Non-oral manifestations in adults with a clinical and molecularly confirmed diagnosis of periodontal Ehlers-Danlos syndrome.

Introduction: Periodontal Ehlers-Danlos Syndrome (pEDS) is a rare autosomal dominant type of EDS characterised by severe early-onset periodontitis, lack of attached gingiva, pretibial plaques, joint hypermobility and skin hyperextensibility as per the 2017 International EDS Classification. In 2016, deleterious pathogenic heterozygous variants were identified in C1R and C1S, which encode components of the complement system. Materials and Methods: Individuals with a clinical suspicion of pEDS were clinically and molecularly assessed through the National EDS Service in London and Sheffield and in genetic services in Austria, Sweden and Australia. Transmission electron microscopy and fibroblast studies were performed in a small subset of patients. Results: A total of 21 adults from 12 families were clinically and molecularly diagnosed with pEDS, with C1R variants in all families. The age at molecular diagnosis ranged from 21-73 years (mean 45 years), male: female ratio 5:16. Features of easy bruising (90%), pretibial plaques (81%), skin fragility (71%), joint hypermobility (24%) and vocal changes (38%) were identified as well as leukodystrophy in 89% of those imaged. Discussion: This cohort highlights the clinical features of pEDS in adults and contributes several important additional clinical features as well as novel deleterious variants to current knowledge. Hypothetical pathogenic mechanisms which may help to progress understanding and management of pEDS are also discussed.

[The Personal Antipsychotic Choice Index]. / De Persoonlijke Antipsychotica Keuzewijzer.

BACKGROUND: More than half of the patients suffering from a first psychotic episode withdraw from antipsychotic medication within the first year of treatment. Shared decision making could enhance the therapeutic relationship and thus adherence. AIM: To describe an online decision aid for the selection of antipsychotic medication: the Personal Antipsychotic Choice Index (www.pakwijzer.nl). METHOD: Per effect and side effect, the 15 most commonly prescribed antipsychotics in the Netherlands have been ranked on the basis of data on the magnitude of a desired effect and the chance of a side effect, based on a systematic literature study. We assigned scores to antipsychotics for each desired and undesired effect and processed these scores in an algorithm. A personal ranking of antipsychotics is calculated based on the value that patients attach to these effects. RESULTS: These desired and undesired criteria used are rated in the PACindex: effectiveness concerning psychotic, depressive and cognitive symptoms, weight gain, sexual dysfunction, drowsiness, hypersomnia, extrapyramidal symptoms, anticholinergic adverse effects, hypersalivation, nausea, dizziness, energy loss, blunted affect/less need for companionship. High level evidence was available for ranking weight gain, sexual dysfunction, menstrual disorders, extrapyramidal symptoms and effectiveness on psychotic symptoms. We used lower level evidence ranking the remaining criteria. CONCLUSION: A ready applicable online choixe index for the use of an antipsychotic agent has been developed and put into use. The PACindex could be updated when new evidence of new antipsychotics became available..

Constitutional 2p16.3 deletion including MSH6 and FBXO11 in a boy with developmental delay and diffuse large B-cell lymphoma.

We describe a case of a boy with neurodevelopmental delay and a diffuse large B-cell lymphoma (DLBCL) in whom we discovered a germline de novo 2p16.3 deletion including MSH6 and part of the FBXO11 gene. A causative role for MSH6 in cancer development was excluded based on tumor characteristics. The constitutional FBXO11 deletion explains the neurodevelopmental delay in the patient. The FBXO11 protein is involved in BCL-6 ubiquitination and BCL-6 is required for the germinal center reaction resulting in B cell differentiation. Somatic loss of function alterations of FBXO11 result in BCL-6 overexpression which is a known driver in DLBCL. We therefore consider that a causative relationship between the germline FBXO11 deletion and the development of DLBCL in this boy is conceivable.

[Monitoring with four recovery phases. First experiences in FACT]. / Monitoren met vier herstelfasen; eerste ervaringen binnen FACT.

