Abstract The incidence of pulmonary non-tuberculous mycobacteria (NTM) disease in otherwise healthy adults is increasing as the population ages. The organisms are ubiquitous so susceptibility ...probably reflects a deficiency in a protective immune response. Here we investigate if singlenucleotide polymorphisms (SNP) affecting cytokines, chemokines and their receptors associate with pulmonary NTM disease. Samples from NTM patients ( n = 79) and healthy controls ( n = 188) were genotyped using TaqMan probes. Of the 16 SNPs assessed, IL28B-rs8099917* TG (rs8099917; P = 0.01, OR = 2.2), TNFA-1031* CC (rs1799964; p = 0.02, OR = 0.48) and IL10-1082* AA (rs1800896; P = 0.001, OR = 0.33) were significantly associated with NTM disease. IL28B-rs8099917 and IL10-1082 have been associated with perturbations of the Th1/Th2 balance, whilst TNFA-1031* CC associates with sensory neuropathy in HIV patients. IL10-1082 warrants further investigation because we observed high production of IL-10 in blood mononuclear cells from NTM patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
Introduction: Up to 25% of cases of ductal carcinoma in situ (DCIS) recur, and half of these recur as invasive breast cancer (IBC). There is no biomarker to predict which DCIS cases will ...recur but it has been suggested that a biomarker would allow de-escalation of the current paradigm of treating most patients with surgery and/or radiotherapy. However, we hypothesize that not all recurrences are genetically similar to the primary DCIS (i.e. non-clonal) and therefore arise de novo. To test this we assembled a large recurrence cohort to explore the clonal relatedness of primary-recurrence tumor pairs prior to proposing a predictive biomarker (Gorringe et al Mod Pathol 2015).
Method: We microdissected and extracted DNA from 65 pairs of primary DCIS and recurrences. Half of these recurrences were IBC. We analyzed 21 pairs by targeted sequencing or low-coverage whole-genome sequencing (LCWGS, 2x depth) and 44 pairs with Whole Exome Sequencing (WES, average depth 95x). We similarly analyzed a set of non-recurrent DCIS cases (n=29) treated with wide local excision and with a minimum of 7 years follow-up. No matched normal samples were available. Several approaches were utilized to investigate clonal relatedness using copy number alterations and mutations (when detected), including the Clonality package (Mauguen et al Biometrics 2018), manual breakpoint inspection (Bollet et al JNCI 2008), and clonality indexes (Schultheis et al JNCI 2016). Phylogenetic analyses were carried out by MEDICC2 (Petkovic et al bioRxiv 2021) on WES samples.
Results: 62% of cases were clonal (40/65), 28% were non-clonal. There were 7/65 that were equivocal, although further validation will be performed. There was no significant difference in clonal relatedness whether the recurrence was IBC or DCIS. IBC recurrent cases showed a significantly higher ploidy than the DCIS recurrences. The final phylogenetic analysis with MEDICC2 will be presented, which will take into account any subclonal whole-genome doubling events. Furthermore, clonal primary DCIS showed a significantly higher number of TP53 mutations compared to non-recurrent and non-clonal primaries (p<0.001, Fisher Exact test) and a higher level of copy number events overall.
Conclusion: Detailed molecular analysis of a large cohort of matched DCIS primary and their recurrences using high sequencing resolution showed a substantial proportion of recurrences were not genetically related to the primary DCIS. Our observations raise the question of whether a tumor intrinsic biomarker alone would be sufficient to predict DCIS recurrences.
Citation Format: Tanjina Kader, Sakshi Mahale, Magnus Zethoven, Hugo Saunders, Dorothea Lesche, David Byrne, Siqi Lai, Lauren Tjoeka, Claire Candido, Maree Pechlevanis, Olivia Craig, Jia-Min Pang, Lisa Devereux, Shona Hendry, Eloise House, Sureshni Jayasinghe, Michael Toss, Islam M. Miligy, Emad Rakha, Stephen Fox, Bruce Mann, Ian Campbell, Kylie Gorringe. Predictive biomarkers of recurrence may not be useful for deescalating treatment of breast ductal carcinoma in situ due to de novo ipsilateral breast carcinoma development abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 43.
