An exciting new era has dawned for the prevention and management of CAD utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for coronary artery disease (CAD) confirm not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Lastly, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.

No description available.

Genome-wide approaches including polygenic risk scores (PRSs) are now widely used in medical research; however, few studies have been conducted in low- and middle-income countries (LMICs), especially in South America. This study was designed to test the transferability of psychiatric PRSs to individuals with different ancestral and cultural backgrounds and to provide genome-wide association study (GWAS) results for psychiatric outcomes in this sample. The PrOMIS cohort (N = 3308) was recruited from prenatal care clinics at the Instituto Nacional Materno Perinatal (INMP) in Lima, Peru. Three major psychiatric outcomes (depression, PTSD, and suicidal ideation and/or self-harm) were scored by interviewers using valid Spanish questionnaires. Illumina Multi-Ethnic Global chip was used for genotyping. Standard procedures for PRSs and GWAS were used along with extra steps to rule out confounding due to ancestry. Depression PRSs significantly predicted depression, PTSD, and suicidal ideation/self-harm and explained up to 0.6% of phenotypic variation (minimum p = 3.9 × 10−6). The associations were robust to sensitivity analyses using more homogeneous subgroups of participants and alternative choices of principal components. Successful polygenic prediction of three psychiatric phenotypes in this Peruvian cohort suggests that genetic influences on depression, PTSD, and suicidal ideation/self-harm are at least partially shared across global populations. These PRS and GWAS results from this large Peruvian cohort advance genetic research (and the potential for improved treatments) for diverse global populations. / National Institutes of Health / Revisión por pares

No description available.

Cardiovascular risk scores predict an individual’s risk of developing cardiovascular disease. Many were developed and validated in study cohorts on risk-factor lowering treatment – a cause of inaccuracy. In addition, risk scores are criticised as being biased towards the elderly due to the prominence of age as a risk predictor. Although present guidelines advocate the use of short-term (5-10 year) absolute risk scores, other approaches to redress this perceived imbalance such as lifetime risk scores are being considered. The overall objective of this thesis is to identify the most appropriate cardiovascular risk score for use in general practice, taking account of the impact of treatment and time on assessed risk. This objective was met by three different methods. First, a systematic review of cardiovascular risk scores was conducted. This explored the derivation of each score, including the extent of treatment. Next, doctors were interviewed in depth to understand their perception and use of risk scores. Finally, mathematical models were devised to determine whether a true difference in life expectancy exists at different ages but the same short-term cardiovascular risk. The models incorporated age-specific case fatality rates, competing risks and time preference to estimate the potential years of life lost due to a five-year treatment delay in different age groups with the same short-term coronary heart disease risk. The findings demonstrate that cardiovascular risk scores do not take account of treatment effects. This significantly affects their application in clinical practice. In addition, there is little difference in potential life years lost between ages at the same risk level because of higher case-fatalities in older people. When time preference is considered, any residual case for treating the same level of short-term risk differently at different ages is abolished. The overall conclusion is that the five to ten-year absolute cardiovascular risk score is the most appropriate approach to primary cardiovascular disease prevention. By overestimating risk in the young, other approaches benefit the few at the expense of the many.

De nombreux facteurs de risque cardiovasculaire comme l’hypercholestérolémie, l’hypertension, et le diabète sont comptés parmi les facteurs de risque modifiables les plus importants pour le déclin cognitif et la démence. L’exposition à ces facteurs de risque au cours de la vie en particulier avant l’âge de 65 ans ainsi que leur agrégation contribuent de manière plus importante au déclin cognitif. Peu d’études se sont intéressées aux mesures composites de risque cardiovasculaire par rapport à la fonction cognitive chez les sujets de moins de 65 ans. L’objectif de cette thèse était d’étudier l’association entre les mesures composites de risque et le déclin cognitif au cours de la phase précocedu vieillissement. Les données de la cohorte Whitehall II dans laquelle les fonctions cognitives ont été mesurées à trois reprises ont été utilisées pour étudier l’association entre le syndrome métabolique et deux scores de risque de Framingham (de maladie cardiovasculaire globale et d’AVC), et la fonction cognitive et le déclin cognitif sur 10 ans. Les scores de risque cardiovasculaire de Framingham ont aussi été comparés avec un score de risque de démence. De toutes les mesures composites de risque étudiées, les scores de risque de Framingham montraient la plus forteassociation avec le déclin cognitif. Un risque cardiovasculaire plus élevé était associé à un déclin plus rapide dans de multiples tests cognitifs dont la fluence verbale, le vocabulaire et la cognition globale. Ces résultats suggèrent d’une part qu’un risque cardiovasculaire plus élevé contribue au déclin cognitif dès la phase précoce de vieillissement et d’autre part que l’estimation du risque cardiovasculaire et son effet sur la fonction cognitive nécessite une approche multifactorielle.L’identification et la réduction de facteurs de risque cardiovasculaire peuvent avoir un impact important sur la réduction du déclin cognitif et de la démence. / Several cardiovascular disease risk factors including, dyslipidemia, high blood pressure, and diabetes have been proposed as important modifiable risk factors for cognitive decline and dementia. These risk factors often co-occur and their aggregation is associated with increased risk of cardiovascular disease and dementia. However, studies of composite measures of cardiovascular disease risk in relation to cognitive outcomes in non-elderly populations are scarce. The aim of this thesis was to examine composite measures of risk in relation to cognition and longitudinal cognitive change amongmiddle-aged adults. Data from the Whitehall II study were used to study the associations between the metabolic syndrome, two Framingham risk scores; the Framingham stroke and general cardiovascular disease risk scores, and cognition, based on three cognitive assessments over 10 years. In addition, these two (cardio)vascular risk scores were compared with the CAIDE dementia risk score. Of all composite measures of risk examined, the two Framingham risk scores were the best predictors of 10-year cognitive decline. Higher cardiovascular risk was associated with faster 10-year decline inmultiple cognitive tests including verbal fluency, vocabulary and global cognition. These results suggest that multiple cardiovascular disease risk factors contribute to cognitive decline starting in midlife and that multi-risk factor models such as cardiovascular risk scores may be better suited to assessing risk of cognitive decline. Early identification and treatment of cardiovascular disease risk factors may offer the possibility of markedly delaying or preventing cognitive decline.

