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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.

Abstract Background The prevalence of obesity is increasing worldwide and prevention is needed. Whole grain has shown potential to lower the risk of obesity, cardiovascular disease and type 2 diabetes. One possible mechanism behind the benefits of whole grain is the gut fermentation of dietary fiber (DF), e.g. non-starch polysaccharides and resistant starch (RS), in whole grain. The purpose of the study is to investigate the effect of whole grain rye-based products on glucose- and appetite regulation. Method Twenty-one healthy subjects were provided four rye-based evening test meals in a crossover overnight study design. The test evening meals consisted of either whole grain rye flour bread (RFB) or a 1:1 ratio of whole grain rye flour and rye kernels bread (RFB/RKB), with or without added resistant starch (+RS). White wheat flour bread (WWB) was used as reference evening meal. Blood glucose, insulin, PYY, FFA, IL-6 as well as breath H2 and subjective rating of appetite were measured the following morning at fasting and repeatedly up to 3.5 h after a standardized breakfast consisting of WWB. Ad libitum energy intake was determined at lunch, 14.5 h after evening test and reference meals, respectively. Results The evening meal with RFB/RKB + RS decreased postprandial glucose- and insulin responses (iAUC) (P

BackgroundWhole grain has shown potential to prevent obesity, cardiovascular disease and type 2 diabetes. Possible mechanism could be related to colonic fermentation of specific indigestible carbohydrates, i.e. dietary fiber (DF). The aim of this study was to investigate effects on cardiometabolic risk factors and appetite regulation the next day when ingesting rye kernel bread rich in DF as an evening meal.MethodWhole grain rye kernel test bread (RKB) or a white wheat flour based bread (reference product, WWB) was provided as late evening meals to healthy young adults in a randomized cross-over design. The test products RKB and WWB were provided in two priming settings: as a single evening meal or as three consecutive evening meals prior to the experimental days. Test variables were measured in the morning, 10.5-13.5 hours after ingestion of RKB or WWB. The postprandial phase was analyzed for measures of glucose metabolism, inflammatory markers, appetite regulating hormones and short chain fatty acids (SCFA) in blood, hydrogen excretion in breath and subjective appetite ratings.ResultsWith the exception of serum CRP, no significant differences in test variables were observed depending on length of priming (P>0.05). The RKB evening meal increased plasma concentrations of PYY (0-120 min, PConclusionThe results indicate that RKB evening meal has an anti-diabetic potential and that the increased release of satiety hormones and improvements of appetite sensation could be beneficial in preventing obesity. These effects could possibly be mediated through colonic fermentation.Trial registrationClinicalTrials.gov NCT02093481.

Although most patients with cystic fibrosis (CF) are diagnosed in early childhood, the diagnosis may be delayed for patients with mild symptoms or single-organ disease. We describe a man with known infertility and a history of productive cough diagnosed with CF at 61 years of age. The patient carries two mutations and one variant in the CF transmembrane conductance regulator gene: 394delTT, P99L and R75Q. During a 15-year follow-up time he has developed significant pulmonary disease.Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract Background Whole grain (WG) intake is associated with reduced risk of obesity, type 2 diabetes and cardiovascular disease, whereas type 2 diabetes increases the risk of cognitive decline and dementia. The purpose of this study was to investigate the effects of short-term intervention with WG rye on cognitive functions, mood and cardiometabolic risk markers in middle-aged test subjects. Method Rye-based breads were provided to 38 healthy test subjects (aged 52-70y) during three consecutive days in a crossover study design, using white wheat flour bread (WWB) as a reference. The rye-based bread consisted of a WG rye kernel/flour mixture (1:1 ratio) supplemented with resistant starch type 2 (RS2) (RB + RS2). The last bread portion was ingested at 2100 h, and cognitive function, mood and cardiometabolic risk markers were determined the following morning, 11 − 14 h post intake. Results In comparison to WWB, the RB + RS2 product increased ratings of mood parameters (valance, P 0.05). RB + RS2 increased insulin sensitivity (P

