Genetic counselors' awareness and attitudes regarding gene therapies.

There are 10 gene therapies (GTs) for hereditary conditions that are currently approved by the Food and Drug Administration (FDA). While prior research demonstrates that the majority of healthcare providers lack knowledge regarding GTs, this has not been explored within the genetic counseling profession. The authors hypothesize that the availability of GTs impacts the genetic counseling profession and that there is variable awareness on this topic among genetic counselors (GCs). We conducted a survey to assess GCs' familiarity with, comfort with, and frequency of discussing FDA-approved GTs at the time of the survey, as well as GCs' perceived impact of and educational experiences related to GT. The survey was distributed through listservs and word of mouth from January through March 2021. One hundred of the 109 responses met eligibility criteria. Respondents were more familiar with onasemnogene abeparvovec-xioi (ZOLGENSMA; Novartis Gene Therapies, Inc., Durham, NC, USA) than voretigene neparvovec-rzyl (LUXTURNA; Spark Therapeutics, Inc., Philadelphia, PA, USA; p < 0.001). Familiarity with, comfort with, and frequency of discussing both GTs varied by specialty but not by years of experience. Fifty-nine percent of respondents (58/98) reported that GTs impact their work, with differences by specialty but not by years of experience. The majority of respondents (93%; 90/97) felt that GCs should be comfortable discussing GTs with patients, and most respondents (83%; 79/95) were interested in additional GT training. Only 38% of respondents (36/95) recalled GT being included in their genetic counseling training program's curriculum, which may be skewed by recent growth of this field. Our results suggest that GCs feel that GTs impact their practice, have discrepant awareness and comfort in this area, and desire additional training on this topic. Further investigation into the actual impact and models for addressing training is warranted and will be critical as the number of approved GTs increases.

Risk of longer-term neurological conditions in the Deepwater Horizon Oil Spill Coast Guard Cohort Study - Five years of follow-up.

BACKGROUND: Long-term neurological health risks associated with oil spill cleanup exposures are largely unknown. We aimed to investigate risks of longer-term neurological conditions among U.S. Coast Guard (USCG) responders to the 2010 Deepwater Horizon (DWH) oil spill. METHODS: We used data from active duty members of the DWH Oil Spill Coast Guard Cohort Study (N=45224). Self-reported oil spill exposures were ascertained from post-deployment surveys. Incident neurological outcomes were classified using International Classification of Diseases, 9th Revision, codes from military health encounter records up to 5.5 years post-DWH. We used Cox Proportional Hazards regression to calculate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for various incident neurological diagnoses (2010-2015). Oil spill responder (n=5964) vs. non-responder (n= 39260) comparisons were adjusted for age, sex, and race, while within-responder comparisons were additionally adjusted for smoking. RESULTS: Compared to those not responding to the spill, spill responders had reduced risks for headache (aHR=0.84, 95% CI: 0.74-0.96), syncope and collapse (aHR=0.74, 95% CI: 0.56-0.97), and disturbance of skin sensation (aHR=0.81, 95% CI: 0.68-0.96). Responders reporting ever (n=1068) vs. never (n=2424) crude oil inhalation exposure were at increased risk for several individual and grouped outcomes related to headaches and migraines (aHR range: 1.39-1.83). Crude oil inhalation exposure was also associated with elevated risks for an inflammatory nerve condition, mononeuritis of upper limb and mononeuritis multiplex (aHR=1.71, 95% CI: 1.04-2.83), and tinnitus (aHR=1.91, 95% CI: 1.23-2.96), a condition defined by ringing in one or both ears. Risk estimates for those neurological conditions were higher in magnitude among responders reporting exposure to both crude oil and oil dispersants than among those reporting crude oil only. CONCLUSION: In this large study of active duty USCG responders to the DWH disaster, self-reported spill cleanup exposures were associated with elevated risks for longer-term neurological conditions.

