Population-based incidence rates of 15 neuromuscular disorders:a nationwide capture-recapture study in the Netherlands

Most neuromuscular disorders are rare, but as a group they are not. Nevertheless, epidemiological data of specific neuromuscular disorders are scarce, especially on the incidence. We applied a capture-recapture approach to a nationwide hospital-based dataset and a patients association-based dataset to estimate the annual incidence rates for fifteen neuromuscular disorders in the Netherlands. The annual incidence rates per 100,000 population varied from 0.03/100,000 (95% CI 0.00 ‒ 0.06) for glycogenosis type 5 to 0.9/100,000 (95% confidence interval 0.7 ‒ 1.0) for myotonic dystrophy type 1. The summed annual incidence rate of these disorders was 4.1 per 100,000 per population. Nine of the provided incidence rates were previously unavailable, three rates were similar to the rates in the literature, and three rates were generally higher compared to previous findings but with overlapping confidence intervals. This study provides nationwide incidence rates for fifteen neuromuscular disorders predominantly diagnosed in adult life, nine which were previously unavailable. The capture-recapture approach provided estimates of the total number of individuals with neuromuscular disorders. To complete the gaps in the knowledge of disease frequencies, there is a need for estimates from an automated, obligatory data collection system of diagnosed and newly diagnosed patients with neuromuscular disorders.</p

Population-based incidence rates of 15 neuromuscular disorders: a nationwide capture-recapture study in the Netherlands

Most neuromuscular disorders are rare, but as a group they are not. Nevertheless, epidemiological data of specific neuromuscular disorders are scarce, especially on the incidence. We applied a capture-recapture approach to a nationwide hospital-based dataset and a patients association-based dataset to estimate the annual incidence rates for fifteen neuromuscular disorders in the Netherlands. The annual incidence rates per 100,000 population varied from 0.03/100,000 (95% CI 0.00 ‒ 0.06) for glycogenosis type 5 to 0.9/100,000 (95% confidence interval 0.7 ‒ 1.0) for myotonic dystrophy type 1. The summed annual incidence rate of these disorders was 4.1 per 100,000 per population. Nine of the provided incidence rates were previously unavailable, three rates were similar to the rates in the literature, and three rates were generally higher compared to previous findings but with overlapping confidence intervals. This study provides nationwide incidence rates for fifteen neuromuscular disorders predominantly diagnosed in adult life, nine which were previously unavailable. The capture-recapture approach provided estimates of the total number of individuals with neuromuscular disorders. To complete the gaps in the knowledge of disease frequencies, there is a need for estimates from an automated, obligatory data collection system of diagnosed and newly diagnosed patients with neuromuscular disorders

Lifelong Exercise Patterns and Cardiovascular Health.

OBJECTIVE: To determine the relationship between lifelong exercise dose and the prevalence of cardiovascular morbidity. PATIENTS AND METHODS: From June 1, 2011, through December 31, 2014, 21,266 individuals completed an online questionnaire regarding their lifelong exercise patterns and cardiovascular health status. Cardiovascular disease (CVD) was defined as a diagnosis of myocardial infarction, stroke, or heart failure, and cardiovascular risk factors (CVRFs) were defined as hypertension, hypercholesterolemia, or type 2 diabetes. Lifelong exercise patterns were measured over a median of 32 years for 405 patients with CVD, 1379 patients with CVRFs, and 10,656 controls. Participants were categorized into nonexercisers and quintiles (Q1-Q5) of exercise dose (metabolic equivalent task [MET] minutes per week). RESULTS: The CVD/CVRF prevalence was lower for each exercise quintile compared with nonexercisers (CVD: nonexercisers, 9.6% vs Q1: 4.4%, Q2: 2.8%, Q3: 2.4%, Q4: 3.6%, Q5: 3.9%; P<.001; CVRF: nonexercisers, 24.6% vs Q1: 13.8%, Q2: 10.2%, Q3: 9.0%, Q4: 9.4%, Q5: 12.0%; P<.001). The lowest exercise dose (Q1) significantly reduced CVD and CVRF prevalence, but the largest reductions were found at 764 to 1091 MET-min/wk for CVD (adjusted odds ratio=0.31; 95% CI, 0.20-0.48) and CVRFs (adjusted odds ratio=0.36; 95% CI, 0.28-0.47). The CVD/CVRF prevalence did not further decrease in higher exercise dose groups. Exercise intensity did not influence the relationship between exercise patterns and CVD or CVRFs. CONCLUSION: These findings demonstrate a curvilinear relationship between lifelong exercise patterns and cardiovascular morbidity. Low exercise doses can effectively reduce CVD/CVRF prevalence, but engagement in exercise for 764 to 1091 MET-min/wk is associated with the lowest CVD/CVRF prevalence. Higher exercise doses do not yield additional benefits