BACKGROUND: Following an audit, the flexible assertive community treatment-teams (FACT-teams), in Winterswijk, the Netherlands, set out to discover a more recovery-oriented approach to treatment and monitoring. Their findings support researching four recovery phases described previously.
AIM: A pilot-study to investigate the possibilities to create a more recovery-oriented working method by applying the four recovery phases - ranging from being overwhelmed by the condition to living past the condition - in FACT-teams.
METHOD: The FACT-teams started to monitor patients during the recovery phases and developed a semi-structured interview that can be used to determine the current recovery phase. After the phase has been determined, a plan is written on how to progress to the next phase.
RESULTS: Monitoring during the recovery phases proved to be useful in showing both succesfull and stagnating treatments. The recovery phases also became part of the standard treatment plans in the electronic patient dossier. An important result of this project was the recovery-oriented interview we developed.
CONCLUSION: Monitoring and interviewing based on the four recovery phases subjectively leads to more in-depth and more recovery-oriented evaluations of treatment. More empirical research into this method is necessary.

Electron microscopy in the diagnosis of Ehlers-Danlos syndromes: correlation with clinical and genetic investigations.

BACKGROUND: The Ehlers-Danlos syndromes (EDS) consist of 13 subtypes with overlapping features including joint hypermobility, skin and vascular fragility and generalized connective tissue friability. As DNA analysis has become the gold standard for investigation of EDS, transmission electron microscopy (TEM) in clinical practice is decreasing. However, owing to the use of next-generation sequencing, the frequency of variants of uncertain significance (VUS) identified using DNA analysis is increasing. We hypothesized that TEM can provide evidence for or against pathogenicity of VUS. OBJECTIVES: The aim of this study was to evaluate the role of TEM in the diagnosis of EDS subtypes. METHODS: Data were collected from patients who underwent a skin biopsy between October 2012 and March 2017 at the London EDS National Diagnostic Service. TEM biopsies were categorized as 'normal' or 'abnormal' according to the description and conclusion in the TEM reports. Definitive diagnoses were reached via a combination of clinical features, structural and functional studies and DNA investigations. RESULTS: The analysis included 177 patients, comprising 30 abnormal and 147 normal TEM reports. A definitive diagnosis of monogenic EDS subtypes was made in 24 patients. Overall, 17 of these 24 patients (71%) had an abnormal biopsy report and seven (29%) had a normal biopsy report. No TEM findings were specifically associated with any EDS subtype, although collagen flowers were present in most patients with a genetically confirmed diagnosis of classical EDS. CONCLUSIONS: TEM analysis of collagen structure may have the potential to provide evidence for or against the pathogenicity of a VUS, but more work is needed to establish a clear role for TEM in this process. What's already known about this topic? Collagen fibril abnormalities can be seen in several Ehlers-Danlos syndrome (EDS) subtypes. What does this study add? This study provides clinical data, transmission electron microscopy (TEM) data and molecular data of one of the largest groups of patients suspected to have a monogenetic EDS subtype. No TEM findings were specifically associated with an EDS subtype. There was a higher percentage (71%) of abnormal biopsy findings in patients with a definitive diagnosis of a monogenetic EDS subtype and where a class 4/5 genetic variant was present.

The antifibrotic potential of a sustained release formulation of a PDGFß-receptor targeted rho kinase inhibitor.

Rho kinase activity in hepatic stellate cells (HSCs) is associated with activation, transformation and contraction of these cells, leading to extracellular matrix production and portal hypertension in liver cirrhosis. Inhibition of rho kinase activity can reduce these activities, but may also lead to side effects, for instance systemic hypotension. This can be circumvented by liver-specific delivery of a rho kinase inhibitor to effector cells. Therefore, we targeted the rho kinase inhibitor Y27632 to the key pathogenic cells in liver fibrosis, i.e. myofibroblasts including activated HSCs that highly express the PDGFß-receptor, using the drug carrier pPB-MSA. This carrier consists of mouse serum albumin (MSA) covalently coupled to several PDGFßR-recognizing moieties (pPB). We aimed to create a prolonged release system of such a targeted construct, by encapsulating pPB-MSA-Y27632 in biodegradable polymeric microspheres, thereby reducing short-lasting peak concentrations and the need for frequent administrations. Firstly, we confirmed the vasodilating potency of PDGFß-receptor targeted Y27632 in vitro in a contraction assay using HSCs seeded on a collagen gel. We subsequently demonstrated the in vivo antifibrotic efficacy of pPB-MSA-Y27632-loaded microspheres in the Mdr2-/- mouse model of progressive biliary liver fibrosis. A single subcutaneous microsphere administration followed by organ harvest one week later clearly attenuated liver fibrosis progression and significantly suppressed the expression of fibrosis related genes, such as several collagens, profibrotic cytokines and matrix metalloproteinases. In conclusion, we demonstrate that polymeric microspheres are suitable as drug delivery system for the sustained systemic delivery of targeted protein constructs with antifibrotic potential, such as pPB-MSA-Y27632. This formulation appears suitable for the sustained treatment of liver fibrosis and possibly other chronic diseases.