COVID-19 is a multisystem disease and patients who survive might have in-hospital complications. These complications are likely to have important short-term and long-term consequences for patients, ...health-care utilisation, health-care system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and effect of COVID-19 complications, particularly in those who survive, using the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK.
We did a prospective, multicentre cohort study in 302 UK health-care facilities. Adult patients aged 19 years or older, with confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 were included in the study. The primary outcome of this study was the incidence of in-hospital complications, defined as organ-specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.
Between Jan 17 and Aug 4, 2020, 80 388 patients were included in the study. Of the patients admitted to hospital for management of COVID-19, 49·7% (36 367 of 73 197) had at least one complication. The mean age of our cohort was 71·1 years (SD 18·7), with 56·0% (41 025 of 73 197) being male and 81·0% (59 289 of 73 197) having at least one comorbidity. Males and those aged older than 60 years were most likely to have a complication (aged ≥60 years: 54·5% 16 579 of 30 416 in males and 48·2% 11 707 of 24 288 in females; aged <60 years: 48·8% 5179 of 10 609 in males and 36·6% 2814 of 7689 in females). Renal (24·3%, 17 752 of 73 197), complex respiratory (18·4%, 13 486 of 73 197), and systemic (16·3%, 11 895 of 73 197) complications were the most frequent. Cardiovascular (12·3%, 8973 of 73 197), neurological (4·3%, 3115 of 73 197), and gastrointestinal or liver (10·8%, 7901 of 73 197) complications were also reported.
Complications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause a substantial strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.
National Institute for Health Research and the UK Medical Research Council.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.
We developed and validated a multivariable ...logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).
74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 95% CI 0·76 to 0·78; calibration-in-the-large 0·00 –0·05 to 0·05); calibration slope 0·96 0·91 to 1·01), and greater net benefit than any other reproducible prognostic model.
The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.
National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.
Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a ...national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use.
We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age (<16 years, 16-49 years, and ≥50 years). In-hospital mortality was measured by use of multilevel Cox proportional hazards, adjusting for demographics, comorbidities, and medications (inhaled corticosteroids, short-acting β-agonists SABAs, and long-acting β-agonists LABAs). Patients with asthma who were taking an inhaled corticosteroid plus LABA plus another maintenance asthma medication were considered to have severe asthma.
75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 8·6% with asthma), 8950 patients aged 16-49 years (1867 20·9% with asthma), and 65 653 patients aged 50 years and older (5918 9·0% with asthma, 10 266 15·6% with chronic pulmonary disease, and 2071 3·2% with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio OR 1·20 95% CI 1·05-1·37; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 1·08-1·27; p<0·0001), and patients aged 50 years and older with chronic pulmonary disease (with or without asthma) were significantly less likely than those without a respiratory condition to receive critical care (adjusted OR 0·66 0·60-0·72 for those without asthma and 0·74 0·62-0·87 for those with asthma; p<0·0001 for both). In patients aged 16-49 years, only those with severe asthma had a significant increase in mortality compared to those with no asthma (adjusted hazard ratio HR 1·17 95% CI 0·73-1·86 for those on no asthma therapy, 0·99 0·61-1·58 for those on SABAs only, 0·94 0·62-1·43 for those on inhaled corticosteroids only, 1·02 0·67-1·54 for those on inhaled corticosteroids plus LABAs, and 1·96 1·25-3·08 for those with severe asthma). Among patients aged 50 years and older, those with chronic pulmonary disease had a significantly increased mortality risk, regardless of inhaled corticosteroid use, compared to patients without an underlying respiratory condition (adjusted HR 1·16 95% CI 1·12-1·22 for those not on inhaled corticosteroids, and 1·10 1·04-1·16 for those on inhaled corticosteroids; p<0·0001). Patients aged 50 years and older with severe asthma also had an increased mortality risk compared to those not on asthma therapy (adjusted HR 1·24 95% CI 1·04-1·49). In patients aged 50 years and older, inhaled corticosteroid use within 2 weeks of hospital admission was associated with decreased mortality in those with asthma, compared to those without an underlying respiratory condition (adjusted HR 0·86 95% CI 0·80-0·92).
Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease.
National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England.
Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed ...co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19.
The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded.
We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives.
In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist.
National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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