BackgroundWhey proteins have insulinogenic properties and the effect appears to originate from a specific postprandial plasma amino acid pattern. The insulinogenic effect can be mimicked by a specific mixture of the five amino acids iso, leu, lys, thr and val.ObjectiveThe objective was to evaluate the efficacy of pre-meal boluses of whey or soy protein with or without added amino acids on glycaemia, insulinemia as well as on plasma responses of incretins and amino acids at a subsequent composite meal. Additionally, plasma ghrelin and subjective appetite responses were studied.DesignIn randomized order, fourteen healthy volunteers were served a standardized composite ham sandwich meal with either water provided (250 ml) during the time course of the meal, or different pre-meal protein drinks (PMPD) (100 ml provided as a bolus) with additional water (150 ml) served to the meal. The PMPDs contained 9 g protein and were based on either whey or soy protein isolates, with or without addition of the five amino acids (iso, leu, lys, thr and val) or the five amino acids + arg.ResultsAll PMPD meals significantly reduced incremental area for plasma glucose response (iAUC) during the first 60 min. All whey based PMPD meals displayed lower glycemic indices compared to the reference meal. There were no significant differences for the insulinemic indices. The early insulin response (iAUC 0-15 min) correlated positively to plasma amino acids, GIP and GLP-1 as well as to the glycemic profile. Additionally, inverse correlations were found between insulin iAUC 0-15 min and the glucose peak.ConclusionThe data suggests that a pre-meal drink containing specific proteins/amino acids significantly reduces postprandial glycemia following a composite meal, in absence of elevated insulinemic excursions. An early phase insulinemic response induced by plasma amino acids and incretins appears to mediate the effect.Trial registrationClinicalTrials.gov NCT01586780

Purpose: This study aimed to characterize clinical and genetic findings in a Swedish cohort with inherited retinal disease (IRD), identify predictors for achieving a molecular diagnosis and evaluate the effects of increased genetic testing over time., Methods: Clinical and genetic data from 324 nonrelated IRD index individuals referred for genetic testing in the Stockholm region between 2016 and 2023 were collected retrospectively and analysed by clinical subtype, age of onset and testing period (2016-2020 vs. 2021-2023). Logistic regression was used to calculate odds ratios for age of onset and family history on the likelihood of achieving a molecular diagnosis., Results: The diagnostic yield was 55% and involved 56 genes. In 10% of solved individuals, the molecular diagnosis refined the clinical diagnosis. For each 1-year increase in age of onset, the odds of achieving a molecular diagnosis decreased by 3% (odds ratio 0.97, 95% confidence interval 0.96-0.98). A positive family history doubled the odds (odds ratio 2.1, 95% confidence interval 1.3-3.4). The use of genetic testing increased 2.1-fold and the number of molecular diagnoses increased 1.6-fold relative to the population of the Stockholm region between the two testing periods., Conclusion: This study adds to the knowledge of the clinical and genetic landscape of IRDs in Sweden and establishes age of onset and family history as significant predictors for achieving a molecular diagnosis. Increased genetic testing on a population level substantially increased the number of individuals receiving a molecular diagnosis with a high diagnostic yield compared to other rare diseases., (© 2024 The Author(s). Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Background: We describe the case of a 47-year-old man referred to a retinal clinic and diagnosed with late-onset retinitis pigmentosa. Surprisingly, genetic testing revealed compound heterozygous pathogenic variants in GNPTG, leading to the diagnosis of the autosomal recessive lysosomal storage disorder mucolipidosis type III gamma. Mucolipidosis type III gamma is typically diagnosed during childhood due to symptoms relating to skeletal dysplasia. Retinal dystrophy is not a common phenotypic feature., Case Presentation: Ophthalmologic examination was consistent with a mild form of retinitis pigmentosa and included fundus photography, measurement of best-corrected visual acuity, optical coherence tomography, electroretinogram and visual field testing. Extraocular findings included joint restriction and pains from an early age leading to bilateral hip replacement by age 30, aortic insufficiency, and hypertension. Genetic analysis was performed by whole genome sequencing filtered for a gene panel of 325 genes associated with retinal disease. Two compound heterozygous pathogenic variants were identified in GNPTG, c.347_349del and c.607dup. The diagnosis of mucolipidosis type III gamma was confirmed biochemically by measurement of increased activities of specific lysosomal enzymes in plasma., Conclusion: To our knowledge this is the first description of retinitis pigmentosa caused by compound heterozygous variants in GNPTG, providing further indications that late-onset retinal dystrophy is part of the phenotypic spectrum of mucolipidosis type III gamma., (© 2023. The Author(s).)

