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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

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

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Influência das gonadotrofinas na regulação da maturação nuclear de oócitos eqüinos Influence of gonadotropins on nuclear maturation of equine oocytes

A maturação in vitro, fecundação e as técnicas de cultivo de embriões na espécie eqüina são extremamente importantes e necessárias para se examinar as causas de repetição de cio, redução de concepção em éguas velhas e também para a preservação da espécie eqüina. Para avaliar o efeito das gonadotrofinas na regulação da maturação nuclear de oócitos eqüinos, folículos com diâmetro entre 5 a 20mm foram aspirados de 551 ovários provenientes de matadouro obtendo-se 408 oócitos aptos para cultivo. Após a aspiração, os oócitos foram avaliados no próprio líquido folicular quanto a sua integridade e distribuídos nos diferentes tratamentos. No Tratamento I (T1) - grupo controle - os oócitos (n=92) foram cultivados em TCM-199 modificado (mod.), com 25mM de HEPES, 2,2mg/ml de bicarbonato de sódio, 1 mi g/ml 17-beta estradiol, 250mi M de piruvato de sódio e 0,4% de albumina sérica bovina. No tratamento 2 (T2), os oócitos (n= 108) foram cultivados no mesmo meio TC M-199 mod. acrescido de lug/ml de hormônio luteinizante suíno (LHs). No Tratamento 3 (T3), os oócitos (n=102) também foram cultivados em TCM-199 mod. porém com 0,5mi g/ml de hormônio folículo estimulante suíno (FSHs) e no Tratamento 4 (T4) os oócitos (n= 106) foram cultivados com 1mi g/ml de LHs e 0,5mi g/ml, de FSHs. Os oócitos dos quatros tratamentos foram cultivados em estufa a 39&deg;C com 5% de CO2 , e 95% de umidade relativa no ar, durante 24 h. Após este período, as células do Cumulus oophorus foram removidas e os oócitos fixados em solução de ácido acético glacial-metanol (1:3) em placas de Petri 10 x 35mm por 24h sendo posteriormente corados com aceto-orceína. O percentual de oócitos em telófase I / metáfase II foi de 55,6% (59/106) para o T4 (FSHs/LHs) e de 53,9% (55/102) para o T3 (FSHs), os quais não diferiram significativamente. No entanto, estes percentuais foram significativamente superiores (p<0,05) aos observados no Tratamento 1 (22,8%; 21/92) e no Tratamento 2 (32,4%; 35/108). Estes resultados demonstram que o FSHs estimula a maturação nuclear in vitro pois o percentual de oócitos maturos aumentou quando os mesmos foram tratados com FSHs/LHs ou com FSHs somente. O LHs isoladamente, nas concentrações utilizadas, não estimula a maturação nuclear em oócitos eqüinos.<br>In vitro maturation, in vitro fertilization and embryo culture in equine are extremely important and necessaries for examining reproductive problems in the mare. The aim of the present study was to determine the effect of gonadotropins on nuclear maturation of equine oocytes. Follicles-smaller than 20mm were aspirated from 551 ovaries obtained at slaughterhouse, 408 oocytes suitable for culture being recovered. After aspiration, oocytes were evaluated in follicular fluid and distributed in four treatments. In the first treatment, control group, oocytes (n=92) were cultured for 24 hours in modifled TCM-199 with 25mM HEPES, 2.2mg/ml sodium bicarbonate, 1mug/ml 17 beta estradiol, 250mu M piruvic acid and 0.4% bovino serum albumin. In the second treatment, oocytes (n=108) were cultured in modified TC M-199 plus 1mu g/ml porcine LH. In the third treatment, 102 oocytes were cultured in modifled TCM-199 with the addition of 0.5mu g/ml porcino FSH and on the fourth treatment oocytes (n=106) were cultured in modifled TC M-199 with 1mu g/ml porcine LH and 0.5mug/ml porcine FSH. All four groups were cultured for 24h in an atmosphere with 5% CO2 at 39&deg;C. Afterwards, cumulus cells were removed and oocytes were fixed in acetic acid-methanol (1:3) solution for 24h and stained with aceto-orcein. A significantly greater percentage of MII was observed in oocytes cultured with FSH/LH 59/106 (55.6%) and with FSH 55/102 (53,9%) than in the other groups. When oocytes were cultured in the presence of porcine LH, only 35/108 (32,4%) reached the MII stage, a similar percentage being obtained with the control group. This results demonstrate that equine oocytes cultured in vitro are stimulated to reach metaphase II when they are cultured in the presence of porcine FSH alone or added with porcine LH. Otherwise, porcine LH alone does not stimulate nuclear maturation beyond that obtained with oocytes cultured in the absence of gonadotropins