Discovering dominant tumor immune archetypes in a pan-cancer census.

Cancers display significant heterogeneity with respect to tissue of origin, driver mutations, and other features of the surrounding tissue. It is likely that individual tumors engage common patterns of the immune system-here "archetypes"-creating prototypical non-destructive tumor immune microenvironments (TMEs) and modulating tumor-targeting. To discover the dominant immune system archetypes, the University of California, San Francisco (UCSF) Immunoprofiler Initiative (IPI) processed 364 individual tumors across 12 cancer types using standardized protocols. Computational clustering of flow cytometry and transcriptomic data obtained from cell sub-compartments uncovered dominant patterns of immune composition across cancers. These archetypes were profound insofar as they also differentiated tumors based upon unique immune and tumor gene-expression patterns. They also partitioned well-established classifications of tumor biology. The IPI resource provides a template for understanding cancer immunity as a collection of dominant patterns of immune organization and provides a rational path forward to learn how to modulate these to improve therapy.

A "data sharing trust" model for rapid, collaborative science.

Complex datasets provide opportunities for discoveries beyond their initial scope. Effective and rapid data sharing and management practices are crucial to realize this potential; however, they are harder to implement than post-publication access. Here, we introduce the concept of a "data sharing trust" to maximize the value of large datasets.

Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity.

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.

Global absence and targeting of protective immune states in severe COVID-19.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1-3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood-including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3 across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.

TRI-SCORE and benefit of intervention in patients with severe tricuspid regurgitation.

BACKGROUND AND AIMS: Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE. METHODS: A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. RESULTS: The TRI-SCORE was low (≤3) in 32%, intermediate (4-5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively). CONCLUSIONS: Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.

Benefit of isolated surgical valve repair or replacement for functional tricuspid regurgitation and long-term outcomes stratified by the TRI-SCORE.

BACKGROUND AND AIMS: Severe tricuspid regurgitation (TR) is associated with increased mortality rates, but benefit of its correction and ideal timing are not clearly determined. This study aimed to identify patient subsets who might benefit from surgery. METHODS: In TRIGISTRY, an international cohort study of consecutive patients with severe isolated functional TR (33 centers, 10 countries), survival rates up to 10 years were compared between patients who underwent isolated tricuspid valve (TV) surgery (repair or replacement) and those conservatively managed, overall and according to TRI-SCORE category (low: ≤3, intermediate: 4-5, high: ≥6). RESULTS: 1,217 were managed conservatively, and 551 underwent isolated TV surgery (200 repairs, 351 replacements). TRI-SCORE distribution was 33% low, 32% intermediate, and 35% high. At 10 years, survival rates were similar between surgical and conservative management (41% vs. 36%; hazard ratio [HR] 0.97; 95% confidence interval [CI] 0.88-1.08, P=0.57). Surgery improved survival compared to conservative management in the low TRI-SCORE category (72% vs. 44%; HR 0.27; 95% CI 0.20-0.37, P<0.0001), but not in the intermediate (36% vs. 37%, HR 1.17; 95%CI 0.98-1.40, P=0.09) or high categories (20% vs. 24%; HR 1.06; 95% CI 0.91-1.25, P=0.45). Both repair and replacement improved survival in the low TRI-SCORE category (84% and 61% vs. 44%; HR 0.11; 95% CI 0.06-0.19, P<0.0001, and HR 0.65; 95% CI 0.47-0.90, P=0.009). Repair showed benefit in the intermediate category (59% vs. 37%; HR 0.49; 95% CI 0.35-0.68, P<0.0001) while replacement was possibly harmful (25% vs. 37%; HR 1.43; 95% CI 1.18-1.72, P=0.0002). CONCLUSIONS: Higher survival rates were observed with repair than replacement and benefit of intervention declined as TRI-SCORE increased with no benefit of any type of surgery in the high TRI-SCORE category. These results emphasize the importance of timely intervention and patient selection to achieve the best outcomes and the need for randomized controlled trials. TRIAL REGISTRATION: TRIGISTRY: ClinicalTrials.gov, NCT05825898.

Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock.

BACKGROUND: Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exists to guide the selection of inotropic agents in clinical practice. METHODS: We randomly assigned patients with cardiogenic shock to receive milrinone or dobutamine in a double-blind fashion. The primary outcome was a composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite outcome. RESULTS: A total of 192 participants (96 in each group) were enrolled. The treatment groups did not differ significantly with respect to the primary outcome; a primary outcome event occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P = 0.47). There were also no significant differences between the groups with respect to secondary outcomes, including in-hospital death (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67). CONCLUSIONS: In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite outcome or important secondary outcomes. (Funded by the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; ClinicalTrials.gov number, NCT03207165.).

