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Journal articleTurtle L, Elliot S, Drake TM, et al., 2024,
Changes in hospital mortality in patients with cancer during the COVID-19 pandemic (ISARIC-CCP-UK): a prospective, multicentre cohort study
, The Lancet Oncology, Vol: 25, Pages: 636-648, ISSN: 1470-2045BACKGROUND: Patients with cancer are at greater risk of dying from COVID-19 than many other patient groups. However, how this risk evolved during the pandemic remains unclear. We aimed to determine, on the basis of the UK national pandemic protocol, how factors influencing hospital mortality from COVID-19 could differentially affect patients undergoing cancer treatment. We also examined changes in hospital mortality and escalation of care in patients on cancer treatment during the first 2 years of the COVID-19 pandemic in the UK. METHODS: We conducted a prospective cohort study of patients aged older than 19 years and admitted to 306 health-care facilities in the UK with confirmed SARS-CoV-2 infection, who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP) across the UK from April 23, 2020, to Feb 28, 2022; this analysis included all patients in the complete dataset when the study closed. The primary outcome was 30-day in-hospital mortality, comparing patients on cancer treatment and those without cancer. The study was approved by the South Central-Oxford C Research Ethics Committee in England (Ref: 13/SC/0149) and the Scotland A Research Ethics Committee (Ref 20/SS/0028), and is registered on the ISRCTN Registry (ISRCTN66726260). FINDINGS: 177 871 eligible adult patients either with no history of cancer (n=171 303) or on cancer treatment (n=6568) were enrolled; 93 205 (52·4%) were male, 84 418 (47·5%) were female, and in 248 (13·9%) sex or gender details were not specified or data were missing. Patients were followed up for a median of 13 (IQR 6-21) days. Of the 6568 patients receiving cancer treatment, 2080 (31·7%) died at 30 days, compared with 30 901 (18·0%) of 171 303 patients without cancer. Patients aged younger than 50 years on cancer treatment had the highest age-adjusted relative risk (hazard ratio [HR] 5·2 [95% CI 4&m
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Journal articleMcNally P, Singh A, McColley SA, et al., 2024,
Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis
, Journal of Cystic Fibrosis, Vol: 23, Pages: 429-435, ISSN: 1569-1993BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.
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Journal articleOgger P, Garcia Martin AM, Jang S, et al., 2024,
SARS-CoV-2 strains bearing the Omicron BA.1 spike protein replicate in C57BL/6 mice
, Frontiers in Immunology, Vol: 15, ISSN: 1664-3224Introduction: SARS-CoV-2, the cause of the COVID pandemic, is an RNA virus with a high propensity to mutate. Successive virus variants, including variants of concern (VOC), have emerged with increased transmission or immune escape. The original pandemic virus and early variants replicated poorly, if at all, in mice at least partly due to a mismatch between the receptor binding domain on the viral spike protein and the murine angiotensin converting enzyme 2 (ACE2). Omicron VOC emerged in late 2021 harboring > 50 new mutations, 35 of them in the spike protein. This variant resulted in a very large wave of infections, even in the face of prior immunity, albeit being inherently less severe than earlier variants. Reflecting the lower severity reported in humans, Omicron displayed attenuated infection in hamsters and also in the K18-hACE2 mouse model. K18-hACE2 mice express both the human ACE2 as well as the endogenous mouse ACE2.Methods: Here we infected hACE2knock-in mice that express only human ACE2 and no murine ACE2, or C57BL/6 wildtype mice with SARS-CoV-2 D614G (first-wave isolate), Delta or Omicron BA.1 variants and assessed infectivity and downstream innate immune responses.Results: While replication of SARS-CoV-2 Omicron was lower in the lungs of hACE2knock-in mice compared with SARS-CoV-2 D614G and VOC Delta, it replicated more efficiently than the earlier variants in C57BL/6 wildtype mice. This opens the opportunity to test the effect of host genetics on SARS-CoV-2 infections in wildtype mice. As a proof of principle, we tested Omicron infection in mice lacking expression of the interferon-alpha receptor-1 (IFNAR1). In these mice we found that loss of type I IFN receptor signaling resulted in higher viral loads in the lungs were detected. Finally, using a chimeric virus of first wave SARS-CoV-2 harboring the Omicron spike protein, we show that Omicron spike increase infection of C57BL/6 wildtype mice, but non-spike genes of Omicron confer attenuation of vir
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Journal articleMcNally P, Davies J, Ciet P, et al., 2024,
Reply to Dournes and Benlala: Hierarchical Computed Tomography Scoring Systems Cannot Discriminate Between Reversible Bronchiectasis and Mucus Plugs
, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 209, Pages: 1039-1040, ISSN: 1073-449X -
Journal articleEfstathiou C, Liew F, Fontanella S, et al., 2024,
Large scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease
, Nature Immunology, Vol: 25, Pages: 607-621, ISSN: 1529-2908One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.
