There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells ...offer promise as immunomodulatory agents.
Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19-induced respiratory failure.
Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis.
At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (
= 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk RR, 0.88; 95% confidence interval, 0.64-1.21;
= 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 interquartile range, 60.0-169.5 in cell patients and 102.0 interquartile range, 54.0-162.5 in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57-3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar.
Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19-related acute respiratory distress syndrome.
A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and ...improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65),
-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.
Bendamustine hydrochloride is an alkylating agent with novel mechanisms of action. This phase II multicenter study evaluated the efficacy and toxicity of bendamustine in patients with B-cell ...non-Hodgkin's lymphoma (NHL) refractory to rituximab.
Patients received bendamustine 120 mg/m(2) intravenously on days 1 and 2 of each 21-day cycle. Outcomes included response, duration of response, progression-free survival, and safety.
Seventy-six patients, ages 38 to 84 years, with predominantly stage III/IV indolent (80%) or transformed (20%) disease were treated; 74 were assessable for response. Twenty-four (32%) were refractory to chemotherapy. Patients received a median of two prior unique regimens. An overall response rate of 77% (15% complete response, 19% unconfirmed complete response, and 43% partial) was observed. The median duration of response was 6.7 months (95% CI, 5.1 to 9.9 months), 9.0 months (95% CI, 5.8 to 16.7) for patients with indolent disease, and 2.3 months (95% CI, 1.7 to 5.1) for those with transformed disease. Thirty-six percent of these responses exceeded 1 year. The most frequent nonhematologic adverse events included nausea and vomiting, fatigue, constipation, anorexia, fever, cough, and diarrhea. Grade 3 or 4 reversible hematologic toxicities included neutropenia (54%), thrombocytopenia (25%), and anemia (12%).
Single-agent bendamustine produced durable objective responses with acceptable toxicity in heavily pretreated patients with rituximab-refractory, indolent NHL. These findings are promising and will serve as a benchmark for future clinical trials in this novel patient population.
Mediastinal infections are a potentially devastating complication of cardiac operations. This study analyzed the frequency, risk factors, and perioperative outcomes of mediastinal infections after ...cardiac operations.
In 2010, 5,158 patients enrolled in a prospective study evaluating infections after cardiac operations and their effect on readmissions and mortality for up to 65 days after the procedure. Clinical and demographic characteristics, operative variables, management practices, and outcomes were compared for patients with and without mediastinal infections, defined as deep sternal wound infection, myocarditis, pericarditis, or mediastinitis.
There were 43 mediastinal infections in 41 patients (cumulative incidence, 0.79%; 95% confidence interval CI 0.60% to 1.06%). Median time to infection was 20.0 days, with 65% of infections occurring after the index hospitalization discharge. Higher body mass index (hazard ratio HR 1.06; 95% CI, 1.01 to 1.10), higher creatinine (HR, 1.25; 95% CI, 1.13 to 1.38), peripheral vascular disease (HR, 2.47; 95% CI, 1.21 to 5.05), preoperative corticosteroid use (HR, 3.33; 95% CI, 1.27 to 8.76), and ventricular assist device or transplant surgery (HR, 5.81; 95% CI, 2.36 to 14.33) were associated with increased risk of mediastinal infection. Postoperative hyperglycemia (HR, 3.15; 95% CI, 1.32 to 7.51) was associated with increased risk of infection in nondiabetic patients. Additional length of stay attributable to mediastinal infection was 11.5 days (bootstrap 95% CI, 1.88 to 21.11). Readmission rates and mortality were five times higher in patients with mediastinal infection than in patients without mediastinal infection.
Mediastinal infection after a cardiac operation is associated with substantial increases in length of stay, readmissions, and death. Reducing these infections remains a high priority, and improving post-operative glycemic management may reduce their risk in patients without diabetes.
WR 112 is a dust-forming carbon-rich Wolf-Rayet (WC) binary with a dusty circumstellar nebula that exhibits a complex asymmetric morphology, which traces the orbital motion and dust formation in the ...colliding winds of the central binary. Unraveling the complicated circumstellar dust emission around WR 112 therefore provides an opportunity to understand the dust formation process in colliding-wind WC binaries. In this work, we present a multi-epoch analysis of the circumstellar dust around WR 112 using seven high spatial resolution (FWHM ∼ 0 3-0 4) N-band (λ ∼ 12 m) imaging observations spanning almost 20 yr and that includes images obtained from Subaru/COMICS in 2019 October. In contrast to previous interpretations of a face-on spiral morphology, we observe clear evidence of proper motion of the circumstellar dust around WR 112 consistent with a nearly edge-on spiral with a θs = 55° half-opening angle and a ∼20 yr period. The revised near edge-on geometry of WR 112 reconciles previous observations of highly variable nonthermal radio emission that was inconsistent with a face-on geometry. We estimate a revised distance to WR 112 of kpc based on the observed dust expansion rate and a spectroscopically derived WC terminal wind velocity of km s−1. With the newly derived WR 112 parameters, we fit optically thin dust spectral energy distribution models and determine a dust production rate of M yr−1, which demonstrates that WR 112 is one of the most prolific dust-making WC systems known.
