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Background The Long-ter M O U tcomes after the Multisystem Inflammatory S yndrome I n C hildren (MUSIC) study aims to characterize the frequency and time course of acute and long-term cardiac and non-cardiac sequelae in multisystem inflammatory syndrome in children associated with COVID-19 (MIS-C), which are currently poorly understood. Methods This multicenter observational cohort study will enroll at least 600 patients Conclusion The MUSIC study, with the largest cohort of MIS-C patients and the longest follow-up period to date, will make an important contribution to our understanding of the acute cardiac and non-cardiac manifestations of MIS-C and the long-term effects of this public health emergency.

Normalizing cardiovascular measurements for body size allows for comparison among children of different ages and for distinguishing pathologic changes from normal physiologic growth. Because of growing interest to use height for normalization, the aim of this study was to develop height-based normalization models and compare them to body surface area (BSA)-based normalization for aortic and left ventricular (LV) measurements. The study population consisted of healthy, non-obese children between 2 and 18 years of age enrolled in the Pediatric Heart Network Echo Z-Score Project. The echocardiographic study parameters included proximal aortic diameters at 3 locations, LV end-diastolic volume, and LV mass. Using the statistical methodology described in the original project, Z-scores based on height and BSA were determined for the study parameters and tested for any clinically significant relationships with age, sex, race, ethnicity, and body mass index (BMI). Normalization models based on height versus BSA were compared among underweight, normal weight, and overweight (but not obese) children in the study population. Z-scores based on height and BSA were calculated for the 5 study parameters and revealed no clinically significant relationships with age, sex, race, and ethnicity. Normalization based on height resulted in lower Z-scores in the underweight group compared to the overweight group, whereas normalization based on BSA resulted in higher Z-scores in the underweight group compared to the overweight group. In other words, increasing BMI had an opposite effect on height-based Z-scores compared to BSA-based Z-scores. Allometric normalization based on height and BSA for aortic and LV sizes is feasible. However, height-based normalization results in higher cardiovascular Z-scores in heavier children, and BSA-based normalization results in higher cardiovascular Z-scores in lighter children. Further studies are needed to assess the performance of these approaches in obese children with or without cardiac disease.

The Single Ventricle Reconstruction (SVR) Trial was the first randomized clinical trial of a surgical approach for treatment of congenital heart disease. Infants with hypoplastic left heart syndrome (HLHS) and other single right ventricle (RV) anomalies were randomized to a modified Blalock Taussig Thomas shunt (mBTTS) or a right-ventricular-to-pulmonary-artery shunt (RVPAS) at the time of the Norwood procedure. The aim of the Long-term Outcomes of Children with HLHS and the Impact of Norwood Shunt Type (SVR III) study is to compare early adolescent outcomes including measures of cardiac function, transplant-free survival, and neurodevelopment, between those who received a mBTTS and those who received an RVPAS.Transplant-free survivors of the SVR cohort were enrolled at 10 to 15 years of age for multifaceted in-person evaluation of cardiac function (cardiac magnetic resonance [CMR], echocardiogram and exercise test) and neurodevelopmental evaluation. Right ventricular ejection fraction measured by CMR served as the primary outcome. Development of arrhythmias, protein losing enteropathy, and other comorbidities were assessed through annual medical history interview. Through the course of SVR III, protocol modifications to engage SVR trial participants were designed to enhance recruitment and retention.Evaluation of long-term outcomes will provide important data to inform decisions about the shunt type placed at the Norwood operation and will improve the understanding of cardiovascular and neurodevelopmental outcomes for early adolescents with HLHS.

Background Growth abnormalities in single-ventricle survivors may reduce quality of life (QoL) and exercise capacity. Methods This multicenter, longitudinal analysis evaluated changes in height and body mass index (BMI) compared to population norms and their relationship to mortality, ventricular morphology, QoL, and exercise capacity in the Pediatric Heart Network Fontan studies. Results Fontan 1 (F1) included 546 participants (12 ± 3.4 years); Fontan 2 (F2), 427 (19 ± 3.4 years); and Fontan 3 (F3), 362 (21 ± 3.5 years), with ~60% male at each time point. Height z-score was −0.67 ± −1.27, −0.60 ± 1.34, and− 0.43 ± 1.14 at F1-F3, lower compared to norms at all time points (P ≤ .001). BMI z-score was similar to population norms. Compared to survivors, participants who died had lower height z-score (P ≤ .001). Participants with dominant right ventricle (n = 112) had lower height z-score (P ≤ .004) compared to dominant left (n = 186) or mixed (n = 64) ventricular morphologies. Higher height z-score was associated with higher Pediatric Quality of Life Inventory for the total score (slope = 2.82 ± 0.52; P ≤ .001). Increase in height z-score (F1 to F3) was associated with increased oxygen consumption (slope = 2.61 ± 1.08; P = .02), whereas, for participants >20 years old, an increase in BMI (F1 to F3) was associated with a decrease in oxygen consumption (slope = −1.25 ± 0.33; P ≤ .001). Conclusions Fontan survivors, especially those with right ventricular morphology, are shorter when compared to the normal population but have similar BMI. Shorter stature was associated with worse survival. An increase in height z-score over the course of the study was associated with better QoL and exercise capacity; an increase in BMI was associated with worse exercise capacity.

Growth is often impaired in infants with congenital heart disease. Poor growth has been associated with worse neurodevelopment, abnormal behavioral state, and longer time to hospital discharge. Nutritional interventions, drug therapy, and surgical palliation have varying degrees of success enhancing growth. Passive range of motion (PROM) improves somatic growth in preterm infants and is safe and feasible in infants with hypoplastic left heart syndrome (HLHS), after their first palliative surgery (Norwood procedure).This multicenter, Phase III randomized control trial of a 21-day PROM exercise or standard of care evaluates growth in infants with HLHS after the Norwood procedure. Growth (weight-, height- and head circumference-for-age z-scores) will be compared at 4 months of age or at the pre-superior cavopulmonary connection evaluation visit, whichever comes first. Secondary outcomes include neonatal neurobehavioral patterns, neurodevelopmental assessment, and bone mineral density. Eligibility include diagnosis of HLHS or other single right ventricle anomaly, birth at ≥37 weeks gestation and Norwood procedure at30 days of age, and family consent. Infants with known chromosomal or recognizable phenotypic syndromes associated with growth failure, listed for transplant, or expected to be discharged within 14 days of screening are excluded.The TEAM 4 Growth trial will make an important contribution to understanding the role of PROM on growth, neurobehavior, neurodevelopment, and BMD in infants with complex cardiac anomalies, who are at high risk for growth failure and developmental concerns.

Delivery of best-practice care for posttraumatic stress disorder (PTSD) is a priority for clinicians working with active duty military personnel and veterans. The PTSD Clinicians Exchange, an Internet-based intervention, was designed to assist in disseminating clinically relevant information and resources that support delivery of key practices endorsed in the Veterans Administration (VA)-Department of Defense (DoD) Clinical Practice Guidelines (CPG) for the Management of Posttraumatic Stress. We conducted a randomized controlled trial to examine the effectiveness of the Clinicians Exchange intervention in increasing familiarity and perceived benefits of 26 CPG-related and emerging practices. The intervention consisted of ongoing access to an Internet resource featuring best-in-class resources for practices, self-management of burnout, and biweekly e-mail reminders highlighting selected practices. Mental health clinicians (N = 605) were recruited from three service sectors (VA, DoD, community); 32.7% of participants assigned to the Internet intervention accessed the site to view resources. Individuals who were offered the intervention increased their practice familiarity ratings significantly more than those assigned to a newsletter-only control condition, d = 0.27, p = .005. From baseline to 12-months, mean familiarity ratings of clinicians in the intervention group increased from 3.0 to 3.4 on scale of 1 (not at all) to 5 (extremely); mean ratings for the control group were 3.2 at both assessments. Clinicians generally viewed the CPG practices favorably, rating them as likely to benefit their clients. The results suggest that Internet-based resources may aid more comprehensive efforts to disseminate CPGs, but increasing clinician engagement will be important.

