The synthesis and metal complexes of some unusual phosphines

The high temperature and pressure synthesis of chlorophosphines from an alkene, white phosphorus and phosphorus trichloride yielded both mono- and diphosphine products. Chain and cyclic alkenes, dienes and terpenes were used as substrates forming chain, ring and bicyclic mono- and diphosphines. Many novel, even unique, chlorophosphines were prepared in good yield and characterised using (^31)P and (^13)C NMR, mass spectroscopy and elemental analysis. Simple alkenes readily reacted forming mono- and 1,2-diphosphines. However 1,5-cyclooctadiene formed a 1,4-addition product after double bond conjugation. Butadiene dimerised prior to reaction, generating either a 2,2'-diphospholane or a 1,4-bridged phosphabicyclic alkane in addition to 1,2- and 1,4-diphosphines. Terpenoid dichlorophosphines were prepared but could not be isolated or characterised, because the substrate isomerised under the reaction conditions generating many similar products. Aromatic rings did not react, although the exocyclic double bond of styrene did undergo reaction. Chiral phosphines were readily produced from unsymmetric pro-chiral, alkenes. Chlorophosphines are versatile precursors and, using standard organophosphorus techniques, were readily converted to phosphines, phosphites and other organophosphorus ligands suitable for chelation. Grignard reagents were used to prepare dimethyl derivatives, alcohols reacted with dichlorophosphines producing diethyl-, dimenthyl- or 1,4-butylphosphite derivatives, Piperazine also reacted although the products could not be fully characterised. Electronic properties (^Mn)χ) of the phosphines in manganese carbonyl halide derivatives were measured as a function of the A(_1)carbonyl stretching frequency. Substituent electronegativity was the most important factor in determining the π-acidity. Some dichloropalladium complexes were studied using 3ip NMR, although phosphine impurities complicated spectral interpretation. Iron and molybdenum hydrides reacted with dichlorophosphines to produce some unusual metal-phosphine compounds

Safety Assessment of a Noninvasive Respiratory Protocol for Adults with COVID-19

As evidence emerged supporting noninvasive strategies for coronavirus disease 2019 (COVID-19)-related respiratory distress, we implemented a noninvasive COVID-19 respiratory protocol (NCRP) that encouraged high-flow nasal cannula (HFNC) and self-proning across our healthcare system. To assess safety, we conducted a retrospective chart review evaluating mortality and other patient safety outcomes after implementation of the NCRP protocol (April 3, 2020, to April 15, 2020) for adult patients hospitalized with COVID-19, compared with preimplementation outcomes (March 15, 2020, to April 2, 2020). During the study, there were 469 COVID-19 admissions. Fewer patients underwent intubation after implementation (10.7% [23 of 215]), compared with before implementation (25.2% [64 of 254]) (P \u3c .01). Overall, 26.2% of patients died (24% before implementation vs 28.8% after implementation; P = .14). In patients without a do not resuscitate/do not intubate order prior to admission, mortality was 21.8% before implementation vs 21.9% after implementation. Overall, we found no significant increase in mortality following implementation of a noninvasive respiratory protocol that decreased intubations in patients with COVID-19

Variation in Early Management Practices in Moderate-to-Severe ARDS in the United States: The Severe ARDS: Generating Evidence Study.

BackgroundAlthough specific interventions previously demonstrated benefit in patients with ARDS, use of these interventions is inconsistent, and patient mortality remains high. The impact of variability in center management practices on ARDS mortality rates remains unknown.Research questionWhat is the impact of treatment variability on mortality in patients with moderate to severe ARDS in the United States?Study design and methodsWe conducted a multicenter, observational cohort study of mechanically ventilated adults with ARDS and Pao2 to Fio2 ratio of ≤ 150 with positive end-expiratory pressure of ≥ 5 cm H2O, who were admitted to 29 US centers between October 1, 2016, and April 30, 2017. The primary outcome was 28-day in-hospital mortality. Center variation in ventilator management, adjunctive therapy use, and mortality also were assessed.ResultsA total of 2,466 patients were enrolled. Median baseline Pao2 to Fio2 ratio was 105 (interquartile range, 78.0-129.0). In-hospital 28-day mortality was 40.7%. Initial adherence to lung protective ventilation (LPV; tidal volume, ≤ 6.5 mL/kg predicted body weight; plateau pressure, or when unavailable, peak inspiratory pressure, ≤ 30 mm H2O) was 31.4% and varied between centers (0%-65%), as did rates of adjunctive therapy use (27.1%-96.4%), methods used (neuromuscular blockade, prone positioning, systemic steroids, pulmonary vasodilators, and extracorporeal support), and mortality (16.7%-73.3%). Center standardized mortality ratios (SMRs), calculated using baseline patient-level characteristics to derive expected mortality rate, ranged from 0.33 to 1.98. Of the treatment-level factors explored, only center adherence to early LPV was correlated with SMR.InterpretationSubstantial center-to-center variability exists in ARDS management, suggesting that further opportunities for improving ARDS outcomes exist. Early adherence to LPV was associated with lower center mortality and may be a surrogate for overall quality of care processes. Future collaboration is needed to identify additional treatment-level factors influencing center-level outcomes.Trial registryClinicalTrials.gov; No.: NCT03021824; URL: www.clinicaltrials.gov

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88–1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. US National Institutes of Health and Operation Warp Spee

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p < 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p < 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p < 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease