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Introduction In the past decades, the opioid crisis has heavily impacted parts of the US society and has been followed by an increase in the use of opioids worldwide. It is of paramount importance that we explore the origins of the US opioid epidemic to develop best practices to tackle the rising tide of opioid overdoses. Areas covered In this expert review, we discuss opioid (over)prescription, change in perception of pain, and false advertisement of opioid safety as the leading causes of the US opioid epidemic. Then, we review the evidence about opioid dependence and addiction potential and provide current knowledge about predictors of aberrant opioid-related behavior. Lastly, we discuss different approaches that were considered or undertaken to combat the rising tide of opioid-related deaths by regulatory bodies, pharmaceutical companies, and health-care professionals. For this expert review, we considered published articles relevant to the topic under investigation that we retrieved from Medline or Google scholar electronic database. Expert opinion The opioid epidemic is a dynamic process with many underlying mechanisms. Therefore, no single approach may be best suited to combat it. In our opinion, the best way forward is to employ multiple strategies to tackle different underlying mechanisms.

Background: The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Prediction models that accurately estimate mortality risk in hospitalized patients could assist medical staff in treatment and allocating limited resources. Aims: To externally validate two promising previously published risk scores that predict in-hospital mortality among hospitalized COVID-19 patients. Methods: Two prospective cohorts were available; a cohort of 1028 patients admitted to one of nine hospitals in Lombardy, Italy (the Lombardy cohort) and a cohort of 432 patients admitted to a hospital in Leiden, the Netherlands (the Leiden cohort). The endpoint was in-hospital mortality. All patients were adult and testedCOVID-19 PCR-positive. Model discrimination and calibration were assessed. Results: The C-statistic of the 4C mortality score was good in the Lombardy cohort (0.85, 95CI: 0.82-0.89) and in the Leiden cohort (0.87, 95CI: 0.80-0.94). Model calibration was acceptable in the Lombardy cohort but poor in the Leiden cohort due to the model systematically overpredicting the mortality risk for all patients. The C -sta-tistic of the CURB-65 score was good in the Lombardy cohort (0.80, 95CI: 0.75-0.85) and in the Leiden cohort (0.82, 95CI: 0.76-0.88). The mortality rate in the CURB-65 development cohort was much lower than the mortality rate in the Lombardy cohort. A similar but less pronounced trend was found for patients in the Leiden cohort. Conclusion: Although performances did not differ greatly, the 4C mortality score showed the best performance. However, because of quickly changing circumstances, model recalibration may be necessary before using the 4C mortality score.

IMPORTANCE Previous venous thrombosis (VT) is associated with risk of future VT, but quantification of risk over the life course is poorly understood. More information is needed for clinicians to understand the association of remote history of VT with the risk of VT in older patients.OBJECTIVE To assess the association between a remote history of VT and the development of VT in older age.DESIGN, SETTING, AND PARTICIPANTS The Age and Thrombosis, Acquired and Genetic Risk Factors in the Elderly case-control study enrolled patients 70 years and older with VT and control individuals 70 years and older without VT between June 2008 and August 2011. The Age and Thrombosis, Acquired and Genetic Risk Factors in the Elderly study is a 2-center, population-based case-control study that was conducted in Burlington, Vermont, in the US and in Leiden, the Netherlands. Consecutively diagnosed patients with an objectively proven episode of VT (deep vein thrombosis of the leg or pulmonary embolism) were included. Control individualswere identified in the same geographic areas as the patients andwere randomly selected. Datawere analyzed between May 2021 and October 2021.EXPOSURES Self-reported remote VT (occurring >10 years before to enrollment).MAIN OUTCOMES AND MEASURES The main outcome was the risk of VT at older age. The association of self-reported history of remote VT with VT at older age was assessed by calculating odds ratios (ORs) as estimates of relative risk with 95% CIs.RESULTS A total of 460 patients with VT and 456 control participants were included. There were slightly more women than men in both groups (60.2% of patients [n = 277] were women and 52.4% of control participants [n = 239] were women), and the mean (range) age of patients was 78.7 (70.0-100.9) years, which was similar to the control participants. Compared with individuals without remote VT, those with a remote history of VT had an increased risk of VT (OR, 2.54; 95% CI, 1.56-4.13). The crude risk estimate was robust to adjustment and time since remote VT, that is, individuals with a VT 10 to 30 years ago (OR, 2.74; 95% CI, 1.34-5.57) and those with a VT more than 30 years ago (OR, 2.42; 95% CI, 1.21-4.84) had a an increased risk of VT. The populationattributable fraction of a remote history of VT was 7.7%.CONCLUSIONS AND RELEVANCE In this study, a remote history of VT was associated with risk of VT in older individuals. This quantification could assist clinicians in advising patients on VT prevention.

