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1.
Sci Rep ; 9(1): 14011, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31570750

RESUMO

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.

2.
BMJ Open ; 9(8): e028689, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31462472

RESUMO

INTRODUCTION: Diagnosing psoriasis in children can be challenging. Early and accurate diagnosis is important to ensure patients receive psoriasis specific treatment and monitoring. It is recognised that the physical, psychological, quality of life, financial and comorbid burden of psoriasis are significant. The aim of this study is to develop clinical examination and history-based diagnostic criteria for psoriasis in children to help differentiate psoriasis from other scaly inflammatory rashes. The criteria tested in this study were developed through a consensus study with a group of international psoriasis experts (International Psoriasis Council). METHODS AND ANALYSIS: Children and young people (<18 years) with psoriasis (cases) and other scaly inflammatory skin diseases (controls) diagnosed by a dermatologist are eligible for recruitment. All participants complete a single research visit including a diagnostic criteria assessment by a trained investigator blinded to the participant's diagnosis. The reference standard of a dermatologist's diagnosis is extracted from the medical record. Sensitivity and specificity of the consensus derived diagnostic criteria will be calculated and the best predictive criteria developed using multivariate logistic regression. ETHICS AND DISSEMINATION: Health Regulatory Authority and National Health Service Research Ethics Committee approvals were granted in February 2017 (REC Ref: 17/EM/0035). Dissemination will be guided by stakeholders; patients, children and young people, dermatologists, primary care and paediatric rheumatologists. The aim is to publish the study results in a high-quality peer-reviewed journal, present the findings at international academic meetings and disseminate more widely through social media and working with patient associations. TRIAL REGISTRATION NUMBER: ISRCTN98851260.

4.
Eur J Vasc Endovasc Surg ; 58(2): 230-242, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230868

RESUMO

OBJECTIVES: The objective of this systematic review and meta-analysis was to summarise available randomised controlled trials (RCTs) of EVLA efficacy, and to define the differences in success rate of variations in wavelength, administered energy, outcome definition, and follow up period. METHODS: A literature search was conducted in Embase, Medline (Ovid-SP), Cochrane Central Database, and Web of Science from inception to November 2017. RCTs with follow up of more than three months were included. The studied outcome was the proportion of patients with EVLA treatment success, defined as absence of reflux or occlusion of the great saphenous vein (GSV). Pooled proportions of anatomical success were compared. Subgroup and meta-regression analysis included wavelengths (short [810, 940, and 980 nm], long [1470, 1500, and 1920 nm]), amount of energy (≤50 J/cm, > 50 J/cm), follow up (≤1 year, > 1 year), outcome definition (occlusion, no reflux), and quality of the studies (low risk of bias, unclear/high risk of bias). RESULTS: Twenty-eight RCTs, with a total of 2829 GSVs were included. The overall success rate of EVLA was 92% (95% CI 90-94%, I2 = 68%). In subgroup analysis, no statistically significant differences were found for long or short wavelengths (95% [95% CI 91-97%] vs. 92% [95% CI 89-94%], p = .15), high or low administered energy (93% [95% CI 89-95%] vs. 92% [95% CI 90-94%], p = .99), long or short follow up (89% [95% CI 84-93%] vs. 93% [95% CI 91-95%], p = .13) and outcome definition (occlusion group 94% [95% CI 91-96%] vs. absence of reflux group 91% [95% CI 87-94%], p = .26). Studies with low risk of bias reported a significantly higher success rate than high or unclear risk of bias (93% [95% CI 90-95%] vs. 89% [95% CI 83-93%], p = .04). CONCLUSIONS: The overall success rate of EVLA is high (92%), even with increasing follow up. Commonly used parameters of EVLA (wavelength, administered energy, and outcome definition) have no influence on the treatment success rate.