Background:The Single Ventricle Reconstruction Trial randomised neonates with hypoplastic left heart syndrome to a shunt strategy but otherwise retained standard of care. We aimed to describe centre-level practice variation at Fontan completion.Methods:Centre-level data are reported as median or median frequency across all centres and range of medians or frequencies across centres. Classification and regression tree analysis assessed the association of centre-level factors with length of stay and percentage of patients with prolonged pleural effusion (>7 days).Results:The median Fontan age (14 centres, 320 patients) was 3.1 years (range from 1.7 to 3.9), and the weight-for-age z-score was −0.56 (−1.35 + 0.44). Extra-cardiac Fontans were performed in 79% (4–100%) of patients at the 13 centres performing this procedure; lateral tunnels were performed in 32% (3–100%) at the 11 centres performing it. Deep hypothermic circulatory arrest (nine centres) ranged from 6 to 100%. Major complications occurred in 17% (7–33%). The length of stay was 9.5 days (9–12); 15% (6–33%) had prolonged pleural effusion. Centres with fewer patients (Conclusions:Fontan perioperative practices varied widely among study centres. Strategies to decrease the duration of pleural effusion and minimise complications may decrease the length of stay. Further research regarding deep hypothermic circulatory arrest is needed to understand its association with prolonged pleural effusion.

Background:Using existing data from clinical registries to support clinical trials and other prospective studies has the potential to improve research efficiency. However, little has been reported about staff experiences and lessons learned from implementation of this method in pediatric cardiology.Objectives:We describe the process of using existing registry data in the Pediatric Heart Network Residual Lesion Score Study, report stakeholders’ perspectives, and provide recommendations to guide future studies using this methodology.Methods:The Residual Lesion Score Study, a 17-site prospective, observational study, piloted the use of existing local surgical registry data (collected for submission to the Society of Thoracic Surgeons-Congenital Heart Surgery Database) to supplement manual data collection. A survey regarding processes and perceptions was administered to study site and data coordinating center staff.Results:Survey response rate was 98% (54/55). Overall, 57% perceived that using registry data saved research staff time in the current study, and 74% perceived that it would save time in future studies; 55% noted significant upfront time in developing a methodology for extracting registry data. Survey recommendations included simplifying data extraction processes and tailoring to the needs of the study, understanding registry characteristics to maximise data quality and security, and involving all stakeholders in design and implementation processes.Conclusions:Use of existing registry data was perceived to save time and promote efficiency. Consideration must be given to the upfront investment of time and resources needed. Ongoing efforts focussed on automating and centralising data management may aid in further optimising this methodology for future studies.

Background Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score. Study design and methods In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion. Results Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion. Conclusions Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define.

Survival for hypoplastic left heart syndrome (HLHS) has improved dramatically. Little is known about early family function, quality of life (QOL), or well-being/adjustment for parents of infants with HLHS. Parent/family outcomes over time, predictors, and differences in 143 mothers and 72 fathers were examined. Parents reported better family function compared with published norms, but 26% experienced family dysfunction. QOL and well-being were significantly lower than adult norms. QOL scores generally declined over time, whereas self-reported well-being improved. Responses from mothers and fathers showed different trends, with mothers having worse scores on most measures and at most time points. Being a single parent was a risk factor for poorer family function, but not for lower individual QOL or well-being. Family characteristics, stress, and coping skills were predictive of outcomes. Parents’ psychosocial responses to the challenges of life with infants with HLHS change over time. Individually tailored psychosocial support is needed.

OBJECTIVES: To determine if neurodevelopmental deficits in children with single-ventricle physiology change with age and early developmental scores predict 6-year outcomes. METHODS: In the Single Ventricle Reconstruction Trial, Bayley Scales of Infant Development, Second Edition, were administered at 14 months of age, and parents completed the Behavior Assessment System for Children, Second Edition (BASC-2) annually from the ages of 2 to 6 years. Scores were classified as average, at risk, or impaired. We calculated sensitivities, specificities, and positive and negative predictive values of earlier tests on 6-year outcomes. RESULTS: Of 291 eligible participants, 244 (84%) completed the BASC-2 at 6 years; more Single Ventricle Reconstruction participants than expected on the basis of normative data scored at risk or impaired on the BASC-2 Adaptive Skills Index at that evaluation (28.7% vs 15.9%; P < .001). Children with Adaptive Skills Composite scores CONCLUSIONS: Many children with hypoplastic left heart syndrome who have low adaptive skills at the age of 6 years will not be identified by screening at earlier ages. With our findings, we highlight the importance of serial evaluations for children with critical congenital heart disease throughout development.

Background Many factors affect outcomes after congenital cardiac surgery. Objectives The RLS (Residual Lesion Score) study explored the impact of severity of residual lesions on post-operative outcomes across operations of varying complexity. Methods In a prospective, multicenter, observational study, 17 sites enrolled 1,149 infants undergoing 5 common operations: tetralogy of Fallot repair (n = 250), complete atrioventricular septal defect repair (n = 249), arterial switch operation (n = 251), coarctation or interrupted arch with ventricular septal defect (VSD) repair (n = 150), and Norwood operation (n = 249). The RLS was assigned based on post-operative echocardiography and clinical events: RLS 1 (trivial or no residual lesions), RLS 2 (minor residual lesions), or RLS 3 (reintervention for or major residual lesions before discharge). The primary outcome was days alive and out of hospital within 30 post-operative days (60 for Norwood). Secondary outcomes assessed post-operative course, including major medical events and days in hospital. Results RLS 3 (vs. RLS 1) was an independent risk factor for fewer days alive and out of hospital (p ≤ 0.008) and longer post-operative hospital stay (p ≤ 0.02) for all 5 operations, and for all secondary outcomes after coarctation or interrupted arch with VSD repair and Norwood (p ≤ 0.03). Outcomes for RLS 1 versus 2 did not differ consistently. RLS alone explained 5% (tetralogy of Fallot repair) to 20% (Norwood) of variation in the primary outcome. Conclusions Adjusting for pre-operative factors, residual lesions after congenital cardiac surgery impacted in-hospital outcomes across operative complexity with greatest impact following complex operations. Minor residual lesions had minimal impact. These findings may provide guidance for surgeons when considering short-term risks and benefits of returning to bypass to repair residual lesions.

Background: Prior ECG standards in children have largely been defined without echo confirmation of normal anatomy. The Pediatric Heart Network Normal Echocardiogram Z-score Project provides a racially diverse age/sex classified group of healthy children with normal echos that included 2170 matched contemporaneous digitally acquired ECGs. We hypothesized that ECG measures and z-scores of left ventricular (LV) dimensions are correlated in healthy children. Methods: This was a secondary analysis of the previously described cohort. Six ECG measures historically associated with LV size (R V5, R V6, S V1, Q III, axis, R V6+S V1), and 13 paired echo measures were identified a-priori with LV Mass (LVMass-z) and left ventricular end diastolic volume (LVEDV-z) z-scores serving as primary echo measurement predictors. Pearson or Spearman correlations were calculated for each of the 78 ECG- echo pairs. Regression analyses were performed to assess how much variance in ECG measures was explained by variation in LV dimensions and by demographic variables (age, sex, race). Results: ECG and echo measurement correlations were significant and concordant in 41/78 (53%), though many were significant and discordant in 13, (17%) or not correlated in 24 (31%). Of the 6 ECG measures of LV size, 5 correlated in the clinically predicted direction for LV Mass-z and LVEDV-z. While many of the correlations were statistically significant, the correlations were weak (0.05-0.25). R 2 was higher for demographic variables than for echo measures in all pairs, but even with demographic variables included, the overall R 2 was < 0.17. Conclusions: In a large, diverse cohort of healthy children, there was a positive association between echo measures of LV dimension and mass and the most commonly used ECG measures of LVH. However, these correlations were weak and most of the variability in ECG measures was explained by factors other than echo derived mass or volume or measured patient demographic variables. These data question the utility of traditional ECG measurements of LV size as standalone indications for further cardiac evaluation in healthy children.

Background: The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in exercise capacity and ventricular performance following six months of treatment with udenafil (87.5 mg twice daily). In this analysis we evaluated whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. Methods: The effect of udenafil on exercise was evaluated within subgroups defined by gender, race, ventricular morphology, and baseline peak oxygen consumption (VO 2 ). Linear regression modeling evaluated for differential response to udenafil (interaction of subgroup with treatment arm). Individual subgroups were excluded if the number of participants was Results: Subgroup analyses demonstrated qualitative improvements in peak VO 2 , work rate at the ventilatory anaerobic threshold (VAT), VO 2 at VAT, and ventilatory efficiency (VE/VCO 2 ) for those randomized to udenafil compared to placebo in all subgroups (Table). There was not a differential response to udenafil based on gender, race, ventricular morphology, or baseline peak VO 2 , although participants in the lowest tertile of baseline peak VO 2 and those with single left ventricles trended toward larger improvements. Conclusion: The relatively uniform improvement among subgroups in response to treatment with udenafil is consistent with the findings from the primary analysis of the FUEL trial. While the absence of a statistically significant differential effect between subgroups suggests that the effect of udenafil may not be gender, race, or morphology specific, and may not vary based on baseline exercise performance, the possibility of a larger improvements in those with poor baseline peak VO 2 and those with single left ventricle warrants further investigation.

Introduction: The Pediatric Heart Network’s Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT 02741115) demonstrated improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle (SV) function in this cohort has not been studied. Methods: Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline in indices of SV systolic, diastolic and global function, atrioventricular valve (AVV) regurgitation and mean Fontan fenestration gradient in the udenafil cohort vs placebo, controlling for ventricular morphology (LV vs. RV/other). Effects of ventricular morphology on echo measures and its interaction over time was also evaluated. Difficult imaging windows limited consistent capture of all measures. Results: The 191 udenafil participants had significantly improved myocardial performance index (p=0.03), AVV inflow peak E and A velocities (p = 0.007 and 0.03), and annular DTI-derived peak e’ velocity (p = 0.008) compared to 195 placebo participants (Table). There were no significant differences in change in SV size, systolic function, AVV regurgitation severity or mean fenestration gradient. Although LV morphology participants had significantly more favorable indices of SV size and function (lower volumes and areas, E/e’ ratio, systolic:diastolic time and AVV regurgitation, and higher annular s’ and e’ velocity) at baseline, there was no differential effect of udenafil by ventricular morphology at 26 weeks. Conclusions: FUEL participants who received udenafil demonstrated a significant improvement in global and diastolic echo indices. The changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular relaxation, which may help explain improved exercise performance in that cohort.

Background/Aims: The Pediatric Heart Network Marfan Trial was a randomized trial comparing atenolol versus losartan on aortic root dilation in 608 children and young adults with Marfan syndrome. Barriers to enrollment included a limited pool of eligible participants, restrictive entry criteria, and a diverse age range that required pediatric and adult expertise. Retention was complicated by a 3-year commitment to a complex study and medication regimen. The Network partnered with the Marfan Foundation, bridging the community with the research. The aims of this study are to report protocol and medication adherence and associated predictive factors, and to describe recruitment and retention strategies. Methods: Recruitment, retention, and adherence to protocol activities related to the primary outcome were measured. Retention was measured by percentage of enrolled participants with 3-year outcome data. Protocol adherence was calculated by completion rates of study visits, ambulatory electrocardiography (Holter monitoring), and quarterly calls. Medication adherence was assessed by the number of tablets or the amount of liquid in bottles returned. Centers were ranked according to adherence (high, medium, and low tertiles). Recruitment, retention, and adherence questionnaires were completed by sites. Descriptive statistics summarized recruitment, retention, and adherence, as well as questionnaire results. Regression modeling assessed predictors of adherence. Results: Completion rates for visits, Holter monitors, and quarterly calls were 99%, 94%, and 96%, respectively. Primary outcome data at 3 years were obtained for 88% of participants. The mean percentage of medication taken was estimated at 89%. Site and age were associated with all measures of adherence. Young adult and African American participants had lower levels of adherence. Higher adherence sites employed more strategies; had more staffing resources, less key staff turnover, and more collaboration with referring providers; utilized the Foundation’s resources; and used a greater number of strategies to recruit, retain, and promote protocol and medication adherence. Conclusion: Overall adherence was excellent for this trial conducted within a National Institutes of Health–funded clinical trial network. Strategies specifically targeted to young adults and African Americans may have been beneficial. Many strategies employed by higher adherence sites are ones that any site could easily use, such as greeting families at non-study hospital visits, asking for family feedback, providing calendars for tracking schedules, and recommending apps for medication reminders. Additional key learnings include adherence differences by age, race, and site, the value of collaborative learning, and the importance of partnerships with patient advocacy groups. These lessons could shape recruitment, retention, and adherence to improve the quality of future complex trials involving rare conditions.

Background Different methods have resulted in variable Z scores for echocardiographic measurements. Using the measurements from 3,215 healthy North American children in the Pediatric Heart Network (PHN) echocardiographic Z score database, the authors compared the PHN model with previously published Z score models. Methods Z scores were derived for cardiovascular measurements using four models (PHN, Boston, Italy, and Detroit). Model comparisons were performed by evaluating (1) overlaid graphs of measurement versus body surface area with curves at Z = −2, 0, and +2; (2) scatterplots of PHN versus other Z scores with correlation coefficients; (3) Bland-Altman plots of PHN versus other Z scores; and (4) comparison of median Z scores for each model. Results For most measurements, PHN Z score curves were similar to Boston and Italian curves but diverged from Detroit curves at high body surface areas. Correlation coefficients were high when comparing the PHN model with the others, highest with Boston (mean, 0.99) and lowest with Detroit (mean, 0.90). Scatterplots suggested systematic differences despite high correlations. Bland-Altman plots also revealed poor agreement at both extremes of size and a systematic bias for most when comparing PHN against Italian and Detroit Z scores. There were statistically significant differences when comparing median Z scores between the PHN and other models. Conclusions Z scores from the multicenter PHN model correlated well with previous single-center models, especially the Boston model, which also had a large sample size and similar methodology. The Detroit Z scores diverged from the PHN Z scores at high body surface area, possibly because there were more subjects in this category in the PHN database. Despite excellent correlation, significant differences in Z scores between the PHN model and others were seen for many measurements. This is important when comparing publications using different models and for clinical care, particularly when Z score thresholds are used to guide diagnosis and management.

Background/Aims:Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.Methods:We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.Results:Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.Conclusions:Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.

