Evaluation of the Finnish Diabetes Risk Score as a screening tool for undiagnosed type 2 diabetes and dysglycaemia among early middle-aged adults in a large-scale European cohort. The Feel4Diabetes-study

Aim: To assess the diagnostic accuracy of the FINDRISC for undiagnosed type 2 diabetes mellitus (T2DM) and dysglycaemia (i.e. the presence of prediabetes or T2DM) among early middle-aged adults from vulnerable groups in a large-scale European cohort. Methods: Participants were recruited from low-socioeconomic areas in high-income countries (HICs) (Belgium-Finland) and in HICs under austerity measures (Greece-Spain) and from the overall population in low/middle-income countries (LMICs) (Bulgaria-Hungary). Study population comprised of 2116 parents of primary-school children from families identified at increased risk of T2DM, based on parental self-reported FINDRISC. Sensitivity (Se), specificity (Sp), area under the receiver operating characteristic curves (AUC-ROC) and the optimal cut-offs of FINDRISC that indicate an increased probability for undiagnosed T2DM or dysglycaemia were calculated. Results: The AUC-ROC for undiagnosed T2DM was 0.824 with optimal cut-off =14 (Se = 68%, Sp = 81.7%) for the total sample, 0.839 with optimal cut-off =15 (Se = 83.3%, Sp = 86.9%) for HICs, 0.794 with optimal cut-off =12 (Se = 83.3%, Sp = 61.1%) for HICs under austerity measures and 0.882 with optimal cut-off =14 (Se = 71.4%, Sp = 87.8%) for LMICs. The AUC-ROC for dysglycaemia was 0.663 with optimal cut-off =12 (Se = 58.3%, Sp = 65.7%) for the total sample, 0.656 with optimal cut-off =12 (Se = 54.5%, Sp = 64.8%) for HICs, 0.631 with optimal cut-off =12 (Se = 59.7%, Sp = 62.0%) for HICs under austerity measures and 0.735 with optimal cut-off =11 (Se = 72.7%, Sp = 70.2%) for LMICs. Conclusion: FINDRISC can be applied for screening primarily undiagnosed T2DM but also dysglycaemia among vulnerable groups across Europe, considering the use of different cut-offs for each subpopulation

Self-reported lifestyle behaviours in families with an increased risk for type 2 diabetes across six European countries: a cross-sectional analysis from the Feel4Diabetes-study

BACKGROUND: A healthy lifestyle decreases the risk of developing type 2 diabetes mellitus. The current cross-sectional study aimed to describe self-reported lifestyle behaviours and compare them to current health guidelines in European Feel4Diabetes-families at risk for developing type 2 diabetes across six countries (Belgium, Finland, Spain, Greece, Hungary and Bulgaria). METHODS: Parents and their children were recruited through primary schools located in low socio-economic status areas. Parents filled out the FINDRISC-questionnaire (eight items questioning age, Body Mass Index, waist circumference, PA, daily consumption of fruit, berries or vegetables, history of antihypertensive drug treatment, history of high blood glucose and family history of diabetes), which was used for the risk assessment of the family. Sociodemographic factors and several lifestyle behaviours (physical activity, sedentary behaviour, water consumption, fruit and vegetable consumption, soft drink consumption, sweets consumption, snack consumption, breakfast consumption) of both adults and children were assessed by parental questionnaires. Multilevel regression analyses were conducted to investigate families'' lifestyle behaviours, to compare these levels to health guidelines and to assess potential differences between the countries. Analyses were controlled for age, sex and socio-economic status. RESULTS: Most Feel4Diabetes-families at risk (parents and their children) did not comply with the guidelines regarding healthy behaviours, set by the WHO, European or national authorities. Less than half of parents and children complied with the physical activity guidelines, less than 15% of them complied with the fruit and vegetable guideline, and only 40% of the children met the recommendations of five glasses of water per day. Clear differences in lifestyle behaviours in Feel4Diabetes-families at risk exist between the countries. CONCLUSIONS: Countries are highly recommended to invest in policy initiatives to counter unhealthy lifestyle behaviours in families at risk for type 2 diabetes development, taking into account country-specific needs. For future research it is of great importance to focus on families at risk in order to counter the development of type 2 diabetes and reduce health inequity. © 2022. The Author(s)

Do physical activity and screen time mediate the association between European fathers' and their children's weight status? Cross-sectional data from the Feel4Diabetes-study

