Temporal trends in associations between severe mental illness and risk of cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: Severe mental illness (SMI; schizophrenia, bipolar disorders (BDs), and other nonorganic psychoses) is associated with increased risk of cardiovascular disease (CVD) and CVD-related mortality. To date, no systematic review has investigated changes in population level CVD-related mortality over calendar time. It is unclear if this relationship has changed over time in higher-income countries with changing treatments. METHODS AND FINDINGS: To address this gap, a systematic review was conducted, to assess the association between SMI and CVD including temporal change. Seven databases were searched (last: November 30, 2021) for cohort or case-control studies lasting ≥1 year, comparing frequency of CVD mortality or incidence in high-income countries between people with versus without SMI. No language restrictions were applied. Random effects meta-analyses were conducted to compute pooled hazard ratios (HRs) and rate ratios, pooled standardised mortality ratios (SMRs), pooled odds ratios (ORs), and pooled risk ratios (RRs) of CVD in those with versus without SMI. Temporal trends were explored by decade. Subgroup analyses by age, sex, setting, world region, and study quality (Newcastle-Ottawa scale (NOS) score) were conducted. The narrative synthesis included 108 studies, and the quantitative synthesis 59 mortality studies (with (≥1,841,356 cases and 29,321,409 controls) and 28 incidence studies (≥401,909 cases and 14,372,146 controls). The risk of CVD-related mortality for people with SMI was higher than controls across most comparisons, except for total CVD-related mortality for BD and cerebrovascular accident (CVA) for mixed SMI. Estimated risks were larger for schizophrenia than BD. Pooled results ranged from SMR = 1.55 (95% confidence interval (CI): 1.33 to 1.81, p < 0.001), for CVA in people with BD to HR/rate ratio = 2.40 (95% CI: 2.25 to 2.55, p < 0.001) for CVA in schizophrenia. For schizophrenia and BD, SMRs and pooled HRs/rate ratios for CHD and CVD mortality were larger in studies with outcomes occurring during the 1990s and 2000s than earlier decades (1980s: SMR = 1.14, 95% CI: 0.57 to 2.30, p = 0.71; 2000s: SMR = 2.59, 95% CI: 1.93 to 3.47, p < 0.001 for schizophrenia and CHD) and in studies including people with younger age. The incidence of CVA, CVD events, and heart failure in SMI was higher than controls. Estimated risks for schizophrenia ranged from HR/rate ratio 1.25 (95% CI: 1.04 to 1.51, p = 0.016) for total CVD events to rate ratio 3.82 (95% CI: 3.1 to 4.71, p < 0.001) for heart failure. Incidence of CHD was higher in BD versus controls. However, for schizophrenia, CHD was elevated in higher-quality studies only. The HR/rate ratios for CVA and CHD were larger in studies with outcomes occurring after the 1990s. Study limitations include the high risk of bias of some studies as they drew a comparison cohort from general population rates and the fact that it was difficult to exclude studies that had overlapping populations, although attempts were made to minimise this. CONCLUSIONS: In this study, we found that SMI was associated with an approximate doubling in the rate ratio of CVD-related mortality, particularly since the 1990s, and in younger groups. SMI was also associated with increased incidence of CVA and CHD relative to control participants since the 1990s. More research is needed to clarify the association between SMI and CHD and ways to mitigate this risk.

Comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study using routine data of faecal calprotectin testing for inflammatory bowel disease.