Health professions education places significant emphasis on learning in the clinical environment. While experiences of workplace learning have been extensively investigated, practices of workplace learning explored through field work have been less utilized. The theoretical framework of teaching and learning regimes acknowledges aspects of power and conflict in its consideration of what guides teachers and learners in their practice of workplace learning. This study aimed to explore practices of workplace learning in the two adjacent healthcare professions; medicine and nursing. We adopted an ethnographic qualitative design. Field observations and follow-up interviews were performed in three clinical departments and the data set comprised 12 full days of observations and 16 formal follow-up interviews. Thematic analysis was performed deductively according to the theoretical framework. Four teaching and learning regimes were found in the data. In the medical context, workplace learning was either practiced as reproduction of current practice or through stimulation of professional development. In the nursing context, workplace learning was either based on development of partnership between student and supervisor or on conditional membership in a professional community. The medical and nursing contexts demonstrated varying underpinnings and assumptions relating to teaching and learning. The respective practices of workplace learning in the medical and nursing context appear to hold substantial differences which might have implications for how we understand practices of workplace learning. We further conclude that the theoretical framework of teaching and learning regimes in this study proved useful in exploring workplace learning., (© 2022. The Author(s).)

Objectives: Many universities offer faculty development to support teachers in developing and improving clinical education in the health professions. Although research shows outcomes on individual levels after faculty development, little is known about its contribution to change within the organisation. To advance current faculty development and ensure that it can support wider educational change in healthcare organisations, a better understanding of educational change practices in these settings is needed. This study therefore explores the experiences of working with educational change in clinical workplaces from the perspective of clinical educators that have undergone faculty development training. The study adopts perspectives on change as influenced by context to include the impact from clinical workplaces on individuals' change work., Methods: A collective case study design with a multi-institutional approach was applied and individual interviews with 14 clinical educators from two universities, one in Sweden and one in South Africa, were conducted. Data were analysed separately before a cross-case analysis was performed, synthesising the findings from both sites., Findings: Participants shared experiences of having limited opportunities to work with educational change beyond their own individual teaching practices within their clinical workplaces. Also, participants appeared to refrain from leading change and rather pursued change on their own or relied on indirect approaches to change. They described several workplace aspects influencing their work, including the organisation and management of teaching, the resources and incentives for teaching and the attitudes and beliefs about teaching within the clinical community., Conclusions: The study shows that clinical educators are part of communities and contexts that shape their approaches to educational change and influence which changes are feasible and which ones are not. It thus adds to the understanding of change as contextual and dynamic and contributes with implications for how to advance faculty development to better support change in practice., (© 2022 The Authors. Medical Education published by Association for the Study of Medical Education and John Wiley & Sons Ltd.)

Heritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (<70 years if hypertensive; all ages if non-hypertensive), (2) thoracic aortic aneurysm (all adults with Z score >3.5 or 2.5-3.5 if non-hypertensive or hypertensive and <60 years; all children with Z score >3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics., Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421)., Results: The diagnostic yield was 35% (GS-first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed., Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time- and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients., Competing Interests: Conflict of Interest An.L. received honoraria from Illumina, Inc. All other authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Approximately 5% of patients with colorectal cancer (CRC) have a Mendelian predisposition for the disease. Identification of the disease-causing genetic variant enables carrier testing and tailored cancer prevention within affected families. To determine the panorama and genetic variation of Mendelian CRC syndromes among referrals at the cancer genetics clinics in Sweden, 850 patients clinically selected for CRC genetic investigation were included in a prospective study that tested for all major hereditary polyposis and nonpolyposis CRC conditions. Genetically defined syndromes were diagnosed in 11% of the patients. Lynch syndrome was predominant (n = 73) followed by familial adenomatous polyposis (n = 12) and MUTYH-associated polyposis (n = 8); the latter of which two patients presented with CRC before polyposis was evident. One patient with a history of adolescent-onset CRC and polyposis had biallelic disease-causing variants diagnostic for constitutional mismatch repair deficiency syndrome. Post-study review of detected variants of unknown clinical significance (n = 129) resulted in the reclassification of variants as likely benign (n = 59) or as diagnostic for Lynch syndrome (n = 2). Our results reveal the panorama of Mendelian CRC syndromes at the cancer genetics clinics in Sweden and show that unified testing for polyposis and nonpolyposis CRC conditions as well as regular reexamination of sequence data improve the diagnostic yield., (© 2022 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

