The association of inflammatory markers with frailty and in-hospital mortality in older COVID-19 patients.

INTRODUCTION: During the COVID19 pandemic, older patients hospitalized for COVID-19 exhibited an increased mortality risk compared to younger patients. While ageing is associated with compromised immune responses and frailty, their contributions and interplay remain understudied. This study investigated the association between inflammatory markers and mortality and potential modification by frailty among older patients hospitalized for COVID-19. METHODS: Data were from three multicenter Dutch cohorts (COVID-OLD, CliniCo, Covid-Predict). Patients were 70 years or older, hospitalized for COVID-19and categorized into three frailty groups: fit (Clinical frailty score (CFS) 1-3), pre-frail (CFS 4-5), and frail (CFS 6-9). Immunological markers (lymphocyte count, neutrophil count, C-reactive protein, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic inflammation index (SII)) were measured at baseline. Associations with in hospital mortality were examined using logistic regression. RESULTS: A total of 1697 patients were included from COVID-OLD, 656 from Covid-Predict, and 574 from CliniCo. The median age was 79, 77, and 78 years for each cohort. Hospital mortality rates were 33 %, 27 % and 39 % in the three cohorts, respectively. A lower CRP was associated with a higher frailty score in all three cohorts (all p < 0.01). Lymphocyte count, neutrophil count, NLR, PLR, or SII, were similar across frailty groups. Higher CRP levels were associated with increased in-hospital mortality risk across all frailty groups, across all cohorts (OR (95 % CI), 2.88 (2.20-3.78), 3.15 (1.95-5.16), and 3.28 (1.87-5.92)), and frailty did not modify the association between inflammatory markers and in-hospital mortality (all p-interaction>0.05). CONCLUSION: While frailty is a significant factor in determining overall outcomes in older patients, our study suggests that the elevated risk of mortality in older patients with frailty compared to fit patients is likely not explained by difference in inflammatory responses.

Older adults exercising ON TIME: protocol for a randomized controlled cross-over study to assess the effect of physical activity timing on insomnia severity.

BACKGROUND: There are increased indications that physical activity timing, irrespective of intensity, impacts insomnia and circadian clock function. Here, we describe the rationale and design of a randomized cross-over study, called ON TIME, to examine the effects of (changing) physical activity timing on insomnia severity and on multiple exploratory outcomes that are linked to circadian clock function. METHODS: We will conduct a randomized cross-over trial in 40 healthy older adults (aged 65 to 75 years) with subclinical or clinical insomnia (Insomnia Severity Index (ISI) scores of ≥ 10) from the Dutch municipality of Leiden and surroundings. Participants will undergo 3 intervention periods (14 days each) consecutively: one sedentary period and two periods of increased physical activity (one period with morning activity and one period with evening activity). The intervention periods are separated by a wash-out period of 1 week. In both active intervention arms, participants will follow coached or uncoached outdoor physical exercise sessions comprising endurance, strength, and flexibility exercises for 14 days. The primary outcome is change in insomnia severity as measured by the ISI. Additional exploratory outcomes include multiple components of objective sleep quality measured with tri-axial accelerometry and subjective sleep quality assessed by questionnaires as well as dim light melatonin onset and 24-h rhythms in heart rate, heart rate variability, breathing rate, oxygen saturation, mood, and objective emotional arousal and stress. Additionally, we will collect diary data on eating patterns (timing and composition). Finally, fasting blood samples will be collected at baseline and after each intervention period for measurements of biomarkers of metabolic and physiological functioning and expression of genes involved in regulation of the biological clock. DISCUSSION: We anticipate that this study will make a significant contribution to the limited knowledge on the effect of physical activity timing. Optimizing physical activity timing has the potential to augment the health benefits of increased physical exercise in the aging population. TRIAL REGISTRATION: Trial was approved by the Medical Ethics Committee Leiden, The Hague, Delft, The Netherlands (June, 2023). The trial was registered in the CCMO-register https://www.toetsingonline.nl/to/ccmo_search.nsf/Searchform?OpenForm under study ID NL82335.058.22 and named ("Ouderen op tijd in beweging" or in English "Older adults exercising on time"). At time of manuscript submission, the trial was additionally registered at ClinicalTrials.gov under study ID: NL82335.058.22 and is awaiting approval.

