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  • Journal article
    Graul E, Nordon C, Rhodes K, Menon S, Al Ammouri M, Kallis C, Ioannides A, Whittaker H, Peters N, Quint Jet al., 2024,

    Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study

    , BMC Pulmonary Medicine, Vol: 24, ISSN: 1471-2466

    BackgroundAn immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation.MethodsWe conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization.ResultsOdds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45).Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.

  • Journal article
    Graul E, Nordon C, Rhodes K, Marshall J, Menon S, Kallis C, Ioannides A, Whittaker H, Peters N, Quint Jet al., 2024,

    Temporal risk of nonfatal cardiovascular events after chronic obstructive pulmonary disease exacerbation: a population-based study

    , American Journal of Respiratory and Critical Care Medicine, Vol: 209, Pages: 960-972, ISSN: 1073-449X

    Rationale: Cardiovascular events following COPD exacerbations are recognised. Studies to date have been post-hoc analyses of trials, did not differentiate exacerbation severity, included death in the cardiovascular outcome, or had insufficient power to explore individual outcomes temporally. Objectives: We explore temporal relationships between moderate and severe exacerbations with incident, non-fatal hospitalised cardiovascular events, in a primary care-derived COPD cohort. Methods: We included people with COPD in England from 2014-2020, using Clinical Practice Research Datalink(CPRD) Aurum primary care database. Index date was first COPD exacerbation, or for those without exacerbation, date upon eligibility. We determined composite and individual cardiovascular events (acute coronary syndrome, arrhythmia, heart failure, ischaemic stroke, pulmonary hypertension) from linked hospital data. Adjusted Cox Regression models estimated average and time-stratified hazard ratios(aHR). Measurements and Main Results: Among 213,466 patients, 146,448 (68.6%) had any exacerbation;119,124 (55.8%) moderate exacerbation and 27,324 (12.8%) a severe exacerbation. 40,773 cardiovascular events were recorded. There was an immediate period of cardiovascular relative rate post any exacerbation (1-14 days,aHR=3.19,95%CI 2.71-3.76), followed by progressively declining yet maintained effects, elevated after one year(aHR=1.84,1.78-1.91). HRs were highest 1-14 days following severe exacerbations (aHR=14.5,12.2-17.3) but highest 14-30 days following moderate exacerbations (aHR=1.94,1.63-2.31). Cardiovascular outcomes with greatest two-week effects post severe exacerbation were arrhythmia (aHR=12.7,10.3-15.7) and heart failure (aHR=8.31,6.79-10.2). Conclusions: Cardiovascular events following moderate exacerbations occur slightly later than severe exacerbations; heightened relative rates remain beyond one year irrespective of severity. The period immediately following exacerbation presents a cr

  • Journal article
    Whittaker H, Quint J, Rothnie K, 2024,

    Cause specific mortality in COPD sub-populations: a cohort study of 339 647 people in England

    , Thorax, Vol: 79, Pages: 202-208, ISSN: 0040-6376

    Background Identifying correlates of cause-specific mortality in patients with chronic obstructive pulmonary disease (COPD) may aid the targeting of therapies to reduce mortality. We determined factors associated with causes of death in a primary care COPD population.Methods Clinical Practice Research Datalink Aurum was linked to Hospital Episode Statistics and death certificate data. People with COPD alive between 1 January 2010 and 1 January 2020 were included. Patient characteristics were defined before the start of follow-up: (a) frequency and severity of exacerbations; (b) emphysema or chronic bronchitis; (c) Global Obstructive Lung Disease (GOLD) groups A–D; and (d) airflow limitation. We used Cox Proportional Hazards regression and competing risks to investigate the association between patient characteristics and risk of all-cause, COPD and cardiovascular (CV) mortality.Results 339 647 people with COPD were included of which 97 882 died during follow-up (25.7% COPD related and 23.3% CV related). Airflow limitation, GOLD group, exacerbation frequency and severity, and COPD phenotype were associated with all-cause mortality. Exacerbations, both increased frequency and severity, were associated with COPD-related mortality (≥2 exacerbations vs none adjusted HR: 1.64, 1.57–1.71; 1 severe vs none adjusted HR: 2.17, 2.04–2.31, respectively). Patients in GOLD groups B–D had a higher risk of COPD and CV mortality compared with GOLD group A (GOLD group D vs group A, adjusted HR for COPD mortality: 4.57, 4.23–4.93 and adjusted HR for CV mortality: 1.53, 1.41–1.65). Increasing airflow limitation was also associated with both COPD and CV mortality (GOLD 4 vs 1, adjusted HR: 12.63, 11.82–13.51 and adjusted HR: 1.75, 1.60–1.91, respectively).Conclusion Poorer airflow limitation, worse functional status and exacerbations had substantial associations with risk of all-cause mortality. Differing results for CV and

  • Journal article
    Uthaikhaifar NC, Iakunchykova O, Cook S, Warren-Gash Cet al., 2024,

    Sleeplessness and incident diabetes above the Arctic circle: a secondary analysis of cohort data from the Tromsø Study

