The allopurinol metabolite, oxypurinol, drives oligoclonal expansions of drug‐reactive T cells in resolved hypersensitivity cases and drug‐naïve healthy donors

Allopurinol (ALP) is a successful drug used in the treatment of gout. However, this drug has been implicated in hypersensitivity reactions that can cause severe to life‐threatening reactions such as Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Individuals who carry the human leukocyte antigen (HLA)‐B*58:01 allotype are at higher risk of experiencing a hypersensitivity reaction (odds ratios ranging from 5.62 to 580.3 for mild to severe reactions, respectively). In addition to the parent drug, the metabolite oxypurinol (OXP) is implicated in triggering T cell‐mediated immunopathology via a labile interaction with HLA‐B*58:01. To date, there has been limited information regarding the T‐cell receptor (TCR) repertoire usage of reactive T cells in patients with ALP‐induced SJS or TEN and, in particular, there are no reports examining paired αβTCRs. Here, using in vitro drug‐treated PBMCs isolated from both resolved ALP‐induced SJS/TEN cases and drug‐naïve healthy donors, we show that OXP is the driver of CD8+ T cell‐mediated responses and that drug‐exposed memory T cells can exhibit a proinflammatory immunophenotype similar to T cells described during active disease. Furthermore, this response supported the pharmacological interaction with immune receptors (p‐i) concept by showcasing (i) the labile metabolite interaction with peptide/HLA complexes, (ii) immunogenic complex formation at the cell surface, and (iii) lack of requirement for antigen processing to elicit drug‐induced T cell responsiveness. Examination of paired OXP‐induced αβTCR repertoires highlighted an oligoclonal and private clonotypic profile in both resolved ALP‐induced SJS/TEN cases and drug‐naïve healthy donors