Introduction This study examined risk factors for secondary traumatic stress (STS) in behavioral health clinicians and whether access to the Post-Traumatic Stress Disorder (PTSD) Clinicians Exchange website mitigated STS risk. Methods A diverse sample of clinicians (N = 605) treating traumatized military populations in Department of Veterans Affairs (VA), Department of Defense, and community practice settings were randomized to a newsletter-only control group or the exchange group. The exchange website included resources for treating PTSD and promoting clinician well-being. Online surveys were administered at 0-, 6-, and 12-months postrandomization. Regression analyses were used to examine the link among risk factors, exchange access, and STS. Results Baseline clinician demographics, experience, total caseload, appeal of evidence-based practices (EBPs), and likelihood of adopting EBPs if required were not linked with STS at the 12-month assessment period. Providing care at the VA, more burnout, less compassion satisfaction, greater trauma caseload, less openness to new EBPs, and greater divergence from EBP procedures were linked with greater STS. Only burnout and divergence were associated with STS after accounting for other significant STS risk factors. Exchange and control group clinicians reported similar STS levels after accounting for burnout and divergence. Conclusions Given that burnout was linked with STS, future intervention may use techniques targeting burnout and STS (eg, emotion regulation strategies). Research exploring the link between divergence from EBPs and STS may inform EBP dissemination efforts and STS interventions. Finally, results highlight the need for research optimizing STS intervention efficacy among clinicians treating military populations.

Sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality, likely comprises heterogeneous disorders with the common phenotype of sudden death without explanation upon postmortem investigation. Previously, we reported that ∼40% of SIDS deaths are associated with abnormalities in serotonin (5-hydroxytryptamine, 5-HT) in regions of the brainstem critical in homeostatic regulation. Here we tested the hypothesis that SIDS is associated with an alteration in serum 5-HT levels. Serum 5-HT, adjusted for postconceptional age, was significantly elevated (95%) in SIDS infants (n = 61) compared with autopsied controls (n = 15) [SIDS, 177.2 ± 15.1 (mean ± SE) ng/mL versus controls, 91.1 ± 30.6 ng/mL] (P = 0.014), as determined by ELISA. This increase was validated using high-performance liquid chromatography. Thirty-one percent (19/61) of SIDS cases had 5-HT levels greater than 2 SDs above the mean of the controls, thus defining a subset of SIDS cases with elevated 5-HT. There was no association between genotypes of the serotonin transporter promoter region polymorphism and serum 5-HT level. This study demonstrates that SIDS is associated with peripheral abnormalities in the 5-HT pathway. High serum 5-HT may serve as a potential forensic biomarker in autopsied infants with SIDS with serotonergic defects.

ObjectiveThe aim of this study was to evaluate the safety and feasibility of a passive range of motion exercise programme for infants with CHD.Study designThis non-randomised pilot study enrolled 20 neonates following Stage I palliation for single-ventricle physiology. Trained physical therapists administered standardised 15–20-minute passive range of motion protocol, for up to 21 days or until hospital discharge. Safety assessments included vital signs measured before, during, and after the exercise as well as adverse events recorded through the pre-Stage II follow-up. Feasibility was determined by the percent of days that >75% of the passive range of motion protocol was completed.ResultsA total of 20 infants were enrolled (70% males) for the present study. The median age at enrolment was 8 days (with a range from 5 to 23), with a median start of intervention at postoperative day 4 (with a range from 2 to 12). The median hospital length of stay following surgery was 15 days (with a range from 9 to 131), with an average of 13.4 (with a range from 3 to 21) in-hospital days per patient. Completion of >75% of the protocol was achieved on 88% of eligible days. Of 11 adverse events reported in six patients, 10 were expected with one determined to be possibly related to the study intervention. There were no clinically significant changes in vital signs. At pre-Stage II follow-up, weight-for-age z-score (−0.84±1.20) and length-for-age z-score (−0.83±1.31) were higher compared with historical controls from two earlier trials.ConclusionA passive range of motion exercise programme is safe and feasible in infants with single-ventricle physiology. Larger studies are needed to determine the optimal duration of passive range of motion and its effect on somatic growth.

Background Dexmedetomidine (DEX) is increasingly used intraoperatively in infants undergoing cardiac surgery. This phase 1 multicentre study sought to: (i) determine the safety of DEX for cardiac surgery with cardiopulmonary bypass; (ii) determine the pharmacokinetics (PK) of DEX; (iii) create a PK model and dosing for steady-state DEX plasma levels; and (iv) validate the PK model and dosing. Methods We included 122 neonates and infants (0–180 days) with D-transposition of the great arteries, ventricular septal defect, or tetralogy of Fallot. Dose escalation was used to generate NONMEM® PK modelling, and then validation was performed to achieve low (200–300 pg ml−1), medium (400–500 pg ml−1), and high (600–700 pg ml−1) DEX plasma concentrations. Results Five of 122 subjects had adverse safety outcomes (4.1%; 95% confidence interval [CI], 1.8–9.2%). Two had junctional rhythm, two had second-/third-degree atrioventricular block, and one had hypotension. Clearance (CL) immediately postoperative and CL on CPB were reduced by approximately 50% and 95%, respectively, compared with pre-CPB CL. DEX clearance after CPB was 1240 ml min−1 70 kg−1. Age at 50% maximum clearance was approximately 2 days, and that at 90% maximum clearance was 18 days. Overall, 96.1% of measured DEX concentrations fell within the 5th–95th percentile prediction intervals in the PK model validation. Dosing strategies are recommended for steady-state DEX plasma levels ranging from 200 to 1000 pg ml−1. Conclusions When used with a careful dosing strategy, DEX results in low incidence and severity of adverse safety events in infants undergoing cardiac surgery with cardiopulmonary bypass. This validated PK model should assist clinicians in selecting appropriate dosing. The results of this phase 1 trial provide preliminary data for a phase 3 trial of DEX neuroprotection. Clinical trials registration NCT01915277.

We appreciate the opportunity to respond to the letter by Ackerman et al. [1], andwe greatly appreciate the effort of the authors of the letter to communicate their concerns to us. We attempt to address these concerns below. Please note that Ms. Laura Crandall has recused herself from this response due to a conflict of interest as a member of the SUDC Foundation, since the letter writers represent the board of the foundation. 1. The major concerns raised in the letter are that the design of the study was not population-based, the cases were accrued retrospectively, and there was inconsistency across medical examiners on the information available to us for review. We have organized our response to address these major and related concerns together first. In the response, we summarize the critique of the authors in italics and then reiterate (in quotation marks) and clarify the text of our original paper in which the points questioned were addressed.

OBJECTIVES: The Residual Lesion Score (RLS) was developed as a novel tool for assessing residual lesions after congenital heart operations based on widely available clinical and echocardiographic characteristics. The RLS ranks postoperative findings as follows: Class 1 (no/trivial residua), Class 2 (minor residua), or Class 3 (major residua or reintervention prior to discharge for residua). The multi-center prospective RLS study aims to analyze the impact of residual lesions on outcomes in common congenital cardiac operations. We hypothesize that RLS will predict postoperative adverse events, resource utilization, mortality and reinterventions by one year postoperatively. METHODS: The study cohort consists of infants ≤12 months of age undergoing definitive surgery for: (1) complete atrioventricular septal defect, (2) tetralogy of Fallot, (3) dextro-transposition of the great arteries with or without intact ventricular septum, (4) single ventricle (Norwood procedure), and (5) coarctation or interrupted/hypoplastic arch with ventricular septal defect. Subjects with major congenital or acquired extra-cardiac anomalies that could independently affect the primary endpoint, which is number of days alive and out of the hospital within 30 days of surgery (60 days for Norwood procedure), were excluded. Secondary outcomes include: ≥1 early major postoperative adverse event; days of intensive care unit and hospital stay, and initial and total ventilator time; mortality/transplant after discharge; unplanned reinterventions after discharge; and cost. All analyses will be performed separately by surgical operation. CONCLUSION: This is the first multi-center prospective validation of a tool for surgical outcome assessment and quality improvement specific to congenital heart surgery.

Burnout is widespread among behavioral health clinicians treating posttraumatic stress disorder (PTSD) among military populations. Intervention-based strategies have shown some benefit in addressing clinician burnout. One Web-based tool, the PTSD Clinicians Exchange, was designed to disseminate clinical best practices for the treatment of PTSD and facilitate self-care to mitigate burnout. This study sought to determine whether this tool could reduce burnout among clinicians treating military populations.A total of 605 behavioral health clinicians from the U.S. Department of Veterans Affairs, the Department of Defense, and the community were enrolled in a randomized controlled trial to test the effectiveness of the PTSD Clinicians Exchange. Clinicians were assessed on demographic characteristics, practice patterns, and organizational support with an online survey at baseline and at 6 and 12 months. Burnout, secondary traumatic stress (STS), and compassion satisfaction were measured with the Professional Quality of Life Scale.At baseline, no differences were observed in mean±SD burnout scores for the intervention (19.9±5.1) and control groups (20.2±5.4). Participation in the Exchange had no effect on burnout score at 12 months; burnout scores remained stable across the study period. In a multivariable stepwise regression model, older age, lower burnout at baseline, and lower STS scores and higher compassion satisfaction scores at 12 months were significantly associated with lower burnout scores.The PTSD Clinicians Exchange did not mitigate burnout among clinicians, possibly because of the content provided, the dissemination mechanism, or participants' limited use of the Web site. These results can be used to inform and enhance future interventions.

BACKGROUND: The reliability of LV systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of left ventricular (LV) size and systolic function in children with normal cardiac anatomy and qualitatively normal function. METHODS: The Pediatric Heart Network Normal Echocardiogram Database collected normal echocardiograms from healthy children ≤18 years old distributed equally by age, gender, and race. A core lab used 2-dimensional echocardiograms to measure LV dimensions from which a separate data coordinating center calculated LV volumes and systolic functional indices. To evaluate interobserver variability, two independent expert pediatric echocardiographic observers re-measured LV dimensions on a subset of studies, while blinded to calculated volumes and functional indices. RESULTS: Of 3215 subjects with measurable images, 552 (17%) had a calculated LV shortening fraction (SF)

Background Heart size and function in children with single right ventricle (RV) anomalies may be influenced by shunt type at the Norwood procedure. We sought to identify shunt-related differences during early childhood after staged surgical palliations using echocardiography. Methods We compared echocardiographic indices of RV, neoaortic, and tricuspid valve size and function at 14 months, pre-Fontan, and 6 years in 241 subjects randomized to a Norwood procedure using either the modified Blalock-Taussig shunt or RV-to-pulmonary-artery shunt. Results At 6 years, the shunt groups did not differ significantly in any measure except for increased indexed neoaortic area in the modified Blalock-Taussig shunt. RV ejection fraction improved between pre-Fontan and 6 years in the RV-to-pulmonary artery shunt group but was stable in the modified Blalock-Taussig shunt group. For the entire cohort, RV diastolic and systolic size and functional indices were improved at 6 years compared with earlier measurements, and indexed tricuspid and neoaortic annular area decreased from 14 months to 6 years. The prevalence of ≥moderate tricuspid and neoaortic regurgitation was uncommon and did not vary by group or time period. Diminished RV ejection fraction at the 14-month study was predictive of late death/transplant; the hazard of late death/transplant when RV ejection fraction was Conclusions By 6 years after staged palliation, shunt type has not impacted RV size and function, and RV and valvar size and function show beneficial remodeling. Poor RV systolic function at 14 months predicts worse late survival independent of the initial shunt type. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00115934.