Birt-Hogg-Dube syndrome (BHDS) (MIM: 135150) is a rare autosomal dominant disorder with variable penetrance, caused by pathogenic variants in the FLCN gene. Only a few hundreds of families have so far been described in the literature. Patients with BHDS present with three distinct symptoms: fibrofolliculomas, pneumothorax due to lung cyst formation, and increased lifetime risk of kidney tumours. The aim of the current study was to estimate the incidence of BHDS in the Swedish population and further describe the clinical manifestations and their frequency. Splice variant c.779+1G>T was the most common pathogenic variant, found in 57% of the families, suggesting this may be a founder mutation in the Swedish population. This was further investigated using haplotype analysis in 50 families that shared a common haplotype. Moreover, according to gnomAD the carrier frequency of the c.779+1G>T variant has been estimated to be 1/3265 in the Swedish population, however our data suggest that the carrier frequency in the Swedish population may be significantly higher. These findings should raise awareness among physicians of different specialties to patients presenting with fibrofolliculomas, pneumothorax and/or kidney tumours. We also stress the importance of consensus recommendations regarding diagnosis and clinical management of this, not that uncommon, syndrome., Competing Interests: The authors have declared that no competing interests exist.

Medical specialists' lifelong learning is essential for improving patients' health. This study identifies affordances for learning general practitioners (GPs) engage in, and explores what influences engagement in those affordances. Eleven GPs were interviewed and the interview transcripts were analysed thematically. Stephen Billett's theoretical framework of workplace participatory practices was used as an analytical lens to explore the topic. Challenging patient cases were identified as the main trigger for engagement in learning. Local, national and international colleagues from the same and other specialties, were found to be an important affordance for learning, as was written material such as websites, journals and recommendations. Other inputs for learning were conferences and courses. Workplace aspects that were essential for GPs to engage in learning related to: place and time to talk, relevance to work, opportunity for different roles, organisation of work and workload, and working climate. Importantly, the study identifies a need for a holistic approach to lifelong learning, including spontaneous and structured opportunities for interaction over time with colleagues, establishment of incentives and arenas for exchange linked to peer learning, and acknowledgement of the workplace as an important place for learning and sufficient time with patients. This study contributes with a deepened understanding of how GPs navigate existing affordances for learning both within and outside their workplaces., Competing Interests: Conflicts of interestThe authors have no conflicts of interest to declare that are relevant to the content of this article.Competing InterestsAuthors are required to disclose financial or non-financial interests that are directly or indirectly related to the work submitted for publication. Please refer to “Competing Interests and Funding” below for more information on how to complete this section., (© The Author(s) 2022.)

An overview of the research literature about physicians' continuing development was conducted and shows that formal learning activities often target individuals and their development, and focus on increasing knowledge and influencing attitudes. Research studies showing changes in practice are less common. Regulated continuous medical education may lead to instrumental approaches to learning. Informal learning occurs continuously during work, is often spontaneous and focussed on problem solving. Patients and colleagues as well as the physical and social environment provide opportunities for learning. Organizations can offer time and space to facilitate physicians' continuing development, enabling possibilities for formal and informal sharing of knowledge to take place, for example, by enabling collegial discussions.

Background: Fetoplacental discrepancies occur in approximately 1-2% of analyzed prenatal cases. They are typically due to confined placental mosaicism, where an aberration is observed in the placental cells but not found in the fetal cells. Confined placental mosaicism usually involves aneuploidies and more sparsely structural chromosomal aberrations. To the best of our knowledge, this is the first reported case of a discrepancy in the analyses of chorionic villus sampling and amniocentesis involving two different structural chromosomal aberrations of chromosome 21., Case Presentation: We report a 33-year-old woman who was referred for a non-invasive prenatal testing due to an increased risk of trisomy 21 gleaned from a combined ultrasound and blood test. The non-invasive prenatal testing showed an increased risk of trisomy 21 with a normalized coverage signal that did not match the fetal cell-free DNA fraction. Rapid aneuploidy detection performed on uncultured chorionic villi indicated mosaicism for trisomy 21. The follow-up analyses revealed discordant chromosomal aberrations: 46,XY,der(21)t(10;21)(p11.21;q10) in the analysis of the chorionic villus sampling and 46,XY, + 21,der(21;21)(q10;q10) in the analysis of the amniocentesis. Thus, the analyses indicated mosaicism for a cell line containing trisomy 21 and a cell line containing a partially duplicated short arm of chromosome 10 in the chorionic villi and complete trisomy 21 resulting from an isochromosome 21 in the amniotic fluid. The analyses of the lymphocytes and the fibroblasts of the woman were normal., Conclusions: We propose a multiple-step mechanism as a possible theoretical explanation for the formation of these discordant structural chromosomal aberrations in the chorionic villi and amniotic fluid. With this case report, we want to highlight the importance of understanding the possible underlying embryological mechanisms when interpreting results from different prenatal analyses.

Background: We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting., Methods: Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams., Results: Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange., Conclusions: Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

Background: Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today's clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance., Methods: This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994-September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation., Results: A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time., Conclusion: A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.

Background: Faculty development is important for advancing teaching practice in health professions education. However, little is known regarding how faculty development outcomes are achieved and how change in practice may happen through these activities. In this study, we explored how clinical educators integrated educational innovations, developed within a faculty development programme, into their clinical workplaces. Thus, the study seeks to widen the understanding of how change following faculty development unfolds in clinical systems., Methods: The study was inspired by case study design and used a longitudinal faculty development programme as a case offering an opportunity to study how participants in faculty development work with change in practice. The study applied activity theory and its concept of activity systems in a thematic analysis of focus group interviews with 14 programme attendees. Participants represented two teaching hospitals, five clinical departments and five different health professions., Results: We present the activity systems involved in the integration process and the contradiction that arose between them as the innovations were introduced in the workplace. The findings depict how the faculty development participants and the clinicians teaching in the workplace interacted to overcome this contradiction through iterative processes of negotiating a mandate for change, reconceptualising the innovation in response to workplace reactions, and reconciliation as temporary equilibria between the systems., Conclusion: The study depicts the complexities of how educational change is brought about in the workplace after faculty development. Based on our findings and the activity theoretical concept of knotworking, we suggest that these complex processes may be understood as collaborative knotworking between faculty development participants and workplace staff through which both the output from faculty development and the workplace practices are transformed. Increasing our awareness of these intricate processes is important for enhancing our ability to make faculty development reach its full potential in bringing educational change in practice.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.

Heterozygous missense or in-frame insertion/deletion mutations in complement 1 subunits C1r and C1s cause periodontal Ehlers-Danlos Syndrome (pEDS), a specific EDS subtype characterized by early severe periodontal destruction and connective tissue abnormalities like easy bruising, pretibial haemosiderotic plaques, and joint hypermobility. We report extensive functional studies of 16 C1R variants associated with pEDS by in-vitro overexpression studies in HEK293T cells followed by western blot, size exclusion chromatography and surface plasmon resonance analyses. Patient-derived skin fibroblasts were analyzed by western blot and Enzyme-linked Immunosorbent Assay (ELISA). Overexpression of C1R variants in HEK293T cells revealed that none of the pEDS variants was integrated into the C1 complex but cause extracellular presence of catalytic C1r/C1s activities. Variants showed domain-specific abnormalities of intracellular processing and secretion with preservation of serine protease function in the supernatant. In contrast to C1r wild type, and with the exception of a C1R missense variant disabling a C1q binding site, pEDS variants had different impact on the cell: retention of C1r fragments inside the cell, secretion of aggregates, or a new C1r cleavage site. Overexpression of C1R variants in HEK293T as well as western blot analyses of patient fibroblasts showed decreased levels of secreted C1r. Importantly, all available patient fibroblasts exhibited activated C1s and activation of externally added C4 in the supernatant while control cell lines secreted proenzyme C1s and showed no increase in C4 activation. The central elements in the pathogenesis of pEDS seem to be the intracellular activation of C1r and/or C1s, and extracellular presence of activated C1s that independently of microbial triggers can activate the classical complement cascade., (Copyright © 2019 Gröbner, Kapferer-Seebacher, Amberger, Redolfi, Dalonneau, Björck, Milnes, Bally, Rossi, Thielens, Stoiber, Gaboriaud and Zschocke.)