Background and purpose Medication overuse headache is a prevalent disorder, with a strong biobehavioural component. Hence, behavioural interventions might effectuate reduction of the overused medication. We assessed in a double-blind manner the efficacy of a behavioural intervention during medication withdrawal therapy. Methods In this concealed, double-blind, randomized controlled trial in medication overuse headache, conducted at the Leiden University Medical Centre, we compared the effect of maximal versus minimal behavioural intervention by a headache nurse during withdrawal therapy. Maximal intervention consisted of an intensive contact schedule, comprising education, motivational interviewing, and value-based activity planning during 12 weeks of withdrawal therapy. Minimal intervention consisted of a short contact only. Patients were unaware of the existence of these treatment arms, as the trial was concealed in another trial investigating botulinum toxin A. Endpoints were successful withdrawal and monthly days of acute medication use after the withdrawal period. Results We enrolled 179 patients (90 maximal, 89 minimal intervention). At Week 12, most patients achieved withdrawal in both groups (82/90 [93%] maximal intervention vs. 75/89 [86%] minimal intervention, odds ratio = 2.44, 95% confidence interval [CI] = 0.83-7.23, p = 0.107). At Week 24, patients in the maximal intervention group had fewer medication days (mean difference = -2.23, 95% CI = -3.76 to -0.70, p = 0.005). This difference receded over time. Change in monthly migraine days did not differ between groups (-6.75 vs. -6.22). Conclusions This trial suggests modest benefit of behavioural intervention by a headache nurse during withdrawal therapy for medication overuse headache, to reduce acute medication use during and shortly after intervention, but extension seems warranted for a prolonged effect

Background The coronavirus disease 2019 (COVID-19) presents an urgent threat to global health. Identification of predictors of poor outcomes will assist medical staff in treatment and allocating limited healthcare resources. Aims The primary aim was to study the value of D-dimer as a predictive marker for in-hospital mortality. Methods This was a cohort study. The study population consisted of hospitalized patients (age >18 years), who were diagnosed with COVID-19 based on real-time PCR at 9 hospitals during the first COVID-19 wave in Lombardy, Italy (Feb-May 2020). The primary endpoint was in-hospital mortality. Information was obtained from patient records. Statistical analyses were performed using a Fine-Gray competing risk survival model. Model discrimination was assessed using Harrell’s C-index and model calibration was assessed using a calibration plot. Results Out of 1049 patients, 507 patients (46%) had evaluable data. Of these 507 patients, 96 died within 30 days. The cumulative incidence of in-hospital mortality within 30 days was 19% (95CI: 16%-23%), and the majority of deaths occurred within the first 10 days. A prediction model containing D-dimer as the only predictor had a C-index of 0.66 (95%CI: 0.61–0.71). Overall calibration of the model was very poor. The addition of D-dimer to a model containing age, sex and co-morbidities as predictors did not lead to any meaningful improvement in either the C-index or the calibration plot. Conclusion The predictive value of D-dimer alone was moderate, and the addition of D-dimer to a simple model containing basic clinical characteristics did not lead to any improvement in model performance.

Genome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants. Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008–2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm2 and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006–2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000–2007). Performance was comparable to the development setting in PIVUS (R2 = 0.63, RMSE = 42.4 cm2, calibration slope = 0.94) but lower in MESA (R2 = 0.44, RMSE = 60.7 cm2, calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements.