BACKGROUND: Meta-analyses of test accuracy studies may provide estimates that are highly improbable in clinical practice. Tailored meta-analysis produces plausible estimates for the accuracy of a test within a specific setting by tailoring the selection of included studies compatible with a specific setting using information from the target setting. The aim of this study was to validate the tailored meta-analysis approach by comparing outcomes from tailored meta-analysis with outcomes from a setting specific test accuracy study. METHODS: A retrospective cohort study of primary care electronic health records provided setting-specific data on the test positive rate and disease prevalence. This was used to tailor the study selection from a review of faecal calprotectin testing for inflammatory bowel disease for meta-analysis using the binomial method and the Mahalanobis distance method. Tailored estimates were compared to estimates from a study of test accuracy in primary care using the same routine dataset. RESULTS: Tailoring resulted in the inclusion of 3/14 (binomial method) and 9/14 (Mahalanobis distance method) studies in meta-analysis. Sensitivity and specificity from tailored meta-analysis using the binomial method were 0.87 (95% CI 0.77 to 0.94) and 0.65 (95% CI 0.60 to 0.69) and 0.98 (95% CI 0.83 to 0.999) and 0.68 (95% CI 0.65 to 0.71), respectively using the Mahalanobis distance method. The corresponding estimates for the conventional meta-analysis were 0.94 (95% CI 0.90 to 0.97) and 0.67 (95% CI 0.57 to 0.76) and for the FC test accuracy study of primary care data 0.93 (95%CI 0.89 to 0.96) and 0.61 (95% CI 0.6 to 0.63) to detect IBD at a threshold of 50 µg/g. Although the binomial method produced a plausible estimate, the tailored estimates of sensitivity and specificity were not closer to the primary study estimates than the estimates from conventional meta-analysis including all 14 studies. CONCLUSIONS: Tailored meta-analysis does not always produce estimates of sensitivity and specificity that lie closer to the estimates derived from a primary study in the setting in question. Potentially, tailored meta-analysis may be improved using a constrained model approach and this requires further investigation.

Altered expression of ACOX2 in non-small cell lung cancer.

Peroxisomes are organelles that play essential roles in many metabolic processes, but also play roles in innate immunity, signal transduction, aging and cancer. One of the main functions of peroxisomes is the processing of very-long chain fatty acids into metabolites that can be directed to the mitochondria. One key family of enzymes in this process are the peroxisomal acyl-CoA oxidases (ACOX1, ACOX2 and ACOX3), the expression of which has been shown to be dysregulated in some cancers. Very little is however known about the expression of this family of oxidases in non-small cell lung cancer (NSCLC). ACOX2 has however been suggested to be elevated at the mRNA level in over 10% of NSCLC, and in the present study using both standard and bioinformatics approaches we show that expression of ACOX2 is significantly altered in NSCLC. ACOX2 mRNA expression is linked to a number of mutated genes, and associations between ACOX2 expression and tumour mutational burden and immune cell infiltration were explored. Links between ACOX2 expression and candidate therapies for oncogenic driver mutations such as KRAS were also identified. Furthermore, levels of acyl-CoA oxidases and other associated peroxisomal genes were explored to identify further links between the peroxisomal pathway and NSCLC. The results of this biomarker driven study suggest that ACOX2 may have potential clinical utility in the diagnosis, prognosis and stratification of patients into various therapeutically targetable options.

The Epidemiology of UK Autoimmune Liver Disease Varies With Geographic Latitude.

BACKGROUND & AIMS: The epidemiology of autoimmune liver disease (AILD) is challenging to study because of the diseases' rarity and because of cohort selection bias. Increased incidence farther from the Equator has been reported for multiple sclerosis, another autoimmune disease. We assessed the incidence of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) in relation to latitude. METHODS: We performed a retrospective cohort study using anonymized UK primary care records from January 1, 2002, to May 10, 2016. All adults without a baseline diagnosis of AILD were included and followed up until the first occurrence of an AILD diagnosis, death, or they left the database. Latitude was measured as registered general practice rounded down to whole degrees. RESULTS: The cohort included 8,590,421 records with 53.3 × 107 years of follow-up evaluation from 694 practices. There were 1314 incident cases of PBC, 396 of PSC, and 1034 of AIH. Crude incidences were as follows: PBC, 2.47 (95% CI, 2.34-2.60); PSC, 0.74 (95% CI, 0.67-0.82); and AIH, 1.94 (95% CI, 1.83-2.06) per 100,000 per year. PBC incidence correlated with female sex, smoking, and deprivation; PSC incidence correlated with male sex and non-smoking; AIH incidence correlated with female sex and deprivation. A more northerly latitude was associated strongly with incidence of PBC: 2.16 (95% CI, 1.79-2.60) to 4.86 (95% CI, 3.93-6.00) from 50°N to 57°N (P = .002) and incidence of AIH: 2.00 (95% CI, 1.65-2.43) to 3.28 (95% CI, 2.53-4.24) (P = .003), but not incidence of PSC: 0.82 (95% CI, 0.60-1.11) to 1.02 (95% CI, 0.64-1.61) (P = .473). Incidence after adjustment for age, sex, smoking, and deprivation status showed similar positive correlations for PBC and AIH with latitude, but not PSC. Incident AIH cases were younger at more northerly latitude. CONCLUSIONS: We describe an association in the United Kingdom between more northerly latitude and the incidence of PBC and AIH that requires both confirmation and explanation.

