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Perinatal brain injury is a primary cause of cerebral palsy, a condition resulting in life-long motor impairment. Infancy is an important period of motor system development, including development of the corticospinal tract (CST), the primary pathway for cortical movement control. The interaction between perinatal stroke recovery, CST organization, and resultant motor outcome in infants is not well understood. Here, we present a protocol for multimodal longitudinal assessment of brain development and motor function following perinatal brain injury using transcranial magnetic stimulation and magnetic resonance imaging to non-invasively measure CST functional and structural integrity across multiple timepoints in infants 3 to 24 months of age. We will further assess the association between cortical excitability, integrity, and motor function. This protocol will identify bioindicators of motor outcome and neuroplasticity, and subsequently inform early detection, diagnosis, and intervention strategies for infants with perinatal stroke, brain bleeds and related diagnoses.

(s): Existing bladder-specific measures lack ability to assess a range of bladder health from poor to optimal health. We report evidence for validity of the self-administered, multidimensional Bladder Health Scales and Function Indices for research in adult women.A cross-sectional population-based validation study with random assignment to paper or electronic administration was conducted using national address-based probability sampling supplemented by purposive sampling of women with lower urinary tract symptoms surrounding 7 clinical research centers. Construct validity of the Bladder Health Scales and Function Indices was guided by Multitrait-Multimethod approach using health and condition-specific questionnaires, bladder diaries, expert ratings of bladder health, and noninvasive bladder function testing. Internal dimensional validity was evaluated using factor analysis; internal reliability was assessed using paired t-tests and 2-way mixed effects Intraclass Correlation Coefficient models. Mode comparisons used chi-square, Fisher Exact or t-tests. Convergent validity was evaluated using Pearson correlations with the external construct measures and known-group validity was established with comparison of women known and unknown to be symptomatic with urinary conditions.The sample included 1,072 participants. Factor analysis identified ten scales with Cronbach's alpha ranging 0.74-0.94. Intraclass correlation coefficients of scales ranged from 0.55-0.94. Convergent validity of ten scales and six indices ranged from 0.52- 0.83. Known-group validity was confirmed for all scales and indices. Item distribution was similar by mode of administration.The paper and electronic forms of the Bladder Health Scales and Function Indices are reliable and valid measures of bladder health for use in women's health research.

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

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.

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...

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.

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.

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.

Attention-deficit/hyperactivity disorder predominantly inattentive (ADHD-PI) and combined (ADHD-C) presentations are likely distinct disorders that differ neuroanatomically, neurochemically, and neuropsychologically. However, to date, little is known about specific white matter (WM) regions differentiating ADHD presentations. This study examined differences in WM microstructure using diffusion tensor imaging (DTI) data from 20 ADHD-PI, 18 ADHD-C, and 27 typically developed children. Voxel-wise analysis of DTI measurements in major fiber bundles was carried out using tract-based spatial statistics (TBSS). Clusters showing diffusivity abnormalities were used as regions of interest for regression analysis between fractional anisotropy (FA) and neuropsychological outcomes. Compared to neurotypicals, ADHD-PI children showed higher FA in the anterior thalamic radiations (ATR), bilateral inferior longitudinal fasciculus (ILF), and in the left corticospinal tract (CST). In contrast, the ADHD-C group exhibited higher FA in the bilateral cingulum bundle (CB). In the ADHD-PI group, differences in FA in the left ILF and ATR were accompanied by axial diffusivity (AD) abnormalities. In addition, the ADHD-PI group exhibited atypical mean diffusivity in the forceps minor (FMi) and left ATR and AD differences in right CB compared to healthy subjects. Direct comparison between ADHD presentations demonstrated radial diffusivity differences in FMi. WM clusters with FA irregularities in ADHD were associated with neurobehavioral performance across groups. In conclusion, differences in WM microstructure in ADHD presentations strengthen the theory that ADHD-PI and ADHD-C are two distinct disorders. Regions with WM irregularity seen in both ADHD presentations might serve as predictors of executive and behavioral functioning across groups. Hum Brain Mapp 37:3323-3336, 2016. © 2016 Wiley Periodicals, Inc.