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Journal articleMichael BD, Dunai C, Needham EJ, et al., 2024,
Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses (vol 14, 8487, 2023)
, NATURE COMMUNICATIONS, Vol: 15 -
Journal articleShankar-Hari M, Calandra T, Soares MP, et al., 2024,
Reframing sepsis immunobiology for translation: towards informative subtyping andtargeted immunomodulatory therapies
, LANCET RESPIRATORY MEDICINE, Vol: 12, Pages: 323-336, ISSN: 2213-2600 -
Journal articleLin G-L, Drysdale SB, Snape MD, et al., 2024,
Targeted metagenomics reveals association between severity and pathogen co-detection in infants with respiratory syncytial virus
, NATURE COMMUNICATIONS, Vol: 15 -
Journal articleJohnson M, Chelysheva I, Öner D, et al., 2024,
A genome-wide association study of respiratory syncytial virus infection severity in infants
, Journal of Infectious Diseases, Vol: 229, Pages: S112-S119, ISSN: 0022-1899BACKGROUND: Respiratory syncytial virus (RSV) is a significant cause of infant morbidity and mortality worldwide; however, understanding the genetic risk factors of severe RSV is incomplete. Neutrophils and monocytes have been previously identified as major cell subsets involved in airway inflammation, however the pathophysiology of these events is also not fully characterised. Given that the majority of children experience at least one RSV infection by the age of two years, but not all develop severe disease, we used genomic and transcriptomic data to explore potential mechanistic biomarkers of disease severity. METHODS: We conducted a genome-wide association study (GWAS) to investigate the genetic factors underlying RSV severity, assessed by the ReSVinet scale, in a cohort of 251 infants aged from 1 week old to 1 year of age. Genotyping data was collected from multiple European study sites as part of the RESCEU Consortium. Data and were analysed following quality control and genotype imputation using the TOPMed server. Generalised linear regression models were employed to assess the impact of genotype on RSV severity. Matrix eQTL in R was used to model the impact of candidate SNPs genotype on gene expression as measured by microarray. RESULTS: While no SNPs reached the genome-wide statistical significance threshold (p < 5 × 10-8), we identified 816 candidate SNPs with a p-value of < 1 × 10-4 and 75 SNPs with a p-value of < 1 × 10-5. Subsequent functional annotation of candidate SNPs highlighted variants previously identified in GWAS studies of inflammatory diseases, and genes relevant to neutrophil trafficking and cytoskeletal functions, including LSP1 and RAB27A. Furthermore, the eQTL analysis revealed that SNPs within the RAB27A locus significantly altered gene expression (FDR p < 0.05). CONCLUSIONS: These findings may provide insights
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Journal articleDevoy E, Hughes D, Alharbi AF, et al., 2024,
What is cystic fibrosis screen positive inconclusive diagnosis? And what is it not?
, ARCHIVES OF DISEASE IN CHILDHOOD-EDUCATION AND PRACTICE EDITION, ISSN: 1743-0585
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