The incidence and prevalence of inflammatory bowel disease in UK primary care: a retrospective cohort study of the IQVIA Medical Research Database.

BACKGROUND: Our knowledge of the incidence and prevalence of inflammatory bowel disease (IBD) is uncertain. Recent studies reported an increase in prevalence. However, they excluded a high proportion of ambiguous cases from general practice. Estimates are needed to inform health care providers who plan the provision of services for IBD patients. We aimed to estimate the IBD incidence and prevalence in UK general practice. METHODS: We undertook a retrospective cohort study of routine electronic health records from the IQVIA Medical Research Database covering 14 million patients. Adult patients from 2006 to 2016 were included. IBD was defined as an IBD related Read code or record of IBD specific medication. Annual incidence and 12-month period prevalence were calculated. RESULTS: The prevalence of IBD increased between 2006 and 2016 from 106.2 (95% CI 105.2-107.3) to 142.1 (95% CI 140.7-143.5) IBD cases per 10,000 patients which is a 33.8% increase. Incidence varied across the years. The incidence across the full study period was 69.5 (95% CI 68.6-70.4) per 100,000 person years. CONCLUSIONS: In this large study we found higher estimates of IBD incidence and prevalence than previously reported. Estimates are highly dependent on definitions of disease and previously may have been underestimated.

Preoperative exercise to improve fitness in patients undergoing complex surgery for cancer of the lung or oesophagus (PRE-HIIT): protocol for a randomized controlled trial.

BACKGROUND: Patients with cancer of the lung or oesophagus, undergoing curative treatment, usually require a thoracotomy and a complex oncological resection. These surgeries carry a risk of major morbidity and mortality, and risk assessment, preoperative optimisation, and enhanced recovery after surgery (ERAS) pathways are modern approaches to optimise outcomes. Pre-operative fitness is an established predictor of postoperative outcome, accordingly, targeting pre-operative fitness through exercise prehabilitation has logical appeal. Exercise prehabilitation is challenging to implement however due to the short opportunity for intervention between diagnosis and surgery. Therefore, individually prescribed, intensive exercise training protocols which convey clinically meaningful improvements in cardiopulmonary fitness over a short period need to be investigated. This project will examine the influence of exercise prehabilitation on physiological outcomes and postoperative recovery and, through evaluation of health economics, the impact of the programme on hospital costs. METHODS: The PRE-HIIT Randomised Controlled Trial (RCT) will compare a 2-week high intensity interval training (HIIT) programme to standard preoperative care in a cohort of thoracic and oesophageal patients who are > 2-weeks pre-surgery. A total of 78 participants will be recruited (39 per study arm). The primary outcome is cardiorespiratory fitness. Secondary outcomes include, measures of pulmonary and physical and quality of life. Outcomes will be measured at baseline (T0), and post-intervention (T1). Post-operative morbidity will also be captured. The impact of PRE-HIIT on well-being will be examined qualitatively with focus groups/interviews post-intervention (T1). Participant's experience of preparation for surgery on the PRE-HIIT trial will also be explored. The healthcare costs associated with the PRE-HITT programme, in particular acute hospital costs, will also be examined. DISCUSSION: The overall aim of this RCT is to examine the effect of tailored, individually prescribed high intensity interval training aerobic exercise on pre-operative fitness and postoperative recovery for patients undergoing complex surgical resections, and the impact on use of health services. TRIAL REGISTRATION: The study is registered with Clinical Trials.Gov (NCT03978325). Registered on 7th June 2019.

The use of electronic healthcare records for colorectal cancer screening referral decisions and risk prediction model development.

BACKGROUND: The database used for the NHS Bowel Cancer Screening Programme (BCSP) derives participant information from primary care records. Combining predictors with FOBTs has shown to improve referral decisions and accuracy. The richer data available from GP databases could be used to complement screening referral decisions by identifying those at greatest risk of colorectal cancer. We determined the availability of data for key predictors and whether this information could be used to inform more accurate screening referral decisions. METHODS: An English BCSP cohort was derived using the electronic notifications received from the BCSP database to GP records. The cohort covered a period between 13th May 2009 to 17th January 2017. Completeness of variables and univariable associations were assessed. Risk prediction models were developed using Cox regression and multivariable fractional polynomials with backwards elimination. Optimism adjusted performance metrics were reported. The sensitivity and specificity of a combined approach using the negative FOBT model plus FOBT positive patients was determined using a probability equivalent to a 3% PPV NICE guidelines level. RESULTS: 292,059 participants aged 60-74 were derived for the BCSP screening cohort. A model including the screening test result had a C-statistic of 0.860, c-slope of 0.997, and R2 of 0.597. A model developed for negative screening results only had a C-statistic of 0.597, c-slope of 0.940, and R2 of 0.062. Risk predictors included in the models included; age, sex, alcohol consumption, IBS diagnosis, family history of gastrointestinal cancer, smoking status, previous negatives and whether a GP had ordered a blood test. For the combined screening approach, sensitivity increased slightly from 53.90% (FOBT only) to 58.82% but at the expense of an increased referral rate. CONCLUSIONS: This research has identified several potential predictors for CRC in a BCSP population. A risk prediction model developed for BCSP FOBT negative patients was not clinically useful due to a low sensitivity and increased referral rate. The predictors identified in this study should be investigated in a refined algorithm combining the quantitative FIT result. Combining data from multiple sources enables fuller patient profiles using the primary care and screening database interface.

Characterising the impact of body composition change during neoadjuvant chemotherapy for pancreatic cancer.

BACKGROUND: Pancreatic Cancer remains a lethal disease for the majority of patients. New chemotherapy agents such as Folfirinox offer therapeutic potential for patients who present with Borderline Resectable disease (BRPC). However, results to date are inconsistent, with factors such as malnutrition limiting successful drug delivery. We sought to determine the prevalence of sarcopenia in BRPC patients at diagnosis, and to quantify body composition change during chemotherapy. METHODS: The diagnostic/restaging CT scans of BRPC patients were analysed. Body composition was measured at L3 using Tomovision Slice-O-Matic™. Total muscle and adipose tissue mass were estimated using validated regression equations. Sarcopenia was defined as per gender- and body mass index (BMI)-specific lumbar skeletal muscle index (LSMI) and muscle attenuation reference values. RESULTS: Seventy-eight patients received neo-adjuvant chemotherapy, and 67 patients underwent restaging CT, at which point a third were deemed resectable. Half were sarcopenic at diagnosis, and sarcopenia was equally prevalent across all BMI categories.. Skeletal muscle and adipose tissue (intra-muscular, visceral and sub-cutaneous) area decreased during chemotherapy (p < 0.0001). Low muscle attenuation was observed in half of patients at diagnosis, and was associated with increased mortality risk. Loss of lean tissue parameters during chemotherapy was associated with an increased mortality risk; specifically fat-free mass, HR 1.1 (95% CI 1.03-1.17, p = 0.003) and skeletal muscle mass, HR 1.21 (95%CI 1.08-1.35, p = 0.001). CONCLUSIONS: Sarcopenia was prevalent in half of patients at the time of diagnosis with BRPC. Low muscle attenuation at diagnosis, coupled with lean tissue loss during chemotherapy, independently increased mortality risk.

Clinical and Demographic Characteristics Associated With Suboptimal Primary Stroke and Transient Ischemic Attack Prevention: Retrospective Analysis.

BACKGROUND AND PURPOSE: Primary prevention of stroke and transient ischemic attack (TIA) is important to reduce the burden of these conditions; however, prescribing of prevention drugs is suboptimal. We aimed to identify individual clinical and demographic characteristics associated with potential missed opportunities for prevention therapy with lipid-lowering, anticoagulant, or antihypertensive drugs before stroke/TIA. METHODS: We analyzed anonymized electronic primary care records from a UK primary care database that covers 561 family practices. Patients with first-ever stroke/TIA, ≥18 years, with diagnosis between January 1, 2009, and December 31, 2013, were included. Missed opportunities for prevention were defined as people with clinical indications for lipid-lowering, anticoagulant, or antihypertensive drugs but not prescribed these drugs before their stroke/TIA. Mixed-effect logistic regression models evaluated the relationship between missed opportunities and individual clinical/demographic characteristics. RESULTS: The inclusion criteria were met by 29 043 people with stroke/TIA. Patients with coronary heart disease, chronic kidney disease, peripheral arterial disease, or diabetes mellitus were at less risk of a missed opportunity for prescription of lipid-lowering and antihypertensive drugs. However, patients with a 10-year cardiovascular disease risk ≥20% but without these diagnoses had increased risk of having a missed opportunity for prescription of lipid-lowering drugs or antihypertensive drugs. Women were less likely to be prescribed anticoagulants but more likely to be prescribed antihypertensive drugs. The elderly (≥85 years of age) were less likely to be prescribed all 3 prevention drugs, compared with people aged 75 to 79 years. CONCLUSIONS: Knowing the patient characteristics predictive of missed opportunities for stroke prevention may help primary care identify and appropriately manage these patients. Improving the management of these groups may reduce their risk and potentially prevent large number of future strokes and TIAs in the population.

Analysis of Effect of National Institute for Health and Care Excellence Clinical Guideline CG168 on Management of Varicose Veins in Primary Care Using the Health Improvement Network Database.

OBJECTIVE/BACKGROUND: In July 2013, new UK guidelines recommended that all patients with symptomatic varicose veins (VV) be referred to a specialist vascular service for consideration of superficial venous intervention (SVI). In the UK, general practitioners (GPs) in primary care control access to publicly funded vascular services provided through the National Health Service. GP awareness and concordance with Clinical Guideline (CG)168 recommendations is vital if patients with VV are to receive evidence-based treatment in line with national recommendations. The aim was to assess the UK-wide impact of new guidelines on GP management of VV using a large database of electronic GP records. METHODS: An eligible population of patients aged ≥ 18 years was analysed over two 18-month periods, before and after guideline publication. Those with a new diagnosis of VV in each time period were analysed in terms of demographics, specialist referral, compression hosiery prescriptions, and recorded SVI. RESULTS: Analysis included approximately two million patients from 285 GP practices. Before and after CG168 cohorts were well matched. Study populations included 13,014 patients before and 12,466 patients after guideline publication. There was an increase in specialist referrals from 24% (n = 3173) to 28% (n = 3457) (Cox hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.09-1.20; p < .001). Median time to referral was 1.5 days. Prescribed compression hosiery declined from 20% (n = 2558) before the new guidelines to 18% (n = 2292) after the new guidelines (HR 0.93, 95% CI 0.88-0.98; p = .008). There were similar increases in proportions recorded as having SVI, from 3.6% (n = 469) before the new guidelines to 4.2% (n = 526) after the new guidelines (HR 1.16, 95% CI 1.02-1.31; p = .023). There was a statistically significant increase in endothermal ablation after CG168. In Cox models, age, sex, Townsend quintile, and body mass index were significantly related to the chance of referral and SVI. CONCLUSION: Encouragingly, following publication of National Institute for Health and Care Excellence CG168, there has been a statistically significant improvement in the management of VV in primary care in line with the CG recommendations.

Risk of chronic kidney disease in young adults with impaired glucose tolerance/impaired fasting glucose: a retrospective cohort study using electronic primary care records.

BACKGROUND: The risk of chronic kidney disease (CKD) is known to be elevated in patients with diabetes mellitus but the risk of young adults aged 18 to 40 years with impaired glucose tolerance/impaired fasting glucose (IGT/IFG) developing CKD is not well characterised. Furthermore, progression of IGT/IFG to diabetes and subsequent CKD development is not well understood. METHODS: A retrospective cohort study was undertaken using The Health Improvement Network (THIN) database, a large dataset of electronic patient records. THIN database is jointly managed by IMS Health Real World Evidence Solution ( http://www.epic-uk.org/index.html ) and In Practice System (InPs). Cases were aged 18 to 40, with a diagnosis of IGT/IFG and registered at a practice contributing to THIN between 2000 and 2015. The study population consisted of 40,092 patients, including 21,454 (53.5%) female and 18,638 (46.5%) male. The median follow-up was approximately 2 years. The outcome was a diagnosis of CKD determined from either clinical coding or laboratory results. For the primary analysis the unadjusted and adjusted relative risk of CKD in IGT/IFG was compared to age, sex and practice matched controls with normoglycaemia. For the secondary analysis we compared the incidence of CKD before to after a diagnosis of type 2 diabetes (T2DM) in the IGT/IFG study cohort. RESULTS: The Incidence Rate Ratio (IRR) for CKD for IGT/IFG compared to normoglycaemia was 4.0 [95% confidence interval (CI), 3.2 to 5.1, P < 0.001]. The adjusted IRR was 2.6 [95% CI, 2.0 to 3.4, P < 0.001]. The unadjusted IRR was 8.8 [95% CI, 7.7 to 10.0, P < 0.001] after IGT/IFG patients had developed T2DM and the adjusted IRR was 6.3 [95% CI, 5.5 to 7.2, P < 0.001]. CONCLUSION: Our results show that young IGT/IFG subjects are also at higher risk of developing CKD. This risk is modulated by the degree of baseline renal function and glucose tolerance, being higher in those developing T2DM.

Physician Support of Smoking Cessation After Diagnosis of Lung, Bladder, or Upper Aerodigestive Tract Cancer.

PURPOSE: Smoking cessation after a diagnosis of lung, bladder, and upper aerodigestive tract cancer appears to improve survival, and support to quit would improve cessation. The aims of this study were to assess how often general practitioners provide active smoking cessation support for these patients and whether physician behavior is influenced by incentive payments. METHODS: Using electronic primary care records from the UK Clinical Practice Research Datalink, 12,393 patients with incident cases of cancer diagnosed between 1999 and 2013 were matched 1 to 1 to patients with incident cases of coronary heart disease (CHD) diagnosed during the same time. We assessed differences in the proportion for whom physicians updated smoking status, advised quitting, and prescribed cessation medications, as well as the proportion of patients who stopped smoking within a year of diagnosis. We further examined whether any differences arose because the physicians were offered incentives to address smoking in patients with CHD and not cancer. RESULTS: At diagnosis, 32.0% of patients with cancer and 18.2% of patients with CHD smoked tobacco. Patients with cancer were less likely than patients with CHD to have their general practitioners update smoking status (OR = 0.18; 95% CI, 0.17-0.19), advise quitting (OR = 0.38; 95% CI, 0.36-0.40), or prescribe medication (OR = 0.67; 95% CI, 0.63-0.73), and they were less likely to have stopped smoking (OR = 0.76; 95% CI, 0.69-0.84). One year later 61.7% of patients with cancer and 55.4% with CHD who were smoking at diagnosis were still smoking. Introducing incentive payments was associated with more frequent interventions, but not for patients with CHD specifically. CONCLUSIONS: General practitioners were less likely to support smoking cessation in patients with cancer than with CHD, and patients with cancer were less likely to stop smoking. This finding is not due to the difference in incentive payments.

Survival following a diagnosis of heart failure in primary care.

Background: Heart failure is a common long term condition affecting around 900 000 people in the UK and patients commonly present to primary care. The prognosis of patients with a code of heart failure in their primary care record is unknown. Objective: The study sought to determine the overall survival rates for patients with heart failure in a primary care population from the time of diagnosis. Methods: Survival analysis was carried out using UK primary care records from The Health Improvement Network (THIN) between 1 January 1998 and 31 December 2012. Patients age 45 or over with a first diagnostic label of heart failure were matched by age, sex and practice to people without heart failure. Outcome was death in the heart failure and no heart failure cohorts. Kaplan-Meier curves were used to compare survival. Age-specific survival rates at 1, 5 and 10 years were determined for men and women with heart failure. Survival rates by year of diagnosis and case definition were also calculated. Results: During the study period, 54313 patients had a first diagnostic code of heart failure. Overall survival rates for the heart failure group were 81.3% (95%CI 80.9-81.6), 51.5% (95%CI 51.0-52.0) and 29.5% (95%CI 28.9-30.2) at 1, 5 and 10 years respectively and did not change over time. Conclusions: In a primary care population, the survival of patients diagnosed with heart failure did not improved over time. Further research is needed to explain these trends and to find strategies to improve outlook.

Under-prescribing of Prevention Drugs and Primary Prevention of Stroke and Transient Ischaemic Attack in UK General Practice: A Retrospective Analysis.

BACKGROUND: Stroke is a leading cause of death and disability; worldwide it is estimated that 16.9 million people have a first stroke each year. Lipid-lowering, anticoagulant, and antihypertensive drugs can prevent strokes, but may be underused. METHODS AND FINDINGS: We analysed anonymised electronic primary care records from a United Kingdom (UK) primary care database that covers approximately 6% of the UK population. Patients with first-ever stroke/transient ischaemic attack (TIA), ≥18 y, with diagnosis between 1 January 2009 and 31 December 2013, were included. Drugs were considered under-prescribed when lipid-lowering, anticoagulant, or antihypertensive drugs were clinically indicated but were not prescribed prior to the time of stroke or TIA. The proportions of strokes or TIAs with prevention drugs under-prescribed, when clinically indicated, were calculated. In all, 29,043 stroke/TIA patients met the inclusion criteria; 17,680 had ≥1 prevention drug clinically indicated: 16,028 had lipid-lowering drugs indicated, 3,194 anticoagulant drugs, and 7,008 antihypertensive drugs. At least one prevention drug was not prescribed when clinically indicated in 54% (9,579/17,680) of stroke/TIA patients: 49% (7,836/16,028) were not prescribed lipid-lowering drugs, 52% (1,647/3,194) were not prescribed anticoagulant drugs, and 25% (1,740/7,008) were not prescribed antihypertensive drugs. The limitations of our study are that our definition of under-prescribing of drugs for stroke/TIA prevention did not address patients' adherence to medication or medication targets, such as blood pressure levels. CONCLUSIONS: In our study, over half of people eligible for lipid-lowering, anticoagulant, or antihypertensive drugs were not prescribed them prior to first stroke/TIA. We estimate that approximately 12,000 first strokes could potentially be prevented annually in the UK through optimal prescribing of these drugs. Improving prescription of lipid-lowering, anticoagulant, and antihypertensive drugs is important to reduce the incidence and burden of stroke and TIA.

Development and validation of an electronic frailty index using routine primary care electronic health record data.

