Population-based Control Subjects Research Articles

Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects

Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.

Risks of Depression and Suicide After Diagnosis With Heart Failure: A National Cohort Study

BackgroundHeart failure (HF) has been associated with psychosocial distress, but other long-term mental health sequelae are unclear. ObjectivesIn this study, the authors sought to determine risks of major depression and suicide, susceptible time periods, and sex-specific differences after HF diagnosis in a large population-based cohort. MethodsA national cohort study was conducted of all 154,572 persons diagnosed with HF at ages 18-75 years during 2002-2017 in Sweden and 1,545,720 age- and sex-matched population-based control subjects who were followed up for major depression and suicide ascertained from nationwide inpatient, outpatient, and death records through 2018. Poisson regression was used to compute incidence rate ratios (IRRs) while adjusting for sociodemographic factors and comorbidities. ResultsHF was associated with increased risks of major depression and death by suicide in both men and women, with highest risks in the first 3 months, then declining to modest risks at ≥12 months after HF diagnosis. Within 3 months after HF diagnosis, adjusted IRRs for new-onset major depression were 3.34 (95% CI: 3.04-3.68) in men and 2.78 (95% CI: 2.51-3.09) in women, and for suicide death were 4.47 (95% CI: 2.62-7.62) in men and 2.82 (95% CI: 1.11-7.12) in women. These risks were elevated regardless of age at HF diagnosis. HF was associated with significantly more depression cases in women (P < 0.001). ConclusionsIn this large national cohort, HF was associated with substantially increased risks of depression and suicide in men and women, with highest risks occurring within 3 months after HF diagnosis. Men and women with HF need timely detection and treatment of depression and suicidality.

MO312: Long-Term Kidney Function Outcome After COVID-19 Associated Acute Kidney Injury and Kidney Replacement Therapy in Intensive Care

BACKGROUND AND AIMSAcute kidney injury (AKI), frequently with concurrent albuminuria and haematuria, is common and increases mortality in COVID-19 infection. We present the clinical course and long-term outcomes of COVID-19 survivors with AKI and continuous kidney replacement therapy (CKRT) with follow-up of kidney function at 6 and 12 months.METHODA total of 29 non-CKD COVID-19 infected patients with AKI required mechanical ventilation and CKRT at the intensive care unit (ICU). Of those, 15 died (52%) and 14 survived. Written informed consent to collect and publish data was obtained from 13 survivors.We estimated eGFR with CKD-EPI creatinine in population-based healthy controls (n = 80, median age 62 years) for comparison.RESULTSA total of 13 survivors, median age 58 years, 85% male, 15% diabetes and median BMI 30 kg/m2. None had CKD before admission or at admission following rehydration.The typical scenario was a normal or slightly elevated creatinine level at admission, normalizing after IV fluids, but rising creatinine from day 8 (median) and the start of CKRT on day 10 (median). Urine analysis was available in 7 patients, of which only 1 had no urinary findings, 6 had albuminuria and/or haematuria and/or leukocyturia. Dialysis could be weaned in all 13 survivors after a median time of 16 days in dialysis (range 1–40 days). The median length of stay at the ICU was 41 days (range 10–72 days) and the median weight loss was 16 kg (range 8–27 kg).The survivors had a median eGFR of 100 mL/min/1.73 m2 (range 66–113) at baseline and a median eGFR of 69 mL/min/1.73 m2 (range 49–97) at 12 months estimated with CKD-EPI creatinine. Population-based control subjects had a median eGFR of 85 mL/min/1.73 m2 estimated CKD-EPI creatinine. Urine analysis was available in 11 patients at 12 months, of which 5 had no urinary findings, 3 had microalbuminuria and 3 had haematuria and/or leukocyturia.Since the weight loss was accompanied by a decline in creatinine, we used both creatinine-based, and cystatin C-based eGFR to evaluate kidney function at 6 month follow-up. At 6 months, the survivors had a median eGFR of 70 mL/min/1.73 m2 (range 44–111) estimated with CKD-EPI creatinine as compared with 46 mL/min/1.73 m2 (range 36–65) estimated with cystatin C eGFR, suggesting that cystatin C-based formulae are clinically more useful after COVID-19 associated critical illness.CONCLUSIONThe AKI mortality in COVID-19 despite CKRT is high, but a substantial number of patients survive and can be weaned off dialysis. Kidney function at 12 months did improve substantially but did not return to its baseline values and was lower compared with healthy age-matched population-based control subjects. Kidney outcome follow-up after COVID-19 and AKI is likely to be important for assessing long-term CKD prognosis and is proposed to be evaluated with both creatinine and cystatin C as well as urinalysis.