Sleep duration irregularity and risk for incident cardiovascular disease in the UK Biobank.

Background: Emerging evidence supports a link between circadian disruption as measured by higher night-to-night variation in sleep duration and increased risk of cardiovascular disease (CVD). It remains unclear whether this association varies by CVD types or may be modified by average sleep duration and genetic risk for CVD. Methods: Our prospective analysis included 86,219 UK Biobank participants who were free from CVD when completing 7 days of accelerometer measurement in 2013-2016. Sleep irregularity was evaluated by the standard deviation (SD) of accelerometer-measured sleep duration over 7 days. Incident major CVD events, defined as fatal or nonfatal myocardial infarction (MI) and stroke, were identified through linkage to Hospital Episode Statistics data until May 31, 2022. Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for associations of sleep duration SD with risk for major CVD events overall and for MI and stroke separately. Results: We documented 2,310 incident cases of major CVD events (MI: 1,183, stroke: 1,175) over 636,258 person-years of follow-up. After adjusting for sociodemographic factors and family history of CVD, the HR (95% CI) associated with a 1-hour increase in sleep duration SD was 1.19 (1.10, 1.27) for CVD (p-trend<0.0001), 1.23 (1.11, 1.35) for MI (p-trend<0.0001), and 1.17 (1.05, 1.29) for stroke (p-trend=0.003). Additional adjustment for lifestyle factors, co-morbidities and sleep-related factors modestly attenuated these associations. Higher sleep irregularity was associated with higher CVD risk irrespective of genetic risk (p-interaction=0.43), but this association was stronger among individuals with longer average sleep duration >8 hours (p-interaction=0.006). Conclusions: Higher night-to-night variation in accelerometer-measured sleep duration was associated with consistently higher risks for major CVD events. The association did not seem to be modified by genetic risk for CVD and was more pronounced in long sleepers.

Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease.

The performance of metabolomics-based prediction scores for mortality in older patients with solid tumors.

Prognostic information is needed to balance benefits and risks of cancer treatment in older patients. Metabolomics-based scores were previously developed to predict 5- and 10-year mortality (MetaboHealth) and biological age (MetaboAge). This study aims to investigate the association of MetaboHealth and MetaboAge with 1-year mortality in older patients with solid tumors, and to study their predictive value for mortality in addition to established clinical predictors. This prospective cohort study included patients aged ≥ 70 years with a solid malignant tumor, who underwent blood sampling and a geriatric assessment before treatment initiation. The outcome was all-cause 1-year mortality. Of the 192 patients, the median age was 77 years. With each SD increase of MetaboHealth, patients had a 2.32 times increased risk of mortality (HR 2.32, 95% CI 1.59-3.39). With each year increase in MetaboAge, there was a 4% increased risk of mortality (HR 1.04, 1.01-1.07). MetaboHealth and MetaboAge showed an AUC of 0.66 (0.56-0.75) and 0.60 (0.51-0.68) for mortality prediction accuracy, respectively. The AUC of a predictive model containing age, primary tumor site, distant metastasis, comorbidity, and malnutrition was 0.76 (0.68-0.83). Addition of MetaboHealth increased AUC to 0.80 (0.74-0.87) (p = 0.09) and AUC did not change with MetaboAge (0.76 (0.69-0.83) (p = 0.89)). Higher MetaboHealth and MetaboAge scores were associated with 1-year mortality. The addition of MetaboHealth to established clinical predictors only marginally improved mortality prediction in this cohort with various types of tumors. MetaboHealth may potentially improve identification of older patients vulnerable for adverse events, but numbers were too small for definitive conclusions. The TENT study is retrospectively registered at the Netherlands Trial Register (NTR), trial number NL8107. Date of registration: 22-10-2019.