Cardiovascular Disease in Adults with Type 1 Diabetes: Looking Beyond Glycemic Control.

PURPOSE OF REVIEW: Despite improvements in treatment, people with type 1 diabetes continue to have increased cardiovascular disease (CVD) risk. Glycemic control does not fully explain this excess CVD risk, so a greater understanding of other risk factors is needed. RECENT FINDINGS: The authors review the relationship between glycemia and CVD risk in adults with type 1 diabetes and summarize evidence regarding other factors that may explain risk beyond glycemia. Insulin resistance, weight gain, sex differences, genetics, inflammation, emerging markers of risk, including lipid subclasses and epigenetic modifications, and future directions are discussed. As glycemic control improves, an increased focus on other CVD risk factors is warranted in type 1 diabetes. Novel markers and precision medicine approaches may improve CVD prediction, but a lack of type 1 diabetes-specific guidelines for lipids, blood pressure, and physical activity are likely impediments to optimal CVD prevention in this high-risk population.

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes.

BACKGROUND: Rare variants in gene coding regions likely have a greater impact on disease-related phenotypes than common variants through disruption of their encoded protein. We searched for rare variants associated with onset of ESKD in individuals with type 1 diabetes at advanced kidney disease stage. METHODS: Gene-based exome array analyses of 15,449 genes in five large incidence cohorts of individuals with type 1 diabetes and proteinuria were analyzed for survival time to ESKD, testing the top gene in a sixth cohort (n=2372/1115 events all cohorts) and replicating in two retrospective case-control studies (n=1072 cases, 752 controls). Deep resequencing of the top associated gene in five cohorts confirmed the findings. We performed immunohistochemistry and gene expression experiments in human control and diseased cells, and in mouse ischemia reperfusion and aristolochic acid nephropathy models. RESULTS: Protein coding variants in the hydroxysteroid 17-ß dehydrogenase 14 gene (HSD17B14), predicted to affect protein structure, had a net protective effect against development of ESKD at exome-wide significance (n=4196; P value=3.3 × 10-7). The HSD17B14 gene and encoded enzyme were robustly expressed in healthy human kidney, maximally in proximal tubular cells. Paradoxically, gene and protein expression were attenuated in human diabetic proximal tubules and in mouse kidney injury models. Expressed HSD17B14 gene and protein levels remained low without recovery after 21 days in a murine ischemic reperfusion injury model. Decreased gene expression was found in other CKD-associated renal pathologies. CONCLUSIONS: HSD17B14 gene is mechanistically involved in diabetic kidney disease. The encoded sex steroid enzyme is a druggable target, potentially opening a new avenue for therapeutic development.

Cardiovascular health in early adulthood predicts the development of coronary heart disease in individuals with type 1 diabetes: 25 year follow-up from the Pittsburgh Epidemiology of Diabetes Complications study.

AIMS/HYPOTHESIS: Type 1 diabetes increases CHD risk. We examined the use of the American Heart Association's cardiovascular health metrics (blood pressure, total cholesterol, glucose/HbA1c, BMI, physical activity, diet, smoking) to predict incidence of CHD among individuals with type 1 diabetes, with the hypothesis that a better American Heart Association health metric profile would be associated with lower incident CHD. METHODS: Prevalence of the seven cardiovascular health metrics was determined using first and second visits from adult participants (mean age 28.6 years) in the Epidemiology of Diabetes Complications prospective cohort study of childhood-onset type 1 diabetes. An ideal metric score (0-7) was defined as the sum of all metrics within the ideal range, and a total metric score (0-14) was calculated based on poor, intermediate and ideal categories for each metric. Incident CHD development (medical record-confirmed CHD death, myocardial infarction, revascularisation, ischaemic electrocardiogram changes or Epidemiology of Diabetes Complications physician-determined angina) over 25 years of follow-up was examined by metric scores. RESULTS: Among 435 participants, BMI, blood pressure, total cholesterol and smoking demonstrated the highest prevalence within the ideal range, while diet and HbA1c demonstrated the lowest. During 25 years of follow-up, 177 participants developed CHD. In Cox models, each additional metric within the ideal range was associated with a 19% lower risk (p = 0.01), and each unit increase in total metric score was associated with a 17% lower risk (p < 0.01) of CHD, adjusting for diabetes duration, estimated glomerular filtration rate, albumin excretion rate, triacylglycerols, depression and white blood cell count. CONCLUSIONS/INTERPRETATION: Among individuals with type 1 diabetes, higher cardiovascular health metric scores were associated with lower risk of incident CHD. The American Heart Association-defined cardiovascular health metrics provide straightforward goals for health promotion that may reduce CHD risk in the type 1 diabetes population. Graphical abstract.

Heterogeneous long-term trajectories of glycaemic control in type 1 diabetes.

AIMS: We aimed to identify long-term HbA1c trajectories and examine associated characteristics in an observational, childhood-onset (<17 years) type 1 diabetes cohort. METHODS: Data are from the Epidemiology of Diabetes Complications study, comprising 405 participants with ≥2 of seven possible HbA1c measurements over follow-up (1988-2013) and available DNA (baseline mean diabetes duration 21 years, 53% men). HbA1c trajectories were estimated using latent class growth models. Baseline and change in participant characteristics were compared across trajectories. RESULTS: Five HbA1c trajectories were identified: low (51%), intermediate stable (22%), improved (19%), high stable (6%), and worsened (2%; not included in analyses). Age, diabetes duration, diabetes onset age, and sex did not differ across trajectories. Characteristics did not differ significantly between intermediate stable and low trajectories at baseline, though albumin excretion rate (AER, p = 0.0002) and estimated glomerular filtration rate (eGFR, p = 0.001) worsened slightly more in intermediate stable over time. Improved and high stable trajectories had higher baseline LDL-c (p = 0.002 and 0.003, respectively). Improved trajectory increased median self-monitoring of blood glucose from <1 to 3.5 times/day (p < 0.0001) and had larger LDL-c improvement (p = 0.004) but greater worsening of AER (p < 0.0001) and eGFR (p < 0.0001) than low. The A allele of rs12970134 (near MC4R) was associated with improved (p = 0.0003) or high stable (p = 0.001) HbA1c trajectory, both patterns with high baseline HbA1c. CONCLUSIONS: Long-term HbA1c trajectories were primarily associated with modifiable factors in this type 1 diabetes cohort. The intermediate stable pattern had a risk factor profile that suggests some protection against adverse metabolic effects of chronic hyperglycaemia, warranting further study.

The effects of hydroxychloroquine on insulin sensitivity, insulin clearance and inflammation in insulin-resistant adults: A randomized trial.

AIM: To determine the effect of hydroxychloroquine (HCQ) on skeletal muscle and liver insulin sensitivity, insulin clearance, inflammation and adipokines. METHODS: Insulin-resistant adults without rheumatic disease were randomized to 13 weeks of HCQ (400 mg/day) versus placebo (double-blinded). Primary outcomes were changes in skeletal muscle and liver insulin sensitivity assessed by hyperinsulinaemic-euglycaemic clamp and stable-isotope tracer methods. Secondary outcomes included insulin clearance, inflammation biomarkers and adipokines. RESULTS: Compared with placebo, HCQ significantly improved skeletal muscle insulin sensitivity by 26% (p = .019) and enhanced systemic glucose clearance (p = .025). By contrast, HCQ had no effect on hepatic insulin sensitivity. HCQ did not affect insulin clearance but decreased circulating IL-6 (p = .01) and increased adiponectin (p = .045). There were no effects on leptin, RBP-4, FGF-21 or C-reactive protein. CONCLUSIONS: HCQ selectively enhances insulin sensitivity and glucose disposal in skeletal muscle, without affecting hepatic insulin sensitivity or insulin clearance. These findings offer a mechanistic explanation for the antidiabetic properties of HCQ and suggest that this medication might be useful in conditions linked to insulin resistance such as type 2 diabetes.

The role of Sociodemographic factors on goal achievement in a community-based diabetes prevention program behavioral lifestyle intervention.

BACKGROUND: The Diabetes Prevention Program (DPP) behavioral lifestyle intervention was effective among a diverse sample of adults with prediabetes. Demonstrated effectiveness in translated versions of the DPP lifestyle intervention (such as Group Lifestyle Balance, DPP-GLB) led to widescale usage with national program oversight and reimbursement. However, little is known about the success of these DPP-translation programs across subgroups of sociodemographic factors. This current effort investigated potential disparities in DPP-translation program primary goal achievement (physical activity and weight) by key sociodemographic factors. METHODS: Data were combined from two 12-month community-based DPP-GLB trials among overweight/obese individuals with prediabetes and/or metabolic syndrome. We evaluated change in weight (kilograms and percent) and activity (MET-hrs/week) and goal achievement (yes/no; ≥5% weight loss and 150 min per week activity) after 6 and 12 months of intervention within and across subgroups of race/ethnicity (non-Hispanic white, non-Hispanic black), employment status, education, income, and gender. RESULTS: Among 240 participants (85%) with complete data, most sociodemographic subgroups demonstrated significant weight loss. However, non-Hispanic white lost more weight at both 6 and 12 months compared to non-Hispanic black participants [median weight loss (IQR), 6 months: 5.7% (2.7-9.0) vs. 1.5% (1.2-7.5) p = .01 and 12 months: 4.8% (1.1-9.6) vs. 1.1% (- 2.0-3.7) p = .01, respectively]. In addition, a larger percentage of non-Hispanic white demonstrated a 5% weight loss at 6 and 12 months. Employment was significantly related to 12-month weight loss, with retired participants being the most successful. Men, participants with graduate degrees, and those with higher income were most likely to meet the activity goal at baseline and 12 months. Differences in physical activity goal achievement across gender, education, and income groups were significant at baseline, attenuated after 6 months, then re-emerged at 12 months. CONCLUSIONS: The DPP-GLB was effective in promoting weight loss and helped to alleviate disparities in physical activity levels after 6 months. Despite overall program success, differences in weight loss achievement by race/ethnicity were found and disparities in activity re-emerged after 12 months of intervention. These results support the need for intervention modification providing more tailored approaches to marginalized groups to maximize the achievement and maintenance of DPP-GLB behavioral goals. TRIAL REGISTRATION: NCT01050205 , NCT02467881 .

A Targeted Multiomics Approach to Identify Biomarkers Associated with Rapid eGFR Decline in Type 1 Diabetes.

BACKGROUND: Individuals with type 1 diabetes (T1D) demonstrate varied trajectories of estimated glomerular filtration rate (eGFR) decline. The molecular pathways underlying rapid eGFR decline in T1D are poorly understood, and individual-level risk of rapid eGFR decline is difficult to predict. METHODS: We designed a case-control study with multiple exposure measurements nested within 4 well-characterized T1D cohorts (FinnDiane, Steno, EDC, and CACTI) to identify biomarkers associated with rapid eGFR decline. Here, we report the rationale for and design of these studies as well as results of models testing associations of clinical characteristics with rapid eGFR decline in the study population, upon which "omics" studies will be built. Cases (n = 535) and controls (n = 895) were defined as having an annual eGFR decline of ≥3 and <1 mL/min/1.73 m2, respectively. Associations of demographic and clinical variables with rapid eGFR decline were tested using logistic regression, and prediction was evaluated using area under the curve (AUC) statistics. Targeted metabolomics, lipidomics, and proteomics are being performed using high-resolution mass-spectrometry techniques. RESULTS: At baseline, the mean age was 43 years, diabetes duration was 27 years, eGFR was 94 mL/min/1.73 m2, and 62% of participants were normoalbuminuric. Over 7.6-year median follow-up, the mean annual change in eGFR in cases and controls was -5.7 and 0.6 mL/min/1.73 m2, respectively. Younger age, longer diabetes duration, and higher baseline HbA1c, urine albumin-creatinine ratio, and eGFR were significantly associated with rapid eGFR decline. The cross-validated AUC for the predictive model incorporating these variables plus sex and mean arterial blood pressure was 0.74 (95% CI: 0.68-0.79; p < 0.001). CONCLUSION: Known risk factors provide moderate discrimination of rapid eGFR decline. Identification of blood and urine biomarkers associated with rapid eGFR decline in T1D using targeted omics strategies may provide insight into disease mechanisms and improve upon clinical predictive models using traditional risk factors.

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen.

BACKGROUND: Although diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown. METHODS: To identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function. RESULTS: Our GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1). CONCLUSIONS: The 16 diabetic kidney disease-associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

The role of coronary artery calcification testing in incident coronary artery disease risk prediction in type 1 diabetes.

AIMS/HYPOTHESIS: We sought to assess the role of coronary artery calcification (CAC) and its progression in predicting incident coronary artery disease (CAD) in individuals with type 1 diabetes using data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. METHODS: The present study examined 292 participants who had at least one CAC measure and were free from CAD at baseline; 181 (62%) had repeat CAC assessments 4-8 years later and did not develop CAD between the two CAC measures. The HRs of incident CAD events were estimated using Cox models in categorised or in appropriately transformed CAC scores. C statistics and net reclassification improvement (NRI) were used to assess the added predictive value of CAC for incident CAD. RESULTS: At baseline, the mean age of participants was 39.4 years and the mean diabetes duration was 29.5 years. There were 76 participants who experienced a first incident CAD event over an average follow-up of 10.7 years. At baseline, compared with those without CAC (Agatston score = 0), the adjusted HR (95% CI) in groups of 1-99, 100-399 and ≥400 was 3.1 (1.6, 6.1), 4.4 (2.0, 9.5) and 4.8 (1.9, 12.0), respectively. CAC density was inversely associated with incident CAD in those with CAC volume ≥100 (HR 0.3 [95% CI 0.1, 0.9]) after adjusting for volume score. Among participants with repeated CAC measures, annual CAC progression was positively associated with incident CAD after controlling for baseline CAC. The HR (95% CI) for above vs below the median annual CAC volume progression was 3.2 (1.2, 8.5). When compared with a model that only included established risk factors, the addition of CAC improved the predictive ability for incident CAD events in the whole group. CONCLUSIONS/INTERPRETATION: CAC is strongly associated with incident CAD events in individuals with type 1 diabetes; its inclusion in CAD risk models may lead to improvement in prediction over established risk factors.

Glucose Management and the Sex Difference in Excess Cardiovascular Disease Risk in Long-Duration Type 1 Diabetes.

PURPOSE OF REVIEW: The protection against CVD observed in women compared to men in the general population is essentially erased in type 1 diabetes. This review will discuss evidence regarding the role of glucose management on CVD risk by sex, with a particular focus on studies of long-duration type 1 diabetes of > 20 years. RECENT FINDINGS: Across studies, women with type 1 diabetes have similar or worse glycemic control compared to men, despite higher rates of intensive insulin therapy. The association between HbA1c and CVD risk does not seem to differ by sex, but few studies have reported on sex-specific analyses. Beyond HbA1c, there is a lack of published data regarding the relationship between other aspects of glucose management and CVD risk by sex in type 1 diabetes. Glucose management factors do not seem to directly account for the increased CVD risk in women with type 1 diabetes, but may influence other risk factors that play a more direct role.

Hemoglobin A1c Level and Cardiovascular Disease Incidence in Persons With Type 1 Diabetes: An Application of Joint Modeling of Longitudinal and Time-to-Event Data in the Pittsburgh Epidemiology of Diabetes Complications Study.

Type 1 diabetes (T1D) is associated with increased risk of cardiovascular disease (CVD), but hyperglycemia (measured by hemoglobin A1c (HbA1c) level), which characterizes T1D, has itself been an inconsistent predictor of CVD incidence. However, only baseline HbA1c or a summary measure (e.g., mean level over follow-up) is usually analyzed. Joint models allow simultaneous modeling of repeatedly measured longitudinal covariates, using random effects, and time-to-event data. We evaluated data from the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing prospective cohort study of childhood-onset T1D that has followed participants since 1986-1988 and has repeatedly found little association between baseline HbA1c or mean follow-up HbA1c and coronary artery disease incidence. Of 561 participants without CVD at baseline, 263 (46.9%) developed CVD over a period of 25 years (1986-2014). In joint models, each 1% unit increase in HbA1c trajectory was associated with a 1.26-fold increased risk of CVD (95% confidence interval: 1.07, 1.45), after adjustment for baseline levels of other CVD risk factors, and a 1.13-fold increased risk (95% confidence interval: 0.99, 1.32) after adjustment for updated mean levels of other CVD risk factors. These findings, which support the need for good glycemic control to prevent CVD in persons with T1D, underscore the importance of utilizing methods incorporating within-subject variation over time when analyzing and interpreting longitudinal cohort study data.

Impact of a community-based lifestyle intervention program on health-related quality of life.

BACKGROUND: The presence of risk factors for type 2 diabetes and cardiovascular disease, or the conditions themselves, contributes to lower health-related quality of life (HRQoL) among adults. Although community-based lifestyle intervention programs have been shown to be effective for improving risk factors for these diseases, the impact of these interventions on HRQoL has rarely been described. PURPOSE: To examine changes in HRQoL following participation in the Group Lifestyle Balance program, a community translation of the Diabetes Prevention Program lifestyle intervention for adults with prediabetes and/or the metabolic syndrome. METHODS: Participants enrolled in the 12-month, 22-session intervention program (N = 223) completed the EuroQol Health Questionnaire (EQ-5D-3L) at baseline, 6, and 12 months. Linear mixed-effects regression models determined change in EQ-5D-visual analog scale (VAS) and Index scores post-intervention. RESULTS: Mean EQ-5D-VAS was improved by +7.38 (SE = 1.03) at 6 months and by +6.73 (SE = 1.06) at 12 months post-intervention (both; p < 0.0001). Mean changes in EQ-5D index values were +0.00 (SE = 0.01; NS) and +0.01 (SE = 0.01; p < 0.05), respectively. Adjusted for age, baseline score, and achieving intervention goals, mean change in EQ-5D-VAS was +11.83 (SE = 1.61) at 6 months and +11.23 (SE = 1.54) at 12 months (both; p < 0.0001). Adjusted mean change in EQ-5D index value was +0.04 (SE = 0.01) at 6 months and +0.05 (SE = 0.01) at 12 months (both; p < 0.01). CONCLUSION: Participation in a community lifestyle intervention program resulted in improved HRQoL among adults with prediabetes and/or the metabolic syndrome. These benefits to HRQoL, together with improved clinical and behavioral outcomes, should increase the appeal of such programs for improving health.

Predicting major outcomes in type 1 diabetes: a model development and validation study.

AIMS/HYPOTHESIS: Type 1 diabetes is associated with a higher risk of major vascular complications and death. A reliable method that predicted these outcomes early in the disease process would help in risk classification. We therefore developed such a prognostic model and quantified its performance in independent cohorts. METHODS: Data were analysed from 1,973 participants with type 1 diabetes followed for 7 years in the EURODIAB Prospective Complications Study. Strong prognostic factors for major outcomes were combined in a Weibull regression model. The performance of the model was tested in three different prospective cohorts: the Pittsburgh Epidemiology of Diabetes Complications study (EDC, n = 554), the Finnish Diabetic Nephropathy study (FinnDiane, n = 2,999) and the Coronary Artery Calcification in Type 1 Diabetes study (CACTI, n = 580). Major outcomes included major CHD, stroke, end-stage renal failure, amputations, blindness and all-cause death. RESULTS: A total of 95 EURODIAB patients with type 1 diabetes developed major outcomes during follow-up. Prognostic factors were age, HbA1c, WHR, albumin/creatinine ratio and HDL-cholesterol level. The discriminative ability of the model was adequate, with a concordance statistic (C-statistic) of 0.74. Discrimination was similar or even better in the independent cohorts, the C-statistics being: EDC, 0.79; FinnDiane, 0.82; and CACTI, 0.73. CONCLUSIONS/INTERPRETATION: Our prognostic model, which uses easily accessible clinical features can discriminate between type 1 diabetes patients who have a good or a poor prognosis. Such a prognostic model may be helpful in clinical practice and for risk stratification in clinical trials.

Sex differences in the associations of HDL particle concentration and cholesterol efflux capacity with incident coronary artery disease in type 1 diabetes: The RETRO HDLc cohort study.

BACKGROUND: In type 1 diabetes, women lose their relative protection (compared to men) against coronary artery disease (CAD), while high-density lipoprotein cholesterol (HDL-C) is less strongly associated with lower CAD risk in women. OBJECTIVE: We aimed to assess whether sex differences in the HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) association with CAD may explain these findings. METHODS: HDL-P (calibrated differential ion mobility analysis) and total and ATP binding cassette transporter A1 (ABCA1)-specific CEC were quantified among 279 men and 271 women with type 1 diabetes (baseline mean age 27·8 years; diabetes duration, 19·6 years). Clinical CAD was defined as CAD death, myocardial infarction and/or coronary revascularization. RESULTS: Women had higher large HDL-P levels and marginally lower concentrations of small HDL-P and ABCA1-specific CEC than men. No sex differences were observed in extra-small HDL-P, medium HDL-P and total CEC. During a median follow-up of 26 years, 37·6 % of men and 35·8 % of women developed CAD (p = 0·72). In multivariable Cox models stratified by sex (pTotal HDL-P x sex interaction=0·01), HDL-P was negatively associated with CAD incidence in both sexes. However, associations were stronger in men, particularly for extra-small HDL-P (hazard ratio (HR)men=0·11, 95 % confidence interval (CI): 0·04-0·30; HRwomen=0·68, 95 % CI: 0·28-1·66; pinteraction=0·001). CEC did not independently predict CAD in either sex. CONCLUSION: Despite few absolute differences in HDL-P concentrations by sex, the HDL-P - CAD association was weaker in women, particularly for extra-small HDL-P, suggesting that HDL-P may be less efficient in providing atheroprotection in women and perhaps explaining the lack of a sex difference in CAD in type 1 diabetes.

Accuracy of Urinalysis for UTI in Spina Bifida.

OBJECTIVES: Urinary tract infections (UTIs) are common, but overdiagnosed, in children with spina bifida. We sought to evaluate the diagnostic test characteristics of urinalysis (UA) findings for symptomatic UTI in children with spina bifida. METHODS: Retrospective cross-sectional study using data from 2 centers from January 1, 2016, to December 31, 2021. Children with myelomeningocele aged <19 years who had paired UA (and microscopy, when available) and urine culture were included. The primary outcome was symptomatic UTI. We used generalized estimating equations to control for multiple encounters per child and calculated area under the receiver operating characteristics curve, sensitivity, and specificity for positive nitrites, pyuria (≥10 white blood cells/high-powered field), and leukocyte esterase (more than trace) for a symptomatic UTI. RESULTS: We included 974 encounters from 319 unique children, of which 120 (12.3%) met our criteria for UTI. Pyuria had the highest sensitivity while nitrites were the most specific. Comparatively, nitrites were the least sensitive and pyuria was the least specific. When the cohort was limited to children with symptoms of a UTI, pyuria remained the most sensitive parameter, whereas nitrites remained the least sensitive. Nitrites continued to be the most specific, whereas pyuria was the least specific. Among all encounters, the overall area under the receiver operating characteristics curve for all components of the UA was lower in children who use clean intermittent catheterizations compared with all others. CONCLUSIONS: Individual UA findings have moderate sensitivity (leukocyte esterase or pyuria) or specificity (nitrites) but overall poor diagnostic accuracy for symptomatic UTIs in children with spina bifida.