Insulin resistance is more severe in patients with primary hyperparathyroidism

BackgroundPrimary hyperparathyroidism is associated with an increased cardiovascular mortality, and its underlying mechanisms remain unclear. Insulin resistance has been suggested with low level of evidence. The goal of this study was to evaluate glucose metabolism and insulin resistance in primary hyperparathyroidism patients, to compare with control subjects, and to identify risk factors for insulin resistance in patients with primary hyperparathyroidism. MethodsCross-sectional study of consecutive primary hyperparathyroidism patients without history of diabetes or severe chronic kidney disease (glomerular filtration rate ≤30 mL/min/1.73 m2). Fasting glucose and insulin were evaluated before parathyroidectomy. Glucose metabolism was compared with population-based control subjects (n = 171). ResultsOne hundred and seventy-four patients with primary hyperparathyroidism (140 females) were included. Mean fasting glucose was 0.983 ± 0.129 g/L, and 63 patients (36%) had prediabetes (>1.0 g/L). Mean Homeostatic model assessment of insulin resistance (HOMA-IR) was 3.386 ± 3.111 mUI/L, and 78 patients (45%) had insulin resistance (HOMA-IR >2.6). Blood calcium levels (0.171; P = .023) and body mass index (0.450; P < .001) were correlated positively with HOMA-IR. Insulin secretion (HOMA-B%) was correlated positively with preoperative systolic blood pressure in mm Hg (0.187; P = .013). In multivariate analysis, classic hypercalcemic primary hyperparathyroidism (18.47, 6.84–49.87; <.001), mild hypercalcemic primary hyperparathyroidism (5.35, 2.40–11.95; <.001), and body mass index (1.27, 1.17–1.38; <.001) remained independent predictors for insulin resistance (HOMA-IR >2.6). When compared with control subjects, mean HOMA-IR was significantly higher in primary hyperparathyroidism patients (3.386 ± 3.111 vs 1.919 ± 1.158; P < .001). ConclusionInsulin resistance was significantly higher in primary hyperparathyroidism patients than in control subjects. The impact of parathyroidectomy on insulin resistance should be evaluated in patients with higher calcium levels.

A longitudinal study of restless legs symptoms among patients with depression

Background The aim of this study was to analyse the relationship between depressive symptoms and clinical depression and restless legs symptoms in a longitudinal primary care setting. Methods The prevalence of restless legs symptoms at baseline and after a six-year follow-up was studied in 474 patients with depressive symptoms and 333 population-based control subjects without depressive symptoms. Depressive symptoms at the baseline and after the six-year follow-up were evaluated with the Beck Depression Inventory (BDI) Second Edition. A psychiatric diagnosis was confirmed with a diagnostic interview (M.I.N.I.). Statistical comparisons between groups were made using analysis of variance (ANOVA) for continuous variables and a chi‐square test or logistic models for categorical variables. Repeated measures were analysed using generalizing estimating equations (GEE) models. Results At baseline the prevalence of restless legs symptoms was 24.3% in control subjects, 43.8% in the patients with depressive symptoms without a depression diagnosis, and 49.3% in clinically depressed patients. During the follow-up up the prevalence of restless legs symptoms declined significantly (p = 0.003). In addition to baseline restless legs symptoms, the prognostic factors for restless legs symptoms among patients with clinical depression were age and BDI score. In the control subjects, moderate and high leisure time physical activity was inversely associated with restless legs symptoms at the follow-up. Conclusions A higher level of baseline depressive symptoms was a risk factor for restless legs symptoms in patients with clinical depression. In the prevention and treatment of restless legs symptoms among the patients with depression, the priority is the effective treatment of depression.