Aims: To quantify metabolic impairment via a one-factor approach with confirmatory factor analysis (CFA) including MRI-derived visceral and subcutaneous adipose tissues and to associate it with diastolic dysfunction. Methods: In this cross-sectional analysis, 916 participants (53% female, mean age (SD): 56 (6)) underwent abdominal and cardiovascular MRI. With CFA a metabolic-load factor of metabolic-syndrome variables and visceral and subcutaneous adipose tissues was constructed. A piecewise structural equation model approach with adjustment for confounding factors was used to determine associations with left-ventricular diastolic function, cardiac morphology and hemodynamics. Results: Model fitting excluding blood pressure and waist circumference but including visceral and subcutaneous adipose tissues, fasting glucose, HDL-c and triglycerides was used to construct the metabolic-load factor. Evaluating measurement invariance demonstrated sex-specificity. Change in mitral early/late peak filling rate ratio was -0.12 for both males [-0.20; -0.05, p > 0.05] and females [-0.17; -0.07, p > 0.001] per SD of metabolicload factor. Change in deceleration time of mitral early filling was -11.83 ms in females [-17.38; -6.27] per SD of metabolic-load factor. Conclusion: A single latent metabolic-load factor via CFA including MRI-derived adipose tissues increased sensitivity for metabolic impairment obsoleting waist circumference and is associated with a decreased leftventricular diastolic function, more apparent in females than in males.

Background To evaluate the association between crowding and transmission of viral respiratory infectious diseases, we investigated the change in transmission patterns of influenza and COVID-19 before and after a mass gathering event (i.e., carnival) in the Netherlands. Methods Information on individual hospitalizations related to the 2017/2018 influenza epidemic were accessed from Statistics Netherlands. The influenza cases were stratified between non-carnival and carnival regions. Distributions of influenza cases were plotted with time and compared between regions. A similar investigation in the early outbreak of COVID-19 was also conducted using open data from the Dutch National Institute for Public Health and the Environment. Results Baseline characteristics between non-carnival and carnival regions were broadly similar. There were 13,836 influenza-related hospitalizations in the 2017/2018 influenza epidemic, and carnival fell about 1 week before the peak of these hospitalizations. The distributions of new influenza-related hospitalizations per 100,000 inhabitants with time between regions followed the same pattern with a surge of new cases in the carnival region about 1 week after carnival, which did not occur in the non-carnival region. The increase of new cases for COVID-19 in the carnival region exceeded that in the non-carnival region about 1 week after the first case was reported, but these results warrant caution as for COVID-19 there were no cases reported before the carnival and social measures were introduced shortly after carnival. Conclusion In this study, a mass gathering event (carnival) was associated with aggravating the spread of viral respiratory infectious diseases.

Genetic risk score (GRS) analysis is a popular approach to derive individual risk prediction models for complex diseases. In venous thrombosis (VT), such type of analysis shall integrate information at the ABO blood group locus, which is one of the major susceptibility loci. However, there is no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when properly assessing association between ABO locus and VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in 5425 cases and 8445 controls from 6 studies, we demonstrate that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal, because 5% of rs8176719-delG carriers do not have an increased risk of developing VT. Instead, we recommend the use of 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B), and rs41302905 (O2), when assessing the impact ofABOlocus on VT risk to avoid any risk misestimation. Compared with the O1 haplotype, the A2 haplotype is associated with a modest increase in VT risk (odds ratio, similar to 1.2), the A1 and B haplotypes are associated with an similar to 1.8-fold increased risk, whereas the O2 haplotype tends to be slightly protective (odds ratio, similar to 0.80). In addition, although the A1 and B blood groups are associated with increased von Willebrand factor and factor VIII plasma levels, only the A1 blood group is associated with ICAM levels, but in an opposite direction, leaving additional avenues to be explored to fully understand the spectrum of biological effects mediated by ABO locus on cardiovascular traits.

Background Several trials to prevent cardiovascular disease by inhibiting cholesteryl ester transfer protein (CETP) have failed, except Randomized EValuation of the Effects of Anacetrapib through Lipid-modification. Thus far, it is unclear to what extent CETP is causally related to measures of atherosclerosis. Objective The aim of the article was to study the causal relationship between genetically determined CETP concentration and carotid intima-media thickness (cIMT) in a population-based cohort study. Methods In the Netherlands Epidemiology of Obesity study, participants were genotyped, and cIMT was measured by ultrasonography. We examined the relation between a weighted genetic risk score for CETP concentration, based on 3 single-nucleotide polymorphisms that have previously been shown to largely determine CETP concentration and cIMT using Mendelian randomization in the total population and in strata by sex, Framingham 10-year risk, (pre)diabetes, high-density lipoprotein cholesterol, triglycerides, and statin use. Results We analyzed 5655 participants (56% women) with a mean age of 56 (range 44–66) years, body mass index of 26 (range 17–61) kg/m 2 , and serum CETP of 2.47 (range 0.68–5.33) μg/mL. There was no evidence for a causal relation between genetically determined CETP and cIMT in the total population, but associations were differently directed in men (16 μm per μg/mL increase in genetically determined CETP; 95% confidence interval: −8, 39) and women (−8 μm; −25, 9). Genetically determined CETP appeared to be associated with cIMT in normoglycemic men (26 μm; −1, 52) and in (pre)diabetic women (48 μm; −2, 98). Conclusion In this population-based study, there was no causal relation between genetically determined CETP concentration and cIMT in the total population although we observed directionally differing effects in men and women. Stratified results suggested associations in individuals with different cardiometabolic risk factor profiles, which require replication.