8.
J Natl Cancer Inst ; 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30802904

RESUMO

BACKGROUND: Skin cancer is common after radiotherapy among childhood cancer survivors (CCSs). We studied risks and risk factors for subsequent skin cancers, with emphasis on radiation dose, exposed skin surface area, and chemotherapeutic agents. METHODS: The DCOG-LATER cohort study includes 5-year Dutch CCSs diagnosed 1963-2001. Subsequent skin cancers were identified from record linkages with the Netherlands Cancer Registry and Dutch Pathology Registry. Incidence rates were compared with general population rates. Multivariable Cox regression models were used, applying a novel method of case-control sampling enabling use of tumor location in cohort analyses. All statistical tests were two-sided. RESULTS: Among 5843 CCSs, 259 developed 1061 basal cell carcinomas (BCCs) (standardized incidence ratio [SIR] = 29.8, 95% confidence interval [CI] = 26.3 to 33.6; excess absolute risk per 10 000 person-years (EAR) = 24.6), 20 had melanoma (SIR = 2.3, 95% CI = 1.4 to 3.5; EAR = 1.1), and 10 had squamous cell carcinoma (SIR = 7.5, 95% CI = 3.6 to 13.8; EAR = 0.8). Cumulative incidence of BCC 40 years after childhood cancer was 19.1% (95% CI = 16.6 to 21.8%) after radiotherapy vs 0.6% expected based on general population rates. After a first BCC, 46.7% had more BCCs later. BCC risk was associated with any radiotherapy to the skin compartment of interest (hazard ratio [HR] = 14.32, 95% CI = 10.10 to 20.29) and with estimated percentage in-field skin surface area (26-75%: HR = 1.99, 95% CI = 1.24 to 3.20; 76-100%: HR = 2.16, 95% CI = 1.33 to 3.53, vs 1-25% exposed; Ptrend among exposed = .002), but not with prescribed radiation dose and likelihood of sun-exposed skin-area. Of all chemotherapy groups examined, only vinca alkaloids increased BCC risk (HR = 1.54, 95% CI = 1.04 to 2.27). CONCLUSION: CCSs have a strongly, 30-fold increased BCC risk. BCC risk appears to increase with increasing skin surface area exposed. This knowledge underscores the need for awareness by survivors and their health care providers.

10.
J Am Acad Dermatol ; 81(4): 963-969.e2, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30586613

RESUMO

BACKGROUND: Determinants and the extent of dry skin in healthy middle-aged and elderly populations have not been well established. OBJECTIVE: We aimed to identify the prevalence and determinants for generalized dry skin (GDS) and localized dry skin (LDS) within a large prospective population-based cohort of middle-aged and elderly individuals of the Rotterdam Study. METHODS: Dry skin was physician-graded as none, localized, or generalized. For GDS and LDS, separate multivariable logistic regression analyses were performed to search for association with participant characteristics, lifestyle factors, environmental factors, several comorbidities, and drug exposure. RESULTS: Among the 5547 eligible participants, 60% had dry skin, of whom a fifth had GDS. Age, female sex, skin color, body mass index, outside temperature, eczema, and chemotherapy in the past were significant determinants for both GDS and LDS. Smoking, the use of statins and diuretics, poorer self-perceived health, and several dermatologic conditions increased the likelihood of having GDS only. Daily cream use was associated with less LDS. LIMITATIONS: Interobserver variability and residual confounding could have influenced our results. Because of our cross-sectional design, we could not infer causality. CONCLUSION: We identified factors significantly associated with dry skin in a general middle-aged and elderly population, with health parameters more strongly associated with GDS.

11.
Nat Commun ; 9(1): 4774, 2018 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429480

RESUMO

The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 individuals. We confirm known loci including MTAP, PLA2G6, and IRF4, and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1, PPARGC1B, HDAC4, FAM208B, DOCK8, and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk (KITLG an exception), while many melanoma risk loci do not alter nevus count. For example, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.