Human leucocyte antigens profiling in Malay female patients with systemic lupus erythematosus: are we the same or different?

ObjectiveSLE is a heterogeneous autoimmune disease, in terms of clinical presentation, incidence and severity across diverse ethnic populations. We investigated the human leucocyte antigens (HLA) profile (ie, HLA-A, HLA-B and...

Patients With Type 2 Diabetes Have an Increased Demand for Pacemaker Treatment: A Comparison With Age- and Sex-Matched Control Subjects From the General Population.

Patients with type 2 diabetes have an increased risk for cardiovascular disease, including arrhythmias. The prevalence of bradyarrhythmia and the subsequent need for treatment with pacemakers (PMs) is less well explored in a contemporary patient population. The current study explores 1) whether patients with type 2 diabetes have an increased demand for PM implantation compared with an age- and sex-matched control population without diabetes and 2) patient characteristics associated with an increased demand for receiving a PM. In this population-matched registry study, a total of 416,247 patients with type 2 diabetes from the Swedish National Diabetes Registry and 2,081,235 age- and sex-matched control subjects selected from the general population were included between 1 January 1998 and 31 December 2012 and followed until 31 December 2013. Mean follow-up time was 7 years. Cox proportional hazards regression analyses were performed to estimate the demand of PM treatment and the factors identifying patients with such demand. Type 2 diabetes was associated with an increased need of PM treatment (hazard ratio 1.65 [95% CI 1.60-1.69]; P < 0.0001), which remained (1.56 [1.51-1.60]; P < 0.0001) after adjustments for age, sex, educational level, marital status, country of birth, and coronary heart disease. Risk factors for receiving a PM included increasing age, HbA1c, BMI, diabetes duration, and lipid- and blood pressure-lowering medication. The need for PM treatment is higher in patients with type 2 diabetes than in matched population-based control subjects. Age, diabetes duration, and HbA1c seem to be risk factors for PM treatment.

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC.

The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

Coronary artery disease is more severe in patients with primary hyperparathyroidism

BackgroundPrimary hyperparathyroidism is associated with an increased cardiovascular mortality, but mechanisms underlying this association are unclear. The goal of this study was to evaluate coronary artery calcifications via the coronary calcification score in primary hyperparathyroidism patients, to compare with control subjects, and to identify risk factors for high to intermediate risk coronary calcification scores (coronary calcification score >100). MethodCross-sectional study of primary hyperparathyroidism patients without a history of coronary artery disease, diabetes, or severe, chronic kidney disease. Coronary calcification scores were compared with a cohort of population-based control subjects. ResultsThe mean coronary calcification score was 120 ± 344 in 130 primary hyperparathyroidism patients. The coronary calcification score was >100 in 27 patients (21%). When compared with control subjects, the percentage of positive coronary calcification scores was similar in primary hyperparathyroidism patients (53% vs 50%); however, positive coronary calcification scores were at the 67th percentile of the control subjects cohort (P < .001). In multivariable regression, patient age (1.1; 1.1–1.2; P < .001), patients in the mild normocalcemic primary hyperparathyroidism group (5.1; 1.1–22.6; P = .037), and the need for antihypertensive medications (6.1; 1.8–20.9; P < .001) remained independent predictors for a coronary calcification score >100. ConclusionPositive coronary calcification scores were greater in primary hyperparathyroidism patients than in population-based control subjects. These study data may provide new criteria for parathyroidectomy in patients with primary hyperparathyroidism.

Risk of first stroke in people with type 2 diabetes and its relation to glycaemic control: A nationwide observational study.