Pharmacokinetics of a sustained release formulation of PDGFß-receptor directed carrier proteins to target the fibrotic liver.

Liver fibrogenesis is associated with excessive production of extracellular matrix by myofibroblasts that often leads to cirrhosis and consequently liver dysfunction and death. Novel protein-based antifibrotic drugs show high specificity and efficacy, but their use in the treatment of fibrosis causes a high burden for patients, since repetitive and long-term parenteral administration is required as most proteins and peptides are rapidly cleared from the circulation. Therefore, we developed biodegradable polymeric microspheres for the sustained release of proteinaceous drugs. We encapsulated the drug carrier pPB-HSA, which specifically binds to the PDGFßR that is highly upregulated on activated myofibroblasts, into microspheres composed of hydrophilic multi-block copolymers composed of poly(l-lactide) and poly ethylene glycol/poly(ϵ-caprolactone), allowing diffusion-controlled release. Firstly, we estimated in mice with acute fibrogenesis induced by a single CCl4 injection the half-life of I125-labeled pPB-HSA at 40 min and confirmed the preferential accumulation in fibrotic tissue. Subsequently, we determined in the Mdr2 −/− mouse model of advanced biliary liver fibrosis how the subcutaneously injected microspheres released pPB-HSA into both plasma and fibrotic liver at 24 h after injection, which was maintained for six days. Although the microspheres still contained protein at day seven, pPB-HSA plasma and liver concentrations were decreased. This reduction was associated with an antibody response against the human albumin-based carrier protein, which was prevented by using a mouse albumin-based equivalent (pPB-MSA). In conclusion, this study shows that our polymeric microspheres are suitable as sustained release formulation for targeted protein constructs such as pPB-HSA. These formulations could be applied for the long-term treatment of chronic diseases such as liver fibrosis.

Workers' health surveillance: implementation of the Directive 89/391/EEC in Europe.

BACKGROUND: European Union (EU) Directive 89/391 addressed occupational health surveillance, which recommends to provide workers with 'access to health surveillance at regular intervals', aiming to prevent work-related and occupational diseases. AIMS: To investigate how EU countries adopted this Directive. METHODS: We invited one selected representative per member state to complete a questionnaire. RESULTS: All 28 EU countries implemented the Directive in some form. Workers' health surveillance (WHS) is available to all workers in 15 countries, while in 12, only specific subgroups have access. In 21 countries, workers' participation is mandatory, and in 22, the employer covers the cost. In 13 countries, access to WHS is not available to all workers but depends on exposure to specific risk factors, size of the enterprise or belonging to vulnerable groups. In 26 countries, the employer appoints and revokes the physician in charge of WHS. Twelve countries have no recent figures, reports or cost-benefit analyses of their WHS programmes. In 15 countries where reports exist, they are often in the native language. CONCLUSIONS: Coverage and quality of occupational health surveillance should be evaluated to facilitate learning from good practice and from scientific studies. We propose a serious debate in the EU with the aim of protecting workers more effectively, including the use of evidence-based WHS programmes.

Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFß-receptor in the fibrotic kidney.

Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFßR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFßR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFßR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.

Novel Algorithms for Improved Sensitivity in Non-Invasive Prenatal Testing.