Introduction: We examined the reproducibility of circulating endothelial cells (CEC) enumeration and activation among youth. Materials and methods: CECs from 151 youth were measured at baseline and 1 week follow-up. Enumeration of CEC in fresh whole blood was determined by direct assessment of buffy coat smears (CD146+ nucleated cells) and activated CEC (%VCAM-1 expression) was determined after immunomagnetic enrichment and co-staining of nuclei, plus positivity for P1H12 and VCAM-1. Results: No statistically significant difference in CEC enumeration (1.2 ± 2.5 vs 1.3 ± 2.2 CEC/milliliter of whole blood, p = 0.745) or activated CEC (57.1 ± 24.4 vs 58.0 ± 21.3 %VCAM-1, p = 0.592) between baseline and 1 week follow-up. Conclusion: On a cohort basis, CEC enumeration and activation are reproducible in youth. Relatively high individual biological variability may limit its clinical utility.

Given the increasing level and scope of biostatistics expertise needed at academic health centers today, we developed best practices guidelines for biostatistics units to be more effective in providing biostatistical support to their institutions, and in fostering an environment in which unit members can thrive professionally. Our recommendations focus on the key areas of: 1) funding sources and mechanisms; 2) providing and prioritizing access to biostatistical resources; and 3) interacting with investigators. We recommend that the leadership of biostatistics units negotiate for sufficient long-term infrastructure support to ensure stability and continuity of funding for personnel, align project budgets closely with actual level of biostatistical effort, devise and consistently apply strategies for prioritizing and tracking effort on studies, and clearly stipulate with investigators prior to project initiation policies regarding funding, lead time, and authorship.

Background: Skeletal and joint disease persists and slowly worsens in individuals with mucopolysaccharidosis type I (MPS I) despite treatment with hematopoietic cell transplantation (HCT) and/or enzyme replacement therapy (ERT). Surrogate biomarkers are crucial for efficient testing of the effects of new and adjunctive therapies on bones and joints in MPS I. Methods: As part of a 9-year observational study of individuals with MPS I, hip, and spine radiographs, and range-of-motion (ROM) were measured annually in years 7-9 and height in years 1-9. Fasting morning plasma and urine samples of inflammatory and bone biomarkers were measured by ELISAs in years 1 and 2. A novel summary score for skeletal disease (i.e. hip and spine radiographs and height Z-score standardized by age and sex) and joint disease (i.e. ROM in shoulders, elbows, and knees) were calculated. Linear regression, adjusting for age, was used to test for associations of change in biomarkers over the first year with the annualized change in summary bone and ROM score, and height Z-score over years 7-9 and 1-9 respectively. Sensitivity analyses removed biomarkers greater than 3 standard deviations from the mean. Results: The cohort included eighteen participants (MPS IH N=14, MPS IA N=4), age 5-16 years, who were 6.7±3.0 years since HCT (MPS IH) or 7.1±2.8 years since ERT initiation (MPS IA). Sensitivity analysis showed an association between increasing interleukin-6 and more rapid worsening of ROM (-31 pg/ml: 95%CI -45 to -18 pg/ml p Conclusions: We have identified two potential candidate surrogate biomarkers of change in skeletal or joint disease over time. Once validated, these biomarkers may prove useful in determining early efficacy of skeletal or joint directed therapies in MPS I.

