Could NICE guidance on the choice of blood pressure lowering drugs be simplified?

Reecha Sofat and colleagues argue that prescribing advice needs updating in the light of recent evidence that all classes of blood pressure lowering drugs are broadly equivalen

Polymorphisms in ARMS2/HTRA1 and complement genes and age-related macular degeneration in India: findings from the INDEYE study.

PURPOSE: Association between genetic variants in complement factor H (CFH), factor B (CFB), component 2 (C2), and in the ARMS2/HTRA1 region with age-related macular degeneration (AMD) comes mainly from studies of European ancestry and case-control studies of late-stage disease. We investigated associations of both early and late AMD with these variants in a population-based study of people aged 60 years and older in India. METHODS: Fundus images were graded using the Wisconsin Age-Related Maculopathy Grading System and participants assigned to one of four mutually exclusive stages based on the worse affected eye (0 = no AMD, 1-3 = early AMD, 4 = late AMD). Multinomial logistic regression was used to derive risk ratios (RR) accounting for sampling method and adjusting for age, sex, and study center. RESULTS: Of 3569 participants, 53.2% had no signs of amd, 45.6% had features of early amd, and 1.2% had late amd. CFH (RS1061170), C2 (RS547154), OR CFB (RS438999) was not associated with early or late AMD. In the ARMS2 locus, RS10490924 was associated with both early (adjusted RR 1.22, 95% confidence interval [CI]: 1.13-1.33, P < 0.0001) and late AMD (adjusted RR 1.81, 95% CI: 1.15-2.86; P = 0.01); rs2672598 was associated only with early AMD (adjusted RR 1.12, 95% CI: 1.02-1.23; P = 0.02); rs10490923 was not associated with early or late AMD. CONCLUSIONS: Two variants in ARMS2/HTRA1 were associated with increased risk of early AMD, and for one of these, the increased risk was also evident for late AMD. The study provides new insights into the role of these variants in early stages of AMD in India

Acute kidney injury in stable COPD and at exacerbation.

BACKGROUND: While acute kidney injury (AKI) alone is associated with increased mortality, the incidence of hospital admission with AKI among stable and exacerbating COPD patients and the effect of concurrent AKI at COPD exacerbation on mortality is not known. METHODS: A total of 189,561 individuals with COPD were identified from the Clinical Practice Research Datalink. Using Poisson and logistic regressions, we explored which factors predicted admission for AKI (identified in Hospital Episode Statistics) in this COPD cohort and concomitant AKI at a hospitalization for COPD exacerbation. Using survival analysis, we investigated the effect of concurrent AKI at exacerbation on mortality (n=36,107) and identified confounding factors. RESULTS: The incidence of AKI in the total COPD cohort was 128/100,000 person-years. The prevalence of concomitant AKI at exacerbation was 1.9%, and the mortality rate in patients with AKI at exacerbation was 521/1,000 person-years. Male sex, older age, and lower glomerular filtration rate predicted higher risk of AKI or death. There was a 1.80 fold (95% confidence interval: 1.61, 2.03) increase in adjusted mortality within the first 6 months post COPD exacerbation in patients suffering from AKI and COPD exacerbation compared to those who were AKI free. CONCLUSION: In comparison to previous studies on general populations and hospitalizations, the incidence and prevalence of AKI is relatively high in COPD patients. Coexisting AKI at exacerbation is prognostic of poor outcome

COPD disease severity and the risk of venous thromboembolic events: a matched case-control study.