An Epigenome-Wide Association Study of DNA Methylation and Proliferative Retinopathy over 28 Years in Type 1 Diabetes.

Purpose: To perform a prospective epigenome-wide association study of DNA methylation (DNAm) and 28-year proliferative diabetic retinopathy (PDR) incidence in type 1 diabetes (T1D). Design: Prospective observational cohort study. Participants: The Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (< 17 years) T1D. Methods: Stereoscopic fundus photographs were taken in fields 1, 2, and 4 at baseline, 2, 4, 6, 8, 16, 23, and 28 years after DNAm measurements. The photos were graded using the modified Airlie House System. In those free of PDR at baseline (n = 265; mean T1D duration of 18 years at baseline), whole blood DNAm (EPIC array) at 683 597 CpGs was analyzed in Cox models for time to event. Associations between significant CpGs and clinical risk factors were assessed; genetic variants associated with DNAm were identified (methylation quantitative trait loci [meQTLs]). Mendelian randomization was used to examine evidence of causal associations between DNAm and PDR. Post hoc regional and functional analyses were performed. Main Outcome Measures: Proliferative diabetic retinopathy was defined as the first instance of a grade of ≥ 60 in at least 1 eye or pan-retinal photocoagulation for PDR. Follow-up time was calculated from the study visit at which DNAm data were available (baseline) until PDR incidence or censoring (December 31, 2018 or last follow-up). Results: PDR incidence was 53% over 28-years' follow-up. Greater DNAm of cg27512687 (KIF16B) was associated with reduced PDR incidence (P = 6.3 × 10-9; false discovery rate [FDR]: < 0.01); 113 cis-meQTLs (P < 5 × 10-8) were identified. Mendelian randomization analysis using the sentinel meQTL as the instrumental variable supported a potentially causal association between cg27512687 and PDR. Cg27512687 was also associated with lower pulse rate and albumin excretion rate and higher estimated glomerular filtration rate, but its association with PDR remained independently significant after adjustment for those factors. In regional analyses, DNAm of FUT4, FKBP1A, and RIN2 was also associated with PDR incidence. Conclusions: DNA methylation of KIF16B, FUT4, FKBP1A, and RIN2 was associated with PDR incidence, supporting roles for epigenetic regulation of iron clearance, developmental pathways, and autophagy in PDR pathogenesis. Further study of those loci may provide insight into novel targets for interventions to prevent or delay PDR in T1D. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

High-Density Lipoprotein Particle Concentration and Size Predict Incident Coronary Artery Disease Events in a Cohort With Type 1 Diabetes.

BACKGROUND: The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL-cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL-P)-rather than HDL-cholesterol-predict incident CAD in type 1 diabetes. METHODS AND RESULTS: Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood-onset type 1 diabetes. HDL-P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow-up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person-years. In multivariable Cox models, neither HDL-cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra-small HDL-P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14-0.50]). Weaker associations were observed for total HDL-P (HR, 0.88 [95% CI, 0.83-0.93]), small HDL (HR, 0.83 [95% CI, 0.68-1.02]), medium HDL (HR, 0.79 [95% CI, 0.71-0.89]), and large HDL (HR, 0.72 [95% CI, 0.59-0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL-P. CONCLUSIONS: Lower concentrations of total HDL-P and HDL subpopulations were positively associated with incident CAD independently of HDL-cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra-small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.