Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device - the SERCA-LVAD TRIAL.

The SERCA-LVAD trial was a phase 2a trial assessing the safety and feasibility of delivering an adeno-associated vector 1 carrying the cardiac isoform of the sarcoplasmic reticulum calcium ATPase (AAV1/SERCA2a) to adult chronic heart failure patients implanted with a left ventricular assist device. The SERCA-LVAD trial was one of a program of AAV1/SERCA2a cardiac gene therapy trials including CUPID1, CUPID 2 and AGENT trials. Enroled subjects were randomised to receive a single intracoronary infusion of 1 × 1013 DNase-resistant AAV1/SERCA2a particles or a placebo solution in a double-blinded design, stratified by presence of neutralising antibodies to AAV. Elective endomyocardial biopsy was performed at 6 months unless the subject had undergone cardiac transplantation, with myocardial samples assessed for the presence of exogenous viral DNA from the treatment vector. Safety assessments including ELISPOT were serially performed. Although designed as a 24 subject trial, recruitment was stopped after five subjects had been randomised and received infusion due to the neutral result from the CUPID 2 trial. Here we describe the results from the 5 patients at 3 years follow up, which confirmed that viral DNA was delivered to the failing human heart in 2 patients receiving gene therapy with vector detectable at follow up endomyocardial biopsy or cardiac transplantation. Absolute levels of detectable transgene DNA were low, and no functional benefit was observed. There were no safety concerns in this small cohort. This trial identified some of the challenges of performing gene therapy trials in this LVAD patient cohort which may help guide future trial design.

Multicentre observational study of surgical system failures in aortic procedures and their effect on patient outcomes.

BACKGROUND: Vascular surgical care has changed dramatically in recent years with little knowledge of the impact of system failures on patient safety. The primary aim of this multicentre observational study was to define the landscape of surgical system failures, errors and inefficiency (collectively termed failures) in aortic surgery. Secondary aims were to investigate determinants of these failures and their relationship with patient outcomes. METHODS: Twenty vascular teams at ten English hospitals trained in structured self-reporting of intraoperative failures (phase I). Failures occurring in open and endovascular aortic procedures were reported in phase II. Failure details (category, delay, consequence), demographic information (patient, procedure, team experience) and outcomes were reported. RESULTS: There were strong correlations between the trainer and teams for the number and type of failures recorded during 88 procedures in phase I. In 185 aortic procedures, teams reported a median of 3 (i.q.r. 2-6) failures per procedure. Most frequent failures related to equipment (unavailability, failure, configuration, desterilization). Most major failures related to communication. Fourteen failures directly harmed 12 patients. Significant predictors of an increased failure rate were: endovascular compared with open repair (incidence rate ratio (IRR) for open repair 0·71, 95 per cent c.i. 0·57 to 0·88; P = 0·002), thoracic aneurysms compared with other aortic pathologies (IRR 2·07, 1·39 to 3·08; P < 0·001) and unfamiliarity with equipment (IRR 1·52, 1·20 to 1·91; P < 0·001). The major failure total was associated with reoperation (P = 0·011), major complications (P = 0·029) and death (P = 0·027). CONCLUSION: Failure in aortic procedures is frequently caused by issues with team-working and equipment, and is associated with patient harm. Multidisciplinary team training, effective use of technology and new-device accreditation may improve patient outcomes.

Persistent regional variation in treatment of hypertension.

OBJECTIVES: To assess regional variation within England in the proportion of people with survey-defined hypertension who were on treatment, and hypothesize if this was due to chance or confounding. STUDY DESIGN: Data from three annual, cross-sectional health examination surveys, the Health Survey for England. METHODS: Nationally representative random samples of the free-living general population were visited by an interviewer and a nurse. Blood pressure was measured with an automated monitor using a standardized protocol (2005: n = 5321, 2006: n = 10,213, 2007: n = 4848). Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, and/or taking prescribed medication to lower blood pressure. RESULTS: In London, a higher proportion of participants with survey-defined hypertension were on anti-hypertensive medication in each separate year's sample compared with the rest of England [2005-2007 average: 61% men, 66% women in London; 43% men, 55% women in England (P for London vs rest of England <0.001 for each sex)]. Regression analysis showed that this regional effect [odds ratio (OR) 1.47 95% confidence interval (CI) 1.94-2.47, P = 0.031] was no longer significant after adjustment for demographic and socio-economic factors (OR 1.37, 95% CI 0.94-1.98, P = 0.101), but was strengthened (OR 1.69, 95% CI 1.09-2.60, P = 0.018) by including longstanding illness, diabetes, cardiovascular disease and health behaviours in the model. CONCLUSIONS: The proportion of hypertensive patients on anti-hypertensive medication was consistently above the national average in London, and this was associated with personal characteristics. Comorbidities increased the effect, even after adjustment for personal characteristics. This result may be due to greater population mobility in London, with more people having new patient health checks. Understanding this variation could enhance treatment nationally and internationally.

Changes in the FEV1/FVC ratio during childhood and adolescence: an intercontinental study.