Few studies have investigated the range and severity of insomnia-related sleep complaints among veterans with posttraumatic stress disorder (PTSD), and the temporal association between insomnia and PTSD severity has yet to be examined. To examine these associations, a large, gender-balanced cohort of veterans (N = 1,649) of the Iraq and Afghanistan conflicts participated in longitudinal assessments of PTSD and insomnia-related symptoms over a period of 2.5 years following enrollment (range: 2-4 years). Data were obtained from multiple sources, including interviews, self-report assessments, and electronic medical record data. Three-fourths (74.0%) of veterans with PTSD diagnoses at Time 1 (T1) reported insomnia-related sleep difficulties on at least half the nights during the past 30 days, and one-third of participants had received a prescription for a sedative-hypnotic drug in the past year. Veterans without PTSD had fewer sleep problems overall, although the prevalence of sleep problems was high among all study participants. In longitudinal, cross-lagged panel models, the frequency of sleep problems at T1 independently predicted increases in PTSD severity at Time 2 (T2), B = 0.27, p.001, after controlling for gender and relevant comorbidities. Conversely, T1 PTSD severity was associated with increasing sleep complaints at T2 but to a lesser degree, B = 0.04, p.001. Moderately high rates of sedative-hypnotic use were seen in veterans with PTSD, with more frequent use in women compared to men (40.4% vs. 35.0%). Sleep complaints were highly prevalent overall and highlight the need for increased clinical focus on this area.Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Gravedad del TEPT y Trastornos del Sueño Relacionados con el Insomnio: Asociaciones Longitudinales en una gran Cohorte, Balanceados por Género. de Veteranos Expuestos al Combate SUEÑO, INSOMNIO Y SEVERIDAD DE TEPT Pocos estudios han investigado el rango y la gravedad de las quejas del sueño relacionadas con el insomnio entre veteranos con trastorno de estrés postraumático (TEPT) y la asociación temporal entre el insomnio y la severidad del TEPT aún no se han examinado. Para examinar estas asociaciones, una gran cohorte de veteranos (N = 1,649) de los conflictos de Irak y Afganistán, balanceados por género, participaron en evaluaciones longitudinales de TEPT y síntomas relacionados con el insomnio durante un período de 2.5 años posteriores a la inscripción (rango: 2-4 años). Los datos se obtuvieron de múltiples fuentes, incluyendo entrevistas, autoevaluaciones y datos de registros médicos electrónicos. Tres cuartos (74.0%) de los veteranos con diagnóstico de TEPT en el tiempo 1 (T1) informaron dificultades de sueño relacionadas con el insomnio en al menos la mitad de las noches durante los últimos 30 días, y un tercio de los participantes habían recibido una prescripción de un fármaco sedante-hipnótico en el último año. Los veteranos sin TEPT tenían menos problemas de sueño en general, aunque la prevalencia de problemas de sueño fue alta entre todos los participantes del estudio. En los modelos longitudinales de panel con retardo cruzado, la frecuencia de los problemas de sueño en T1 predijeron independientemente aumentos en la severidad del TEPT en el Tiempo 2 (T2), B = 0.27, p.001, después controlar por género y comorbilidades relevantes. Por el contrario, la gravedad del TEPT en T1 se asoció con un aumento de las quejas de sueño en T2 pero en menor grado, B = 0.04, p.001. Se observaron tasas moderadamente altas de uso de hipnóticos-sedativos en veteranos con TEPT, con un uso más frecuente en mujeres comparadas con hombres (40.4% vs. 35.0%). En general las quejas de sueño fueron altamente prevalentes y destacan la necesidad de una mayor focalización clínica en esta área.Traditional and Simplified Chinese Abstracts by the Asian Society for Traumatic Stress Studies (AsianSTSS) 簡體及繁體中文撮要由亞洲創傷心理研究學會翻譯 PTSD Severity and Insomnia-Related Sleep Disturbances: Longitudinal Associations in a Large, Gender-Balanced Cohort of Combat-Exposed Veterans Traditional Chinese 標題: PTSD嚴重度與失眠相關的睡眠問題:針對有戰鬥經歷的退役軍人的大型、性別平均世代研究中的縱貫關連 撮要: 少有研究檢視患創傷後壓力症(PTSD)的退役軍人其失眠相關的睡眠問題的幅度和嚴重度, 而失眠與PTSD嚴重度的時間性關連亦未受檢視。為檢視以上關連, 我們進行了一個大型、性別平均的世代研究(N = 1,649), 樣本為曾參與伊拉克和阿富汗戰爭的退役軍人, 他們自參與研究後, 接受為期2.5年 (值域:2-4年) 的PTSD與失眠相關症狀的縱貫評估。我們從多個來源取得數據, 包括面談、自評測量、電子醫療記錄數據。在時點1(T1)患PTSD的退役軍人當中, 四分之三(74.0%)在過去30天內, 至少一半日子有失眠相關的睡眠問題, 而三分一的樣本在過去一年取得鎮靜催眠藥處方。雖然樣本的睡眠問題普遍率高, 但無患PTSD的退役軍人整體來說有較少睡眠問題。在縱貫的交叉延宕模型裡, 以性別和相關共病作對照後, T1的睡眠問題頻率獨立地預測到時點2(T2)的PTSD嚴重度提升(B = 0.27, p.001)。相反, T1的PTSD嚴重度跟T2的睡眠問題上升有關, 但關連較小(B = 0.04, p.001)。患PTSD的退役軍人使用鎮靜催眠藥比率偏高, 女性使用的頻率較男性高(40.4% 比對 35.0%)。整體來說, 睡眠問題非常普遍, 凸顯臨床治療應多加注意這個領域。 Simplified Chinese 标题: PTSD严重度与失眠相关的睡眠问题:针对有战斗经历的退役军人的大型、性别平均世代研究中的纵贯关连 撮要: 少有研究检视患创伤后压力症(PTSD)的退役军人其失眠相关的睡眠问题的幅度和严重度, 而失眠与PTSD严重度的时间性关连亦未受检视。为检视以上关连, 我们进行了一个大型、性别平均的世代研究(N = 1,649), 样本为曾参与伊拉克和阿富汗战争的退役军人, 他们自参与研究后, 接受为期2.5年 (值域:2-4年) 的PTSD与失眠相关症状的纵贯评估。我们从多个来源取得数据, 包括面谈、自评测量、电子医疗记录数据。在时点1(T1)患PTSD的退役军人当中, 四分之三(74.0%)在过去30天内, 至少一半日子有失眠相关的睡眠问题, 而三分一的样本在过去一年取得镇静催眠药处方。虽然样本的睡眠问题普遍率高, 但无患PTSD的退役军人整体来说有较少睡眠问题。在纵贯的交叉延宕模型里, 以性别和相关共病作对照后, T1的睡眠问题频率独立地预测到时点2(T2)的PTSD严重度提升(B = 0.27, p.001)。相反, T1的PTSD严重度跟T2的睡眠问题上升有关, 但关连较小(B = 0.04, p.001)。患PTSD的退役军人使用镇静催眠药比率偏高, 女性使用的频率较男性高(40.4% 比对 35.0%)。整体来说, 睡眠问题非常普遍, 凸显临床治疗应多加注意这个领域。.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short-term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double blind, placebo controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co., Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Sudden unexplained death in childhood (SUDC), while rare, accounts for an important fraction of unexpected deaths in children >1 year of age. Previously we reported an association between febrile seizures, hippocampal maldevelopment, and sudden, unexpected deaths in young children (1–6 years), termed “hippocampal maldevelopment associated with sudden death (HMASD).” Here, we characterize in greater detail the hippocampal pathology in a large cohort of cases (n = 42) of this entity, and attempt to define possible new entities responsible for sudden, unexplained death in young children without HMASD/febrile seizure phenotypes. We performed comparative analysis on cases, which we classified in a cohort of 89 sudden and unexpected deaths as HMASD, explained deaths, SUDC with febrile seizure phenotype (SUDC-FS) but without hippocampal pathology, and SUDC (without hippocampal pathology or febrile seizure phenotype). The frequency of each subgroup was: HMASD 48 % (40/83); SUDC 27 % (22/83); SUDC-FS 18 % (15/83); explained 7 % (6/83). HMASD was characterized clinically by sudden, sleep-related death, term birth, and discovery in the prone position. Key morphologic features of HMASD were focal granule cell bilamination of the dentate gyrus with or without asymmetry and/or malrotation of the hippocampus, associated with significantly increased frequencies of 11 other developmental abnormalities. We identified no other distinct phenotype in the unexplained categories, except for an association of febrile seizures without hippocampal maldevelopment. HMASD is a distinct clinicopathologic entity characterized by a likely developmental failure of neuronal migration in the dentate gyrus. Future research is needed to determine the causal role of HMASD in sudden death in early childhood.

Purpose The purpose of this study was to determine the major subcategories and clinicopathologic features of sudden unexpected death in young children in a large retrospective cohort, and to confirm the association of sudden unexplained death in children (abbreviated by us for unexplained deaths as SUDC) with hippocampal pathology and/or febrile seizures. Methods We undertook analysis of a retrospective cohort of 151 cases, of which 80 % (121/151) were subclassified as SUDC, 11 % (16/151) as explained, 7 % (10/151) as undetermined, and 3 % (4/151) as seizure-related. Results There were no significant differences between SUDC and explained cases in postnatal, gestational, or postconceptional age, frequency of preterm birth, gender, race, or organ weights. In contrast, 96.7 % (117/121) of the SUDC group were discovered during a sleep period compared to 53.3 % (8/15) of the explained group (p

Objective To examine whether medical decisions regarding evaluation and management of musculoskeletal pain conditions varied systematically by characteristics of the patient or provider. Methods We conducted a balanced factorial experiment among primary care physicians in the US. Physicians (n = 192) viewed 2 videos of different patients (actors) presenting with pain: undiagnosed sciatica symptoms or diagnosed knee osteoarthritis. Systematic variations in patient gender, socioeconomic status, and race and physician gender and experience (

Resins used in dental composites, derived from bisphenol-A (BPA), have been shown to alter immune cells. The objective of this study was to explore children's immune function changes in relation to resin composite treatment.We conducted secondary data analysis of the New England Children's Amalgam Trial immune function substudy (N = 59). Immune function was measured pre-treatment and up to five times post-treatment through 5-year follow-up. Multivariable generalized linear regression models were used to estimate the association between three classes of resin composites (bisphenol-A-diglycidyl-dimethacrylate [BisGMA]-based flowables used for preventive sealants; urethane dimethacrylate [UDMA]-based compomer restorations; bisGMA-based restorations) and changes in immune function markers measured annually.Total white blood cell counts and responsiveness of T cells or neutrophils were not appreciably altered by composite treatment levels. Changes in B cell responsiveness were greater throughout follow-up among children with more bisGMA-based composite restorations, which opposed findings for amalgam treatment levels. Monocyte responsiveness changes were decreased at 6 months with greater treatment, but not over longer follow-up.Results of this analysis showed no overt immune function alterations associated with resin composites. Additional research regarding lymphocyte activation may be warranted given the consistency of results within these analyses and with a prior study showing increased B cell activation.