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Risk factors for thiopurine-induced myelosuppression and infections in inflammatory bowel disease patients with a normal TPMT genotype

Background: Leucopenia is a common side effect in patients treated with thiopurines. Variants in the thiopurine S-methyltransferase (TPMT) gene are the best-known risk factor, but only explain up to 25% of leucopenia cases. Aim: To identify the clinical risk factors for thiopurine-induced leucopenia in patients without a common TPMT variant, and explore if these patients are at increased risk for infections. Methods: Post hoc analysis of the Thiopurine response Optimisation by Pharmacogenetic testing in Inflammatory bowel disease Clinics (TOPIC) trial. For this analysis, patients without a variant in TPMT (*2, *3A or*3C) were included. Uni- and multivariate Cox-proportional hazard models were used to identify risk factors for leucopenia and infections. Leucopenia was defined as a white blood cell (WBC) count <3.0 × 109/L and infections were classified according to the Common Terminology Criteria for Adverse Events. Results: Sixty hundred and ninety-five patients (90.6%) included in the TOPIC-trial had no variant in TPMT, of which 45 (6.5%) developed leucopenia. Median time to leucopenia was 56 (29-112) days. Multivariate analysis showed that use of mercaptopurine compared to azathioprine was associated with leucopenia (hazard ratio [HR] 2.61 [95% CIs, 1.39-4.88; P <.01]) and a higher baseline WBC count was protective (HR 0.80 [95% CIs, 0.71-0.89; P <.01]). Risk factors for infections were older age (per 10 year; HR 2.07 [95% CIs, 1.18-3.63; P =.01]) and concomitant use of biologic drugs (HR 2.15 [95% CIs, 1.14-4.07; P =.02]). Conclusions: Low baseline WBC count and mercaptopurine, due to a relatively higher dose, were risk factors for thiopurine-induced leucopenia in patients without a TPMT variant

WorkflowNet2BPEL4WS : a tool for translating unstructured workflow processes to readable BPEL

This paper presents WorkflowNet2BPEL4WS a tool to automatically map a graphical workflow model expressed in terms of Workflow Nets (WF-nets) onto BPEL. The Business Process Execution Language for Web Services (BPEL) has emerged as the de-facto standard for implementing processes and is supported by an increasing number of systems (cf. the IBM WebSphere Choreographer and the Oracle BPEL Process Manager). While being a powerful language, BPEL is difficult to use. Its XML representation is very verbose and only readable for the trained eye. It offers many constructs and typically things can be implemented in many ways, e.g., using links and the flow construct or using sequences and switches. As a result only experienced users are able to select the right construct. Some vendors offer a graphical interface that generates BPEL code. However, the graphical representations are a direct reflection of the BPEL code and not easy to use by end-users. Therefore, we provide a mapping from WF-nets to BPEL. This mapping builds on the rich theory of Petri nets and can also be used to map other languages (e.g., UML, EPC, BPMN, etc.) onto BPEL. To evaluate WorkflowNet2BPEL4WS we used more than 100 processes modeled using Protos (the most widely used business process modeling tool in the Netherlands), automatically converted these into CPN Tools, and applied our mapping. The results of these evaluation are very encouraging and show the applicability of our approach

Cost-Effectiveness of Colorectal Cancer Surveillance in Hodgkin Lymphoma Survivors Treated with Procarbazine and/or Infradiaphragmatic Radiotherapy