To compare markers of cardiovascular health in youth diagnosed with attention deficit hyperactivity disorder (ADHD) by the use of stimulant medication with healthy controls.Children and adolescents (n = 85; mean age 11.2 ± 2.8 years; 66 boys) diagnosed with ADHD using a stimulant and 53 siblings without ADHD (mean age 11.1 ± 3.8 years; 28 boys) were included in this cross-sectional study. Measured variables included blood pressure, heart rate (HR), HR variability: SD of the RR interval and low frequency to high frequency ratio, carotid-radial pulse wave velocity, carotid artery augmentation index (AIx), radial artery AIx, brachial artery flow-mediated dilation, and digital reactive hyperemic index.Compared with control patients, participants with ADHD had greater resting systolic blood pressure (3.9 mm Hg, 95% CI [1.2-6.7], P = .005), diastolic blood pressure (5.5 mm Hg, 95% CI [3.2-7.8], P .001), HR (9.2 beats/min, 95% CI [6.0-12.3], P .001), low frequency to high frequency ratio (0.55, 95% CI [0.22-0.89], P = .001), carotid AIx (7.2%, 95% CI [1.9-12.5], P = .008), and pulse wave velocity (0.36 m/s, 95% CI [-0.05, 0.78], P = .089), and lower SD of the RR interval (-33.7 milliseconds, 95% CI [-46.1, -21.3], P .001). Neither flow-mediated dilation nor reactive hyperemic index was significantly different.Children and adolescents being treated with a stimulant medication for ADHD exhibited signs of altered cardiac autonomic function, characterized by increased sympathetic tone, and showed evidence of arterial stiffening.

Object The accurate placement of cerebral ventricular shunt catheters in hydrocephalus is an important clinical problem. Malfunction of shunts remains their most common complication and greatest liability, and the influence of catheter position on shunt function remains poorly defined. The objectives of this study were as follows: 1) determine the accuracy of intraventricular catheter placement with respect to a historically favored target, defined as a 1-cm radius sphere at the anterior lip of the ipsilateral foramen of Monro; 2) confirm that this target represents a satisfactory site for frontal and occipital catheter placement by examining whether inaccuracy is associated with more shunt failures; and 3) determine whether catheter trajectory, use of image confirmation, or other factors are associated with either the accuracy or the longevity of shunts. Methods A retrospective cohort analysis was conducted on 236 patients with 426 ventricular shunts placed or revised at the University of Minnesota over a 10-year period. Results Accuracy of shunt placement was optimal in 43.9% of patients and suboptimal or poor in 56.1% of patients. Time to failure was significantly affected by the accuracy of catheter placement with respect to the ipsilateral foramen of Monro, with a 57% higher risk of failure with suboptimal placement (hazard ratio [HR] 1.57, 95% CI 1.26–1.96; p < 0.001) and a 66% higher risk with poor placement (HR 1.66, 95% CI 1.45–1.89; p < 0.001) relative to optimal placement. The odds of highly suboptimal or unacceptable placement were significantly increased by lack of any intraoperative imaging (OR 5.89, 95% CI 2.36–14.65; p < 0.001). Use of a nonfrontal posterior trajectory also showed a trend toward poor placement (OR 1.64, p = 0.138). Conclusions The historical target for catheter tip placement within 1 cm of the foramen of Monro in the ipsilateral lateral ventricle was associated with significantly longer revision-free survival compared with other locations. This effect remained significant after adjusting for age and whether there was a prior history of shunting. The accuracy of catheter placement in both pediatric and adult patients was strongly associated with use of intraoperative fluoroscopic confirmation. In analyses comparing intraoperative fluoroscopy and no imaging, there was a non–statistically significant difference in the 3-year time to failure, but the worst-case scenario of catastrophic short-term failure was almost completely avoided with fluoroscopy. The authors conclude that accuracy of placement is critical for shunt survival, and that use of intraoperative imaging confirmation may optimize outcomes by avoiding the majority of unacceptable placements.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients.The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls.MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory.A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (± SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm(2)/mmHg versus 0.16 ± 0.05 mm(2)/mmHg; adjusted p=0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p0.001). cCSD in MPS patients was lower than that of controls (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients.Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.

Diagnosis of cerebral palsy (CP) after perinatal stroke is often delayed beyond infancy, a period of rapid neuromotor development with heightened potential for rehabilitation. This study sought to assess whether the presence or absence of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) could be an early biomarker of atypical development within the first year of life. In 10 infants with perinatal stroke, motor outcome was assessed with a standardized movement assessment. Single-pulse TMS was utilized to assess presence of MEPs. Younger infants (3&ndash, 6 months CA, n = 5, 4/5 (80%)) were more likely to present with an MEP from the more-affected hemisphere (MAH) compared to older infants (7&ndash, 12 months CA, n = 5, 0/5, (0%)) (p = 0.048). Atypical movement was demonstrated in the majority of infants with an absent MEP from the MAH (5/6, 83%) compared to those with a present MEP (1/4, 25%) (p = 0.191). We found that age influences the ability to elicit an MEP from the MAH, and motor outcome may be related to MAH MEP absence. Assessment of MEPs in conjunction with current practice of neuroimaging and motor assessments could promote early detection and intervention in infants at risk of CP.

