Genetic study of cognitive function

Dissecting the genetics of Alzheimer’s disease (AD) and Parkinson’s disease (PD) has contributed significantly to our understanding of the pathogenesis of neurodegeneration in these two complex disorders. For AD, three highly penetrant genes (APP, PSEN1 and PSEN2) and one susceptibility gene (APOE) have been identified. For PD, seven genes (SNCA, Parkin, UCHL1, NR4A2, DJ1, PINK1 and LRRK2) have been found. These genes explain only a small proportion of AD and PD patients and are mostly associated with an early onset presentation of the disease. APOE remains the only common gene, which increases the risk of both rare early and late onset AD. The ongoing challenge is to unravel the genetics of the most frequent forms of these complex disorders. In the present paper, we briefl y review the state of the art in the genetics of AD and PD. We also discuss the prospects of finding new genes associated with common forms of these diseases in light of two hypotheses concerning the genetic variation of complex diseases: common disease/ common variants and common disease/rare variants

Predicting keratinocyte carcinoma in patients with actinic keratosis: development and internal validation of a multivariable risk-prediction model

Background: Patients with actinic keratosis (AK) are at increased risk for developing keratinocyte carcinoma (KC) but predictive factors and their risk rates are unknown. Objectives: To develop and internally validate a prediction model to calculate the absolute risk of a first KC in patients with AK. Methods: The risk-prediction model was based on the prospective population-based Rotterdam Study cohort. We hereto analysed the data of participants with at least one AK lesion at cohort baseline using a multivariable Cox proportional hazards model and included 13 a priori defined candidate predictor variables considering phenotypic, genetic and lifestyle risk factors. KCs were identified by linkage of the data with the Dutch Pathology Registry. Results: Of the 1169 AK participants at baseline, 176 (15·1%) developed a KC after a median follow-up of 1·8 years. The final model with significant predictors was obtained after backward stepwise selection and comprised the presence of four to nine AKs [hazard ratio (HR) 1·68, 95% confidence interval (CI) 1·17–2·42], 10 or more AKs (HR 2·44, 95% CI 1·65–3·61), AK localization on the upper extremities (HR 0·75, 95% CI 0·52–1·08) or elsewhere except the head (HR 1·40, 95% CI 0·98–2·01) and coffee consumption (HR 0·92, 95% CI 0·84–1·01). Evaluat

The influence of treatment in alpine and moderate maritime climate on the composition of the skin microbiome in patients with difficult to treat atopic dermatitis

Background: The skin microbiome, characterized by an overgrowth of Staphylococcus aureus, plays an important role in the pathogenesis of atopic dermatitis (AD). Multidisciplinary treatment in alpine climate is known for its positive effect on disease severity in children with AD and can result in a different immune response compared with moderate maritime climate. However, the effect on the composition of the skin microbiome in AD is unknown. Objective: To determine the effect of treatment in alpine climate and moderate maritime climate on the microbiome for lesional and non-lesional skin in children with difficult to treat AD. Results: Alpine climate treatment led to a significant change in the microbiota on lesional skin, whereas no significant change was found after moderate maritime climate. On both lesional and non-lesional skin, we observed a significant increase in Shannon diversity and a significant decrease in both Staphylococcus abundance and S aureus load after alpine climate treatment. The decrease in S aureus was significantly larger on lesional skin following alpine climate treatment compared with moderate maritime climate treatment. Staphylococcus epidermidis load was stable over time. Conclusions and clinical relevance: Alpine climate treatment leads to significant changes in the composition of the skin microbiome in children with AD, mainly caused by a reduction in the Staphylococcus genus. This study shows new perspectives in the potential mode of action for therapies in AD

Differences in rate of complete excision of basal cell carcinoma by dermatologists, plastic surgeons and general practitioners

__Background:__ Due to the increasing incidence of basal cell carcinoma (BCC) and rising health care costs, health care insurance companies seek ways to shift skin surgery for BCC from secondary to primary care. __Objectives:__ To study the differences in complete excision of BCC by general practitioners (GPs), dermatologists, and plastic surgeons. Methods: A retrospective cross-sectional study of pathology records of 2,986 standard excisions of primary BCCs performed by a GP, dermatologist, or plastic surgeon in the area of Southwest Netherlands between 2008 and 2014. To compare the risk of an incomplete BCC excision between the specialties, the odds ratio (OR) was used adjusted for patient age, sex, tumor site, size, and histological subtype. __Results:__ BCCs were completely excised by GPs in 70%, which was lower than the 93% by dermatologists and 83% by plastic surgeons (p < 0.001). Compared to the dermatologist, BCCs which were excised by a GP were 6 times higher at risk of an incomplete excision (adjusted OR 6, 95% CI 5-8) and 2 times higher at risk when excised by a plastic surgeon (adjusted OR 2, 95% CI 2-3). __Conclusion:__ BCCs were more often completely exc