Baseline Gastric Volume in Fasting Diabetic Patients Is Not Higher than That in Nondiabetic Patients: A Cross-sectional Noninferiority Study.

BACKGROUND: The physiology of diabetes mellitus can increase the risk of perioperative aspiration, but there is limited and contradictory evidence on the incidence of "full stomach" in fasting diabetic patients. The aim of this study is to assess the baseline gastric content (using gastric ultrasound) in diabetic and nondiabetic patients scheduled for elective surgery who have followed standard preoperative fasting instructions. METHODS: This was a prospective, noninferiority study of 180 patients (84 diabetic and 96 nondiabetic patients). Bedside ultrasound was used for qualitative and quantitative assessment of the gastric antrum in the supine and right lateral decubitus positions. Fasting gastric volume was estimated based on the cross-sectional area of the gastric antrum and a validated model. The hypothesis was that diabetic patients would not have a higher baseline fasting gastric volume compared to nondiabetic patients, with a noninferiority margin of 0.4 ml/kg. Secondary aims included the comparison of the incidence of full stomach (solid content or more than 1.5 mL/kg of clear fluid), estimation of the 95th percentile of the gastric volume distribution in both groups, and examination of the association between gastric volume, glycemic control, and diabetic comorbidities. RESULTS: The baseline gastric volume was not higher in diabetic patients (0.81 ± 0.61 ml/kg) compared to nondiabetic patients (0.87 ± 0.53 ml/kg) with a mean difference of -0.07 ml/kg (95% CI, -0.24 to 0.10 ml/kg). A total of 13 (15.5%) diabetic and 11 (11.5%) nondiabetic patients presented more than 1.5 ml/kg of gastric volume (95% CI for difference, -7.1 to 15.2%). There was little correlation between the gastric volume and either the time since diagnosis or HbA1C. CONCLUSIONS: The data suggest that the baseline gastric volume in diabetic patients who have followed standard fasting instructions is not higher than that in nondiabetic patients.

Electric Field-Driven Self-Assembly of Gold Nanoparticle Monolayers on Silicon Substrates.

Nanoparticles (NPs) bridge the gap between bulk materials and their equivalent molecular/atomic counterparts. The physical, optical, and electronic properties of individual NPs alter with the changes in their surrounding environment at the nanoscale. Similarly, the characteristics of thin films of NPs depend on their lateral and volumetric densities. Thus, attaining single monolayers of these NPs would play a vital role in the improved characteristics of semiconductor devices such as nanosensors, field effect transistors, and energy harvesting devices. Developing nanosensors, for instance, requires precise methods to fabricate a monolayer of NPs on selected substrates for sensing and other applications. Herein, we developed a physical fabrication method to form a monolayer of NPs on a planar silicon surface by creating an electric field of intensity 5.71 × 104 V/m between parallel plates of a capacitor, by applying a DC voltage. The physics of monolayer formation caused by an externally applied electric field on the gold NPs (Au-NPs) of size 20 nm in diameter and possesses a zeta potential of -250 to -290 mV, is further analyzed with the help of the finite element simulation. The enhanced electric field, in the order of 108 V/m, around the Au-NPs indicates a high surface charge density on the NPs, which results in a high electric force per unit area that guides them to settle uniformly on the surface of the silicon substrate.

Enabling, Decagram-Scale Synthesis of Macrocyclic MCL-1 Inhibitor ABBV-467.

ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.

A hood shield reduces postdoffing contamination during simulated COVID-19 airway management: an exploratory, simulation-based randomized study.

PURPOSE: SARS-CoV-2 poses a significant occupational health threat to health care workers performing aerosol-generating medical procedures, with a threefold increased risk of a positive test and predicted infection compared with the general population. Nevertheless, the personal protective equipment (PPE) configuration that provides better protection with lower contamination rates is still unknown. METHODS: We enrolled 40 practitioners with airway management training (anesthesiologists, anesthesia assistants/nurses) in an exploratory, simulation-based randomized study. We evaluated the performance of a novel, locally designed hood (n = 20) in terms of protection from surrogate contamination using an ultraviolet (UV) marker during a standardized urgent intubation procedure and a simulated episode of coughing in a high-fidelity simulation setting compared with standard PPE (n = 20). The primary outcome was the presence of residual UV fluorescent contamination on any base clothing or exposed skin of the upper body after doffing PPE assessed by a blinded evaluator. RESULTS: The proportion of participants with residual contamination on any base clothing or exposed skin of the upper body after doffing was less than half in the hood PPE group compared with the standard PPE group (8/20 [40%] vs 18/20 [90%], respectively; P = 0.002). CONCLUSIONS: Compared with standard PPE, enhanced PPE with a locally designed prototype hood was associated with reduced contamination of the upper torso and fewer body areas being exposed to droplets after a simulated aerosol-generating scenario without designed airflow. STUDY REGISTRATION: ClinicalTrials.gov (NCT04373096); registered 4 May 2020.