Item does not contain fulltext OBJECTIVE: To study the relative contribution of surrogates for mechanical stress and systemic processes with osteoarthritis (OA) in weight-bearing and non-weight-bearing joints. METHODS: The Netherlands Epidemiology of Obesity study is a population-based cohort including 6673 participants (range 45-65 years, 56% women, median body mass index 26 kg/m(2)). Weight (kg) and fat mass (kg) were measured, fat-free mass (kg) was calculated. The metabolic syndrome was defined following the Adult Treatment Panel III criteria. Knee and hand OA were defined according to the American College of Rheumatology clinical criteria.Logistic regression analyses were performed to associate surrogates for mechanical stress (such as weight, fat-free mass) and systemic processes (such as metabolic syndrome) with OA in knees alone, knees and hands or hands alone, adjusted for age, sex, height, smoking, education and ethnicity, and when appropriate for metabolic factors and weight. RESULTS: Knee, knee and hand, and hand OA were present in 10%, 4% and 8% of the participants, respectively. Knee OA was associated with weight and fat-free mass, adjusted for metabolic factors (OR 1.49 (95% CI 1.32 to 1.68) and 2.05 (1.60 to 2.62), respectively). Similar results were found for OA in knees and hands (OR 1.51 (95% CI 1.29 to 1.78) and 2.17 (95% CI 1.52 to 3.10) respectively). Hand OA was associated with the metabolic syndrome, adjusted for weight (OR 1.46 (95% CI 1.06 to 2.02)). CONCLUSIONS: In knee OA, whether or not in co-occurrence with hand OA, surrogates for mechanical stress are suggested to be the most important risk factors, whereas in hand OA alone, surrogates for systemic processes are the most important risk factors.

Item does not contain fulltext Purpose To test the hypothesis that hepatic triglyceride content is associated with subclinical vascular impairment and is not confounded by various cardiometabolic risk factors. Materials and Methods This study was approved by the institutional review board, and all participants gave written informed consent. In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity study, a population-based cohort study, 1899 participants (52% men; mean age, 55 years +/- 6 [standard deviation]) underwent magnetic resonance (MR) spectroscopy and MR imaging to assess hepatic triglyceride content, aortic pulse wave velocity (PWV), and visceral fat. Carotid intima-media thickness (IMT) was acquired and measured by trained research nurses according to standard procedures. Multivariate regression analyses were used to study associations of hepatic triglyceride content with total and regional aortic PWV and carotid IMT while adjusting for several possible confounding factors, including the metabolic syndrome. Results Total aortic PWV (mean difference, 0.5 m/sec; 95% confidence interval [CI]: 0.3, 0.7) and carotid IMT (mean difference, 37 mum; 95% CI: 25, 49) were higher in participants with hepatic steatosis. After adjusting for various covariates, a 10-fold increase in hepatic triglyceride content was associated with an increased mean aortic PWV of 0.19 m/sec (95% CI: 0.03, 0.36) in total and an increased mean aortic PWV of 0.42 m/sec (95% CI: 0.03, 0.81) in the abdominal segment. A 10-fold increase in hepatic triglyceride content was also associated with an increased mean carotid IMT of 15 mum (95% CI: 0, 29) but not after additional adjustments for visceral and total body fat. Conclusion In this relatively large population-based cohort study, hepatic triglyceride content was associated with aortic pulse wave velocity and carotid IMT. These associations were only partly explained by the metabolic syndrome and visceral adiposity, suggesting a possible specific contribution of hepatic steatosis to subclinical vascular impairment. (c) RSNA, 2017 Online supplemental material is available for this article.