Association Between Accelerometer-Measured Irregular Sleep Duration and Type 2 Diabetes Risk: A Prospective Cohort Study in the UK Biobank.

OBJECTIVE: To evaluate the association between irregular sleep duration and incident diabetes in a U.K. population over 7 years of follow-up. RESEARCH DESIGN AND METHODS: Among 84,421 UK Biobank participants (mean age: 62 years) who were free of diabetes at the time of providing accelerometer data in 2013-2015 and prospectively followed until May 2022, sleep duration variability was quantified by the within-person SD of 7-night accelerometer-measured sleep duration. We used Cox proportional hazard models to estimate hazard ratios (HRs) for incident diabetes (identified from medical records, death register, and/or self-reported diagnosis) according to categories of sleep duration SD. RESULTS: There were 2,058 incident diabetes cases over 622,080 person-years of follow-up. Compared with sleep duration SD ≤ 30 min, the HR (95% CI) was 1.15 (0.99, 1.33) for 31-45 min, 1.28 (1.10, 1.48) for 46-60 min, 1.54 (1.32, 1.80) for 61-90 min, and 1.59 (1.33, 1.90) for ≥91 min, after adjusting for age, sex, and race. We found a nonlinear relationship (p nonlinearity 0.0002), with individuals with a sleep duration SD of >60 vs. ≤60 min having 34% higher diabetes risk (95% CI 1.22, 1.47). Further adjustment for lifestyle, comorbidities, environmental factors, and adiposity attenuated the association (HR comparing sleep duration SD of >60 vs. ≤60 min: 1.11; 95% CI 1.01, 1.22). The association was stronger among individuals with lower diabetes polygenic risk score (PRS; P interaction ≤ 0.0264) and longer sleep duration (P interaction ≤ 0.0009). CONCLUSIONS: Irregular sleep duration was associated with higher diabetes risk, particularly in individuals with a lower diabetes PRS and longer sleep duration.

Preparing for future pandemics: frailty associates with mortality in hospitalised older people during the entire COVID-19 pandemic, a Dutch multicentre cohort study.

PURPOSE: Viral mutations and improved prevention or treatment options may have changed the association of frailty with mortality throughout the COVID-19 pandemic. We investigated how associations of frailty with in-hospital mortality changed throughout the pandemic in older people hospitalised for COVID-19. METHODS: The COVID-OLD study included COVID-19 patients aged ≥ 70 years hospitalised during the first (early 2020), second (late 2020), third (late 2021) or fourth wave (early 2022). Based on the clinical frailty scale, patients were categorised as fit (1-3), pre-frail (4-5) or frail (6-9). Associations of frailty with in-hospital mortality were assessed with pairwise comparisons with fit as reference category and modelled using binary logistic regression adjusted for age and sex. RESULTS: This study included 2362 patients (mean age 79.7 years, 60% men). In the first wave, in-hospital mortality was 46% in patients with frailty and 27% in fit patients. In-hospital mortality decreased in each subsequent wave to 25% in patients with frailty and 11% in fit patients in the fourth wave. After adjustments, an overall higher risk of in-hospital mortality was found in frail (OR 2.26, 95% CI: 1.66-3.07) and pre-frail (OR 1.73, 95% CI: 1.27-2.35) patients compared to fit patients, which did not change over time (p for interaction = 0.74). CONCLUSIONS: Frailty remained associated with a higher risk of in-hospital mortality throughout the entire COVID-19 pandemic, although overall in-hospital mortality rates decreased. Frailty therefore remains a relevant risk factor in all stages of a pandemic and is important to consider in prevention and treatment guidelines for future pandemics.

The role of genetically-influenced phospholipid transfer protein activity in lipoprotein metabolism and coronary artery disease.

