An exploration into the causal relationships between educational attainment, intelligence, and wellbeing: an observational and two-sample Mendelian randomisation study.

Educational attainment is associated with a range of positive outcomes, yet its impact on wellbeing is unclear, and complicated by high correlations with intelligence. We use genetic and observational data to investigate for the first time, whether educational attainment and intelligence are causally and independently related to wellbeing. Results from our multivariable Mendelian randomisation demonstrated a positive causal impact of a genetic predisposition to higher educational attainment on wellbeing that remained after accounting for intelligence, and a negative impact of intelligence that was independent of educational attainment. Observational analyses suggested that these associations may be subject to sex differences, with benefits to wellbeing greater for females who attend higher education compared to males. For intelligence, males scoring more highly on measures related to happiness were those with lower intelligence. Our findings demonstrate a unique benefit for wellbeing of staying in school, over and above improving cognitive abilities, with benefits likely to be greater for females compared to males.

Childhood correlates and young adult outcomes of trajectories of emotional problems from childhood to adolescence.

BACKGROUND: Emotional problems, especially anxiety, have become increasingly common in recent generations. Few population-based studies have examined trajectories of emotional problems from early childhood to late adolescence or investigated differences in psychiatric and functional outcomes. METHODS: Using the Avon Longitudinal Study of Parents and Children (ALSPAC, n = 8286, 50.4% male), we modeled latent class growth trajectories of emotional problems, using the parent-reported Strength and Difficulties Questionnaire emotional scale (SDQ-E) on seven occasions (4-17 years). Psychiatric outcomes in young adulthood (21-25 years) were major depressive disorder (MDD), generalized anxiety disorder (GAD), and self-harm. Functional outcomes were exam attainment, educational/occupational status, and social relationship quality. RESULTS: We identified four classes of emotional problems: low (67.0%), decreasing (18.4%), increasing (8.9%), and persistent (5.7%) problems. Compared to those in the low class, individuals with decreasing emotional problems were not at elevated risk of any poor adult outcome. Individuals in the increasing and persistent classes had a greater risk of adult MDD (RR: 1.59 95% CI 1.13-2.26 and RR: 2.25 95% CI 1.49-3.41) and self-harm (RR: 2.37 95% CI 1.91-2.94 and RR: 1.87 95% CI 1.41-2.48), and of impairment in functional domains. Childhood sleep difficulties, irritability, conduct and neurodevelopmental problems, and family adversity were associated with a persistent course of emotional problems. CONCLUSIONS: Childhood emotional problems were common, but those whose symptoms improved over time were not at increased risk for adverse adult outcomes. In contrast, individuals with persistent or adolescent-increasing emotional problems had a higher risk of mental ill-health and social impairment in young adulthood which was especially pronounced for those with persistent emotional problems.

Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Telephone delivery of psychological interventions: Balancing protocol with patient-centred care.

Common mental health problems of anxiety and depression affect significant proportions of the global population. Within the UK, and increasingly across western countries, a key policy response has been the introduction of high volume, low intensity psychological assessment and treatment services, such as the NHS's Improving Access to Psychological Therapies (IAPT) service, the largest service delivery model yet to be implemented at a national level (England). IAPT may be delivered in face-to-face meetings or over the telephone, as well as through other media. In order to increase access and achieve wide reach with efficient use of resources, IAPT's service models utilise relatively structured and standardised protocols, whilst aiming simultaneously to deliver a tailored and personalised experience for patients. Previous research has revealed that this can be a challenging balance for front-line practitioners to strike. Here we report research into the telephone delivery of guided self-help, low intensity interventions within IAPT, examining the challenges faced in remote delivery when combining structure with personalisation during assessment and treatment sessions. We show the ways in which the lack of flexibility in adhering to a system-driven structure can displace, defer or disrupt the emergence of the patient's story, thereby compromising the personalisation and responsiveness of the service. Our study contributes new insights to our understanding of the association between personalisation, engagement and patient experience within high volume, low-intensity psychological treatment services. Our research on the telephone delivery of IAPT is particularly timely in view of the current global Covid-19 health crisis, as a result of which face-to-face delivery of IAPT has had to be (temporarily) suspended.