The term ‘postmarketing surveillance’ refers to analyses for the purpose of detecting adverse drug reactions in data accumulated after a medicinal product has been authorized by a regulatory agency [1-3]. The current regulatory process has systematic provisions for obtaining important data needed to ensure the safety of novel drugs almost exclusively during premarketing testing [4]. However, premarketing trials frequently do not have sufficient power to reliably detect important adverse drug reactions [5].

To investigate the association between hepatic triglyceride content and left ventricular (LV) diastolic function while taking potential confounding factors into account, including the components of the metabolic syndrome.The study was approved by the institutional review board, and all participants gave informed consent. In this cross-sectional analysis of baseline data from the Netherlands Epidemiology of Obesity study, a population-based, prospective cohort study, participants (45% men; mean age ± standard deviation, 55.3 years ± 6.2) underwent magnetic resonance (MR) spectroscopy and MR imaging to assess hepatic triglyceride content and LV diastolic heart function (ratio of peak filling rates of the early filling phase and atrial contraction [E/A ratio]). Multivariate linear regression analysis was performed while adjusting for confounding factors, and results were additionally stratified according to body mass index.Adjustment for age, sex, heart rate, alcohol consumption, pack-years of smoking, all components of the metabolic syndrome, and visceral adiposity attenuated crude observed associations. A 10-fold increase in hepatic triglyceride content was associated with a change in mean E/A ratio of -0.004 (95% confidence interval [CI]: -0.134, 0.125) in the total study population, -0.194 (95% CI: -0.430, 0.042) in the normal-weight subgroup, 0.079 (95% CI: -0.090, 0.248) in the overweight subgroup, and -0.109 (95% CI: -0.186, -0.032) in the obese subgroup.Fatty liver itself could, at least in obesity, pose a risk of myocardial dysfunction above and beyond known cardiovascular risk factors that are clustered within the metabolic syndrome. The association in the obese subgroup was small, and future studies with larger samples sizes are required to investigate to what extent the association exists and differs in normal-weight, overweight, and obese persons to unravel its clinical relevance.

Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE.In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters.To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.

In contrast to structured, integrated risk assessment in primary care, unstructured risk factor screening outside primary care and corresponding recommendations to consult a general practitioner (GP) are often based on one abnormal value of a single risk factor. This study investigates the advantages and disadvantages of unstructured screening of blood pressure and cholesterol outside primary care.After the baseline visit of the Netherlands Epidemiology of Obesity study (population-based prospective cohort study in persons aged 45-65 years, recruited 2008-2012) all participants received a letter with results of blood pressure and cholesterol, and a recommendation to consult a GP if results were abnormal. Four years after the start of the study, participants received a questionnaire about the follow-up of their results.The study population consisted of 6343 participants, 48% men, mean age 56 years, mean body mass index 30 kg/m(2). Of all participants 66% had an abnormal result and, of these, 49% had a treatment indication based on the risk estimation system SCORE-NL 2006. Of the 25% of the participants who did not consult a GP, 40% had a treatment indication. Of the participants with an abnormal result 19% were worried, of whom 60% had no treatment indication.In this population 51% of the participants with an abnormal result had unnecessarily received a recommendation to consult a GP, and 10% were unnecessarily worried. GPs should be informed about the complete risk assessment, and only participants at intermediate or high risk should receive a recommendation to consult a GP.

Background The use of thromboprophylaxis to prevent clinically apparent venous thromboembolism after knee arthroscopy or casting of the lower leg is disputed. We compared the incidence of symptomatic venous thromboembolism after these procedures between patients who received anticoagulant therapy and those who received no anticoagulant therapy. Methods We conducted two parallel, pragmatic, multicenter, randomized, controlled, open-label trials with blinded outcome evaluation: the POT-KAST trial, which included patients undergoing knee arthroscopy, and the POT-CAST trial, which included patients treated with casting of the lower leg. Patients were assigned to receive either a prophylactic dose of low-molecular-weight heparin (for the 8 days after arthroscopy in the POT-KAST trial or during the full period of immobilization due to casting in the POT-CAST trial) or no anticoagulant therapy. The primary outcomes were the cumulative incidences of symptomatic venous thromboembolism and major bleeding within 3 months after the procedure. Results In the POT-KAST trial, 1543 patients underwent randomization, of whom 1451 were included in the intention-to-treat population. Venous thromboembolism occurred in 5 of the 731 patients (0.7%) in the treatment group and in 3 of the 720 patients (0.4%) in the control group (relative risk, 1.6; 95% confidence interval [CI], 0.4 to 6.8; absolute difference in risk, 0.3 percentage points; 95% CI, -0.6 to 1.2). Major bleeding occurred in 1 patient (0.1%) in the treatment group and in 1 (0.1%) in the control group (absolute difference in risk, 0 percentage points; 95% CI, -0.6 to 0.7). In the POT-CAST trial, 1519 patients underwent randomization, of whom 1435 were included in the intention-to-treat population. Venous thromboembolism occurred in 10 of the 719 patients (1.4%) in the treatment group and in 13 of the 716 patients (1.8%) in the control group (relative risk, 0.8; 95% CI, 0.3 to 1.7; absolute difference in risk, -0.4 percentage points; 95% CI, -1.8 to 1.0). No major bleeding events occurred. In both trials, the most common adverse event was infection. Conclusions The results of our trials showed that prophylaxis with low-molecular-weight heparin for the 8 days after knee arthroscopy or during the full period of immobilization due to casting was not effective for the prevention of symptomatic venous thromboembolism. (Funded by the Netherlands Organization for Health Research and Development; POT-KAST and POT-CAST ClinicalTrials.gov numbers, NCT01542723 and NCT01542762 , respectively.).