12.
Br J Cancer ; 119(11): 1339-1346, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30410059

RESUMO

BACKGROUND: Clinical diagnosis of early melanoma (Breslow thickness less than 0.8 mm) is crucial to disease-free survival. However, it is subjective and can be exceedingly difficult, leading to missed melanomas, or unnecessary excision of benign pigmented skin lesions. An objective technique is needed to improve the diagnosis of early melanoma. METHODS: We have developed a method to improve diagnosis of (thin) melanoma, based on Raman spectroscopy. In an ex vivo study in a tertiary referral (pigmented lesions) centre, high-wavenumber Raman spectra were collected from 174 freshly excised melanocytic lesions suspicious for melanoma. Measurements were performed on multiple locations within the lesions. A diagnostic model was developed and validated on an independent data set of 96 lesions. RESULTS: Approximately 60% of the melanomas included in this study were melanomas in situ. The invasive melanomas had an average Breslow thickness of 0.89 mm. The diagnostic model correctly classified all melanomas (including in situ) with a specificity of 43.8%, and showed a potential improvement of the number needed to treat from 6.0 to 2.7, at a sensitivity of 100%. CONCLUSION: This work signifies an important step towards accurate and objective clinical diagnosis of melanoma and in particular melanoma with Breslow thickness <0.8 mm.

13.
JAMA Dermatol ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30484823

RESUMO

Importance: Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential, but epidemiologic data are poor. Changes to the National Cancer Registration and Analysis Service (NCRAS) in England have allowed more accurate data analysis of primary and metastatic cSCC since 2013. Objective: To assess the national incidence of cSCC and metastatic cSCC (mcSCC) in England from 2013 through 2015. Design, Setting, and Participants: This national population-based study identified a cohort of patients with cSCC and mcSCC in England from January 1, 2013, through December 31, 2015. Patients were identified using diagnostic codes derived from pathology reports in the NCRAS. Data were analyzed from March 1, 2017, through March 1, 2018. Main Outcomes and Measures: Incidence rates across sex and risk factors for cSCC were derived from the NCRAS data. Risk of occurrence of mcSCC among the population with cSCC was assessed with Cox proportional hazards regression analysis to determine indicators of mcSCC. Results: Among the 76 977 patients with first primary cSCC in 2013 through 2015 (62.7% male; median age, 80 years [interquartile range, 72-86 years]), the age-standardized rates for the first registered cSCC in England from 2013 through 2015 were 77.3 per 100 000 person-years (PY) (95% CI, 76.6-78.0) in male patients and 34.1 per 100 000 PY (95% CI, 33.7-34.5) in female patients. Increased primary cSCC tumor count was observed in older, white male patients in lower deprivation quintiles. After a maximum follow-up of 36 months, cumulative incidence of mcSCC developed in 1.1% of women and 2.4% of men with a primary cSCC. Significant increases in the risk of metastasis with adjusted hazard rates of approximately 2.00 were observed in patients who were aged 80 to 89 years (hazard ratio [HR], 1.23; 95% CI, 1.07-1.43), 90 years or older (HR, 1.35; 95% CI, 1.09-1.66), male (HR, 1.79; 95% CI, 1.52-2.10), immunosuppressed (HR, 1.99; 95% CI, 1.64-2.42), and in higher deprivation quintiles (HR for highest quintile, 1.64; 95% CI, 1.35-2.00). Primary cSCC located on the ear (HR, 1.70; 95% CI, 1.42-2.03) and lip (HR, 1.85; 95% CI, 1.29-2.63) were at highest risk of metastasis. Conclusions and Relevance: This study presents the first national study of the incidence of mcSCC. With limited health care resources and an aging population, accurate epidemiologic data are essential for informing future health care planning, identifying high-risk patients, and evaluating skin cancer prevention policies.