Abstract Nutritional status affects every aspect of a child?s health. Thorough nutritional assessment is hampered by the lack of a single comprehensive tool, which can cover all aspects of nutritional assessment. In three distinct studies, this thesis investigated the nutritional status of hospitalised children, children with coeliac disease and children with inflammatory bowel disease. Study 1 The objectives of this study were to assess prevalence of malnutrition and nutritional risk, and define demographic and anthropometric factors associated with nutritional risk among hospitalized children. In this cross sectional study, 157 hospitalised children were assessed for nutritional status using nutritional risk score (NRS) and anthropometric measurements. We found that 4.5%, 8.9%, 15.1% and 10.4% children were wasted, stunted, overweight and obese respectively. However, with the NRS, 47.8% of the children were at high nutritional risk. These children at high risk had lower weight for age (p=0.02), lower BMI percentiles for age (p=0.001) and longer hospitalization (p=0.001) than children at no risk. Study 2 The objectives of this study were to determine nutritional parameters in children with coeliac disease. Twenty-five children with coeliac disease and an equal number of age and gender matched controls were enrolled and anthropometric measurements, BIA and leptin levels were analysed in all. No significant differences were found between the children with coeliac disease and controls in these parameters. BMI percentile correlated with leptin levels in children with coeliac disease. Study 3 The objectives of this study were to determine anthropometric parameters and leptin levels in children with IBD and ascertain if BMI correlates with leptin levels in these children. Thirty children with IBD and 60 age and gender matched controls were enrolled. Anthropometric measurements and leptin levels were analysed and compared with controls. IBD children had significantly low weight for age (p=0.002), BMI percentiles (p=0.001) and leptin levels (p=0.009) compared to controls. There was a correlation between BMI and leptin levels in IBD children. In conclusion, this thesis has shown that one quarter of hospitalized children were overweight or obese, and further, that half of the hospitalised children were at high risk of nutritional deterioration and these children had longer hospital stay than children at no risk. Children with coeliac disease had similar anthropometric measurements, body compartments and leptin levels to controls. However, children with IBD had lower anthropometric measurements and leptin levels, indicating under-nutrition. Nutritional assessment should be a mandatory part of clinical management with nutritional status assessed by various tools including NRS, anthropometry, BIA and leptin levels.

Abstract Nutritional status affects every aspect of a child?s health. Thorough nutritional assessment is hampered by the lack of a single comprehensive tool, which can cover all aspects of nutritional assessment. In three distinct studies, this thesis investigated the nutritional status of hospitalised children, children with coeliac disease and children with inflammatory bowel disease. Study 1 The objectives of this study were to assess prevalence of malnutrition and nutritional risk, and define demographic and anthropometric factors associated with nutritional risk among hospitalized children. In this cross sectional study, 157 hospitalised children were assessed for nutritional status using nutritional risk score (NRS) and anthropometric measurements. We found that 4.5%, 8.9%, 15.1% and 10.4% children were wasted, stunted, overweight and obese respectively. However, with the NRS, 47.8% of the children were at high nutritional risk. These children at high risk had lower weight for age (p=0.02), lower BMI percentiles for age (p=0.001) and longer hospitalization (p=0.001) than children at no risk. Study 2 The objectives of this study were to determine nutritional parameters in children with coeliac disease. Twenty-five children with coeliac disease and an equal number of age and gender matched controls were enrolled and anthropometric measurements, BIA and leptin levels were analysed in all. No significant differences were found between the children with coeliac disease and controls in these parameters. BMI percentile correlated with leptin levels in children with coeliac disease. Study 3 The objectives of this study were to determine anthropometric parameters and leptin levels in children with IBD and ascertain if BMI correlates with leptin levels in these children. Thirty children with IBD and 60 age and gender matched controls were enrolled. Anthropometric measurements and leptin levels were analysed and compared with controls. IBD children had significantly low weight for age (p=0.002), BMI percentiles (p=0.001) and leptin levels (p=0.009) compared to controls. There was a correlation between BMI and leptin levels in IBD children. In conclusion, this thesis has shown that one quarter of hospitalized children were overweight or obese, and further, that half of the hospitalised children were at high risk of nutritional deterioration and these children had longer hospital stay than children at no risk. Children with coeliac disease had similar anthropometric measurements, body compartments and leptin levels to controls. However, children with IBD had lower anthropometric measurements and leptin levels, indicating under-nutrition. Nutritional assessment should be a mandatory part of clinical management with nutritional status assessed by various tools including NRS, anthropometry, BIA and leptin levels.