A standardised protocol for the evaluation of small extracellular vesicles in plasma by imaging flow cytometry.

Flow cytometry provides robust, multi-parametric and quantitative information on single cells which also exhibits enormous potential as a tool for small particle characterisation. Small extracellular vesicle (sEV) detection by flow cytometry remains compromised due to the high prevalence of swarm detection, which is defined by the simultaneous illumination of more than one sEV, recorded as a single event. Detection of sEVs by imaging flow cytometry presents a major advantage by having the ability to resolve single particles from swarm detection based on the image features recorded for each event. In this study, we provide a simplified protocol that facilitates the removal of both swarm events and aggregated particles to improve the accuracy of sEV analysis. Our results indicate that imaging flow cytometry should be at the forefront as a robust and sensitive technique for sEV characterisation.

Quantitative bias analysis of the association of type 2 diabetes mellitus with 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153).

An association between serum concentrations of persistent organic pollutants (POPs), such as 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153), and risk of type 2 diabetes mellitus (T2DM) has been reported. Conditional on body mass index (BMI) and waist circumference (WC), a higher serum PCB-153 concentration may be a marker of T2DM risk because it reflects other aspects of obesity that are related to T2DM risk and to PCB-153 clearance. To estimate the amount of residual confounding by other aspects of obesity, we performed a quantitative bias analysis on the results of a specific study. A physiologically-based pharmacokinetic (PBPK) model was developed to predict serum levels of PCB-153 for a simulated population. T2DM status was assigned to simulated subjects based on age, sex, BMI, WC, and visceral adipose tissue mass. The distributions of age, BMI, WC, and T2DM prevalence of the simulated population were tailored to closely match the target population. Analysis of the simulated data showed that a small part of the observed association appeared to be due to residual confounding. For example, the predicted odds ratio of T2DM that would have been obtained had the results been adjusted for visceral adipose tissue mass, for the ≥90th percentile of PCB-153 serum concentration, was 6.60 (95% CI 2.46-17.74), compared with an observed odds ratio of 7.13 (95% CI 2.65-19.13). Our results predict that the association between PCB-153 and risk of type 2 diabetes mellitus would not be substantially changed by additional adjustment for visceral adipose tissue mass in epidemiologic analyses. Confirmation of these predictions with longitudinal data would be reassuring.

Maternal high fat diet induces early cardiac hypertrophy and alters cardiac metabolism in Sprague Dawley rat offspring.

BACKGROUND AND AIM: Maternal high fat diets (mHFD) have been associated with an increased offspring cardiovascular risk. Recently we found that the class IIa HDAC-MEF2 pathway regulates gene programs controlling fatty acid oxidation in striated muscle. This same pathway controls hypertrophic responses in the heart. We hypothesized that mHFD is associated with activation of signal controlling class II a HDAC activity and activation of genes involved in fatty acid oxidation and cardiac hypertrophy in offspring. METHODS AND RESULTS: Female Sprague Dawley rats were fed either normal fat diet (12%) or high fat diet (43%) three weeks prior to mating, remaining on diets until study completion. Hearts of postnatal day 1 (PN1) and PN10 pups were collected. Bioenergetics and respiration analyses were performed in neonatal ventricular cardiomyocytes (NVCM). In offspring exposed to mHFD, body weight was increased at PN10 accompanied by increased body fat percentage and blood glucose. Heart weight and heart weight to body weight ratio were increased at PN1 and PN10, and were associated with elevated signalling through the AMPK-class IIa HDAC-MEF2 axis. The expression of the MEF2-regulated hypertrophic markers ANP and BNP were increased as were expression of genes involved in fatty acid oxidation. However this was only accompanied by an increased protein expression of fatty acid oxidation enzymes at PN10. NVCM isolated from these pups exhibited increased glycolysis and an impaired substrate flexibility. CONCLUSION: Combined, these results suggest that mHFD induces signalling and transcriptional events indicative of reprogrammed cardiac metabolism and of cardiac hypertrophy in Sprague Dawley rat offspring.