To compare stroke incidence in people with type 2 diabetes (T2D) with that in a matched control group, and to investigate whether glucose exposure in people with T2D can predict a first-time stroke event and mortality. In a nationwide observational cohort study, individuals with T2D were linked in the Swedish National Diabetes Register and matched with five individual population-based control subjects. We calculated crude incidence rates and 95% confidence intervals (CIs), and used Cox regression and multivariable hazard ratios (HRs), to estimate the risk of stroke and mortality in relation to glycated haemoglobin (HbA1c) levels. A total of 406 271 people with T2D (age 64.1 ± 12.4 years, 45.7% women) and 2086 440 control subjects (age 64.0 ± 12.4 years, 45.7% women) were included. During a median follow-up of 7.3 years, 26 380 people with T2D (6.5%) versus 92 375 control subjects (4.4%) were diagnosed with a stroke. The incidence rate was 10.12 events per 1000 person-years versus 7.26 events per 1000 person-years (HR 1.54, 95% CI 1.52-1.56). In the T2D group after multivariable adjustments, the HRs for stroke stratified by HbA1c level were: 54-64 mmol/mol: 1.27 (95% CI 1.22-1.32); 65-75 mmol/mol: 1.68 (95% CI 1.60-1.76); 76-86 mmol/mol: 1.89 (95% CI, 1.75-2.05); and > 87 mmol/mol: 2.14 (95% CI 1.90-2.42), respectively, compared with the reference category of HbA1c ≤53 mmol/mol. There was a stepwise increased risk of death after stroke, for every 10-mmol/mol categorical increment of HbA1c (HR 1.71; 95% CI 1.47-2.00) for the highest HbA1c category. An increased risk of stroke and death was associated with poor glycaemic control in people with T2D.

Genomic structural variations lead to dysregulation of important coding and non-coding RNA species in dilated cardiomyopathy.

The transcriptome needs to be tightly regulated by mechanisms that include transcription factors, enhancers, and repressors as well as non‐coding RNAs. Besides this dynamic regulation, a large part of phenotypic variability of eukaryotes is expressed through changes in gene transcription caused by genetic variation. In this study, we evaluate genome‐wide structural genomic variants (SVs) and their association with gene expression in the human heart. We detected 3,898 individual SVs affecting all classes of gene transcripts (e.g., mRNA, miRNA, lncRNA) and regulatory genomic regions (e.g., enhancer or TFBS). In a cohort of patients (n = 50) with dilated cardiomyopathy (DCM), 80,635 non‐protein‐coding elements of the genome are deleted or duplicated by SVs, containing 3,758 long non‐coding RNAs and 1,756 protein‐coding transcripts. 65.3% of the SV‐eQTLs do not harbor a significant SNV‐eQTL, and for the regions with both classes of association, we find similar effect sizes. In case of deleted protein‐coding exons, we find downregulation of the associated transcripts, duplication events, however, do not show significant changes over all events. In summary, we are first to describe the genomic variability associated with SVs in heart failure due to DCM and dissect their impact on the transcriptome. Overall, SVs explain up to 7.5% of the variation of cardiac gene expression, underlining the importance to study human myocardial gene expression in the context of the individual genome. This has immediate implications for studies on basic mechanisms of cardiac maladaptation, biomarkers, and (gene) therapeutic studies alike.

Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guérin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK.

Until recently, evidence that protection from the bacillus Calmette-Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK's universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. Two case-control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0-19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10-29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case-cohort analysis based on Cox regression. In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5-10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10-15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10-15 years after vaccination and 57% (95% CI 33% to 72%) 15-20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading. The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination. Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading. The National Institute for Health Research Health Technology Assessment programme. During the conduct of the study, Jonathan Sterne, Ibrahim Abubakar and Laura C Rodrigues received other funding from NIHR; Ibrahim Abubakar and Laura C Rodrigues have also received funding from the Medical Research Council. Punam Mangtani received funding from the Biotechnology and Biological Sciences Research Council.

