A preliminary audit of medical and aid provision in English Rugby union clubs:compliance with Regulation 9

BackgroundGoverning bodies are largely responsible for the monitoring and management of risks associated with a safe playing environment, yet adherence to regulations is currently unknown. The aim of this study was to investigate and evaluate the current status of medical personnel, facilities, and equipment in Rugby Union clubs at regional level in England.MethodsA nationwide cross-sectional survey of 242 registered clubs was undertaken, where clubs were surveyed online on their current medical personnel, facilities, and equipment provision, according to regulation 9 of the Rugby Football Union (RFU).ResultsOverall, 91 (45. 04%) surveys were returned from the successfully contacted recipients. Of the completed responses, only 23.61% (n = 17) were found to be compliant with regulations. Furthermore, 30.56% (n = 22) of clubs were unsure if their medical personnel had required qualifications; thus, compliance could not be determined. There was a significant correlation (p = −0.029, r = 0.295) between club level and numbers of practitioners. There was no significant correlation indicated between the number of practitioners/number of teams and number of practitioners/number of players. There were significant correlations found between club level and equipment score (p = 0.003, r = −0.410), club level and automated external defibrillator (AED) access (p = 0.002, r = −0.352) and practitioner level and AED access (p = 0.0001, r = 0.404). Follow-up, thematic analysis highlighted widespread club concern around funding/cost, awareness, availability of practitioners and AED training.ConclusionThe proportion of clubs not adhering overall compliance with Regulation 9 of the RFU is concerning for player welfare, and an overhaul, nationally, is required

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

¹H NMR (400 MHz, CDCl₃) (top) and ¹³C NMR (100 MHz, CDCl₃) (bottom) spectra of 4,6-dimethoxypyridin-3-yl)boronic acid (30).

1H NMR (400 MHz, CDCl3) (top) and 13C NMR (100 MHz, CDCl3) (bottom) spectra of 4,6-dimethoxypyridin-3-yl)boronic acid (30).</p

S18 Fig -

Example fluorescence over time graph (A) and IC50 (B) for AnCoA4 following 30 minute preincubation and example fluorescence over time graph (C) and IC50 (D) for AnCoA4 following 90 minute preincubation. (TIF)</p

¹H NMR (400 MHz, CDCl₃) (top) and ¹³C NMR (100 MHz, CDCl₃) (bottom) spectra of [4-(benzyloxy)-2-(trifluoromethyl)phenyl]methanol (19).

1H NMR (400 MHz, CDCl3) (top) and 13C NMR (100 MHz, CDCl3) (bottom) spectra of [4-(benzyloxy)-2-(trifluoromethyl)phenyl]methanol (19).</p

Example fluorescence versus time graphs for each of the inhibitors studied at the concentrations used to generate the dose response curves (Fig 3).

ΔF340/380 refers to the ratio of fluorescence emission following excitation at 340 nm and 380 nm. Data has been baseline corrected to zero. Ca2+ addback is initiated at t = 30 seconds. Data points are presented as mean ± SEM (n = 3).</p

A time series schematic for the Ca²⁺ addback protocol.

A time series schematic for the Ca2+ addback protocol.</p

¹H NMR (400 MHz, DMSO-D₆) (top) and ¹³C NMR (100 MHz, DMSO-D₆) (bottom) spectra of 2,6-difluoro-<i>N</i>-(1<i>H</i>-pyrazol-3-yl)benzamide (21).

1H NMR (400 MHz, DMSO-D6) (top) and 13C NMR (100 MHz, DMSO-D6) (bottom) spectra of 2,6-difluoro-N-(1H-pyrazol-3-yl)benzamide (21).</p

Chemical structures of the small molecule SOCE inhibitors examined in this study and their common names.

Chemical structures of the small molecule SOCE inhibitors examined in this study and their common names.</p

Synthetic route to 7-azaindole (12).

Calcium (Ca2+) is a key second messenger in eukaryotes, with store-operated Ca2+ entry (SOCE) being the main source of Ca2+ influx into non-excitable cells. ORAI1 is a highly Ca2+-selective plasma membrane channel that encodes SOCE. It is ubiquitously expressed in mammals and has been implicated in numerous diseases, including cardiovascular disease and cancer. A number of small molecules have been identified as inhibitors of SOCE with a variety of potential therapeutic uses proposed and validated in vitro and in vivo. These encompass both nonselective Ca2+ channel inhibitors and targeted selective inhibitors of SOCE. Inhibition of SOCE can be quantified both directly and indirectly with a variety of assay setups, making an accurate comparison of the activity of different SOCE inhibitors challenging. We have used a fluorescence based Ca2+ addback assay in native HEK293 cells to generate dose-response data for many published SOCE inhibitors. We were able to directly compare potency. Most compounds were validated with only minor and expected variations in potency, but some were not. This could be due to differences in assay setup relating to the mechanism of action of the inhibitors and highlights the value of a singular approach to compare these compounds, as well as the general need for biorthogonal validation of novel bioactive compounds. The compounds observed to be the most potent against SOCE in our study were: 7-azaindole 14d (12), JPIII (17), Synta-66 (6), Pyr 3 (5), GSK5503A (8), CM4620 (14) and RO2959 (7). These represent the most promising candidates for future development of SOCE inhibitors for therapeutic use.</div