Abstract Nutritional status affects every aspect of a child?s health. Thorough nutritional assessment is hampered by the lack of a single comprehensive tool, which can cover all aspects of nutritional assessment. In three distinct studies, this thesis investigated the nutritional status of hospitalised children, children with coeliac disease and children with inflammatory bowel disease. Study 1 The objectives of this study were to assess prevalence of malnutrition and nutritional risk, and define demographic and anthropometric factors associated with nutritional risk among hospitalized children. In this cross sectional study, 157 hospitalised children were assessed for nutritional status using nutritional risk score (NRS) and anthropometric measurements. We found that 4.5%, 8.9%, 15.1% and 10.4% children were wasted, stunted, overweight and obese respectively. However, with the NRS, 47.8% of the children were at high nutritional risk. These children at high risk had lower weight for age (p=0.02), lower BMI percentiles for age (p=0.001) and longer hospitalization (p=0.001) than children at no risk. Study 2 The objectives of this study were to determine nutritional parameters in children with coeliac disease. Twenty-five children with coeliac disease and an equal number of age and gender matched controls were enrolled and anthropometric measurements, BIA and leptin levels were analysed in all. No significant differences were found between the children with coeliac disease and controls in these parameters. BMI percentile correlated with leptin levels in children with coeliac disease. Study 3 The objectives of this study were to determine anthropometric parameters and leptin levels in children with IBD and ascertain if BMI correlates with leptin levels in these children. Thirty children with IBD and 60 age and gender matched controls were enrolled. Anthropometric measurements and leptin levels were analysed and compared with controls. IBD children had significantly low weight for age (p=0.002), BMI percentiles (p=0.001) and leptin levels (p=0.009) compared to controls. There was a correlation between BMI and leptin levels in IBD children. In conclusion, this thesis has shown that one quarter of hospitalized children were overweight or obese, and further, that half of the hospitalised children were at high risk of nutritional deterioration and these children had longer hospital stay than children at no risk. Children with coeliac disease had similar anthropometric measurements, body compartments and leptin levels to controls. However, children with IBD had lower anthropometric measurements and leptin levels, indicating under-nutrition. Nutritional assessment should be a mandatory part of clinical management with nutritional status assessed by various tools including NRS, anthropometry, BIA and leptin levels.

Abstract Nutritional status affects every aspect of a child?s health. Thorough nutritional assessment is hampered by the lack of a single comprehensive tool, which can cover all aspects of nutritional assessment. In three distinct studies, this thesis investigated the nutritional status of hospitalised children, children with coeliac disease and children with inflammatory bowel disease. Study 1 The objectives of this study were to assess prevalence of malnutrition and nutritional risk, and define demographic and anthropometric factors associated with nutritional risk among hospitalized children. In this cross sectional study, 157 hospitalised children were assessed for nutritional status using nutritional risk score (NRS) and anthropometric measurements. We found that 4.5%, 8.9%, 15.1% and 10.4% children were wasted, stunted, overweight and obese respectively. However, with the NRS, 47.8% of the children were at high nutritional risk. These children at high risk had lower weight for age (p=0.02), lower BMI percentiles for age (p=0.001) and longer hospitalization (p=0.001) than children at no risk. Study 2 The objectives of this study were to determine nutritional parameters in children with coeliac disease. Twenty-five children with coeliac disease and an equal number of age and gender matched controls were enrolled and anthropometric measurements, BIA and leptin levels were analysed in all. No significant differences were found between the children with coeliac disease and controls in these parameters. BMI percentile correlated with leptin levels in children with coeliac disease. Study 3 The objectives of this study were to determine anthropometric parameters and leptin levels in children with IBD and ascertain if BMI correlates with leptin levels in these children. Thirty children with IBD and 60 age and gender matched controls were enrolled. Anthropometric measurements and leptin levels were analysed and compared with controls. IBD children had significantly low weight for age (p=0.002), BMI percentiles (p=0.001) and leptin levels (p=0.009) compared to controls. There was a correlation between BMI and leptin levels in IBD children. In conclusion, this thesis has shown that one quarter of hospitalized children were overweight or obese, and further, that half of the hospitalised children were at high risk of nutritional deterioration and these children had longer hospital stay than children at no risk. Children with coeliac disease had similar anthropometric measurements, body compartments and leptin levels to controls. However, children with IBD had lower anthropometric measurements and leptin levels, indicating under-nutrition. Nutritional assessment should be a mandatory part of clinical management with nutritional status assessed by various tools including NRS, anthropometry, BIA and leptin levels.