RéSUMé: OBJECTIF: Le SRAS-CoV-2 représente une menace importante pour la santé au travail des travailleurs de la santé réalisant des interventions médicales générant des aérosols, avec un risque trois fois plus élevé de test positif au SRAS-CoV-2 et d'infection prédite au SRAS-CoV-2 par rapport à la population générale. Néanmoins, la configuration optimale des équipements de protection individuelle (EPI) offrant la meilleure protection avec des taux de contamination plus faibles est encore inconnue. MéTHODE: Nous avons recruté 40 praticiens ayant une formation en prise en charge des voies aériennes (anesthésiologistes, assistants en anesthésie/personnel infirmier) dans le cadre d'une étude exploratoire randomisée de simulation. Nous avons évalué la performance d'un nouveau capuchon conçu localement (n = 20) par rapport aux EPI standards (n = 20) en termes de protection contre la contamination de substitution à l'aide d'un marqueur ultraviolet (UV) au cours d'une procédure d'intubation urgente normalisée et d'un épisode simulé de toux dans un environnement de simulation haute fidélité. Le critère d'évaluation principal était la présence d'une contamination résiduelle par fluorescence UV sur les vêtements de base ou la peau exposée du haut du corps après le retrait des EPI telle qu'évaluée par un évaluateur en aveugle. RéSULTATS: La proportion de participants présentant une contamination résiduelle sur les vêtements de base ou la peau exposée du haut du corps après le retrait des équipements de protection était de moins de la moitié dans le groupe ayant porté le capuchon par rapport au groupe EPI standard (8/20 [40 %] vs 18/20 [90 %], respectivement; P = 0,002). CONCLUSION: Par rapport aux EPI standards, les EPI améliorés avec un prototype de capuchon conçu localement étaient associés à une contamination réduite du haut du torse et à moins de zones du corps exposées aux gouttelettes après une mise en situation simulée de génération d'aérosols sans flux d'air préconçu. ENREGISTREMENT DE L'éTUDE: clinicaltrials.gov (NCT04373096); enregistrée le 4 mai 2020.

Regional anesthesia and analgesia in patients with spastic cerebral palsy undergoing orthopedic surgery: a historical cohort study.

PURPOSE: We sought to examine the incidence of severe postoperative pain in patients with cerebral palsy (CP) in the first 48 hr after surgery performed under combined regional and general anesthesia and its association with patient and surgical factors. METHODS: In a historical cohort study, we reviewed the electronic records of 452 patients with spastic CP who underwent orthopedic surgeries of the upper and lower extremities from April 2016 to February 2020. Collected data included patient characteristics, American Society of Anesthesiologists Physical Status, details of anesthesia and surgery, types of regional anesthesia applied, success rate of anesthesia, incidence of severe pain, and adverse events. RESULTS: We analyzed data from 440 patients; 404 patients underwent lower extremity surgery, 20 upper extremity surgery, and 15 both, and one patient required stem cell injection. All patients received general anesthesia before block performance. Single-injection neuraxial anesthesia was performed in 241 (54.8%) patients, brachial plexus block in 27 (6.1%) patients, and femoral/sciatic nerve blocks in 17 (3.9%) patients. Continuous neuraxial, brachial plexus, and femoral/sciatic nerve blocks were performed in 149 (33.9%), four (0.9%), and seven (1.6%) of the patients, respectively. Major and complex major surgeries were performed in 161 (36.6%) and 72 (16.4%) patients, respectively and continuous catheters were inserted in 50.3% of patients undergoing major surgery and in 91.7% of patients undergoing complex major surgery. Severe pain was reported by the caregivers of 68 (15.5%) patients who received nonopioid analgesic interventions. CONCLUSION: Despite the use of regional anesthesia, approximately 15% of patients with spastic CP undergoing orthopedic surgery for spastic cerebral palsy experienced severe pain that responded to treatment adjustments. STUDY REGISTRATION: CTRI.nic.in (027002); registered 5 August 2020.