A variant of the castor zinc finger 1 (CASZ1) gene is differentially associated with the clinical classification of chronic venous disease

Recent reports have suggested a reproducible association between the rs11121615 SNP, located within an intron of the castor zinc finger 1 (CASZ1) gene, and varicose veins. This study aimed to determine if this variant is also differentially associated with the various clinical classifications of chronic venous disease (CVD). The rs11121615 SNP was genotyped in two independent cohorts from New Zealand (n = 1876 controls /1606 CVD cases) and the Netherlands (n = 1626/2966). Participants were clinically assessed using well-established CVD criteria. The association between the rs11121615 C-allele and varicose veins was validated in both cohorts. This was strongest in those with higher clinical severity classes and was not significant in those with non-varicose vein CVD. Functional analysis of the rs11121615 variant demonstrated that the risk allele was associated with increased enhancer activity. This study demonstrates that the CASZ1 gene associated C-allele of rs11121615 has a significant, reproducible, association with CVD (CEAP C ≥ 2 meta-odds ratio 1.31, 95% CI 1.27-1.34, P = 1 × 10-98, PHet = 0.25), but not with non-varicose vein (CEAP C1, telangiectasia or reticular veins) forms of venous disease. The effect size of this association therefore appears to be susceptible to influence by phenotypic heterogeneity, particularly if a cohort includes a large number of cases with lower severity CVD

Democratic Leadership - A local story

Leadership is traditionally viewed as an individual property and researched from the perspective of behaviours, traits or characteristics that these individuals possess. Notions of democratic leadership can offer early childhood centres a more expansive conception of leadership to include children, teachers and families. This study explores the possibility of positioning all stakeholders in an early childhood centre as leaders by repositioning leadership as a jointly constructed, emergent process. Drawing on an existing feature of the kindergarten programme, that of regular excursions within the local community, connections are interwoven between children’s inquires, democratic principles and elements of place based education. Using narratives from five excursions in the local community the study experiments with Leadership-as-practice to analyse how these excursions fostered democratic and inclusive participation of children and adults. Inquiry as a form of participatory democracy is a key feature of decision-making and provides a common purpose for community excursions while encouraging leadership opportunities. The study reveals the potential of leadership-as-practice, underpinned by democratic values as an approach to leadership in early childhood organisations, enabling leader/follower roles to be blurred and learning to be co constructed during dialogue. The local community holds enormous capacity as a system to facilitate democratic leadership and promote place based learning and citizenship education. This study recognises that democratic leadership exists in tension with current neo liberal beliefs and therefore positions itself as a counter to the current market driven early childhood environment. The underlying belief of this study is that leadership can occur as a collaborative practice, emerging through day to day experiences and seeks to contribute to the slowly emerging body of research concerned with early childhood leadership.

Genome-wide meta-analysis identifies eight new susceptibility loci for cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (SCC) is one of the most common cancers in the United States. Previous genome-wide association studies (GWAS) have identified 14 single nucleotide polymorphisms (SNPs) associated with cutaneous SCC. Here, we report the largest cutaneous SCC meta-analysis to date, representing six international cohorts and totaling 19,149 SCC cases and 680,049 controls. We discover eight novel loci associated with SCC, confirm all previously associated loci, and perform fine mapping of causal variants. The novel SNPs occur within skin-specific regulatory elements and implicate loci involved in cancer development, immune regulation, and keratinocyte differentiation in SCC susceptibility

Design, implementation and initial findings of COVID-19 research in the Rotterdam Study

The Rotterdam Study is an ongoing prospective, population-based cohort study that started in 1989 in the city of Rotterdam, the Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. It focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. In response to the COVID-19 pandemic, a substudy was designed and embedded within the Rotterdam Study. On the 20th of April, 2020, all living non-institutionalized participants of the Rotterdam Study (n = 8732) were invited to participate in this sub-study by filling out a series of questionnaires administered over a period of 8 months. These questionnaires included questions on COVID-19 related symptoms and risk factors, characterization of lifestyle and mental health changes, and determination of health care seeking and health care avoiding behavior during the pandemic. As of May 2021, the questionnaire had been sent out repeatedly for a total of six times with an overall response rate of 76%. This article provides an overview of the rationale, design, and implementation of this sub-study nested within the Rotterdam Study. Finally, initial results on participant characteristics and prevalence of COVID-19 in this community-dwelling population are shown.</p

Mutations in a TGF-β Ligand, TGFB3, Cause Syndromic Aortic Aneurysms and Dissections

BACKGROUND Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-b signaling. OBJECTIVES This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-b signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-b signaling in association with up-regulation of the expression of TGF-b ligands. CONCLUSIONS Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk