Ir(III) complexes of diamine ligands for asymmetric ketone hydrogenation

The use of a combination of IrCl3 with a series of ligands derived from the C2-symmetric diamine diphenylethanediamine (DPEN) forms a catalyst capable of the asymmetric hydrogenation of ketones in up to 85% ee

Toxicity and Surgical Complication Rates of Neoadjuvant Atezolizumab in Patients with Muscle-invasive Bladder Cancer Undergoing Radical Cystectomy: Updated Safety Results from the ABACUS Trial

[Background] There are limited data on toxicity and surgical safety associated with neoadjuvant programmed death ligand 1 (PD-L1) inhibitors prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC).[Objective] To present a comprehensive safety analysis of the largest neoadjuvant series, with focus on timing and severity of toxicity and surgical complications occurring after neoadjuvant atezolizumab in patients with MIBC enrolled in the ABACUS trial.[Design, setting, and participants] ABACUS (NCT02662309) is an open-label, multicenter, phase II trial for patients with histologically confirmed (T2-T4aN0M0) MIBC, awaiting RC. Patients either were ineligible or refused cisplatin-based neoadjuvant chemotherapy.[Intervention] Two cycles of neoadjuvant atezolizumab (1200 mg, every 3 wk) followed by RC.[Outcome measurements and statistical analysis] Description of atezolizumab toxicity profile in the neoadjuvant setting, impact on surgery, and delayed immune-mediated adverse events (AEs) were assessed.[Results and limitations] Ninety-five patients received treatment. Of them, 44% (42/95) had atezolizumab-related AEs during the neoadjuvant period (fatigue [20%], decreased appetite [6%], and transaminases increased [6%]). Treatment-related grade 3–5 AEs occurred in 11% (10/95) of patients during the study. Of the patients, 21% (20/95) received only one cycle of atezolizumab due to AEs; 92% (87/95) underwent RC. No surgery was delayed due to atezolizumab-related toxicities. Surgical complications occurred in 62% (54/87) of patients. Of these patients, 43% (37/87) and 20% (17/87) had minor (grade 1–2) and major (grade 3–5) complications, respectively. Thirteen of 87 (15%) patients had post-RC atezolizumab-related AEs, including adrenal insufficiency and transaminases increased. Three deaths occurred during the period of study-related interventions (one non–treatment-related aspiration pneumonia, one immune-related myocardial infarction, and one cardiogenic shock after RC). Not all surgical safety parameters were available.[Conclusions] Two cycles of neoadjuvant atezolizumab are well tolerated and do not seem to impact surgical complication rates. Owing to the long half-life, AEs may occur in the postoperative period, including endocrine abnormalities requiring attention and intervention.[Patient summary] Here, we report a comprehensive dataset of patients receiving neoadjuvant immune checkpoint inhibitors before radical cystectomy. Treatment with neoadjuvant atezolizumab is safe and does not seem to complicate surgery significantly.Queen Mary University of London was the Sponsor of the study. Roche granted QMUL funding for the study. J. Bull and M. Jacobson also provided financial support for aspects of the biomarker analysis. We acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network, and La Roche-Hoffmann for funding.Peer reviewe

The killer within: Endogenous bacteria accelerate oyster mortality during sustained anoxia