BACKGROUND: Hodgkin lymphoma survivors treated with infradiaphragmatic radiotherapy (IRT) and/or procarbazine have an increased risk of developing colorectal cancer. We investigated the cost-effectiveness of colorectal cancer surveillance in Dutch Hodgkin lymphoma survivors to determine the optimal surveillance strategy for different Hodgkin lymphoma subgroups. METHODS: The Microsimulation Screening Analysis-Colon model was adjusted to reflect colorectal cancer and other-cause mortality risk in Hodgkin lymphoma survivors. Ninety colorectal cancer surveillance strategies were evaluated varying in starting and stopping age, interval, and modality [colonoscopy, fecal immunochemical test (FIT, OC-Sensor; cutoffs: 10/20/47 μg Hb/g feces), and multi-target stool DNA test (Cologuard)]. Analyses were also stratified per primary treatment (IRT and procarbazine or procarbazine without IRT). Colorectal cancer deaths averted (compared with no surveillance) and incremental cost-effectiveness ratios (ICER) were primary outcomes. The optimal surveillance strategy was identified assuming a willingness-to-pay threshold of €20,000 per life-years gained (LYG). RESULTS: Overall, the optimal surveillance strategy was annual FIT (47 μg) from age 45 to 70 years, which might avert 70% of colorectal cancer deaths in Hodgkin lymphoma survivors (compared with no surveillance; ICER:€18,000/LYG). The optimal surveillance strategy in Hodgkin lymphoma survivors treated with procarbazine without IRT was biennial FIT (47 μg) from age 45 to 70 years (colorectal cancer mortality averted 56%; ICER:€15,000/LYG), and when treated with IRT and procarbazine, annual FIT (47 μg) surveillance from age 40 to 70 was most cost-effective (colorectal cancer mortality averted 75%; ICER:€13,000/LYG). CONCLUSIONS: Colorectal cancer surveillance in Hodgkin lymphoma survivors is cost-effective and should commence earlier than screening occurs in population screening programs. For all subgroups, FIT surveillance was the most cost-effective strategy. IMPACT: Colorectal cancer surveillance should be implemented in Hodgkin lymphoma survivors

Exome sequencing identifies DYNC2H1 mutations as a common cause of asphyxiating thoracic dystrophy (Jeune syndrome) without major polydactyly, renal or retinal involvement

Background: Jeune asphyxiating thoracic dystrophy (JATD) is a rare, often lethal, recessively inherited chondrodysplasia characterised by shortened ribs and long bones, sometimes accompanied by polydactyly, and renal, liver and retinal disease. Mutations in intraflagellar transport (IFT) genes cause JATD, including the IFT dynein-2 motor subunit gene DYNC2H1. Genetic heterogeneity and the large DYNC2H1 gene size have hindered JATD genetic diagnosis.Aims and methods: to determine the contribution to JATD we screened DYNC2H1 in 71 JATD patients JATD patients combining SNP mapping, Sanger sequencing and exome sequencing.Results and conclusions: we detected 34 DYNC2H1 mutations in 29/71 (41%) patients from 19/57 families (33%), showing it as a major cause of JATD especially in Northern European patients. This included 13 early protein termination mutations (nonsense/frameshift, deletion, splice site) but no patients carried these in combination, suggesting the human phenotype is at least partly hypomorphic. In addition, 21 missense mutations were distributed across DYNC2H1 and these showed some clustering to functional domains, especially the ATP motor domain. DYNC2H1 patients largely lacked significant extra-skeletal involvement, demonstrating an important genotype–phenotype correlation in JATD. Significant variability exists in the course and severity of the thoracic phenotype, both between affected siblings with identical DYNC2H1 alleles and among individuals with different alleles, which suggests the DYNC2H1 phenotype might be subject to modifier alleles, non-genetic or epigenetic factors. Assessment of fibroblasts from patients showed accumulation of anterograde IFT proteins in the ciliary tips, confirming defects similar to patients with other retrograde IFT machinery mutations, which may be of undervalued potential for diagnostic purpose