Negative effect of treatment with mGluR5 negative allosteric modulator AFQ056 on blood biomarkers in young individuals with Fragile X syndrome.

Background: Fragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3-6 years. Objectives: The current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome. Design: A double-blind placebo-controlled parallel-group flexible-dose forced titration design. Methods: Blood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels' detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected. Results: This research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome. Conclusion: Our findings of the lack of association between clinical improvement and biomarkers' levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints. Registration: ClincalTrials.gov NCT02920892.

Gender-specific changes in well-being in older people with coronary heart disease: evidence from the English Longitudinal Study of Ageing.

OBJECTIVES: The objective of this study is to investigate gender-specific trajectories in well-being among older people with coronary heart disease (CHD) and to compare them with those of healthy people. METHOD: The study included a sample of 4496 participants from the first three waves of the English Longitudinal Study of Ageing (2002-2003 to 2006-2007). We measured well-being using quality of life (CASP-19; 'control', 'autonomy', 'pleasure' and 'self-realization') and depressive caseness (three or more symptoms on the CESD-8; Centre for Epidemiologic Study Depression scale). RESULTS: After adjustment, at two- and four-years follow-ups, women had three points higher quality of life than men (p < 0.001). When looking at each quality of life's domain we found that women reported higher scores of autonomy compared to men. The gender difference in the probability of having depressive caseness reduced to 7 percentage points at four-year follow-up from 13 percentage points in the previous occasions. Men's quality of life declined progressively over time by 3 points (p < 0.001) (equivalent to the effect of having diabetes) but no changes in prevalence of depressive caseness were found. Women's quality of life only declined after four-year follow-up by less than 2 points (p < 0.001), while in the same period their probability of reporting depressive caseness reduced by 6 percentage points (p < 0.001). CONCLUSION: Women had better quality of life than men in the two and four years following a CHD event, and were not more likely than men to report depressive caseness in the long term. Men's quality of life deteriorated progressively over time, among women it did not deteriorate in the first two years following a CHD event; women had a long-term improvement in depressive caseness.

Factors associated with remission of eczema in children: a population-based follow-up study.

The aim of this study was to analyse factors associated with remission of atopic dermatitis (AD) in childhood. A population-based AD cohort of 894 children aged 1-3 years from a cross-sectional baseline study in 2000 was followed up in 2005. The association between remission, background, health, lifestyle, and environmental variables was estimated with crude and multivariable logistic regression. At follow-up, 52% of the children had remission. Independent factors at baseline predicting remission were: milder eczema (adjusted odds ratio (aOR), 1.43; 95% confidence interval (95% CI) 1.16-1.77); later onset of eczema (aOR 1.40; 95% CI 1.08-1.80); non-flexural eczema (aOR 2.57; 95% CI 1.62-4.09); no food allergy (aOR 1.51; 95% CI 1.11-2.04), and rural living (aOR 1.48; 95% CI 1.07-2.05). Certain aspects of AD and rural living were important for remission, but despite the initial hypotheses to the contrary, the environmental factors examined in this paper were not substantial predictors of remission.

The bidirectional association between depressive symptoms and gait speed: evidence from the English Longitudinal Study of Ageing (ELSA).