Contains fulltext : 137063.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To investigate if the amount of fat mass (FM) or skeletal muscle mass (SMM) is more strongly associated with knee osteoarthritis (OA), in both men and women. METHODS: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45-65 years, including 5313 participants (53% female, median body mass index (BMI) 29.9 kg/m(2)). FM (kg), fat percentage, SMM (kg) and skeletal muscle (SM) percentage were estimated using bioelectrical impedance analysis (BIA). Clinical OA was defined following the ACR criteria. Structural OA was defined based on magnetic resonance imaging (MRI) in 1142 participants. Logistic regression analyses were used to examine the associations of all body composition measures with clinical and structural knee OA per standard deviation (SD), stratified by sex and adjusted for age and height. RESULTS: Clinical or structural OA was present in 25% and 14% of women and 12% and 13% of men, respectively. FM and fat percentage were positively associated with clinical knee OA in men and women. SMM was positively associated, while the SM percentage was negatively associated with clinical OA in both men and women. The FM/SMM ratio was positively associated with clinical OA. All determinants showed even stronger ORs for structural knee OA. In men, SMM was more strongly associated with knee OA as compared to FM whereas in women, FM was most strongly associated. CONCLUSION: Especially a high FM/SMM ratio seems to be unfavorable in knee OA. In men, SMM is most strongly associated with knee OA whereas in women FM seems to be of most importance.

Contains fulltext : 137745.pdf (Publisher’s version ) (Open Access) Changes in endothelial glycocalyx are one of the earliest changes in development of cardiovascular disease. The endothelial glycocalyx is both an important biological modifier of interactions between flowing blood and the vessel wall, and a determinant of organ perfusion. We hypothesize that deeper penetration of erythrocytes into the glycocalyx is associated with reduced microvascular perfusion. The population-based prospective cohort study (the Netherlands Epidemiology of Obesity [NEO] study) includes 6,673 middle-aged individuals (oversampling of overweight and obese individuals). Within this cohort, we have imaged the sublingual microvasculature of 915 participants using sidestream darkfield (SDF) imaging together with a recently developed automated acquisition and analysis approach. Presence of RBC (as a marker of microvascular perfusion) and perfused boundary region (PBR), a marker for endothelial glycocalyx barrier properties for RBC accessibility, were assessed in vessels between 5 and 25 microm RBC column width. A wide range of variability in PBR measurements, with a mean PBR of 2.14 microm (range: 1.43-2.86 microm), was observed. Linear regression analysis showed a marked association between PBR and microvascular perfusion, reflected by RBC filling percentage (regression coefficient beta: -0.034; 95% confidence interval: -0.037 to -0.031). We conclude that microvascular beds with a thick ("healthy") glycocalyx (low PBR), reflects efficient perfusion of the microvascular bed. In contrast, a thin ("risk") glycocalyx (high PBR) is associated with a less efficient and defective microvascular perfusion.

