Refinement of a published gene-physical activity interaction impacting HDL-cholesterol: role of sex and lipoprotein subfractions.

Large-scale gene-environment interaction (GxE) discovery efforts often involve compromises in the definition of outcomes and choice of covariates for the sake of data harmonization and statistical power. Consequently, refinement of exposures, covariates, outcomes, and population subsets may be helpful to establish often-elusive replication and evaluate potential clinical utility. Here, we used additional datasets, an expanded set of statistical models, and interrogation of lipoprotein metabolism via nuclear magnetic resonance (NMR)-based lipoprotein subfractions to refine a previously discovered GxE modifying the relationship between physical activity (PA) and HDL-cholesterol (HDL-C). This GxE was originally identified by Kilpeläinen et al., with the strongest cohort-specific signal coming from the Women's Genome Health Study (WGHS). We thus explored this GxE further in the WGHS (N = 23,294), with follow-up in the UK Biobank (UKB; N = 281,380), and the Multi-Ethnic Study of Atherosclerosis (MESA; N = 4,587). Self-reported PA (MET-hrs/wk), genotypes at rs295849 (nearest gene: LHX1), and NMR metabolomics data were available in all three cohorts. As originally reported, minor allele carriers of rs295849 in WGHS had a stronger positive association between PA and HDL-C (pint = 0.002). When testing a range of NMR metabolites (primarily lipoprotein and lipid subfractions) to refine the HDL-C outcome, we found a stronger interaction effect on medium-sized HDL particle concentrations (M-HDL-P; pint = 1.0×10-4) than HDL-C. Meta-regression revealed a systematically larger interaction effect in cohorts from the original meta-analysis with a greater fraction of women (p = 0.018). In the UKB, GxE effects were stronger both in women and using M-HDL-P as the outcome. In MESA, the primary interaction for HDL-C showed nominal significance (pint = 0.013), but without clear differences by sex and with a greater magnitude using large, rather than medium, HDL-P as an outcome. Towards reconciling these observations, further exploration leveraging NMR platform-specific HDL subfraction diameter annotations revealed modest agreement across all cohorts in the interaction affecting medium-to-large particles. Taken together, our work provides additional insights into a specific known gene-PA interaction while illustrating the importance of phenotype and model refinement towards understanding and replicating GxEs.

Heterogeneous effects on type 2 diabetes and cardiovascular outcomes of genetic variants and traits associated with fasting insulin.

Hyperinsulinemia is a complex and heterogeneous phenotype that characterizes molecular alterations that precede the development of type 2 diabetes (T2D). It results from a complex combination of molecular processes, including insulin secretion and insulin sensitivity, that differ between individuals. To better understand the physiology of hyperinsulinemia and ultimately T2D, we implemented a genetic approach grouping fasting insulin (FI)-associated genetic variants based on their molecular and phenotypic similarities. We identified seven distinctive genetic clusters representing different physiologic mechanisms leading to rising FI levels, ranging from clusters of variants with effects on increased FI, but without increased risk of T2D (non-diabetogenic hyperinsulinemia), to clusters of variants that increase FI and T2D risk with demonstrated strong effects on body fat distribution, liver, lipid, and inflammatory processes (diabetogenic hyperinsulinemia). We generated cluster-specific polygenic scores in 1,104,258 individuals from five multi-ancestry cohorts to show that the clusters differed in associations with cardiometabolic traits. Among clusters characterized by non-diabetogenic hyperinsulinemia, there was both increased and decreased risk of coronary artery disease despite the non-increased risk of T2D. Similarly, the clusters characterized by diabetogenic hyperinsulinemia were associated with an increased risk of T2D, yet had differing risks of cardiovascular conditions, including coronary artery disease, myocardial infarction, and stroke. The strongest cluster-T2D associations were observed with the same direction of effect in non-Hispanic Black, Hispanic, non-Hispanic White, and non-Hispanic East Asian populations. These genetic clusters provide important insights into granular metabolic processes underlying the physiology of hyperinsulinemia, notably highlighting specific processes that decouple increasing FI levels from T2D and cardiovascular risk. Our findings suggest that increasing FI levels are not invariably associated with adverse cardiometabolic outcomes.

Precision subclassification of type 2 diabetes: a systematic review.

BACKGROUND: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients. METHODS: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches. RESULTS: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes. CONCLUSION: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.

In people with type 2 diabetes there may be differences in the way people present, including for example, their symptoms, body weight or how much insulin they make. We looked at recent publications describing research in this area to see whether it is possible to separate people with type 2 diabetes into different subgroups and, if so, whether these groupings were useful for patients. We found that it is possible to group people with type 2 diabetes into different subgroups and being in one subgroup can be more strongly linked to the likelihood of developing complications over others. This might mean that in the future we can treat people in different subgroups differently in ways that improves their treatment and their health but it requires further study.

Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.

Systematic review of precision subclassification of type 2 diabetes.

Heterogeneity in type 2 diabetes presentation, progression and treatment has the potential for precision medicine interventions that can enhance care and outcomes for affected individuals. We undertook a systematic review to ascertain whether strategies to subclassify type 2 diabetes are associated with improved clinical outcomes, show reproducibility and have high quality evidence. We reviewed publications that deployed 'simple subclassification' using clinical features, biomarkers, imaging or other routinely available parameters or 'complex subclassification' approaches that used machine learning and/or genomic data. We found that simple stratification approaches, for example, stratification based on age, body mass index or lipid profiles, had been widely used, but no strategy had been replicated and many lacked association with meaningful outcomes. Complex stratification using clustering of simple clinical data with and without genetic data did show reproducible subtypes of diabetes that had been associated with outcomes such as cardiovascular disease and/or mortality. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into meaningful groups. More studies are needed to test these subclassifications in more diverse ancestries and prove that they are amenable to interventions.

Genetic predisposition to macronutrient preference and workplace food choices.

Prior research identified genetic variants influencing macronutrient preference, but whether genetic differences underlying nutrient preference affect long-term food choices is unknown. Here we examined the associations of polygenic scores for carbohydrate, fat, and protein preference with 12 months' workplace food purchases among 397 hospital employees from the ChooseWell 365 study. Food purchases were obtained retrospectively from the hospital's cafeteria sales data for the 12 months before participants were enrolled in the ChooseWell 365 study. Traffic light labels, visible to employees when making purchases, measured the quality of workplace purchases. During the 12-month study period, there were 215,692 cafeteria purchases. Each SD increase in the polygenic score for carbohydrate preference was associated with 2.3 additional purchases/month (95%CI, 0.2 to 4.3; p = 0.03) and a higher number of green-labeled purchases (ß = 1.9, 95%CI, 0.5-3.3; p = 0.01). These associations were consistent in subgroup and sensitivity analyses accounting for additional sources of bias. There was no evidence of associations between fat and protein polygenic scores and cafeteria purchases. Findings from this study suggest that genetic differences in carbohydrate preference could influence long-term workplace food purchases and may inform follow-up experiments to enhance our understanding of the molecular mechanisms underlying food choice behavior.

Diagnostic performance of questionnaires to identify individuals with impaired fasting glucose in Mexican adult population.

AIMS: To evaluate the diagnostic performance of five questionnaires to identify impaired fasting glucose (IFG) in Mexican adult population. METHODS: The study included 23,311 subjects from five cohorts, three composed of individuals who sought medical advice in their first level clinics or participated in research studies and two representative surveys of the Mexican population. The reference standard was IFG which was defined as a fasting glucose ≥ 100 mg/dL. Diagnostic performance was evaluated with specificity, sensitivity, positive and negative predictive values, area under the curve, and the proportion of correctly classified individuals. RESULTS: The prevalence of IFG ranged from 14.4 to 48.1 % across the cohorts. Diagnostic performance of the questionnaires varied in each cohort depending on IFG prevalence. The questionnaires designed by Rojas, American Diabetes Association and International Diabetes Federation had the best performance considering the correct classification (>66.0 %) of subjects in all cohorts. However, Rojas' questionnaire had the best balance between sensitivity and specificity across the cohorts. CONCLUSION: In the Mexican population, considering different scenarios, the Rojas' questionnaire had the best diagnostic performance. The implementation of questionnaires for the identification of prediabetes and undiagnosed diabetes requires further study in specific populations.

Metabolomic markers of glucose regulation after a lifestyle intervention in prediabetes.

INTRODUCTION: Disentangling the specific factors that regulate glycemia from prediabetes to normoglycemia could improve type 2 diabetes prevention strategies. Metabolomics provides substantial insights into the biological understanding of environmental factors such as diet. This study aimed to identify metabolomic markers of regression to normoglycemia in the context of a lifestyle intervention (LSI) in individuals with prediabetes. RESEARCH DESIGN AND METHODS: We conducted a single-arm intervention study with 24 weeks of follow-up. Eligible study participants had at least one prediabetes criteria according to the American Diabetes Association guidelines, and body mass index between 25 and 45 kg/m2. LSI refers to a hypocaloric diet and >150 min of physical activity per week. Regression to normoglycemia (RNGR) was defined as achieving hemoglobin A1c (HbA1c) <5.5% in the final visit. Baseline and postintervention plasma metabolomic profiles were measured using liquid chromatography-tandem mass spectrometry. To select metabolites associated with RNGR, we conducted the least absolute shrinkage and selection operator-penalized regressions. RESULTS: The final sample was composed of 82 study participants. Changes in three metabolites were significantly associated with regression to normoglycemia; N-acetyl-D-galactosamine (OR=0.54; 95% CI 0.32 to 0.82), putrescine (OR=0.90, 95% CI 0.81 to 0.98), and 7-methylguanine (OR=1.06; 95% CI 1.02 to 1.17), independent of HbA1c and weight loss. In addition, metabolomic perturbations due to LSI displayed enrichment of taurine and hypotaurine metabolism pathway (p=0.03) compatible with biomarkers of protein consumption, lower red meat and animal fats and higher seafood and vegetables. CONCLUSIONS: Evidence from this study suggests that specific metabolomic markers have an influence on glucose regulation in individuals with prediabetes after 24 weeks of LSI independently of other treatment effects such as weight loss.

Nontargeted and Targeted Metabolomic Profiling Reveals Novel Metabolite Biomarkers of Incident Diabetes in African Americans.

Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or "known" and 2,342 nontargeted or "unknown" compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)-a community cohort of self-identified African Americans-who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of <0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose. Of these, 144 and 68 associations, respectively, replicated in a multiethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ = 0.29), and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.

Evaluation of a Web Platform to Record Lifestyle Habits in Subjects at Risk of Developing Type 2 Diabetes in a Middle-Income Population: Prospective Interventional Study.

BACKGROUND: Lifestyle is the focus of type 2 diabetes (T2D) prevention strategies. Prevention strategies using mobile health (mHealth)-based therapy have shown positive results for T2D prevention in high-income settings, but little is known about their effectiveness in low- and middle-income populations where the burden of T2D is substantial. "Vida Sana" is a web platform designed to record lifestyle habits and medication use within a lifestyle change program. OBJECTIVE: We sought to identify the barriers, feasibility, usability, and effectiveness of Vida Sana to record lifestyle habits in subjects at risk of developing T2D in a middle-income setting. METHODS: This was a 3-month prospective interventional study in Mexican individuals. A total of 77 subjects at risk of T2D (with prediabetes and BMI between 24 and 40 kg/m2) were selected. Feasibility was assessed by study retention. Usability was evaluated with the System Usability Scale (SUS). Effectiveness measures included changes in weight, body composition, BMI, glycated hemoglobin A1c (HbA1c), and fasting blood glucose from baseline to 3 months. Linear regression models were used to account for covariates. RESULTS: The feasibility of Vida Sana was 42%, with 33 subjects using the platform, and the usability was 48.7 (SD 14.24). Reported barriers to platform usage were; difficulty in accessing the platform from difficulty of use (12 subjects, 36%), lack of time to record their habits (11 subjects, 34%), lack of interest to record their habits (6 subjects, 18%), and lack of resources (4 subjects, 11%). The platform was effective for lowering glucose in fasting (-3.1 mg/dL vs -0.11 [SD 8.08] mg/dL; P=.038) and at 2 hours (-16.9 mg/dL vs 2.5 [SD 26.1] mg/dL; P=.045), body fat percentage (-1.3 [-2.2 to -0.7] vs -1.02 [-1.9 to -0.3]; P=.02), and waist circumference (-3.2 [SD 5.1] cm vs -1.7 [SD 5.0] cm; P=.02) independent of their age, sex, treatment, and education level. CONCLUSIONS: The use of the web platform was effective for improving glycemic and anthropometric parameters in a population at risk of developing diabetes. Improving accessibility and ease of navigation could improve the acceptance of digital health solutions in a middle-income population.

Mecanosensores en el cambio de fenotipo de la musculatura lisa vascular / Mechanosensors and phenotype changes in vascular smooth muscle

Resumen: Introducción: Las células de la musculatura lisa vascular (CMLV) se caracterizan por mantener cierto grado de desdiferenciación, variando su fenotipo entre el contráctil y el secretor, de acuerdo con las necesidades del tejido, y el contráctil predominante en condiciones fisiológicas. Cualquier alteración del estímulo mecánico, ya sea en el flujo sanguíneo o la tensión mecánica ejercida sobre las CMLV, conducen a cambios de su fenotipo y remodelamiento de la vasculatura, lo que puede constituir el punto de inflexión de varias patologías relevantes en la salud pública como, por ejemplo, la hipertensión arterial. Objetivo: Realizar una revisión sobre los mecanosensores y las vías transduccionales conocidas e implicadas en el cambio de fenotipo de las CMLV. Metodología: Se realizó una búsqueda sistemática en las bases de datos PubMed, Scopus, Google Académico y Scielo sobre la mantención y cambio de fenotipo de las células de la musculatura lisa vascular asociado principalmente a el estrés mecánico, la participación de los mecanosensores más relevantes y las vías de señalización involucrados en este proceso. Conclusión: Los mecanosensores implicados en el cambio de fenotipo de las CMLV contemplan principalmente receptores acoplados a proteína G, moléculas de adhesión y canales iónicos activados por estiramiento. Los estudios se han concentrado en la activación o inhibición de vías como las proteínas quinasas activadas por mitógenos (MAPK), la vía AKT, mTOR y factores transcripcionales que regulan la expresión de genes de diferenciación y/o desdiferenciación, como las miocardinas. Existen además otros receptores involucrados en la respuesta al estrés mecánico, como los receptores tirosina quinasas. A pesar de la importancia que reviste el conocimiento de los mecanosensores y las vías implicadas en el cambio de fenotipo de las CMLV, así como el papel que cumplen en el establecimiento de patologías vasculares, es aún escaso el conocimiento que se tiene sobre los mismos.

Abstract: Introduction: Vascular smooth muscle cells (VS- MCs) are characterized by maintaining a certain de- gree of dedifferentiation. VSMCs may vary their phenotype between contractile and secretory according to tissue needs. Under physiological conditions, the predominant phenotype is contractile. Any alteration of the mechanical stimulus, either in the blood flow or the mechanical stress exerted on the VSMCs, leads to changes in their phenotype and remodeling of the vasculature. These changes can constitute the turning point in several hypertension and other diseases relevant in public health. Objective: To review the main mechanosensor and transduction pathways involved changes in VSMCs phenotype. Methods: A systematic search of PubMed, Scopus, Google Scholar and Scielo databases was carried out to ascertain the state of the art regarding the maintenance and change of VSMCs phenotype mainly associated with mechanical stress. Additionally, the participation of the most relevant mechanosensors and the signaling pathways involved in this process are discussed. Conclusion: The mechanosensors involved in the change in VSMCs phenotype mainly contempla- te G-protein-coupled receptors, adhesion molecules, and stretch-activated ion channels. Studies have been focused on the activation or inhibition of MAPK, AKT, mTOR, pathways and transcriptional factors that regulate the expression of differentiation and/or des differentiation genes such as Myocardins. There are also other receptors involved in the response to mechanical stress such as the tyrosine kinases receptor. Although the importance of understanding mechanosensors, the signaling pathways involved in VSMC phenotype switching and their role in the establishment of vascular pathologies, knowledge about them is limited.

GEM: scalable and flexible gene-environment interaction analysis in millions of samples.

MOTIVATION: Gene-environment interaction (GEI) studies are a general framework that can be used to identify genetic variants that modify the effects of environmental, physiological, lifestyle or treatment effects on complex traits. Moreover, accounting for GEIs can enhance our understanding of the genetic architecture of complex diseases and traits. However, commonly used statistical software programs for GEI studies are either not applicable to testing certain types of GEI hypotheses or have not been optimized for use in large samples. RESULTS: Here, we develop a new software program, GEM (Gene-Environment interaction analysis in Millions of samples), which supports the inclusion of multiple GEI terms, adjustment for GEI covariates and robust inference, while allowing multi-threading to reduce computation time. GEM can conduct GEI tests as well as joint tests of genetic main and interaction effects for both continuous and binary phenotypes. Through simulations, we demonstrate that GEM scales to millions of samples while addressing limitations of existing software programs. We additionally conduct a gene-sex interaction analysis on waist-hip ratio in 352 768 unrelated individuals from the UK Biobank, identifying 24 novel loci in the joint test that have not previously been reported in combined or sex-specific analyses. Our results demonstrate that GEM can facilitate the next generation of large-scale GEI studies and help advance our understanding of the genetic architecture of complex diseases and traits. AVAILABILITY AND IMPLEMENTATION: GEM is freely available as an open source project at https://github.com/large-scale-gxe-methods/GEM. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Gene-environment interaction analysis incorporating sex, cardiometabolic diseases, and multiple deprivation index reveals novel genetic associations with COVID-19 severity.

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors (obesity and type 2 diabetes [T2D], tested jointly), and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the PGF gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

Hyperventilation maneuver during EEG in children with epilepsy after the COVID-19 pandemic. Is a routine procedure necessary?

OBJECTIVE: Hyperventilation (HV) is one of the main and basic activation methods during ambulatory electroencephalogram (EEG), unless medical reasons contraindicate it. During the COVID-19 pandemic, with the high risk of human-to-human infection, local guidelines and recommendations have been developed that suggest not to perform the HV maneuver routinely. Our objective was to characterize patients who present positive HV in an epilepsy center. METHODS: We analyzed retrospectively all the ambulatory EEGs performed during one year in our specialized ambulatory child and adolescent epilepsy center, and describe patients with positive maneuver. RESULTS: A total of 305 EEGs were performed. Patients under 3 years and 11 months were excluded as well as all patients that did not fill up the criteria for epilepsy diagnosis. From the 252 EEGs that were included in the study, 194 EEGs (77%) were classified as abnormal and 58 (23%) as normal. From these same 252 EEGs, 150 EEG finished correctly the HV maneuver. Physiological slowing response was found in 54 EEGs (36%), no changes (negative) in 83 (55%), and abnormal response (positive) in 13 EEGs (9%). The 13 HV-positive EEGs showed 4 patients with an increase of epileptiform activity, 3 patients experienced an increase of basal preregistered abnormal slowing, and 6 EEGs showed trigger of bilaterally synchronous and symmetric 2-4 Hz spike-and-slow wave discharges and absences. None of these last 6 patients needed more than 3 minutes to elicit the paroxysmal discharge. SIGNIFICANCE: Based on these findings and according with other studies, the low positivity and high specificity of the HV maneuver support the idea that HV could be excluded during the COVID-19 pandemic situation, and also reevaluate whether it could be changed to a complementary maneuver, restricted only for cases where absence epilepsy is suspected. Larger studies will be needed to reaffirm this proposal.

Clinical and metabolomic predictors of regression to normoglycemia in a population at intermediate cardiometabolic risk.

BACKGROUND: Impaired fasting glucose (IFG) is a prevalent and potentially reversible intermediate stage leading to type 2 diabetes that increases risk for cardiometabolic complications. The identification of clinical and molecular factors associated with the reversal, or regression, from IFG to a normoglycemia state would enable more efficient cardiovascular risk reduction strategies. The aim of this study was to identify clinical and biological predictors of regression to normoglycemia in a non-European population characterized by high rates of type 2 diabetes. METHODS: We conducted a prospective, population-based study among 9637 Mexican individuals using clinical features and plasma metabolites. Among them, 491 subjects were classified as IFG, defined as fasting glucose between 100 and 125 mg/dL at baseline. Regression to normoglycemia was defined by fasting glucose less than 100 mg/dL in the follow-up visit. Plasma metabolites were profiled by Nuclear Magnetic Resonance. Multivariable cox regression models were used to examine the associations of clinical and metabolomic factors with regression to normoglycemia. We assessed the predictive capability of models that included clinical factors alone and models that included clinical factors and prioritized metabolites. RESULTS: During a median follow-up period of 2.5 years, 22.6% of participants (n = 111) regressed to normoglycemia, and 29.5% progressed to type 2 diabetes (n = 145). The multivariate adjusted relative risk of regression to normoglycemia was 1.10 (95% confidence interval [CI] 1.25 to 1.32) per 10 years of age increase, 0.94 (95% CI 0.91-0.98) per 1 SD increase in BMI, and 0.91 (95% CI 0.88-0.95) per 1 SD increase in fasting glucose. A model including information from age, fasting glucose, and BMI showed a good prediction of regression to normoglycemia (AUC = 0.73 (95% CI 0.66-0.78). The improvement after adding information from prioritized metabolites (TG in large HDL, albumin, and citrate) was non-significant (AUC = 0.74 (95% CI 0.68-0.80), p value = 0.485). CONCLUSION: In individuals with IFG, information from three clinical variables easily obtained in the clinical setting showed a good prediction of regression to normoglycemia beyond metabolomic features. Our findings can serve to inform and design future cardiovascular prevention strategies.

Gene-Environment Interaction Analysis Incorporating Sex, Cardiometabolic Diseases, and Multiple Deprivation Index Reveals Novel Genetic Associations With COVID-19 Severity.

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors [obesity and type 2 diabetes (T2D), tested jointly], and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the placental growth factor (PGF) gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

Spanish Version of the System Usability Scale for the Assessment of Electronic Tools: Development and Validation.

BACKGROUND: The System Usability Scale (SUS) is a common metric used to assess the usability of a system, and it was initially developed in English. The implementation of electronic systems for clinical counseling (eHealth and mobile health) is increasing worldwide. Therefore, tools are needed to evaluate these applications in the languages and regional contexts in which the electronic tools are developed. OBJECTIVE: This study aims to translate, culturally adapt, and validate the original English version of the SUS into a Spanish version. METHODS: The translation process included forward and backward translation. Forward translations were made by 2 native Spanish speakers who spoke English as their second language, and a backward translation was made by a native English speaker. The Spanish SUS questionnaire was validated by 10 experts in mobile app development. The face validity of the questionnaire was tested with 10 mobile phone users, and the reliability testing was conducted among 88 electronic application users. RESULTS: The content validity index of the new Spanish SUS was good, as indicated by a rating of 0.92 for the relevance of the items. The questionnaire was easy to understand, based on a face validity index of 0.94. The Cronbach α was .812 (95% CI 0.748-0.866; P<.001). CONCLUSIONS: The new Spanish SUS questionnaire is a valid and reliable tool to assess the usability of electronic tools among Spanish-speaking users.

Contribution of Known Genetic Risk Variants to Dyslipidemias and Type 2 Diabetes in Mexico: A Population-Based Nationwide Study.

Dyslipidemias are common risk factors for the development of chronic disorders including type 2 diabetes (T2D). Over 100 associated loci have been identified but few reports have evaluated the population attributable fraction captured by them in population-based nationwide surveys. Therefore, we determined the population contribution of a set of known genetic risk variants to the development of dyslipidemias and T2D in Mexico. This study included 1665 participants from a Mexican National Health Survey carried out in the year 2000. It is a probabilistic complex sample survey of households, which comprises representative data at a national level. 103 previously reported SNPs associated with different dyslipidemias or T2D were genotyped and used to compute polygenic risk scores. We found that the previously known variants associated with dyslipidemias explain at most 7% of the total risk variance of lipid levels. In contrast, the known genetic risk component for T2D explained a negligible amount of variance (0.1%). Notably, variants derived from the Native-American ancestry have the strongest effect and contribute with a high proportion of the variance. These results support the need for additional studies aimed to identify specific genetic risk variants for Mexican population.

Unidad de Hospitalización Domiciliaria del Hospital del Mar. Equipo de atención psiquiátrica domiciliaria en el área de Barcelona / Psychiatric Home Hospitalization Unit of the Hospital del Mar. A crisis resolution and home treatment team in Barcelona

Introducción: A pesar del desarrollo de la hospitalización domiciliaria en España durante los últimos años, es llamativa la escasez de literatura. El siguiente estudio pretende exponer los datos obtenidos por la Unidad de Hospitalización a Domicilio de Psiquiatría del Hospital del Mar (HADMar). HADMar es un programa de hospitalización domiciliaria creado hace 2años, que recibe pacientes procedentes de servicios comunitarios y hospitalarios con un seguimiento limitado en el tiempo. Al alta, el paciente es derivado a la unidad de referencia ambulatoria apropiada para cada caso. Material y métodos: Se seleccionó a todos los pacientes visitados desde 2015 hasta la actualidad. Se llevó a cabo un estudio descriptivo que define las características sociodemográficas de la muestra. Las variables clínicas estudiadas fueron la gravedad de los síntomas, el riesgo de suicidio y los cambios en la funcionalidad. Resultados: Un total de 135 pacientes fueron incluidos en la muestra. La edad media de los pacientes fue de 44,6 años y no hubo diferencias entre ambos sexos. De ellos, 26 pacientes tenían un historial de intentos autolíticos y el 11,1% vivían solos. El 51,1% fueron diagnosticados de un trastorno psicótico. La puntuación media en la escala GEP en la variable gravedad de los síntomas psiquiátricos fue 2,39 y el riesgo medio de suicidio 0,49. La puntuación de EEAG al alta era mayor que al ingreso. Conclusiones: Los resultados obtenidos en nuestro estudio son consistentes con resultados reportados en estudios previos. Los equipos de hospitalización domiciliaria han demostrado ser una alternativa a la hospitalización tradicional. Sin embargo, se necesitan más estudios que apoyen estos resultados

Introduction: Although home hospitalization has begun to develop widely in recent years there is a notable lack of studies. The following study includes data from the Psychiatric Home Hospitalization Unit of the Hospital del Mar (HADMar). This program has been running for 2years and takes place in a socio-demographically depressed area in Barcelona. It receives patients from community and hospital services. Monitoring is limited in time and at discharge patient are referred to the ambulatory unit. Material and methods: All patients visited from 2015 to the present time were selected. A total of 135 patients were included in the sample. A qualitative descriptive study was carried out in order to define the socio-demographic characteristics. The severity of symptoms, suicidal risk and changes in the functionality were considered as clinical outcomes. Results: The mean age of patients was 44.6 years and there were no gender differences. A total of 26 patients had a history of suicidal attempts and 11.1% lived alone; 51.1% were diagnosed with a psychotic disorder. The mean GEP score for the severity of the psychiatric symptoms was 2.39 and the mean risk of suicide was 0.49. There is an increase in the EEAG score from admission to discharge, which means an improvement in the functionality of patients. Conclusions: The results obtained in our study are consistent with previous results. Home crisis intervention teams have proved to be an alternative to traditional hospitalization. However, more studies are needed to support these results

Glucocorticoids Decrease Longitudinal Bone Growth in Pediatric Kidney Transplant Recipients by Stimulating the FGF23/FGFR3 Signaling Pathway.

Renal transplantation (RTx) is an effective therapy to improve clinical outcomes in pediatric patients with terminal chronic kidney disease. However, chronic immunosuppression with glucocorticoids (GCs) reduces bone growth and BMD. The mechanisms causing GC-induced growth impairment have not been fully clarified. Fibroblast growth factor 23 (FGF23) is a peptide hormone that regulates phosphate homeostasis and bone growth. In pathological conditions, FGF23 excess or abnormal FGF receptors (FGFR) activity leads to bone growth impairment. Experimental data indicate that FGF23 expression is induced by chronic GC exposure. Therefore, we hypothesize that GCs impair bone growth by increasing FGF23 expression, which has direct effects on bone growth plate. In a post hoc analysis of a multicentric randomized clinical trial of prepubertal RTx children treated with early GC withdrawal or chronic GC treatment, we observed that GC withdrawal was associated with improvement in longitudinal growth and BMD, and lower plasma FGF23 levels as compared with a chronic GC group. In prepubertal rats, GC-induced bone growth retardation correlated with increased plasma FGF23 and bone FGF23 expression. Additionally, GC treatment decreased FGFR1 expression whereas it increased FGFR3 expression in mouse tibia explants. The GC-induced bone growth impairment in tibiae explants was prevented by blockade of FGF23 receptors using either a pan-FGFR antagonist (PD173074), a C-terminal FGF23 peptide (FGF23180-205) which blocks the binding of FGF23 to the FGFR-Klotho complex or a specific FGFR3 antagonist (P3). Finally, local administration of PD173074 into the tibia growth plate ameliorated cartilage growth impairment in GC-treated rats. These results show that GC treatment partially reduces longitudinal bone growth via upregulation of FGF23 and FGFR3 expression, thus suggesting that the FGF23/Klotho/FGFR3 axis at the growth plate could be a potential therapeutic target for the management of GC-induced growth impairment in children.