Crop Updates 2000 - Pulses

This session covers fifty nine papers from different authors: 1.1999 PULSE INDUSTRY HIGHLIGHTS 2. CONTRIBUTORS 3. BACKGROUND 4. SUMMARY OF PREVIOUS RESULTS 5. 1999 REGIONAL ROUNDUP 6. Northern Agricultural Region, W. O’Neill, AGWEST 7. Central Agricultural Region J. Russell and R.J. French AGWEST 8. Great Southern and Lakes N. Brandon, C. Gaskin and N. Runciman, AGWEST 9. Esperance Mallee M. Seymour, AGWEST PULSE PRODUCTION AGRONOMY AND GENETIC IMPROVEMENT 10. Faba Bean 11. Desi chickpea Traits associated with drought resistance in chickpea, J. Berger, N.C. Turner, CLIMA and CSIRO Plant Industry, R.J. French, AGWEST, R. Carpenter, C. Ludwig and R. Kenney, CSIRO Plant Industry 12. Genotype x environment analysis of chickpea adaptation, J. Berger and N. Turner, CLIMA and CSIRO Plant Industry, and K.H.M. Siddique, AGWEST 13. Carbon fixation by chickpea pods under terminal drought, Q. Ma, CLIMA, M.H. Behboudian, Massey University, New Zealand, N.C. Turner and J.A. Palta, CLIMA, and CSIRO Plant Industry 14. Influence of terminal drought on growth and seed quality, M.H. Behboudian, Massey University, New Zealand, Q. Ma, CLIMA, N.C. Turner and J.A. Palta, CSIRO Plant Industry 15. Resistance to chilling at flowering and to budworm, H. Clarke, CLIMA Chickpea nodulation survey, J. Stott and J. Howieson, Centre for Rhizobium Studies, Murdoch University 16. Kabuli chickpea 17. Premium quality kabuli chickpea development in the ORIA, K.H.M. Siddique CLIMA and AGWEST, K.L. Regan, AGWEST, R. Shackles, AGWEST 18. International screening for Ascochyta blight resistance, K.H.M. Siddique CLIMA and AGWEST, C. Francis, CLIMA, K.L. Regan, AGWEST, N. Acikgoz and N. Atikyilmaz, AARI, Turkey and R.S. Malholtra, ICARDA, Syria 19. Agronomic evaluation of Ascochyta resistant kabuli germplasm in WA, K.H.M. Siddique CLIMA and AGWESTC. Francis, CLIMA, K.L. Regan and M. Baker, AGWEST 20. Field Pea 21. Lentil 22. ACIAR project J. Clements, K.H.M. Siddique CLIMA and AGWEST and C. Francis CLIMA 23. Vetch 24. Rust, M. Seymour, AGWEST 25. Narbon bean 26. Agronomy, M. Seymour, AGWEST 27. Lupinus species 28. Screening lupins for tolerance to alkaline/calcareous soils, C. Tang, CLIMA andUniversity of WAand J.D. Brand, WAITE, University of Adelaide 29. Lathyrus development, C. Hanbury and K.H.M. Siddique, CLIMA and AGWEST 30. Sheep feeding studies, C. White, CSIRO, Perth, C. Hanbury, CLIMA and K.H.M. Siddique, CLIMA and AGWEST 31. Lathyrus: a potential new ingredient in pig diets, B.P. Mullan, C.D. Hanbury and K.H.M. Siddique, AGWEST 32. Species comparison 33. Species for horticultural rotations, K.H.M. Siddique, AGWEST, R. Lancaster and I. Guthridge AGWEST 34. Marrow fat field pea shows promise in the southwest, K.H.M. Siddique, AGWEST, N. Runciman, AGWEST, and I. Pritchard, AGWEST, 35. Pulses on grey clay soils, P. Fisher, M. Braimbridge, J. Bignell, N. Brandon, R. Beermier, W. Bowden, AGWEST 36. Nutrient management of pulses 37. Summary of pulse nutrition studies in WA, M.D.A. Bolland, K.H.M. Siddique, G.P. Riethmuller, and R.F. Brennan, AGWEST 38. Pulse species response to phosphorus and zinc, S. Lawrence, Zed Rengel, University of WA, S.P. Loss, CSBP futurefarm, M.D.A. Bolland, .H.M. Siddique, W. Bowden, AGWEST 39. Gypsum 40. Antitranspirants seed priming DEMONSTRATION OF PULSES IN THE FARMING SYSTEM 41. Foliar and soil applied nutrients for field peas in the south coast mallee,M. Seymour, AGWEST, and P. Vedeniapine, Phosyn Ltd 42. Demonstration of pulse species at Kendenup, C. Kirkwood, Farmer, Katanning, R. Beermier, N. Runciman and N. Brandon, AGWEST 43. Kabuli chickpea demonstration at Gnowangerup, R. Beermier and N. Brandon, AGWEST 44. Lathyrus sativus demonstration at Mindarabin, N. Brandon and R. Beermier, AGWEST 45. New field pea varieties in the central eastern region, J. Russell, AGWEST DISEASE AND PEST MANAGEMENT 46. Ascochyta blight of chickpea 47. Botrytis grey mould (BGM) of chickpea 48. Fungal disease diagnostics, Pulse disease diagnostics, D. Wright, AGWEST Plant Laboratories 49. Viruses in pulses, Luteovirus infection in field pea and faba bean crops, and viruses in seed, L. Latham, CLIMA and AGWEST, R. Jones, AGWEST 50. Screening of pulse species for pea seed-borne mosaic virus, L. Latham, CLIMAand AGWEST, and R. Jones, AGWEST 51. CMV in chickpea: effect of seed-borne sources on virus spread and seed yield, R. Jones, AGWEST and L. Latham, CLIMA and AGWEST 52. Insect pests 53. Evaluation of transgenic field pea against the pea weevil,M.J. de Sousa Majer, School of Environmental Biology, Curtin University of Technology,, D. Hardie, and N.C. Turner, CSIRO Division of Plant Industry 54. Development of a molecular marker for pea weevil resistance in field pea, Oonagh Byrne, CLIMA, Darryl Hardie, AGWEST and Penny Smith, UWA 55. Aphid feeding damage to faba bean and lentil crops, Françoise Berlandier, AGWEST 56. Taxonomy and control of bruchids in pulses, N. Keals, CLIMA, D. Hardie and R. Emery, AGWEST, 57. ACKNOWLEDGMENTS 58. PUBLICATIONS BY PULSE PRODUCTIVITY PROJECT STAFF 59. VARIETIES PRODUCED AND COMMERCIALLY RELEASE

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Background Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.Methods The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 µg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 µg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (antispike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.Findings Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).Interpretation Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

TCR_Explore: A novel webtool for T cell receptor repertoire analysis

T cells expressing either alpha-beta or gamma-delta T cell receptors (TCR) are critical sentinels of the adaptive immune system, with receptor diversity being essential for protective immunity against a broad array of pathogens and agents. Programs available to profile TCR clonotypic signatures can be limiting for users with no coding expertise. Current analytical pipelines can be inefficient due to manual processing steps, open to data entry errors and have multiple analytical tools with unique inputs that require coding expertise. Here we present a bespoke webtool designed for users irrespective of coding expertise, coined ‘TCR_Explore’, enabling analysis either derived via Sanger sequencing or next generation sequencing (NGS) platforms. Further, TCR_Explore incorporates automated quality control steps for Sanger sequencing. The creation of flexible and publication ready figures are enabled for different sequencing platforms following universal conversion to the TCR_Explore file format. TCR_Explore will enhance a user’s capacity to undertake in-depth TCR repertoire analysis of both new and pre-existing datasets for identification of T cell clonotypes associated with health and disease. The web application is located at https://tcr-explore.erc.monash.edu for users to interactively explore TCR repertoire datasets