Introduction Obesity, usually characterized by the body mass index (BMI), is a risk factor for hand osteoarthritis (OA). We investigated whether adipose tissue and abdominal fat distribution are associated with hand OA. Methods The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45 to 65 years, including 5315 participants (53% women, median BMI 29.9 kg/m2). Fat percentage and fat mass (FM) (kg) were estimated using bioelectrical impedance analysis. The waist-to-hip ratio (WHR) was calculated. In 1721 participants, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) (cm2) were assessed using abdominal MR imaging. Hand OA was defined according to the ACR criteria. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for the association of fat percentage, FM, WHR, VAT and SAT with hand OA using logistic regression analyses per standard deviation, stratified by sex and adjusted for age. Results Hand OA was present in 8% of men and 20% of women. Fat percentage was associated with hand OA in men (OR 1.34 (95% CI 1.11 to 1.61)) and women (OR 1.26 (1.05 to 1.51)), as was FM. WHR was associated with hand OA in men (OR 1.45 (1.13 to 1.85)), and to a lesser extent in women (OR 1.17 (1.00 to 1.36)). Subgroup analysis revealed that VAT was associated with hand OA in men (OR1.33 (1.01 to 1.75)). This association increased after additional adjustment for FM (OR 1.51 (1.13 to 2.03)). Conclusions Fat percentage, FM and WHR were associated with hand OA. VAT was associated with hand OA in men, suggesting involvement of visceral fat in hand OA.

BACKGROUND Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P = 0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P = 0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.)

Summary. Background: Previous studies have provided contradictory results regarding the interaction between the CYP2C9 and VKORC1 genotypes affecting various outcome measures. Objectives: We aimed to provide a definite answer regarding the question whether there exists a gene–gene interaction between the CYP2C9 and VKORC1 genotypes affecting the anticoagulant effect of phenprocoumon and acenocoumarol. Patients/Methods: The EU-PACT cohort dataset, which contains data on 624 phenprocoumon and 471 acenocoumarol patients, was used. Patient characteristics, pharmacogenetic data, International Normalized Ratios (INRs) and dosages were available. We investigated whether there was an interaction between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability during the first 180 days of phenprocoumon and acenocoumarol therapy, in addition to the effect of the separate genotypes. The interaction effect was investigated by adding the product term of the CYP2C9 and VKORC1 genotype classes for four different commonly used CYP2C9 classifications to the linear regression model – for the outcome measure maintenance dose – or to the Cox regression models – for the outcome measures time to severe over-anticoagulation and time to achieve stability. Results: No significant interactions – all P-values above 0.23 for phenprocoumon and 0.30 for acenocoumarol – were observed for all outcome measures. Conclusions: There are no interactions between the CYP2C9 and VKORC1 genotypes affecting the maintenance dose, time to severe over-anticoagulation and time to achieve stability for phenprocoumon and acenocoumarol.

Background: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. Objectives: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. Patients/Methods: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. Results: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1); FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. Conclusions: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.

Clotting factor V has a dual function in coagulation: after activation, procoagulant factor V stimulates the formation of thrombin, whereas anticoagulant factor V acts as a cofactor for activated protein C (APC) in the degradation of factor VIII/VIIIa, thereby reducing thrombin formation. In the present study, we evaluated whether plasma factor V levels, either decreased or increased, are associated with venous thrombosis. High procoagulant factor V levels may enhance prothrombinase activity and increase the thrombosis risk. Low anticoagulant factor V levels could reduce APC- cofactor activity in the factor VIII inactivation (APC-resistant phenotype), which might also promote thrombosis. Low factor V levels in combination with factor V Leiden could lead to a more severe APC-resistant phenotype (pseudohomozygous APC resistance). To address these issues, we have measured factor V antigen (factor V:Ag) levels in 474 patients with thrombosis and 474 control subjects that were part of the Leiden Thrombophilia Study (LETS). Factor V:Ag levels increased by 7.6 U/dL for every successive 10 years of age. Mean factor V:Ag levels were 134 (range 41 to 305) U/dL in patients and 132 (range 47 to 302) U/dL in controls. Neither high nor low factor V:Ag levels were associated with venous thrombosis. We found that factor V:Ag and factor VIII antigen levels in plasma were correlated, but factor V did not modify the thrombotic risk of high factor VIII levels. The normalized APC ratio was not influenced by the factor V:Ag level in subjects with or without factor V Leiden. We conclude that neither low nor high factor V:Ag levels are associated with venous thrombosis and that factor V:Ag levels do not mediate the thrombotic risk associated with high factor VIII levels. Chemicals/CAS: factor V Leiden; Factor V, 9001-24-5; Factor VIII, 9001-27-8; Protein C