BACKGROUND: Depressive symptoms and physical performance are inversely associated, but it is unclear whether their association is bidirectional. We examined whether the association between depressive symptoms and physical performance measured using gait speed is bidirectional. METHODS: We used a national sample of 4,581 community-dwelling people aged 60 years and older from the English Longitudinal Study of Ageing (from 2002-03 to 2008-09). We fitted Generalized Estimating Equation (GEE) regression models to analyse repeated measurements of gait speed (m/sec) and elevated depressive symptoms (defined as a score of ≥4 on the eight-item Center for Epidemiological Studies-Depression scale). RESULTS: Slower gait speed was associated with elevated depressive symptoms both concurrently and two years later. After adjustment for previous depressive symptoms and sociodemographic, clinical, lifestyle, psychosocial, and cognitive factors the concurrent association was partially explained (Odds Ratio [OR] 0.42, 95% confidence interval [CI], 0.30 to 0.59, per 1m/sec increase in gait speed) and the two-year lagged association fully (OR 0.75, 95% CI, 0.56 to 1.00). Elevated depressive symptoms were associated with slower gait speed. Full adjustment for covariates (including previous gait speed) partially explained both the concurrent (ß regression coefficient [ß] -0.038, 95% CI, -0.050 to -0.026, for participants with elevated depressive symptoms compared with those with no or one symptom) and the two-year lagged associations (ß -0.017, 95% CI, -0.030 to -0.005). Subthreshold depressive symptoms (defined as a score of two or three on the eight-item Center for Epidemiological Studies-Depression scale) were also associated with slower gait speed. Full adjustment for covariates partially explained both the concurrent (ß -0.029, 95% CI, -0.039 to -0.019, for participants with subthreshold symptoms compared with those with no or one symptom) and the two-year lagged associations (ß -0.011, 95% CI, -0.021 to -0.001). CONCLUSIONS: The inverse association between gait speed and depressive symptoms appears to be bidirectional.

Incidence of pregnancy among women accessing antiretroviral therapy in urban Malawi: a retrospective cohort study.

Although previous studies investigated pregnancy rates among women on antiretroviral therapy (ART), incidence of, and factors associated with pregnancy among these women remain poorly understood. We, therefore, conducted a retrospective cohort study at a large public HIV clinic in Lilongwe, Malawi, between July 2007 and December 2010. At each clinic visit, pregnancy status was assessed. Time to event analysis was conducted using Poisson regression. Among 4,738 women, 589 pregnancies were observed. Pregnancy incidence was 9.3/100 person-years. After 6 months on ART, women on ART had similar total fertility rates to women in the urban population. In multivariable analysis, increasing age and advanced WHO clinical stage were associated with decreased probability of becoming pregnant while higher body mass index and longer time on ART were associated with increased probability of becoming pregnant. We recommend that ART clinics integrate comprehensive family planning services to address reproductive health needs among women on ART.

Cohort profile: the English longitudinal study of ageing.

The English Longitudinal Study of Ageing (ELSA) is a panel study of a representative cohort of men and women living in England aged ≥50 years. It was designed as a sister study to the Health and Retirement Study in the USA and is multidisciplinary in orientation, involving the collection of economic, social, psychological, cognitive, health, biological and genetic data. The study commenced in 2002, and the sample has been followed up every 2 years. Data are collected using computer-assisted personal interviews and self-completion questionnaires, with additional nurse visits for the assessment of biomarkers every 4 years. The original sample consisted of 11 391 members ranging in age from 50 to 100 years. ELSA is harmonized with ageing studies in other countries to facilitate international comparisons, and is linked to financial and health registry data. The data set is openly available to researchers and analysts soon after collection (http://www.esds.ac.uk/longitudinal/access/elsa/l5050.asp).

Social gradients in oral health in older adults: findings from the English longitudinal survey of aging.

OBJECTIVES: We examined prospective associations between socioeconomic position (SEP) markers and oral health outcomes in a national sample of older adults in England. METHODS: Data were from the English Longitudinal Survey of Aging, a national cohort study of community-dwelling people aged 50 years and older. SEP markers (education, occupation, household income, household wealth, subjective social status, and childhood SEP) and sociodemographic confounders (age, gender, and marital status) were from wave 1. We collected 3 self-reported oral health outcomes at wave 3: having natural teeth (dentate vs edentate), self-rated oral health, and oral impacts on daily life. Using multivariate logistic regression models, we estimated associations between each SEP indicator and each oral health outcome, adjusted for confounders. RESULTS: Irrespective of SEP marker, there were inverse graded associations between SEP and edentulousness, with proportionately more edentate participants at each lower SEP level. Lower SEP was also associated with worse self-rated oral health and oral impacts among dentate, but not among edentate, participants. CONCLUSIONS: There are consistent and clear social gradients in the oral health of older adults in England, with disparities evident throughout the SEP hierarchy.