In children, the ratio of forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) is reportedly constant or falls linearly with age, whereas the ratio of residual volume (RV) to total lung capacity (TLC) remains constant. This seems counter-intuitive given the changes in airway properties, body proportions, thoracic shape and respiratory muscle function that occur during growth. The age dependence of lung volumes, FEV1/FVC and RV/TLC were studied in children worldwide. Spirometric data were available for 22,412 healthy youths (51.4% male) aged 4-20 yrs from 15 centres, and RV and TLC data for 2,253 youths (56.7% male) from four centres; three sets included sitting height (SH). Data were fitted as a function of age, height and SH. In childhood, FVC outgrows TLC and FEV1, leading to falls in FEV1/FVC and RV/TLC; these trends are reversed in adolescence. Taking into account SH materially reduces differences in pulmonary function within and between ethnic groups. The highest FEV1/FVC ratios occur in those shortest for their age. When interpreting lung function test results, the changing pattern in FEV1/FVC and RV/TLC should be considered. Prediction equations for children and adolescents should take into account sex, height, age, ethnic group, and, ideally, also SH.

Time trends in childhood and adolescent obesity in England from 1995 to 2007 and projections of prevalence to 2015.

BACKGROUND: The aim was to examine the 1995-2007 childhood and adolescent obesity trends and project prevalence to 2015 by age group and social class. METHODS: Participants were children aged 2-10 and adolescents aged 11-18 years from general population households in England studied using repeated cross-sectional surveys. Obesity was computed using international standards. Prevalence projections to 2015 were based on extrapolation of linear and non-linear trends. RESULTS: Obesity prevalence increased from 1995 to 2007 from 3.1% to 6.9% among boys, and 5.2% to 7.4% among girls. There are signs of a levelling off trend past 2004/5. Assuming a linear trend, the 2015 projected obesity prevalence is 10.1% (95% CI 7.5 to 12.6) in boys and 8.9% (5.8 to 12.1) in girls, and 8.0% (4.5, 11.5) in male and 9.7% (6.0, 13.3) in female adolescents. Projected prevalence in manual social classes is markedly higher than in non-manual classes [boys: 10.7% (6.6 to 14.9) vs 7.9% (3.7 to 12.1); girls: 11.2% (7.0 to 15.3) vs 5.4% (1.3 to 9.4); male adolescents: 10.0% (5.2 to 14.8) vs 6.7% (3.4 to 10.0); female adolescents: 10.4% (5.0 to 15.8) vs 8.3% (4.3 to 12.4)]. CONCLUSION: If the trends in young obesity continue, the percentage and numbers of obese young people in England will increase considerably by 2015 and the existing obesity gap between manual and non-manual classes will widen further. This highlights the need for public health action to reverse recent trends and narrow social inequalities in health.

Ethnic inequalities in access to and outcomes of healthcare: analysis of the Health Survey for England.

BACKGROUND: Ethnic/racial inequalities in access to and quality of healthcare have been repeatedly documented in the USA. Although there is some evidence of inequalities in England, research is not so extensive. Ethnic inequalities in use of primary and secondary health services, and in outcomes of care, were examined in England. METHODS: Four waves of the Health Survey for England were analysed, a representative population survey with ethnic minority oversamples. Outcome measures included use of primary and secondary healthcare services and clinical outcomes of care (controlled, uncontrolled and undiagnosed) for three conditions - hypertension, raised cholesterol and diabetes. RESULTS: Ethnic minority respondents were not less likely to use GP services. For example, the adjusted odds ratios for Indian, Pakistani and Bangladeshi versus white respondents were 1.29 (95% confidence intervals 1.07 to 1.54), 1.32 (1.10 to 1.58) and 1.35 (1.10 to 1.65) respectively. Similarly, there were no ethnic inequalities for the clinical outcomes of care for hypertension and raised cholesterol, and, on the whole, no inequalities in outcomes of care for diabetes. There were ethnic inequalities in access to hospital services, and marked inequalities in use of dental care. CONCLUSION: Ethnic inequalities in access to healthcare and the outcomes of care for three conditions (hypertension, raised cholesterol and diabetes), for which treatment is largely provided in primary care, appear to be minimal in England. Although inequalities may exist for other conditions and other healthcare settings, particularly internationally, the implication is that ethnic inequalities in healthcare are minimal within NHS primary care.

Using the lower limit of normal for the FEV1/FVC ratio reduces the misclassification of airway obstruction.

