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Background: Toileting behaviors are increasingly recognized as factors potentially contributing to development of lower urinary tract symptoms (LUTS). Objectives: To examine adult women's toileting behaviors and LUTS across age and race/ethnicity groups and relationships between toileting behaviors and LUTS. Design: Planned secondary analysis of questionnaire data collected in a focus group study on bladder health. Settings: Questionnaires were completed at the conclusion of focus groups conducted in community settings affiliated with seven research centers across the United States. Participants: Community-living women regardless of LUTS status. Methods: Forty-four focus groups were conducted with 360 adolescent and adult cisgender women. After each focus group, participants completed questionnaires to assess toileting behaviors (Toileting Behaviors-Women's Elimination Behaviors Scale (TB-WEB)) and their experience of LUTS (Lower Urinary Tract Symptom Tool), This analysis includes quantitative data from the subgroup of 316 participants who completed the questionnaires. Results: Participants ranged in age from 18 to 93 years (Mean= 50.2 years). A significant effect for age was found for delayed voiding behavior, reported by 76.5% of women ages 18–25 years and 21.9% of those 75+ years (p

Goals The goal of this study was to evaluate whether proton pump inhibitor (PPI) use is cross-sectionally associated with hypomagnesemia and whether hypomagnesemia mediates the prospective association between PPIs and cardiovascular disease (CVD) risk. Background Use of PPIs has been associated with hypomagnesemia, primarily in case reports or within insurance databases. Both PPI use and low serum magnesium (Mg) have been associated with modestly higher CVD risk. Yet, the interrelation between PPI use and Mg in relation to CVD risk is unclear. Study The 4436 Atherosclerosis Risk in Communities participants without prevalent CVD at visit 5 (baseline, 2011-2013) were included. Multivariable relative risk regression was used for cross-sectional analyses between PPI and hypomagnesemia prevalence (≤0.75 mmol/L). Incident CVD (defined by atrial fibrillation, coronary heart disease, CVD mortality, heart failure, stroke) was identified through 2017. Multivariable Cox regression was used to examine the PPI-CVD association. Results Participants were mean±SD aged 75±5 years; 63% were women, 23% Black, and 24% were PPI users. PPI users had 1.24-fold (95% confidence interval: 1.08-1.44) higher prevalence of hypomagnesemia than nonusers. Over a median 5 years of follow-up, 684 incident CVD events occurred. PPI users had higher CVD risk [hazard ratio (95% confidence interval) 1.31 (1.10-1.57)] than nonusers. The effect estimate was largely unchanged when hypomagnesemia was added to the model as a potential mediator. Conclusions In this elderly community-based study, PPI users had a higher prevalence of hypomagnesemia than in nonusers. PPI users also had higher CVD risk than nonusers; however, it appears unlikely that hypomagnesemia explains associations of PPIs with CVD risk.

Background: Little research to date has investigated the spectrum of bladder health in women, including both bladder function and well-being. Therefore, we expanded our previous baseline analysis of bladder health in the Boston Area Community Health (BACH) Survey to incorporate several additional measures of bladder-related well-being collected at the 5-year follow-up interview, including one developed specifically for women. Methods: At follow-up, participants reported their frequency of 15 lower urinary tract symptoms (LUTS), degree of life impact from and thought related to urinary symptoms or pelvic/bladder pain/discomfort, and perception of their bladder condition. Prevalence ratios were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. The BACH Survey was approved by the New England Research Institutes Institutional Review Board and all participants provided written informed consent. Results: Generally similar findings were observed in the 5-year cross-sectional analysis as at baseline, irrespective of how we categorized LUTS or measured bladder-related well-being. Approximately one in five women (16.2%–18.0% of 2527 eligible women) reported no LUTS and no diminished bladder-related well-being, the majority (55.8%–65.7%) reported some LUTS and/or diminished well-being, and a further one in five (16.9%–26.6%) reported the maximum frequency, number, or degree of LUTS and/or diminished well-being. Measures of storage function (urinating again after

When conducting a meta-analysis involving prevalence data for an outcome with several subtypes, each of them is typically analyzed separately using a univariate meta-analysis model. Recently, multivariate meta-analysis models have been shown to correspond to a decrease in bias and variance for multiple correlated outcomes compared to univariate meta-analysis, when some studies only report a subset of the outcomes. In this article, we propose a novel Bayesian multivariate random effects model to account for the natural constraint that the prevalence of any given subtype cannot be larger than that of the overall prevalence. Extensive simulation studies show that this new model can reduce bias and variance when estimating subtype prevalences in the presence of missing data, compared to standard univariate and multivariate random effects models. The data from a rapid review on occupation and lower urinary tract symptoms by the Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium are analyzed as a case study to estimate the prevalence of urinary incontinence and several incontinence subtypes among women in suspected high risk work environments.

Author(s): Schmitz, Kathryn H; Bavendam, Tamara; Brady, Sonya S; Brubaker, Linda; Burgio, Kathryn; Harlow, Bernard L; James, Aimee; Lukacz, Emily S; Miller, Janis M; Newman, Diane K; Palmer, Mary H; Rudser, Kyle; Sutcliffe, Siobhan; Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium | Abstract: AimsPrior research on lower urinary tract symptoms (LUTS) has focused on the treatment and management of these conditions with scant attention to prevention. The Prevention of Lower Urinary Tract Symptoms (PLUS) Research Consortium was formed to address the complexities of preventing LUTS and promoting bladder health.MethodsHerein, we describe challenges faced and strategies used to develop the PLUS Research Consortium into an engaged and productive transdisciplinary scientific team. We apply four previously defined team science phases (development, conceptualization, implementation, and translation) to frame our progress.ResultsStrategies to progress through the development phase included the generation of a shared mission, and valuing of other disciplinary perspectives. The conceptualization phase included generating a shared language and developing a team transdisciplinary orientation. During the implementation phase, the group developed roles and procedures and focused on conflict management. The translation phase includes continued refinement of the mission and goals, implementation of research protocols, and robust dissemination of the scientific work products related to bladder health.ConclusionA diverse group has matured into a productive transdisciplinary team science consortium. Achieving this outcome required dedicated effort for each member to engage in activities that often required more time than single discipline research activities. Provision of the necessary time and tools has fostered a transdisciplinary team science culture and rich research agenda that reflects the complexity of the health issue to be addressed. Our experience may be useful for others embarking on team science projects.

Background: Healthcare disparities associated with race/ethnicity and low English proficiency are well established in the US. We sought to determine if there are race/ethnic differences in anti-obesity medication prescription rates among youth with severe obesity (body mass index (BMI) ≥1.2 times the 95th percentile and/or BMI ≥35 kg/m2) treated in a pediatric weight management clinic (PWMC). We secondarily sought to determine if, among youth from families in whom English was not the primary language, there are differences in prescription rates between those using an interpreter during visits and those not. Methods: We reviewed electronic health records of youth 2–18 years old with severe obesity seen at a PWMC from 2012–2020. Race/ethnicity was self-reported and categorized as Non-Hispanic White (NHW), Hispanic/Latino, Non-Hispanic Black (NHB), Asian, American Indian/Alaska Native and Mixed. Anti-obesity medicines included stimulants (i.e. phentermine, lisdexamfetamine), topiramate, naltrexone (± bupropion), and glucagon-like peptide-1 agonists. We used Poisson regression models with robust standard errors to compare incidence rates of medicine prescription (incidence rate ratio (IRR), accounting for visit frequency) within the first 1 and 3 years of being followed in a PWMC. We controlled for age, baseline degree of obesity (percent of the 95th BMI percentile (%BMIp95)), number of obesity-related comorbidities (i.e. insulin resistance, hypertension, fatty liver), area-level socioeconomic status (median household income based on ZIP code), and interpreter use. We repeated similar analyses among families in whom English was not the primary language, comparing those using an interpreter with those not. Results: From 2012–2020, 1258 youth (mean age 11.8 years; %BMIp95 143%) were seen in our PWMC (57% NHW, 19% Hispanic/Latino, 16% NHB) of which 26% were prescribed anti-obesity medication. 86% primarily spoke English and 5.2% used an interpreter. There were no statistically significant differences in the IRR of prescriptions by race/ethnicity at 1 and 3 years; however, although not statistically significant point estimates suggest Hispanic/Latino youth being prescribed medication less often at 1 (IRR 0.71; p=0.08) and 3 (IRR 0.75; p=0.13) years compared to NHW. Among non-primary English speakers, rates of prescriptions were higher at 1 (IRR 5.7; p Conclusions: We found no significant race/ethnic differences in anti-obesity medication prescriptions; however, Hispanic/Latino youth received fewer prescriptions, albeit not statistically significant. Among non-primary English speakers, use of an interpreter was associated with increased prescriptions. Our results suggest that addressing healthcare disparities and language barriers may improve care delivery for youth with obesity.

