Mechanisms of photoprotection by 20-hydroxyvitamin D3, a naturally occurring 1a25-dihydroxyvitamin D3 analogue

The mechanism of the photoprotection byve effect of the active metabolite of vitamin D3, 1, 25 dihydroxyvitamin D (1,25(OH)2D) against UVR-induced DNA damage and immunosuppression is not completely understood. It has been shown that vitamin D-like compounds and analogues are similarly photoprotective without inducing hypercalcaemic toxicity and that photoprotection from UVR is affected by gender. The aim of the study was to test whether 20(OH)D, a CYP11A1biological metabolite of 1,25(OH)2D and tetrahydrocurcumin (THC), a vitamin D like compound, would reduce UVR-induced DNA damage in primary human keratinocytes and Skh:Hr1 mice, and inflammatory oedema and immune suppression in Skh:Hr1 mice. The mechanism of photoprotection by 1,25(OH)2D and 20(OH)D was tested using inhibitors of the Wnt signalling pathway (IWR-1) and chloride channels (DIDS). The influence of gender on photoprotection against DNA damage and immunosuppression was assessed using Skh:Hr1 mice and oestrogen receptor- knock out (ERβKO) mice. 20(OH)D and THC were as photoprotective as 1,25(OH)2D against UVR-induced DNA damage in vitro and in vivo 3 hours following UVR exposure. In primary human keratinocytes, DIDS reversed the protective effect of 1,25(OH)2D and 20(OH)D against UVR-induced DNA damage. IWR-1 alone was protective against UVR-induced DNA damage, and did not cause reversal of photoprotection by 1,25(OH)2D and 20(OH)D. 20(OH)D was as effective as 1,25(OH)2D in reducing UVR-induced skin inflammation and immunosuppression in Skh:Hr1 mice. UVR-induced immunosuppression and DNA damage was greater in males than females. ERβKO mice were more susceptible to UVR-induced immunosuppression than wild type controls and the photoprotective effect of 1,25(OH)2D and 20(OH)D was reduced. This study showed that that 20(OH)D is photoprotective against UVR-induced DNA damage, inflammation and immunosuppression in a non-genomic manner, and demonstrated a potential interaction between ERβ and the actions of VDR ligands in photoprotection

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

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. 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-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. 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%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated 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 (median 10 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, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or 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 other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Genomic reconstruction of the SARS-CoV-2 epidemic in England

AbstractThe evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.</jats:p