Pharmacogenetic GWAS meta-analysis of LDL cholesterol response to statins

Cardiolog

Development of a key performance indicator system to benchmark relative paratransit performance

The Americans with Disabilities Act of 1990 prohibits discrimination against people with disabilities. US transit agencies are therefore required to offer services to eligible customers that complement the mobility opportunities provided to the general public on fixed-route public transit. While these paratransit services are necessary and just, they represent a proportionally large cost to agencies: approximately eight times the cost per boarding compared to fixed-route bus service. To be able to identify opportunities for (cost) efficiencies, and to further improve the quality of paratransit services offered, the twenty agencies of the American Bus Benchmarking Group (ABBG) decided to benchmark their relative performance in paratransit management and operations. To ensure comparability of agencies’ performance and hence ensure the usefulness of the benchmarking program, a key performance indicator system was developed and associated data items were defined in detail. The scope of this system went beyond the data already provided to the National Transit Database, both in amount and granularity of data collected, as well as the detail of definitions. This paper describes the challenges, respective solutions, and other lessons identified during four years of paratransit benchmarking development led by Imperial College London, the ABBG facilitators. The paper provides transit agencies and authorities as well as benchmarking practitioners and academics an opportunity to apply these lessons for the further benefit of paratransit services and their customers around the U.S

Genes, inflammation, and age-related diseases

The general objective of this thesis was to investigate associations between genetic variants involved in inflammation and epigenetics and age-related diseases in an elderly cohort to get more insights in the patho-physiological mechanisms involved in age-related diseases, like cardiovascular disease, cognitive decline and cancer. For all analyses we used data of the participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). We have shown that subjects carrying genetic variants coding for a high pro-inflammatory profile or a low anti-inflammatory profile have an increased risk to develop cardiovascular disease and cognitive decline. Moreover, they tend to have an increased risk of dying as a consequence of cancer. Furthermore we have provided first evidence that the process of epigenetics can play an important role in the patho-physiology of age-related diseases. Future research is necessary to investigate how we can corporate these results into clinical practice. For example, Anti-inflammatory and immunosuppressive mechanisms may be attractive targets for disease prevention and/or treatment.UBL - phd migration 201

Circulating interleukin-10 and risk of cardiovascular events: a prospective study in the elderly at risk

<p><b>Objective:</b> The goal of this study was to examine the association of the antiinflammatory interleukin-10 (IL-10) with risk of cardiovascular disease (CVD).</p> <p><b>Methods and Results:</b> In the PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) cohort, we related baseline concentrations of circulating IL-10 to risk of CVD events in a nested case (n=819)-control (n=1618) study of 3.2 years of follow-up. Circulating IL-10 showed few strong associations with classical risk factors but was positively correlated with IL-6 and C-reactive protein. IL-10 was positively associated with risk of CVD events (odds ratio [OR] 1.17, 95% CI 1.05 to 1.31 per unit increase in log IL-10) after adjusting for classical risk factors and C-reactive protein. Furthermore, IL-10 was associated more strongly with CVD risk among those with no previous history of CVD (OR 1.42, 95% CI 1.18 to 1.70), compared with those with previous CVD (OR 1.04, 95% CI 0.90 to 1.19; P=0.018). Overall, IL-10 showed a modest ability to add discrimination to classical risk factors (C-statistic +0.005, P=0.002).</p> <p><b>Conclusion:</b> Baseline circulating levels of the antiinflammatory IL-10 are positively associated with risk of CVD among the elderly without prior CVD events, although the association is less evident in those with a history of CVD. Additional epidemiological and mechanistic studies investigating the role of IL-10 in CVD are warranted.</p&gt

Subclinical thyroid dysfunction and cognitive decline in old age

<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p> <p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p> <p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p> <p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p&gt

Subclinical thyroid dysfunction and cognitive decline in old age

<p>Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).</p> <p>Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) <0.45 mU/L or >4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.</p> <p>Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.</p> <p>Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.</p&gt

Association of complement receptor 1 gene polymorphisms with cognitive function

Previous evidence suggest involvement of the complement receptor 1 (CR1) in development of Alzheimer’s disease. We investigated the association of CR1 gene polymorphisms with cognitive function in older subjects. Single nucleotide polymorphisms (SNPs) within the CR1 region on chromosome 1 (n = 73) were assessed in 5,244 participants in the PROspective Study of Pravastatin in the Elderly at Risk (51.9% female, mean age 75.3 yr). Linear regression, adjusted for age, sex, country, and use of pravastatin, was used to assess the association between the SNPs and cognitive function. All 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. Eighteen were independent, according to a relatively stringent R2 threshold of >0.8 with LDlink. Twelve of the 18 investigated CR1 SNPs were significantly associated with a decline in cognitive function (all P < 0.05). These data indicate that genetic variation within the CR1 gene is associated not only with Alzheimer’s disease, but also with general cognitive function during late life

Borderline Q-waves in individuals without overt cardiovascular disease: relations with adiposity, subclinical atherosclerosis and vascular stiffness

