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Background Various prediction models have been developed to predict the risk of kidney failure in patients with CKD. However, guideline-recommended models have yet to be compared head to head, their validation in patients with advanced CKD is lacking, and most do not account for competing risks. Methods To externally validate 11 existing models of kidney failure, taking the competing risk of death into account, we included patients with advanced CKD from two large cohorts: the European Quality Study (EQUAL), an ongoing European prospective, multicenter cohort study of older patients with advanced CKD, and the Swedish Renal Registry (SRR), an ongoing registry of nephrology-referred patients with CKD in Sweden. The outcome of the models was kidney failure (defined as RRT-treated ESKD). We assessed model performance with discrimination and calibration. Results The study included 1580 patients from EQUAL and 13,489 patients from SRR. The average c statistic over the 11 validated models was 0.74 in EQUAL and 0.80 in SRR, compared with 0.89 in previous validations. Most models with longer prediction horizons overestimated the risk of kidney failure considerably. The 5-year Kidney Failure Risk Equation (KFRE) overpredicted risk by 10%-\18%. The four- and eight-variable 2-year KFRE and the 4-year Grams model showed excellent calibration and good discrimination in both cohorts. Conclusions Some existing models can accurately predict kidney failure in patients with advanced CKD. KFRE performed well for a shorter time frame (2 years), despite not accounting for competing events. Models predicting over a longer time frame (5 years) overestimated risk because of the competing risk of death. The Grams model, which accounts for the latter, is suitable for longer-term predictions (4 years).

Background: Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (estimated glomerular filtration rate, eGFR). The relationship of polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. Methods: We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS (N=765,348) and UK Biobank GWAS (90% of the cohort; N=451,508), followed by best parameter selection using the remaining 10% of UK Biobank (N=45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study (N=8,866) with incident chronic kidney disease, kidney failure, and acute kidney injury. We also examined associations between the PRS and 4,877 plasma proteins measured at at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. Results: The developed PRS showed significant associations with all outcomes with hazard ratios (95% CI) per 1 SD lower PRS ranged from 1.06 (1.01, 1.11) to 1.33 (1.28, 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin-C, collagen alpha-1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for 5 proteins including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. Conclusions: A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.

Summary: Background: Galectin-3 (gal-3) is a β-galactoside-binding lectin associated tissue fibrosis and inflammation. There is limited understanding of the relationship between gal-3 and vascular health. Our aim was to assess the association between gal-3 and arterial stiffness in older adults. Methods: We conducted a cross-sectional study of 4275 participants (mean age of 75 years) from the Atherosclerosis Risk in Communities (ARIC) Study. Central arterial stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). We evaluated the association of gal-3 with cfPWV using multivariable linear regression. Results: The median (interquartile range) gal-3 concentration was 16.5 (13.8, 19.8) ng/mL and mean cfPWV was 1163±303 cm/s. Higher gal-3 concentration was associated with greater central arterial stiffness after adjustment for age, sex, race-center, heart rate, systolic blood pressure, anti-hypertensive medication use, and current smoking status (β=36.4 cm/s change in cfPWV per log unit change in gal-3; 95% CI: 7.2, 65.5, p=0.015). The association was attenuated after adjusting for additional cardiovascular risk factors (β=17.3, 95% CI: −14.4, 49.0). Conclusions: In community-dwelling older adults, gal-3 concentration was associated with central arterial stiffness, likely sharing common pathways with traditional cardiovascular risk factors.

A potential role of dietary lipids in the management of hepatic glycogen storage diseases (GSDs) has been proposed, but no consensus on management guidelines exists. The aim of this study was to describe current experiences with dietary lipid manipulations in hepatic GSD patients. An international study was set up to identify published and unpublished cases describing hepatic GSD patients with a dietary lipid manipulation. A literature search was performed according to the Cochrane Collaboration methodology through PubMed and EMBASE (up to December 2018). All delegates who attended the dietetics session at the IGSD2017, Groningen were invited to share unpublished cases. Due to multiple biases, only data on GSDIII were presented. A total of 28 cases with GSDIII and a dietary lipid manipulation were identified. Main indications were cardiomyopathy and/or myopathy. A high fat diet was the most common dietary lipid manipulation. A decline in creatine kinase concentrations (n = 19, P

BACKGROUND The degree of ileal organic matter (OM) fermentation appears to be comparable to hindgut fermentation in growing pigs. OBJECTIVES This study aimed to determine if dietary fiber sources with known different total gastrointestinal tract (GIT) fermentability in humans affect ileal and hindgut microbial communities and ileal fermentation in growing pigs used as an animal model for human adults. METHODS Male pigs (21 kg bodyweight; 9 wk old; PIC Camborough 46 × PIC boar 356L; n = 8/diet) were fed for 42 d a diet containing cellulose (CEL, low fermentability) as the sole fiber source (4.5%) or diets in which half of the CEL was replaced by moderately fermentable fiber, psyllium (PSY), or kiwifruit (KF) fiber. For each diet, terminal jejunal (substrate) and ileal (inoculum) digesta were collected from euthanized animals for in vitro ileal fermentation (2 h). Terminal ileal (substrate) and cecal (inoculum) digesta were used for in vitro hindgut fermentation (24 h). After in vitro fermentations, OM fermentation and short-chain fatty acid (SCFA) production were determined. Ileal digesta and feces were collected for microbial analysis. Data were analyzed by 2-factor ANOVA (diet × GIT region). RESULTS In vitro ileal OM fermentation was on average 22% and comparable to hindgut OM fermentation. Ileal and hindgut OM fermentation, SCFA production, and microbial community composition changed (P

Background Circulating high sensitivity cardiac troponin T (hs‐cTnT) is associated with incidence of atrial fibrillation (AF), but the association of changes in hs‐cTnT over time on incident AF has not been explored. Hypothesis Six‐year increase in circulating hs‐cTnT will be associated with increased risk of AF and will contribute to improved prediction of incident AF. Methods We conducted a prospective cohort analysis of 8431 participants from the Atherosclerosis Risk in Communities (ARIC) study. hs‐cTnT change was categorized at visit 2 and 4 as undetectable (

Minimal residual disease (MRD) diagnostics are implemented in most clinical protocols for patients with acute lymphoblastic leukaemia (ALL) and are mostly performed using rearranged immunoglobulin (IG) and/or T-cell receptor (TR) gene rearrangements as molecular polymerase chain reaction targets. Unfortunately, in 5–10% of patients no or no sensitive IG/TR targets are available, and patients therefore cannot be stratified appropriately. In the present study, we used fusion genes and genomic deletions as alternative MRD targets in these patients, which retrospectively revealed appropriate MDR stratification in 79% of patients with no (sensitive) IG/TR target, and a different risk group stratification in more than half of the cases.

T cell exhaustion is associated with failure to clear chronic infections and malignant cells. Defining the molecular mechanisms of T cell exhaustion and reinvigoration is essential to improving immunotherapeutic modalities. Here we confirmed pervasive phenotypic, functional and transcriptional differences between memory and exhausted antigen-specific CD8+ T cells in human hepatitis C virus (HCV) infection before and after treatment. After viral cure, phenotypic changes in clonally stable exhausted T cell populations suggested differentiation toward a memory-like profile. However, functionally, the cells showed little improvement, and critical transcriptional regulators remained in the exhaustion state. Notably, T cells from chronic HCV infection that were exposed to antigen for less time because of viral escape mutations were functionally and transcriptionally more similar to memory T cells from spontaneously resolved HCV infection. Thus, the duration of T cell stimulation impacts exhaustion recovery, with antigen removal after long-term exhaustion being insufficient for the development of functional T cell memory. Lauer and colleagues examine CD8+ T cells following cure of human hepatitis C virus (HCV) infection. CD8+ T cells exposed to chronic HCV-specific activation show durable functional, phenotypic and transcriptional exhaustion that is maintained even after antigen stimulus is removed.

Contains fulltext : 248734.pdf (Publisher’s version ) (Open Access) Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. For many years guidelines have listed optimal preventive therapy. More recently, novel therapeutic options have broadened the options for state-of-the-art CV risk management (CVRM). In the majority of patients with CVD, risk lowering can be achieved by utilising standard preventive medication combined with lifestyle modifications. In a minority of patients, add-on therapies should be considered to further reduce the large residual CV risk. However, the choice of which drug combination to prescribe and in which patients has become increasingly complicated, and is dependent on both the absolute CV risk and the reason for the high risk. In this review, we discuss therapeutic decisions in CVRM, focusing on (1) the absolute CV risk of the patient and (2) the pros and cons of novel treatment options.

Peripheral artery disease (PAD) and chronic exertional compartment syndrome (CECS) both cause exercise-induced lower limb pain. CECS is mostly described in young individuals and may therefore not be considered in older patients with intermittent claudication. The aim of our study was to identify differences in characteristics and symptomatology between patients with CECS and PAD that may help in recognizing CECS in patients ≥50 years with exercise-induced lower limb pain.In this case-control study, patients with CECS ≥50 years were selected from a prospectively followed cohort and compared with a sample of newly diagnosed patients with PAD ≥50 years. A questionnaire assessed frequency and severity of lower limb pain, tightness, cramps, muscle weakness, and altered skin sensation at rest and during exercise.At rest, patients with CECS (n = 43, 42% female, 57 years; range, 50-76 years) reported significantly more pain, tightness, muscle weakness and altered skin sensation (all P .01) than patients with PAD (n = 41, 39% female, 72 years; range, 51-93 years). Having CECS was associated with a significantly higher combined symptom score at rest (P = .02). During exercise, patients with CECS experienced more tightness, muscle weakness and altered sensation (P .01), but not pain and cramps (P = .36; P = .70). Exercise-induced complaints occurred much later in patients with CECS than in patients with PAD (15 minutes vs 4 minutes; P .01). Persistence of pain over 4.5 minutes proved most discriminative for the presence of CECS (sensitivity, 95%; specificity, 54%; positive predictive value, 65%). Exercise cessation completely alleviated complaints in all patients with PAD (n = 41) but not in 73% (n = 29) of the patients with CECS. Ongoing discomfort strongly predicted the presence of CECS (sensitivity, 73%; specificity, 100%; positive predictive value, 100%).Patients with CECS ≥50 years report a symptom pattern that is different from patients with PAD. These differences may aid vascular surgeons in identifying older patients with CECS.

Background and aims: Age-related kidney function decline is accelerated in patients with coronary heart disease (CHD). CHD and chronic kidney disease may share common etiologies. We examined plasma fatty acids (FAs) as novel biomarkers of kidney function decline after myocardial infarction (MI). Methods and results: The analysis included 2329 Dutch post–MI patients aged 60-80y (Alpha Omega Cohort) most receiving state-of-the-art medications. Plasma FAs (% total FAs) in cholesteryl esters were assessed at baseline (2002–2006), and ∼40 months change in creatinine-cystatin C based glomerular filtration rate was estimated (eGFR, in ml/min per 1.73 m2). Beta coefficients for annual eGFR change in relation to plasma linoleic acid (LA; 50.1% of total FAs in CE), omega-3 FAs (EPA + DHA; 1.7%), odd-chain FAs (C15:0 and C17:0; 0.2%), and C14:0 (0.7%) were obtained from linear regression analyses adjusted for age, sex, smoking, and alcohol intake. Mean baseline eGFR ±SD was 78.5 ± 18.7, which declined by 4.7 ± 13.1 during follow-up, or 1.4 ± 3.9 per year. The annual decline in eGFR was less in patients with higher plasma LA (adjusted beta: 0.40 for LA >47 vs ≤ 47%, 95% CI: 0.01; 0.78; p = 0.046). Associations of plasma LA with annual eGFR decline were stronger in 437 patients with diabetes (1.21, 0.24; 2.19) and in 402 patients with CKD (eGFR

