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

Ploidy determination in Musa germplasm using pollen and chloroplast characteristics

We attempted to determine ploidy level in the gametophyte and the sporophyte of Musa using pollen and chloroplast characteristics, respectively. In the gametophyte, interploidy differences accounted for 63.8 % of the genetic variance for pollen diameter and 87.5% for pollen stainability, the remainder being attributable to intraploidy differences among clones. While pollen count and stainability effectively separated triploid accessions from diploids or tetraploids, they did not discriminate between diploids and tetraploids. In the sporophyte, the relative contributions of interploidy and intraploidy differences to genetic variation in the number of chloroplasts in stomatal guard cells were 70.8% and 29.2%, respectively. Although pollen diameter and chloroplast number increased with ploidy, the use of the sporophytic parameter appears to provide a more satisfactory means of estimating ploidy status in Musa

Comparative analysis of phenotypic and genoytpic diversity among plantain landraces (Musa spp., AAB group)

Genetic diversity amongst 76 plantain landraces has been studied using RAPD analysis at two levels of intensity and compared with groupings based on phenotypic indices and morphotype. There was a good correlation (R2=0.78) between estimates of genetic diversity based on 76 RAPD bands and 164 RAPD bands. However, there was a poor correlation between RAPD-based estimates of genetic diversity and a phenotypic index based on agronomic characters. There was also a poor correlation between RAPD analyses and morphotype group (based on bunch type and stature). These results suggest that the traditional designations of plantain landraces based on morphotype do not provide a true reflection of overall genetic divergence. Similarly, classification systems using phenotypic indices based on agronomic characters may not provide accurate taxonomic differentiation. The level of genetic divergence within morphogroups based on bunch type suggests that True Horn plantains are derived from False Horn plantains which in turn are derived from French plantains. Genetic divergence was found to be generally quite low within the plantain landrace genepool, which is consistent with the proposed evolution of this germplasm through somatic mutation of a relatively small number of introductions. However, putative synonyms/duplicates have been shown to be genetically distinct. In contrast, a group of 12 landraces have been identified that are highly distinct from one another (showing 20–35% dissimilarity). Fertile members of this group may be useful for generating genetically diverse 2x and 4x breeding populations that can be used in breeding secondary triploid hybrid plantain varieties

Comparison of DNA marker and pedigreebased methods of genetic analysis in plantain and banana (Musa spp.) clones; II: predicting hybrid performance

Pedigree and DNA marker-based methods were used to predict the performance of triploid progeny from tetraploid-diploid crosses, based on parental heterozygosity, genetic relatedness, and expected contribution to their progeny. There was no significant correlation between parental and progeny performance. Prediction of progeny bunch weight was best when based on genealogical distance and equal parental contribution. Predicted fruit size was most accurate when DNA marker data were used and the assumption of an unequal parental contribution was made. Consideration of parental heterozygosity produced larger residuals for all traits. No statistically significant differences were found between the mean residuals obtained under the assumption of an equal vs an unequal contribution of the 4x and 2x genotypes to their 3x progeny, regardless of the method used to estimate genetic relationships

Comparison of DNA marker and pedigree-based methods of genetic analysis of plantain and banana (Musa spp.) clones; I: estimation of genetic relationships

Traditional approaches to the breeding of Musa crops are highly demanding in terms of both time and space. However, the application of molecular genetic analysis may dramatically improve breeding efficiency. The objectives of the present study were to compare pedigree and DNA marker methods of estimating genetic relationships across and within generations among diploid, triploid and tetraploid accessions of plantain and banana. Pedigree-based estimates of parent-offspring relationships were substantially different from those obtained from molecular data. The marker-based contribution of triploid maternal accessions to their diploid offspring was greater than expected from published models of meiosis in Musa. Conversely, the maternal contribution to tetraploid offspring was less than expected. Pedigree-based similarity was smallest for clones with no common parent and greatest for full-sibs. There was no association between marker-based similarity and pedigree relationships. While DNA markers may provide a more accurate description of genetic relatedness, this study suggests that pedigree-based analysis may prove useful for the selection of prospective parental combinations in Musa breeding

Perspectives on the application of biotechnology to assist the genetic enhancement of plantain and banana (Musa spp.)

Bananas and plantains (Musa spp.) are the most important tropical fruit crops. They form an integral component of the farming systems in the humid agroecological zones of the tropics. A broad array of applied cell and molecular techniques are increasingly being used worldwide to facilitate and enhance the handling and improvement of plantain and banana germplasm. Tissue culture is used for germplasm exchange, conservation and rapid multiplication, while in vitro seed germination (based on embryo culture or rescue) plays a critical role in generating hybrid plants. DNA marker systems have been developed in Musa to assist germplasm management, selection within the breeding pool or gene introgression from wild species, and for disease diagnosis. Likewise, genetic transformation using the particle gun method or through Agrobacterium co-cultivation shows potential for the genetic betterment of the crop. This article discusses the applications of biotechnology for the genetic enhancement of banana and plantain. It highlights current advances by research teams across the world and reviews progress in molecular breeding of Musa by the International Institute of Tropical Agriculture and its collaborators