Purpose: This study aims to explore the role of three specific factors within the child-environment interaction process - engagement, independence and social interactions - in influencing development and learning of children with disabilities in inclusive preschool settings. The main question is whether children can be categorised in homogenous groups based on engagement, independence and social interactions (proximal variables within a biopsychosocial framework of human development). The study also examined whether children with the same diagnosis would group together or separately, when trying to identify clusters of engagement, independence and social interactions, and additionally whether such clusters vary as a function of individual child characteristics, and/or as a function of structural and process characteristics of preschool environment. Methods: Data was taken from an intervention study conducted in mainstream preschools in Portugal. A person-centered cluster analysis was conducted to explore group membership of children with various diagnoses, based on their engagement, independence and social interaction profiles. Results: Results show that children clustered based on similarity of engagement, independence and social interaction patterns, rather than on diagnosis. Besides, it was found that quality of peer interaction was the only predictor of cluster membership. Conclusion: These findings support the argument that participation profiles may be more informative for intervention purposes than diagnostic categories, and that preschool process quality, namely peer interaction, is crucial for children's participation.

Many medical universities offer educational development activities to support clinical teachers in their teaching role. Research has focused on the scope and effectiveness of such activities and on why individual teachers attend. However, systemic perspectives that go beyond a focus on individual participants are scarce in the existing literature. Employing activity theory, we explored how clinical teachers' engagement in educational development was affected by the systems they act within. Three focus groups were held with clinical teachers from different professions. A thematic analysis was used to map the contradictions between the systems that the participants were part of and the manifestations of these contradictions in the system of education. In our model, clinical teachers were part of three activity systems directed by the objects of patient care, research and education respectively. Contradictions arose between these systems as their objects were not aligned. This manifested through the enacted values of the academic hospital, difficulties establishing educational discussions in the clinical workplace, the transient nature of educational employments, and impediments to developing a teacher identity. These findings offer insights into the complexities of engaging in educational development as clinical teachers' priorities interact with the practices and values of the academic hospital, suggesting that attention needs to shift from individual teachers to developing the systems in which they work.

Background: Lynch Syndrome is an autosomal dominant cancer syndrome caused by pathogenic germ-line variants in one of the DNA-mismatch-repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 . Carriers are predisposed to colorectal and endometrial cancer, but also other cancer types. The purpose of this retrospective study was to characterize the tumour spectrum of the Swedish Lynch syndrome families., Methods: Data were obtained from genetically verified 235 Lynch families from five of the six health care regions in Sweden. The material was stratified for gender, primary cancer, age and mutated gene and the relative proportions of specific cancer types were compared to those in the general population., Results: A total of 1053 family members had 1493 cancer diagnoses of which 1011 were colorectal or endometrial cancer. Individuals with pathogenic variants in MLH1 and MSH2 comprised 78% of the cohort. Among the 482 non-colorectal/non-endometrial cancer diagnoses, MSH2 carriers demonstrated a significantly increased proportion of urinary tract, gastric, small bowel, ovarian and non-melanoma skin cancer compared to the normal population. MLH1 carriers had an elevated proportion of gastrointestinal cancers (gastric, small bowel, pancreas), while MSH6 carriers had more ovarian cancer than expected. Gastric cancer was predominantly noted in older generations., Conclusion: Lynch syndrome confers an increased risk for multiple cancers other than colorectal and endometrial cancer. The proportions of other cancers vary between different MMR genes, with highest frequency in MSH2 -carriers. Gender and age also affect the tumour spectrum, demonstrating the importance of additional environmental and constitutional parameters in determining the predisposition for different cancer types., Competing Interests: None.The study was approved by the Regional Ethical Review Board in Stockholm, Sweden. Diary number 2002–241 and Diary number 2014–1320-31.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Individuals with a history of colorectal or endometrial cancer younger than 50 years of age or with relatives younger than 50 years of age with a history of any of these malignances should be referred to clinical genetics for further diagnostic examinations and genetic counseling. Lynch syndrome is caused by mutations in mismatch repair genes and implicates an increased risk for colorectal cancer as well as endometrial cancer. Routine surveillance for this group of individuals regarding colorectal cancer by means of colonoscopy and endometrial cancer by means of transvaginal ultrasound as well as endometrial biopsies is recommended annually or biennially. Several preventive measures are under development, such as chemoprevention and vaccination. During 2015 we investigated reasons for diagnosis among those registered at Karolinska University Hospital. We found that a substantial part of this group of individuals was diagnosed in conjunction with their diagnosis of cancer; a prerequisite in order to offer at-risk individuals preventive measures is to improve identification of these individuals and offer them presymptomatic genetic testing in order to identify predisposing mutations.

