Plasma ApoE elevations are associated with NAFLD:The PREVEND Study

Non-alcoholic fatty liver disease (NAFLD) is featured by increased plasma very low density lipoproteins (VLDL). The extent to which plasma apolipoprotein E (ApoE) levels are elevated in NAFLD is unclear. We determined whether plasma ApoE is elevated in subjects with suspected NAFLD. Plasma ApoE and genotypes were determined in 6,762 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. A Fatty Liver Index (FLI) >= 60 was used as a proxy of NAFLD. A total of 1,834 participants had a FLI >= 60, which coincided with increased triglycerides, non-HDL cholesterol, ApoB and ApoE (all P<0.001). In multivariable linear regression analysis, plasma ApoE levels were positively associated with an elevated FLI when taking account of ApoE genotypes and other clinical and laboratory covariates (fully adjusted model: beta = 0.201, P<0.001). Stratified analysis for ApoE genotypes (ApoE epsilon 3 epsilon 3 homozygotes, ApoE epsilon 2 carriers, and ApoE epsilon 3 epsilon 4 and epsilon 4 epsilon 4 carriers combined), also showed positive associations of plasma ApoE levels with an elevated FLI in each group (all P<0.001). In conclusion, it is suggested that NAFLD is characterized by increased plasma ApoE levels, even when taking account of the various ApoE geno-types. Increased plasma ApoE may contribute to altered VLDL metabolism and to increased atherosclerosis susceptibility in NAFLD

Higher Sodium Intake Assessed by 24 Hour Urinary Sodium Excretion Is Associated with Non-Alcoholic Fatty Liver Disease:The PREVEND Cohort Study

A higher sodium intake is conceivably associated with insulin resistant conditions like obesity, but associations of non-alcoholic fatty liver disease (NAFLD) with a higher sodium intake determined by 24 hours (24 h) urine collections are still unclear. Dietary sodium intake was measured by sodium excretion in two complete consecutive 24 h urine collections in 6132 participants of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort. Fatty Liver Index (FLI) >= 60 and Hepatic Steatosis Index (HSI) >36 were used as proxies of suspected NAFLD. 1936 (31.6%) participants had an FLI >= 60, coinciding with the increased prevalence of type 2 diabetes (T2D), metabolic syndrome, hypertension and history of cardiovascular disease. Sodium intake was higher in participants with an FLI >= 60 (163.63 +/- 61.81 mmol/24 h vs. 136.76 +/- 50.90 mmol/24 h, p = 60 was positively associated with a higher sodium intake when taking account for T2D, a positive cardiovascular history, hypertension, alcohol intake, smoking and medication use (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.44-1.64, p 36 showed similar results. Associations remained essentially unaltered after adjustment for body surface area or waist/hip ratio. In conclusion, suspected NAFLD is a feature of higher sodium intake. Insulin resistance-related processes may contribute to the association of NAFLD with sodium intake

Participation and autonomy in the first 10 months after diagnosis of ALS:a longitudinal study

Introduction: More insight is needed into participation in daily activities and autonomy among patients with amyotrophic lateral sclerosis (ALS). Aims of this study were (1) to describe the course of participation restrictions and autonomy in participation during the first 10 months after diagnosis; (2) to study the influence of the rate of ALS progression on the course of participation. Methods: Secondary analysis of data from the longitudinal multicenter FACTS-2-ALS study. Self-report questionnaires were administered at inclusion (T0; n = 71), at 4 months (T1), 7 months (T2), 10 months (T3) after inclusion. Median duration of follow-up was 10.0 months. Participation restrictions were assessed using the sum of the Mobility Range and Social Behavior subscales of the Sickness Impact profile-68 (SIPSOC). Autonomy in participation was assessed using the Impact on Participation and Autonomy (IPA) Questionnaire. Fast disease progression was defined as an increase of 1.1 points per month or more on the ALS Functional Rating Scale. Results: Patients reported participation restrictions in all subscales while having mild physical limitations. There was a decrease of participation over time (restrictions and autonomy). This decrease was greatest in patients with fast disease progression. Disease progression negatively influenced movement-related participation more than social interaction domains. Rate of disease progression was more strongly related to SIPSOC scores compared to IPA scores. Discussion: Preserving participation may be an important determinant of quality of care for patients with ALS. Rate of progression of the disease should be taken into account as it was found to be significantly associated with the level of participation

Branched chain amino acids are associated with metabolic complications in liver transplant recipients

Background: Obesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations. Methods: Cross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients. Results: 336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P &lt; 0.001) and T2D (P = 0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18–2.20, P = 0.003) for MetS and 1.60 (95%CI: 1.14–2.23, P = 0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P = 0.002). Conclusion: Elevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx.</p

