Search

Background Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induced thrombocytopenia. Dabigatran provides anticoagulation for an in vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits. Methods Nonlinear mixed effects models were used to estimate dabigatran parameters for a two-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/ml was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy and anticoagulated with IV dabigatran (six animals) or heparin (four animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 min. Measurement of activated clotting time, thromboelastometric reaction time, and blood gases were performed during CPB. Then, the animals were euthanized, and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy. Results The observed dabigatran concentrations during CPB were greater than the target concentration, ranging from 137 ± 40 μg/ml at 5 min of CPB to 428 ± 150 μg/ml at 60 min, and 295 ± 35 μg/ml at 120 min. All rabbits completed 2 h of CPB without visible thrombosis. In the two groups, reaction time values were elevated, reaching 10,262 ± 4,198 s (dabigatran group) and 354 ± 141 s (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran- and heparin-treated animals. Conclusions In this first-use, proof-of-concept study, the authors have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Psychedelics and related compounds have shown efficacy for the treatment of a variety of conditions that are prevalent among older adults, including mood disorders, the psychological distress associated with a serious medical illness, post-traumatic stress disorder (PTSD), and prolonged grief disorder. Psychedelics also have properties that could help provide therapeutic benefits for patients with dementing disorders, as well as promoting personal growth among healthy older adults. This article focuses on psilocybin, a classic psychedelic, and MDMA, a substituted amphetamine with properties similar to classic psychedelics. Both act on the 5HT

Introduction: Popliteal artery aneurysms are in most cases asymptomatic but cause significant complications if ruptured. An acute popliteal aneurysm rupture is relatively rare, and few cases have been documented secondary to blunt trauma. Common presenting signs and symptoms include distal limb ischemia and absent dorsalis pedis pulses. Timely management and recognition of this rare presentation are crucial as this condition can result in limb loss or death if not treated in a timely manner. Case Report: An 80-year-old man with history of hypertension presented to the emergency department complaining of inability to feel sensation below his left knee after falling from ground level. Physical examination was pertinent for bounding radial and femoral pulses bilaterally, although absent dorsalis pedis and posterior tibial pulses to the left lower extremity. Computed tomography angiography identified occlusion of the left superficial femoral arterial lumen associated with a ruptured popliteal aneurysm, approximately eight centimeters in size. He immediately received unfractionated heparin and was admitted to the hospital for left medial thigh exploration and decompressive dermatofasciotomy. Conclusion: After confirmation of popliteal aneurysmal rupture with advanced imaging, heparinization and vascular surgery consultation are critical steps that should be taken to prevent limb loss.

We combine methods to identify substorms and geomagnetic storms into a single, novel method that identifies four categories: quiet times, storm only, substorm only, substorms in storms. We employ Birkeland current density data from the Active Magnetosphere and Planetary Electrodynamics Response Experiment (AMPERE) between 2010–2017 and use our new combined identification method to sort data in this range into one of the four categories. We then subsample such that each category comprises the same number of data, in order that each category behaves statistically similarly. We then examine the large global behaviour of each category for the first time. We find that the mean current density is larger during substorms and its standard deviation is larger during geomagnetic storms. We assess the kurtosis and variance of the underlying distributions, and determine that the kurtosis is far higher during geomagnetic storms than during substorms. We use the survival function to quantify the probability of current densities above set thresholds and find that current densities which are above a low threshold are more likely during substorms, but that extreme currents are far more likely during geomagnetic storms. We shift the data into an adaptive coordinate system defined by the boundary between Regions 1 and 2 Birkeland current and demonstrate that extreme currents are most likely to flow within Region 2 current during geomagnetic storms. This is consistent with the literature on geomagnetic storms driving extreme behaviour, but unexpected in a paradigm of the current systems in which Region 1 current is generally larger.

Lunar Vertex is a mission at the intersection of multiple science communities, from planetary geology to space plasma physics. As the first Payloads and Research Investigations on the Surface of the Moon (PRISM1) investigation, scheduled for delivery to the Reiner Gamma (RG) magnetic anomaly in 2024 aboard a commercial lunar lander, Lunar Vertex will unravel the nature of the RG anomaly, the connection to and origin of the associated lunar swirl surface feature, and the structure and impact of the “mini-magnetosphere” in this region. Lunar Vertex includes a suite of magnetometers (Vector Magnetometer – Lander; VML), a fixed-mounted set of cameras (Vertex Camera Array; VCA), and a low-energy ion and electron plasma analyzer (Magnetic Anomaly Plasma Spectrometer; MAPS) on the lander. In addition, a second suite of commercial fluxgate magnetometers (Vector Magnetometer – Rover; VMR) and a multispectral imager (Rover Multispectral Microscope; RMM) are mounted on a dedicated rover that will traverse a distance of at least 500 m from the lander, providing additional multi-point measurements. The combination of magnetic field measurements taken during cruise and descent by VML and during surface operations by both VML and VMR will characterize the surface magnetic field within a strong lunar magnetic anomaly. The combined magnetic field and plasma measurements from VML and MAPS will provide direct observations of plasma populations reaching the lunar surface and the associated local magnetic field configuration. Furthermore, the lunar regolith within the RG magnetic anomaly and over different regions of the associated lunar swirl will be characterized by RMM and VCA to reveal the surface texture, composition, and particle distribution around both the lander and rover locations and the correspondence to potential surface weathering processes.