BACKGROUND: It is generally accepted that people with chronic obstructive pulmonary disease (COPD) are at increased risk of vascular disease, including venous thromboembolism (VTE). While it is plausible that the risk of arterial and venous thrombotic events is greater still in certain subgroups of patients with COPD, such as those with more severe airflow limitation or more frequent exacerbations, these associations, in particular those between venous events and COPD severity or exacerbation frequency, remain largely untested in large population cohorts. METHODS: A total of 3,594 patients with COPD with a first VTE event recorded during January 1, 2004 to December 31, 2013, were identified from the Clinical Practice Research Datalink dataset and matched on age, sex, and general practitioner practice (1:3) to patients with COPD with no history of VTE (n=10,782). COPD severity was staged by degree of airflow limitation (ie, GOLD stage) and by COPD medication history. Frequent exacerbators were defined as patients with COPD with ≥ 2 exacerbations in the 12-month period prior to their VTE event (for cases) or their selection as a control (for controls). Conditional logistic regression was used to estimate the association between disease severity or exacerbation frequency and VTE. RESULTS: After additional adjustment for nonmatching confounders, including body mass index, smoking, and heart-related comorbidities, there was evidence for an association between increased disease severity and VTE when severity was measured either in terms of lung function impairment (odds ratio [OR]moderate:mild =1.16; 95% confidence intervals [CIs] =1.03, 1.32) or medication usage (ORsevere:mild/moderate =1.17; 95% CIs =1.06, 1.26). However, there was no evidence to suggest that frequent exacerbators were at greater risk of VTE compared with infrequent exacerbators (OR =1.06; 95% CIs =0.97, 1.15). CONCLUSION: COPD severity defined by airflow limitation or medication usage, but not exacerbation frequency, appears to be associated with VTE events in people with COPD. This finding highlights the disconnect between disease activity and severity in COPD

Influenza-like illness in acute myocardial infarction patients during the winter wave of the influenza A H1N1 pandemic in London: a case-control study.

OBJECTIVE: To investigate recent respiratory and influenza-like illnesses (ILIs) in acute myocardial infarction patients compared with patients hospitalised for acute non-vascular surgical conditions during the second wave of the 2009 influenza A H1N1 pandemic. DESIGN: Case-control study. SETTING: Coronary care unit, acute cardiology and acute surgical admission wards in a major teaching hospital in London, UK. PARTICIPANTS: 134 participants (70 cases and 64 controls) aged ≥40 years hospitalised for acute myocardial infarction and acute surgical conditions between 21 September 2009 and 28 February 2010, frequency-matched for gender, 5-year age-band and admission week. PRIMARY EXPOSURE: ILI (defined as feeling feverish with either a cough or sore throat) within the last month. SECONDARY EXPOSURES: Acute respiratory illness within the last month not meeting ILI criteria; nasopharyngeal and throat swab positive for influenza virus. RESULTS: 29 of 134 (21.6%) participants reported respiratory illness within the last month, of whom 13 (9.7%) had illnesses meeting ILI criteria. The most frequently reported category for timing of respiratory symptom onset was 8-14 days before admission (31% of illnesses). Cases were more likely than controls to report ILI-adjusted OR 3.17 (95% CI 0.61 to 16.47)-as well as other key respiratory symptoms, and were less likely to have received influenza vaccination-adjusted OR 0.46 (95% CI 0.19 to 1.12)-although the differences were not statistically significant. No swabs were positive for influenza virus. CONCLUSIONS: Point estimates suggested that recent ILI was more common in patients hospitalised with acute myocardial infarction than with acute surgical conditions during the second wave of the influenza A H1N1 pandemic, and influenza vaccination was associated with cardioprotection, although the findings were not statistically significant. The study was underpowered, partly because the age groups typically affected by acute myocardial infarction had low rates of infection with the pandemic influenza strain compared with seasonal influenza

Fulfilling the Promise of Personalized Medicine? Systematic Review and Field Synopsis of Pharmacogenetic Studies

BACKGROUND: Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics). OBJECTIVES: We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research. DATA SOURCES: Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION CRITERIA: We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans. STUDY APPRAISAL AND SYNTHESIS METHODS: Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study. RESULTS: From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25 ratio 1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40-222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (por=4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines. SYSTEMATIC REVIEW REGISTRATION NUMBER: Not Registered