Non-invasive prenatal testing (NIPT) of cell-free DNA in maternal plasma, which is a mixture of maternal DNA and a low percentage of fetal DNA, can detect fetal aneuploidies using massively parallel sequencing. Because of the low percentage of fetal DNA, methods with high sensitivity and precision are required. However, sequencing variation lowers sensitivity and hampers detection of trisomy samples. Therefore, we have developed three algorithms to improve sensitivity and specificity: the chi-squared-based variation reduction (χ2VR), the regression-based Z-score (RBZ) and the Match QC score. The χ2VR reduces variability in sequence read counts per chromosome between samples, the RBZ allows for more precise trisomy prediction, and the Match QC score shows if the control group used is representative for a specific sample. We compared the performance of χ2VR to that of existing variation reduction algorithms (peak and GC correction) and that of RBZ to trisomy prediction algorithms (standard Z-score, normalized chromosome value and median-absolute-deviation-based Z-score). χ2VR and the RBZ both reduce variability more than existing methods, and thereby increase the sensitivity of the NIPT analysis. We found the optimal combination of algorithms was to use both GC correction and χ2VR for pre-processing and to use RBZ as the trisomy prediction method.

A de novo mutation in ZMYND11, a candidate gene for 10p15.3 deletion syndrome, is associated with syndromic intellectual disability.

We report a boy with severe syndromic intellectual disability who has a de novo mutation in the ZMYND11 gene. Arguments for pathogenicity of this mutation are found in cases from the literature, especially several with 10p15.3 deletions, harbouring ZMYND11. Additional reports of ZMYND11 mutations in cases with syndromic intellectual disability are needed before the ZMYND11 mutation identified in our case can be considered as definitely pathogenic.

Osteogenesis imperfecta: clinical diagnosis, nomenclature and severity assessment.

Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Undergraduate teaching of occupational medicine in European schools of medicine.

PURPOSE: General practitioners play or should play a role in occupational medicine (OM), either in diagnosing occupational diseases or in counseling on return to work. Nevertheless, their training has been reported to be insufficient in most single country studies. AIMS: The objectives of this study were to analyze the content and extent of undergraduate teaching of OM in European medical schools. METHODS: An e-mail questionnaire survey of the teaching of OM to undergraduates was undertaken from December 2010 to April 2011 in all medical schools and medical faculties listed in 27 European countries (n = 305). RESULTS: Among the 305 universities identified, 135 answered to the questionnaire, giving a response rate of 44%. The mean number of hours given to formal instruction in occupational medicine to medical undergraduates was 25.5 h. Nevertheless, this number of hours varied widely between countries, but also within countries. Overall, 27% of medical schools gave their students 10 h of teaching or less, 52% 20 h or less and 69% 30 h or less. Whereas occupational diseases and principles of prevention were covered in most schools, disability and return to work were very poorly represented among the topics that were taught to students. CONCLUSION: Dedicated undergraduate teaching on occupational health or OM in European medical schools is present in most medical schools, usually at a low level, but is very variable between and within countries. Medical schools across Europe are very unequal to provide qualifying doctors education on the topics they will frequently come across in their working lives.

Effect evaluation of a self-management program for dutch workers with a chronic somatic disease: a randomized controlled trial.

PURPOSE: The objective of this study is to investigate the effect of a Self-Management Program for workers with a chronic disease. This program is based on the Chronic Disease Self-Management Program of Stanford University, modified for workers with a chronic somatic disease. METHODS: In a randomized controlled trial, the effectiveness of a Self-Management Program was evaluated. Participants were randomly assigned to the experimental group (n = 57) and the control group (n = 47). The experimental group received an intervention, the control group received care as usual. Primary outcome measures were self-efficacy at work and the attitude towards self-management at work. Secondary outcomes were the SF-12 health survey questionnaire, job satisfaction and intention to change job. The results were measured at baseline, after the intervention and 8 months after the intervention. RESULTS: The attitude towards self-management at work (enjoyment) improved after 8 months for the intervention group (p = 0.030). No other outcome variable differed significantly. As an interaction effect, it was found that low educated workers developed a better physical health quality (SF-12) in the intervention group compared with the control group. The attitude towards self-management at work (importance) improved in the intervention group for older and female workers and the attitude toward enjoying self-management at work improved for female workers only. CONCLUSION: The results show that low educated workers, older workers and women benefit significantly more from the training than higher educated workers, younger workers and men.

