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

Chlorinated Dehydrocurvularins and Alterperylenepoxide A from <i>Alternaria</i> sp. AST0039, a Fungal Endophyte of <i>Astragalus lentiginosus</i>

Investigation of <i>Alternaria</i> sp. AST0039, an endophytic fungus obtained from the leaf tissue of <i>Astragalus lentiginosus</i>, led to the isolation of (−)-(10<i>E</i>,15<i>S</i>)-4,6-dichloro-10­(11)-dehydrocurvularin (<b>1</b>), (−)-(10<i>E</i>,15<i>S</i>)-6-chloro-10­(11)-dehydrocurvularin (<b>2</b>), (−)-(10<i>E</i>,15<i>S</i>)-10­(11)-dehydrocurvularin (<b>3</b>), and alterperylenepoxide A (<b>4</b>) together with scytalone and α-acetylorcinol. Structures of <b>1</b> and <b>4</b> were established from their spectroscopic data, and the relative configuration of <b>4</b> was determined with the help of nuclear Overhauser effect difference data. All metabolites were evaluated for their cytotoxic activity and ability to induce heat-shock and unfolded protein responses. Compounds <b>2</b> and <b>3</b> exhibited cytotoxicity to all five cancer cell lines tested and increased the level of the pro-apoptotic transcription factor CHOP, but only <b>3</b> induced the heat-shock response and caused a strong unfolded protein response

Geopyxins A–E, <i>ent</i>-Kaurane Diterpenoids from Endolichenic Fungal Strains <i>Geopyxis</i> aff. <i>majalis</i> and <i>Geopyxis</i> sp. AZ0066: Structure–Activity Relationships of Geopyxins and Their Analogues

Four new <i>ent</i>-kaurane diterpenoids, geopyxins A–D (<b>1</b>–<b>4</b>), were isolated from <i>Geopyxis</i> aff. <i>majalis</i>, a fungus occurring in the lichen <i>Pseudevernia intensa</i>, whereas <i>Geopyxis</i> sp. AZ0066 inhabiting the same host afforded two new <i>ent</i>-kaurane diterpenoids, geopyxins E and F (<b>5</b> and <b>6</b>), together with <b>1</b> and <b>3</b>. The structures of <b>1</b>–<b>6</b> were established on the basis of their spectroscopic data, while the absolute configurations were assigned using modified Mosher’s ester method. Methylation of <b>1</b>–<b>3</b>, <b>5</b>, and <b>6</b> gave their corresponding methyl esters <b>7</b>–<b>11</b>. On acetylation, <b>1</b> and <b>7</b> yielded their corresponding monoacetates <b>12</b> and <b>14</b> and diacetates <b>13</b> and <b>15</b>. All compounds were evaluated for their cytotoxic and heat-shock induction activities. Compounds <b>2</b>, <b>7</b>–<b>10</b>, <b>12</b>, <b>14</b>, and <b>15</b> showed cytotoxic activity in the low micromolar range against all five cancer cell lines tested, but only compounds <b>7</b>–<b>9</b>, <b>14</b>, and <b>15</b> were found to activate the heat-shock response at similar concentrations. From a preliminary structure–activity perspective, the electrophilic α,β-unsaturated ketone carbonyl motif present in all compounds except <b>6</b> and <b>11</b> was found to be necessary but not sufficient for both cytotoxicity and heat-shock activation