Background During the first wave of COVID-19 it was hypothesized that COVID-19 is subject to multi-wave seasonality, similar to Influenza-Like Illnesses since time immemorial. One year into the pandemic, we aimed to test the seasonality hypothesis for COVID-19. Methods We calculated the average annual time-series for Influenza-Like Illnesses based on incidence data from 2016 till 2019 in the Netherlands, and compared these with two COVID-19 time-series during 2020/2021 for the Netherlands. We plotted the time-series on a standardized logarithmic infection scale. Finally, we calculated correlation coefficients and used univariate regression analysis to estimate the strength of the association between the time-series of COVID-19 and Influenza-Like Illnesses. Results The time-series for COVID-19 and Influenza-Like Illnesses were strongly and highly significantly correlated. The COVID-19 peaks were all during flu season, and lows were all in the opposing period. Finally, COVID-19 meets the multi-wave characteristics of earlier flu-like pandemics, namely a short first wave at the tail-end of a flu season, and a longer and more intense second wave during the subsequent flu season. Conclusions We conclude that seasonal patterns of COVID-19 incidence and Influenza-Like Illnesses incidence are highly similar, in a country in the temperate climate zone, such as the Netherlands. Further, the COVID-19 pandemic satisfies the criteria of earlier respiratory pandemics, namely a first wave that is short-lived at the tail-end of flu season, and a second wave that is longer and more severe. This seems to imply that the same factors that are driving the seasonality of Influenza-Like Illnesses are causing COVID-19 seasonality as well, such as solar radiation (UV), temperature, relative humidity, and subsequently seasonal allergens and allergies., Highlights • Time-series of COVID-19 and Influenza-Like illnesses have highly similar seasonal patterns in the Netherlands. • COVID-19 satisfies the seasonal criteria of earlier flu-like pandemics. • The implication is that the seasonal factors driving flu season, are also responsible for COVID-19 seasonality. • Determined seasonality by applying comparative time-series analysis and a standardized logarithmic infection scale.

Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values

Introduction Laboratory studies suggest an involvement of growth differentiation factor 15 (GDF-15) in metabolic dysregulation. However, the utility of GDF-15 for assessing risk of cardiometabolic outcomes has not been rigorously examined among older adults. Methods We conducted a cross-sectional analysis of older adults who attended visit 6 (2016–2017) of the Atherosclerosis Risk in Communities (ARIC) Study. We used multivariable logistic regression to quantify cross-sectional associations of GDF-15 (in quartiles) with prevalent diabetes, obesity, atherosclerotic cardiovascular disease (ASCVD), subclinical myocardial stress/injury (assessed by NT-proB-type Natriuretic Peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT]), and heart failure (HF). Results Among 3792 ARIC study participants (mean age 80 years, 59% women, 23% Blacks and 77% Whites, mean GDF-15: 2094.9 pg/mL [SD: 1395.6]), higher GDF-15 concentrations (highest vs. lowest quartile) were positively associated with diabetes (adjusted odds ratio [aOR]:] : 2.48, 95% CI : 1.89, 3.26), ASCVD (aOR: 1.57, 95% CI: 1.16, 2.11), increased hscTnT (aOR: 2.27, 95%CI: 1.54, 3.34), increased NT-proBNP (aOR: 1.98, 95%CI: 1.46, 2.70), and HF (aOR: 3.22, 95%CI : 2.13, 4.85), in models adjusted for demographics and traditional cardiovascular risk factors. Conclusions In this sample of older US black and whites, increased GDF-15 was positively associated with diabetes, ASCVD, HF, and markers of subclinical myocardial stress or injury. These results illustrate the diverse aspects of the link between GDF-15 and diseases states, and its potential utility as robust biomarker of adverse cardiometabolic outcomes.

Background Although intensive blood pressure reduction has cardiovascular benefits, the absolute benefit is greater in those at higher cardiovascular disease (CVD) risk. Objectives This study examined whether N-terminal pro-B-type natriuretic peptide (NT-proBNP) helps identify subjects at higher risk for CVD events across systolic blood pressure (SBP), diastolic blood pressure (DBP), or pulse pressure (PP) categories. Methods Participants from the ARIC (Atherosclerosis Risk In Communities) study visit 4 (1996 to 98) were grouped according to SBP, DBP, or PP categories and further stratified by NT-proBNP categories. Cox regression models were used to estimate hazard ratios for incident CVD (coronary heart disease, ischemic stroke, or heart failure hospitalization) and mortality across combined NT-proBNP and/or BP categories, adjusting for CVD risk factors. Results There were 9,309 participants (age: 62.6 ± 5.6 years; 58.3% women) with 2,416 CVD events over a median follow-up of 16.7 years. Within each SBP, DBP, or PP category, a higher category of NT-proBNP (100 to Conclusions Elevated NT-proBNP is independently associated with CVD and mortality across SBP, DBP, and PP categories and helps identify subjects at the highest risk. Participants with stage 1 hypertension but elevated NT-proBNP had greater cardiovascular risk compared with those with stage 2 SBP but lower NT-proBNP. Future studies are needed to evaluate use of biomarker-based strategies for CVD risk assessment to assist with initiation or intensification of BP treatment.

BackgroundWe recently showed that seasonal patterns of COVID-19 incidence and Influenza-Like Illnesses incidence are highly similar, in a country in the temperate climate zone, such as the Netherlands (latitude: 52°N). We hypothesize that in The Netherlands the same environmental factors and mobility trends that are associated with the seasonality of flu-like illnesses are predictors of COVID-19 seasonality as well.MethodsWe used meteorological, pollen/hay fever and mobility data from the Netherlands with its 17.4 million inhabitants. For the reproduction number of COVID-19 (Rt), we used data from the Dutch State Institute for Public Health. This Rt metric is a daily estimate that is based on positive COVID-19 tests in the Netherlands in hospitals and municipalities. For all datasets we selected the overlapping period of COVID-19 and the first allergy season: from February 17, 2020 till September 21, 2020 (total number of measurements: n = 218), the end of pollen season. Backward stepwise multiple linear regression was used to develop an environmental prediction model of the Rt of COVID-19. Next, we studied whether adding mobility trends to an environmental model improved the predictive power.ResultsBy means of stepwise backward multiple linear regression four highly significant (p value < 0.01) predictive factors are selected in our combined model: temperature, solar radiation, hay fever incidence, and mobility to indoor recreation locations. Our combined model explains 87.5% of the variance of Rt of COVID-19 and has a good and highly significant fit: F(4, 213) = 374.2, p-value < 0.00001. The combined model had a better overall predictive performance compared to a solely environmental model, which still explains 77.3% of the variance of Rt, and a good and highly significant fit: F(4, 213) = 181.3, p < 0.00001.ConclusionsWe conclude that the combined mobility and environmental model can adequately predict the seasonality of COVID-19 in a country with a temperate climate like the Netherlands. In this model higher solar radiation, higher temperature and hay fever are related to lower COVID-19 reproduction, and mobility to indoor recreation locations with increased COVID-19 spread.HighlightsThe seasonality of COVID-19 can be well-explained by environmental factors and mobility.A combined model explains 87.5% of the variance of the reproduction number of COVID-19Inhibitors of the reproduction number of COVID-19 are higher solar radiation, and seasonal allergens/allergies.Mobility, especially to indoor recreation locations, increases the reproduction number of COVID-19.Temperature has no direct effect on the reproduction number of COVID-19, but affects mobility and seasonal allergens.Adding mobility trends to an environmental model improves the predictive value regarding the reproduction number of COVID-19.

INTRODUCTION: Patients with inborn errors of metabolism causing fasting intolerance can experience acute metabolic decompensations. Long-term data on outcomes using emergency letters are lacking.METHODS: This is a retrospective, observational, single-center study of the use of emergency letters based on a generic emergency protocol in patients with hepatic glycogen storage diseases (GSD) or fatty acid oxidation disorders (FAOD). Data on hospital admissions, initial laboratory results and serious adverse events were collected. Subsequently, the website www.emergencyprotocol.net was generated in the context of the CONNECT MetabERN eHealth project following multiple meetings, protocol revisions and translations.RESULTS: Representing 470 emergency protocol years, 127 hospital admissions were documented in 54/128(42%) patients who made use of emergency letters generated based on the generic emergency protocol. Hypoglycemia (here defined as glucose concentration 5 years. Convulsions, coma or death were not documented. By providing basic information, emergency letters for individual patients with hepatic GSD or the main FAOD can be generated at www.emergencyprotocol.net, in 9 different languages.DISCUSSION: Generic emergency protocols are safe and easy for home management by the caregivers and the first hour in-hospital management to prevent metabolic emergencies in patients with hepatic GSD and medium-chain Acyl CoA dehydrogenase deficiency. The website www.emergencyprotocol.net is designed to support families and healthcare providers to generate personalized emergency letters for patients with hepatic GSD and the main FAOD. This article is protected by copyright. All rights reserved.

Glycogen storage disease type IIIa (GSDIIIa) is an inborn error of carbohydrate metabolism caused by a debranching enzyme deficiency. A subgroup of GSDIIIa patients develops severe myopathy. The purpose of this study was to investigate whether acute nutritional ketosis (ANK) in response to ketone-ester (KE) ingestion is effective to deliver oxidative substrate to exercising muscle in GSDIIIa patients. This was an investigator-initiated, researcher-blinded, randomized, crossover study in six adult GSDIIIa patients. Prior to exercise subjects ingested a carbohydrate drink (~66 g, CHO) or a ketone-ester (395 mg/kg, KE) + carbohydrate drink (30 g, KE + CHO). Subjects performed 15-minute cycling exercise on an upright ergometer followed by 10-minute supine cycling in a magnetic resonance (MR) scanner at two submaximal workloads (30% and 60% of individual maximum, respectively). Blood metabolites, indirect calorimetry data, and in vivo 31P-MR spectra from quadriceps muscle were collected during exercise. KE + CHO induced ANK in all six subjects with median peak βHB concentration of 2.6 mmol/L (range: 1.6-3.1). Subjects remained normoglycemic in both study arms, but delta glucose concentration was 2-fold lower in the KE + CHO arm. The respiratory exchange ratio did not increase in the KE + CHO arm when workload was doubled in subjects with overt myopathy. In vivo 31P MR spectra showed a favorable change in quadriceps energetic state during exercise in the KE + CHO arm compared to CHO in subjects with overt myopathy. Effects of ANK during exercise are phenotype-specific in adult GSDIIIa patients. ANK presents a promising therapy in GSDIIIa patients with a severe myopathic phenotype. Trial registration number: ClinicalTrials.gov identifier: NCT03011203.