BackgroundPost-traumatic stress disorder (PTSD) is associated with elevated risk for metabolic syndrome (MetS). However, the direction of this association is not yet established, as most prior studies employed cross-sectional designs. The primary goal of this study was to evaluate bidirectional associations between PTSD and MetS using a longitudinal design.MethodA total of 1355 male and female veterans of the conflicts in Iraq and Afghanistan underwent PTSD diagnostic assessments and their biometric profiles pertaining to MetS were extracted from the electronic medical record at two time points (spanning ~2.5 years, n = 971 at time 2).ResultsThe prevalence of MetS among veterans with PTSD was just under 40% at both time points and was significantly greater than that for veterans without PTSD; the prevalence of MetS among those with PTSD was also elevated relative to age-matched population estimates. Cross-lagged panel models revealed that PTSD severity predicted subsequent increases in MetS severity (β = 0.08, p = 0.002), after controlling for initial MetS severity, but MetS did not predict later PTSD symptoms. Logistic regression results suggested that for every 10 PTSD symptoms endorsed at time 1, the odds of a subsequent MetS diagnosis increased by 56%.ConclusionsResults highlight the substantial cardiometabolic concerns of young veterans with PTSD and raise the possibility that PTSD may predispose individuals to accelerated aging, in part, manifested clinically as MetS. This demonstrates the need to identify those with PTSD at greatest risk for MetS and to develop interventions that improve both conditions.

Resin-based dental restorations may intra-orally release their components and bisphenol A. Gestational bisphenol A exposure has been associated with poorer executive functioning in children.To examine whether exposure to resin-based composite restorations is associated with neuropsychological development in children.Secondary analysis of treatment level data from the New England Children's Amalgam Trial, a 2-group randomized safety trial conducted from 1997 to 2006. Children (N=534) aged 6-10 y with ≥2 posterior tooth caries were randomized to treatment with amalgam or resin-based composites (bisphenol-A-diglycidyl-dimethacrylate-composite for permanent teeth; urethane dimethacrylate-based polyacid-modified compomer for primary teeth). Neuropsychological function at 4- and 5-year follow-up (N=444) was measured by a battery of tests of executive function, intelligence, memory, visual-spatial skills, verbal fluency, and problem-solving. Multivariable generalized linear regression models were used to examine the association between composite exposure levels and changes in neuropsychological test scores from baseline to follow-up. For comparison, data on children randomized to amalgam treatment were similarly analyzed.With greater exposure to either dental composite material, results were generally consistent in the direction of slightly poorer changes in tests of intelligence, achievement or memory, but there were no statistically significant associations. For the four primary measures of executive function, scores were slightly worse with greater total composite exposure, but statistically significant only for the test of Letter Fluency (10-surface-years β=-0.8, SE=0.4, P=0.035), and the subtest of color naming (β=-1.5, SE=0.5, P=0.004) in the Stroop Color-Word Interference Test. Multivariate analysis of variance confirmed that the negative associations between composite level and executive function were not statistically significant (MANOVA, P=0.18). Results for greater amalgam exposure were mostly nonsignificant in the opposite direction of slightly improved scores over follow-up.Dental composite restorations had statistically insignificant associations of small magnitude with impairments in neuropsychological test change scores over 4- or 5-years of follow-up in this trial.

Aim To assess the feasibility of collecting electronic pain data from thalassaemia patients, based on its acceptability and convenience to the participants and study team. Methods Participants in the Thalassemia Clinical Research Network Assessment of Pain Survey Study completed the Brief Pain Inventory (BPI) quarterly by paper or phone interview. Participants in a substudy completed the BPI Short Form daily over three non-consecutive transfusion cycles through an automated telephone system. Results The consent rate for the main study was 93%, with 93% retention. The substudy had 75% retention, with more than 75% of scheduled calls completed. Regular monitoring of enrolment, missed calls, data quality, and the performance of the subcontractor for the automated system was crucial to fulfillment of the study goals. Conclusions Use of electronic data collection for patient-reported outcomes was convenient for both patients and study personnel but required human interactions beyond the automated system to maximise data quantity and quality.

Objective: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. Study design: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. Results: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤.003) and psychosocial (P

The role of the cerebral cortex in the cognitive deficits in preterm survivors is poorly understood. Periventricular leukomalacia (PVL), the key feature of encephalopathy of prematurity, is characterized by periventricular necrotic foci and diffuse gliosis in the surrounding cerebral white matter. Here, we tested the hypothesis that reductions in the density of layer I neurons and/or pyramidal neurons in layers III and/or V are associated with PVL, indicating cortical pathology potentially associated with cognitive deficits in long-term survivors. In controls (23 gestational weeks to 18 postnatal months) (n = 15), a lack of significant differences in pyramidal density among incipient Brodmann areas suggested that cytoarchitectonic differences across functional areas are not fully mature in the fetal and infant periods. There was a marked reduction (38%) in the density of layer V neurons in all areas sampled in the PVL cases (n = 17) compared to controls (n = 12) adjusted for postconceptional age at or greater than 30 weeks, when the six-layer cortex is visually distinct (P < 0.024). This may reflect a dying-back loss of somata complicating transection of layer V axons projecting through the necrosis in the underlying white matter. This study underscores the potential role of secondary cortical injury in the encephalopathy of prematurity.

Project There is limited literature concerning the effect of urinary flow rate on mercury excretion at low-level exposure. The aim of the present study is to examine the influence of urinary flow rate on mercury excretion in children. Also of interest is the influence of flow rate on creatinine excretion and creatinine-corrected mercury, which arisearises with spot urine samples. Procedure A substudy of the New England Children's Amalgam Trial collected pairs of urine samples from children aged 10–16 years: a timed overnight collection and a spot daytime sample collected the following day. These samples were analyzed for mercury and creatinine concentration. Regression analysis was used to model the effect of urinary flow rate in the timed overnight samples. A paired t -test compared concentrations and creatinine-corrected mercury between overnight and daytime samples. Results Creatinine excretion rate (mg/h) increased significantly with urinary flow rate (mL/h), whereas creatinine concentration (g/L) decreased with flow rate. We found a non-significant increase in mercury excretion rate (ng/h) with flow rate, and mercury concentration decreased with flow rate. Mercury and creatinine concentrations were significantly higher in the overnight compared to daytime samples. For creatinine-corrected mercury, no significant impact of urinary flow rate was found. Conclusions Although the creatinine excretion rate, and probably the mercury excretion rate, increased with urinary flow rate, the mercury/creatinine ratio seemed relatively unaffected by urinary flow rate.

Recently, we reported hippocampal and temporal lobe abnormalities in 5 toddlers with sudden unexplained death in childhood (SUDC). The association of these anomalies with a high incidence (40%) of individual/family histories of simple febrile seizures in the cases raised concern that febrile seizures can be associated with death. In a series of 64 toddlers with sudden death, we tested the hypothesis that an SUDC subset is characterized by hippocampal and temporal lobe maldevelopment and an individual and/or family history of simple familial seizures. Cases of sudden and unexplained death in children aged 1.0 to 5.9 years (median 1.7 years) were divided into groups based upon a history of febrile or nonfebrile seizures, familial febrile seizures, and autopsy classification of cause of death. Forty-nine of the 64 cases (77%) were classified as SUDC, of which 40% had an individual/family history of febrile seizures. Of the 26 SUDC cases with available hippocampal sections, 62% (16/26) had hippocampal and temporal lobe anomalies, including 82% (9/11) of cases with an individual/family history of febrile seizures. Cases with these anomalies were all found dead during a sleep period, typically in the prone (87%) position. We conclude that a potential new entity may account for the majority of SUDC in toddlers, defined by sleep-related death in the prone position, individual/family history of febrile seizures, and hippocampal and temporal lobe anomalies. The mechanism of death appears analogous to sudden death in (temporal lobe) epilepsy, with a putative unwitnessed seizure during sleep leading to airway occlusion and death. This study mandates further research into the potential link between simple febrile seizures and death.