BACKGROUND: frailty is an especially problematic expression of population ageing. International guidelines recommend routine identification of frailty to provide evidence-based treatment, but currently available tools require additional resource. OBJECTIVES: to develop and validate an electronic frailty index (eFI) using routinely available primary care electronic health record data. STUDY DESIGN AND SETTING: retrospective cohort study. Development and internal validation cohorts were established using a randomly split sample of the ResearchOne primary care database. External validation cohort established using THIN database. PARTICIPANTS: patients aged 65-95, registered with a ResearchOne or THIN practice on 14 October 2008. PREDICTORS: we constructed the eFI using the cumulative deficit frailty model as our theoretical framework. The eFI score is calculated by the presence or absence of individual deficits as a proportion of the total possible. Categories of fit, mild, moderate and severe frailty were defined using population quartiles. OUTCOMES: outcomes were 1-, 3- and 5-year mortality, hospitalisation and nursing home admission. STATISTICAL ANALYSIS: hazard ratios (HRs) were estimated using bivariate and multivariate Cox regression analyses. Discrimination was assessed using receiver operating characteristic (ROC) curves. Calibration was assessed using pseudo-R(2) estimates. RESULTS: we include data from a total of 931,541 patients. The eFI incorporates 36 deficits constructed using 2,171 CTV3 codes. One-year adjusted HR for mortality was 1.92 (95% CI 1.81-2.04) for mild frailty, 3.10 (95% CI 2.91-3.31) for moderate frailty and 4.52 (95% CI 4.16-4.91) for severe frailty. Corresponding estimates for hospitalisation were 1.93 (95% CI 1.86-2.01), 3.04 (95% CI 2.90-3.19) and 4.73 (95% CI 4.43-5.06) and for nursing home admission were 1.89 (95% CI 1.63-2.15), 3.19 (95% CI 2.73-3.73) and 4.76 (95% CI 3.92-5.77), with good to moderate discrimination but low calibration estimates. CONCLUSIONS: the eFI uses routine data to identify older people with mild, moderate and severe frailty, with robust predictive validity for outcomes of mortality, hospitalisation and nursing home admission. Routine implementation of the eFI could enable delivery of evidence-based interventions to improve outcomes for this vulnerable group.

Implementing a physiotherapy led cancer exercise programme in a National Cancer Centre: the FIXCAS study.

OBJECTIVES: To examine the feasibility of implementing a 10-week exercise-based cancer rehabilitation programme in a national cancer centre. DESIGN: A single-arm prospective feasibility study. SETTING: An outpatient physiotherapy department. PARTICIPANTS: Forty de-conditioned cancer survivors (<1 year post completion of treatment). INTERVENTIONS: A 10-week programme of twice weekly group-based supervised exercise sessions. MAIN OUTCOME MEASURES: A mixed methods approach was used. The primary outcome of the study was feasibility, evaluated in terms of recruitment, adherence, attrition and stakeholder acceptance of the programme. Secondary outcomes examined the effect of the exercise intervention on physical function and quality of life measures. RESULTS: Forty patients (age 60 (SD 10.6) years; n = 12 breast cancer, n = 11 lung cancer, n = 7 prostate cancer, n = 5 colorectal cancer, n = 5 other) participated. In total 82% (n = 33) participants completed the post-programme assessment. Deterioration of health and concerns over COVID-19 were the most common reasons for dropout (both n = 2). Adherence to both the supervised exercise classes and home exercise programme was high (78% and 94% respectively). No adverse events were recorded during the intervention or assessments. Qualitative feedback from stakeholders highlighted the acceptability of the programme as well as many perceived benefits of the exercise programme. Improvements in three quality of life sub-scales (physical function, role function and emotional function), physical activity levels and aerobic fitness levels were found post-intervention. CONCLUSION: It appears feasible to offer a 10-week exercise programme to patients attending a national cancer centre, with adequate recruitment, retention and adherence rates and high acceptability among stakeholders. CONTRIBUTION OF THE PAPER.

An Analysis of JADE2 in Non-Small Cell Lung Cancer (NSCLC).

The JADE family comprises three members encoded by individual genes and roles for these proteins have been identified in chromatin remodeling, cell cycle progression, cell regeneration and the DNA damage response. JADE family members, and in particular JADE2 have not been studied in any great detail in cancer. Using a series of standard biological and bioinformatics approaches we investigated JADE2 expression in surgically resected non-small cell lung cancer (NSCLC) for both mRNA and protein to examine for correlations between JADE2 expression and overall survival. Additional correlations were identified using bioinformatic analyses on multiple online datasets. Our analysis demonstrates that JADE2 expression is significantly altered in NSCLC. High expression of JADE2 is associated with a better 5-year overall survival. Links between JADE2 mRNA expression and a number of mutated genes were identified, and associations between JADE2 expression and tumor mutational burden and immune cell infiltration were explored. Potential new drugs that can target JADE2 were identified. The results of this biomarker-driven study suggest that JADE2 may have potential clinical utility in the diagnosis, prognosis and stratification of patients into various therapeutically targetable options.