Background Cardiac markers such as high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B natriuretic peptide (NTproBNP) are predictors of developing acute kidney injury (AKI) during hospitalization for surgery or revascularization. However, their associations with the long-term risk of AKI in the general population are uncharacterized. Methods We conducted a prospective cohort study in 10 669 participants of the Atherosclerosis Risk in Communities Study (visit 4, 1996–1998, mean age, 63 years, 56% female, 22% black race) to examine the association of plasma concentrations of hs-cTnT and NTproBNP with the incident hospitalization with AKI. We used multivariable Cox regression analysis to estimate hazard ratios (HRs). Results During follow-up, 1907 participants had an incident hospitalization with AKI. Participants with higher concentrations of hs-cTnT had a higher risk of hospitalization with AKI in a graded fashion (adjusted HR, 1.88 [95%CI , 1.59–2.21] for ≥14 ng/L, 1.36 [1.18–1.57] for 9–13 ng/L, and 1.16 [1.03–1.30] for 5-8 ng/L compared to Conclusions In middle-aged to older black and white adults in the community, higher concentrations of hs-cTnT and NTproBNP were robustly associated with an increased risk of hospitalization with AKI. These results suggest the usefulness of hs-cTnT and NT-proBNP to identify people at risk of AKI in the general population.

Aims In the era of personalized medicine, it is of utmost importance to be able to identify subjects at the highest cardiovascular (CV) risk. To date, single biomarkers have failed to markedly improve the estimation of CV risk. Using novel technology, simultaneous assessment of large numbers of biomarkers may hold promise to improve prediction. In the present study, we compared a protein-based risk model with a model using traditional risk factors in predicting CV events in the primary prevention setting of the European Prospective Investigation (EPIC)-Norfolk study, followed by validation in the Progressione della Lesione Intimale Carotidea (PLIC) cohort. Methods and results Using the proximity extension assay, 368 proteins were measured in a nested case–control sample of 822 individuals from the EPIC-Norfolk prospective cohort study and 702 individuals from the PLIC cohort. Using tree-based ensemble and boosting methods, we constructed a protein-based prediction model, an optimized clinical risk model, and a model combining both. In the derivation cohort (EPIC-Norfolk), we defined a panel of 50 proteins, which outperformed the clinical risk model in the prediction of myocardial infarction [area under the curve (AUC) 0.754 vs. 0.730; P < 0.001] during a median follow-up of 20 years. The clinically more relevant prediction of events occurring within 3 years showed an AUC of 0.732 using the clinical risk model and an AUC of 0.803 for the protein model (P < 0.001). The predictive value of the protein panel was confirmed to be superior to the clinical risk model in the validation cohort (AUC 0.705 vs. 0.609; P < 0.001). Conclusion In a primary prevention setting, a proteome-based model outperforms a model comprising clinical risk factors in predicting the risk of CV events. Validation in a large prospective primary prevention cohort is required to address the value for future clinical implementation in CV prevention., Graphical Abstract Graphical Abstract

Purpose Determination of intra-oral surface areas might contribute to our understanding of the physiology of the oral cavity and oral diseases. In previous studies, the intra-oral surface area was determined using a laborious and technically challenging method. Our aim was to develop an easy and non-invasive method to determine the intra-oral surface areas. Methods In this study, we used cone-beam computed tomography (CBCT) and digital analysis in 20 human cadavers to determine various intra-oral surface areas, based on digital segmentation. Next, we explored whether there was a relationship between various intra-oral surface areas and anthropometric measurements of the head using Pearson correlation coefficient. Results Using CBCT and digital analysis, it was possible to determine various intra-oral surface areas. On average, the total intra-oral surface area was 173 ± 19 cm2. Moderate, statistical significant correlations were observed between (1) the length of the head and the palatal surface area, as well as (2) the depth of the head and the surface area of the tongue. These correlations suggest the feasibility of estimating intra-oral surface areas without relying on CBCT imaging. Conclusions This study presents a technique for measuring the intra-oral surface areas by CBCT imaging in combination with digital analysis. The results of this study suggest that anthropometric measurements of the head might be used to estimate the surface areas of the palate and tongue.

Context Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. Objective Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. Design DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. Setting General community. Participants Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). Main Outcome Measure Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. Results DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [HR] 1.30, 95% confidence interval [CI], 1.07-1.58; women: HR 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: HR 1.12, 95% CI, 1.01-1.25; women: HR 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization (HR 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. Conclusions Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.

Context Sex differences exist in heart failure (HF) phenotypes, but there is limited research on the role of sex hormones in HF and its subtypes. Objective To examine the associations of total testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex hormone-binding globulin (SHBG) with incident HF, HF with preserved ejection fraction (HFpEF), and HF with reduced ejection fraction (HFrEF). Design Atherosclerosis Risk in Communities (ARIC) study (prospective cohort study). Median follow-up is 19.2 years. Setting General community. Participants 4107 men and 4839 postmenopausal women, with mean age of 63.2 (standard deviation [SD] 5.7) and 62.8 (5.5) years, respectively. Exposure Plasma sex hormone levels were measured at visit 4 (1996-1998). Main Outcome Measures Incident HF events were identified through hospital discharge codes and death certificates. Results The Hazard Ratios for HF associated with 1 SD decrease in log-transformed total testosterone, DHEA-S, and SHBG were 1.10 (95% confidence interval 1.03, 1.17), 1.07 (1.00, 1.15), and 1.04 (0.96, 1.11) in men, and 1.05 (0.99, 1.13), 1.17 (1.09, 1.24), and 0.93 (0.85, 1.01) in women, respectively. The associations between sex hormones with subtypes of HF had similar patterns but were attenuated and became statistically insignificant. Conclusion In this prospective cohort, lower levels of endogenous testosterone and DHEA-S in men and DHEA-S in postmenopausal women were associated with the development of HF. Similar directions of association in both sexes and both HF subtypes suggest that sex hormones play a role in the development of HF through common pathways regardless of sex.

Aims Elevated lipoprotein(a) [Lp(a)] is strongly associated with an increased cardiovascular disease (CVD) risk. We previously reported that pro-inflammatory activation of circulating monocytes is a potential mechanism by which Lp(a) mediates CVD. Since potent Lp(a)-lowering therapies are emerging, it is of interest whether patients with elevated Lp(a) experience beneficial anti-inflammatory effects following large reductions in Lp(a). Methods and results Using transcriptome analysis, we show that circulating monocytes of healthy individuals with elevated Lp(a), as well as CVD patients with increased Lp(a) levels, both have a pro-inflammatory gene expression profile. The effect of Lp(a)-lowering on gene expression and function of monocytes was addressed in two local sub-studies, including 14 CVD patients with elevated Lp(a) who received apolipoprotein(a) [apo(a)] antisense (AKCEA-APO(a)-LRx) (NCT03070782), as well as 18 patients with elevated Lp(a) who received proprotein convertase subtilisin/kexin type 9 antibody (PCSK9ab) treatment (NCT02729025). AKCEA-APO(a)-LRx lowered Lp(a) by 47% and reduced the pro-inflammatory gene expression in monocytes of CVD patients with elevated Lp(a), which coincided with a functional reduction in transendothelial migration capacity of monocytes ex vivo (−17%, P Conclusion Potent Lp(a)-lowering following AKCEA-APO(a)-LRx, but not modest Lp(a)-lowering combined with LDL-C reduction following PCSK9ab treatment, reduced the pro-inflammatory state of circulating monocytes in patients with elevated Lp(a). These ex vivo data support a beneficial effect of large Lp(a) reductions in patients with elevated Lp(a).

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. Methods and Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.

The aim of this preregistered EEG study was to show how expectations about enhanced or impaired performance through transcranial stimulation affect feelings of agency and error processing. Using a single-blind experimental design, participants (N = 57) were attached to a transcranial direct current stimulation (tDCS) device, and in different blocks, they were verbally instructed to expect enhanced or impaired cognitive performance, or no effects of the brain stimulation. In all cases, but unbeknownst to the participants, we used an inert sham tDCS protocol. Subsequently, we measured their response to errors on a cognitive control task. Our expectancy manipulation was successful: participants reported improved subjective performance in the enhancement compared with the impairment condition—even though objective performance was kept at a constant level across conditions. Participants reported the highest feelings of agency over their task performance in the control condition, and lowest feelings of agency in the impairment condition. The expectancy manipulation did not affect the error-related negativity (ERN) in association with incorrect responses. During the induction phase, expecting impaired versus enhanced performance increased frontal theta power, potentially reflecting a process of increased cognitive control allocation. Our findings show that verbally induced manipulations can affect subjective performance on a cognitive control task, but that stronger manipulations (e.g., through conditioning) are necessary to induce top-down effects on neural error processing.

Dietary fibre fermentation in humans and monogastric animals is considered to occur in the hindgut, but it may also occur in the lower small intestine. This study aimed to compare ileal and hindgut fermentation in the growing pig fed a human-type diet using a combined in vivo/in vitro methodology. Five pigs (23 (sd 1·6) kg body weight) were fed a human-type diet. On day 15, pigs were euthanised. Digesta from terminal jejunum and terminal ileum were collected as substrates for fermentation. Ileal and caecal digesta were collected for preparing microbial inocula. Terminal jejunal digesta were fermented in vitro with a pooled ileal digesta inoculum for 2 h, whereas terminal ileal digesta were fermented in vitro with a pooled caecal digesta inoculum for 24 h. The ileal organic matter fermentability (28 %) was not different from hindgut fermentation (35 %). However, the organic matter fermented was 66 % greater for ileal fermentation than hindgut fermentation (P = 0·04). Total numbers of bacteria in ileal and caecal digesta did not differ (P = 0·09). Differences (P < 0·05) were observed in the taxonomic composition. For instance, ileal digesta contained 32-fold greater number of the genus Enterococcus, whereas caecal digesta had a 227-fold greater number of the genus Ruminococcus. Acetate synthesis and iso-valerate synthesis were greater (P < 0·05) for ileal fermentation than hindgut fermentation, but propionate, butyrate and valerate synthesis was lower. SCFA were absorbed in the gastrointestinal tract location where they were synthesised. In conclusion, a quantitatively important degree of fermentation occurs in the ileum of the growing pig fed a human-type diet.

OBJECTIVE Incorporation of comorbidity burden to inform diabetes management in older adults remains challenging. High-sensitivity cardiac troponins are objective, quantifiable biomarkers that may improve risk monitoring in older adults. We assessed the associations of elevations in high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) with comorbidities and improvements in mortality risk stratification. RESEARCH DESIGN AND METHODS We used logistic regression to examine associations of comorbidities with elevations in either troponin (≥85th percentile) among 1,835 participants in the Atherosclerosis Risk in Communities (ARIC) Study with diabetes (ages 67–89 years, 43% male, 31% black) at visit 5 (2011–2013). We used Cox models to compare associations of high cardiac troponins with mortality across comorbidity levels. RESULTS Elevations in either troponin (≥9.4 ng/L for hs-cTnI, ≥25 ng/L for hs-cTnT) were associated with prevalent coronary heart disease, heart failure, chronic kidney disease, pulmonary disease, hypoglycemia, hypertension, dementia, and frailty. Over a median follow-up of 6.2 years (418 deaths), both high hs-cTnI and high hs-cTnT further stratified mortality risk beyond comorbidity levels; those with a high hs-cTnI or hs-cTnT and high comorbidity were at highest mortality risk. Even among those with low comorbidity, a high hs-cTnI (hazard ratio 3.0 [95% CI 1.7, 5.4]) or hs-cTnT (hazard ratio 3.3 [95% CI 1.8, 6.2]) was associated with elevated mortality. CONCLUSIONS Many comorbidities were reflected by both hs-cTnI and hs-cTnT; elevations in either of the troponins were associated with higher mortality risk beyond comorbidity burden. High-sensitivity cardiac troponins may identify older adults at high mortality risk and be useful in guiding clinical care of older adults with diabetes.