Plasma Calprotectin Levels Associate with Suspected Metabolic-Associated Fatty Liver Disease and All-Cause Mortality in the General Population

Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis, metabolic dysregulation, and neutrophilic inflammation. In this study, we hypothesized that systemic levels of plasma calprotectin, as a biomarker of neutrophilic inflammation, may be associated with suspected MAFLD. Plasma calprotectin levels were measured in subjects (n = 5446) participating in the Prevention of Renal and Vascular ENd-stage Disease (PREVEND) cohort study. Suspected MAFLD was defined by the fatty liver index (FLI ≥ 60) and hepatic steatosis index (HSI ≥ 36) as proxies. Plasma calprotectin levels were significantly higher in subjects with FLI ≥ 60 (0.57 [IQR: 0.42–0.79] mg/L, n = 1592) (p < 0.001) compared to subjects with FLI < 60 (0.46 [0.34–0.65] mg/L, n = 3854). Multivariable logistic regression analyses revealed that plasma calprotectin levels were significantly associated with suspected MAFLD (FLI ≥ 60), even after adjustment for potential confounding factors, including current smoking, alcohol consumption, hypertension, diabetes, cardiovascular diseases, insulin resistance (HOMA-IR), hs-CRP, eGFR, and total cholesterol levels (OR 1.19 [95% CI: 1.06–1.33], p = 0.003). Interaction analyses revealed significant effect modifications for the association between plasma calprotectin and suspected MAFLD by BMI (p < 0.001) and hypertension (p = 0.003), with the strongest associations in subjects with normal BMI and without hypertension. Prospectively, plasma calprotectin levels were significantly associated with all-cause mortality after adjustment for potential confounding factors, particularly in subjects without suspected MAFLD (FLI < 60) (hazard ratio (HR) per doubling: 1.34 (1.05–1.72), p < 0.05). In conclusion, higher plasma calprotectin levels are associated with suspected MAFLD and with the risk of all-cause mortality, the latter especially in subjects without suspected MAFLD

Effectiveness, usability and acceptability of a smart inhaler programme in patients with asthma:protocol of the multicentre, pragmatic, open-label, cluster randomised controlled ACCEPTANCE trial

Introduction Suboptimal asthma control is associated with incorrect inhaler use and poor medication adherence, which could lead to unfavourable clinical and economic outcomes. Smart inhaler programmes using electronic monitoring devices (EMDs) could support self-management and increase medication adherence and asthma control. However, evidence on long-term benefits and acceptability is scarce. This study aims to investigate the effectiveness of a smart inhaler asthma self-management programme on medication adherence and clinical outcomes in adults with uncontrolled asthma, to evaluate its acceptability and to identify subgroups who would benefit most based on patient characteristics.Methods and analysis This open-label cluster randomised controlled trial of 12 months will be conducted in primary care in the Netherlands. General practices will be randomly assigned to either intervention or control group. We aim to include 242 patients. The intervention consists of (1) an EMD attached to the patient’s inhaler that measures medication use; (2) a smartphone application to set medication reminders, receive motivational messages and track asthma symptoms; and (3) a portal for healthcare professionals to view data on medication use. The control group is passively monitored by the EMD but cannot view their inhaler data or receive feedback. Eligible patients are adults with suboptimal controlled asthma (Asthma Control Questionnaire score ≥0.75) with evidence of non-adherence established by the EMD during a 6-week run-in period. Primary outcome is the difference in mean medication adherence between intervention and control group. Secondary outcomes include asthma control, asthma-related quality of life, exacerbations, acceptance, cost-effectiveness and whether the effect of the intervention on medication adherence and asthma control is modified by patient characteristics (eg, self-efficacy, medication beliefs and eHealth literacy).Trial registration numberNL7854

Branched Chain Amino Acids are associated with Metabolic Complications in Liver Transplant Recipients

BACKGROUND: Obesity, dyslipidemia and type 2 diabetes (T2D) contribute substantially to increased cardiovascular morbidity and mortality in patients after orthotopic liver transplantation (OLTx). Elevated plasma branched chain amino acids (BCAA) are linked to metabolic disturbances and cardiovascular disease (CVD) risk profiles in several non-OLTx populations. METHODS: Cross-sectional analysis of liver transplant recipients from TransplantLines, a single-center biobank and cohort study. BCAA plasma levels were measured by means of nuclear-magnetic resonance spectroscopy. CVD and cardiometabolic factors were collected by using data from electronic patient records. Associations were determined between BCAA plasma levels and T2D, Metabolic Syndrome (MetS), CVD as well as mTOR inhibition in liver transplant recipients. RESULTS: 336 Patients were divided into sex-stratified tertiles of total BCAA. MetS (P<0.001) and T2D (P=0.002) were significantly more frequent in subjects in the highest BCAA tertile. In logistic regression analyses, the multivariable adjusted odds ratio (OR) per 1 standard deviation increase in BCAA was 1.68 (95%CI: 1.18-2.20, P=0.003) for MetS and 1.60 (95%CI: 1.14-2.23, P=0.006) for T2D. Use of Sirolimus (mTOR inhibitor) was significantly associated with higher BCAA plasma levels, independent of age, sex, time after OLTx, MetS and other immunosuppressive medication (adjusted P=0.002). CONCLUSION: Elevated BCAA plasma levels are associated with T2D, MetS and use of Sirolimus in liver transplant recipients. BCAA plasma levels may represent a valuable biomarker for cardiometabolic complications after OLTx