RéSUMé: OBJECTIF: Nous avons cherché à examiner l'incidence de la douleur postopératoire sévère chez les personnes atteintes de paralysie cérébrale (PC) au cours des 48 premières heures suivant une chirurgie réalisée sous anesthésie régionale et générale combinée et son association avec les facteurs liés aux patient·es et les facteurs chirurgicaux. MéTHODE: Dans une étude de cohorte historique, nous avons examiné les dossiers électroniques de 452 personnes atteintes de PC spastique ayant bénéficié de chirurgies orthopédiques des membres supérieurs et inférieurs d'avril 2016 à février 2020. Les données recueillies comprenaient les caractéristiques des patient·es, le statut physique selon l'American Society of Anesthesiologists, les détails de l'anesthésie et de la chirurgie, les types d'anesthésie régionale appliqués, le taux de réussite de l'anesthésie, l'incidence de la douleur intense et les événements indésirables. RéSULTATS: Nous avons analysé les données de 440 patient·es; 404 ont bénéficié d'une chirurgie des membres inférieurs, 20 d'une chirurgie des membres supérieurs et 15 des deux, et une personne a nécessité une injection de cellules souches. Tou·tes les patient·es ont reçu une anesthésie générale avant la réalisation du bloc. Une anesthésie neuraxiale à injection unique a été réalisée chez 241 patient·es (54,8 %), un bloc du plexus brachial chez 27 patient·es (6,1 %) et des blocs du nerf fémoral/sciatique chez 17 (3,9 %) patient·es. Des blocs nerveux neuraxiaux, du plexus brachial et fémoraux/sciatiques continus ont été réalisés chez 149 (33,9 %), quatre (0,9 %) et sept (1,6 %) personnes, respectivement. Des chirurgies majeures et complexes ont été réalisées chez 161 (36,6 %) et 72 (16,4 %) patient·es, respectivement, et des cathéters continus ont été insérés chez 50,3 % des personnes bénéficiant d'une intervention chirurgicale majeure et chez 91,7 % des personnes bénéficiant d'une chirurgie majeure complexe. Une douleur intense a été signalée par le personnel soignant chez 68 patient·es (15,5 %) ayant reçu des interventions analgésiques non opioïdes. CONCLUSION: Malgré l'utilisation de l'anesthésie régionale, environ 15 % des patient·es atteint·es de PC spastique bénéficiant d'une chirurgie orthopédique pour leur paralysie cérébrale spastique ont ressenti une douleur intense qui a répondu aux ajustements du traitement. ENREGISTREMENT DE L'éTUDE: CTRI.nic.in (027002); enregistrée le 5 août 2020.

Metal-on-crosslinked polyethylene in total hip arthroplasty - an excellent combination at fifteen to twenty years of follow-up.

PURPOSE: Cross-linked polyethylene (PE) has been used with great clinical success in total hip arthroplasty (THA) since its debut in the late 1990's. However, reports regarding this bearing couple near the end of its second decade of service are still scant. The aim of this study was to first determine the long term clinical and radiological results and second Investigate what factors affect wear rates using a metal-on-crosslinked PE bearing articulation. METHODS: 55 THAs using a single brand of cross-linked liner, cementless cup and 28 mm hip ball were performed in 44 patients. Age, sex, Charlson Comorbidity Index (CCI) and need for revision surgery were recorded. Linear and volumetric wear was determined using the Martell method. RESULTS: Mean age at operation was 51.2 (29-73 ± 12.1) years. Mean duration of follow-up was 16.9 years (range 15.0-20.1 ± 1.1 years). Osteolysis was not present in the latest follow-up radiographs. Median linear and volumetric wear rate was 0.038 mm/year (95% CI 0.032-0.047) and 7.115mm3/year (95% CI 6.92-17.25) respectively. Acetabular component position was not found to be related to both linear and volumetric wear. No significant difference was found in the linear and volumetric wear rates of thinner and thicker liners (8 mm or below and > 8 mm) (p = 0.849 and p = 0.64 respectively). CONCLUSION: Metal-on-crosslinked PE is associated with low linear and volumetric wear rates which has virtually obviated osteolysis and has translated to excellent survivorship even at long term follow up. In-vivo oxidation does not appear to be of clinical concern at this point.