BACKGROUND: Most research on parenting and childhood obesity and obesity-related behaviours has focused on mothers while fathers have been underrepresented. Yet, recent literature has suggested that fathers uniquely influence their children''s lifestyle behaviours, and hence could also affect their weight status, but this has not yet been scientifically proven. Therefore, the present study aimed to determine whether the association between fathers'' weight status and their children''s weight status is mediated by fathers'' and children''s movement behaviours (i.e. physical activity (PA) and screen time (ST)). METHODS: Cross-sectional data of 899 European fathers and their children were analyzed. Fathers/male caregivers (mean age =¿43.79¿±¿5.92¿years, mean BMI =¿27.08¿±¿3.95) completed a questionnaire assessing their own and their children''s (mean age =¿8.19¿±¿0.99¿years, 50.90% boys, mean BMIzscore =¿0.44¿±¿1.07) movement behaviours. Body Mass Index (BMI, in kg/m2) was calculated based on self-reported (fathers) and objectively measured (children) height and weight. For children, BMI z-scores (SD scores) were calculated to obtain an optimal measure for their weight status. Serial mediation analyses were performed using IBM SPSS 25.0 Statistics for Windows to test whether the association between fathers'' BMI and children''s BMI is mediated by fathers'' PA and children''s PA (model 1) and fathers'' ST and children''s ST (model 2), respectively. RESULTS: The present study showed a (partial) mediation effect of fathers'' PA and children''s PA (but not father''s ST and children''s ST) on the association between fathers'' BMI and children''s BMI (model for PA; coefficient: 0.001, 95% CI: [0.0001, 0.002]; model for ST; coefficient: 0.001, 95% CI: [0.000, 0.002]). Furthermore, fathers'' movement behaviours (PA and ST) were positively associated with their children''s movement behaviours (PA and ST) (model for PA, coefficient: 0.281, SE: 0.023, p <¿0.001; model for ST, coefficient: 0.345, SE: 0.025, p¿<¿0.001). CONCLUSIONS: These findings indicate that the influence of fathers on their children''s weight status partially occurs through the association between fathers'' PA and children''s PA (but not their ST). As such, intervening by focusing on PA of fathers but preferably of both members of the father-child dyad (e.g. engaging fathers and their children in co-PA) might be a novel and potentially effective strategy for interventions aiming to prevent childhood overweight and obesity. Longitudinal studies or intervention studies confirming these findings are however warranted to make meaningful recommendations for health intervention and policy. TRIAL REGISTRATION: The Feel4Diabetes-study is registered with the clinical trials registry http://clinicaltrials.gov , ID: 643708

Graphite and Hexagonal Boron-Nitride Possess the Same Interlayer Distance. Why?

Graphite and hexagonal boron nitride (h-BN) are two prominent members of the family of layered materials possessing a hexagonal lattice. While graphite has non-polar homo-nuclear C-C intra-layer bonds, h-BN presents highly polar B-N bonds resulting in different optimal stacking modes of the two materials in bulk form. Furthermore, the static polarizabilities of the constituent atoms considerably differ from each other suggesting large differences in the dispersive component of the interlayer bonding. Despite these major differences both materials present practically identical interlayer distances. To understand this finding, a comparative study of the nature of the interlayer bonding in both materials is presented. A full lattice sum of the interactions between the partially charged atomic centers in h-BN results in vanishingly small monopolar electrostatic contributions to the interlayer binding energy. Higher order electrostatic multipoles, exchange, and short-range correlation contributions are found to be very similar in both materials and to almost completely cancel out by the Pauli repulsions at physically relevant interlayer distances resulting in a marginal effective contribution to the interlayer binding. Further analysis of the dispersive energy term reveals that despite the large differences in the individual atomic polarizabilities the hetero-atomic B-N C6 coefficient is very similar to the homo-atomic C-C coefficient in the hexagonal bulk form resulting in very similar dispersive contribution to the interlayer binding. The overall binding energy curves of both materials are thus very similar predicting practically the same interlayer distance and very similar binding energies.Comment: 18 pages, 5 figures, 2 table

Methodology of the health economic evaluation of the Feel4Diabetes-study

Background: The clinical and economic burden of type 2 diabetes mellitus on society is rising. Effective and efficient preventive measures may stop the increasing prevalence, given that type 2 diabetes mellitus is mainly a lifestyle-driven disease. The Feel4Diabetes-study aimed to tackle unhealthy lifestyle (unhealthy diet, lack of physical activity, sedentary behaviour, and excess weight) of families with a child in the first grades of elementary school. These schools were located in regions with a relatively low socio-economic status in Belgium, Bulgaria, Finland, Greece, Hungary and Spain. Special attention was paid to families with a high risk of developing type 2 diabetes mellitus. Methods: The aim of this paper is to describe the detailed methodology of the intervention’s cost-effectiveness analysis. Based on the health economic evaluation of the Toybox-study, both a decision analytic part and a Markov model have been designed to assess the long-term (time horizon of 70 year with one-year cycles) intervention’s value for money. Data sources used for the calculation of health state incidences, transition probabilities between health states, health state costs, and health state utilities are listed. Intervention-related costs were collected by questionnaires and diaries, and attributed to either all families or high risk families only. Conclusions: The optimal use of limited resources is pivotal. The future results of the health economic evaluation of the Feel4Diabetes-study will contribute to the efficient use of those resources.Publication of this supplement was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement n° 643708

Recessive Retinopathy Consequent on Mutant G-Protein β Subunit 3 (GNB3)

IMPORTANCE: Mutations in phototransduction and retinal signaling genes are implicated in many retinopathies. To our knowledge, GNB3 encoding the G-protein β subunit 3 (Gβ3) has not previously been implicated in human disease. OBSERVATIONS: In this brief report, whole-exome sequencing was conducted on a patient with distinct inherited retinal disease presenting in childhood, with a phenotype characterized by nystagmus, normal retinal examination, and mild disturbance of the central macula on detailed retinal imaging. This sequencing revealed a homozygous GNB3 nonsense mutation (c.124C>T; p.Arg42Ter). Whole-exome sequencing was conducted from April 2015 to July 2015. CONCLUSIONS AND RELEVANCE: Expressed in cone photoreceptors and ON-bipolar cells, Gβ3 is essential in phototransduction and ON-bipolar cell signaling. Knockout of Gnb3 in mice results in dysfunction of cone photoreceptors and ON-bipolar cells and a naturally occurring chicken mutation leads to retinal degeneration. Identification of further affected patients may allow description of the phenotypic and genotypic spectrum of disease associated with GNB3 retinopathy

Clinical Features of a Retinopathy Associated With a Dominant Allele of the RGR Gene

Purpose: We describe the clinical features in two pedigrees with dominantly inherited retinopathy segregating the previously reported frameshifting mutation, c.836dupG (p.Ile280Asn*78) in the terminal exon of the RGR gene, and compare their haplotypes to that of the previously reported pedigree. Methods: The probands were ascertained at West Virginia University Eye Institute (WVU) and Moorfields Eye Hospital (MEH) through next generation sequencing (NGS) and whole genome sequencing (WGS) respectively. Clinical data included visual acuity (VA), visual fields, fundus autofluorescence (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Haplotype analysis was performed using Sanger sequencing of the DNA from the molecularly ascertained individuals from the three pedigrees. Results: Nine heterozygous mutation carriers were identified in two families. Four carriers were asymptomatic; five carriers had variable VA reduction, visual field constriction, and experienced difficulty under dim illumination. Fundus examination of the asymptomatic carriers showed diffuse or reticular pigmentation of the retina; the symptomatic carriers had chorioretinal atrophy. FAF imaging showed widespread signal loss in advanced retinopathy, and reticular hyperautofluorescence in mild cases. OCT showed loss of outer retinal lamina in advanced disease. ERG showed moderate-to-severe rod–cone dysfunction in two symptomatic carriers; and was normal in three asymptomatic carriers. A shared haplotype flanking the mutation of up to 6.67 Mb was identified in both families. Within this region, 1.27 Mb were shared with the first family reported with this retinopathy. Conclusions: The clinical data suggest a variable and slow degeneration of the RPE. A shared chromosomal segment surrounding the RGR gene suggests a single ancestral mutational event underlying all three families

Feel4Diabetes healthy diet score: Development and evaluation of clinical validity

Background: The aim of this paper is to present the development of the Feel4Diabetes Healthy Diet Score and to evaluate its clinical validity. Methods: Study population consisted of 3268 adults (63% women) from high diabetes risk families living in 6 European countries. Participants filled in questionnaires at baseline and after 1 year, reflecting the dietary goals of the Feel4Diabetes intervention. Based on these questions the Healthy Diet Score was constructed, consisting of the following components: breakfast, vegetables, fruit and berries, sugary drinks, whole-grain cereals, nuts and seeds, low-fat dairy products, oils and fats, red meat, sweet snacks, salty snacks, and family meals. Maximum score for each component was set based on its estimated relative importance regarding T2DM risk, higher score indicating better quality of diet. Clinical measurements included height, weight, waist circumference, heart rate, blood pressure, and fasting blood sampling, with analyses of glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides. Analysis of (co) variance was used to compare the Healthy Diet Score and its components between countries and sexes using baseline data, and to test differences in clinical characteristics between score categories, adjusted for age, sex and country. Pearson''s correlations were used to study the association between changes from baseline to year 1 in the Healthy Diet Score and clinical markers. To estimate reproducibility, Pearson''s correlations were studied between baseline and 1 year score, within the control group only. Results: The mean total score was 52.8 ± 12.8 among women and 46.6 ± 12.8 among men (p < 0.001). The total score and its components differed between countries. The change in the Healthy Diet Score was significantly correlated with changes in BMI, waist circumference, and total and LDL cholesterol. The Healthy Diet Score as well as its components at baseline were significantly correlated with the values at year 1, in the control group participants. Conclusion: The Feel4Diabetes Healthy Diet Score is a reproducible method to capture the dietary information collected with the Feel4Diabetes questionnaire and measure the level of and changes in the adherence to the dietary goals of the intervention. It gives a simple parameter that associates with clinical risk factors in a meaningful manner

A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies

Despite rapid advances in the identification of genes involved in disease, the predictive power of the genotype remains limited, in part owing to poorly understood effects of second-site modifiers. Here we demonstrate that a polymorphic coding variant of RPGRIP1L (retinitis pigmentosa GTPase regulator-interacting protein-1 like), a ciliary gene mutated in Meckel-Gruber (MKS) and Joubert (JBTS) syndromes, is associated with the development of retinal degeneration in individuals with ciliopathies caused by mutations in other genes. As part of our resequencing efforts of the ciliary proteome, we identified several putative loss-of-function RPGRIP1L mutations, including one common variant, A229T. Multiple genetic lines of evidence showed this allele to be associated with photoreceptor loss in ciliopathies. Moreover, we show that RPGRIP1L interacts biochemically with RPGR, loss of which causes retinal degeneration, and that the Thr229-encoded protein significantly compromises this interaction. Our data represent an example of modification of a discrete phenotype of syndromic disease and highlight the importance of a multifaceted approach for the discovery of modifier alleles of intermediate frequency and effect.This work was supported by grants R01EY007961 from the National Eye Institute (H.K. and A.S.), R01HD04260 from the National Institute of Child Health and Development (N.K.), R01DK072301, R01DK075972 (N.K.), R01DK068306, R01DK064614, R01DK069274 (F.H.), NRSA fellowship F32 DK079541 (E.E.D.) from the National Institute of Diabetes, Digestive and Kidney disorders, Intramural program of NEI (A.S.), the Macular Vision Research Foundation (N.K.), the Foundation for Fighting Blindness (H.K., S.S.B., A.S. and N.K.), the Foundation for Fighting Blindness Canada (R.K.K.), Le Fonds de la recherche en sante du Québec (FRSQ) (R.K.K.), Research to Prevent Blindness (A.S.), Harold Falls Collegiate Professorship (A.S.), the Midwest Eye Banks and Transplantation Center (H.K.), the Searle Scholars Program (M.A.B.), the Deutsche Forschungsgemeinschaft (DFG grant BE 3910/4-1; C.B.) the UK Medical Research Council (grant number G0700073; C.A.J.), NIHR Biomedical Research Centre for Ophthalmology (S.S.B.) and EU-GENORET Grant LSHG-CT-2005-512036 (S.S.B.). F.H. is an investigator of the Howard Hughes Medical Institute (HHMI) and a Doris Duke Distinguished Clinical Scientist (DDCF)

ATP-Dependent Unwinding of U4/U6 snRNAs by the Brr2 Helicase Requires the C Terminus of Prp8

The spliceosome is a highly dynamic machine requiring multiple RNA-dependent ATPases of the DExD/H-box family. A fundamental unanswered question is how their activities are regulated. Brr2 function is necessary for unwinding the U4/U6 duplex, a step essential for catalytic activation of the spliceosome. Here we show that Brr2-dependent dissociation of U4/U6 snRNAs in vitro is activated by a fragment from the C terminus of the U5 snRNP protein Prp8. In contrast to its helicase-stimulating activity, this fragment inhibits Brr2 U4/U6-dependent ATPase activity. Notably, U4/U6 unwinding activity is not stimulated by fragments carrying alleles of prp8 that in humans confers an autosomal dominant form of retinitis pigmentosa. Because Brr2 activity must be restricted to prevent premature catalytic activation, our results have important implications for fidelity maintenance in the spliceosome