Severe mental illness and chronic kidney disease: a cross-sectional study in the United Kingdom

OBJECTIVE: We investigated the burden of chronic kidney disease (CKD) among patients with severe mental illness (SMI). METHODS: We identified patients with SMI among all those aged 25–74 registered in the UK Clinical Practice Research Datalink as on March 31, 2014. We compared the prevalence of CKD (two measurements of estimated glomerular filtration rate <60 mL/min/1.73 m2 for ≥3 months) and renal replacement therapy between patients with and without SMI. For patients with and without a history of lithium prescription separately, we used logistic regression to examine the association between SMI and CKD, adjusting for demographics, lifestyle characteristics, and known CKD risk factors. RESULTS: The CKD prevalence was 14.6% among patients with SMI and a history of lithium prescription (n = 4,295), 3.3% among patients with SMI and no history of lithium prescription (n = 24,101), and 2.1% among patients without SMI (n = 2,387,988; P < 0.001). The prevalence of renal replacement therapy was 0.23%, 0.15%, and 0.11%, respectively (P = 0.012). Compared to patients without SMI, the fully adjusted odds ratio for CKD was 6.49 (95% CI 5.84–7.21) for patients with SMI and a history of lithium prescription and 1.45 (95% CI 1.34–1.58) for patients with SMI and no history of lithium prescription. The higher prevalence of CKD in patients with SMI may, in part, be explained by more frequent blood testing as compared to the general population. CONCLUSION: CKD is identified more commonly among patients with SMI than in the general population

Cohort profile: biological pathways of risk and resilience in Syrian refugee children (BIOPATH)

The BIOPATH cohort was established to explore the interplay of psychosocial and biological factors in the development of resilience and mental health problems in Syrian refugee children. Based in Lebanon, a middle-income country significantly impacted by the refugee crisis, it is the first such cohort of refugees in the Middle East. Families were recruited from informal tented settlements in the Beqaa region using purposive cluster sampling. At baseline (October 2017–January 2018), N = 3188 individuals participated [n = 1594 child–caregiver dyads; child gender, 52.6% female; mean (SD) age = 11.44 (2.44) years, range = 6–19]. Re-participation rate at 1-year follow-up was 62.8%. Individual interviews were conducted with children and primary caregivers and biological samples collected from children. Measures include: (1) children’s well-being and mental health problems (using tools validated against clinical interviews in a subsample of the cohort); (2) psychosocial risk and protective factors at the level of the individual (e.g. coping strategies), family (e.g. parent–child relationship), community (e.g. collective efficacy), and wider context (e.g. services); (3) saliva samples for genetic and epigenetic (methylation) analyses; (4) hair samples to measure cortisol, dehydroepiandrosterone (DHEA) and testosterone. This cohort profile provides details about sampling and recruitment, data collection and measures, demographic data, attrition and potential bias, key findings on resilience and mental health problems in children and strengths and limitations of the cohort. Researchers interested in accessing data should contact Professor Michael Pluess at Queen Mary University of London, UK (e-mail: [email protected]). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00127-022-02228-8

Data Resource Profile: Cardiovascular disease research using linked bespoke studies and electronic health records (CALIBER)

The goal of cardiovascular disease (CVD) research using linked bespoke studies and electronic health records (CALIBER) is to provide evidence to inform health care and public health policy for CVDs across different stages of translation, from discovery, through evaluation in trials to implementation, where linkages to electronic health records provide new scientific opportunities. The initial approach of the CALIBER programme is characterized as follows: (i) Linkages of multiple electronic heath record sources: examples include linkages between the longitudinal primary care data from the Clinical Practice Research Datalink, the national registry of acute coronary syndromes (Myocardial Ischaemia National Audit Project), hospitalization and procedure data from Hospital Episode Statistics and cause-specific mortality and social deprivation data from the Office of National Statistics. Current cohort analyses involve a million people in initially healthy populations and disease registries with ∼105 patients. (ii) Linkages of bespoke investigator-led cohort studies (e.g. UK Biobank) to registry data (e.g. Myocardial Ischaemia National Audit Project), providing new means of ascertaining, validating and phenotyping disease. (iii) A common data model in which routine electronic health record data are made research ready, and sharable, by defining and curating with meta-data >300 variables (categorical, continuous, event) on risk factors, CVDs and non-cardiovascular comorbidities. (iv) Transparency: all CALIBER studies have an analytic protocol registered in the public domain, and data are available (safe haven model) for use subject to approvals. For more information, e-mail [email protected]

