Massive open online courses (MOOCs) in genomic variant interpretation: An innovative education strategy for the growing genetic counselor workforce.

The growth in genomic testing in healthcare requires a highly trained specialist workforce to ensure evidence based clinical germline variant interpretation. Genetic counselors form a core part of the clinical genomics multidisciplinary team (MDT) and represent a growing workforce participating in variant interpretation from data analysis to the patient consultation. Standardized, high-quality variant interpretation training for Genetic Counselors has historically been ad hoc and variable, with existing programs lacking capacity to reach the entire workforce. To address the requirement for scalable variant interpretation training for genomics healthcare professionals (HCPs), two Massive Open Online Courses (MOOCs) were developed. We analyzed the data from 17 Genetic counselors, as part of an evaluation cohort completing the first run of these MOOCs. Overall genetic counselors enjoyed the courses, felt they were clinically relevant and would recommend them to colleagues. Common challenges amongst the genetic counseling workforces included utilizing relevant databases and finding time in the workday to complete training. These findings suggest MOOCs could be an acceptable option to ensure a consistent and transferrable high standard of training, complimentary to existing curricula. They also hold the potential to facilitate large-scale education to update the genetic counseling workforce when changes in variant interpretation guidance occur

Carotid artery stiffness in metabolic syndrome: Sex differences

Introduction: The effect of metabolic syndrome (MS) on carotid stiffness (CS) in the context of gender is under research. Objective: We examined the relationship between the MS and CS in men (M) and women (W) and investigated if the impact of cardiovascular risk factors on CS is modulated by gender. Patients and Methods: The study included 419 subjects (mean age 54.3 years): 215 (51%) with MS (109 W and 106 M) and 204 (49%) without MS (98 W and 106 M). Carotid intima-media thickness (IMT) and CS parameters (beta stiffness index (beta), Peterson’s elastic modulus (Ep), arterial compliance (AC) and one-point pulse wave velocity (PWV-beta)) were measured with the echo-tracking (eT) system. Results: ANCOVA demonstrated that MS was associated with elevated CS indices (p = 0.003 for beta and 0.025 for PWV-beta), although further sex-specific analysis revealed that this relationship was significant only in W (p = 0.021 for beta). Age was associated with CS in both M and W, pulse pressure (PP) and body mass index turned out to be determinants of CS solely in W, while the effect of mean arterial pressure (MAP) and heart rate was more pronounced in M. MANOVA performed in subjects with MS revealed that age and diabetes mellitus type 2 were determinants of CS in both sexes, diastolic blood pressure and MAP – solely in M and systolic blood pressure, PP and waist circumference – solely in W (the relationship between the waist circumference and AC was paradoxical). Conclusion: The relationship between MS and CS is stronger in W than in M. In subjects with MS, various components of arterial pressure exert different sex-specific effects on CS – with the impact of the pulsative component of arterial pressure (PP) observed in W and the impact of the steady component (MAP) observed in M

First-trimester or second-trimester screening, or both, for Down's syndrome

BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters.METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency).RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening.CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates

Assessment of mutagenic activity of methyl- and phenylphenanthrenes based on Salmonella test and micronucleus test

Polycyclic aromatic hydrocarbons (PAHs) are widely spread environmental pollutants mainly originating from anthropogenic sources such as fossil fuel combustion, industries, and others. Although a large body of literature exists on the toxicity and carcinogenicity of PAHs, primarily benzo[a]pyrene, toxicity data for phenanthrene deriveratives are very limited. The main aim of the experiment was to investigate if there exists correlation between molecular structure and mutagenic activity of four phenanthrene derivatives: 1 methylphenanthrene, 4 methylphenanthrene, 1 phenylphenanthrene, and 4 phenylphenanthrene. An Ames assay using two strains of histidine dependent Salmonella Typhimurium (TA98 and TA100) was conducted to assess the mutagenic activity of studied compounds both in the presence (+S9) and in the absence (-S9) of an exogenous source of metabolic activation. The compounds were also tested in an in vitro chromosome aberration assay in which V-79 cells were exposed to the phenanthrene derivatives investigated both in the presence and in the absence of metabolic activation. The phenylphenanthrenes showed no mutagenic effect. These compounds occasionally induced significant decrease in the number of revertants in the Ames test. The greatest mutagenic effects were observed for 1 methylphenanthrene after metabolic activation (+S9). In the micronucleus test the greatest mutagenic effect was observed for 4 methylphenanthrene also in the presence of metabolic activation system. The results obtained are comparable to those reported earlier for the methylphenanthrenes

ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF- levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF- levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D

Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case-control study.