Development of an Automated and Scalable Virtual Assistant to Aid in PPE Adherence: A Study with Implications for Applications within Anesthesiology.

Virtual assistants (VAs) are conversational agents that are able to provide cognitive aid. We developed a VA device for donning and doffing personal protective equipment (PPE) procedures and compared it to live human coaching to explore the feasibility of using VAs in the anesthesiology setting. An automated, scalable, voice-enabled VA was built using the Amazon Alexa device and Alexa Skills application. The device utilized voice-recognition technology to allow a touch-free interactive user experience. Audio and video step-by-step instructions for proper donning and doffing of PPE were programmed and displayed on an Echo Show device. The effectiveness of VA in aiding adherence to PPE protocols was compared to traditional human coaching in a randomized, controlled, single-blinded crossover design. 70 anesthesiologists, anesthesia assistants, respiratory therapists, and operating room nurses performed both donning and doffing procedures, once under step-by-step VA instructional guidance and once with human coaching. Performance was assessed using objective performance evaluation donning and doffing checklists. More participants in the VA group correctly performed the step of "Wash hands for 20 seconds" during both donning and doffing tests. Fewer participants in the VA group correctly performed the steps of "Put cap on and ensure covers hair and ears" and "Tie gown on back and around neck". The mean doffing total score was higher in the VA group; however, the donning score was similar in both groups. Our study demonstrates that it is feasible to use commercially available technology to create a voice-enabled VA that provides effective step-by-step instructions to healthcare professionals.

Transcatheter mitral valve repair for inotrope dependent cardiogenic shock - Design and rationale of the CAPITAL MINOS trial.

BACKGROUND: Functional mitral regurgitation (MR) is an important clinical consideration in patients with heart failure. Transcatheter edge-to-edge repair (TEER) has emerged as a useful therapeutic tool for patients with chronic heart failure, however the role of TEER in patients with cardiogenic shock (CS) and MR has not yet been studied in a randomized trial. The Transcatheter Mitral Valve Repair for Inotrope Dependent Cardiogenic Shock (CAPITAL MINOS) trial was therefore designed to determine if TEER improves clinical outcomes in the CS population. METHODS AND DESIGN: The CAPITAL MINOS trial is an open-label, multi-center randomized clinical trial comparing TEER to medical therapy in patients with CS and MR. A total of 144 patients with Society for Cardiovascular Angiography and Interventions (SCAI) class C or D CS and at least 3+ MR will be randomized in a 1:1 ratio to TEER or medical therapy alone. The primary outcome will be a composite of in-hospital all-cause mortality, cardiac transplantation, implantation of durable left ventricular assist device, or discharge on palliative inotropic therapy. Patients will be followed for the duration of their index hospitalization for the primary outcome. Secondary outcomes include 6 month mortality. IMPLICATIONS: The CAPITAL MINOS trial will determine whether TEER improves outcomes in patients with CS and MR and will be an important step in optimizing treatment for this high-risk patient population.

Activation of cannabinoid-2 receptor protects against Pseudomonas aeruginosa induced acute lung injury and inflammation.

BACKGROUND: Bacterial pneumonia is a major risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Pseudomonas aeruginosa (PA), an opportunistic pathogen with an increasing resistance acquired against multiple drugs, is one of the main causative agents of ALI and ARDS in diverse clinical settings. Given the anti-inflammatory role of the cannabinoid-2 receptor (CB2R), the effect of CB2R activation in the regulation of PA-induced ALI and inflammation was tested in a mouse model as an alternative to conventional antibiotic therapy. METHODS: In order to activate CB2R, a selective synthetic agonist, JWH133, was administered intraperitoneally (i.p.) to C57BL/6J mice. Furthermore, SR144528 (a selective CB2R antagonist) was administered in combination with JWH133 to test the specificity of the CB2R-mediated effect. PA was administered intratracheally (i.t.) for induction of pneumonia in mice. At 24 h after PA exposure, lung mechanics were measured using the FlexiVent system. The total cell number, protein content, and neutrophil population in the bronchoalveolar lavage fluid (BALF) were determined. The bacterial load in the whole lung was also measured. Lung injury was evaluated by histological examination and PA-induced inflammation was assessed by measuring the levels of BALF cytokines and chemokines. Neutrophil activation (examined by immunofluorescence and immunoblot) and PA-induced inflammatory signaling (analyzed by immunoblot) were also studied. RESULTS: CB2R activation by JWH133 was found to significantly reduce PA-induced ALI and the bacterial burden. CB2R activation also suppressed the PA-induced increase in immune cell infiltration, neutrophil population, and inflammatory cytokines. These effects were abrogated by a CB2R antagonist, SR144528, further confirming the specificity of the CB2R-mediated effects. CB2R-knock out (CB2RKO) mice had a significantly higher level of PA-induced inflammation as compared to that in WT mice. CB2R activation diminished the excess activation of neutrophils, whereas mice lacking CB2R had elevated neutrophil activation. Pharmacological activation of CB2R significantly reduced the PA-induced NF-κB and NLRP3 inflammasome activation, whereas CB2KO mice had elevated NLRP3 inflammasome. CONCLUSION: Our findings indicate that CB2R activation ameliorates PA-induced lung injury and inflammation, thus paving the path for new therapeutic avenues against PA pneumonia.

No Benefits of Adding Dexmedetomidine, Ketamine, Dexamethasone, and Nerve Blocks to an Established Multimodal Analgesic Regimen after Total Knee Arthroplasty.

BACKGROUND: An optimal opioid-sparing multimodal analgesic regimen to treat severe pain can enhance recovery after total knee arthroplasty. The hypothesis was that adding five recently described intravenous and regional interventions to multimodal analgesic regimen can further reduce opioid consumption. METHODS: In a double-blinded fashion, 78 patients undergoing elective total knee arthroplasty were randomized to either (1) a control group (n = 39) that received spinal anesthesia with intrathecal morphine, periarticular local anesthesia infiltration, intravenous dexamethasone, and a single injection adductor canal block or (2) a study group (n = 39) that received the same set of analgesic treatments plus five additional interventions: local anesthetic infiltration between the popliteal artery and capsule of the posterior knee, intraoperative intravenous dexmedetomidine and ketamine, and postoperatively, one additional intravenous dexamethasone bolus and two additional adductor canal block injections. The primary outcome measure was 24-h cumulative opioid consumption after surgery and secondary outcomes were other analgesics, patient recovery, functional outcomes, and adverse events. RESULTS: Opioid consumption was not different between groups at 24 h (oral morphine equivalents, mean ± SD; study: 23.7 ± 18.0 mg vs. control: 29.3 ± 18.7 mg; mean difference [95% CI], -5.6 mg [-2.7 to 13.9]; P = 0.189) and all other time points after surgery. There were no major differences in pain scores, quality of recovery, or time to reach rehabilitation milestones. Hypotensive episodes occurred more frequently in the study group (25 of 39 [64.1%] vs. 13 of 39 [33.3%]; P = 0.010). CONCLUSIONS: In the presence of periarticular local anesthesia infiltration, intrathecal morphine, single-shot adductor canal block and dexamethasone, the addition of five analgesic interventions-local anesthetic infiltration between the popliteal artery and capsule of the posterior knee, intravenous dexmedetomidine, intravenous ketamine, an additional intravenous dexamethasone dose, and repeated adductor canal block injections-failed to further reduce opioid consumption or pain scores or to improve functional outcomes after total knee arthroplasty.

Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson's Disease.

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

Study of synergistic disinfection by UVC and positive/negative air ions for aerosolized Escherichia coli, Salmonella typhimurium, and Staphylococcus epidermidis in ventilation duct flow.

The efficacy of the in-duct application of ultraviolet waveband C (UVC) emitting at 254 nm wavelength and air ions against aerosolized bacteria was studied in a full-scale 9-m long ventilation duct. Combined positive and negative ion polarities (bipolar ions) and combined UVC and ions were tested. The UVC was generated by a mercury-type UVC lamp and air ions were generated by positive and negative polarity ionizers. Escherichia coli (E. coli), Salmonella typhimurium (S. typhimurium), and Staphylococcus epidermidis (S. epidermidis)were tested at a concentration of 108 to 109 cells in 50 ml of sterilized distilled water. The case in which the positive ionizer was placed first, followed by the negative ionizer, demonstrated significantly higher disinfection efficiencies for E. coli (p = 0.007) and S. typhimurium (p < 0.001), but lower efficiency for S. epidermidis (p = 0.01) than the reversed sequence. The combination of UVC (3.71 J/m2 ) and air ions (1.13 × 1012  ions/m3 for positive ions and 8.00 × 1011  ions/m3 for negative ions) led to higher inactivation than individual disinfection agents operating under the same dose. A synergetic inactivation effect was observed for S. epidermidis under the combined UVC and positive ion case, while the combined UVC and negative ion case showed significant synergy effects for E. coli and S. typhimurium.