Higher Levels and Intensity of Physical Activity Are Associated with Reduced Mortality among Community Dwelling Older People.

Introduction. There is limited evidence on physical activity and mortality in older people. Methods. People aged 75-84 years (n = 1449) participating in a randomized trial of health screening in UK general practice were interviewed about their physical activity (PA) and were assessed for a wide range of health and social problems. Mortality data were collected over 7 years of followup. Results. Full information on PA and potential confounders was available in 946 people. Those in the highest third of duration of PA had a lower mortality, confounder-adjusted Hazard Ratio (HR) = 0.74, and 95% Confidence Interval (CI) 0.56-0.97, compared to the lowest third. Similar benefits were seen when categorized by intensity of PA, with those in the highest group having a lower mortality, confounder-adjusted HR = 0.61, and 95% CI 0.47-0.79, compared to the lowest category. Conclusions. Our results suggest the importance of providing older people with opportunities for physical activity.

BMI and waist circumference as predictors of well-being in older adults: findings from the English Longitudinal Study of Ageing.

The aim of this study is to examine the association of BMI and waist circumference (WC), with a quality of life (QoL) indicator designed for older ages (CASP19), and with depressive symptoms (Centre for Epidemiologic Studies Depression Scale). We included 8,688 individuals aged ≥52 years who participants of Wave 2 (2004-2005) and Wave 3 (2006-2007) of the English Longitudinal Study of Ageing (ELSA). To explore cross-sectional relationships (2004-2005), we fitted regression models for BMI and WC (included simultaneously) as our predictors of QoL and depressive symptoms adjusted for covariates. To explore longitudinal relationships, BMI and waist at baseline (2004-2005) were related to the each outcome variable measured at follow-up (2006-2007), and adjusted for baseline characteristics (2004-2005). For a given BMI, larger WC was associated with lower QoL and higher risk of depressive symptoms for women in cross-sectional and longitudinal analyses. By contrast for a given WC increased BMI for women was positively associated with QoL and lower odds of depressive symptoms. In men, for a given BMI, increased WC was related to QoL only cross-sectionally; neither WC nor BMI at baseline were associated with depressive symptoms (cross-sectionally or longitudinally). In conclusion among older people, for a given BMI, increased WC was related with higher risk of poor QoL and, for women, of depressive symptoms; whereas for a given WC, increased BMI had a protective effect on QoL for women.

Life expectancy in relation to cardiovascular risk factors: 38 year follow-up of 19,000 men in the Whitehall study.

OBJECTIVE: To assess life expectancy in relation to cardiovascular risk factors recorded in middle age. DESIGN: Prospective cohort study. SETTING: Men employed in the civil service in London, England. PARTICIPANTS: 18 863 men examined at entry in 1967-70 and followed for 38 years, of whom 13,501 died and 4811 were re-examined in 1997. MAIN OUTCOME MEASURES: Life expectancy estimated in relation to fifths and dichotomous categories of risk factors (smoking, "low" or "high" blood pressure (>or=140 mm Hg), and "low" or "high" cholesterol (>or=5 mmol/l)), and a risk score from these risk factors. RESULTS: At entry, 42% of the men were current smokers, 39% had high blood pressure, and 51% had high cholesterol. At the re-examination, about two thirds of the previously "current" smokers had quit smoking shortly after entry and the mean differences in levels of those with high and low levels of blood pressure and cholesterol were attenuated by two thirds. Compared with men without any baseline risk factors, the presence of all three risk factors at entry was associated with a 10 year shorter life expectancy from age 50 (23.7 v 33.3 years). Compared with men in the lowest 5% of a risk score based on smoking, diabetes, employment grade, and continuous levels of blood pressure, cholesterol concentration, and body mass index (BMI), men in the highest 5% had a 15 year shorter life expectancy from age 50 (20.2 v 35.4 years). CONCLUSION: Despite substantial changes in these risk factors over time, baseline differences in risk factors were associated with 10 to 15 year shorter life expectancy from age 50.