Severe spinal cord decompression illness after an uneventful North Sea dive.

The aim of this case report is to illustrate that, even under moderate conditions, a dive can result in spinal cord decompression illness (DCI). The diver in question completed five dives with the same profile. The first four included substantial physical strain, while the final dive was for observation only, without physical strain. The spinal cord was the target organ for DCI. We discuss the roles of various diver-related risk factors and of factors related to the dive itself. Older divers have a higher risk for decompression incidents. The nature of the dive profile is a major factor in the uptake and release of inert gas. Physical exertion during pressure-exposure boosts the inert gas load, increases bubbling in tissues and raises the risk of DCI in the decompression phase of the dive. We discuss the causal involvement of such risk factors in this case, given the characteristics of the diver and the circumstances of the dive. Finally, we want to express our concern for physical fitness and smoking habits, especially for divers over the age of 40.

Workers with a chronic disease and work disability. Problems and solutions.

The prevalence of chronic diseases in the age group 18-65 years is high. Cardiometabolic conditions and musculoskeletal diseases are the most frequent chronic diseases. Depending on disease and comorbidity, the employment rates are considerably lower than for healthy individuals. Chronically ill workers may have problems in meeting job demands, they may experience physical, cognitive or sensory limitations, have fatigue or pain complaints or other disease symptoms. Psychological distress, depressive feelings, feelings of shame or guilt, lack of coping or communicative skills, and non-supportive colleagues and supervisors may add to work-related problems. The ICF Model (International Classification of Functioning, Disability and Health) of the WHO offers a framework for understanding and considering health-related problems at work and finding solutions. Interventions to prevent problems in functioning, sickness absence and work disability may focus on the worker, the workplace, or health care. Multidisciplinary vocational rehabilitation, exercise therapy, cognitive behavioural interventions, workplace interventions and empowerment are interventions with at least some evidence of effectiveness. Future policy could focus more on promotion of workers' health and future research should include the interests and motivations of employers concerning disability management, skills of line managers, the feasibility of interventions to prevent work disability and the context sensitivity of study outcomes.

Ethical issues of genetic susceptibility testing for occupational diseases: opinions of trainees in a high-risk job.

PURPOSE: Genetic research has opened up possibilities for identification of persons with an increased susceptibility for occupational disease. However, regulations considering the ethical issues that are inevitably associated with the use of genetic tests for susceptibility for occupational diseases are scarce. We investigated whether opinions of an intended stakeholder group, that is, student nurses, are sufficiently addressed by existing recommendations. METHODS: Attitudes and opinions of Dutch student nurses toward a genetic test for susceptibility to occupational contact eczema were studied in a qualitative setup using focus groups, interviews and electronic questionnaires. The results were compared with guidelines and recommendations extracted from the literature. RESULTS: Sixty-nine percent of the student nurses said they would partake in a genetic test for susceptibility to occupational contact eczema when available. Concerns were expressed regarding the difficulty of interpreting test results, the utility of the test result in practice and the necessity of genetic tests for non-severe diseases. For the issue of privacy and confidentiality, the students expressed few worries and much confidence. The existing guidelines largely covered the students' opinions. Still, the data emphasized the need for good individual risk communication both before and after testing, taking into account that the test concerns susceptibility. CONCLUSIONS: Comparing the students' statements with the issues addressed by the guidelines, we conclude that the guidelines should pay more attention to risk communication and practical advice accompanying the test results.

170 GHz Uni-Traveling Carrier Photodiodes for InP-based photonic integrated circuits.

We demonstrate the capability of fabricating extremely high-bandwidth Uni-Traveling Carrier Photodiodes (UTC-PDs) using techniques that are suitable for active-passive monolithic integration with Multiple Quantum Well (MQW)-based photonic devices. The devices achieved a responsivity of 0.27 A/W, a 3-dB bandwidth of 170 GHz, and an output power of -9 dBm at 200 GHz. We anticipate that this work will deliver Photonic Integrated Circuits with extremely high bandwidth for optical communications and millimetre-wave applications.