Derivation and Validation of a 10-Year Risk Score for Symptomatic Abdominal Aortic Aneurysm: Cohort Study of Nearly 500 000 Individuals.

BACKGROUND: Abdominal aortic aneurysm (AAA) can occur in patients who are ineligible for routine ultrasound screening. A simple AAA risk score was derived and compared with current guidelines used for ultrasound screening of AAA. METHODS: United Kingdom Biobank participants without previous AAA were split into a derivation cohort (n=401 820, 54.6% women, mean age 56.4 years, 95.5% White race) and validation cohort (n=83 816). Incident AAA was defined as first hospital inpatient diagnosis of AAA, death from AAA, or an AAA-related surgical procedure. A multivariable Cox model was developed in the derivation cohort into an AAA risk score that did not require blood biomarkers. To illustrate the sensitivity and specificity of the risk score for AAA, a theoretical threshold to refer patients for ultrasound at 0.25% 10-year risk was modeled. Discrimination of the risk score was compared with a model of US Preventive Services Task Force (USPSTF) AAA screening guidelines. RESULTS: In the derivation cohort, there were 1570 (0.40%) cases of AAA over a median 11.3 years of follow-up. Components of the AAA risk score were age (stratified by smoking status), weight (stratified by smoking status), antihypertensive and cholesterol-lowering medication use, height, diastolic blood pressure, baseline cardiovascular disease, and diabetes. In the validation cohort, over 10 years of follow-up, the C-index for the model of the USPSTF guidelines was 0.705 (95% CI, 0.678-0.733). The C-index of the risk score as a continuous variable was 0.856 (95% CI, 0.837-0.878). In the validation cohort, the USPSTF model yielded sensitivity 63.9% and specificity 71.3%. At the 0.25% 10-year risk threshold, the risk score yielded sensitivity 82.1% and specificity 70.7% while also improving the net reclassification index compared with the USPSTF model +0.176 (95% CI, 0.120-0.232). A combined model, whereby risk scoring was combined with the USPSTF model, also improved prediction compared with USPSTF alone (net reclassification index +0.101 [95% CI, 0.055-0.147]). CONCLUSIONS: In an asymptomatic general population, a risk score based on patient age, height, weight, and medical history may improve identification of asymptomatic patients at risk for clinical events from AAA. Further development and validation of risk scores to detect asymptomatic AAA are needed.

Association Between Walking Pace and Stroke Incidence: Findings From the UK Biobank Prospective Cohort Study.

Background and Purpose- Stroke incidence in younger and middle-aged people is growing. Despite this, its associations in this subset of the stroke population are unknown, and prevention strategies are not tailored to meet their needs. This study examined the association between self-reported walking pace and incident stroke. Methods- Data from the UK Biobank were used in a prospective population-based study. Three hundred and sixty-three thousand, one hundred and thirty-seven participants aged 37 to 73 years (52% women) were recruited. The associations of self-reported walking pace with stroke incidence over follow-up were investigated using Cox proportional-hazard models. Results- Among 363,137 participants, 2705 (0.7%) participants developed a fatal or nonfatal stroke event over the mean follow-up period of 6.1 years (interquartile range, 5.4-6.7). Slow walking pace was associated with a higher hazard for stroke incidence (hazard ratio [HR], 1.45 [95% CI, 1.26-1.66]; P<0.0001). Stroke incidence was not associated with walking pace among people <65 years of age. However, slow walking pace was associated with a higher risk of stroke among participants aged ≥65 years (HR, 1.42 [95% CI, 1.17-1.72]; P<0.0001). A higher risk for stroke was observed on those with middle (HR, 1.28 [95% CI, 1.01-1.63]; P=0.039) and higher (HR, 1.29 [95% CI, 1.05-1.69]; P=0.012) deprivation levels but not in the least deprived individuals. Similarly, overweight (HR, 1.30 [95% CI, 1.04-1.63]; P=0.019) and obese (HR, 1.33 [95% CI, 1.09-1.63]; P=0.004) but not normal-weight individuals had a higher risk of stroke incidence. Conclusions- Slow walking pace was associated with a higher risk of stroke among participants over 64 years of age in this population-based cohort study. The addition of the measurement of self-reported walking pace to primary care or public health clinical consultations may be a useful screening tool for stroke risk.

Static Socio-Ecological COVID-19 Vulnerability Index and Vaccine Hesitancy Index for England.

BACKGROUND: Population characteristics can be used to infer vulnerability of communities to COVID-19, or to the likelihood of high levels of vaccine hesitancy. Communities harder hit by the virus, or at risk of being so, stand to benefit from greater resource allocation than their population size alone would suggest. This study reports a simple but efficacious method of ranking small areas of England by relative characteristics that are linked with COVID-19 vulnerability and vaccine hesitancy. METHODS: Publicly available data on a range of characteristics previously linked with either poor COVID-19 outcomes or vaccine hesitancy were collated for all Middle Super Output Areas of England (MSOA, n=6790, excluding Isles of Scilly), scaled and combined into two numeric indices. Multivariable linear regression was used to build a parsimonious model of vulnerability (static socio-ecological vulnerability index, SEVI) in 60% of MSOAs, and retained variables were used to construct two simple indices. Assuming a monotonic relationship between indices and outcomes, Spearman correlation coefficients were calculated between the SEVI and cumulative COVID-19 case rates at MSOA level in the remaining 40% of MSOAs over periods both during and out with national lockdowns. Similarly, a novel vaccine hesitancy index (VHI) was constructed using population characteristics aligned with factors identified by an Office for National Statistics (ONS) survey analysis. The relationship between the VHI and vaccine coverage in people aged 12+years (as of 2021-06-24) was determined using Spearman correlation. The indices were split into quintiles, and MSOAs within the highest vulnerability and vaccine hesitancy quintiles were mapped. FINDINGS: The SEVI showed a moderate to strong relationship with case rates in the validation dataset across the whole study period, and for every intervening period studied except early in the pandemic when testing was highly selective. The SEVI was more strongly correlated with case rates than any of its domains (rs 0·59 95% CI 0.57-0.62) and outperformed an existing MSOA-level vulnerability index. The VHI was significantly negatively correlated with COVID-19 vaccine coverage in the validation data at the time of writing (rs -0·43 95% CI -0·46 to -0·41). London had the largest number and proportion of MSOAs in quintile 5 (most vulnerable/hesitant) of SEVI and VHI concurrently. INTERPRETATION: The indices presented offer an efficacious way of identifying geographical disparities in COVID-19 risk, thus helping focus resources according to need. FUNDING: Funder: Integrated Covid Hub North East. AWARD NUMBER: n/a. GRANT RECIPIENT: Fiona Matthews.

Explaining the deprivation gap in COVID-19 mortality rates: A decomposition analysis of geographical inequalities in England.

One of the most consistent and worrying features of the COVID-19 pandemic globally has been the disproportionate burden of the epidemic in the most deprived areas. Most of the literature so far though has focused on estimating the extent of these inequalities. There has been much less attention paid to exploring the main pathways underpinning them. In this study, we employ the syndemic pandemic theoretical framework and apply novel decomposition methods to investigate the proportion of the COVID-19 mortality gap by area-level deprivation in England during the first wave of the pandemic (January to July 2020) was accounted for by pre-existing inequalities in the compositional and contextual characteristics of place. We use a decomposition approach to explicitly quantify the independent contribution of four inequalities pathways (vulnerability, susceptibility, exposure and transmission) in explaining the more severe COVID-19 outcomes in the most deprived local authorities compared to the rest. We find that inequalities in transmission (73%) and in vulnerability (49%) factors explained the highest proportion of mortality by deprivation. Our results suggest that public health agencies need to develop short- and long-term strategies to alleviate these underlying inequalities in order to alleviate the more severe impacts on the most vulnerable communities.

Trends in life expectancy and healthy life years at birth and age 65 in the UK, 2008-2016, and other countries of the EU28: An observational cross-sectional study.

BACKGROUND: As society ages, promoting the health of the extra years of life is of paramount importance for health, social care and pension provision. Increases in life expectancy in the UK and elsewhere have slowed in recent years, but the reasons for this are unclear. No formal comparison of trends in healthy life years between the UK and the other countries of the EU28 in recent times has been published. These countries are geographically proximate, and share many social, cultural and demographic properties, making them interesting and useful comparators, especially as the UK prepared to leave the European Union in 2020. METHODS: We calculated sex-specific healthy life years (HLY), unhealthy life years (ULY), mild and severe ULY at birth and age 65 using life tables and age-specific prevalence of activity limitation amongst the EU28 between 2008 and 2016 from EuroHex. Trends in life expectancy, HLY, ULY and proportion of life spent healthy (HLY%) were compared. We then decomposed HLY temporal changes into relative effects of changes in healthy life and mortality, by age group. FINDINGS: Life expectancy at birth, and age 65, in the UK were increasing rapidly in 2008 but slowed around 2011. Germany, Portugal and France showed evidence of a similar slowing. HLY at birth in the UK decreased, whereas it increased in most EU28 countries. The UK experienced a period of absolute expansion of unhealthy life in both sexes. The reduction in HLY at birth in the UK was mainly attributable to increases in unhealthy life in younger age groups. INTERPRETATION: The UK's performance relative to the other countries of the EU28 was poor after 2011, combining static life expectancy and reductions in healthy life years. These trends suggest that the UK government's Ageing Society Grand Challenge (to increase the healthy life expectancy by five years by 2035) will be difficult to attain. FUNDING: National Institute for Health Research (NIHR) Policy Research Programme conducted through the NIHR Older People and Frailty Policy Research Unit, PR-PRU-1217-21502. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Can vaccination roll-out be more equitable if population risk is taken into account?

BACKGROUND: COVID-19 vaccination in many countries, including England, has been prioritised primarily by age. However, people of the same age can have very different health statuses. Frailty is a commonly used metric of health and has been found to be more strongly associated with mortality than age among COVID-19 inpatients. METHODS: We compared the number of first vaccine doses administered across the 135 NHS Clinical Commissioning Groups (CCGs) of England to both the over 50 population and the estimated frail population in each area. Area-based frailty estimates were generated using the English Longitudinal Survey of Ageing (ELSA), a national survey of older people. We also compared the number of doses to the number of people with other risk factors associated with COVID-19: atrial fibrillation, chronic kidney disease, diabetes, learning disabilities, obesity and smoking status. RESULTS: We estimate that after 79 days of the vaccine program, across all Clinical Commissioning Group areas, the number of people who received a first vaccine per frail person ranged from 4.4 (95% CI 4.0-4.8) and 20.1 (95% CI 18.3-21.9). The prevalences of other risk factors were also poorly associated with the prevalence of vaccination across England. CONCLUSIONS: Vaccination with age-based priority created area-based inequities in the number of doses administered relative to the number of people who are frail or have other risk factors associated with COVID-19. As frailty has previously been found to be more strongly associated with mortality than age for COVID-19 inpatients, an age-based priority system may increase the risk of mortality in some areas during the vaccine roll-out period. Authorities planning COVID-19 vaccination programmes should consider the disadvantages of an age-based priority system.

Multimorbidity and the risk of major adverse kidney events: findings from the UK Biobank cohort.

BACKGROUND: Multimorbidity [the presence of two or more long-term conditions (LTCs)] is associated with a heightened risk of mortality, but little is known about its relationship with the risk of kidney events. METHODS: Associations between multimorbidity and major adverse kidney events [MAKE: the need for long-term kidney replacement therapy, doubling of serum creatinine, fall of estimated glomerular filtration rate (eGFR) to <15 mL/min/1.73 m2 or 30% decline in eGFR] were studied in 68 505 participants from the UK Biobank cohort. Participants were enrolled in the study between 2006 and 2010. Associations between LTC counts and MAKE were tested using survival analyses accounting for the competing risk of death. RESULTS: Over a median follow-up period of 12.0 years, 2963 participants had MAKE. There were associations between LTC count categories and the risk of MAKE [one LTC adjusted subhazard ratio (sHR) = 1.29, 95% confidence interval (CI) 1.15-1.45; two LTCs sHR = 1.74 (95% CI 1.55-1.96); and three or more LTCs sHR = 2.41 (95% CI 2.14-2.71)]. This finding was more pronounced when only cardiometabolic LTCs were considered [one LTC sHR = 1.58 (95% CI 1.45-1.73); two LTCs sHR = 3.17 (95% CI 2.80-3.59); and three or more LTCs sHR = 5.24 (95% CI 4.34-6.33)]. Combinations of LTCs associated with MAKE were identified. Diabetes, hypertension and coronary heart disease featured most commonly in high-risk combinations. CONCLUSIONS: Multimorbidity, and in particular cardiometabolic multimorbidity, is a risk factor for MAKE. Future research should study groups of patients who are at high risk of progressive kidney disease based on the number and type of LTCs.

Ethnic differences in prevalence of actionable HbA1c levels in UK Biobank: implications for screening.

INTRODUCTION: Early detection and treatment of diabetes as well as its prevention help lessen longer-term complications. We determined the prevalence of pre-diabetes and undiagnosed diabetes in the UK Biobank and standardized the results to the UK general population. RESEARCH DESIGN AND METHODS: This cross-sectional study analyzed baseline UK Biobank data on plasma glycated hemoglobin (HbA1c) to compare the prevalence of pre-diabetes and undiagnosed diabetes mellitus in white, South Asian, black, and Chinese participants. The overall and ethnic-specific results were standardized to the UK general population aged 40-70 years of age. RESULTS: Within the UK Biobank, the overall crude prevalence was 3.6% for pre-diabetes, 0.8% for undiagnosed diabetes, and 4.4% for either. Following standardization to the UK general population, the results were similar at 3.8%, 0.8%, and 4.7%, respectively. Crude prevalence was much higher in South Asian (11.0% pre-diabetes; 3.6% undiagnosed diabetes; 14.6% either) or black (13.8% pre-diabetes; 3.0% undiagnosed diabetes; 16.8% either) participants. Only six middle-aged or old-aged South Asian individuals or seven black would need to be tested to identify an HbA1c result that merits action. CONCLUSIONS: Single-stage population screening for pre-diabetes or undiagnosed diabetes in middle-old or old-aged South Asian and black individuals using HbA1c could be efficient and should be considered.

A retrospective study of more than 400 feline nasal biopsy samples in the UK (2006-2013).

OBJECTIVES: The main objective of this study was to utilise a large database from a UK-based, commercial veterinary diagnostic laboratory to ascertain the prevalence of different forms of nasal disease within the feline population. Further objectives included using this database to detect any breed, sex or age predilections, or associations between the degree of brachycephalism, and the different conditions diagnosed. METHODS: Records from the laboratory were searched for feline submissions received between 31 May 2006 and 31 October 2013. For all samples taken from the nasal cavity, the diagnosis was recorded together with the breed, age, sex and neuter status of the cat, whether the clinical presentation was uni- or bilateral and whether a nasal discharge was present. Pedigree breeds were further subclassified according to skull conformation into brachycephalic, mesocephalic and dolichocephalic. Logistic regression models were constructed to assess the adjusted magnitude of association of significant risk factors with each disease, and each disease was also used as a potential independent risk factor for each other disease. RESULTS: The most prevalent nasal disease was rhinitis, followed by neoplasia and polyps. The most commonly diagnosed neoplasm was lymphoma, followed by adenocarcinoma and undifferentiated carcinoma, with benign tumours being very uncommon. No significant association was found between skull conformation and nasal diseases. The only statistically significant association was polyps being more likely to arise in younger male cats, with a mesocephalic skull conformation and no nasal discharge. CONCLUSIONS AND RELEVANCE: No significant association was found between skull conformation and nasal diseases, contrary to what might be expected. The only significant association found between any of the potential risk factors and various forms of nasal disease was polyps being more likely to arise in younger cats; other identified associations are only likely to be weak.

Author Correction: Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Grip Strength and Walking Pace and Cardiovascular Disease Risk Prediction in 406,834 UK Biobank Participants.

OBJECTIVE: To investigate whether the addition of grip strength and/or self-reported walking pace to established cardiovascular disease (CVD) risk scores improves their predictive abilities. PATIENTS AND METHODS: A total of 406,834 participants from the UK Biobank, with baseline measurements between March 13, 2006, and October 1, 2010, without CVD at baseline were included in this study. Associations of grip strength and walking pace with CVD outcomes were investigated using Cox models adjusting for classical risk factors (as included in established risk scores), and predictive utility was determined by changes in C-index and categorical net reclassification index. RESULTS: Over a median of 8.87 years of follow-up (interquartile range 3, 8.25-9.47 years), there were 7274 composite fatal/nonfatal events (on the basis of the American College of Cardiology/American Heart Association [ACC/AHA] outcome) and 1955 fatal events (on the basis of the Systematic Coronary Risk Evaluation [SCORE] risk score). Both grip strength and walking pace were inversely associated with CVD outcomes after adjusting for classical risk factors. Addition of grip strength (change in C-index: ACC/AHA, +0.0017; SCORE, +0.0047), usual walking pace (ACC/AHA, +0.0031; SCORE, +0.0130), and both combined (ACC/AHA, +0.0041; SCORE, +0.0148) improved the C-index and also improved the net reclassification index (grip, +0.55%; walking pace, +0.53%; combined, 1.12%). CONCLUSION: The present study has found that the addition of grip strength or usual walking pace to existing risk scores results in improved CVD risk prediction, with an additive effect when both are added. As both these measures are cheap and easy to administer, these tools could provide an important addition to CVD risk screening, although further external validation is required.

Glomerular filtration rate by differing measures, albuminuria and prediction of cardiovascular disease, mortality and end-stage kidney disease.

Chronic kidney disease is common in the general population and associated with excess cardiovascular disease (CVD), but kidney function does not feature in current CVD risk-prediction models. We tested three formulae for estimated glomerular filtration rate (eGFR) to determine which was the most clinically informative for predicting CVD and mortality. Using data from 440,526 participants from UK Biobank, eGFR was calculated using serum creatinine, cystatin C (eGFRcys) and creatinine-cystatin C. Associations of each eGFR with CVD outcome and mortality were compared using Cox models and adjusting for atherosclerotic risk factors (per relevant risk scores), and the predictive utility was determined by the C-statistic and categorical net reclassification index. We show that eGFRcys is most strongly associated with CVD and mortality, and, along with albuminuria, adds predictive discrimination to current CVD risk scores, whilst traditional creatinine-based measures are weakly associated with risk. Clinicians should consider measuring eGFRcys as part of cardiovascular risk assessment.

Disease and pharmacologic risk factors for first and subsequent episodes of equine laminitis: A cohort study of free-text electronic medical records.

Electronic medical records from first opinion equine veterinary practice may represent a unique resource for epidemiologic research. The appropriateness of this resource for risk factor analyses was explored as part of an investigation into clinical and pharmacologic risk factors for laminitis. Amalgamated medical records from seven UK practices were subjected to text mining to identify laminitis episodes, systemic or intra-synovial corticosteroid prescription, diseases known to affect laminitis risk and clinical signs or syndromes likely to lead to corticosteroid use. Cox proportional hazard models and Prentice, Williams, Peterson models for repeated events were used to estimate associations with time to first, or subsequent laminitis episodes, respectively. Over seventy percent of horses that were diagnosed with laminitis suffered at least one recurrence. Risk factors for first and subsequent laminitis episodes were found to vary. Corticosteroid use (prednisolone only) was only significantly associated with subsequent, and not initial laminitis episodes. Electronic medical record use for such analyses is plausible and offers important advantages over more traditional data sources. It does, however, pose challenges and limitations that must be taken into account, and requires a conceptual change to disease diagnosis which should be considered carefully.

Prevalence, survival analysis and multimorbidity of chronic diseases in the general veterinarian-attended horse population of the UK.

The average age of the global human population is increasing, leading to increased interest in the effects of chronic disease and multimorbidity on health resources and patient welfare. It has been posited that the average age of the general veterinarian-attended horse population of the UK is also increasing, and therefore it could be assumed that chronic diseases and multimorbidity would pose an increasing risk here also. However, evidence for this trend in ageing is very limited, and the current prevalence of many chronic diseases, and of multimorbidity, is unknown. Using text mining of first-opinion electronic medical records from seven veterinary practices around the UK, Kaplan-Meier and Cox proportional hazard modelling, we were able to estimate the apparent prevalence among veterinarian-attended horses of nine chronic diseases, and to assess their relative effects on median life expectancy following diagnosis. With these methods we found evidence of increasing population age. Multimorbidity affected 1.2% of the study population, and had a significant effect upon survival times, with co-occurrence of two diseases, and three or more diseases, leading to 6.6 and 21.3 times the hazard ratio compared to no chronic disease, respectively. Laminitis was involved in 74% of cases of multimorbidity. The population of horses attended by UK veterinarians appears to be aging, and chronic diseases and their co-occurrence are common features, and as such warrant further investigation.