BACKGROUND: There are limited data comparing the relative associations of various BMI metrics with adiposity and cardiometabolic risk factors in youth. OBJECTIVE: Examine correlations of 7 different BMI metrics with adiposity, cardiometabolic risk factors, and biomarkers (i.e. blood pressure, waist circumference, cholesterol, leptin, insulin, high molecular weight adiponectin, high-sensitivity c-reactive protein (hsCRP)). METHODS: This was a cross-sectional analysis of youth in all BMI categories. BMI metrics: BMI z-score (BMIz), extended BMIz (ext. BMIz), BMI percentile (BMIp), percent of the BMI 95th percentile (%BMI(p95)), percent of the BMI median (%BMI(p50)), triponderal mass index (TMI), and BMI (BMI). Correlations between these BMI metrics and adiposity, visceral adiposity, cardiometabolic risk factors and biomarkers were summarized using Pearson’s correlations. RESULTS: Data from 371 children and adolescents ages 8–21 years old were included in our analysis: 52% were female; 20.2% with Class I obesity, 20.5% with Class II, and 14.3% with Class III obesity. BMIp consistently demonstrated lower correlations with adiposity, risk factors, and biomarkers (r = 0.190–0.768) than other BMI metrics. The %BMI(p95) and %BMI(p50) were marginally more strongly correlated with measures of adiposity as compared to other BMI metrics. The ext.BMIz did not meaningfully outperform BMIz. CONCLUSION: Out of all the BMI metrics evaluated, %BMI(p95) and %BMI(p50) were the most strongly correlated with measures of adiposity. %BMI(p95) has the benefit of being used currently to define obesity and severe obesity in both clinical and research settings. BMIp consistently had the lowest correlations. Future research should evaluate the longitudinal stability of various BMI metrics and their relative associations with medium to long-term changes in adiposity and cardiometabolic outcomes in the context of intervention trials.

Aim: We assessed reproducibility of endothelial microparticles (EMPs) enumeration among youth. Methods & results: Four microparticle (MP) indices – total MP per microliter platelet free plasma (PFP), total EMPs per microliter PFP, percent activated EMPs and percent lactadherin positive (LACT[+]) of total EMPs – were measured at two visits (baseline and 7 ± 3 days follow-up) to determine reproducibility overall and by obesity status. We examined CD31+ or CD144+ with CD41-EMP events of size 0.3–1.0 μm. No statistically significant differences were observed between visits for any of the four MP indices. The within-participant and between-participant coefficient of variation was acceptable (range: 1.13–2.37) with good intraclass-correlation coefficient for all indices except total MP per microliter (range: 0.10–1.00). Conclusion: Total EMPs per microliter PFP, percent-activated EMPs and percent LACT(+) of total EMPs are reproducible among youth.

Purpose: Many adult survivors of childhood cancer are at high-risk of developing cardiovascular disease. Cancer therapy may cause damage to the vascular endothelium, thereby initiating atherosclero...

ObjectivePrevious research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I.MethodsVolumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls.ResultsThe MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT.ConclusionsWe found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

Background: Alpha-1-antitrypsin (A1AT) deficiency (A1ATD) is characterized by accelerated degradation of lung function. We examined our experience with lung transplantation for chronic obstructive pulmonary disease (COPD) with and without A1ATD to compare survival and rates of postoperative surgical complications. Methods: Patients with A1ATD and non-A1ATD COPD undergoing lung transplantation from 1988−2015 at our institution were analyzed. Complications were categorized into non-gastroenteritis gastrointestinal (GI), wound, airway, and reoperation for bleeding. Overall and complication-free survival were evaluated using Kaplan-Meier curves and Cox proportional hazards models. Results: Three hundred and eighty-five patients underwent lung transplant for COPD (98 A1ATD). For A1ATD, 56.1% underwent single lung transplantation (80.6% for COPD). Early overall and complication-free survival was worse for A1ATD, but this trend reversed at longer follow up. Unadjusted estimated survival showed advantage for COPD at 90 days and 1 year, which attenuated by 5 years and reversed at 10 years (P

Introduction: Endothelial activation represents one of the earliest signs of the atherosclerotic process. Microparticles (MPs) in plasma, particularly endothelial MPs (EMPs) are reproducible biomarkers of endothelial dysfunction with a simple blood draw. The goal of this study was to examine the association of obesity with MPs, EMPs (CD31+/CD41– and/or CD 144+/CD31–), and activated EMPs (CD106+). Hypothesis: We hypothesized that higher body mass index (BMI), body fat percent (BF%), and visceral adipose tissue (VAT) would be associated with higher levels of MPs, EMPs, and activated EMPs. Methods: This was a cross-sectional study of 280 children and adolescents ages 8-18 years old. Whole venous blood was collected and processed for platelet free-plasma (PFP) collection less than 3 hours after being drawn. PFP samples were prepared using serial centrifugations and then frozen as 100 μl aliquots at -80 ° C. MPs were measured using flow cytometry with size ranging from 0.3 to 1.0 μm. EMPs were defined as MP with CD31+/CD41– and/or CD 144+/CD31–. Active EMP was identified as EMP with CD 106+. BF% and VAT were measured using dual X-ray absorptiometry. Linear (total MPs and EMPs) and logistic (activated EMPs) regression models were used to examine the associations with adiposity group, BF%, and VAT, adjusting for Tanner stage, sex, and race. Results: The mean age of the cohort was 12.7 years, consisting of 147 females and BMI distribution: 112 normal-weight, 77 overweight/obesity, 91 severe obesity. Youth with overweight/obesity and severe obesity had higher numbers of total MPs (28,690 per μL PFP/g [-2,315, 59,695], p=0.07 and 52,744 per μL PFP/g [22,163, 83,324], p85 th percentile compared to youth with a BMI th percentile. In the entire cohort, BF% (odds ratio, 1.02 [1.00, 1.04], p=0.108) and VAT (odds ratio, 1.00 [1.00, 1.00], p=0.472) were not significantly associated with active EMPs. Conclusions: Higher levels of endothelial cell damage and activation were associated with obesity and excess adiposity in youth. The potential role of MPs and EMPs as useful biomarkers of cardiovascular disease risk merits further study.