    , BMJ Public Health, Vol: 2, ISSN: 2753-4294

    Introduction Circadian misalignment and sleep quality are intertwined processes that are both associated with diabetes. The association between sleep quality and incident diabetes has not been previously investigated in populations living at polar latitudes who experience extreme seasonal daylight variation and may be at greater risk of circadian misalignment. Using data from adult residents of Tromsø, Norway, this study investigates the association of poor sleep quality, as indicated by self-reported sleeplessness, and incident diabetes above the Arctic circle.Research design and methods Secondary analysis of cohort data from the Tromsø Study. The study cohort consists of adults who attended both the fourth (Tromsø4) and seventh (Tromsø7) surveys conducted in 1995 and 2016, respectively. Only individuals with complete data were included. Multivariable logistic regression was used to examine the association between sleeplessness measured in Tromsø4 and incident diabetes measured in participants followed up to Tromsø7, adjusted for other diabetes risk factors.Results Among 10 875 individuals (mean 41 years of age at baseline, 53.6% women), 21.2% (n=2302) reported experiencing sleeplessness at baseline. Diabetes incidence risk over follow-up (20 years) was 7.2% (n=784); incidence risk among individuals reporting sleeplessness was 8.8%, compared with 6.8% among unexposed individuals. After adjustment, sleeplessness-exposed individuals in the study cohort were found to have 23% greater odds (ORadj 1.23, 95% CI 1.03 to 1.47, p=0.022) of incident diabetes.Conclusions Sleep quality is associated with incident diabetes in a population living above the Arctic circle. The direction and strength of association is consistent with findings from other geographical regions.

  • Journal article
    Graul E, Stone P, Massen G, Hatam S, Adamson A, Denaxas S, Peters N, Quint Jet al., 2023,

    Determining prescriptions in electronic healthcare record data: methods for development of standardized, reproducible drug codelists

    , JAMIA Open, Vol: 6, Pages: 1-11, ISSN: 2574-2531

    Objective:To develop a standardizable, reproducible method for creating drug codelists that incorporates clinical expertise and is adaptable to other studies and databases. Materials and Methods: We developed methods to generate drug codelists and tested this using the Clinical Practice Research Datalink (CPRD) Aurum database. accounting for missing data in the database. We generated codelists for 1) cardiovascular disease and 2) inhaled Chronic Obstructive Pulmonary Disease (COPD) therapies, applying them to a sample cohort of 335,931 COPD patients. We compared comprehensively searching on all search variables (A) to B) chemical and C) ontological information only.Results: In Search A we determined 165,150 patients prescribed cardiovascular drugs(49.2% of cohort), and 317,963 prescribed COPD inhalers (94.7% of cohort). Considering output per value set, Search C missed substantial prescriptions, including vasodilator anti-hypertensives (A and B:19,696 prescriptions; C:1,145) and SAMA inhalers (A and B:35,310; C:564).Discussion: We recommend the full methods (A) for comprehensiveness. There are special considerations when generating adaptable and generalizable drug codelists, including fluctuating status, cohort-specific drug indications, underlying hierarchical ontology, and statistical analyses. Conclusions: Methods must have end-to-end clinical input, and be standardizable, reproducible, and understandable to all researchers across data contexts.

  • Journal article
    Tong K, Hopstock L, Cook S, 2023,

    The association of C-reactive protein with future development of diabetes: a population-based 7-year cohort study among Norwegian adults aged 30 and older in the Tromsø Study 2007 – 2016

    , BMJ Open, Vol: 13, ISSN: 2044-6055

    Objectives The extent to which observed associations between high-sensitivity C-reactive protein (hs-CRP) and incident diabetes are explained by obesity and hypertension remains unclear. This study aimed to investigate the association of hs-CRP with developing diabetes in a Norwegian general population sample.Design A cohort study using two population-based surveys of the Tromsø Study: the sixth survey Tromsø6 (2007–2008) as baseline and the seventh survey Tromsø7 (2015–2016) at follow-up.Setting Tromsø municipality of Norway, a country with increasing proportion of older adults and a high prevalence of overweight, obesity and hypertension.Participants 8067 women and men without diabetes, aged 30–87 years, at baseline Tromsø6 who subsequently also participated in Tromsø7.Outcome measures Diabetes defined by self-reported diabetes, diabetes medication use and/or HbA1c≥6.5% (≥48 mmol/mol) was modelled by logistic regression for the association with baseline hs-CRP, either stratified into three quantiles or as continuous variable, adjusted for demographic factors, behavioural and cardiovascular risk factors, lipid-lowering medication use, and hypertension. Interactions by sex, body mass index (BMI), hypertension or abdominal obesity were assessed by adding interaction terms in the fully adjusted model.Results There were 320 (4.0%) diabetes cases after 7 years. After multivariable adjustment including obesity and hypertension, individuals in the highest hs-CRP tertile 3 had 73% higher odds of developing diabetes (OR 1.73; p=0.004; 95% CI 1.20 to 2.49) when compared with the lowest tertile or 28% higher odds of incidence per one-log of hs-CRP increment (OR 1.28; p=0.003; 95% CI 1.09 to 1.50). There was no evidence for interaction between hs-CRP and sex, hypertension, BMI or abdominal obesity.Conclusions Raised hs-CRP was associated with future diabetes development in a Norwegian