Enzyme replacement and substrate reduction therapies have significantly improved outcomes in patients with Type 1 Gaucher disease (GD1), but do not completely return glucocerebroside levels to the normal range nor prevent continuing tissue injury. Preliminary biomarker analyses indicate a role for oxidative stress and inflammation in GD1 pathophysiology. Thus, additional treatment strategies that target oxidative stress and inflammation have the potential to ameliorate both systemic and brain symptoms and may alter disease progression. N-acetylcysteine (NAC), a FDA-approved medication with antioxidant/anti-inflammatory activity, is also available as an inexpensive dietary supplement with a good safety profile. Our objective is to determine whether oxidative stress and inflammation in the blood and brains of individuals with GD1 can be altered with orally administered NAC. In this open-label study, we have currently enrolled 13 patients who received NAC at 3600mg/day dose. Blood sample collection for biomarker analysis and brain imaging using magnetic resonance spectroscopy (MRS) was done before and following 3 months of NAC. Total glutathione in red blood cells, which is a measure of oxidative stress, and plasma NAC concentrations were measured using a validated liquid chromatography/mass spectrometry method. Intracellular antioxidant enzyme activity and plasma markers for inflammation and lipid and protein modifications were measured using colorimetric and immunoassays. Interim analysis of data from 10 patients revealed that NAC at this dose did not significantly alter any of the neurochemical markers. However, validated MRS markers related to neuronal health such as N-acetyl aspartate (NAA) and glutamate showed trends toward improvement. Similar trends were also observed in blood antioxidant and inflammatory biomarkers. Pharmacokinetic analysis using serial samples collected 90-days after NAC regimen is underway to determine if a dose increase is warranted. If these favorable trends subsequently are shown to be significant, NAC could be a new adjunctive therapeutic option.

Abnormal cerebral spinal fluid (CSF) characteristics were previously reported in children with severe mucopolysaccharidosis type I (MPS IH Hurler syndrome), a progressive lysosomal storage disease associated with rapid neurocognitive decline, worsening multi-system organ dysfunction, and early death. The present objective was to evaluate whether intrathecal (IT) enzyme replacement therapy (ERT) added to intravenous ERT and hematopoietic cell transplantation (HCT) is associated with attenuation of CSF abnormalities and whether this change has clinical correlates. Twenty-four MPS IH patients received IT ERT at four time points in the peri-transplant period. At these times, CSF opening pressure (OP), heparin sulfate (HS), non-reducing ends (NRE I0S0 and I0S6), heparin cofactor II thrombin complex (HCIIT), and inflammatory markers were measured. Neurocognitive functioning (i.e., infant IQ) was quantified at baseline, 1 year after HCT, and 2 years after HCT. There were no adverse events due to the administration of IT ERT. An association between attenuated CSF biomarkers and IQ change following transplant was examined. Significant reductions in CSF abnormalities were seen between time points 1 and 2, i.e. prior to HCT, for OP, NRE I0S0 and I0S6, and HCTIIT (p=0.036, 0.001, 0.006, and 0.026, respectively), and across time points 1 through 4 for NRE I0S0 and I0S6, HS, and HCIIT (p

PURPOSE: Skeletal disease causes significant morbidity in mucopolysaccharidoses (MPS), and bone remodeling processes in MPS have not been well characterized. The objective of this study was to determine if biomarkers of bone turnover are abnormal in children with specific MPS disorders (i.e. MSP-I, MPS-II, and MPS-VI) compared to healthy children. METHODS: A cross-sectional study was performed of serum biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP], osteocalcin) and urine biomarkers of bone resorption (pyridinoline, deoxypyridinoline) in MPS and healthy controls. Measures of physical function and pain were obtained using the Children’s Health Questionnaire (CHQ). RESULTS: The cohort consisted of 39 children with MPS (MPS-I = 26; MPS-II = 11; MPS-VI = 4) and 51 healthy children. Adjusting for sex and Tanner stage group, MPS individuals had statistically significant increases for osteocalcin ( p< 0.001), with trends toward higher BSAP (p = 0.054) and urinary pyridinoline (p = 0.084). These biomarkers were not significantly associated with CHQ bodily pain and physical-function scores. CONCLUSION: Osteocalcin was increased in children with MPS disorders, with trends for increases in BSAP and urinary pyridinoline, suggesting that bone remodeling is altered in children with MPS. Future studies to assess the ability of these biomarkers to quantify and monitor MPS skeletal disease in response to therapy are needed.

To determine muscular strength differences in patients with MPS-I, II, and VI versus age- and sex-matched healthy controls.Dominant leg isokinetic knee extension strength was measured at 90 and 120 degrees per second (d/s) using a dynamometer in 30 subjects with MPS and 42 controls (5-16 yrs). MPS-I was further divided into MPS-IA (attenuated) and MPS-IH (severe). Strength measures analyzed were peak torque (PkT), peak torque per unit body weight (PkT/BW) and per unit lean body mass (PkT/LBM), and average power (AP).Following adjusting strength measures for age, MPS-IH and MPS-II had significantly lower strength measures for all variables at both angular velocities. MPS-VI had significantly lower PkT, PkT/LBM, and AP compared to controls at 90 and 120d/s. In contrast, MPS-IA was not significantly different from controls for any strength variable at either angular velocity.The results of this study suggest that decrements in skeletal muscle strength depend on MPS diagnosis and severity of disease. Children with MPS-IH demonstrate the greatest difference in muscular strength compared to healthy controls.

Objectives To compare clinical characteristics and patient-reported outcomes in seropositive versus seronegative primary Sjogren’s syndrome patients (pSS) and to investigate the effect of serological status on the prevalence of chronic pain, comorbidity and health quality.

Bone loss has been observed within the first six months after hematopoietic cell transplantation (HCT) in both children and adults. While there is some evidence that bone formation may be reduced in children after HCT, it is currently unknown if bone resorption is increased. The objective of this prospective study was to evaluate changes in markers of bone resorption over the first six months after pediatric HCT. Twenty-six participants (8 females) age 10.9±3.4 years entered the study prior to HCT. Bone resorption was measured by urine deoxypyridinoline (DPD) and pyridinoline (PYD), and by plasma N-telopeptide (NTX) and C-telopeptide (CTX). Seventeen participants who completed day +30 visit and either day +100 or +180 visits were included in the analysis. DPD increased between days +30 and +100 (mean change 11.3 nmol/nmol creatinine; p=0.012) and between days +30 and +180 (13.7 nmol/nmol creatinine; p=0.036). PYD increased between days +30 and +100 (32 nmBCE/L; p=0.019). CTX increased between baseline and day +100 (5.9 μg/L; p=0.012). Changes in NTX levels were not statistically significant. This study shows that markers of bone resorption increase in children after HCT, suggesting that increased resorption may be a contributing factor to the pathophysiology of bone loss after pediatric HCT.