16 pages, 5 figures, 2 tablesSustained periods of anoxia, driven by eutrophication, threaten coastal marine systems and can lead to mass mortalities of even resilient animals such as bivalves. While mortality rates under anoxia are well-studied, the specific mechanism(s) of mortality are less clear. We used a suite of complementary techniques (LT50, histology, 16S rRNA amplicon sequencing, and valvometry) to show that the proliferation of anaerobic bacteria within eastern oysters (Crassostrea virginica) accelerates mortality rate under anoxic conditions. Manipulative laboratory experiments revealed that oyster survival under anoxic conditions was halved when bacteria were present compared to when they were excluded by the broad-spectrum antibiotic chloramphenicol. Histological assessments supported this mechanism and showed infiltration of bacteria in oysters that were not treated with antibiotics compared to a general lack of bacteria when oysters were treated with antibiotics. 16S rRNA amplicon sequencing failed to identify any particular genera of bacteria responsible for mortality, rather a diversity of endogenous anaerobic and/or sulfate-reducing bacteria were common among oysters. In addition, monitoring of oyster valve gaping behavior in the field revealed that oysters showed remarkable valve closure synchrony when first exposed to anoxia. However, oysters periodically opened throughout anoxia/hypoxia in both the lab and field, suggesting that the infiltration of exogenous bacteria from the environment may also influence mortality rates under natural settings. Coupled with previous studies, we posit that mass mortality events in a wide range of coastal bivalves are likely the result of co-morbidity from asphyxiation and bacterial processesThis study was funded by L'Étang Ruisseau Bar Ltd. in partnership with the Department of Fisheries and Oceans of Canada (Aquaculture Collaborative Research and Development Program, project 17-G-02 led by M.R.S.C.), a NSERC Discovery Grant to R.F. (RGPIN-2017-04294), and a Total Development Fund from the New Brunswick Department of Agriculture, Aquaculture and Fisheries to R.F.Peer reviewe

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Development of a risk prediction model of potentially avoidable readmission for patients hospitalised with community-acquired pneumonia: study protocol and population

Introduction 30-day readmission rate is considered an adverse outcome reflecting suboptimal quality of care during index hospitalisation for community-acquired pneumonia (CAP). However, potentially avoidable readmission would be a more relevant metric than all-cause readmission for tracking quality of hospital care for CAP. The objectives of this study are (1) to estimate potentially avoidable 30-day readmission rate and (2) to develop a risk prediction model intended to identify potentially avoidable readmissions for CAP.Methods and analysis The study population consists of consecutive patients admitted in two hospitals from the community or nursing home setting with pneumonia. To qualify for inclusion, patients must have a primary or secondary discharge diagnosis code of pneumonia. Data sources include routinely collected administrative claims data as part of diagnosis-related group prospective payment system and structured chart reviews. The main outcome measure is potentially avoidable readmission within 30 days of discharge from index hospitalisation. The likelihood that a readmission is potentially avoidable will be quantified using latent class analysis based on independent structured reviews performed by four panellists. We will use a two-stage approach to develop a claims data-based model intended to identify potentially avoidable readmissions. The first stage implies deriving a clinical model based on data collected through retrospective chart review only. In the second stage, the predictors comprising the medical record model will be translated into International Classification of Diseases, 10th revision discharge diagnosis codes in order to obtain a claim data-based risk model.The study sample consists of 1150 hospital stays with a diagnosis of CAP. 30-day index hospital readmission rate is 17.5%.Ethics and dissemination The protocol was reviewed by the Comité de Protection des Personnes Sud Est V (IRB#6705). Efforts will be made to release the primary study results within 6 months of data collection completion.Trial registration number ClinicalTrials.gov Registry (NCT02833259)

Key role for respiratory CD103(+) dendritic cells, IFN-γ, and IL-17 in protection against Streptococcus pneumoniae infection in response to α-galactosylceramide.

International audienceBACKGROUND: Exogenous activation of pulmonary invariant natural killer T (iNKT) cells, a population of lipid-reactive αβ T lymphocytes, with use of mucosal α-galactosylceramide (α-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to α-GalCer-mediated protection against lethal infection with Streptococcus pneumoniae serotype 1, a major respiratory pathogen in humans. METHODS AND RESULTS: α-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103(+) subset, play a major role in the activation (IFN-γ and IL-17 release) of pulmonary iNKT cells, whereas alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4 hours) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-γ and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17-associated genes as revealed by transcriptomic analysis. CONCLUSIONS: These data imply a new function for pulmonary CD103(+) DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-γ and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae