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Axially chiral biaryls, as exemplified by 1,1′-bi-2-naphthol (BINOL), are key components of catalysts, natural products and medicines. These materials are synthesized conventionally in enantioenriched form through metal-mediated cross coupling, de novo construction of an aromatic ring, point-to-axial chirality transfer or an atropselective transformation of an existing biaryl. Here, we report a highly enantioselective organocatalytic method for the synthesis of atropisomeric biaryls by a cation-directed O -alkylation. Treatment of racemic 1-aryl-2-tetralones with a chiral quinidine-derived ammonium salt under basic conditions in the presence of an alkylating agent leads to atropselective O -alkylation with e.r. up to 98:2. Oxidation with DDQ gives access to C 2 -symmetric and non-symmetric BINOL derivatives without compromising e.r. We propose that the chiral ammonium counterion differentiates between rapidly equilibrating atropisomeric enolates, leading to highly atropselective O -alkylation. This dynamic kinetic resolution process offers a general approach to the synthesis of enantioenriched atropisomeric materials. A chiral ammonium salt mediates a dynamic kinetic resolution of racemic α-aryl ketones by atropselective O -alkylation. Oxidation with DDQ gives access to C 2 -symmetric and non-symmetric BINOL derivatives in high yields and with high enantioselectivity.

Objectives To assess the overall effect of vitamin D supplementation on risk of acute respiratory tract infection, and to identify factors modifying this effect.Design Systematic review and meta-analysis of individual participant data (IPD) from randomised controlled trials.Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomised Controlled Trials Number registry from inception to December 2015.Eligibility criteria for study selection Randomised, double blind, placebo controlled trials of supplementation with vitamin D3 or vitamin D2 of any duration were eligible for inclusion if they had been approved by a research ethics committee and if data on incidence of acute respiratory tract infection were collected prospectively and prespecified as an efficacy outcome.Results 25 eligible randomised controlled trials (total 11 321 participants, aged 0 to 95 years) were identified. IPD were obtained for 10 933 (96.6%) participants. Vitamin D supplementation reduced the risk of acute respiratory tract infection among all participants (adjusted odds ratio 0.88, 95% confidence interval 0.81 to 0.96; P for heterogeneity <0.001). In subgroup analysis, protective effects were seen in those receiving daily or weekly vitamin D without additional bolus doses (adjusted odds ratio 0.81, 0.72 to 0.91) but not in those receiving one or more bolus doses (adjusted odds ratio 0.97, 0.86 to 1.10; P for interaction=0.05). Among those receiving daily or weekly vitamin D, protective effects were stronger in those with baseline 25-hydroxyvitamin D levels <25 nmol/L (adjusted odds ratio 0.30, 0.17 to 0.53) than in those with baseline 25-hydroxyvitamin D levels ≥25 nmol/L (adjusted odds ratio 0.75, 0.60 to 0.95; P for interaction=0.006). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (adjusted odds ratio 0.98, 0.80 to 1.20, P=0.83). The body of evidence contributing to these analyses was assessed as being of high quality.Conclusions Vitamin D supplementation was safe and it protected against acute respiratory tract infection overall. Patients who were very vitamin D deficient and those not receiving bolus doses experienced the most benefit.Systematic review registration PROSPERO CRD42014013953.

AbstractObjectiveTo determine the effect of population level implementation of a test-and-treat approach to correction of suboptimal vitamin D status (25-hydroxyvitamin D (25(OH)D) <75 nmol/L) on risk of all cause acute respiratory tract infection and covid 19.DesignPhase 3 open label randomised controlled trial.SettingUnited Kingdom.Participants6200 people aged ≥16 years who were not taking vitamin D supplements at baseline.InterventionsOffer of a postal finger prick test of blood 25(OH)D concentration with provision of a six month supply of lower dose vitamin D (800 IU/day, n=1550) or higher dose vitamin D (3200 IU/day, n=1550) to those with blood 25(OH)D concentration <75 nmol/L, compared with no offer of testing or supplementation (n=3100). Follow-up was for six months.Main outcome measuresThe primary outcome was the proportion of participants with at least one swab test or doctor confirmed acute respiratory tract infection of any cause. A secondary outcome was the proportion of participants with swab test confirmed covid-19. Logistic regression was used to calculate odds ratios and associated 95% confidence intervals. The primary analysis was conducted by intention to treat.ResultsOf 3100 participants offered a vitamin D test, 2958 (95.4%) accepted and 2674 (86.3%) had 25(OH)D concentrations <75 nmol/L and received vitamin D supplements (n=1328 lower dose, n=1346 higher dose). Compared with 136/2949 (4.6%) participants in the no offer group, at least one acute respiratory tract infection of any cause occurred in 87/1515 (5.7%) in the lower dose group (odds ratio 1.26, 95% confidence interval 0.96 to 1.66) and 76/1515 (5.0%) in the higher dose group (1.09, 0.82 to 1.46). Compared with 78/2949 (2.6%) participants in the no offer group, 55/1515 (3.6%) developed covid-19 in the lower dose group (1.39, 0.98 to 1.97) and 45/1515 (3.0%) in the higher dose group (1.13, 0.78 to 1.63).ConclusionsAmong people aged 16 years and older with a high baseline prevalence of suboptimal vitamin D status, implementation of a population level test-and-treat approach to vitamin D supplementation was not associated with a reduction in risk of all cause acute respiratory tract infection or covid-19.Trial registrationClinicalTrials.gov NCT04579640.