Out-of-hospital trauma triage is the process of using field-based information to determine which patients require immediate transport to a trauma center. Although simple in concept, the practice of out-of-hospital triage is quite complex. Identification of high-risk injured patients in the field is based on limited information obtained during a relatively short period of time in an often chaotic setting, all of which contribute to an imperfect process. The original out-of-hospital trauma triage criteria were generated by national consensus conferences and published by the American College of Surgeons Committee on Trauma (ACSCOT) in 1976.1 The first “step” of these criteria includes physiologic measures, which are intended to identify the highest risk trauma patients. Target ranges for the three core physiologic measures (i.e., Glasgow Coma Scale [GCS] score, systolic blood pressure [SBP], and respiratory rate) have changed very little during the last 20 years.1,2 Although there have been numerous studies evaluating the out-of-hospital trauma triage guidelines,3-16 few studies have rigorously evaluated potential revisions of the ACSCOT step 1 physiologic criteria. The current step 1 physiologic criteria are believed to identify the highest risk trauma patients,4,5,7,8,12,13 although questions persist regarding the utility of certain components of the criteria (e.g., respiratory rate), the ranges used, and whether additional physiologic measures would further improve predictive value. Previous studies assessing these measures have primarily focused on patients transported directly to major trauma centers, which can introduce selection bias and inflate the apparent predictive value of the criteria. The potential value of additional physiologic measures (e.g., shock index [pulse/SBP], pulse rate, and pulse oximetry) remains unclear, as does the relative utility of combining physiologic measures. Further, although out-of-hospital intubation has been suggested to be predictive of mortality and poor neurologic outcome,17 intubation is not explicitly included in the ACSCOT guidelines. Other authors have questioned field intubation as an indicator of resource need.18 Improving field triage guidelines may allow for more accurate selection of patients in need of immediate trauma center resources, identification of those most likely to benefit from early aggressive resuscitative care, and assist in selecting appropriate patients for field-based interventional therapies. Among injured adults evaluated by emergency medical service (EMS) providers in 11 North American sites, we sought to (1) provide an unbiased estimate of the incidence of mortality and prolonged hospital stay among patients meeting ACSCOT step 1 field physiologic criteria and (2) assess whether more restrictive criteria (with or without demographic and mechanism information) would improve the specificity of this step without missing an excessive number of high-risk patients.

Background and Objectives Dynamic oximetry provides a new way to assess the effect of blood storage on the oxygen transport rate (OTR). Materials and Methods In dynamic oximetry, the rate at which oxyhemoglobin becomes deoxyhemoglobin is measured optically, thereby, indirectly measuring the rate at which oxygen leaves the red blood cell (RBC) making it available for transfer to tissues. Extending the physiologic diffusion time in an in vitro apparatus, consisting of a diffusion system and gas exchanger capable of controlling the surface area and the time of exposure for oxygenation and deoxygenation, makes OTR measurement feasible. Eight normal blood donor units, collected in adenine, dextrose, sorbitol, sodium chloride and mannitol , were stored for 8 weeks under standard conditions and serially sampled for OTR. Results We report that the OTR at the time of blood bank donation appears to be singular for each donor, that the interdonor differences are maintained over time, and that the individual OTR increased 1·72-fold (95% CI 1·51, 1·95) over 8 weeks, adjusting for sex, age and plasma cholesterol level. Conclusion Oxygen transport rate increases during storage; blood units with similar haemoglobin content may have significant differences in OTR. Studies examining blood parameters at the time of donation and blood storage on patient outcomes should consider measuring OTR, as it may contribute to differences in observed efficacy of tissue oxygenation.

Elevated urine albumin excretion is an established risk factor for cardiovascular disease. Increased cardiovascular risk may be partly mediated by abnormalities in lipoprotein metabolism. We examined cross-sectional associations of urine albumin-creatinine ratio (ACR) with standard lipid measurements and with lipoprotein particle concentrations measured by nuclear magnetic resonance (NMR) in the Multi-Ethnic Study of Atherosclerosis.Among 5633 participants who were not using lipid-lowering medications, greater ACR was associated with greater triglyceride concentration and lesser high density lipoprotein cholesterol concentration (women only), but not with low density lipoprotein (LDL) cholesterol calculated using conventional methods. In contrast, unadjusted mean small LDL particle concentrations measured by NMR were 770, 827 and 935 nmol/L for women (p0.001) and 996, 1030 and 1040 nmol/L for men (p=0.037) among participants with normal, high normal and elevated ACR. Adjusting for age, race/ethnicity, diabetes, impaired fasting glucose, hypertension, smoking, medications, body mass index and serum creatinine, each two-fold greater ACR was associated with an increase in small LDL particle concentration of 27 nmol/L for women (p0.001) and 14 nmol/L for men (p=0.008). Greater ACR was also associated with greater intermediate density lipoprotein particle concentration and smaller mean LDL particle size.Mild elevations of urine ACR are associated with atherogenic lipoprotein abnormalities that are not directly observed with a standard lipid panel.