Effect on non-vascular outcomes of lowering LDL cholesterol in patients with chronic kidney disease: results from the Study of Heart and Renal Protection.

BACKGROUND: Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of major atherosclerotic events among patients with chronic kidney disease (CKD), with no evidence of an excess risk of cancer or death from any non-vascular cause. However, non-randomized data have suggested that statin therapy may have effects (both adverse and beneficial) on particular non-vascular conditions that do not cause death. METHODS: The Study of Heart and Renal Protection (SHARP) randomized patients with CKD to simvastatin 20 mg plus ezetimibe 10 mg (simvastatin/ezetimibe) daily versus matching placebo. Participants were followed up at least 6 monthly and all post-randomization serious adverse events (SAEs) were recorded. This supplementary analysis reports the effects of treatment on non-vascular SAEs, overall, by system of disease, by baseline characteristics, and by duration of follow-up. RESULTS: During a median of 4.9 years follow-up, similar numbers of participants in the two groups experienced at least one non-vascular SAE (3551 [76.4%] simvastatin/ezetimibe vs 3537 [76.6%] placebo; risk ratio [RR] 0.99, 95% confidence interval [CI] 0.95-1.04). There was no good evidence of any significant effect of simvastatin/ezetimibe on SAEs attributed to any particular nonvascular disease system (of 43 comparisons, only 3 yielded an uncorrected p value < 0.05, of which the smallest was p = 0.02). The relative risk of any nonvascular SAE did not vary significantly among particular prognostic subgroups or by duration of follow-up. CONCLUSIONS: In the SHARP trial, allocation to simvastatin/ezetimibe combination therapy was not associated with any significant non-vascular hazard. TRIALS REGISTRATION: SHARP was retrospectively registered after the first participant was enrolled in 2003 at ISRCTN (ISRCTN54137607 on 31 January 2005: http://www.isrctn.com/ISRCTN54137607) and ClinicalTrials.gov (NCT00125593 on 29 July 2005: https://clinicaltrials.gov/ct2/show/NCT00125593).

Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care.

This trial compared the effects of daily treatment with vitamin D or placebo for 1 year on blood tests of vitamin D status. The results demonstrated that daily 4000 IU vitamin D3 is required to achieve blood levels associated with lowest disease risks, and this dose should be tested in future trials for fracture prevention. INTRODUCTION: The aim of this trial was to assess the effects of daily supplementation with vitamin D3 4000 IU (100 µg), 2000 IU (50 µg) or placebo for 1 year on biochemical markers of vitamin D status in preparation for a large trial for prevention of fractures and other outcomes. METHODS: This is a randomized placebo-controlled trial in 305 community-dwelling people aged 65 years or older in Oxfordshire, UK. Outcomes included biochemical markers of vitamin D status (plasma 25-hydroxy-vitamin D [25[OH]D], parathyroid hormone [PTH], calcium and alkaline phosphatase), cardiovascular risk factors and tests of physical function. RESULTS: Mean (SD) plasma 25(OH)D levels were 50 (18) nmol/L at baseline and increased to 137 (39), 102 (25) and 53 (16) nmol/L after 12 months in those allocated 4000 IU, 2000 IU or placebo, respectively (with 88%, 70% and 1% of these groups achieving the pre-specified level of >90 nmol/L). Neither dose of vitamin D3 was associated with significant deviation outside the normal range of PTH or albumin-corrected calcium. The additional effect on 25(OH)D levels of 4000 versus 2000 IU was similar in all subgroups except for body mass index, for which the further increase was smaller in overweight and obese participants compared with normal-weight participants. Supplementation with vitamin D had no significant effects on cardiovascular risk factors or on measures of physical function. CONCLUSIONS: After accounting for average 70% compliance in long-term trials, doses of 4000 IU vitamin D3 daily may be required to achieve plasma 25(OH)D levels associated with lowest disease risk in observational studies.