Inequalities in health at older ages: a longitudinal investigation of the onset of illness and survival effects in England.

BACKGROUND: previous studies have suggested a decline in the relationship between socioeconomic circumstances and health or functioning in later life, but this may be due to survival effects. OBJECTIVE: to examine whether wealth gradients in the incidence of illness decline with age, and, if so, whether this decline is explained by differential mortality. METHODS: the study included participants in the first two waves of the English Longitudinal Study of Ageing (ELSA), a large national longitudinal study of the population aged 50+ in England, who reported good health, no functional impairment, or no heart disease at baseline. Wealth inequalities in onset of illness over 2 years were examined across age groups, with and without the inclusion of mortality. Outcome measures were functional impairment, heart disease, self-reported health, and all-cause mortality (in conjunction with self-reported health and disability) or circulatory-related mortality (in relation to heart disease). RESULTS: wealth predicted onset of functional impairment equally across age groups. For self-reported health and heart disease, wealth gradients in the onset of illness declined with age. Selective mortality contributed to this decline in the oldest age groups. CONCLUSIONS: socioeconomic inequality in developing new health problems persist into old age for certain illnesses, particularly functional impairment, but not for heart disease. Selective mortality explains only some of the decline in health inequalities with age.

Do general practices provide equitable access to physical activity interventions?

BACKGROUND: Exercise referral schemes are widespread across England. National guidance emphasises the need to engage groups that are disadvantaged. AIM: To examine the influence of socioeconomic deprivation on referral to, and use of, exercise referral schemes. DESIGN OF STUDY: Cross-sectional analysis of patients referred by general practices to exercise referral schemes between 2004 and 2006. SETTING: Six primary care trusts (PCTs) in Greater London. METHOD: Routine data about patients who had been referred to exercise referral schemes were used to estimate risk ratios for referral by general practice deprivation quintile, odds ratios (ORs) for uptake, and ORs for completion of exercise referral schemes by patients' deprivation status quintile. RESULTS: All 317 general practices in the six PCTs were included in the referral analysis. Referrals were less likely from general practices serving advantaged socioeconomic areas (adjusted risk ratio for trend across deprivation quintiles 0.84; 95% confidence interval [CI] = 0.76 to 0.93). This study found no association between patients' deprivation status and their likelihood of taking up (adjusted OR, least versus most deprived quintile 1.05; 95% CI = 0.83 to 1.33) or completing the scheme (adjusted OR 1.23; 95% CI = 0.84 to 1.79). CONCLUSION: General practices within areas of deprivation were more likely to refer patients to exercise referral schemes than practices in more advantaged areas. Once referred, it was found that patients living in areas of deprivation were as likely to take up and to complete the scheme as those living in more advantaged locations. Research is needed to identify the organisational and contextual factors that allow this pattern of service delivery, which appears to facilitate access to care among patients who live in areas of deprivation.

Self reported receipt of care consistent with 32 quality indicators: national population survey of adults aged 50 or more in England.