14.
Eur J Epidemiol ; 2018 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-30255328

RESUMO

Advanced glycation end products (AGEs) accumulate in tissues with aging and may influence age-related diseases. They can be estimated non-invasively by skin autofluorescence (SAF) using the AGE Reader™. Serum 25-hydroxyvitamin D3 (25(OH)D3) may inhibit AGEs accumulation through anti-oxidative and anti-inflammatory properties but evidence in humans is scarce. The objective was to investigate the association between serum 25(OH)D3 and SAF in the population-based cohort study. Serum 25(OH)D3 and other covariates were measured at baseline. SAF was measured on average 11.5 years later. Known risk factors for AGE accumulation such as higher age, BMI, and coffee intake, male sex, smoking, diabetes, and decreased renal function were measured at baseline. Linear regression models were adopted to explore the association between 25(OH)D3 and SAF with adjustment for confounders. Interaction terms were tested to identify effect modification. The study was conducted in the general community. 2746 community-dwelling participants (age ≥ 45 years) from the Rotterdam Study were included. Serum 25(OH)D3 inversely associated with SAF and explained 1.5% of the variance (unstandardized B = - 0.002 (95% CI[- 0.003, - 0.002]), standardized ß = - 0.125), independently of known risk factors and medication intake. The association was present in both diabetics (B = - 0.004 (95% CI[- 0.008, - 0.001]), ß = - 0.192) and non-diabetics (B = - 0.002 (95% CI[- 0.003, - 0.002]), ß = - 0.122), both sexes, both smokers and non-smokers and in each RS subcohort. Serum 25(OH)D3 concentration was significantly and inversely associated with SAF measured prospectively, also after adjustment for known risk factors for high SAF and the number of medication used, but the causal chain is yet to be explored in future studies.Clinical Trial Registry (1) Netherlands National Trial Register: Trial ID: NTR6831 ( http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831 ). (2) WHO International Clinical Trials Registry Platform: under shared catalogue number NTR6831 ( www.who.int/ictrp/network/primary/en/ ).

15.
PLoS Genet ; 14(9): e1007640, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30248107

RESUMO

Hair plays an important role in primates and is clearly subject to adaptive selection. While humans have lost most facial hair, eyebrows are a notable exception. Eyebrow thickness is heritable and widely believed to be subject to sexual selection. Nevertheless, few genomic studies have explored its genetic basis. Here, we performed a genome-wide scan for eyebrow thickness in 2961 Han Chinese. We identified two new loci of genome-wide significance, at 3q26.33 near SOX2 (rs1345417: P = 6.51×10-10) and at 5q13.2 near FOXD1 (rs12651896: P = 1.73×10-8). We further replicated our findings in the Uyghurs, a population from China characterized by East Asian-European admixture (N = 721), the CANDELA cohort from five Latin American countries (N = 2301), and the Rotterdam Study cohort of Dutch Europeans (N = 4411). A meta-analysis combining the full GWAS results from the three cohorts of full or partial Asian descent (Han Chinese, Uyghur and Latin Americans, N = 5983) highlighted a third signal of genome-wide significance at 2q12.3 (rs1866188: P = 5.81×10-11) near EDAR. We performed fine-mapping and prioritized four variants for further experimental verification. CRISPR/Cas9-mediated gene editing provided evidence that rs1345417 and rs12651896 affect the transcriptional activity of the nearby SOX2 and FOXD1 genes, which are both involved in hair development. Finally, suitable statistical analyses revealed that none of the associated variants showed clear signals of selection in any of the populations tested. Contrary to popular speculation, we found no evidence that eyebrow thickness is subject to strong selective pressure.