Background: Characteristics and risk factors associated with electrocardiographic borderline Q-waves are not fully elucidated, especially in individuals without overt cardiovascular disease (CVD). Also, the relation of isolated and non-isolated borderline Q-waves with subclinical atherosclerosis and vascular stiffness is unknown. Methods and results: We included 5746 Netherlands Epidemiology of Obesity study participants without overt CVD. Participants were divided in three groups: no Q-waves (93.7%), isolated (4.6%) and non-isolated borderline Q-waves (1.7%). Borderline Q-waves were defined as Minnesota Codes 1.2.x and 1.3.x and non-isolated as ≥1 of abnormal QRS axis, left ventricular hypertrophy or ST/T abnormalities. Several characteristics and measures of body fat were assessed. Vascular stiffness was assessed by pulse wave velocity (PWV) and subclinical atherosclerosis by carotid intima-media thickness (cIMT). Percentage of men, alcohol intake, blood pressure and fasting glucose concentrations were, compared with no Q-waves, higher in the isolated and highest in the non-isolated borderline Q-wave group. Isolated borderline Q-waves were associated with higher body mass index (difference compared with no Q-waves: 1.0 kg/m2; 95%CI: 0.3–1.7; p-value: 0.006), waist circumference (3.4 cm; 1.0–5.8; 0.005), and visceral adipose tissue (21.9 cm2; 7.4–36.3; 0.003) and differences were even larger for non-isolated borderline Q-waves. Compared with no Q-waves, non-isolated borderline Q-waves were associated with higher PWV (1.2 m/s; 0.4–2.0; 0.004) and cIMT (23.4 μm; 3.0–43.8; 0.024), whereas isolated borderline Q-waves were not. Conclusion: Cardiovascular risk factors and measures of body fat, especially abdominal adiposity, were higher in participants with isolated borderline Q-waves, compared with no Q-waves, and highest in the non-isolated borderline Q-wave group. Non-isolated borderline Q-waves were associated with subclinical atherosclerosis and vascular stiffness. Future studies should investigate potential added value of borderline Q-waves in CVD prediction

The association of kidney function and cognitive decline in older patients at risk of cardiovascular disease: a longitudinal data analysis

Background: Chronic kidney disease (CKD) has been identified as a significant direct marker for cognitive decline, but controversy exists regarding the magnitude of the association of kidney function with cognitive decline across the different CKD stages. Therefore, the aim of this study was to investigate the association of kidney function with cognitive decline in older patients at high risk of cardiovascular disease, using data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Methods Data of 5796 patients of PROSPER were used. Strata were made according to clinical stages of CKD based on estimated glomerular filtration rate; < 30 ml/min/1.73m2 (stage 4), 30-45 ml/min/1.73m2 (stage 3b), 45-60 ml/min/1.73m2 (stage 3a) and ≥ 60 ml/min/1.73m2 (stage 1–2). Cognitive function and functional status was assessed at six different time points and means were compared at baseline and over time, adjusted for multiple prespecified variables. Stratified analyses for history of vascular disease were executed. Results: Mean age was 75.3 years and 48.3% participants were male. Mean follow-up was 3.2 years. For all cognitive function tests CKD stage 4 compared to the other stages had the worst outcome at baseline and a trend for faster cognitive decline over time. When comparing stage 4 versus stage 1–2 over time the estimates (95% CI) were 2.23 (0.60–3.85; p = 0.009) for the Stroop-Colour-Word test, − 0.33 (− 0.66–0.001; p = 0.051) for the Letter-Digit-Coding test, 0.08 (− 0.06–0.21; p = 0.275) for the Picture-Word-Learning test with immediate recall and − 0.07 (− 0.02–0.05; p = 0.509) for delayed recall. This association was most present in patients with a history of vascular disease. No differences were found in functional status. Conclusion: In older people with vascular burden, only severe kidney disease (CKD stage 4), but not mild to modest kidney disease (CKD stage 3a and b), seem to be associated with cognitive impairment at baseline and cognitive decline over time. The association of severe kidney failure with cognitive impairment and decline over time was more outspoken in patients with a history of vascular disease, possibly due to a higher probability of polyvascular damage, in both kidney and brain, in patients with proven cardiovascular disease

Ventricular repolarization is associated with cognitive function, but not with cognitive decline and brain Magnetic Resonance Imaging (MRI) measurements in older adults

We aimed to investigate the cross-sectional and longitudinal associations of electrocardiogram (ECG)-based QT, QTc, JT, JTc, and QRS intervals with cognitive function and brain magnetic resonance imaging (MRI) measurements in a cohort of older individuals at increased risk for cardiovascular disease, but free of known arrhythmias. We studied 4627 participants (54% female, mean age 75 years) enrolled in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Ten-second ECGs were conducted at baseline. Cognitive function was tested at baseline and repeated during a mean follow-up time of 3.2 years. Structural MRIs were conducted in a subgroup of 535 participants. Analyses were performed with multivariable (repeated) linear regression models and adjusted for cardiovascular risk-factors, co-morbidities, and cardiovascular drug use. At baseline, longer QT, JT, JTc—but not QTc and QRS intervals—were associated with a worse cognitive performance. Most notably, on the Stroop Test, participants performed 3.02 (95% CI 0.31; 5.73) seconds worse per standard deviation higher QT interval, independent of cardiovascular risk factors and medication use. There was no association between longer ventricular de- or repolarization and structural brain measurements. Therefore, specifically ventricular repolarization was associated with worse cognitive performance in older individuals at baseline but not during follow-up