BACKGROUND: Phospholipid transfer protein (PLTP) transfers surface phospholipids between lipoproteins and as such plays a role in lipoprotein metabolism, but with unclear effects on coronary artery disease (CAD) risk. We aimed to investigate the associations of genetically-influenced PLTP activity with 1-H nuclear magnetic resonance (1H-NMR) metabolomic measures and with CAD. Furthermore, using factorial Mendelian randomization (MR), we examined the potential additional effect of genetically-influenced PLTP activity on CAD risk on top of genetically-influenced low-density lipoprotein-cholesterol (LDL-C) lowering. METHODS: Using data from UK Biobank, genetic scores for PLTP activity and LDL-C were calculated and dichotomised based on the median, generating four groups with combinations of high/low PLTP activity and high/low LDL-C levels for the factorial MR. Linear and logistic regressions were performed on 168 metabolomic measures (N = 58,514) and CAD (N = 318,734, N-cases=37,552), respectively, with results expressed as ß coefficients (in standard deviation units) or odds ratios (ORs) and 95% confidence interval (CI). RESULTS: Irrespective of the genetically-influenced LDL-C, genetically-influenced low PLTP activity was associated with a higher HDL particle concentration (ß [95% CI]: 0.03 [0.01, 0.05]), smaller HDL size (-0.14 [-0.15, -0.12]) and higher triglyceride (TG) concentration (0.04 [0.02, 0.05]), but not with CAD (OR 0.99 [0.97, 1.02]). In factorial MR analyses, genetically-influenced low PLTP activity and genetically-influenced low LDL-C had independent associations with metabolomic measures, and genetically-influenced low PLTP activity did not show an additional effect on CAD risk. CONCLUSIONS: Low PLTP activity associates with higher HDL particle concentration, smaller HDL particle size and higher TG concentration, but no association with CAD risk was observed.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People With Type 2 Diabetes.

OBJECTIVE: To identify genetic risk factors for incident cardiovascular disease (CVD) among people with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: We conducted a multiancestry time-to-event genome-wide association study for incident CVD among people with T2D. We also tested 204 known coronary artery disease (CAD) variants for association with incident CVD. RESULTS: Among 49,230 participants with T2D, 8,956 had incident CVD events (event rate 18.2%). We identified three novel genetic loci for incident CVD: rs147138607 (near CACNA1E/ZNF648, hazard ratio [HR] 1.23, P = 3.6 × 10-9), rs77142250 (near HS3ST1, HR 1.89, P = 9.9 × 10-9), and rs335407 (near TFB1M/NOX3, HR 1.25, P = 1.5 × 10-8). Among 204 known CAD loci, 5 were associated with incident CVD in T2D (multiple comparison-adjusted P < 0.00024, 0.05/204). A standardized polygenic score of these 204 variants was associated with incident CVD with HR 1.14 (P = 1.0 × 10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.

Genome-wide characterization of circulating metabolic biomarkers.

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism1-7. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases8-11. Here we present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. We identify more than 400 independent loci and assign probable causal genes at two-thirds of these using manual curation of plausible biological candidates. We highlight the importance of sample and participant characteristics that can have significant effects on genetic associations. We use detailed metabolic profiling of lipoprotein- and lipid-associated variants to better characterize how known lipid loci and novel loci affect lipoprotein metabolism at a granular level. We demonstrate the translational utility of comprehensively phenotyped molecular data, characterizing the metabolic associations of intrahepatic cholestasis of pregnancy. Finally, we observe substantial genetic pleiotropy for multiple metabolic pathways and illustrate the importance of careful instrument selection in Mendelian randomization analysis, revealing a putative causal relationship between acetone and hypertension. Our publicly available results provide a foundational resource for the community to examine the role of metabolism across diverse diseases.

No evidence linking sleep traits with white blood cell counts: Multivariable-adjusted and Mendelian randomization analyses.

BACKGROUND: Disturbances in habitual sleep have been associated with multiple age-associated diseases. However, the biological mechanisms underpinning these associations remain largely unclear. We assessed the possible involvement of the circulating immune system by determining the associations between sleep traits and white blood cell counts using multivariable-adjusted linear regression and Mendelian randomization. METHODS: Cross-sectional multivariable-adjusted linear regression analyses were done using participants within the normal range of total white blood cell counts (>4.5 × 109 and <11.0 × 109/µL) from UK Biobank. For the sleep traits, we examined (short and long) sleep duration, chronotype, insomnia symptoms and daytime dozing. Two-sample Mendelian randomization analyses were done using instruments for sleep traits derived from European-ancestry participants from UK Biobank (over 410,000 participants) and using SNP-outcome data derived from European-ancestry participants from the Blood Cell Consortium (N = 563,946) to which no data from UK Biobank contributed. RESULTS: Using data from 357,656 participants (mean [standard deviation] age: 56.5 [8.1] years, and 44.4% men), we did not find evidence that disturbances in any of the studied sleep traits were associated with differences in blood cell counts (total, lymphocytes, neutrophiles, eosinophiles and basophiles). Also, we did not find associations between disturbances in any of the studied sleep traits and white blood cell counts using Mendelian Randomization. CONCLUSION: Based on the results from two different methodologies, disturbances in habitual sleep are unlikely to cause changes in blood cell counts and thereby differences in blood cell counts are unlikely to be underlying the observed sleep-disease associations.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, and together may provide a more complete picture of sleep health, while also illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p<8.3e-9), along with 341 previously reported loci (p<5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h2=0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections to behavioral, psychological, and cardiometabolic traits.

Genome-Wide Interaction Analysis With DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

BACKGROUND: The Dietary Approaches to Stop Hypertension (DASH) diet score lowers blood pressure (BP). We examined interactions between genotype and the DASH diet score in relation to systolic BP. METHODS: We analyzed up to 9 420 585 single nucleotide polymorphisms in up to 127 282 individuals of 6 population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (n=35 660) and UK Biobank (n=91 622) and performed European population-specific and cross-population meta-analyses. RESULTS: We identified 3 loci in European-specific analyses and an additional 4 loci in cross-population analyses at Pinteraction<5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency, 0.03) and the DASH diet score (Pinteraction=4e-8; P for heterogeneity, 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (Pinteraction=9.4e-7) and 0.20±0.06 mm Hg (Pinteraction=0.001) in Cohorts for Heart and Aging Research in Genomic Epidemiology and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P=4e-273) and cis-DNA methylation quantitative trait loci variants (P=1e-300). Although the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by single nucleotide polymorphisms potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. CONCLUSIONS: We demonstrated gene-DASH diet score interaction effects on systolic BP in several loci. Studies with larger diverse populations are needed to validate our findings.

Hydrocortisone-associated death and hospital length of stay in patients with sepsis: A retrospective cohort of large-scale clinical care data.

PURPOSE: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in the prevention of death in septic patients. Here we evaluated the association between hydrocortisone treatment and mortality in patients diagnosed with sepsis in a large-scale clinical dataset. METHODS: Data from patients between 2008 and 2019 were extracted from the retrospective Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients who received hydrocortisone after diagnosis were matched using propensity-score matching with patients who did not, to balance confounding (by indication and contraindication) factors between the groups. 90-day mortality and survivors' length of hospital stay was compared between patients who did or did not receive hydrocortisone. RESULTS: A total of 31,749 septic patients were included in the study (mean age: 67, men: 57.3%, in-hospital mortality: 15.6%). 90-day mortality was higher among the 1802 patients receiving hydrocortisone when compared with the 6348 matched non-users (hazard ratio: 1.35, 95% CI: 1.24-1.47). Hydrocortisone treatment was also associated with increased in-hospital mortality (40.9% vs. 27.6%, p < 0.0001) and prolonged hospital stay in those who survived until discharge (median 12.6 days vs. 10.8 days, p < 0.0001). Stratification for age, gender, ethnicity, occurrence of septic shock, and the need for vasopressor drug administration such as (nor)epinephrine did not reveal sub-population(s) benefiting of hydrocortisone use. CONCLUSION: Hydrocortisone treatment is associated with increased risk of death as well as prolonged hospital stay in septic patients. Although residual confounding (by indication) cannot be ruled out completely due to the observational nature of the study, the present study suggests clinical implication of hydrocortisone use in patients with sepsis.