16.
J Invest Dermatol ; 2018 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-30130619

RESUMO

Current treatments for seborrheic dermatitis provide only temporary relief. Therefore, identifying modifiable lifestyle factors may help reduce disease burden. The objective of this study was to determine whether specific dietary patterns or total antioxidant capacity are associated with seborrheic dermatitis. Participants of the Rotterdam Study with a skin examination and a food frequency questionnaire were included. Total antioxidant capacity was assessed on the basis of ferric reducing antioxidant potential of each food item. Dietary patterns were identified with principal component analysis (PCA). Multivariable logistic regression analyses were used to assess the association between total antioxidant capacity, dietary pattern-derived PCA factors, and seborrheic dermatitis adjusted for confounders. In total, 4,379 participants were included, of whom 636 (14.5%) had seborrheic dermatitis. The PCA identified vegetable, Western, fat-rich and fruit dietary patterns. The fruit pattern was associated with a 25% lower risk (quartile 1 vs. quartile 4: adjusted odds ratio = 0.76, 95% confidence interval = 0.58-0.97, P = 0.03), and the Western pattern with a 47% increased risk (quartile 1 vs. quartile 4: adjusted odds ratio = 1.47; 95% confidence interval = 0.98-2.20, P = 0.03), but only for females. Other factors were not associated with seborrheic dermatitis. In conclusion, a high fruit intake was associated with less seborrheic dermatitis, whereas high adherence to a "Western" dietary pattern in females was associated with more seborrheic dermatitis.

17.
Dermatology ; 234(3-4): 86-91, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30086541

RESUMO

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 excised by dermatologists than by GPs and plastic surgeons. Dermatologists probably perform better because of their extensive training and high experience in BCC care. To minimize incomplete BCC excision, GPs should receive specific training before the shift of BCC care from secondary to primary care is justifiable.

18.
J Am Acad Dermatol ; 2018 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-30092331

RESUMO

BACKGROUND: Based on increased cardio-metabolic comorbidities, inflammation and an overlap in genetics with Alzheimer's disease, psoriasis patients may be at risk for cognitive dysfunction and dementia. OBJECTIVE: To compare cognition, magnetic resonance imaging (MRI)-markers and dementia risk in psoriasis and non-psoriasis participants in the population-based Rotterdam Study. METHODS: We identified 318 psoriatic and 9678 non-psoriatic participants (mean age: 66.1 years, 58% women). The association of psoriasis with cognitive function, mild cognitive impairment (MCI) and MRI-markers of brain damage was examined by linear and logistic regression. Dementia risk was calculated using Cox regression. Models were adjusted for age, gender, education and cardio-vascular risk factors. RESULTS: Cognitive test scores and volumetric, microstructural, focal measures on brain MRI did not differ between psoriasis (28% systemic/UV treatment) and non-psoriasis participants and psoriasis was not associated with MCI (adjusted odd ratio 0.87, (95% Confidence Interval (CI): 0.53-1.43)). During 115.000 person-years of follow-up, 810 incident dementia cases (15 among psoriasis patients) occurred. After adjusting for confounders, psoriasis was associated with a lower risk of developing dementia (adjusted hazard ratio 0.50, (95% CI: 0.28-0.91)). LIMITATIONS: Limited dementia cases among psoriasis patients. CONCLUSIONS: In this population-based study, psoriasis was not associated with preclinical markers or higher dementia risk.

19.
Br J Cancer ; 119(4): 429-434, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29961756

RESUMO

BACKGROUND: A small minority of patients present with locally advanced cutaneous Squamous Cell Carcinoma (cSCC). The aim of this study was to evaluate the effectiveness of Tumour necrosis factor α (TNF) and melphalan based isolated limb perfusion (TM-ILP) as a limb saving strategy for locally advanced extremity cSCC. METHODS: A retrospective search from prospectively maintained databases, at two tertiary referral centers, was performed to identify patients treated with TM-ILP for locally advanced cSSC of an extremity between 2000 and 2015. RESULTS: A total of 30 patients treated with TM-ILP for cSCC were identified, with a median age of 71 years (36-92) and 50% female. Response could not be evaluated in 3 patients. After a median follow up of 25 months, the overall response rate was 81% (n = 22), with 16 patients having a complete response (CR, 59%). A total of 7 patients developed local recurrence, with a median time to recurrence of 9 months (Interquartile Range 7-10). Progressive disease was observed in 5 patients (19%). Limb salvage rate was 80%. The overall 2-year survival was 67%. CONCLUSIONS: TM-ILP should be considered as an option in patients with locally advanced cSCC in specialised centers, resulting in a high limb salvage rate.

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