Summary Background Weight loss in children and adolescents with type 2 diabetes (T2D) is associated with improved glycaemic control. Objectives To assess the effects of liraglutide vs placebo on body mass index (BMI) and weight parameters in children and adolescents with T2D using data from the ellipse trial (NCT01541215). Methods The ellipse trial randomized participants (10‐85th percentile, T2D, glycated haemoglobin [HbA1c] 7.0%‐11.0% [if diet‐ and exercise‐treated] or 6.5% to 11.0% [if treated with metformin, basal insulin or both]) to liraglutide or placebo. This post‐hoc analysis evaluated changes from baseline to weeks 26 and 52 in absolute BMI, percent change in BMI and other weight‐related parameters. Changes were assessed by liraglutide overall (all doses) and liraglutide by dose (0.6, 1.2 and 1.8 mg/day) vs placebo using a pattern mixture model of observed data, with missing observations imputed from each treatment group. Results In total, 134 participants were included. There were statistically significant differences between groups in certain parameters, including absolute BMI (estimated treatment difference [ETD] –0.89 kg/m2; 95% confidence interval [CI] –1.71,–0.06) and percent change in BMI (ETD –2.73%; 95% CI –5.15,–0.30) at week 52, but none at week 26. Dose‐dependent effects were not observed for liraglutide vs placebo for all BMI/weight parameters. Conclusions Compared with placebo, liraglutide was associated with statistically significant reductions in BMI/weight parameters at week 52, but not week 26, in children and adolescents with T2D.

Background Bladder health is an understudied state and difficult to measure due to lack of valid and reliable instruments. While condition specific questionnaires assess presence, severity and degree of bother from lower urinary tract symptoms, the absence of symptoms is insufficient to assume bladder health. This study describes the methodology used to validate a novel bladder health instrument to measure the spectrum of bladder health from very healthy to very unhealthy in population based and clinical research. Methods Three samples of women are being recruited: a sample from a nationally representative general population and two locally recruited clinical center samples—women with a targeted range of symptom severity and type, and a postpartum group. The general population sample includes 694 women, 18 years or older, randomly selected from a US Postal delivery sequence file. Participants are randomly assigned to electronic or paper versions of the bladder health instrument along with a battery of criterion questionnaires and a demographic survey; followed by a retest or a two-day voiding symptom diary. A total of 354 women around 7 clinical centers are being recruited across a spectrum of self-reported symptoms and randomized to mode of completion. They complete the two-day voiding symptom diary as well as a one-day frequency volume diary prior to an in-person evaluation with a standardized cough stress test, non-invasive urine flowmetry, chemical urine analysis and post void residual measurement. Independent judge ratings of bladder health are obtained by interview with a qualified health care provider. A total of 154 postpartum women recruited around 6 of the centers are completing similar assessments within 6–12 weeks postpartum. Dimensional validity will be evaluated using factor analysis and principal components analysis with varimax rotation, and internal consistency with Cronbach’s alpha. Criterion validity will be assessed using multitrait-multimethod matrix including correlations across multiple data sources and multiple types of measures. Discussion We aim to validate a bladder health instrument to measure the degree of bladder health within the general population and among women (including postpartum) recruited from local clinical centers. Trial registration NCT04016298 Posted July 11, 2019 (https://www.clinicaltrials.gov/ct2/show/NCT04016298?cond=bladder+health&draw=2&rank=1).

Background Circulating endothelial cells (CECs) reflect early changes in endothelial health; however, the degree to which CEC number and activation is related to adiposity and cardiovascular risk factors in youth is not well described. Methods and Results Youth in this study (N=271; aged 8–20 years) were classified into normal weight (body mass index [BMI] percentage P >0.05). Youth with severe obesity had a higher degree of CEC activation compared with normal weight youth (8.3%; 95% CI, 1.1–15.6 [ P =0.024]). Higher CEC number was associated with greater body fat percentage (0.02 per percentage; 95% CI, 0.00–0.03 [ P =0.020]) and systolic blood pressure percentile (0.01 per percentage; 95% CI, 0.00–0.01 [ P =0.035]). Higher degree of CEC activation was associated with greater visceral adipose tissue (5.7% per kg; 95% CI, 0.4–10.9 [ P =0.034]) and non–high‐density lipoprotein cholesterol (0.11% per mg/dL; 95% CI, 0.01–0.21 [ P =0.039]). Conclusions Methods of CEC quantification are associated with adiposity and cardiometabolic risk factors and may potentially reflect accelerated atherosclerosis as early as childhood.

PurposeWe describe the item development and cognitive evaluation process used in creating the Prevention of Lower Urinary Tract Symptoms Bladder Health Instrument (PLUS-BHI).Materials and methodsQuestions assessing bladder health were developed using reviews of published items, expert opinion, and focus groups' transcript review. Candidate items were tested through cognitive interviews with community-dwelling women and an online panel survey. Items were assessed for comprehension, language, and response categories and modified iteratively to create the PLUS-BHI.ResultsExisting measures of bladder function (storage, emptying, sensation components) and bladder health impact required modification of time frame and response categories to capture a full range of bladder health. Of the women 167 (18-80 years old) completed individual interviews and 791 women (18-88 years) completed the online panel survey. The term "bladder health" was unfamiliar for most and was conceptualized primarily as absence of severe urinary symptoms, infection, or cancer. Coping mechanisms and self-management strategies were central to bladder health perceptions. The inclusion of prompts and response categories that captured infrequent symptoms increased endorsement of symptoms across bladder function components.ConclusionsBladder health measurement is challenged by a lack of awareness of normal function, use of self-management strategies to mitigate impact on activities, and a common tendency to overlook infrequent lower urinary tract symptoms. The PLUS-BHI is designed to characterize the full spectrum of bladder health in women and will be validated for research use.

Gaucher disease is an autosomal recessive metabolic disorder caused by mutations in GBA1, which encodes for the lysosomal hydrolase enzyme, β-glucocerebrosidase. The resulting misfolded protein can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The enzyme deficiency leads to accumulation of its substrates, glucosylceramide and glucosylsphingosine, within macrophage lysosomes and with prominent disease manifestations in macrophage rich tissues. Resultant lysosomal pathology and impaired autophagy leads to redox imbalance, mitochondrial dysfunction and intracellular oxidative stress. Here we have systematically examined a role for oxidative stress in individuals affected by Gaucher disease. We compared multiple oxidative stress biomarkers in plasma and red blood cell samples from patients who are currently untreated, with those who are stable on standard-of-care therapy, and with healthy controls. We found significant differences in key oxidative stress biomarkers in untreated patients compared to healthy control. In treated patients, results generally fell between the controls and the untreated patients. Interestingly, even asymptomatic and minimally symptomatic untreated patients had evidence of significant systemic oxidative stress. We conclude that underlying oxidative stress may contribute to Gaucher disease pathophysiology including long-term adverse outcomes such as Parkinsonism and malignancies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for Gaucher disease and other lysosomal storage disorders.

Summary Background Lower urinary tract symptoms (LUTS) are common in children and adolescents. Non-invasive tests evaluating bladder function are generally preferred over invasive tests, yet few studies have explored the range of normative values for these tests in healthy, asymptomatic children. Objective To define normative reference ranges for non-invasive tests of bladder function in healthy, asymptomatic girls and adolescents. Study design A comprehensive search strategy was performed in seven electronic databases through October 2019. English-language studies reporting data on voiding frequency, voided and postvoid residual volumes (PVR) and uroflowmetry results in healthy, asymptomatic girls (mean age ≥ 5 years) were included. Two independent reviewers performed study review, data extraction, and quality assessment. Overall mean estimates and 95% confidence intervals for each bladder function parameter were calculated using random effects models, and 95% normative reference values were estimated. Results Ten studies met eligibility criteria for the meta-analysis (n = 2143 girls, age range: 3–18). Mean estimates of maximum voided volume and PVR were 233.4 ml (95% CI 204.3–262.6; n = 1 study) and 8.6 ml (95% CI 4.8–12.4; n = 2 studies) respectively. Pooled mean estimates for uroflowmetry parameters were: 21.5 ml/s (95% CI 20.5–2.5) for maximum flow rate (n = 6 studies), 12.5 ml/s (95% CI 11.2–13.8) for mean flow rate (n = 6 studies), 6.8 s (95% CI 4.4–9.3) for time to maximum flow (n = 3 studies), 15.7 s (95% CI 13.0–18.5) for flow time (n = 3 studies), and 198.7 ml (95% CI 154.2–234.2) for voided volume (n = 9 studies). No studies reported estimates of voiding frequency. Between-study heterogeneity was high (89.0–99.6%). Conclusions Although we were able to calculate pooled mean estimates for several parameters, the small number of included studies and the wide age ranges of participants preclude generalization of reference values to all healthy girls. Further research is needed to determine normative reference values within specific age groups.