Prenatal, intrapartum, and postnatal factors are associated with pediatric eosinophilic esophagitis

Multiple lines of evidence point to the potential importance of early-life environmental factors in the rapid increase in the incidence of eosinophilic esophagitis (EoE), but potential exposures have not been extensively studied. We sought to assess the association between prenatal, intrapartum, and postnatal factors and the development of pediatric EoE using a case-control study. Patients with EoE were recruited from an existing registry at Cincinnati Children's Hospital Medical Center (CCHMC). Population-based community control subjects were identified from a separate CCHMC registry. Mothers of study subjects were contacted and completed a Web-based questionnaire. Crude and adjusted models were used to estimate associations. Mothers of 127 cases and 121 control subjects were included. We observed a positive association between several early-life factors and EoE, including prenatal (maternal fever: adjusted odds ratio [aOR], 3.18; 95% CI, 1.27-7.98; preterm labor: aOR, 2.18; 95% CI, 1.06-4.48), intrapartum (cesarean delivery: aOR, 1.77; 95% CI, 1.01, 3.09), and infancy (antibiotic use: aOR, 2.30; 95% CI, 1.21-4.38; use of an acid suppressant: aOR, 6.05; 95% CI, 2.55-14.40) factors. We observed an inverse association between having a furry pet in infancy and EoE (aOR, 0.58; 95% CI, 0.34-0.97). No associations were observed for breast-feeding or maternal multivitamin or folic acid supplement use. Early-life factors, including maternal fever, preterm labor, cesarean delivery, and antibiotic or acid suppressant use ininfancy, were associated with risk of pediatric EoE; having apet in the home was protective. These results add to growing evidence that implicate early-life exposures in EoE pathogenesis.

PCSK9 variant, long-chain n–3 PUFAs, and risk of nonfatal myocardial infarction in Costa Rican Hispanics1–3

Background: Previous studies have indicated that the cardioprotective effects of long-chain (LC) n–3 (ω-3) polyunsaturated fatty acids (PUFAs) may vary across various ethnic populations. Emerging evidence has suggested that the gene-environment interaction may partly explain such variations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was shown to have a mutually regulating relation with LC n–3 PUFAs and also to reduce the risk of cardiovascular diseases (CVDs). Therefore, we hypothesized that certain PCSK9 genetic variants may modify the association between LC n–3 PUFA intake and CVD risk.Objective: We determined whether a PCSK9 variant (rs11206510), which has been identified for early onset myocardial infarction (MI), modified the association of LC n–3 PUFAs with nonfatal MI risk in Costa Rican Hispanics.Design: We analyzed cross-sectional data from 1932 case subjects with a first nonfatal MI and 2055 population-based control subjects who were living in Costa Rica to examine potential gene-environment interactions. Two-sided P values <0.05 were considered significant.Results: We observed a significant interaction between the PCSK9 rs11206510 genotype and LC n–3 PUFA intake on nonfatal MI risk (P-interaction = 0.012). The OR of nonfatal MI was 0.84 (95% CI: 0.72, 0.98) per 0.1% increase in total energy intake from LC n–3 PUFAs in protective-allele (C-allele) carriers, whereas the corresponding OR (95% CI) in non–C-allele carriers was 1.02 (95% CI: 0.95, 1.10). Similar results were observed when we examined the association between docosahexaenoic acid, which is one type of LC n–3 PUFA, and nonfatal MI risk (P-interaction = 0.003).Conclusion: LC n–3 PUFA intake is associated with a lower risk of nonfatal MI in C-allele carriers of PCSK9 rs11206510 (n = 799) but not in non–C-allele carriers (n = 3188).

Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity.

Some Shanghai Clinical Center f a role of Niemann-Pick type C1 (NPC1) for obesity traits. However, whether the loss-of-function mutations in NPC1 cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous NPC1 mutations on adiposity. We found that male NPC1+/- carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male NPC1+/- mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the NPC1 gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in NPC1 (minor allele frequency <1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, P = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare NPC1 variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function NPC1 mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of NPC1 in the familial NP-C disease.

Dietary n-3 Fatty Acid, α-Tocopherol, Zinc, vitamin D, vitamin C, and β-carotene are Associated with Age-Related Macular Degeneration in Japan.