PURPOSE: The aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis. METHODS: A hospital-based case-control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol. RESULTS: After adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD. CONCLUSIONS: This study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation

Body-mass index adjustments to increase the validity of body fatness assessment in UK black African and South Asian children: a cross-sectional calibration study

BackgroundExcess childhood body fatness, overweightness, and obesity are a major public health challenge in the UK. Accurate assessments, usually based on body-mass index (BMI), are crucial. However, recent studies have demonstrated that BMI underestimates body fatness in South Asian children and overestimates it in black African children. These errors are a concern in these ethnic minority populations, particularly UK South Asians, who are at high risk of obesity, type 2 diabetes, and cardiovascular disease. We aimed to develop BMI adjustments for these children to ensure that BMI relates to body fatness in the same way as for white European children.MethodsFour recent UK population-based studies, which used deuterium dilution assessments of fat mass as a reference method, were pooled to include 1725 children (52% girls) aged 4–12 years (mean 9·3, SD 1·6) of white European, South Asian, and black African origins. A height-standardised fat-mass index (FMI) was derived to represent body fatness. Linear regression models were fitted, separately by sex, to quantify ethnic differences in BMI–FMI associations and to provide ethnic-specific BMI adjustments.FindingsThe FMI derived for this study population and used in analyses was fat mass/height5, which was independent of height for the 4–12-year age-group. BMI consistently underestimated body fatness in South Asians, requiring a BMI adjustment of +1·12 kg/m2 (95% CI 0·83–1·41) for boys and +1·07 (0·74–1·39) for girls, irrespective of age and FMI. BMI overestimated body fatness in black Africans. However, adjustments for black African children were more complex, with statistically significant interactions between black African ethnicity and FMI (p=0·004 boys, p=0·003 girls) and between FMI and age-group (p\u3c0·0001 boys and girls). BMI adjustments therefore varied by age-group and FMI level, between −0·24 and −2·84 kg/m2 for boys and between −0·22 and −2·86 kg/m2 for girls for unadjusted BMI values of 13 kg/m2 in 10–12 year-olds and 25 kg/m2 in 4–6 year-olds, respectively.InterpretationBMI underestimated body fatness in South Asians and overestimated it in black Africans. Ethnic-specific adjustments—increasing BMI in South Asians and reducing BMI in black Africans—can improve the accuracy of body fatness assessment in these children.FundingThis work was supported by the British Heart Foundation (grant ref PG/15/19/31336) and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care (South London) (grant ref CLAHRC-2013-10022). Primary data collection was funded by the British Heart Foundation (PG/11/42/28895), BUPA Foundation (TBF-S09-019), Child Growth Foundation (GR 10/03), and Wellcome Trust (WT094129MA). MF is supported by Great Ormond Street Hospital Childrens\u27 Charity

Visual Acuity Measures Do Not Reliably Detect Childhood Refractive Error - an Epidemiological Study

PURPOSE: To investigate the utility of uncorrected visual acuity measures in screening for refractive error in white school children aged 6-7-years and 12-13-years. METHODS: The Northern Ireland Childhood Errors of Refraction (NICER) study used a stratified random cluster design to recruit children from schools in Northern Ireland. Detailed eye examinations included assessment of logMAR visual acuity and cycloplegic autorefraction. Spherical equivalent refractive data from the right eye were used to classify significant refractive error as myopia of at least 1DS, hyperopia as greater than +3.50DS and astigmatism as greater than 1.50DC, whether it occurred in isolation or in association with myopia or hyperopia. RESULTS: Results are presented from 661 white 12-13-year-old and 392 white 6-7-year-old school-children. Using a cut-off of uncorrected visual acuity poorer than 0.20 logMAR to detect significant refractive error gave a sensitivity of 50% and specificity of 92% in 6-7-year-olds and 73% and 93% respectively in 12-13-year-olds. In 12-13-year-old children a cut-off of poorer than 0.20 logMAR had a sensitivity of 92% and a specificity of 91% in detecting myopia and a sensitivity of 41% and a specificity of 84% in detecting hyperopia. CONCLUSIONS: Vision screening using logMAR acuity can reliably detect myopia, but not hyperopia or astigmatism in school-age children. Providers of vision screening programs should be cognisant that where detection of uncorrected hyperopic and/or astigmatic refractive error is an aspiration, current UK protocols will not effectively deliver

Are Ethnic and Gender Specific Equations Needed to Derive Fat Free Mass from Bioelectrical Impedance in Children of South Asian, Black African-Caribbean and White European Origin? Results of the Assessment of Body Composition in Children Study

Background Bioelectrical impedance analysis (BIA) is a potentially valuable method for assessing lean mass and body fat levels in children from different ethnic groups. We examined the need for ethnic- and gender-specific equations for estimating fat free mass (FFM) from BIA in children from different ethnic groups and examined their effects on the assessment of ethnic differences in body fat. Methods Cross-sectional study of children aged 8–10 years in London Primary schools including 325 South Asians, 250 black African-Caribbeans and 289 white Europeans with measurements of height, weight and arm-leg impedance (Z; Bodystat 1500). Total body water was estimated from deuterium dilution and converted to FFM. Multilevel models were used to derive three types of equation {A: FFM = linear combination(height+weight+Z); B: FFM = linear combination(height2/Z); C: FFM = linear combination(height2/Z+weight)}. Results Ethnicity and gender were important predictors of FFM and improved model fit in all equations. The models of best fit were ethnicity and gender specific versions of equation A, followed by equation C; these provided accurate assessments of ethnic differences in FFM and FM. In contrast, the use of generic equations led to underestimation of both the negative South Asian-white European FFM difference and the positive black African-Caribbean-white European FFM difference (by 0.53 kg and by 0.73 kg respectively for equation A). The use of generic equations underestimated the positive South Asian-white European difference in fat mass (FM) and overestimated the positive black African-Caribbean-white European difference in FM (by 4.7% and 10.1% respectively for equation A). Consistent results were observed when the equations were applied to a large external data set. Conclusions Ethnic- and gender-specific equations for predicting FFM from BIA provide better estimates of ethnic differences in FFM and FM in children, while generic equations can misrepresent these ethnic differences