High Plasma Levels of Betaine, a Trimethylamine N-Oxide Related Metabolite, are Associated with Severity of Cirrhosis

Background and Aims: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of impaired hepatic flavin monooxygenase expression. Here, we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity. Methods: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score. Results: Plasma betaine was on average 60% higher (p < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively). Conclusion: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity and decrease after liver transplantation

The Dutch LATER physical outcomes set for self-reported data in survivors of childhood cancer

Purposes: Studies investigating self-reported long-term morbidity in childhood cancer survivors (CCS) are using heterogeneous outcome definitions, which compromises comparability and include (un)treated asymptomatic and symptomatic outcomes. We generated a Dutch LATER core set of clinically relevant physical outcomes, based on self-reported data. Clinically relevant outcomes were defined as outcomes associated with clinical symptoms or requiring medical treatment. Methods: First, we generated a draft outcome set based on existing questionnaires embedded in the Childhood Cancer Survivor Study, British Childhood Cancer Survivor Study, and Dutch LATER study. We added specific outcomes reported by survivors in the Dutch LATER questionnaire. Second, we selected a list of clinical relevant outcomes by agreement among a Dutch LATER experts team. Third, we compared the proposed clinically relevant outcomes to the severity grading of the Common Terminology Criteria for Adverse Events (CTCAE). Results: A core set of 74 self-reported long-term clinically relevant physical morbidity outcomes was established. Comparison to the CTCAE showed that 36% of these clinically relevant outcomes were missing in the CTCAE. Implications for Cancer Survivors: This proposed core outcome set of clinical relevant outcomes for self-reported data will be used to investigate the self-reported morbidity in the Dutch LATER study. Furthermore, this Dutch LATER outcome set can be used as a starting point for international harmonization for long-term outcomes in survivors of childhood cancer

Profoundly Disturbed Lipoproteins in Cirrhotic Patients:Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein

Detailed information regarding lipoprotein concentrations and subfractions in cirrhotic patients before and after orthotopic liver transplantation (OLT) is lacking. Lipoprotein-Z (LP-Z) is a recently characterised abnormal, hepatotoxic free cholesterol-rich low-density lipoprotein (LDL)-like lipoprotein. We determined the lipoprotein profiles, including LP-Z, in cirrhotic patients and OLT recipients and assessed the prognostic significance of LP-Z on the OLT waiting list. We performed analyses in cirrhotic transplant candidates and non-cirrhotic OLT recipients. A population-based cohort was used as reference. The setting was a University hospital. Lipoprotein particle concentrations and subfractions were measured by nuclear magnetic resonance spectroscopy. In the cirrhotic patients (N = 130), most measures of triglyceride-rich lipoproteins (TRL), LDL, and high-density lipoproteins (HDL) were much lower compared to the OLT recipients (N = 372) and controls (N = 6027) (p &amp;lt; 0.01). In the OLT recipients, many lipoprotein variables were modestly lower, but HDL-cholesterol, triglycerides, and TRL and HDL size were greater vs. the control population. LP-Z was measurable in 40 cirrhotic patients and 3 OLT recipients (30.8% vs. 0.8%, p &amp;lt; 0.001). The cirrhotic patients with measurable LP-Z levels had profoundly lower HDL-cholesterol and particle concentrations (p &amp;lt; 0.001), and worse Child Pugh Turcotte classifications and MELD scores. The presence of LP-Z (adjusted for age, sex, and MELD score) predicted worse survival in cirrhotic patients (HR per 1 LnSD increment: 1.11, 95%CI 1.03-1.19, p = 0.003). In conclusion, cirrhotic patients have considerably lower plasma concentrations of all major lipoprotein classes with changes in lipoprotein subfraction distribution. After OLT, these lipoprotein abnormalities are in part reversed. LP-Z is associated with cirrhosis. Its presence may translate in disturbed HDL metabolism and worse survival.</p