A multilayer acoustic treatment constructed of fibrous acoustic absorption material combined with dissipative acoustic material achieves a low profile and is lightweight and multi-functional, with properties that are desirable for NVH (noise, vibration, and harshness) treatments. The dissipative material consists of microfibers and acoustically active particles; this material was introduced in the last SAE NVH conference: A Novel Dissipative Acoustic Material [1].In this paper, the acoustic performance of the multilayer treatment was evaluated by using random incidence absorption and transmission loss measurements, as well as in-vehicle experiments. Absorption and transmission loss were additionally modeled using the transmission matrix method (TMM). In the in-vehicle test, an OEM wheelhouse liner with Trim, for an SUV, was evaluated utilizing this new multilayer 3M treatment.

BackgroundThe COVID-19 pandemic has been characterized by ongoing evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with concomitant variation in viral transmissibility and morbidity. Within specific timeframes and geographic areas, multiple SARS-CoV-2 variants have coexisted in the human population, each characterized by distinct biologic and clinical features, such as varying susceptibility to neutralizing monoclonal antibodies (nMAbs), a major frontline treatment. As part of an observational real-world data study of the effectiveness of nMAbs for treatment of COVID-19, SARS-CoV-2 viral samples were obtained from patients under treatment, generating paired clinical and genomics data. This paper describes the processing pipeline and findings from the genomics portion of this combined data set.MethodsSARS-CoV-2 sequences were generated from 14,796 diagnostic samples from four large U.S. health systems between July 2020 and March 2022. Among nMAbs-treated patients, samples were collected on the same day as, or prior to, treatment with nMAbs. Thus, these samples represent a snapshot of SARS-CoV-2 variants circulating in the respective patient groups, as opposed to variants that arose in response to specific treatments.Health systems collected viral samples and performed library creation and sequencing according to local protocols, using tiled ARTIC amplicon primers. FASTQ files were submitted to a study data platform and processed through a common pipeline. This pipeline enabled a unified approach to quality control, assembly, and production of genomics features for downstream analysis.ResultsAlpha and pre-Alpha SARS-CoV-2 lineages were predominant in the data set prior to June 2021. From June 2021 through November 2021, Delta was the dominant variant. Beginning in December 2021, Omicron was dominant. A variety of mutations associated with decreased nMAbs binding to the spike proteinin vitrowere detected, including lineage-defining mutations and non-lineage-defining mutations such as E340A, G446V, and S494P. Distinct patterns of sequence gaps and ambiguous base calls were associated with distinct variants.ConclusionsThe distribution of SARS-CoV-2 variants, per WHO nomenclature, across epochs in this data set matched concurrent CDC genomic surveillance results across the U.S. Detection of putative nMAbs escape mutations within clinical samples was consistent with FDA decisions to amend EUAs as variants emerged. This genomics data set provides an opportunity to examine associations between SARS-CoV-2 genomic variation and clinical outcomes in the associated EHR data set. The expansion of real-world data sets such as this to study the relationship between viral sequence and treatment outcomes could provide the foundation for future efforts to achieve near-real-time understanding of clinical outcomes related to genomic variation over time, and evidence to update treatment decisions more rapidly and to greater effect during ongoing and future pandemics.

Cladding-pumped Raman lasers have often been cited for their potential for brightness enhancement, but so far have never achieved high power and beam quality simultaneously. By utilizing a novel fiber geometry with a larger cladding to core ratio than current high power Raman fiber lasers for brightness enhancement (BE-RFLs), a noise-seeded Raman fiber laser pumped by a 100 ns pulsed laser with record beam quality is achieved with M^2 = 1.3 and 0.4 mJ 1st Stokes output, with an instantaneous brightness enhancement of 60. The results here support the hypothesis that the limiting factor to high beam quality in BE-RFLs is Raman conversion in the pump cladding, rather than higher order core modes as in most conventional fiber lasers.

A large body of research suggests that previously reward-associated stimuli can capture attention. Recent evidence also suggests that value-driven attentional biases can occur for a particular category of objects. However, it is unclear how broadly these category-level attentional biases can generalize. In the present study, we examined whether value-driven attentional biases can generalize to new exemplars of a category or semantically related categories using a modified version of the value-driven attentional capture paradigm. In an initial training phase, participants searched for two categories of objects and were rewarded for correctly fixating members of one target category. In a subsequent test phase, participants searched for two new categories of objects. A new exemplar of one of the previous target categories or a member of a semantically related category could appear as a critical distractor in this phase. Participants were more likely to initially fixate the critical distractor and fixated the distractor longer when it was a new exemplar of the previously rewarded category. However, similar findings were not observed for members of semantically related categories. Together, these findings suggest that the generalization of value-based attentional priority is category-specific.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

In this paper, I discuss common endogeneity problems found in entrepreneurship research. I show how entrepreneurship researchers, particularly those working with observational data, typically face several specific endogeneity threats in a given study. I then show through a series of simulated of datasets instrument variable approaches that effectively address endogeneity in a variety of research designs. I discuss best-practice recommendations for integrating instrument variables into entrepreneurship research at the study design phase, and outline potential sources for instruments.

ImportanceEvidence on the effectiveness and safety of COVID-19 therapies across a diverse population with varied risk factors is needed to inform clinical practice.ObjectiveTo assess the safety of neutralizing monoclonal antibodies (nMAbs) for the treatment of COVID-19 and their association with adverse outcomes.Design, Setting, and ParticipantsThis retrospective cohort study included 167 183 patients from a consortium of 4 health care systems based in California, Minnesota, Texas, and Utah. The study included nonhospitalized patients 12 years and older with a positive COVID-19 laboratory test collected between November 9, 2020, and January 31, 2022, who met at least 1 emergency use authorization criterion for risk of a poor outcome.ExposureFour nMAb products (bamlanivimab, bamlanivimab-etesevimab, casirivimab-imdevimab, and sotrovimab) administered in the outpatient setting.Main Outcomes and MeasuresClinical and SARS-CoV-2 genomic sequence data and propensity-adjusted marginal structural models were used to assess the association between treatment with nMAbs and 4 outcomes: all-cause emergency department (ED) visits, hospitalization, death, and a composite of hospitalization or death within 14 days and 30 days of the index date (defined as the date of the first positive COVID-19 test or the date of referral). Patient index dates were categorized into 4 variant epochs: pre-Delta (November 9, 2020, to June 30, 2021), Delta (July 1 to November 30, 2021), Delta and Omicron BA.1 (December 1 to 31, 2021), and Omicron BA.1 (January 1 to 31, 2022).ResultsAmong 167 183 patients, the mean (SD) age was 47.0 (18.5) years; 95 669 patients (57.2%) were female at birth, 139 379 (83.4%) were White, and 138 900 (83.1%) were non-Hispanic. A total of 25 241 patients received treatment with nMAbs. Treatment with nMAbs was associated with lower odds of ED visits within 14 days (odds ratio [OR], 0.76; 95% CI, 0.68-0.85), hospitalization within 14 days (OR, 0.52; 95% CI, 0.45-0.59), and death within 30 days (OR, 0.14; 95% CI, 0.10-0.20). The association between nMAbs and reduced risk of hospitalization was stronger in unvaccinated patients (14-day hospitalization: OR, 0.51; 95% CI, 0.44-0.59), and the associations with hospitalization and death were stronger in immunocompromised patients (hospitalization within 14 days: OR, 0.31 [95% CI, 0.24-0.41]; death within 30 days: OR, 0.13 [95% CI, 0.06-0.27]). The strength of associations of nMAbs increased incrementally among patients with a greater probability of poor outcomes; for example, the ORs for hospitalization within 14 days were 0.58 (95% CI, 0.48-0.72) among those in the third (moderate) risk stratum and 0.41 (95% CI, 0.32-0.53) among those in the fifth (highest) risk stratum. The association of nMAb treatment with reduced risk of hospitalizations within 14 days was strongest during the Delta variant epoch (OR, 0.37; 95% CI, 0.31-0.43) but not during the Omicron BA.1 epoch (OR, 1.29; 95% CI, 0.68-2.47). These findings were corroborated in the subset of patients with viral genomic data. Treatment with nMAbs was associated with a significant mortality benefit in all variant epochs (pre-Delta: OR, 0.16 [95% CI, 0.08-0.33]; Delta: OR, 0.14 [95% CI, 0.09-0.22]; Delta and Omicron BA.1: OR, 0.10 [95% CI, 0.03-0.35]; and Omicron BA.1: OR, 0.13 [95% CI, 0.02-0.93]). Potential adverse drug events were identified in 38 treated patients (0.2%).Conclusions and RelevanceIn this study, nMAb treatment for COVID-19 was safe and associated with reductions in ED visits, hospitalization, and death, although it was not associated with reduced risk of hospitalization during the Omicron BA.1 epoch. These findings suggest that targeted risk stratification strategies may help optimize future nMAb treatment decisions.

Cladding-pumped Raman lasers have often been cited for their potential for brightness enhancement, but so far have never achieved high power and beam quality simultaneously. By utilizing a fiber geometry with a larger cladding to core ratio than current high power Raman fiber lasers for brightness enhancement (BE-RFLs), a noise-seeded Raman fiber laser pumped by a 100 ns pulsed laser with record beam quality is achieved with M2=1.3 and 0.4 mJ first Stokes output, with an instantaneous brightness enhancement of 60. The results here support the hypothesis that the limiting factor to high beam quality in BE-RFLs is Raman conversion in the pump cladding, rather than higher order core modes as in most conventional fiber lasers.