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Belongingness has been argued to be a prerequisite for students' learning in the clinical setting but making students feel like they belong to the workplace is a challenge. From a sociocultural perspective, workplace participatory practices is a framework that views clinical learning environments to be created in interaction between students and the workplace and hence, are dependent on them both. The aim of this study was to explore the interdependence between affordances and engagement in clinical learning environments. The research question was: How are nursing students influenced in their interactions with clinical learning environments?, Methods: An observational study with field observations and follow-up interviews was performed. The study setting comprised three academic teaching hospitals. Field observations included shadowing undergraduate nursing students during entire shifts. Fifty-five hours of field observations and ten follow-up interviews with students, supervisors and clinical managers formed the study data. A thematic approach to the analysis was taken and performed iteratively with the data collection., Results: The results revealed that students strived to fill out the role they were offered in an aspirational way but that they became overwhelmed when given the responsibility of care. When students' basic values did not align with those enacted by the workplace, they were not willing to compromise their own values. Workplaces succeeded in inviting students into the community of nurses and the practice of care. Students demonstrated hesitance regarding their desire to belong to the workplace community., Conclusion: The results imply that the challenge for clinical education is not to increase the experience of belongingness but to maintain students' critical and reflective approach to health care practice. Additionally, results suggest students to be included as an important stakeholder in creating clinical learning environments rather than being viewed as consumer of clinical education.

Aim: Surveillance with colonoscopy in risk groups for colorectal cancer needs to be based on an adequate selection of individuals to examine and a well-devised timing. To stratify the risk of finding neoplasia at colonoscopy, a cohort with increased familial risk of colorectal cancer was studied., Patients and Methods: Based on family history, 1,203 individuals with at least two-fold increased risk of colorectal cancer were offered regular colonoscopies. The impact of different variables in the family history was assessed by logistic regression for the prevalence of adenoma and advanced adenoma. Findings at first colonoscopy were assessed regarding the association with risk of future lesions., Results: The prevalence of advanced lesions, when controlling for age, was associated with the number of first-degree relatives with colorectal cancer, with an age below 50 years for the youngest family member with colorectal cancer, but not with gender. Family history had a low impact on the prevalence of simple adenoma. The risk of future advanced lesions was only associated with the prevalence of advanced lesions at the screening colonoscopy, whereas a finding of subsequent adenoma was associated with advanced lesions, adenomas and hyperplastic polyps., Conclusion: Adenomas and advanced lesions were not associated with the same risk factors. In the present study, the most important risk factors for advanced lesions, including cancer, were the number of first-degree relatives and a young family member with colorectal cancer. Findings of simple adenomas and hyperplastic polyps did not seem to be associated with subsequent advanced lesions., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background and Aims: There is clear evidence of reduced morbidity and mortality from regular colonoscopy programs in patients with Lynch syndrome (LS). Today, also individuals with empirically increased risks of colorectal cancer (CRC) are offered colonoscopic surveillance. The aim was to compare the findings at the first screening colonoscopy in LS carriers, and individuals with an increased risk of bowel cancer due to family history of CRC with a control population., Methods: Altogether 1397 individuals with an increased risk for CRC were divided in four risk groups: one with LS carriers and three groups with individuals with different family history of CRC. The findings were compared between the different risk groups and a control group consisting of 745 individuals from a control population who took part in a population-based colonoscopy study., Results: In LS, 30% of the individuals had adenomas and 10% advanced adenomas. The corresponding figures in the other risk groups were 14-24% and 4-7%, compared with 10% and 3% in the control group. The relative risk of having adenomas and advanced adenomas was, compared to controls, significantly higher for all risk groups except the group with the lowest risk. Age was a strong predictor for adenomas and advanced adenomas in both risk individuals and controls., Conclusions: Individuals with a family history of CRC have a high prevalence and cumulative risk of adenomas and advanced adenomas, and screening is motivated also in this risk group.

The aim of this study was to study the intrinsic system behind interprofessional clinical learning environments. Two health care units were selected on the basis of having received a reward for best clinical learning organization. Interviews were carried out with health care staff/clinical supervisors from different professions. The interviews were transcribed and analysed according to qualitative content analysis, and categories and themes were identified. Analysis revealed two different systems of clinical learning environments. In one, the interplay between the structural aspects dominated, and in the other, the interplay between the cultural aspects dominated. An important similarity between the environments was that a defined role for students in the organization and interprofessional teamwork around supervision across professional borders was emphasized.