This case-control study reports the association between nutrient intake and neovascular age-related macular degeneration (AMD) in Japan. The nutrient intake of 161 neovascular AMD cases from two university hospitals and 369 population-based control subjects from a cohort study was assessed using a brief-type self-administered questionnaire on diet history, which required respondent recall of the usual intake of 58 foods during the preceding month. Energy-adjusted nutrient intake values were compared between the groups. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% CIs adjusted for smoking history, age, sex, chronic disease history, supplement use, and alcohol consumption. Logistic regression analysis demonstrated that low intakes of n-3 fatty acid, α-tocopherol, zinc, vitamin D, vitamin C, and β-carotene were associated with neovascular AMD (Trend P < 0.0001 for n-3 fatty acid, Trend P < 0.0001 for α-tocopherol, Trend P < 0.0001 for zinc, Trend P = 0.002 for vitamin D, Trend P = 0.04 for vitamin C, Trend P = 0.0004 for β-carotene). There was no association with retinol or cryptoxanthin intake and neovascular AMD (P = 0.67, 0.06).

Changes in Bone Mineral Density in the Year after Critical Illness.

Critical illness may be associated with increased bone turnover and loss of bone mineral density (BMD). Prospective evidence describing long-term changes in BMD after critical illness is needed to further define this relationship. To measure the change in BMD and bone turnover markers (BTMs) in subjects 1 year after critical illness compared with population-based control subjects. We studied adult patients admitted to a tertiary intensive care unit (ICU) who required mechanical ventilation for at least 24 hours. We measured clinical characteristics, BTMs, and BMD during admission and 1 year after ICU discharge. We compared change in BMD to age- and sex-matched control subjects from the Geelong Osteoporosis Study. Sixty-six patients completed BMD testing. BMD decreased significantly in the year after critical illness at both femoral neck and anterior-posterior spine sites. The annual decrease was significantly greater in the ICU cohort compared with matched control subjects (anterior-posterior spine, -1.59%; 95% confidence interval, -2.18 to -1.01; P < 0.001; femoral neck, -1.20%; 95% confidence interval, -1.69 to -0.70; P < 0.001). There was a significant increase in 10-year fracture risk for major fractures (4.85 ± 5.25 vs. 5.50 ± 5.52; P < 0.001) and hip fractures (1.57 ± 2.40 vs. 1.79 ± 2.69; P = 0.001). The pattern of bone resorption markers was consistent with accelerated bone turnover. Critically ill individuals experience a significantly greater decrease in BMD in the year after admission compared with population-based control subjects. Their bone turnover biomarker pattern is consistent with an increased rate of bone loss.

Left ventricular systolic dysfunction inoutpatients with peripheral atherosclerotic vascular disease: prevalence and association with location of arterial disease.

We aimed to determine the prevalence of left ventricular systolic dysfunction (LVSD) in outpatients with peripheral atherosclerotic vascular disease (PAVD). Further, the associations of stenotic internal carotid artery disease (SICAD) and lower extremity artery disease (LEAD) with LVSD were evaluated. In the Peripheral Artery Disease in Västmanland study, consecutive outpatients with ultrasonographically identified mild to severe stenosis in the internal carotid artery or symptoms of claudication combined with either ankle brachial index of ≤0.90 or ultrasonographic occlusive findings were included (n = 437). Population-based control subjects were matched to the patients (n = 395). LVSD was defined as echocardiographically determined left ventricular ejection fraction (LVEF) <55%, and moderate or greater LVSD was defined as LVEF <45%. The prevalence of LVSD was significantly greater in patients than in controls (13.7% vs. 6.1%, P < 0.001). The prevalence of moderate or greater LVSD in participants not on treatment with a combination of angiotensin-converting enzyme inhibitor and beta-blocker was 2.3% in patients and 1.3% in controls (P = 0.31). When LEAD and SICAD were analysed together, adjusted for potential confounders, SICAD [odds ratio (OR) 2.54, 95% confidence interval (CI) 1.03-6.32], but not LEAD (OR 1.59, 95% CI 0.80-3.18), was independently associated with LVSD. In outpatients with PAVD, we found a 13.7% prevalence of LVSD. However, the prevalence of at least moderate LVSD in patients not on treatment with angiotensin-converting enzyme inhibitor and a beta-blocker was only 2.3% and not significantly different from controls. Stenotic artery disease in the internal carotid artery, but not in the lower extremities, was independently associated with LVSD.

