SNP associations and genetic-parameter estimation for nose and hoof pigmentation in Corriedale sheep

Published Online 7/6/23 OnlinePublContext. Quantity and quality of both meat and wool are important for selection programs of the dual-purpose Corriedale sheep. In Corriedales, black pigmentation of nose skin and hooves is preferred as part of the breed standard. However, within the breed, pigmentation can vary from none to complete pigmentation. Aims. The aim was to discover single-nucleotide polymorphisms (SNPs) and genes associated with nose and hoof pigmentation and to estimate genetic parameters of nose and hoof pigmentation, wool traits and meat traits. Methods. The phenotype and genotype data on Corriedale lambs (n = 764) produced from 44 sires (12 studs) and 300 ewes in 2017–2019 were used in this study. Lambs were slaughtered at 6–7 months of age. Nose pigmentation and hoof pigmentation were scored on a five-point scale, where no pigmentation was scored 0 and complete pigmentation was scored 5. Wool-and meat-quality traits were measured, including greasy fleece weight, fibre diameter, weaning weight, hot standard carcass weight and intramuscular fat percentage. The lambs were genotyped with the GGPOvine50K SNP chip. A genome-wide association study (GWAS) was conducted. Genetic parameters and bivariate analyses were estimated using ASReml-R. Results. The lambs had a mean nose-pigmentation score of 3.69 and hoof-pigmentation score of 4.12. The nose pigmentation (h2 = 0.58) and hoof pigmentation (h2 = 0.51) were highly heritable and highly correlated (rG = 0.73). The GWAS identified a genome-wide significant SNP (OAR19_33278780.1) associated with nose pigmentation (q-value = 0.04). This SNP is positioned in a known pigmentation gene, melanocyte-inducing transcription factor (MITF ). The same SNP was the sixth-most associated SNP for hoof pigmentation but did not reach significance level. OAR19_33278780.1 also had a significant effect on back conformation and weaning weight. Conclusions. The results of these analyses have provided information and an understanding of the genetics for pigmentation of nose and hooves in Corriedale sheep. Implications. Nose and hoof pigmentation are highly genetically correlated with each other, but with no negative effects on production traits.J. E. Aldersey, M. S. Khatkar, P. J. Blackwood, C. E. Blackwood, J. M. Pitchford, H. Gordon, S. C. Welsh and W. S. Pitchfor

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

E. coli nitroreductase/CB1954: In vitro studies into a potential system for feline cancer gene therapy

Investigations were carried out to identify a suitable prodrug activating system for feline gene therapy with the eventual aim of treating feline thyroid disease and feline neoplasia. The E. coli nitroreductase (NTR)/CB1954 prodrug activating system was evaluated in vitro in feline cells by transient transfection with a nitroreductase expressing construct and subsequent treatment with the prodrug CB1954. The feline cells successfully expressed E. coli nitroreductase, which was able to activate the prodrug CB1954 resulting in cytotoxicity to both transformed and adjacent cells (a bystander effect) in vitro. In the absence of nitroreductase, CB1954 was non-toxic to feline cells. In addition, the nitroreductase gene was expressed in rat thyroid cells under the control of the cell type specific feline thyroglobulin promoter. This paper demonstrates that the E. coli nitroreductase/CB1954 system may be suitable for in vivo feline gene therapy, and further investigations are warranted

E. coli nitroreductase/CB1954: In vitro studies into a potential system for feline cancer gene therapy

Investigations were carried out to identify a suitable prodrug activating system for feline gene therapy with the eventual aim of treating feline thyroid disease and feline neoplasia. The E. coli nitroreductase (NTR)/CB1954 prodrug activating system was evaluated in vitro in feline cells by transient transfection with a nitroreductase expressing construct and subsequent treatment with the prodrug CB1954. The feline cells successfully expressed E. coli nitroreductase, which was able to activate the prodrug CB1954 resulting in cytotoxicity to both transformed and adjacent cells (a bystander effect) in vitro. In the absence of nitroreductase, CB1954 was non-toxic to feline cells. In addition, the nitroreductase gene was expressed in rat thyroid cells under the control of the cell type specific feline thyroglobulin promoter. This paper demonstrates that the E. coli nitroreductase/CB1954 system may be suitable for in vivo feline gene therapy, and further investigations are warranted

Correlation of pretreatment polarographically measured oxygen pressures with quantified contrast-enhanced power doppler ultrasonography in spontaneous canine tumors and their impact on outcome after radiation therapy

Purpose: To evaluate the use of noninvasive quantified contrast-enhanced power Doppler ultrasonography as a surrogate in the estimation of tumor hypoxia measured by invasive pO2 histography in canine tumors. Material and Methods: Data of pretreatment tumor oxygenation status, tumor vascularity and blood volume, and tumor response after radiation therapy was collected in 48 spontaneous malignant oral tumors (Table 1). Tumor oxygenation status was correlated to vascularity and blood volume, and influences on outcome after treatment were analyzed. Results: Although vascularity and blood volume correlated moderately with median pO2 (r = 0.51 and 0.61; p = 0.001 and < 0.0001) and percentage of pO2 readings ≤ 2.5, 5, and 10 mmHg (r = –0.37 to –0.42; p < 0.01–0.03) for all tumors, they did not correlate within the different histology groups (p = 0.06–0.9). For all tumors, pretreatment oxygenation status, vascularity and blood volume were not found to be of prognostic value (Tables 2 and 3). Conclusion: These analyses show that quantified contrast-enhanced power Doppler ultrasonography does not represent a noninvasive indirect method to assess tumor hypoxia measured by invasive pO2 histography. Both technologies were nonprognostic indicators in spontaneous malignant canine oral tumors