Purpose: The aim of this article is to examine the component of "personal factors" described as a contextual factor in the ICF and ICF-CY., Methods: A critical examination of the construct of "personal factors" and description of the component was made with reference to conceptual and taxonomic criteria., Results: The "personal factors" component in the ICF/ICF-CY is not defined, there is no taxonomy of codes, there is no explicit purpose stated for its use and no guidelines are provided for its application. In spite of these constraints, the component of "personal factors" is being applied as part of the classifications. Such uncontrolled applications constitute significant risks for the status of ICF/ICF-CY as the WHO reference classification in that: (a) the component is accepted for use by default simply by being applied; (b) component content is expanded with idiosyncratic exemplars by users; and (c) there is potential misuse of "personal factors" in documenting personal attributes, including "blaming the victim"., Conclusion: In the absence of formal codes, any application of the component of "personal factors" lacks the legitimacy that documentation with a scientific taxonomy should provide. Given the growing use of the ICF/ICF-CY globally, a priority for the revision process should be to determine if there is in fact need for "personal" or any other factors in the ICF/ICF-CY., Implications for Rehabilitation: A central contribution of the ICF/ICF-CY is the universal language of codes for the components of body structure, body function, activities and participation and Environmental Factors. As such the codes provide taxonomical legitimacy and power for documenting dimensions of functioning and disability in clinical and rehabilitation contexts. As there are no codes of "personal factors", there is no basis for documentation of the component. Demographic information, if needed for identification, should be recorded in customary formats, independent of any component or codes of the ICF/ICF-CY.

Aims: To investigate the perceived impact of oral health-related quality of life problems in individuals with Ehlers-Danlos syndrome., Methods: Members of the Swedish Ehlers-Danlos Syndrome Association completed the Oral Health Impact Profile (OHIP-14). Of the 250 participating individuals, 223 were women, and they were the main focus of the analyses. The results were compared with a previous study of the oral health impact on quality of life in the Swedish population. Statistical methods used for comparison were the Student t and chi-square tests., Results: The mean OHIP-14 value for the entire Ehlers-Danlos syndrome group was 11.1. The mean for women was 11.8, which was significantly higher than 6.8 of the comparison group. The OHIP-14 score varied among age groups, and the highest mean value was found in the age group between 56 and 65 years of age. The most statistically significant differences between the subjects with Ehlers-Danlos syndrome and the comparison group were found for OHIP items 3, 4, and 8: "I have had pain in the mouth," "I have had discomfort when eating," and "I have been forced to interrupt meals.", Conclusion: It is well-known that Ehlers-Danlos syndrome has a considerable impact on health-related quality of life, and this study is the first to reveal that women with Ehlers-Danlos syndrome report a low oral health-related quality of life as measured with the OHIP-14. Dimensions that were particularly relevant were physical pain, psychologic discomfort, and handicap.

The tumor suppressor adenomatous polyposis coli (APC) has recently been implicated in parathyroid development. We here report clinical, histopathological and molecular investigations in parathyroid tumors arising in two patients; one familial adenomatous polyposis (FAP) syndrome patient carrying a constitutional APC mutation, and one Lynch syndrome patient demonstrating a germline MLH1 mutation as well as a non-classified, missense alteration of the APC gene. We sequenced the entire APC gene in tumor and constitutional DNA from both cases, assessed the levels of APC promoter 1A and 1B methylation by bisulfite Pyrosequencing analysis and performed immunohistochemistry for APC and parafibromin. In addition, copy number analysis regarding the APC gene on chromosome 5q21-22 was performed using qRT-PCR. Histopathological workup confirmed both tumors as parathyroid adenomas without signs of malignancy or atypia. No somatic mutations or copy number changes for the APC gene were discovered in the tumors; however, in both cases, the APC promoter 1A was hypermethylated while the APC promoter 1B was unmethylated. APC promoter 1B-specific mRNA and total APC mRNA levels were higher than in normal parathyroid samples. Immunohistochemical analyses revealed strong APC protein immunoreactivity and positive parafibromin expression in both parathyroid tumors. Absence of additional somatic APC mutations and copy number changes in addition to the positive APC immunoreactivity obtained suggest that the tumors arose without biallelic inactivation of the APC tumor suppressor gene. The finding of an unmethylated APC promoter 1B and high APC 1B mRNA levels could explain the maintained APC protein expression. Moreover, the findings of positive parafibromin and APC immunoreactivity as well as a low MIB-1 proliferation index and absence of histopathological features of malignancy/atypical adenoma indicate that the parathyroid adenomas arising in these patients did not harbor malignant potential.