Clinical Utility of PCR for Common Viruses in Acute Respiratory Illness

Acute respiratory illness (ARI) accounts for a large proportion of all visits to pediatric health facilities. Quantitative real-time polymerase chain reaction (qPCR) analyses allow sensitive detection of viral nucleic acids, but it is not clear to what extent specific viruses contribute to disease because many viruses have been detected in asymptomatic children. Better understanding of how to interpret viral findings is important to reduce unnecessary use of antibiotics. To compare viral qPCR findings from children with ARI versus asymptomatic control subjects. Nasopharyngeal aspirates were collected from children aged ≤5 years with ARI and from individually matched, asymptomatic, population-based control subjects during a noninfluenza season. Samples were analyzed by using qPCR for 16 viruses. Respiratory viruses were detected in 72.3% of the case patients (n = 151) and 35.4% of the control subjects (n = 74) (P = .001). Rhinovirus was the most common finding in both case patients and control subjects (47.9% and 21.5%, respectively), with a population-attributable proportion of 0.39 (95% confidence interval: 0.01 to 0.62). Metapneumovirus, parainfluenza viruses, and respiratory syncytial virus were highly overrepresented in case patients. Bocavirus was associated with ARI even after adjustment for coinfections with other viruses and was associated with severe disease. Enterovirus and coronavirus were equally common in case patients and control subjects. qPCR detection of respiratory syncytial virus, metapneumovirus, or parainfluenza viruses in children with ARI is likely to be causative of disease; detection of several other respiratory viruses must be interpreted with caution due to high detection rates in asymptomatic children.

Circulating Markers of Endothelial Dysfunction and Platelet Activation in Patients with Severe Symptomatic Cerebral Small Vessel Disease

Background: Small deep infarcts (SDI), also called lacunar infarcts, resulting from the occlusion of deep branch arteries, account for 25% of ischemic strokes. The physiopathology of the disease remains largely unknown. However, evidence about the role of endothelial dysfunction has emerged. Whereas chronic platelet activation is of major importance in acute thrombosis of large atherosclerotic arteries, its role in SDI remains unclear. Frequently associated risk factors are hypertension and diabetes mellitus. The aim of this study was to determine platelet and endothelial activation in patients with recent SDI in comparison to population-based control subjects matched for age, sex and vascular risk factors. Methods: Platelet activation markers (activated glycoprotein IIb/IIIa, P-selectin and platelet microparticles), shear-induced platelet aggregation (SIPA) studied in the SIPAgreg device at 4,000 s^-1, endothelial activation markers [including von Willebrand factor (vWF) antigen and homocysteine] and high-sensitivity C-reactive protein (hsCRP) were measured in 74 consecutive patients with recent SDI, in whom detectable large artery atherosclerosis or cardiac embolism had been ruled out. Blood samples were collected 1 and 3 months after symptom onset. These factors were also measured in 74 population-based controls with no stroke history and matched for age, sex, hypertension and diabetes. Results: One month after symptom onset, the patients had similar levels of platelet activation to matched controls (p > 0.40 for all comparisons). In contrast, endothelial activation parameters were increased in patients in comparison to controls (vWF: p = 0.002 and homocysteinemia/creatinemia: p = 0.025). The level of hsCRP was slightly increased in patients compared to controls (p = 0.059). At 3 months, we observed a significant decrease in vWF and hsCRP levels in patients (median change in vWF = 10%, p = 0.004; median change in hsCRP = 0.4 mg/l, p = 0.02). Homocysteine levels and all platelet parameters remained unchanged at this time compared to at 1 month. Conclusions: Our results confirm that chronic platelet activation, when compared to controls matched for age, sex and vascular risk factors, did not seem to play a central role in the pathophysiology of lacunar stroke. In contrast, we found markers of endothelial dysfunction, the role of which in the occurrence of lacunar infarction has still to be clarified in further studies.