INTRODUCTION: Low serum magnesium (Mg) is associated with an increased incidence of atrial and ventricular arrhythmias. A richer phenotyping of arrhythmia indices, such as burden or frequency, may provide etiologic insights. OBJECTIVES: To evaluate cross-sectional associations of serum Mg with burden of atrial arrhythmias [atrial fibrillation (AF), premature atrial contractions (PAC), supraventricular tachycardia (SVT)], and ventricular arrhythmias [premature ventricular contractions (PVC), non-sustained ventricular tachycardia (NSVT)] over 2-weeks of ECG monitoring. METHODS: We included 2,513 ARIC Study visit 6 (2016-2017) participants who wore the Zio XT Patch—a leadless, ambulatory ECG-monitor—for up to 2-weeks. Serum Mg was modeled categorically and continuously. AF burden was categorized as intermittent or continuous based on the percent of analyzable time spent in AF. Other arrhythmia burdens were defined by the average number of abnormal beats per day. Linear regression was used for continuous outcomes; logistic and multinomial regression were used for categorical outcomes. RESULTS: Participants were mean±SD age 79±5 years, 58% were women and 25% black. Mean serum Mg was 0.82±0.08 mmol/F and 19% had hypomagnesemia (

(1) Background: Magnesium supplementation may be effective for the prevention of cardiometabolic diseases, but the mechanisms are unclear. Proteomic approaches can assist in identifying the underlying mechanisms. (2) Methods: We collected repeated blood samples from 52 individuals enrolled in a double-blind trial which randomized participants 1:1 to oral magnesium supplementation (400 mg magnesium/day in the form of magnesium oxide) or a matching placebo for 10 weeks. Plasma levels of 91 proteins were measured at baseline with follow-up samples using the Olink Cardiovascular Disease III proximity extension assay panel and were modeled as arbitrary units in a log2 scale. We evaluated the effect of oral magnesium supplementation for changes in protein levels and the baseline association between serum magnesium and protein levels. The Holm procedure was used to adjust for multiple comparisons. (3) Results: Participants were 73% women, 94% white, and had a mean age of 62. Changes in proteins did not significantly differ between the two intervention groups after correction for multiple comparisons. The most statistically significant effects were on myoglobin [difference &minus, 0.319 log2 units, 95% confidence interval (CI) (&minus, 0.550, &minus, 0.088), p = 0.008], tartrate-resistant acid phosphatase type 5 (&minus, 0.187, (&minus, 0.328, &minus, 0.045), p = 0.011), tumor necrosis factor ligand superfamily member 13B (&minus, 0.181, (&minus, 0.332, &minus, 0.031), p = 0.019), ST2 protein (&minus, 0.198, (&minus, 0.363, &minus, 0.032), p = 0.020), and interleukin-1 receptor type 1 (&minus, 0.144, (&minus, 0.273, &minus, 0.015), p = 0.029). Similarly, none of the associations of baseline serum magnesium with protein levels were significant after correction for multiple comparisons. (4) Conclusions: Although we did not identify statistically significant effects of oral magnesium supplementation in this relatively small study, this study demonstrates the value of proteomic approaches for the investigation of mechanisms underlying the beneficial effects of magnesium supplementation. Clinical Trials Registration: ClinicalTrials.gov NCT02837328.

Background The normal rate of subclinical vascular aging from adolescence to young adulthood has not been well‐characterized. We conducted a 5‐year longitudinal study among adolescents with normal‐weight, obesity, and/or type 2 diabetes mellitus to examine trajectories of early vascular aging. Methods and Results Adolescents (mean [SD] age 17.6 [3.5]; 35.3% male) had either normal weight (n=141), obesity (n=156), or type 2 diabetes mellitus (n=151) at baseline. Primary metrics used for early vascular aging included measures of vascular structure (carotid intima‐media thickness [cIMT]; common, internal, and bulb) and arterial stiffness (carotid‐femoral pulse wave velocity, and augmentation index). Longitudinal (5‐year) outcomes were examined using generalized estimating equations adjusting for baseline value, sex, race, and age. Compared with participants with normal weight, those with obesity had greater positive change in common cIMT (0.05 mm [0.03, 0.06]; P P =0.033), internal cIMT (0.03 mm [0.01, 0.05]; P P =0.001), and those with type 2 diabetes mellitus had greater positive change in common cIMT (0.05 mm [0.04, 0.07]; P P P P P P P =0.01), internal cIMT (0.008 mm [0.003, 0.013]; P =0.001), and pulse wave velocity carotid‐femoral (0.066 m/sec [0.002, 0.130]; P =0.042). Conclusions These longitudinal data support the hypothesis that the presence of obesity, type 2 diabetes mellitus, and elevated baseline systolic blood pressure in early life accelerates the progression of risk factors key in the development of early vascular aging.

Introduction: Apolipoproteins are key regulators of cholesterol transport and clearance with each apolipoprotein having a specific protective or atherogenic role. The relationship between subclinical cardiovascular risk and each of the apolipoproteins in the pediatric population is insufficiently described within the literature. Therefore, the purpose of this study was to examine the association of apolipoproteins with measures of vascular structure and function in pediatric population. Hypothesis: We hypothesized apolipoprotein AI, AII, and CII would demonstrate a positive association, and apolipoprotein B, B/AI ratio, CIII, CIII/CII ratio, and E a negative association with carotid intima-media thickness (cIMT) and carotid-radial pulse wave velocity (PWV). Methods: A cross-sectional study of 338 children and adolescents (160 males, 178 females) aged 8-21 years (mean age 13.0±2.8 years) with a range of adiposities from normal body weight to severe obesity (mean BMI 26.8±8.9 kg/m 2 ). Apolipoproteins (AI, AII, B, CII, CIII, and E) were measured via human apolipoprotein magnetic bead panel (Millipore, MA, USA). Ultrasound imaging of the carotid artery was used to measure cIMT. PWV, a measure of arterial stiffness, was assessed via applanation tonometry (SphygmoCor TM ). Total body fat percent (BF%) was measured using dual X-ray absorptiometry. Linear regression models were adjusted for Tanner stage, sex, and race with further adjustments for BF%. Data are presented as mean [95% CI] with Holms-adjusted p-values to account for multiple testing. All apolipoprotein ratios were scaled to 0.1 μg/mL. Methods: There were significant positive associations between PWV and apolipoproteins: AII (0.036 m/sec per 10 μg/mL [0.017, 0.056], p = 0.010), E (0.158 m/sec per 10 μg/mL [0.08, 0.235], p = 0.002), and CIII/CII ratio (0.033 [0.014, 0.052], p = 0.019). After adding BF% to the models, PWV remained positively associated with higher levels of apolipoproteins: AII (0.036 m/sec per 10 μg/mL [0.016, 0.055], p = 0.012), E (0.161 m/sec per 10 μg/mL [0.082, 0.239], p = 0.002), and CIII/CII ratio (0.033 [0.014, 0.052], p = 0.02). Before accounting for multiple testing, apolipoprotein CIII/CII ratio was positively associated with cIMT (0.001 [0, 0.003], p = 0.033), but failed to maintain significance after p-value correction. Otherwise, there were no significant associations between any apolipoprotein and cIMT in the presence or absence of BF%. Conclusions: These findings suggest higher levels of apolipoprotein AII, E, and CIII/CII ratio are associated with higher arterial stiffness (PWV) in pediatrics, both in the presence and absence of excess body fat. Apolipoproteins, specifically AII, E, and CIII/CII ratio, may exert their effects on vascular function (PWV) before altering vascular structure (cIMT), which is congruent with the chronological pathophysiology of atherosclerosis.

Background Cardiovascular disease frequently causes morbidity and mortality in mucopolysaccharidoses (MPS); however, cardiovascular anatomy and dysfunction in MPS IVA (Morquio A disease) is not well described. Consequently, the study aimed to compare carotid artery structure and elasticity of MPS IVA patients with other MPS patients and healthy control subjects, and quantitate frequency of MPS IVA cardiac structural and functional abnormalities. Methods Prospective, multi-center echocardiogram and carotid ultrasound evaluations of 12 Morquio A patients were compared with other MPS and healthy control subjects. Average differences between groups were adjusted for age, sex, and height with robust variance estimation for confidence intervals and P-values. Results Morquio A patients demonstrated significantly higher (P P P = 0.003) than control subjects and other MPS patients. Aortic root dilatation was noted in 56% of the Morquio A cohort, which also had highly prevalent mitral (73%) and aortic (82%) valve thickening, though hemodynamically significant valve dysfunction was less frequent (9%). Conclusions Increased carotid elasticity in Morquio A patients is an unexpected contrast to the reduced elasticity observed in other MPS. These Morquio A cIMT findings corroborate MPS IVA arterial post-mortem reports and are consistent with cIMT of other MPS. Aortic root dilatation in Morquio A indicates arterial elastin dysfunction, but their carotid hyperelasticity indicates other vascular intima/media components, such as proteoglycans, may also influence artery function. Studying MPS I and IVA model systems may uniquely illuminate the function of glycosaminoglycan-bearing proteoglycans in arterial health.

Background:This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation.Methods:We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children’s hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls.Results:All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences −30.13 mg/cm3 (p = 0.041), −0.31 mm (p = 0.043), and −6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were −0.46 ± 1.1 and −0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex.Conclusions:In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

We investigated the safety, feasibility, and efficacy of transcranial direct current stimulation (tDCS) combined with constraint-induced movement therapy (CIMT) in children and young adults with unilateral cerebral palsy. Twenty participants were randomized to receive active or sham tDCS. The intervention consisted of 10 consecutive weekday sessions of tDCS applied to the non-lesioned hemisphere (20 min) concurrently with CIMT (120 min). Participants, caregivers, and interventionists were blinded to group assignment. The primary safety outcome investigated adverse events. The primary behavioral outcome was the Assisting Hand Assessment. All 20 participants (mean age = 12.7 yrs, range = 7.4–21.6 years) were evaluated for the primary outcomes. No serious adverse events occurred, and the most commonly reported minor adverse events were headache and itchiness. Both groups demonstrated a significant improvement in hand function after the intervention, although no significant effect of tDCS was observed (between-group difference = −2.18, 95% CI = [−6.48, 2.12], p = 0.30). Although hand function improved overall, no significant differences between intervention groups were found. Children with preserved corticospinal tract circuitry from the lesioned hemisphere, compared to those without, showed greater improvement in hand function (mean difference = 3.04, 95% CI = [−0.64, 6.72], p = 0.099). Our study demonstrates the safety and feasibility of serial sessions of tDCS, and presents preliminary evidence for the effect of CST circuitry on outcomes following tDCS/CIMT. Future work in children with unilateral cerebral palsy should focus on the optimal dosing and consider individual brain circuitry when describing response to combined interventions. Clinical Trials Registration Clinicaltrials.gov NCT 02250092 .

Background. Neurorehabilitation interventions in children with unilateral cerebral palsy (UCP) target motor abilities in daily life yet deficits in hand skills persist. Limitations in the less-affected hand may affect overall bimanual hand skills. Objective. To compare hand function, by timed motor performance on the Jebsen-Taylor Test of Hand Function (JTTHF) and grip strength of children with UCP to children with typical development (CTD), aged 8 to 18 years old. Exploratory analyses compared hand function measures with regard to neurophysiological outcomes measured by transcranial magnetic stimulation and between group comparisons of hemispheric motor threshold. Methods. Baseline hand skills were evaluated in 47 children (21 UCP; 26 CTD). Single-pulse transcranial magnetic stimulation testing assessed corticospinal tract and motor threshold. Results. The mean difference of the less-affected hand of children with UCP to the dominant hand of CTD on the JTTHF was 21.4 seconds (95% CI = 9.32-33.46, P = .001). The mean difference in grip strength was −30.8 N (95% CI = −61.9 to 0.31, P = .052). Resting motor thresholds between groups were not significant, but age was significantly associated with resting motor threshold ( P < .001; P = .001). Children with UCP ipsilateral pattern of motor representation demonstrated greater mean differences between hands than children with contralateral pattern of motor representation ( P < .001). All results were adjusted for age and sex. Conclusions. The less-affected hand in children with UCP underperformed the dominant hand of CTD. Limitations were greater in children with UCP ipsilateral motor pattern. Rehabilitation in the less-affected hand may be warranted. Bilateral hand function in future studies may help identify the optimal rehabilitation and neuromodulatory intervention.

Transcranial direct current stimulation (tDCS) is increasingly researched as an adjuvant to motor rehabilitation for children with hemiparesis. The optimal method for the primary motor cortex (M1) somatotopic localization for tDCS electrode placement has not been established. The objective, therefore, was to determine the location of the M1 derived using the 10/20 electroencephalography (EEG) system and transcranial magnetic stimulation (TMS) in children with hemiparesis (CWH) and a comparison group of typically developing children (TDC). We hypothesized a difference in location for CWH but not for TDC. The 2 locations were evaluated in 47 children (21 CWH, 26 TDC). Distances between the locations were measured pending presence of a motor evoked potential. Distances between the EEG and TMS locations that exceeded the 2.5 cm × 2.5 cm rubber electrode area are reported in percentages [95% confidence interval] in CWH—nonlesioned hemisphere was 68.8% [41.3-89.0], lesioned: 85.7% [57.2-98.2]; TDC—dominant hemisphere 73.9% [51.6-89.8], nondominant: 82.6% [61.2-95.0]. Distances that exceeded the 3 × 5 cm electrode sponge area in CWH—nonlesioned was 25.0% [7.3-52.4], lesioned was 28.6% [8.4-58.1]; TDC—dominant was 52.2% [30.6-73.2], nondominant was 43.5 [23.2-65.5]). Distances that exceeded the 5 × 7 cm electrode sponge area in CWH—nonlesioned was 18.8% [4.0-45.6] and lesioned was 21.4% [4.7-50.8]; TDC—dominant was 21.7% [7.5-43.7] and nondominant was 26.1% [10.2-48.4]. Individual variability in brain somatotopic organization may influence surface scalp localization of underlying M1 in children regardless of neurologic impairment. Findings suggest further investigation of optimal tDCS electrode placement. EEG and TMS methods reveal variability in localizing M1 in children regardless of stroke diagnosis. This study was registered on clinicaltrials.gov NCT020I5338.

Purpose The primary aim of this proposed study is to evaluate brain reorganization patterns in infants with perinatal stroke between 3 and 5 months of age using transcranial magnetic stimulation and magnetic resonance imaging, with the addition of the General Movements Assessment. A secondary aim is to demonstrate feasibility and safety of infant-appropriate brain assessment protocols. Methods Ten infants with perinatal stroke will be enrolled. In this exploratory study, infants will first receive magnetic resonance imaging scanning during natural sleep to examine their corticospinal tract integrity. Infants will then receive transcranial magnetic stimulation to assess their corticomotor excitability. A General Movements Assessment video of at least 5 minutes will also be recorded. Discussion Study results will enhance our understanding of brain reorganization in infants with perinatal stroke. We expect these results will also guide the development of early interventions designed to mitigate maladaptive neuroplastic changes and improve long-term motor outcomes.

Summary Background In adults, poor sleep quality is associated with increased obesogenic eating behaviours; less is known about this relationship in youth. The objectives of this study were to assess the strength of association between fatigue‐related quality of life (QoL) and eating behaviours among youth and to describe the associations in participants with percent body fat (%BF) above and below the 90th percentile for sex and age. Methods Caregiver‐reported measures of fatigue (Pediatric QoL Multidimensional Fatigue Scale) and eating behaviours (Child Eating Behaviour Questionnaire) were obtained from participants aged 8–17 years. %BF was measured by iDXA and grouped by sex‐ and age‐specific percentiles. Multiple linear regression adjusting for age, sex and race/ethnicity was used. Results Of the 352 participants (49% male), 44.6% had %BF >90th percentile. General, sleep/rest and cognitive fatigue QoL was inversely associated with food approach behaviours: food responsiveness, enjoyment of food, emotional overeating and desire to drink. For participants with %BF >90th percentile, higher general fatigue QoL was associated with higher satiety responsiveness (0.13; 95% confidence interval [CI 0.03, 0.24]). For participants with %BF ≤90th percentile, higher general fatigue QoL was associated with less satiety responsiveness (−0.16; 95% CI [−0.31, −0.01]). Conclusion Less fatigue symptoms were associated with less behaviours associated with food approach among paediatric participants. For participants with %BF >90th percentile, less symptoms of general fatigues corresponded with more satiety. Though causation has yet to be established, youth with elevated %BF should be screened for fatigue symptoms and offered counselling on sleep hygiene or a sleep medicine referral to help mitigate weight gain.

Ionized Mg (iMg) is considered the biologically active fraction of circulating total Mg (tMg). It is possible that iMg may be a more physiologically relevant marker than tMg. Using data from a double-blind pilot randomized controlled trial, we tested (1) whether oral Mg supplementation will increase iMg concentrations compared with placebo and (2) the relationship between iMg and tMg at baseline. Additionally, we evaluated the agreement between iMg measured in fresh whole blood versus stored samples. A total of fifty-nine participants were randomized 1:1 to oral Mg supplementation (400 mg/day, Mg Oxide) or placebo for 10 weeks. Fasting blood samples were obtained at baseline and follow-up. The analysis used linear regression and an intent-to-treat approach. Participants were generally healthy, the mean age was 62, and 73% were female. The baseline iMg and tMg were modestly and positively associated (r = 0.50). The ratio of baseline iMg to tMg was 64%. The mean supplement effect on iMg was 0.03 mmol/L (95% CI:0.01, 0.05) for Mg supplementation versus placebo. The supplement effect on iMg was not statistically significantly different according to baseline iMg status (above/below median). Compared to fresh blood, iMg was consistently higher in refrigerated and frozen samples by 0.14 and 0.20 mmol/L, respectively. In this relatively healthy adult population, Mg supplementation over 10 weeks resulted in increased iMg concentrations. Whether iMg is a more appropriate measure of Mg status than tMg, and the public health or clinical utility of measuring iMg remains to be determined.

Background Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. Methods This 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. Results The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. Conclusions Laronidase seemed to improve growth in participants

Type 1 Gaucher disease (GD1), a glycosphingolipid storage disorder caused by deficient activity of lysosomal glucocerebrosidase, is classically considered non-neuronopathic. However, current evidence challenges this view. Multiple studies show that mutations in GBA1 gene and decreased glucocerebrosidase activity are associated with increased risk for Parkinson disease. We tested the hypothesis that subjects with GD1 will show neurochemical abnormalities consistent with cerebral involvement. We performed Magnetic Resonance Spectroscopy at 7 T to quantify neurochemical profiles in participants with GD1 (n = 12) who are on stable therapy. Age and gender matched healthy participants served as controls (n = 13). Neurochemical profiles were obtained from parietal white matter (PWM), posterior cingulate cortex (PCC), and putamen. Further, in the GD1 group, the neurochemical profiles were compared between individuals with and without a single L444P allele. We observed significantly lower levels of key neuronal markers, N-acetylaspartate, γ-aminobutyric acid, glutamate and glutamate-to-glutamine ratio in PCC of participants with GD1 compared to healthy controls (P

Central nervous system manifestations of mucopolysaccharidosis type I (MPS I) such as cognitive impairment, hydrocephalus, and spinal cord compression are inadequately treated by intravenously-administered enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase). While hematopoietic stem cell transplantation treats neurological symptoms, this therapy is not generally offered to attenuated MPS I patients. This study is a randomized, open-label, controlled pilot study of intrathecal laronidase in eight attenuated MPS I patients with cognitive impairment. Subjects ranged between 12years and 50years old with a median age of 18years. All subjects had received intravenous laronidase prior to the study over a range of 4 to 10years, with a mean of 7.75years. Weekly intravenous laronidase was continued throughout the duration of the study. The randomization period was one year, during which control subjects attended all study visits and assessments, but did not receive any intrathecal laronidase. After the first year, all eight subjects received treatment for one additional year. There was no significant difference in neuropsychological assessment scores between control or treatment groups, either over the one-year randomized period or at 18 or 24months. However, there was no significant decline in scores in the control group either. Adverse events included pain (injection site, back, groin), headache, neck spasm, and transient blurry vision. There were seven serious adverse events, one judged as possibly related (headache requiring hospitalization). There was no significant effect of intrathecal laronidase on cognitive impairment in older, attenuated MPS I patients over a two-year treatment period. A five-year open-label extension study is underway.

Previous research has demonstrated the mutation, c.712T>A (p.L238Q) of the gene for α-L- iduronidase (IDUA) in patients with Hurler-Scheie syndrome is relatively severe when paired with a nonsense or deletion or splice-site mutation. This mutation was also found to be associated with psychiatric symptoms. This research presents longitudinal data and protein analysis to further investigate the severity and natural history of these unique patients. Methods: Six patients heterozygous for L238Q were compared to six patients with Hurler-Scheie without the L238Q mutations. Somatic burden of disease, IQ, memory, attention, adaptive functioning and behavioral measures were given yearly over 2 to 4 years from 2009 to 2014. The impact of L238Q on the IDUA enzyme was examined using 7 bioinformatics tools and a 3D structural analysis. Results: Similar to the cross sectional study, the L238Q patients had more severe abnormalities in IQ, attention, adaptive functioning, and behavioral functioning than the comparison group. There were no major differences between the two groups in change over time; IQ for both groups was stable with some behavioral areas showing improvement. Over time, both groups declined in visual spatial memory and, attention/visual processing. They also showed increased anxiety. Structural and bioinformatics analysis of the L238Q suggest that this mutation causes a significant reduction in the IDUA enzyme's potential catalytic activity, and this mutation may be more severe than other mutations contributing to the Hurler-Scheie syndrome phenotype, presumably causing the psychiatric disease. Conclusion: L238Q patients demonstrate severe neurocognitive and neurobehavioral deficits but are relatively stable. Like the comparison group, decreasing visual spatial memory and attention and increasing anxiety suggest more intervention in life skills and emotional social supports are needed. Keywords: Hurler-Scheie syndrome, α-L-iduronidase, Mucopolysaccharidosis (MPS), L238Q mutation, Neurocognition

INTRODUCTION Subclinical cardiovascular risks of secondhand smoke (SHS) exposure among children and adolescents remains insufficiently described. METHODS This was a cross-sectional study of 298 children and adolescents (48.0% male, body mass index: 27.0±8.9kg/m2), including 49 self-reported cases with SHS. Arterial elasticity and stiffness (distensibility, compliance, incremental elastic modulus [IEM]) were obtained via ultrasound imaging in the abdominal aorta, brachial, and carotid arteries. A one-way analysis of variance compared differences between groups, and multiple linear regression adjusted for covariates. RESULTS SHS was associated with lower abdominal aorta diameter distensibility (aDD) (13.4±3.6% vs. 16.0±5.2%, p=0.009), and abdominal aorta cross-sectional distensibility (aCSD) (28.8±8.3% vs. 35.1±12.2% p=0.009), as well as higher abdominal aorta IEM (aIEM) (1241±794mmHg vs. 935±388mmHg, p=0.001). After adjustment for covariates, aDD (p=0.047), aCSD (p=0.040), and aIEM (p=0.017) remained significant; this significance persisted with the additional adjustment of percent body fat. Measures of brachial and carotid compliance and distensibility were not associated with SHS. CONCLUSIONS SHS was associated with abdominal aorta stiffness; the majority of vascular measures within the brachial and carotid artery remained unaffected following adjustment for covariates, including hypertension and adiposity. SHS may predispose individuals to increased abdominal aorta stiffness, an artery previously reported to exhibit increased susceptibility to atherosclerosis.

BACKGROUND Tracheostomy is an important adjunct for lung transplant patients requiring prolonged ventilation. We explored the effects of post-transplant tracheostomy on survival and bronchiolitis obliterans syndrome after lung transplant. METHODS A retrospective, single center analysis was performed on all lung transplant recipients during the Lung Allocation Score (LAS) era. Risk factors for post-transplant tracheostomy or death within 30 days were assessed. Kaplan-Meier estimates and Cox proportional hazards models were used to examine the association between tracheostomy within 30 days after transplant and survival at 1 and 3 years. A total of 403 patients underwent single or bilateral lung transplant between May 2005 and February 2016 with complete data for 352 cases, and 35 patients (9.9%) underwent tracheostomy or died (N = 10, 2.8%) within 30 days. RESULTS In adjusted analyses, primary graft dysfunction grade 3 (PGD3) was associated with a composite end point of tracheostomy or death within 30 days (HR 3.11 (1.69, 5.71), P-value

Background: Epidemiologic observations have raised hypotheses regarding increased potato consumption as a correlate of weight gain, adiposity and diabetes risk, while nut consumption has been associated with weight control and metabolic health Furthermore, human diets are complex with phytochemicals potentially impacting the digestion and absorption of macro-and micronutrients We asked whether increased daily consumption of potatoes influences energy balance relative to almonds Methods: A randomized, controlled trial (30-day) of adult humans (n=180) prescribed daily, calorie-matched (300 kcal/day, n=60 subjects/group) consumption of either 1) almonds, 2) white potato French fries, or 3) white potato French fries with spices selected for alpha-glucosidase inhibitory properties Subjects were measured at baseline and completion (30-days) for primary (body fat measured by dual-energy x-ray absorptiometry, DXA) and secondary outcomes (body weight and markers of carbohydrate metabolism and insulin resistance) Results: A total of n=180 subjects were randomized to treatment groups, with sex (67 78% female), age (mean±SD, 30 35±8 74 years), BMI (26 11±4 15 kg/m2) and weight (75 56±15 44 kg) at baseline There were n=12 dropouts and n=3 terminations due to COVID19 follow-up limitations Change (completion minus baseline) in total fat mass by DXA was not significantly different among groups (mean (95% CI);Almonds: 214 88g (-5 15,434 92);Potatoes: 18 55g (-207 40,244 51);Potatoes+Spice mix: 231 05g (-1 33,463 43);p=0 347), nor change in fasting glucose (p=0 413), insulin (p=0 301) or HbA1c (p=0 234) Change in body weight was significantly different among groups (p=0 013;Almonds: 0 46kg (0 09,0 84);Potatoes: -0 26kg (-0 65,0 13);Potatoes+Spice mix: 0 45kg (0 06,0 85) Conclusions: There was no significant difference in the primary outcome of body fat change with 30 days of consumption of potatoes versus almonds

Background Perinatal brain injuries often impact the corticospinal system, leading to motor impairment and cerebral palsy. Although transcranial magnetic stimulation (TMS) has been widely used to study corticospinal connectivity in adults and older children, similar studies of young infants are limited. Objectives The objective was to establish the safety and feasibility of advanced TMS assessments of the corticospinal connectivity of young infants with perinatal brain injury. Design This was a pilot, cross-sectional study of 3- to 12-month-old (corrected age) infants with perinatal stroke or intracranial hemorrhage. Methods Six participants (2 term, 4 preterm) were assessed with stereotactic neuronavigation-guided TMS. Single-pulse TMS was applied to each hemisphere and responses were recorded simultaneously from both upper limbs. During data collection, vital signs and stress responses were measured to assess safety. Developmental motor outcomes were evaluated using the General Movements Assessment and Bayley Scales of Infant and Toddler Development (3rd edition). A clinical diagnosis of cerebral palsy was recorded, if available. Results No adverse events occurred during TMS testing. All sessions were well tolerated. Contralateral motor evoked responses were detected in 4 of 6 participants. Both contralateral and ipsilateral responses were observed in 2 of 6 participants. Limitations TMS responses were not obtained in all participants. This could be related to the location of brain injury or developmental stage of the corticospinal system controlling the wrist flexor muscle group from which responses were recorded. Conclusions This study provides a summary of the framework for performing novel TMS assessments in infants with perinatal brain injury. Implementing this approach to measure corticospinal connectivity in hypothesis-driven studies in young infants appears to be justified. Such studies could inform the characterization of corticospinal development and the neural mechanisms driving recovery following early interventions.

Background: Little research to date has focused on lower urinary tract symptom (LUTS) prevention and bladder health promotion in women. To address this gap, the Prevention of LUTS Research Consortium developed the following working bladder health definition: "A complete state of physical, mental, and social well-being related to bladder function [that] permits daily activities [and] allows optimal well-being." To begin to inform and quantify this definition, we used data from the Boston Area Community Health Survey, drawing upon its rare collection of information on LUTS and LUTS-specific interference with activities. Methods: At baseline, participants reported their frequency of 15 LUTS and interference with 7 activities. Prevalence ratios (PRs) were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. Results: Of the 3169 eligible participants, 17.5% reported no LUTS or interference, whereas the remaining 82.5% reported some frequency of LUTS/interference: 15.1% rarely; 21.7% a few times; 22.6% fairly often/usually; and 22.9% almost always. LUTS independently associated with interference were urgency incontinence, any incontinence, urgency, nocturia, perceived frequency, and urinating again after

Combined non-invasive brain stimulation (NIBS) and rehabilitation interventions have the potential to improve function in children with unilateral cerebral palsy (UCP), however their effects on developing brain function are not well understood. In a proof-of-principle study, we used single-pulse transcranial magnetic stimulation (TMS) to measure changes in corticospinal excitability and relationships to motor performance following a randomized controlled trial consisting of 10 days of combined constraint-induced movement therapy (CIMT) and cathodal transcranial direct current stimulation (tDCS) applied to the contralesional motor cortex. Twenty children and young adults (mean age = 12 years, 9 months, range = 7 years, 7 months, 21 years, 7 months) with UCP participated. TMS testing was performed before, after, and 6 months after the intervention to measure motor evoked potential (MEP) amplitude and cortical silent period (CSP) duration. The association between neurophysiologic and motor outcomes and differences in excitability between hemispheres were examined. Contralesional MEP amplitude decreased as hypothesized in five of five participants receiving active tDCS immediately after and 6 months after the intervention, however no statistically significant differences between intervention groups were noted for MEP amplitude [mean difference = -323.9 μV, 95% CI = (-989, 341), p = 0.34] or CSP duration [mean difference = 3.9 ms, 95% CI = (-7.7, 15.5), p = 0.51]. Changes in corticospinal excitability were not statistically associated with improvements in hand function after the intervention. Across all participants, MEP amplitudes measured in the more-affected hand from both contralesional (mean difference = -474.5 μV) and ipsilesional hemispheres (-624.5 μV) were smaller compared to the less-affected hand. Assessing neurophysiologic changes after tDCS in children with UCP provides an understanding of long-term effects on brain excitability to help determine its potential as a therapeutic intervention. Additional investigation into the neurophysiologic effects of tDCS in larger samples of children with UCP are needed to confirm these findings.

Background: In adolescents with severe obesity, long-term weight loss maintenance using lifestyle therapy alone is hampered by numerous biological adaptations favoring weight regain such as increased appetite and sense of food palatability and decreased satiety and resting energy expenditure. Anti-obesity pharmacotherapy may have a role in mitigating some of these physiological adaptations, thereby enhancing weight loss maintenance. We conducted a randomized, double-blind, placebo-controlled clinical trial to evaluate the effect of the glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide extended release (XR) on the maintenance of BMI reduction and improvements in cardiometabolic risk factors induced by short-term meal replacement therapy (MRT) among adolescents with severe obesity. Methods: One-hundred adolescents ages 12 to

Mucopolysaccharidosis IH (MPS IH, Hurler syndrome) naturally leads to death within the first decade of life, primarily from cardiac and pulmonary causes. To determine how hematopoietic stem cell transplantation (HSCT) has altered mortality, we analyzed our institution’s 30-year experience of patients with MPS IH undergoing HSCT. Using chart review and the National Death Index, we determined survival status of 134 patients (males = 69) with MPS IH transplanted between 9/16/1983 and 7/25/2013 on 12/31/2013. Analysis included descriptive statistics, Kaplan-Meier curves, and regression analysis by Cox proportional hazards model. Overall survival (95% CI) at one- and 25-years was 70% (62–78%) and 37% (19–55%), respectively. From 2004 onward, overall survival at one- and 8-years was 84% (73–96%) and 81% (69–94%), respectively, compared to 65% (55–74%) and 57% (47–67%) prior to 2004 (Log-rank p = 0.032). Regardless of era, male survival was significantly better than female (HR 0.40, [95% CI: 0.21–0.74], p = 0.004). The cumulative incidence of death (95% CI) at 25 years was 63% (45–81%); incidence of pulmonary-related death was the highest at 27% (10–41%) compared to 8% (0.3–16%) for cardiac, 12% (6–17%) for infectious disease, and 16% (3–27%) from other complications. HSCT has increased survival in MPS IH beyond the third decade of life and decreased the incidence of cardiac mortality, but deaths after the third year post-HSCT occur in excess of expected US mortality. It is important to determine if improved transplant strategies since 2004 result in better long-term survival in the current patient population.

Objective To assess the safety and efficacy of short-term meal replacement therapy followed by topiramate for body mass index (BMI) reduction in adolescents with severe obesity. Methods Adolescents (ages 12–18 years) with severe obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m2) were recruited for this double-blind, randomized, placebo-controlled trial. Participants completed 4 weeks of meal replacement therapy followed by randomization (1:1) to either 24 weeks of topiramate 75 mg/day or placebo. Mean changes were compared between groups. Results Thirty adolescents (mean age 15.2 ± 1.7 years, mean BMI 40.3 ± 4.6 kg/m2) completed the meal replacement phase and were randomized; 21 completed the study. The difference in mean percent change in BMI between the topiramate and placebo groups was not significant (−1.9%; 95% CI: −5.2% to +1.5%; P = 0.291). Significant improvements in visceral fat and very-low-density lipoprotein cholesterol were observed in the topiramate compared with the placebo group. There were no concerning changes in neurocognitive function or bone health. Conclusions In this pilot study, 4 weeks of meal replacement therapy followed by 24 weeks of low-dose topiramate compared with meal replacement therapy alone did not result in significant BMI reduction for adolescents with severe obesity.

Purpose: In Pompe disease, a deficiency of acid α-glucosidase enzyme activity leads to pathologic accumulation of glycogen in tissues. Phenotype heterogeneity in Pompe includes an infantile form and late-onset forms (juvenile- and adult-onset forms). Symptoms common to all phenotypes include progressive muscle weakness and worsening respiratory function. Patients with late-onset forms of Pompe disease commonly complain of chronic fatigue and generalized muscle weakness prior to being diagnosed with Pompe disease, and this may lead to consideration of hypothyroidism in the differential diagnosis. This study aimed to evaluate the prevalence of hypothyroidism in the adult-onset form of Pompe disease. Methods: Electronic chart review was performed at the Advanced Therapies Clinic at the University of Minnesota Medical Center (UMMC) to identify patients with late-onset Pompe disease. The identified charts were reviewed for a co-diagnosis of hypothyroidism. A query was made to the clinical data repository at UMMC searching diagnosis ICD9 code 244.9 (hypothyroidism not otherwise specified) and/or presence of levothyroxine from 2011 to 2014 in patients 18 years of age and older. Results: The clinical data repository found a prevalence of hypothyroidism of 3.15% (56,072 of 1,782,720 patients) in the adult patient population at UMMC. Ten adult patients with Pompe disease were identified, five with the diagnosis of hypothyroidism (50%, 95% CI: 23.7, 76.3, p

The purposes of this study were to characterize the impact of depression and anxiety on the severity of obesity among youth seeking weight management treatment and to determine the extent to which emotional eating mediates the relationship between depression and/or anxiety and degree of obesity. This cross-sectional, retrospective chart review of 102 adolescent patients from a weight management clinic analyzed demographics, body mass index, depression (Patient Health Questionnaire-9), and anxiety (Generalized Anxiety Disorder Scale-7) screens and the Child Eating Behavior Questionnaire, Emotional Over-Eating subscale. After adjusting for demographics and emotional eating, the odds of having severe obesity versus obesity were 3.5 times higher for patients with depression compared with those without (odds ratio [OR] = 3.5; 95% CI = 1.1, 11.3; P = .038) and nearly 5 times higher for those with anxiety (OR = 4.9; CI = 1.2, 20.9; P = .030). Emotional eating, however, was not a mediator between depression/anxiety and degree of adiposity.

Objectives: The behavioral, adaptive and quality of life characteristics of attenuated mucopolysaccharidosis type II (MPS II) have not been well studied. Understanding changes over time in the attenuated phenotype may assist in helping achieve better outcomes in long-term function. This longitudinal study investigates these outcomes in relation to age, somatic disease burden, and IQ. Specifically, somatic disease burden is a major challenge for these patients, even with treatment with enzyme replacement therapy. Methods: 15 patients, 10 between ages 6 and

Introduction The mucopolysaccharidoses (MPSs) are a group of rare genetic lysosomal disorders with progressive multisystem involvement. An MPS-specific physical symptom scale was developed and introduced a Physical Symptom Score (PSS) to quantify the somatic disease burden across MPS I, II and VI. Hypothesis Somatic burden of disease in patients with attenuated MPS I, II and VI as measured by the PSS will be positively associated with age and negatively associated with neuropsychological functions [i.e. full scale intelligence quotient (FSIQ) and attention]. Materials and methods Forty-eight patients with attenuated MPS I (n = 24), II (n = 14), and VI (n = 10) aged 6 to 32 years on enzyme replacement therapy who were enrolled in “Longitudinal Studies of Brain Structure and Functions in MPS Disorders” across seven centers. Somatic disease burden was measured by the PSS. Neuropsychological functions were measured by the Wechsler Abbreviated Scale of Intelligence (WASI) and Test of Variables of Attention (TOVA). Results PSS was positively associated with age in attenuated MPS I (P, Highlights • MPS-specific physical symptom scale introduced a Physical Symptom Score (PSS) by quantifying the somatic disease burden • PSS was significantly positively associated with age in attenuated MPS I, MPS II and MPS VI • PSS was significantly negatively associated with Full Scale IQ (FSIQ) in attenuated MPS I and in MPS VI • PSS was not statistically significantly associated with FSIQ in MPS II, but had similar direction as other two groups • • There were no previous studies that examined the association of PSS in MPS disorders with neuropsychological functions