Spatio-temporal detachment of homogeneous electron transfer in controlling selectivity in mediated organic electrosynthesis.

In electrosynthesis, electron transfer (ET) mediators are normally chosen such that they are more easily reduced (or oxidised) than the substrate for cathodic (or anodic) processes; setting the electrode potential to the mediator therefore ensures selective heterogeneous ET with the mediator at the electrode, rather than the substrate. The current work investigates the opposite, and counter intuitive, situation for a successful mediated electroreductive process where the mediator (phenanthrene) has a reduction potential that is negative to that of the substrate, and the cathode potential is set negative to both (Eele < EM < Es). Simulations reveal a complex interplay between mass transport, the relative concentrations of the mediator and substrate as well as the heterogeneous and homogeneous rate constants for multiple steps, which under suitable conditions, leads to separation of the homogeneous chemistry in a reaction layer detached from the electrode. Reaction layer detachment is a spatio-temporal effect arising due to opposing fluxes of the mediator radical anion M˙- and the substrate 1, which ultimately prevents 1 from reaching the electrode, thereby affording a different reaction pathway. Simulations representative of unstirred batch (1D) and flow (2D) electrolysis are presented, which qualitatively reproduce the experimental selectivity outcomes for mediated and unmediated electroreductive cyclisation of aryl iodide 1. The potential to use highly reducing homogeneous ET agents, possessing reduction potentials beyond those of the substrates, offers exciting opportunities in mediated electrosynthesis.

Effects of BNT162b2 mRNA vaccine on COVID-19 infection and hospitalisation amongst older people: matched case control study for England.

BACKGROUND: The BNT162b2 mRNA vaccine has been shown to be effective at preventing serious COVID-19 events in clinical trials. There is less evidence on effectiveness in real-world settings, especially for older people. Here, we aimed to estimate vaccine effectiveness in the context of the rapid NHS mass-vaccination programme in England, exploiting age-based vaccination eligibility thresholds to minimise and correct for selection bias. METHODS: We studied 170,226 individuals between the ages of 80 and 83 years from community settings outside care homes who received one dose of BNT162b2 mRNA between the 15 and 20 December 2020 and were scheduled a second dose 21 days later. We matched these vaccine recipients to slightly younger (aged 76-79 years) persons not yet eligible to receive the vaccine on gender, area of residence, area deprivation, health status, living arrangements, acute illness, and history of seasonal flu vaccination. We compared their rates of COVID-19 positivity and hospitalisation in the subsequent 45 days. We adjusted for the increasing concentration of COVID-19 positivity in the control population caused by the requirement to have no COVID-19 symptoms prior to vaccination. RESULTS: Emergency hospital admissions were 51.0% (95% confidence interval 19.9 to 69.5%) lower and positive COVID-19 tests were 55.2% (40.8 to 66.8%) lower for vaccinated individuals compared to matched controls 21 to 27 days after first vaccination. Emergency admissions were 75.6% (52.8 to 87.6%) lower, and positive COVID-19 tests were 70.1% (55.1 to 80.1%) lower 35 to 41 days after first vaccination when 79% of participants had received a second dose within 26 days of their first dose. CONCLUSIONS: Receipt of the BNT162b2 mRNA vaccine is effective at reducing COVID-19 hospitalisations and infections. The nationwide vaccination of older adults in England with the BNT162b2 mRNA vaccine reduced the burden of COVID-19.

One-Pot Substitution of Aliphatic Alcohols Mediated by Sulfuryl Fluoride.

The Mitsunobu reaction is a powerful transformation for the one-pot activation and substitution of aliphatic alcohols. Significant efforts have focused on modifying the classic conditions to overcome problems associated with purification from phosphine-based byproducts. Herein, we report a phosphine free method for alcohol activation and substitution that is mediated by sulfuryl fluoride. This new method is effective for a wide range of primary alcohols using phthalimide, di-tert-butyl-iminodicarboxylate, and aromatic thiol nucleophiles in 74 % average yield. Activated carbon nucleophiles and a deactivated phenol were also effective for this reaction in good yields. Secondary alcohols were also successful substrates using aryl thiols, affording the corresponding sulfides in 56 % average yield with enantiomeric ratios up to 99:1. This new protocol has a distinct synthetic advantage over many existing phosphine-based methods as the byproducts are readily separable. This feature was exploited in several examples that did not require chromatography for purification. Furthermore, the mild reaction conditions enabled further in situ derivatization for the one-pot conversion of alcohols to amines or sulfones. This method also provides a boarder nucleophile scope compared to existing phosphine-free methods.

Inequalities in suicide rates associated with deprivation in England from 2004 to 2019.