ObjectivesTo adapt and apply a model for evaluating the functional benefits and cost efficiency of specialist inpatient rehabilitation to the Australian context, comparing functional outcomes and savings in the cost of ongoing care after acquired brain injury.DesignAn observational cohort analysis of prospectively collected clinical data from admission to discharge, with follow-up to 3 years.SettingA newly established state-wide inpatient postacute rehabilitation unit in Victoria, Australia for patients with moderate to severe acquired brain injury.ParticipantsThis study included consecutive patients admitted to the programme during its first 2 years’ operation (January 2016 to December 2017). Inclusion criteria consisted of complete outcome measures recorded on admission and discharge, total n=196, mean age 44.6 years (range 17–78), males:females 72:28%, aetiology:trauma n=124 (63%), stroke n=42 (21%), diffuse n=18 (9%) and other-mixed n=12 (7%).InterventionsSpecialist inpatient multidisciplinary rehabilitation.Outcome measuresDependency and care costs: Northwick Park Dependency Scale/Care Needs Assessment (NPCNA); Functional independence: UK Functional Assessment Measure. Cost efficiency: (a) Time is taken to offset rehabilitation costs by savings in NPCNA-estimated costs of ongoing care and (b) net projected lifetime savings.ResultsMedian length of stay 75 (IQR: 33.5–169.5) days, mean episode costs were $A147 044 (95% CI $A126 436, $A167 652). There was a significant reduction in dependency between admission and discharge on all measures (Holm-Bonferroni corrected p<0.001) which was sustained at follow-up in those traced at 1–3 years. Savings were greatest in the highest-dependency group. Estimated mean overall reduction in ‘weekly care costs’ was $A7206, offsetting the cost of rehabilitation within 5.53 months (95% CI 2.27, 8.78). Mean projected net lifetime savings were $A13.4 million (95% CI $A11.4, $A15.4) per patient.ConclusionsThis study provides proof of principle for use of the NPCNA cost-efficiency model outside the UK and yields further evidence that rehabilitation for patients with complex disabilities represents value for money. For every dollar spent on inpatient rehabilitation in this cohort, an estimated $A91 was saved in ongoing care costs.

Introduction and objectivesRandomised controlled trials of vitamin D to prevent acute respiratory infection have yielded mixed results. We conducted an individual patient data (IPD) meta-analysis to identify factors that may explain this heterogeneity.MethodsWe performed an IPD meta-analysis of 25 trials of vitamin D supplementation with incidence of acute respiratory infection as a pre-specified outcome (total 11,321 participants, aged 0 to 95 years). We used one-step logistic regression with random effects adjusting for age, sex, study duration and clustering by study. Pre-specified sub-group analyses were done to determine whether effects of vitamin D on risk of acute respiratory infection varied according to baseline 25-hydroxyvitamin D (25[OH]D) concentration or dosing regimen.ResultsIPD were obtained for 10,933/11,321 (96.6%) participants. Vitamin D supplementation reduced risk of acute respiratory infection among all participants (adjusted Odds Ratio [aOR] 0.88, 95% CI: 0.81 to 0.96, P = 0.003; P for heterogeneity < 0.001). Sub-group analysis revealed a strong protective effect among individuals with baseline 25(OH) D < 25 nmol/L (aOR 0.62, 95% CI: 0.45 to 0.83, P = 0.002), not seen among those with higher levels (aOR 0.91, 95% CI: 0.78 to 1.05; Pinteraction = 0.01). A protective effect was also seen in individuals receiving daily or weekly vitamin D without additional bolus doses (aOR 0.81, 95% CI: 0.72 to 0.91, P < 0.001), but not in those receiving one or more bolus doses (aOR 0.97, 95% CI: 0.86 to 1.10, Pinteraction = 0.05). Vitamin D did not influence the proportion of participants experiencing at least one serious adverse event (aOR 0.98, 95% CI: 0.80 to 1.20, P = 0.83). The body of evidence contributing to these analyses was assessed as being of high quality.ConclusionsVitamin D supplementation was safe, and it protected against acute respiratory infection overall. Very deficient individuals and those not receiving bolus doses experienced the most benefit.