Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD

Spin-current amplification by stimulated spin pumping

Stimulated emission is a process during which an atomic system gives away energy to create a coherent photon. It is fundamental to the operation of the optical amplifier. Here we propose two mechanisms for amplifying AC spin currents in a solid-state magnetic medium by a stimulated spin pumping process. The first is synchronous and consists of phase-locked pulses that perturb a precessing magnetic moment. The second is asynchronous and is driven by DC spin currents. The amplification relies on a non-adiabatic interaction taking place in a ferromagnetic medium in which the magnetic moment emits spin angular momentum in the form of spin current before equilibrating with the environment. The pumped spin current amplifies or absorbs the injected AC spin current mimicking the operation of the optical gain medium as readily seen from the gain saturation profiles. The mechanisms we propose are a first step towards a realistic spin current amplifier.Comment: 17 pages, 4 figure

The Impact of Sample Size Misestimations on the Interpretation of ARDS Trials:Systematic Review and Meta-analysis

Background: Indeterminate randomized controlled trials (RCTs) in ARDS may arise from sample size misspecification, leading to abandonment of efficacious therapies. Research Questions: If evidence exists for sample size misspecification in ARDS RCTs, has this led to rejection of potentially beneficial therapies? Does evidence exist for prognostic enrichment in RCTs using mortality as a primary outcome? Study Design and Methods: We identified 150 ARDS RCTs commencing recruitment after the 1994 American European Consensus Conference ARDS definition and published before October 31, 2020. We examined predicted-observed sample size, predicted-observed control event rate (CER), predicted-observed average treatment effect (ATE), and the relationship between observed CER and observed ATE for RCTs with mortality and nonmortality primary outcome measures. To quantify the strength of evidence, we used Bayesian-averaged meta-analysis, trial sequential analysis, and Bayes factors. Results: Only 84 of 150 RCTs (56.0%) reported sample size estimations. In RCTs with mortality as the primary outcome, CER was overestimated in 16 of 28 RCTs (57.1%). To achieve predicted ATE, interventions needed to prevent 40.8% of all deaths, compared with the original prediction of 29.3%. Absolute reduction in mortality ≥ 10% was observed in 5 of 28 RCTs (17.9%) but was predicted in 21 of 28 RCTs (75.0%). For RCTs with mortality as the primary outcome, no association was found between observed CER and observed ATE (pooled OR: β = –0.04; 95% credible interval, –0.18 to 0.09). We identified three interventions that are not currently standard of care with a Bayesian-averaged effect size of &gt; 0.20 and moderate strength of existing evidence: corticosteroids, airway pressure release ventilation, and noninvasive ventilation. Interpretation: Reporting of sample size estimations was inconsistent in ARDS RCTs, and misspecification of CER and ATE was common. Prognostic enrichment strategies in ARDS RCTs based on all-cause mortality are unlikely to be successful. Bayesian methods can be used to prioritize interventions for future effectiveness RCTs.</p

The Ferris ferromagnetic resonance technique: principles and applications

Measurements of ferromagnetic resonance (FMR) are pivotal to modern magnetism and spintronics. Recently, we reported on the Ferris FMR technique, which relies on large-amplitude modulation of the externally applied magnetic field. It was shown to benefit from high sensitivity while being broadband. The Ferris FMR also expanded the resonance linewidth such that the sensitivity to spin currents was enhanced as well. Eventually, the spin Hall angle ({\theta}_SH) was measurable even in wafer-level measurements that require low current densities to reduce the Joule heating. Despite the various advantages, analysis of the Ferris FMR response is limited to numerical modeling where the linewidth depends on multiple factors such as the field modulation profile and the magnetization saturation. Here, we describe in detail the basic principles of operation of the Ferris FMR and discuss its applicability and engineering considerations. We demonstrated these principles in a measurement of the orbital Hall effect taking place in Cu, using an Au layer as the orbital to spin current converter. This illustrates the potential of the Ferris FMR for the future development of spintronics technology

Case Report: Organ procurement in a DCD donor with ovarian thecoma: abdominal NRP enabled timely and safe resection, pathological confirmation, and successful kidney transplantation

BackgroundDonation after circulatory death (DCD) may be complicated by incidental findings, including tumor lesions that require urgent diagnosis. Here, we describe the case of a DCD donor with a large adnexal mass. Abdominal normothermic regional perfusion (A-NRP) enabled the safe resection of the mass, real-time pathological analysis, and subsequent kidney transplantation.Case summaryA 60-year-old woman suffered a hypoxic cardiac arrest and subsequently remained in a deep coma with poor neurological prognostic indicators. In accordance with her presumed wishes, life support was withdrawn, and a controlled DCD procedure with A-NRP was initiated. Imaging revealed a 27-cm adnexal mass. Laboratory markers showed elevated cancer antigen 125 (CA 125) but low cancer antigen 19-9 (CA 19-9) and carcinoembryonic antigen (CEA), and cytology was negative. Bilateral oophorectomy was performed under A-NRP, and the frozen section excluded malignancy, with final pathology confirming an ovarian thecoma. Both kidneys were procured; only the left kidney was transplanted successfully. The recipient experienced immediate diuresis and regained stable renal function at 1 month.DiscussionThis case illustrates how A-NRP provides oxygenated perfusion while allowing time for surgical excision and a pathological diagnosis of incidental tumors. It prevented unnecessary donor exclusion and enabled transplantation.ConclusionIn selected DCD donors with incidental lesions, A-NRP can safely bridge the diagnostic process, preserve organ viability, and expand the donor pool

Efficient generation of spin currents by the Orbital Hall effect in pure Cu and Al and their measurement by a Ferris-wheel ferromagnetic resonance technique at the wafer level

We present a new ferromagnetic resonance (FMR) method that we term the Ferris FMR. It is wideband, has significantly higher sensitivity as compared to conventional FMR systems, and measures the absorption line rather than its derivative. It is based on large-amplitude modulation of the externally applied magnetic field that effectively magnifies signatures of the spin-transfer torque making its measurement possible even at the wafer-level. Using the Ferris FMR, we report on the generation of spin currents from the orbital Hall effect taking place in pure Cu and Al. To this end, we use the spin-orbit coupling of a thin Pt layer introduced at the interface that converts the orbital current to a measurable spin current. While Cu reveals a large effective spin Hall angle exceeding that of Pt, Al possesses an orbital Hall effect of opposite polarity in agreement with the theoretical predictions. Our results demonstrate additional spin- and orbit- functionality for two important metals in the semiconductor industry beyond their primary use as interconnects with all the advantages in power, scaling, and cost

Ajout de kétamine dans les PCA d’opiacés: une revue systématique avec meta-analyses

La kétamine est souvent utilisée en postopératoire comme adjuvant d’opiacés dans l’antalgie contrôlée par le patient (PCA = patient controlled analgesia). Les bénéfices et risques de cette adjonction restent indéterminés. L’objectif de cette revue systématique et méta-analyse est de définir l’impact clinique de l’adjonction de kétamine sur l’intensité de la douleur, la consommation cumulée de morphine, l’incidence des nausées et vomissements postopératoires (NVPO), les évènements indésirables respiratoires et le risque d’hallucination. La recherche systématique dans les bases de données (Medline, Embase, Cochrane) a permis de sélectionner 19 études randomisées. Après méta-analyses, nos résultats mettent en évidence dans le groupe kétamine, un effet bénéfique sur l’intensité de la douleur, la consommation d’opiacés et l’incidence de NVPO. Le risque d’hallucination n’est pas augmenté et l’effet sur les évènements respiratoires indésirables reste incertain. La fiabilité de ces résultats est confirmée par les analyses « TSA » (trial sequential analyses)

VV-ECMO in ARDS: past, present and future

Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition, first described in 1967.1 57 years later, ARDS is one of the leading causes of acute respiratory failure and remains associated with a high mortality rate, ranging from 34 to 46%.2 Annually, ARDS impacts about 3 millions of patients worldwide, with about 200,000 cases reported in the United States each year, resulting in nearly 75,000 deaths.3 Despite decades of research, the management of ARDS remains supportive. In fact, more than 150 RCTs were conducted since ARDS first description. To date, no specific pharmacologic therapies have been successfully developed and only few interventions have resulted in a significant reduction in mortality rate. Protective mechanical ventilation and prone positioning currently represent the cornerstone of ARDS management. However, some patients are refractory to optimal conventional management. In life-threatening situations, ECLS has been proposed as a potential rescue strategy. Since the first successful case described in 1972,4 and after several negative trials, ECMO has finally become an established treatment for refractory ARDS. In fact, recent guidelines advocate for its use in selected patients and high-volume centers (strong recommendation, moderate level of evidence).5 This thesis aims to review the historical perspective and evidence supporting the use of VV- ECMO in the management of ARDS. The introduction is divided into two parts. The first part will introduce ARDS, and the second part will focus on the aims, key principles, historical perspective and evidence associated with this technique in ARDS. Then, a line of work will present and highlight the methodological limitations of RCTs conducted in ARDS, the impact of the timing of implantation of ECLS in ARDS, the maternal and fetal outcome of pregnant patients rescued with ECMO in severe ARDS, and the management of mechanical ventilation during ECMO support. Finally, based on these findings, the research agenda will be reviewed and discussed.</p

Extracorporeal membrane oxygenation in COVID-19 associated acute respiratory distress syndrome: A narrative review

Venovenous extracorporeal membrane oxygenation (VV-ECMO) is an established rescue therapy in the management of refractory acute respiratory distress syndrome (ARDS). Although ECMO played an important role in previous respiratory viral epidemics, concerns about the benefits and usefulness of this technique were raised during the coronavirus disease 2019 (COVID-19) pandemic. Indeed, the mortality rate initially reported in small case series from China was concerning and exceeded 90%. A few months later, the critical care community published the findings from several observational cohorts on the use of extracorporeal membrane oxygenation (ECMO) in COVID-19-related ARDS. Contrary to the preliminary results, data from the first surge supported the use of ECMO in experienced centers because the mortality rate was comparable to those from the ECMO to Rescue Lung Injury in Severe ARDS (EOLIA) trial or other large prospective studies. However, the mortality rate of the population with severe disease evolved during the pandemic, in conjunction with changes in the management of the disease and the occurrence of new variants. The results from subsequent studies confirmed that the outcomes mainly depend on strict patient selection and center expertise. In comparison with non-COVID-related ARDS, the duration of ECMO for COVID-related ARDS was longer and increased over time. Clinicians and decision-makers must integrate this finding in the ECMO decision-making process to plan their ICU capacity and resource allocation. This narrative review summarizes the current evidence and specific considerations for ECMO use in COVID-19-associated ARDS