Delirium in older patients with COVID-19: Prevalence, risk factors and clinical outcomes across the first three waves of the pandemic.

OBJECTIVES: Delirium is a serious condition, which poses treatment challenges during hospitalisation for COVID-19. Improvements in testing, vaccination and treatment might have changed patient characteristics and outcomes through the pandemic. We evaluated whether the prevalence and risk factors for delirium, and the association of delirium with in-hospital mortality changed through the pandemic. METHODS: This study was part of the COVID-OLD study in 19 Dutch hospitals including patients ≥70 years in the first (spring 2020), second (autumn 2020) and third wave (autumn 2021). Multivariable logistic regression models were used to study risk factors for delirium, and in-hospital mortality. Differences in effect sizes between waves were studied by including interaction terms between wave and risk factor in logistic regression models. RESULTS: 1540, 884 and 370 patients were included in the first, second and third wave, respectively. Prevalence of delirium in the third wave (12.7%) was significantly lower compared to the first (22.5%) and second wave (23.5%). In multivariable-adjusted analyses, pre-existing memory problems was a consistent risk factor for delirium across waves. Previous delirium was a risk factor for delirium in the first wave (OR 4.02), but not in the second (OR 1.61) and third wave (OR 2.59, p-value interaction-term 0.028). In multivariable-adjusted analyses, delirium was not associated with in-hospital mortality in all waves. CONCLUSION: Delirium prevalence declined in the third wave, which might be the result of vaccination and improved treatment strategies. Risk factors for delirium remained consistent across waves, although some attenuation was seen in the second wave.

Genome-Wide Interaction Analysis with DASH Diet Score Identified Novel Loci for Systolic Blood Pressure.

Objective: We examined interactions between genotype and a Dietary Approaches to Stop Hypertension (DASH) diet score in relation to systolic blood pressure (SBP). Methods: We analyzed up to 9,420,585 biallelic imputed single nucleotide polymorphisms (SNPs) in up to 127,282 individuals of six population groups (91% of European population) from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (CHARGE; n=35,660) and UK Biobank (n=91,622) and performed European population-specific and cross-population meta-analyses. Results: We identified three loci in European-specific analyses and an additional four loci in cross-population analyses at P for interaction < 5e-8. We observed a consistent interaction between rs117878928 at 15q25.1 (minor allele frequency = 0.03) and the DASH diet score (P for interaction = 4e-8; P for heterogeneity = 0.35) in European population, where the interaction effect size was 0.42±0.09 mm Hg (P for interaction = 9.4e-7) and 0.20±0.06 mm Hg (P for interaction = 0.001) in CHARGE and the UK Biobank, respectively. The 1 Mb region surrounding rs117878928 was enriched with cis-expression quantitative trait loci (eQTL) variants (P = 4e-273) and cis-DNA methylation quantitative trait loci (mQTL) variants (P = 1e-300). While the closest gene for rs117878928 is MTHFS, the highest narrow sense heritability accounted by SNPs potentially interacting with the DASH diet score in this locus was for gene ST20 at 15q25.1. Conclusion: We demonstrated gene-DASH diet score interaction effects on SBP in several loci. Studies with larger diverse populations are needed to validate our findings.

Gene-educational attainment interactions in a multi-population genome-wide meta-analysis identify novel lipid loci.