Current models for flu-like epidemics insufficiently explain multi-cycle seasonality. Meteorological factors alone, including the associated behavior, do not predict seasonality, given substantial climate differences between countries that are subject to flu-like epidemics or COVID-19. Pollen is documented to be allergenic, it plays a role in immuno-activation and defense against respiratory viruses, and seems to create a bio-aerosol that lowers the reproduction number of flu-like viruses. Therefore, we hypothesize that pollen may explain the seasonality of flu-like epidemics, including COVID-19, in combination with meteorological variables. We have tested the Pollen-Flu Seasonality Theory for 2016–2020 flu-like seasons, including COVID-19, in the Netherlands, with its 17.4 million inhabitants. We combined changes in flu-like incidence per 100 K/Dutch residents (code: ILI) with pollen concentrations and meteorological data. Finally, a predictive model was tested using pollen and meteorological threshold values, inversely correlated to flu-like incidence. We found a highly significant inverse correlation of r(224) = −0.41 (p, Graphical abstract Unlabelled Image, Highlights • Testing pollen-flu seasonality theory for 2016–2020 in the Netherlands, overlapping COVID-19 • Pollen have allergenic and immuno-activating properties. • Highly significant inverse correlation between pollen and flu-like incidence. • Solar radiation is a co-inhibitor of flu-like epidemics. • COVID-19 does not break with seasonality pattern, but more data are needed for conclusion.

Rationale & Objective Both hypo- and hyperkalemia can cause fatal cardiac arrhythmias. Although predialysis serum potassium level is a known modifiable risk factor for death in patients receiving hemodialysis, especially for hypokalemia, this risk may be underestimated. Therefore, we investigated the relationship between predialysis serum potassium level and death in incident hemodialysis patients and whether there is an optimum level. Study Design Prospective multicenter cohort study. Setting & Participants 1,117 incident hemodialysis patients (aged >18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 study were included and followed from their first hemodialysis treatment until death, transplantation, switch to peritoneal dialysis, or a maximum of 10 years. Exposure Predialysis serum potassium levels were obtained every 6 months and divided into 6 categories: ≤4.0 mmol/L, >4.0 mmol/L to ≤4.5 mmol/L, >4.5 mmol/L to ≤5.0 mmol/L, >5.0 mmol/L to ≤5.5 mmol/L (reference), >5.5 mmol/L to ≤6.0 mmol/L, and >6.0 mmol/L. Outcomes 6-month all-cause mortality. Analytical Approach Cox proportional hazards and restricted cubic spline analyses with time-dependent predialysis serum potassium levels were used to calculate the adjusted HRs for death. Results At baseline, the mean age of the patients was 63 years (standard deviation, 14 years), 58% were men, 26% smoked, 24% had diabetes, 32% had cardiovascular disease, the mean serum potassium level was 5.0 mmol/L (standard deviation, 0.8 mmol/L), 7% had a low subjective global assessment score, and the median residual kidney function was 3.5 mL/min/1.73 m2 (IQR, 1.4-4.8 mL/min/1.73 m2). During the 10-year follow-up, 555 (50%) deaths were observed. Multivariable adjusted HRs for death according to the 6 potassium categories were as follows: 1.42 (95% CI, 1.01-1.99), 1.09 (95% CI, 0.82-1.45), 1.21 (95% CI, 0.94-1.56), 1 (reference), 0.95 (95% CI, 0.71-1.28), and 1.32 (95% CI, 0.97-1.81). Limitations Shorter intervals between potassium measurements would have allowed for more precise mortality risk estimations. Conclusions We found a U-shaped relationship between serum potassium level and death in incident hemodialysis patients. A low predialysis serum potassium level was associated with a 1.4-fold stronger risk of death than the optimal level of approximately 5.1 mmol/L. These results may imply the cautious use of potassium-lowering therapy and a potassium-restricted diet in patients receiving hemodialysis., Graphical abstract

Background The incidence and prevalence of older patients with kidney failure who are dependent on dialysis is increasing. However, observational studies showed limited or no benefit of dialysis on mortality in subgroups of these patients when compared to conservative care. As the focus is shifting towards health-related quality of life (HRQoL), current evidence of effects of conservative care or dialysis on HRQoL in older patients is both limited and biased. Dialysis comes with both high treatment burden for patients and high costs for society; better identification of patients who might not benefit from dialysis could result in significant cost savings. The aim of this prospective study is to compare HRQoL, clinical outcomes, and costs between conservative care and dialysis in older patients. Methods The DIALysis or not: Outcomes in older kidney patients with GerIatriC Assessment (DIALOGICA) study is a prospective, observational cohort study that started in February 2020. It aims to include 1500 patients from 25 Dutch and Belgian centres. Patients aged ≥70 years with an eGFR of 10–15 mL/min/1.73m2 are enrolled in the first stage of the study. When dialysis is initiated or eGFR drops to 10 mL/min/1.73m2 or lower, the second stage of the study commences. In both stages nephrogeriatric assessments will be performed annually, consisting of questionnaires and tests to assess most common geriatric domains, i.e. functional, psychological, somatic, and social status. The primary outcome is HRQoL, measured with the Twelve-item Short-Form Health Survey. Secondary outcomes are clinical outcomes (mortality, hospitalisation, functional status, cognitive functioning, frailty), cost-effectiveness, and decisional regret. All outcomes are (repeated) measures during the first year of the second stage. The total follow-up will be a maximum of 4 years with a minimum of 1 year in the second stage. Discussion By generating more insight in the effects of conservative care and dialysis on HRQoL, clinical outcomes, and costs, findings of this study will help patients and physicians make a shared decision on the best individual treatment option for kidney failure. Trial registration The study was registered in the Netherlands Trial Register (NL-8352) on 5 February 2020.