  • Journal article
    Lenoir A, Whittaker H, Gayle A, Jarvis D, Quint Jet al., 2023,

    Mortality in non-exacerbating COPD: a longitudinal analysis of UK primary care data

    , Thorax, Vol: 78, Pages: 904-911, ISSN: 0040-6376

    Introduction: Non-exacerbating patients with chronic obstructive pulmonary disease (COPD) are a less studied phenotype. We investigated clinical characteristics, mortality rates and causes of death among non-exacerbating compared with exacerbating patients with COPD.Methods: We used data from the Clinical Practice Research Datalink, Hospital Episode Statistics and Office for National Statistics between 1 January 2004 and 31 December 2018. Ever smokers with a COPD diagnosis with minimum 3 years of baseline information were included. We compared overall using Cox regression and cause-specific mortality rates using competing risk analysis, adjusted for age, sex, deprivation, smoking status, body mass index, GOLD stage and comorbidities. Causes of death were identified using International Classification of Diseases-10 codes.Results: Among 67 516 patients, 17.3% did not exacerbate during the 3-year baseline period. Mean follow-up was 4 years. Non-exacerbators were more likely to be male (63.3% vs 52.4%, p<0.001) and less often had a history of asthma (33.9% vs 43.6%, p<0.001) or FEV1<50% predicted (23.7 vs 31.8%) compared with exacerbators. Adjusted HR for overall mortality in non-exacerbators compared with exacerbators was 0.62 (95% CI 0.56 to 0.70) in the first year of follow-up and 0.87 (95% CI 0.83 to 0.91) thereafter. Non-exacerbating patients with COPD died less of respiratory causes than exacerbators (29.2% vs 40.3%) and more of malignancies (29.4% vs 23.4%) and cardiovascular diseases (26.2% vs 22.9%). HRs for malignant and circulatory causes of death were increased after the first year of follow-up.Discussion: In this primary care cohort, non-exacerbators showed distinct clinical characteristics and lower mortality rates. Non-exacerbators were equally likely to die of respiratory, malignant or cardiovascular diseases.

  • Journal article
    Whittaker H, Nordon C, Rubino A, Morris T, Xu Y, De Nigris E, Mullerova H, Quint Jet al., 2023,

    Frequency and severity of respiratory infections prior to COPD diagnosis and risk of subsequent post-diagnosis COPD exacerbations and mortality: EXACOS-UK health care data study

    , Thorax, Vol: 78, Pages: 760-766, ISSN: 0040-6376

    ObjectiveLittle is known about how lower respiratory tract infections (LRTIs) before chronic obstructive pulmonary disease (COPD) are associated with future exacerbations and mortality. We investigated this association in COPD patients in England. MethodsClinical Practice Research Datalink Aurum, Hospital Episode Statistics, and Office of National Statistics data were used. Start of follow-up was patient’s first ever COPD diagnosis date and a 1-year baseline period prior to start of follow-up was used to find mild LRTIs (GP events/no antibiotics), moderate LRTIs (GP events +antibiotics), and severe LRTIs (hospitalised). Patients were categorised as having: none, 1 mild only, 2+ mild only, 1 moderate, 2+ moderate, and 1+ severe. Negative binomial regression modelled the association between baseline LRTIs and subsequent COPD exacerbations and Cox regression was used to investigate mortality. ResultsIn 215,234 COPD patients, increasing frequency and severity of mild and moderate LRTIs were associated with increased rates of subsequent exacerbations compared to no recorded LRTIs (1 mild adjusted IRR 1.16, 95%CI 1.14-1.18, 2+ mild IRR 1.51, 95%CI 1.46-1.55, 1 moderate IRR 1.81, 95%CI 1.78-1.85, 2+ moderate IRR 2.55, 95%CI 2.48-2.63). Patients with 1+ severe LRTI (vs. no baseline LRTIs) also showed an increased rate of future exacerbations (adjusted IRR 1.75, 95%CI, 1.70-1.80). This pattern of association was similar for risk of all-cause and COPD-related mortality however, patients with 1+ severe LRTIs had the highest risk of all-cause and COPD mortality. ConclusionIncreasing frequency and severity of LRTIs prior to COPD diagnosis were associated with increasing rates of subsequent exacerbations, and increasing risk all-cause and COPD-related mortality.

  • Journal article
    Massen GM, Stewart I, Quint JK, 2023,

    Response to: Consensus and agreements on the classification of fibrotic diseases

    , QJM: an international journal of medicine, ISSN: 1460-2393
  • Journal article
    Pikoula M, Kallis C, Madjiheurem S, Quint JK, Bafadhel M, Denaxas Set al., 2023,

    Evaluation of data processing pipelines on real-world electronic health records data for the purpose of measuring patient similarity

    , PLOS ONE, Vol: 18, ISSN: 1932-6203

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