BACKGROUND: Although addressing inequality has been a public and political priority for decades, inequalities in health, wealth, and other societal domains persist in England. In Ireland, rates of suicide are twice as high in the most deprived decile of society compared with the least deprived. Trends in the association between deprivation and suicide in England are unclear. AIM: To describe the relationship between deprivation and suicide in England in 2019 and analyse trends in this relationship over time. METHOD: Data on rate of suicide and Index of Multiple Deprivation (IMD) for each local authority in England for 2018 and 2004 were obtained from the Office for National Statistics' publicly available databases. The mean suicide rate for each quintile of deprivation was calculated, and means compared using ANOVA. The correlation coefficients between IMD and suicide rate were calculated for both 2004 and 2019. Steiger's test was used to compare coefficients over time. RESULTS: In 2019, the suicide rate in the least deprived quintile was 8.7 per 100 000 person-years, compared with 8.3 in 2004. This increased across each quintile to 11.1 suicides per 100 000 person-years in the most deprived quintile in 2019 (ANOVA: P<0.001), and to 11.7 in 2004 (ANOVA: P<0.001). The correlation coefficient between IMD and suicide rate in 2004 was 0.43, compared with 0.33 in 2019. Steiger's test demonstrated no significant difference between coefficients over time (P = 0.16). CONCLUSION: Suicide is associated with deprivation in England. Despite significant research and policy effort, there has been no improvement in this association between 2004 and 2019.

Blood glucose and insulin concentrations after alpha-2-agonists administration in horses with and without insulin dysregulation.

BACKGROUND: In metabolically stable horses, alpha-2-agonists suppress insulin secretion with transient hyperglycemia and rebound hyperinsulinemia. In horses with insulin dysregulation (ID), the effect of alpha-2-agonists has not been investigated; however, both the alpha-2-agonist-induced suppression of insulin secretion and rebound hyperinsulinemia could have clinical relevance. HYPOTHESIS/OBJECTIVES: In horses with ID, alpha-2-agonists will alter insulin and glucose dynamics. ANIMALS: Seven horses with ID and 7 control horses. METHODS: In this randomized crossover study, xylazine hydrochloride (1.1 mg/kg) or detomidine hydrochloride (30 µg/kg) were administered IV, and blood was collected for glucose and insulin concentrations at 0, 15, 30, 45, 60, 90, 120, 150, 180, and 300 minutes after administration. Horses received each drug in a random order with a 24-hour washout period between drugs. Percent change in glucose and insulin concentrations was compared between groups, drugs, and over time with P < .05 considered significant. RESULTS: A significant time-dependent effect of both alpha-2-agonists on glucose and insulin concentrations in control and ID horses was identified (P = .01 for all comparisons). There was no significant effect of sedative selection and endocrine status on blood glucose concentration in either group; however, in ID horses, xylazine administration resulted in severe rebound hyperinsulinemia whereas detomidine administration did not (P = .02). CONCLUSIONS AND CLINICAL IMPORTANCE: Alpha-2-agonists have a significant effect on glucose and insulin concentrations in horses. In ID horses, detomidine could minimize hyperinsulinemia when compared to xylazine.

Immunoreactive insulin stability in horses at risk of insulin dysregulation.

BACKGROUND: Diseases associated with insulin dysregulation (ID), such as equine metabolic syndrome and pituitary pars intermedia dysfunction, are of interest to practitioners because of their association with laminitis. Accurate insulin concentration assessment is critical in diagnosing and managing these diseases. HYPOTHESIS/OBJECTIVES: To determine the effect of time, temperature, and collection tube type on insulin concentrations in horses at risk of ID. ANIMALS: Eight adult horses with body condition score >6/9. METHODS: In this prospective study, subjects underwent an infeed oral glucose test 2 hours before blood collection. Blood samples were divided into ethylenediaminetetraacetic acid, heparinized, or serum tubes and stored at 4 or 20°C. Tubes were centrifuged and analyzed for insulin by a chemiluminescent assay over 8 days. Changes in insulin concentrations were compared with a linear mixed effects model. RESULTS: An overall effect of time, tube type and temperature was identified (P = .01, P = 0.001, and P = 0.001, respectively). Serum and heparinized samples had similar concentrations for 3 days at 20°C and 8 days at 4°C; however, after 3 days at 20°C, heparinized samples had significantly higher insulin concentrations (P = .004, P = .03, and P = .03 on consecutive days). Ethylenediaminetetraacetic acid samples had significantly lower insulin concentrations regardless of time and temperature (P = .001 for all comparisons). CONCLUSIONS AND CLINICAL IMPORTANCE: These results suggest an ideal protocol to determine insulin concentrations involves using serum or heparinized samples with analysis occurring within 3 days at 20°C or 8 days at 4°C.