Individuals with chronic kidney disease are at an increased risk for cardiovascular disease. This risk may partially be explained by a chronic inflammatory state in these patients, reflected by increased arterial wall and cellular inflammation. Statin treatment decreases cardiovascular risk and arterial inflammation in non-CKD subjects. In patients with declining kidney function, cardiovascular benefit resulting from statin therapy is attenuated, possibly due to persisting inflammation. In the current study, we assessed the effect of statin treatment on arterial wall and cellular inflammation. Fourteen patients with chronic kidney disease stage 3 or 4, defined by an estimated Glomerular Filtration Rate between 15 and 60 mL/min/1.73 m2, without cardiovascular disease were included in a single center, open label study to assess the effect of atorvastatin 40 mg once daily for 12 weeks (NTR6896). At baseline and at 12 weeks of treatment, we assessed arterial wall inflammation by 18F-fluoro-deoxyglucose positron-emission tomography computed tomography (18F-FDG PET/CT) and the phenotype of circulating monocytes were assessed. Treatment with atorvastatin resulted in a 46% reduction in LDL-cholesterol, but this was not accompanied by an attenuation in arterial wall inflammation in the aorta or carotid arteries, nor with changes in chemokine receptor expression of circulating monocytes. Statin treatment does not abolish arterial wall or cellular inflammation in subjects with mild to moderate chronic kidney disease. These results imply that CKD-associated inflammatory activity is mediated by factors beyond LDL-cholesterol and specific anti-inflammatory interventions might be necessary to further dampen the inflammatory driven CV risk in these subjects.

Background: Elevated cardiac troponin levels in blood are associated with increased risk of cardiovascular diseases and mortality. Cardiac troponin levels are heritable, but their genetic architecture remains elusive. Methods: We conducted a transethnic genome-wide association analysis on high-sensitivity cTnT (cardiac troponin T; hs-cTnT) and high-sensitivity cTnI (cardiac troponin I; hs-cTnI) levels in 24 617 and 14 336 participants free of coronary heart disease and heart failure from 6 population-based cohorts, followed by a series of bioinformatic analyses to decipher the genetic architecture of hs-cTnT and hs-cTnI. Results: We identified 4 genome-wide significant loci for hs-cTnT including a novel locus rs3737882 in PPFIA4 and 3 previously reported loci at NCOA2 , TRAM1 , and BCL2 . One known locus at VCL was replicated for hs-cTnI. One copy of C allele for rs3737882 was associated with a 6% increase in hs-cTnT levels (minor allele frequency, 0.18; P =2.80×10 −9 ). We observed pleiotropic loci located at BAG3 and ANO5 . The proportions of variances explained by single-nucleotide polymorphisms were 10.15% and 7.74% for hs-cTnT and hs-cTnI, respectively. Single-nucleotide polymorphisms were colocalized with BCL2 expression in heart tissues and hs-cTnT and with ANO5 expression in artery, heart tissues, and whole blood and both troponins. Mendelian randomization analyses showed that genetically increased hs-cTnT and hs-cTnI levels were associated with higher odds of atrial fibrillation (odds ratio, 1.38 [95% CI, 1.25–1.54] for hs-cTnT and 1.21 [95% CI, 1.06–1.37] for hs-cTnI). Conclusions: We identified a novel genetic locus associated with hs-cTnT in a multiethnic population and found that genetically regulated troponin levels were associated with atrial fibrillation.

Background: Chronic exertional compartment syndrome (CECS) of the anterior leg compartment (ant-CECS) is frequently treated with a minimally invasive fasciotomy. Several operative techniques and operative devices exist, but none have been compared in a systematic and randomized manner. Purpose: To compare efficacy, safety, and postoperative pain of a novel operative device (FascioMax fasciotome) with a widely accepted device created by Due and Nordstrand (Due fasciotome) during a minimally invasive fasciotomy for ant-CECS. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Patients with bilateral isolated ant-CECS between October 2013 and April 2018 underwent a minimally invasive fasciotomy using the FascioMax fasciotome in 1 leg and the Due fasciotome in the contralateral leg in a single operative session. Symptom reduction at 3 to 6 months and >1 year, postoperative pain within the first 2 weeks, peri- and postoperative complications, and ability to regain sports were assessed using diaries, physical examination, and timed questionnaires. Results: Included in the study were 50 patients (66% female; median age, 22 years [range, 18-65 years]). No differences between the devices were found in terms of perioperative complications (both had none), minor postoperative complications including hematoma and superficial wound infection (overall complication rate: FascioMax, 8% vs Due, 6%), or reduction of CECS-associated symptoms at rest and during exercise. At long-term follow-up (>1 year), 82% of the patients were able to regain their desired type of sport, and 67% (33/49) were able to exercise at a level that was comparable with or higher than before their CECS-associated symptoms started. Conclusion: Both the FascioMax and the Due performed similarly in terms of efficacy, safety, and levels of pain within the first 2 weeks postoperatively. Registration: NL4274; Netherlands Trial Register.