Estimates of genetic parameters of distal limb fracture and superficial digital flexor tendon injury in UK Thoroughbred racehorses.

A retrospective cohort study of distal limb fracture and superficial digital flexor tendon (SDFT) injury in Thoroughbred racehorses was conducted using health records generated by the British Horseracing Authority (BHA) between 2000 and 2010. After excluding records of horses that had both flat and jump racing starts, repeated records were reduced to a single binary record per horse (n = 66,507, 2982 sires), and the heritability of each condition was estimated using residual maximum likelihood (REML) with animal logistic regression models. Similarly, the heritability of each condition was estimated for the flat racing and jump racing populations separately. Bivariate mixed models were used to generate estimates of genetic correlations between SDFT injury and distal limb fracture. The heritability of distal limb fracture ranged from 0.21 to 0.37. The heritability of SDFT injury ranged from 0.31 to 0.34. SDFT injury and distal limb fracture were positively genetically correlated. These findings suggest that reductions in the risk of the conditions studied could be attempted using targeted breeding strategies.

Preliminary genetic analyses of important musculoskeletal conditions of Thoroughbred racehorses in Hong Kong.

A retrospective cohort study of important musculoskeletal conditions of Thoroughbred racehorses was conducted using health records generated over a 15 year period (n=5062, 1296 sires). The prevalence of each condition in the study population was: fracture, 13%; osteoarthritis, 10%; suspensory ligament injury, 10%; and tendon injury, 19%. Linear and logistic sire and animal regression models were built to describe the binary occurrence of these musculoskeletal conditions, and to evaluate the significance of possible environmental risk factors. The heritability of each condition was estimated using residual maximum likelihood (REML). Bivariate mixed models were used to generate estimates of genetic correlations between each pair of conditions. Heritability estimates of fracture, osteoarthritis, suspensory ligament and tendon injury were small to moderate (range: 0.01-0.20). Fracture was found to be positively genetically correlated with both osteoarthritis and suspensory ligament injury. These results suggest that there is a significant genetic component involved in the risk of the studied conditions. Due to positive genetic correlations, a reduction in prevalence of one of the correlated conditions may effect a reduction in risk of the other condition.

Trypanosoma brucei cathepsin-L increases arrhythmogenic sarcoplasmic reticulum-mediated calcium release in rat cardiomyocytes.

AIMS: African trypanosomiasis, caused by Trypanosoma brucei species, leads to both neurological and cardiac dysfunction and can be fatal if untreated. While the neurological-related pathogenesis is well studied, the cardiac pathogenesis remains unknown. The current study exposed isolated ventricular cardiomyocytes and adult rat hearts to T. brucei to test whether trypanosomes can alter cardiac function independent of a systemic inflammatory/immune response. METHODS AND RESULTS: Using confocal imaging, T. brucei and T. brucei culture media (supernatant) caused an increased frequency of arrhythmogenic spontaneous diastolic sarcoplasmic reticulum (SR)-mediated Ca(2+) release (Ca(2+) waves) in isolated adult rat ventricular cardiomyocytes. Studies utilising inhibitors, recombinant protein and RNAi all demonstrated that this altered SR function was due to T. brucei cathepsin-L (TbCatL). Separate experiments revealed that TbCatL induced a 10-15% increase of SERCA activity but reduced SR Ca(2+) content, suggesting a concomitant increased SR-mediated Ca(2+) leak. This conclusion was supported by data demonstrating that TbCatL increased Ca(2+) wave frequency. These effects were abolished by autocamtide-2-related inhibitory peptide, highlighting a role for CaMKII in the TbCatL action on SR function. Isolated Langendorff perfused whole heart experiments confirmed that supernatant caused an increased number of arrhythmic events. CONCLUSION: These data demonstrate for the first time that African trypanosomes alter cardiac function independent of a systemic immune response, via a mechanism involving extracellular cathepsin-L-mediated changes in SR function.