Risk of acute respiratory infection and acute cardiovascular events following acute respiratory infection among adults with increased cardiovascular risk in England between 2008 and 2018: a retrospective, population-based cohort study

BACKGROUND: Although acute respiratory infections can lead to cardiovascular complications, the effect of underlying cardiovascular risk on the incidence of acute respiratory infections and cardiovascular complications following acute respiratory infection in individuals without established cardiovascular disease is unknown. We aimed to investigate whether cardiovascular risk is associated with increased risk of acute respiratory infection and acute cardiovascular events after acute respiratory infection using 10 years of linked electronic health record (EHR) data in England. METHODS: In this retrospective, population-based cohort study we used EHRs from primary care providers registered on the Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases in England. Eligible individuals were aged 40-64 years, did not have established cardiovascular disease or a chronic health condition that would make them eligible for influenza vaccination, were registered at a general practice contributing to the CPRD, and had linked Hospital Episode Statistics Admitted Patient Care data in England from Sept 1, 2008, to Aug 31, 2018. We classified cardiovascular risk on the basis of diagnosed hypertension and overall predicted cardiovascular risk, estimated by use of the QRISK2 risk-prediction tool (comparing a score of ≥10% [increased risk] with a score of <10% [low risk]). Using multivariable Poisson regression models, we calculated incidence rate ratios (IRRs) for systemic acute respiratory infection. Among individuals who had an acute respiratory infection, we used multivariable Cox regression to calculate hazard ratios (HRs) for the risk of acute cardiovascular events within 1 year of infection. FINDINGS: We identified 6 075 321 individuals aged 40-64 years with data in the CPRD and linked data in the Hospital Episode Statistics Admitted Patient Care database between Sept 1, 2008, and Aug 31, 2018. Of these individuals, 4 212 930 (including 526 480 [12·5%] with hypertension and 607 087 [14·4%] with a QRISK2 score of ≥10%) were included in the assessment of the incidence of acute respiratory infection. After adjusting for confounders (age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, smoking status, and consultation frequency in the hypertension analysis; and alcohol consumption and consultation frequency in the QRISK2 analysis), the incidence of acute respiratory infection was higher in individuals with hypertension than those without (IRR 1·04 [95% CI 1·03-1·05]) and higher in those with a QRISK2 score of 10% or higher than in those with a QRISK2 score of less than 10% (1·39 [1·37-1·40]). Of the 442 408 individuals who had an acute respiratory infection, 4196 (0·9%) had an acute cardiovascular event within 1 year of infection. After adjustment (for age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, and smoking status in the hypertension analysis; and for alcohol consumption in the QRISK2 analysis), hypertension (HR 1·98 [95% CI 1·83-2·15]) and a QRISK2 score of 10% or higher (3·65 [3·42-3·89]) were associated with a substantially increased risk of acute cardiovascular events after acute respiratory infection. INTERPRETATION: People with increased cardiovascular risk but without diagnosed cardiovascular disease, measured by diagnosed hypertension or overall predicted cardiovascular risk, could benefit from influenza and pneumococcal vaccine prioritisation to reduce their risk of both acute respiratory infection and cardiovascular complications following an acute respiratory infection. FUNDING: British Heart Foundation and the Wellcome Trust