Design and baseline characteristics of the PerfectFit study: A multicenter cluster-randomized trial of a lifestyle intervention in employees with increased cardiovascular risk

Background: The prevalence of unhealthy lifestyles and preventable chronic diseases is high. They lead to disabilities and sickness absence, which might be reduced if health promotion measures were applied. Therefore, we developed the PerfectFit health promotion intervention with a "blended care"-approach, which consists of a web-based health risk assessment (HRA) including tailored and personalized advice, followed by motivational interviewing (MI). We hypothesize that adding MI to a web-based HRA leads to better health outcomes. The objective is to describe the design and baseline characteristics of the PerfectFit study, which is being conducted among employees with high cardiovascular risk in the military workforce, the police organization and an academic hospital. Methods: PerfectFit is a cluster randomized controlled trial, consisting of two arms. Based on cardiovascular risk profiling, done between 2012 and 2014, we included employees based on one or more risk factors and motivation to participate. One arm is the 'limited' health program (control) that consists of: (a) an HRA as a decision aid for lifestyle changes, including tailored and personalized advice, and pros and cons of the options, and (b) a newsletter every 3 months. The other arm is the 'extensive' program (intervention), which is additionally offered MI-sessions by trained occupational physicians, 4 face-to-face and 3 by telephone, and is offered more choices of health promotion activities in the HRA. During the follow-up period, participants choose the health promotion activities they personally prefer. After six and twelve months, outcomes will be assessed by online questionnaires. After twelve months the cardiovascular risk profiling will be repeated. The primary outcome is self-reported general health. Secondary outcomes are self-reported work ability, CVD-risk score, sickness absence, productivity loss at work, participation in health promotion activities, changes in lifestyle (smoking, alcohol consumption, physical activity, stress management) and body mass index. Furthermore, a process evaluation and an economic analysis will be performed. Discussion: Additional coaching using MI is expected to be a key factor for success of the web-based HRA in employees with increased cardiovascular risk. This "blended care"-approach may be an essential strategy for effective health promotion activities. Trial registration: Dutch Trial Register by registration number NTR4894, 14/11/2014

Translational and Regulatory Challenges for Exon Skipping Therapies

Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.status: publishe

Mutation in exon 1a of PLEC, leading to disruption of plectin isoform 1a, causes autosomal-recessive skin-only epidermolysis bullosa simplex

PLEC, the gene encoding the cytolinker protein plectin, has eight tissue-specific isoforms in humans, arising by alternate splicing of the first exon. To date, all PLEC mutations that cause epidermolysis bullosa simplex (EBS) were found in exons common to all isoforms. Due to the ubiquitous presence of plectin in mammalian tissues, EBS from recessive plectin mutations is always associated with extracutaneous involvement including muscular dystrophy, pyloric atresia and cardiomyopathy. We studied a consanguineous family with sisters having isolated blistering suggesting EBS. Skin disease started with foot blisters at walking age and became generalized at puberty while sparing mucous membranes. DNA sequencing revealed a homozygous nonsense mutation (c.46C>T; p.Arg16X) in the first exon of the plectin variant encoding plectin isoform 1a (P1a). Immunofluorescence antigen mapping, transmission electron microscopy, western blot analysis and qRT-PCR were performed on patient skin and cultured keratinocytes, control myocardium and striated muscle samples. We found hypoplastic hemidesmosomes and intra-epidermal ‘pseudo-junctional' cleavage fitting EBS. Screening for cardiomyopathy and muscle dystrophy showed no abnormalities. We report the first cases of autosomal-recessive EBS from P1a deficiency affecting skin, while mucous membranes, heart and muscle are spared. The dominant expression of the P1a isoform in epidermal basal cell layer and cultured keratinocytes suggests that mutations in the first exon of isoform 1a cause skin-only EBS without extracutaneous involvement. Our study characterizes yet another of the eight isoforms of plectin and adds a tissue-specific phenotype to the spectrum of ‘plectinopathies' produced by mutations of unique first exons of this gen

Perfectfit @ work : Effectiveness of blended web-based workplace health promotion programs

Cardiovascular disease (CVD) is the leading cause of death throughout the world, and is associated with morbidity and decreased employability. The prevalence of CVD and of people at risk for CVD (e.g. obesity, diabetes or hypertension) has been increasing. A healthy lifestyle is important in the prevention of CVD. Thus, effective preventive health initiatives aimed at a healthy lifestyle to decrease cardiovascular risks are beneficial to health and would improve sustainable employability of workers. In this thesis, the association between CVD and exit from paid employment was investigated, followed by intervention-studies on two ‘blended’ workplace health promotion programs, a combination of eHealth and motivational interviewing. We found positive changes in health behavior and health outcomes in both health programs. These findings show that blended workplace health promotion programs are promising in improving health and employability in employees at increased cardiovascular risk. Recommendations for future practice and research are made

Learning from European regulator-initiated studies for regulatory decision making

Drug developers have displayed a growing interest in using real-word evidence (RWE) in the pre-marketing phase. Together with initiatives like DARWIN EU®, this interest encourages regulators to initiate their own observational clinical studies, which could be included in regulatory decision making. The Regulatory Science Network Netherlands (RSNN) organised an expert meeting in 2022 to discuss scenarios and learnings related to these regulator-initiated studies, of which the main points (e.g., transparency, independency and stakeholder interaction) have been published previously. In this review, the authors add their own views, underlining the importance of reproducibility and stakeholder interaction. Stakeholders should collaborate to embrace regulator-initiated studies in a timely and transparent manner to realise an optimal European framework for generating RWE to be included in the regulatory decision-making process.</p