected with the respiratory system (such as hoarseness, cough, sore throat pain, or dyspnoea), eyes (such as redness, dryness, watering, strain) and other symptoms (for example, concentration deficiency, headache, fatigue), which they associated with air pollution. Problems with the eyes were the most common. There was no correlation between the frequency of symptom occurrence and the distance or cycling frequency. People who chose low-traffic routes were less likely to suffer from cough, hoarseness, or dyspnoea than people who chose high-traffic routes. Only 9.8% of the respondents used protection measures such as masks. Choosing a proper route and avoiding high-traffic seem to be crucial when it comes to symptom occurrence, and perhaps also to long-term health effects. City councils should plan cycling routes in low-traffic areas to minimize negative smog effects. Protection measures, such as the use of masks, should also be more actively promoted.Zanieczyszczenie powietrza jest jednym z głównych problemów środowiskowych. Jego konsekwencje zdrowotne szczególnie dotyczą osób spędzających znaczną ilość czasu na zewnątrz, m.in. rowerzystów. Celem pracy była ocena występowania objawów chorobowych związanych z zanieczyszczeniem powietrza wśród wrocławskich rowerzystów. W badaniu wykorzystano ankietę rozprzestrzenianą drogą internetową. Grupę badaną stanowiło 599 ankietowanych – wrocławskich rowerzystów. 83,14% wrocławskich rowerzystów w czasie jazdy na rowerze lub bezpośrednio po niej odczuwa objawy ze strony układu oddechowego (chrypka, kaszel, ból gardła, duszność), narządu wzroku (zaczerwienienie oczu, suchość, łzawienie, uczucie piasku pod powiekami) bądź inne objawy (np. zaburzenia koncentracji, bóle głowy, nadmierne zmęczenie), które bezpośrednio wiąże z zanieczyszczeniem powietrza. Najczęstsze dolegliwości dotyczą narządu wzroku. Brak jest korelacji statystycznej między częstością występowania objawów a długością pokonywanej trasy lub częstotliwością jazdy na rowerze, niemniej osoby, które wybierają trasy o niższym natężeniu ruchu istotnie rzadziej odczuwają objawy takie jak kaszel, chrypka czy duszność niż osoby poruszające się głównymi arteriami miasta. Zaledwie 9,8% ankietowanych korzysta ze środków chroniących przed zanieczyszczeniami np. masek przeciwsmogowych. Odpowiedni dobór trasy jazdy na rowerze polegający na unikaniu miejsc o dużym natężeniu ruchu wydaje się być kluczowy dla ograniczenia występowania objawów chorobowych, a być może również dla długofalowych następstw zdrowotnych związanych z zanieczyszczeniem powietrza. Wydaje się, że ze względów zdrowotnych polityka miejska powinna dążyć do propagowania tras rowerowych przebiegających możliwie przez tereny zielone (na przykład parki w centrach miast) zamiast tworzenia ścieżek rowerowych przy drogach o najwyższym natężeniu ruchu. Rozsądne wydaje się również propagowanie wśród rowerzystów środków ochrony przeciwsmogowej

Staphylococcal SplB serine protease utilizes a novel molecular mechanism of activation

Staphylococcal SplB protease belongs to the chymotrypsin family. Chymotrypsin zymogen is activated by proteolytic processing at the N terminus, resulting in significant structural rearrangement at the active site. Here, we demonstrate that the molecular mechanism of SplB protease activation differs significantly and we characterize the novel mechanism in detail. Using peptide and protein substrates we show that the native signal peptide, or any N-terminal extension, has an inhibitory effect on SplB. Only precise N-terminal processing releases the full proteolytic activity of the wild type analogously to chymotrypsin. However, comparison of the crystal structures of mature SplB and a zymogen mimic show no rearrangement at the active site whatsoever. Instead, only the formation of a unique hydrogen bond network, distant form the active site, by the new N-terminal glutamic acid of mature SplB is observed. The importance of this network and influence of particular hydrogen bond interactions at the N terminus on the catalytic process is demonstrated by evaluating the kinetics of a series of mutants. The results allow us to propose a consistent model where changes in the overall protein dynamics rather than structural rearrangement of the active site are involved in the activation process