Changes in Earth's surface temperatures caused by anthropogenic emissions of greenhouse gases are expected to affect global and regional precipitation regimes. Interactions between changing ...precipitation regimes and other aspects of global change are likely to affect natural and managed terrestrial ecosystems as well as human society. Although much recent research has focused on assessing the responses of terrestrial ecosystems to rising carbon dioxide or temperature, relatively little research has focused on understanding how ecosystems respond to changes in precipitation regimes. Here we review predicted changes in global and regional precipitation regimes, outline the consequences of precipitation change for natural ecosystems and human activities, and discuss approaches to improving understanding of ecosystem responses to changing precipitation. Further, we introduce the Precipitation and Ecosystem Change Research Network (PrecipNet), a new interdisciplinary research network assembled to encourage and foster communication and collaboration across research groups with common interests in the impacts of global change on precipitation regimes, ecosystem structure and function, and the human enterprise.
Celotno besedilo
Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering ...and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of ‘difficult-to-treat depression’ (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.
The primary objective of this multicenter registry was to study the prognostic value of positron emission tomography (PET) myocardial perfusion imaging (MPI) and the improved classification of risk ...in a large cohort of patients with suspected or known coronary artery disease (CAD).
Limited prognostic data are available for MPI with PET.
A total of 7,061 patients from 4 centers underwent a clinically indicated rest/stress rubidium-82 PET MPI, with a median follow-up of 2.2 years. The primary outcome of this study was cardiac death (n = 169), and the secondary outcome was all-cause death (n = 570). Net reclassification improvement (NRI) and integrated discrimination analyses were performed.
Risk-adjusted hazard of cardiac death increased with each 10% myocardium abnormal with mildly, moderately, or severely abnormal stress PET (hazard ratio HR: 2.3 95% CI: 1.4 to 3.8; p = 0.001, HR: 4.2 95% CI: 2.3 to 7.5; p < 0.001, and HR: 4.9 95% CI: 2.5 to 9.6; p < 0.0001, respectively normal MPI: referent). Addition of percent myocardium ischemic and percent myocardium scarred to clinical information (age, female sex, body mass index, history of hypertension, diabetes, dyslipidemia, smoking, angina, beta-blocker use, prior revascularization, and resting heart rate) improved the model performance (C-statistic 0.805 95% CI: 0.772 to 0.838 to 0.839 95% CI: 0.809 to 0.869) and risk reclassification for cardiac death (NRI 0.116 95% CI: 0.021 to 0.210), with smaller improvements in risk assessment for all-cause death.
In patients with known or suspected CAD, the extent and severity of ischemia and scar on PET MPI provided powerful and incremental risk estimates of cardiac death and all-cause death compared with traditional coronary risk factors.
Objectives:
Visiting restaurants and bars, particularly when doing so indoors, can increase transmission risk of SARS-CoV-2, the virus that causes COVID-19, among people who are not fully vaccinated. ...We aimed to understand US adults’ self-reported protective behaviors when getting food from restaurants during the COVID-19 pandemic when vaccines were not widely available.
Methods:
We used online nationwide survey data from January 2021 to assess self-reported restaurant-related behaviors of respondents (n = 502). We also used multiple logistic regression models to examine associations between respondents’ characteristics and these restaurant-related behaviors.
Results:
Half (49.7%) of respondents reported eating indoors at a restaurant at least once in the month before the survey. Respondents most likely to report eating inside restaurants were in the youngest age category (18-34 y), had personal COVID-19 experience, or indicated they felt safe eating inside a restaurant. Among respondents who had gotten food from a restaurant, more than 65% considered each of the following factors as important in their restaurant dining decision: whether the restaurant staff were wearing face masks, the restaurant requires face masks, other customers are wearing face masks, seating was spaced at least 6 feet apart, someone in their household was at risk for severe COVID-19 illness, and the restaurant was crowded. The most common protective behavior when eating at a restaurant was wearing a face mask; 44.9% of respondents who had eaten at a restaurant wore a face mask except when actively eating or drinking.
Conclusion:
The need for practicing prevention strategies, especially for those not up to date with COVID-19 vaccines, will be ongoing. Our findings can inform COVID-19 prevention messaging for public health officials, restaurant operators, and the public.
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