AIM: The prevalence of airway obstruction varies widely with the definition used. OBJECTIVES: To study differences in the prevalence of airway obstruction when applying four international guidelines to three population samples using four regression equations. METHODS: We collected predicted values for forced expiratory volume in 1 s/forced vital capacity (FEV(1)/FVC) and its lower limit of normal (LLN) from the literature. FEV(1)/FVC from 40 646 adults (including 13 136 asymptomatic never smokers) aged 17-90+years were available from American, English and Dutch population based surveys. The prevalence of airway obstruction was determined by the LLN for FEV(1)/FVC, and by using the Global Initiative for Chronic Obstructive Lung Disease (GOLD), American Thoracic Society/European Respiratory Society (ATS/ERS) or British Thoracic Society (BTS) guidelines, initially in the healthy subgroup and then in the entire population. RESULTS: The LLN for FEV(1)/FVC varied between prediction equations (57 available for men and 55 for women), and demonstrated marked negative age dependency. Median age at which the LLN fell below 0.70 in healthy subjects was 42 and 48 years in men and women, respectively. When applying the reference equations (Health Survey for England 1995-1996, National Health and Nutrition Examination Survey (NHANES) III, European Community for Coal and Steel (ECCS)/ERS and a Dutch population study) to the selected population samples, the prevalence of airway obstruction in healthy never smokers aged over 60 years varied for each guideline: 17-45% of men and 7-26% of women for GOLD; 0-18% of men and 0-16% of women for ATS/ERS; and 0-9% of men and 0-11% of women for BTS. GOLD guidelines caused false positive rates of up to 60% when applied to entire populations. CONCLUSIONS: Airway obstruction should be defined by FEV(1)/FVC and FEV(1) being below the LLN using appropriate reference equations.

Birth weight and blood pressure in childhood: results from the Health Survey for England.

Findings of previous reports relating low birth weight with raised blood pressure in childhood and adolescence have been inconsistent. The present study uses cross-sectional data from a series of nationally representative annual surveys--the Health Survey for England--between 1995 and 2002, totaling a sample of 15 629 children aged 5 to 15. A significant negative relationship between birth weight, in quartiles or dichotomized as low (<2.5 kg) and normal (> or =2.5 kg) and systolic blood pressure was apparent. Linear regression analyses confirmed these findings. When current weight was included in the model, the strength of the relationship increased. An interaction term between birth weight and current weight was not significant. A life-course plot for those aged 13 to 15 (n=3900), converting the weight measurements at birth and as a teenager to standard deviation scores to make the regression coefficients comparable, showed the importance of weight gain on blood pressure (1 standard deviation increase in weight from birth to age 13 to 15 was associated with an increase in systolic blood pressure of 0.8 mm Hg). Separating those with low and normal birth weight demonstrated that the increase in weight from birth to adolescence had an effect on blood pressure in both those with low and normal birth weight. Postnatal changes in size have a more important effect on blood pressure in childhood and adolescence than birth weight. Reducing the prevalence of overweight among children may reduce their systolic blood pressure importantly and, particularly among children with lower birth weight, the prevalence of hypertension later in life.

Prediction equations for normal and low lung function from the Health Survey for England.

The aim of this study was to derive new spirometric reference equations for the English population, using the 1995/1996 Health Survey for England, a large nationally representative cross-sectional study. The measurements used were the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) of a sample of 6,053 "healthy" (nonsmokers with no reported diagnosis of asthma or respiratory symptoms) White people aged > or = 16 yrs. Multiple regression analysis, with age and height as predictors, was carried out to estimate prediction equations for mean FEV1, FVC and FEV1/FVC, separately for males and females. A method based on smoothing multiple estimates of the fifth percentiles of residuals was used to derive prediction equations for the lower limit of normal lung function. The new equations fit the current English adult population considerably better than the European Coal and Steel Community equations, and the proportions of people with "low" (below the fifth percentile) lung function are closer to those expected throughout the whole adult age range (16 to > 75 yrs). For the age ranges the studies share in common, the new equations give estimates close to those derived from other nonlinear equations in recent studies. It is, therefore, suggested that these newly developed prediction equations be used for the White English population in both epidemiological studies and clinical practice.

Association between smoking and blood pressure: evidence from the health survey for England.

Cigarette smoking causes acute blood pressure (BP) elevation, although some studies have found similar or lower BPs in smokers compared with nonsmokers. Cross-sectional data from 3 years (1994 to 1996) of the annual Health Survey for England were used to investigate any difference in BP between smokers and nonsmokers in a nationally representative sample of adults (>/=16 years old). Randomly selected adults (33 860; 47% men) with valid body mass index (BMI) and BP measurements provided data on smoking status (never, past, or current) and were stratified into younger (16 to 44 years old) and older (>/=45 years old) age groups. Analyses provided between 89% and 94% power to detect a difference of 2 mm Hg systolic BP between smokers and nonsmokers in the 4 age/gender strata (alpha=0.05). Older male smokers had higher systolic BP adjusted for age, BMI, social class, and alcohol intake than did nonsmoking men. No such differences were seen among younger men or for diastolic blood pressure in either age group. Among women, light smokers (1 to 9 cigarettes/d) tended to have lower BPs than heavier smokers and never smokers, significantly so for diastolic BP. Among men, a significant interaction between BMI and the BP-smoking association was observed. In women, BP differences between nonsmokers and light smokers were most marked in those who did not drink alcohol. These data show that any independent chronic effect of smoking on BP is small. Differences between men and women in this association are likely to be due to complex interrelations among smoking, alcohol intake, and BMI.