Compomer restorations release fluoride to help prevent future caries. We tested the hypothesis that compomer is associated with fewer future caries compared with amalgam. The five-year New England Children’s Amalgam Trial recruited 534 children aged 6–10 yrs with ≥ 2 carious posterior teeth. Children were randomized to receive compomer or amalgam restorations in primary posterior teeth, placed with a fluoride-releasing bonding agent. The association between restorative material and future caries was assessed by survival analysis. Average follow-up of restorations (N = 1085 compomer, 954 amalgams) was 2.8 + 1.4 yrs in 441 children. No significant difference between materials was found in the rate of new caries on different surfaces of the same tooth. Incident caries on other teeth appeared slightly more quickly after placement of compomer restorations (p = 0.007), but the difference was negligible after 5 yrs. Under the conditions of this trial, we found no preventive benefit to fluoride-releasing compomer compared with amalgam.

– Objective: To measure the 5-year caries increment among high-risk children during their participation in the New England Children’s Amalgam Trial (NECAT), and to evaluate sociodemographic factors that may account for any observed disparities. Methods: NECAT recruited 534 children aged 6–10 with at least two decayed posterior occlusal surfaces from urban Boston and rural Maine. After restoration of baseline caries and application of sealants to sound surfaces, NECAT continued to provide free comprehensive semiannual dental care to participants. The net caries increment of children who completed the 5-year follow-up (n = 429) was calculated and predictors of caries increment were investigated using multivariate negative binomial models. Results: The majority of children (89%) experienced new caries by the end of the 5-year follow-up. Almost half (45%) had at least one newly decayed surface by the first annual visit. At year 5, the mean number of new decayed teeth was 4.5 ± 3.6 (range 0–25) and surfaces was 6.9 ± 6.5 (range 0–48). Time trends showed a noticeably higher increment rate among older children and young teenagers. Multivariate models showed that age (P

We previously identified immunocytochemical evidence of nitrative and oxidative injury in premyelinating oligodendrocytes in periventricular leukomalacia (PVL). Here, we tested the hypothesis that free radical injury occurs in the overlying cerebral cortex and subplate neurons in PVL. We immunostained for nitrotyrosine, malondialdehyde, and hydroxynonenal adducts and scored neuron staining density in PVL (n = 11) and non-PVL (n = 15) cases (postconceptional ages from 34 to 109 weeks). Analysis of covariance controlled for age. Mean malondialdehyde scores in PVL cases were increased over controls (p = 0.005). Hydroxynonenal scores increased with age only in PVL cases (diagnosis vs age interaction; p = 0.024). Nitrotyrosine scores were not significantly increased. In 11 PVL and 23 control cases between 20 and 183 postconceptional weeks, cells morphologically consistent with subplate and Cajal-Retzius neurons showed qualitatively increased free radical modification in PVL over control cases with statistically significant odds ratios for hydroxynonenal and nitrotyrosine in both subplate neurons and Cajal-Retzius cells. Glial fibrillary acidic protein and CD68 scores for reactive astrocytes and microglia, respectively, were not significantly increased, suggesting a minimal inflammatory response. Thus, oxidative/nitrative damage to cortical and "pioneer" neurons, although mild overall, may contribute to cortical volume loss and cognitive/behavioral impairment in survivors of prematurity.

Objective: This study aims to prospectively examine the trends and reasons for the underutilization of free semiannual preventive dental care provided to children with unmet dental needs who participated in the 5-year New England Children's Amalgam Trial. Methods: Children aged 6 to 10 at baseline (1997-99) with ≥2 posterior carious teeth were recruited from rural Maine (n = 232) and urban Boston (n = 266). Interviewer-administered questionnaires assessed demographic and personal characteristics. Reasons for missed appointments were recorded during follow-up and are descriptively presented. We used an ordinal logistic regression to analyze the utilization of semiannual dental visits. Results: On average, urban children utilized 69 percent of the visits and rural children utilized 82 percent of the visits. For both sites, utilization steadily decreased until the end of the 5-year trial. Significant predictors of underutilization in the multivariate model for urban children were non-White race, household welfare use, deep debt, and distance to dental clinic. Among the relatively less-diverse rural children, caregiver education level and a greater number of decayed tooth surfaces at baseline (i.e., need for care) were significantly associated with underutilization. Among all children, the common reasons for missed visits included guardian scheduling and transportation difficulties; reasons among urban participants also indicated a low priority for dental care. Conclusions: Among these children with unmet dental needs, the provision of free preventive dental care was insufficient to remove the disparities in utilization and did not consistently result in high utilization through follow-up. Differences between educational levels, ethnicities, and rural/urban location suggest that public health programs need to target the social settings in which financial burdens exist.

Children may be at particular risk from toxic effects of mercury (Hg). Previous studies of hair (organic) and urine (inorganic) Hg levels in US children were unable to assess Hg levels while accounting for exposure to amalgam dental restorations. This analysis describes, over a 5-year period, levels and correlates/predictors of scalp hair (H-Hg) and urinary (U-Hg) mercury in 534 New England Children's Amalgam Trial (NECAT) participants, aged 6-10 years and without exposure to dental amalgam at baseline.Mean H-Hg levels were between 0.3 and 0.4 microg/g over 5 years. 17-29% of children had H-Hg levelsor = 0.5 microg/g, and 5.0 to 8.5% of children had levelsor = 1 microg/g, in any given study year. In adjusted models, fish consumption frequency was the most robust predictor of high H-Hg. U-Hg mean levels were between 0.7 and 0.9 microg/g creatinine over two years. The percentage of those with U-Hgor 2.3 microg/g creatinine ranged from 4% to 6%. Number of amalgam restorations had a significant dose-response relationship with U-Hg level. Daily gum chewing in the presence of amalgam was associated with high U-Hg.

BackgroundMercury is nephrotoxic and dental amalgam is a source of mercury exposure.MethodsChildren 6–10 years of age (n = 534) with two or more posterior teeth with caries but no prior amalgam res...

The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.

Objectives: Previous research shows increased dental decay among immigrants, but little is known about the oral health of the growing population of children of immigrants. We compared the children of immigrants to the children of US-born caregivers in their caries experience at enrollment and their new caries increments during the 5-year New England Children's Amalgam Trial (NECAT). Methods: NECAT recruited 283 Boston-area children aged 6 to 10 with untreated caries and offered free semiannual preventive and restorative dental care during the trial. Sociodemographic factors and caregiver immigrant status were assessed through interviews. Multivariate negative binomial models evaluated the association between caregiver immigrant status and clinically assessed carious surfaces. Results: Forty percent of these Boston-area children had immigrant caregivers. At baseline, the children of immigrants had more carious surfaces (11.5 versus 9.4, adjusted for race/ethnicity, age, gender, and caregiver smoking status). Caregiver language preference explained some of this association. Immigrant status and language preference were not associated with 5-year caries increments. Conclusions: Prevalent disparities in the unmet dental needs of the immigrants' children were quickly ameliorated during participation in NECAT. Dental initiatives that target neighborhoods and are sensitive to acculturation levels may help improve and maintain the oral health of immigrant families.