Autologous and allogeneic hematopoietic stem cell transplantation in follicular lymphoma.

INTRODUCTION: High-dose chemotherapy and autologous stem cell transplantation (ASCT) improve survival in follicular lymphoma; however, relapse remains the most common cause of death. The lower risk of relapse with allogeneic SCT (alloSCT) is offset by a high transplant-related mortality (TRM). AREAS COVERED: English articles indexed in the MEDLINE database were reviewed to discuss the role of graft purging, rituximab maintenance after ASCT, reduced-intensity conditioning (RIC) alloSCT, T-cell depletion, donor lymphocyte infusion (DLI) and alternate donor sources. EXPERT OPINION: Optimal salvage consolidation strategy may utilize ASCT following non-total body irradiation-based conditioning regimen in second remission. Rituximab maintenance after ASCT may improve molecular remission but is not yet shown to improve overall survival. RIC alloSCT permits its use in older and less-fit patients. Studies with T-cell depleted graft failed to reduce TRM despite a decline in graft-versus-host disease; however, these studies did demonstrate a therapeutic role of DLI in post-transplant relapses. In recent years, haploidentical and umbilical cord blood donors have emerged as alternative donor sources, with outcomes comparable to matched unrelated donor SCT. In the future, incorporation of novel therapeutic agents, improved risk-adapted treatment strategies, and advancement of transplant techniques may provide a better chance of survival.

Cyclic di-GMP-mediated repression of swarming motility by Pseudomonas aeruginosa PA14 requires the MotAB stator.

The second messenger cyclic diguanylate (c-di-GMP) plays a critical role in the regulation of motility. In Pseudomonas aeruginosa PA14, c-di-GMP inversely controls biofilm formation and surface swarming motility, with high levels of this dinucleotide signal stimulating biofilm formation and repressing swarming. P. aeruginosa encodes two stator complexes, MotAB and MotCD, that participate in the function of its single polar flagellum. Here we show that the repression of swarming motility requires a functional MotAB stator complex. Mutating the motAB genes restores swarming motility to a strain with artificially elevated levels of c-di-GMP as well as stimulates swarming in the wild-type strain, while overexpression of MotA from a plasmid represses swarming motility. Using point mutations in MotA and the FliG rotor protein of the motor supports the conclusion that MotA-FliG interactions are critical for c-di-GMP-mediated swarming inhibition. Finally, we show that high c-di-GMP levels affect the localization of a green fluorescent protein (GFP)-MotD fusion, indicating a mechanism whereby this second messenger has an impact on MotCD function. We propose that when c-di-GMP level is high, the MotAB stator can displace MotCD from the motor, thereby affecting motor function. Our data suggest a newly identified means of c-di-GMP-mediated control of surface motility, perhaps conserved among Pseudomonas, Xanthomonas, and other organisms that encode two stator systems.

Haemodynamical stress in mouse aortic arch with atherosclerotic plaques: Preliminary study of plaque progression.

Atherosclerotic plaques develop at particular sites in the arterial tree, and this regional localisation depends largely on haemodynamic parameters (such as wall shear stress; WSS) as described in the literature. Plaque rupture can result in heart attack or stroke and hence understanding the development and vulnerability of atherosclerotic plaques is critically important. The purpose of this study is to characterise the haemodynamics of blood flow in the mouse aortic arch using numerical modelling. The geometries are digitalised from synchrotron imaging and realistic pulsatile blood flow is considered under rigid wall assumptions. Two cases are considered; arteries with and without plaque. Mice that are fed under fat diet present plaques in the aortic arch whose size is dependent on the number of weeks under the diet. The plaque distribution in the region is however relatively constant through the different samples. This result underlines the influence of the geometry and consequently of the wall shear stresses for plaque formation with plaques growing in region of relative low shear stresses. A discussion of the flow field in real geometry in the presence and absence of plaques is conducted. The presence of plaques was shown to alter the blood flow and hence WSS distribution, with regions of localised high WSS, mainly on the wall of the brachiocephalic artery where luminal narrowing is most pronounced. In addition, arch plaques are shown to induce recirculation in the blood flow, a phenomenon with potential influence on the progression of the plaques. The oscillatory shear index and the relative residence time have been calculated on the geometry with plaques to show the presence of this recirculation in the arch, an approach that may be useful for future studies on plaque progression.

Phenotype standardization for statin-induced myotoxicity.

Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.

Factors affecting the development of atrial fibrillation and atrial flutter (AF/AFL) following autologous hematopoietic SCT (auto-HSCT).

The use of autologous hematopoietic SCT (auto-HSCT) has expanded to include older patients. Increasing age is a well-appreciated risk factor for the development of atrial fibrillation and/or atrial flutter (AF/AFL) in the general population. As more elderly patients undergo auto-HSCT, the risk of developing AF/AFL post transplant may also increase. However, few data evaluating other risk factors for the development of AF/AFL following auto-HSCT exist. Therefore, we performed a retrospective study to determine the incidence of AF/AFL following auto-HSCT and to determine the risk factors associated with the development of AF/AFL. Patients who developed AF/AFL were compared with a group of patients who received auto-HSCT within the same time period (April 1999 to May 2005) and were within 5 years of age. Of the 516 patients who underwent auto-HSCT at the University of Nebraska Medical Center 44 (8.5%) developed AF/AFL at a median time of 4 days (range, days 1-9) following auto-HSCT. In multivariate analysis, risk factors for developing AF/AFL were older age, odds ratio and 95% CI of 1.14 (1.07-1.21), elevated serum creatinine level, 2.69 (1.00-7.22), history of previous arrhythmia, 9.33 (3.01-28.99), and history of previous mediastinal irradiation, 11.12 (1.33-92.96).

X-ray velocimetry within the ex vivo carotid artery.

X-ray velocimetry offers a non-invasive method by which blood flow, blood velocity and wall shear stress can be measured in arteries prone to atherosclerosis. Analytical tools for measuring haemodynamics in artificial arteries have previously been developed and here the first quantification of haemodynamics using X-ray velocimetry in a living mammalian artery under physiologically relevant conditions is demonstrated. Whole blood seeded with a clinically used ultrasound contrast agent was pumped with a steady flow through live carotid arterial tissue from a rat, which was kept alive in a physiological salt solution. Pharmacological agents were then used to produce vascular relaxation. Velocity measurements were acquired with a spatial resolution of 14 µm × 14 µm and at a rate of 5000 acquisitions per second. Subtle velocity changes that occur are readily measurable, demonstrating the ability of X-ray velocimetry to sensitively and accurately measure haemodynamics ex vivo. Future applications and possible limitations of the technique are discussed, which allows for detailed living tissue investigations to be carried out for various disease models, including atherosclerosis and diabetic vasculopathy.

Aspirin for the older person: report of a meeting at the Royal Society of Medicine, London, 3rd November 2011.

On November 23rd 2011, the Aspirin Foundation held a meeting at the Royal Society of Medicine in London to review current thinking on the potential role of aspirin in preventing cardiovascular disease and reducing the risk of cancer in older people. The meeting was supported by Bayer Pharma AG and Novacyl.

Randomised controlled trials: important but overrated?

Practising physicians individualise treatments, hoping to achieve optimal outcomes by tackling relevant patient variables. The randomised controlled trial (RCT) is universally accepted as the best means of comparison. Yet doctors sometimes wonder if particular patients might benefit more from treatments that fared worse in the RCT comparisons. Such clinicians may even feel ostracised by their peers for stepping outside treatments based on RCTs and guidelines. Are RCTs the only acceptable evaluations of how patient care can be assessed and delivered? In this controversy we explore the interpretation of RCT data for practising clinicians facing individualised patient choices. First, critical care anaesthetists John Boylan and Brian Kavanagh emphasise the dangers of bias and show how Bayesian approaches utilise prior probabilities to improve posterior (combined) probability estimates. Secondly, Jane Armitage, of the Clinical Trial Service Unit in Oxford, argues why RCTs remain essential and explores how the quality of randomisation can be improved through systematic reviews and by avoiding selective reporting.