OBJECTIVE: To assess the receipt of effective healthcare interventions in England by adults aged 50 or more with serious health conditions. DESIGN: National structured survey questionnaire with face to face interviews covering medical panel endorsed quality of care indicators for both publicly and privately provided care. SETTING: Private households across England. PARTICIPANTS: 8688 participants in the English longitudinal study of ageing, of whom 4417 reported diagnoses of one or more of 13 conditions. MAIN OUTCOME MEASURES: Percentage of indicated interventions received by eligible participants for 32 clinical indicators and seven questions on patient centred care, and aggregate scores. RESULTS: Participants were eligible for 19 082 items of indicated care. Receipt of indicated care varied substantially by condition. The percentage of indicated care received by eligible participants was highest for ischaemic heart disease (83%, 95% confidence interval 80% to 86%), followed by hearing problems (79%, 77% to 81%), pain management (78%, 73% to 83%), diabetes (74%, 72% to 76%), smoking cessation (74%, 71% to 76%), hypertension (72%, 69% to 76%), stroke (65%, 54% to 76%), depression (64%, 57% to 70%), patient centred care (58%, 57% to 60%), poor vision (58%, 54% to 63%), osteoporosis (53%, 49% to 57%), urinary incontinence (51%, 47% to 54%), falls management (44%, 37% to 51%), osteoarthritis (29%, 26% to 32%), and overall (62%, 62% to 63%). Substantially more indicated care was received for general medical (74%, 73% to 76%) than for geriatric conditions (57%, 55% to 58%), and for conditions included in the general practice pay for performance contract (75%, 73% to 76%) than excluded from it (58%, 56% to 59%). CONCLUSIONS: Shortfalls in receipt of basic recommended care by adults aged 50 or more with common health conditions in England were most noticeable in areas associated with disability and frailty, but few areas were exempt. Efforts to improve care have substantial scope to achieve better health outcomes and particularly need to include chronic conditions that affect quality of life of older people.

Plasma homocysteine, but not folate or vitamin B-12, predicts mortality in older people in the United Kingdom.

There is uncertainty about the importance of plasma levels of homocysteine, vitamin B-12, and folate for all-cause and cardiovascular disease (CVD) mortality in older people. We examined the associations between plasma levels of folate, vitamin B-12, and homocysteine, and all-cause and CVD mortality among community-dwelling adults aged > or = 75 y living in the United Kingdom. In a population-based prospective cohort study, 853 men and women aged > or = 75 y were examined in 1995-98 as part of the Medical Research Council Trial of Assessment and Management of Older People in the Community. During a median follow-up of 7.6 y (5528 person-years of follow-up), 429 individuals (50.3%) died, including 185 from CVD. Individuals with plasma homocysteine levels in the top one-third compared with the bottom one-third had a 2-fold higher risk of all-cause mortality (hazard ratio, 2.20; 95% CI, 1.76, 2.75; P < 0.001) and CVD mortality (hazard ratio, 1.96; 95% CI, 1.39, 2.78; P < 0.001) after adjustment for age, sex, and other covariates. There was no association of plasma folate or vitamin B-12 levels with mortality. Our results extend previously reported associations of homocysteine with mortality, and the absence of associations of folate and vitamin B-12 with mortality, to the older population.

Socioeconomic status and health: the role of subjective social status.

Studies have suggested that subjective social status (SSS) is an important predictor of health. This study examined the link between SSS and health in old age and investigated whether SSS mediated the associations between objective indicators of socioeconomic status and health. It used cross-sectional data from the second wave (2004-2005) of the English Longitudinal Study of Ageing, which were collected through personal interviews and nurse visits. The study population consisted of 3368 men and 4065 women aged 52 years or older. The outcome measures included: self-rated health, long-standing illness, depression, hypertension, diabetes, central obesity, high-density lipoprotein cholesterol, triglycerides, fibrinogen, and C-reactive protein. The main independent variable was SSS measured using a scale representing a 10-rung ladder. Wealth, education, and occupational class were employed as covariates along with age and marital status and also, in additional analyses, as the main independent variables. Gender-specific logistic and linear regression analyses were performed. In age-adjusted analyses SSS was related positively to almost all health outcomes. Many of these relationships remained significant after adjustment for covariates. In men, SSS was significantly (p

Biomarkers of inflammation predict both vascular and non-vascular mortality in older men.