Introduction: Educational attainment, widely used in epidemiologic studies as a surrogate for socioeconomic status, is a predictor of cardiovascular health outcomes. Methods: A two-stage genome-wide meta-analysis of low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), and triglyceride (TG) levels was performed while accounting for gene-educational attainment interactions in up to 226,315 individuals from five population groups. We considered two educational attainment variables: "Some College" (yes/no, for any education beyond high school) and "Graduated College" (yes/no, for completing a 4-year college degree). Genome-wide significant (p < 5 × 10-8) and suggestive (p < 1 × 10-6) variants were identified in Stage 1 (in up to 108,784 individuals) through genome-wide analysis, and those variants were followed up in Stage 2 studies (in up to 117,531 individuals). Results: In combined analysis of Stages 1 and 2, we identified 18 novel lipid loci (nine for LDL, seven for HDL, and two for TG) by two degree-of-freedom (2 DF) joint tests of main and interaction effects. Four loci showed significant interaction with educational attainment. Two loci were significant only in cross-population analyses. Several loci include genes with known or suggested roles in adipose (FOXP1, MBOAT4, SKP2, STIM1, STX4), brain (BRI3, FILIP1, FOXP1, LINC00290, LMTK2, MBOAT4, MYO6, SENP6, SRGAP3, STIM1, TMEM167A, TMEM30A), and liver (BRI3, FOXP1) biology, highlighting the potential importance of brain-adipose-liver communication in the regulation of lipid metabolism. An investigation of the potential druggability of genes in identified loci resulted in five gene targets shown to interact with drugs approved by the Food and Drug Administration, including genes with roles in adipose and brain tissue. Discussion: Genome-wide interaction analysis of educational attainment identified novel lipid loci not previously detected by analyses limited to main genetic effects.

Time-to-Event Genome-Wide Association Study for Incident Cardiovascular Disease in People with Type 2 Diabetes Mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2D) confers a two- to three-fold increased risk of cardiovascular disease (CVD). However, the mechanisms underlying increased CVD risk among people with T2D are only partially understood. We hypothesized that a genetic association study among people with T2D at risk for developing incident cardiovascular complications could provide insights into molecular genetic aspects underlying CVD. METHODS: From 16 studies of the Cohorts for Heart & Aging Research in Genomic Epidemiology (CHARGE) Consortium, we conducted a multi-ancestry time-to-event genome-wide association study (GWAS) for incident CVD among people with T2D using Cox proportional hazards models. Incident CVD was defined based on a composite of coronary artery disease (CAD), stroke, and cardiovascular death that occurred at least one year after the diagnosis of T2D. Cohort-level estimated effect sizes were combined using inverse variance weighted fixed effects meta-analysis. We also tested 204 known CAD variants for association with incident CVD among patients with T2D. RESULTS: A total of 49,230 participants with T2D were included in the analyses (31,118 European ancestries and 18,112 non-European ancestries) which consisted of 8,956 incident CVD cases over a range of mean follow-up duration between 3.2 and 33.7 years (event rate 18.2%). We identified three novel, distinct genetic loci for incident CVD among individuals with T2D that reached the threshold for genome-wide significance (P<5.0×10-8): rs147138607 (intergenic variant between CACNA1E and ZNF648) with a hazard ratio (HR) 1.23, 95% confidence interval (CI) 1.15 - 1.32, P=3.6×10-9, rs11444867 (intergenic variant near HS3ST1) with HR 1.89, 95% CI 1.52 - 2.35, P=9.9×10-9, and rs335407 (intergenic variant between TFB1M and NOX3) HR 1.25, 95% CI 1.16 - 1.35, P=1.5×10-8. Among 204 known CAD loci, 32 were associated with incident CVD in people with T2D with P<0.05, and 5 were significant after Bonferroni correction (P<0.00024, 0.05/204). A polygenic score of these 204 variants was significantly associated with incident CVD with HR 1.14 (95% CI 1.12 - 1.16) per 1 standard deviation increase (P=1.0×10-16). CONCLUSIONS: The data point to novel and known genomic regions associated with incident CVD among individuals with T2D.