Natural killer cell lymphoma shares strikingly similar molecular features with a group of non-hepatosplenic γδ T-cell lymphoma and is highly sensitive to a novel aurora kinase A inhibitor in vitro.

Natural killer (NK) cell lymphomas/leukemias are rare neoplasms with an aggressive clinical behavior. The majority of the cases belong to extranodal NK/T-cell lymphoma, nasal type (ENKTL) in the current WHO classification scheme. Gene-expression profiling (GEP) of 21 ENKTL and NK-cell lymphoma/leukemia patients, 17 NK- and T-cell lines and 5 indolent NK-cell large-granular-lymphocytic proliferation was performed and compared with 125 peripheral T-cell lymphoma (PTCL) patients previously studied. The molecular classifier derived for ENKTL patients was comprised of 84 transcripts with the majority of them contributed by the neoplastic NK cells. The classifier also identified a set of γδ-PTCLs both in the ENKTL cases as well as in cases initially classified as PTCL-not otherwise specified. These γδ-PTCLs expressed transcripts associated with the T-cell receptor (TCR)/CD3 complex, suggesting T cell rather than NK-cell lineage. They were very similar to NK-cell tumors by GEP, but were distinct from cytotoxic (αß)-PTCL and hepatosplenic T-cell lymphoma, indicating derivation from an ontogenically and functionally distinct subset of γδ T cells. They showed distinct expression of Vγ9, Vδ2 transcripts and were positive for TCRγ, but negative for TCRß by immunohistochemistry. Targeted inhibition of two oncogenic pathways (AURKA and NOTCH-1) by small-molecular inhibitors induced significant growth arrest in NK-cell lines, thus providing a rationale for clinical trials of these inhibitors in NK-cell malignancies.

Sodium appetite in adult rats following ω-3 polyunsaturated fatty acid deficiency in early development.

We examined the effect of ω-3 polyunsaturated fatty acid (PUFA) deficiency during development on sodium appetite. Being raised on an ω-3 PUFA deficient diet increased the intake of 0.5M NaCl following furosemide-induced sodium depletion by 40%. This occurred regardless of the diet they were maintained on later in life, and the increased consumption persisted for 3 days. In a second study, animals were administered furosemide and low-dose captopril. Sodium consumption of deficient raised animals was again higher than that of the control raised. Fos immunoreactivity in brain areas associated with sodium appetite and excretion were not influenced by diet. Our findings indicate that inadequate dietary ω-3 PUFA during development results in an exaggerated sodium appetite later in life.

Identifying co-morbidity in surgical patients using administrative data with the Royal College of Surgeons Charlson Score.

BACKGROUND: Surgical outcomes are influenced by co-morbidity. The Royal College of Surgeons (RCS) Co-morbidity Consensus Group was convened to improve existing instruments that identify co-morbidity in International Classification of Diseases tenth revision administrative data. METHODS: The RCS Charlson Score was developed using a coding philosophy that enhances international transferability and avoids misclassifying complications as co-morbidity. The score was validated in English Hospital Episode Statistics data for abdominal aortic aneurysm (AAA) repair, aortic valve replacement, total hip replacement and transurethral prostate resection. RESULTS: With exception of AAA, patients with co-morbidity were older and more likely to be admitted as an emergency than those without. All patients with co-morbidity stayed longer in hospital, required more augmented care, and had higher in-hospital and 1-year mortality rates. Multivariable prognostic models incorporating the RCS Charlson Score had better discriminatory power than those that relied only on age, sex, admission method (elective or emergency) and number of emergency admissions in the preceding year. CONCLUSION: The RCS Charlson Score identifies co-morbidity in surgical patients in England at least as well as existing instruments. Given its explicit coding philosophy, it may be used as a co-morbidity scoring instrument for international comparisons.