AIMS: To compare the predictive value of inflammatory biomarkers and lipids for vascular and non-vascular mortality in older men. METHODS AND RESULTS: The relevance of inflammatory biomarkers and lipids for vascular and non-vascular mortality was assessed in a prospective study of 5360 men (mean age 77 years) followed for 7 years. Vascular mortality was positively associated with log C-reactive protein (lnCRP), fibrinogen and total/HDL-C (high-density lipoprotein cholesterol), and inversely associated with albumin [age adjusted hazard ratio (HR) per 2-SD higher usual level (approximately the difference between the top and the bottom thirds of the distribution): 2.09 for lnCRP; 1.70 for fibrinogen; 0.50 for albumin and 1.45 for total/HDL-C]. The associations with the inflammatory markers were attenuated after adjustment for established risk factors, including lipids [adjusted HRs: 1.86 (lnCRP); 1.44 (fibrinogen); 0.51 (albumin)], and further attenuated (and, for fibrinogen, no longer predictive) after adjustment for each other [fully adjusted HRs: 1.60 (lnCRP); 1.01 (fibrinogen); 0.61 (albumin)]. Higher CRP and lower albumin levels were also associated with significantly raised non-vascular mortality independently of other characteristics [fully adjusted HRs: 1.62 (lnCRP); 0.65 (albumin)]. CONCLUSION: In this cohort of older men, higher CRP and lower albumin levels strongly predicted both vascular and non-vascular mortality, independently of other characteristics.

Survival in relation to angina symptoms and diagnosis among men aged 70-90 years: the Whitehall Study.

BACKGROUND: While the excess mortality associated with a diagnosis of angina, myocardial infarction in middle-aged individuals is well established, there is little available evidence on the natural history of angina in population-based studies of older people. DESIGN: We conducted a 5-year follow-up of 6655 older men aged 67-90 years (mean age 77 years) who participated in the Whitehall Study of London Civil Servants. METHODS: Survival was examined in relation to a diagnosis of angina or myocardial infarction and to angina symptoms in a population-based study of older men living in the United Kingdom in the late 1990s. RESULTS: Compared with men without a diagnosis of myocardial ischaemia (n=5219), a diagnosis of angina alone (n=617), myocardial infarction alone (n=421) or both (n=398) were associated with about a threefold, fourfold and sixfold higher risk of death from coronary heart disease, respectively. Median expectation of life at age 70 years was reduced by about 2, 5 and 6 years for those with angina, myocardial infarction, or both, respectively. Current symptoms of angina among those without previously diagnosed angina, was associated with a 2-fold higher risk of coronary heart disease mortality than those without either diagnosis or symptoms. CONCLUSIONS: Both angina symptoms and diagnosis have a significant adverse effect on survival among men aged 70-90 years highlighting the importance of diagnosis and appropriate treatment of angina in old age.

Cross-sectional survey of older peoples' views related to influenza vaccine uptake.

BACKGROUND: The population's views concerning influenza vaccine are important in maintaining high uptake of a vaccine that is required yearly to be effective. Little is also known about the views of the more vulnerable older population over the age of 74 years. METHODS: A cross-sectional survey of community dwelling people aged 75 years and over wh, previous participant was conducted using a postal questionnaire. Responses were analysed by vaccine uptake records and by socio-demographic and medical factors. RESULTS: 85% of men and 75% of women were vaccinated against influenza in the previous year. Over 80% reported being influenced by a recommendation by a health care worker. The most common reason reported for non uptake was good health (44%), or illness considered to be due to the vaccine (25%). An exploration of the crude associations with socio-economic status suggested there may be some differences in the population with these two main reasons. 81% of people reporting good health lived in owner occupied housing with central heating vs. 63% who did not state this as a reason (p = 0.04), whereas people reporting ill health due to the vaccine was associated with poorer social circumstances. 11% lived in the least deprived neighbourhood compared to 36% who did not state this as a reason (p = 0.05) and were less likely to be currently married than those who did not state this as a reason (25% vs 48% p = 0.05). CONCLUSION: Vaccine uptake was high, but non uptake was still noted in 1 in 4 women and 1 in 7 men aged over 74 years. Around 70% reported they would not have the vaccine in the following year. The divergent reasons for non-uptake, and the positive influence from a health care worker, suggests further uptake will require education and encouragement from a health care worker tailored towards the different views for not having influenza vaccination. Non-uptake of influenza vaccine because people viewed themselves as in good health may explain the modest socio-economic differentials in influenza vaccine uptake in elderly people noted elsewhere. Reporting of ill-health due to the vaccine may be associated with a different, poorer background.