Percent Body Fat and Weight Status of Youth Participating in Pediatric Weight Management Programs in the Pediatric Obesity Weight Evaluation Registry.

Factors associated with change in percent body fat (%BF) of children in pediatric weight management (PWM) care may differ from those associated with change in weight status. Objective: To describe %BF and weight status at initial visits to 14 PWM sites, identify differences by sex, and evaluate factors associated with change over 6 months. Methods: Initial visits of 2496 males and 2821 females aged 5-18 years were evaluated. %BF was measured using bioelectrical impedance analysis. Results: Sex-specific logistic regressions [806 males (32.3%), 837 females (29.7%)] identified associations with primary outcomes: lower %BF and metabolically impactful ≥5-point drop in percent of the 95th BMI percentile (%BMIp95) over 6 months. At the initial visit, males had lower %BF and higher %BMIp95 than females. Over 6 months, males had significantly (p < 0.001) greater median drop in %BF (-1.4% vs. -0.4%) and %BMIp95 (-3.0% vs. -1.9%) and a higher frequency of decreased %BF (68.9% vs. 57.8%), but similar percentage with ≥5-point %BMIp95 drop (36.5% vs. 32.4%; p = 0.080). For males, factors significantly associated with decreased %BF (older age, ≥6 visits, lack of developmental or depression/anxiety concerns) were not related to having a ≥5-point %BMIp95 drop. For females, lack of depression/anxiety concern was significantly associated with decreased %BF but was not associated with ≥5-point %BMIp95 drop. Conclusions: There are differences by sex in initial visit %BF and %BMIp95 and in characteristics associated with changes in these measures. PWM interventions should consider evaluating body composition and sex-stratifying outcomes.

Evidence-Based Assessment of Congenital Heart Disease Genes to Enable Returning Results in a Genomic Study.

BACKGROUND: Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study. METHODS: Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey. RESULTS: A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results. CONCLUSIONS: The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.

Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort.

BACKGROUND: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. METHODS: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. RESULTS: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. CONCLUSIONS: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.

Synergistic association of fluid overload and acute kidney injury on outcomes in pediatric cardiac ECMO: a retrospective analysis of the KIDMO database.

BACKGROUND: Acute kidney injury (AKI) and fluid overload (FO) are associated with poor outcomes in children receiving extracorporeal membrane oxygenation (ECMO). Our objective is to evaluate the impact of AKI and FO on pediatric patients receiving ECMO for cardiac pathology. METHODS: We performed a secondary analysis of the six-center Kidney Interventions During Extracorporeal Membrane Oxygenation (KIDMO) database, including only children who underwent ECMO for cardiac pathology. AKI was defined using Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria. FO was defined as < 10% (FO-) vs. ≥ 10% (FO +) and was evaluated at ECMO initiation, peak during ECMO, and ECMO discontinuation. Primary outcomes were mortality and length of stay (LOS). RESULTS: Data from 191 patients were included. Non-survivors (56%) were more likely to be FO + than survivors at peak ECMO fluid status and ECMO discontinuation. There was a significant interaction between AKI and FO. In the presence of AKI, the adjusted odds of mortality for FO + was 4.79 times greater than FO- (95% CI: 1.52-15.12, p = 0.01). In the presence of FO + , the adjusted odds of mortality for AKI + was 2.7 times higher than AKI- [95%CI: 1.10-6.60; p = 0.03]. Peak FO + was associated with a 55% adjusted relative increase in LOS [95%CI: 1.07-2.26, p = 0.02]. CONCLUSIONS: The association of peak FO + with mortality is present only in the presence of AKI + . Similarly, AKI + is associated with mortality only in the presence of peak FO + . FO + was associated with LOS. Studies targeting fluid management have the potential to improve LOS and mortality outcomes. A higher resolution version of the Graphical abstract is available as Supplementary information.

Efficacy of supermarket and web-based interventions for improving dietary quality: a randomized, controlled trial.

Dietary interventions may best be delivered at supermarkets, which offer convenience, accessibility, full food inventories and, increasingly, in-store registered dietitians, online shopping and delivery services. In collaboration with a large retail supermarket chain, we conducted a multisite supermarket and web-based intervention targeting nutrition trial (no. NCT03895580), randomizing participants (n = 247 (139 women and 108 men)) 2:2:1 to two levels of dietary education (Strategy 1 and Strategy 2) or an enhanced control group that included educational components beyond the routine standard of care. Both Strategies 1 and 2 included individualized, in-person, dietitian-led, purchasing data-guided interventions. Strategy 2 also included online tools for shopping, home delivery, selection of healthier purchases, meal planning and healthy recipes. The primary endpoint was change in dietary approaches to stop hypertension (DASH) score (a measure of adherence to the DASH diet) from baseline to 3 months. The primary endpoint was met because, at 3 months, the DASH score increased by 4.7 more for the combined Strategy 1 and Strategy 2 groups than for the control group (95% confidence interval (CI) (0.9, 8.5), P = 0.02). In a prespecified hierarchical test, at 3 months, DASH score increased by 3.8 more for the Strategy 2 group than for the Strategy 1 group (95% CI (0.8, 6.)9, P = 0.01). This trial demonstrates the efficacy of data-guided, supermarket-based, dietary interventions and modern online shopping tools in improving dietary quality in a free-living, community-based population. The trial also demonstrates the opportunity for academic investigators to collaborate with retailers to design and rigorously test comprehensive healthcare interventions.

Design and rationale for the supermarket and web-based intervention targeting nutrition (SuperWIN) for cardiovascular risk reduction trial.

PURPOSE: The prevalence of chronic diseases is increasing largely due to suboptimal dietary habits. It is not known whether individualized, supermarket-based, nutrition education delivered by registered dietitians, utilizing the advantages of the in-store and online environments, and electronically collected purchasing data, can increase dietary quality. METHODS AND RESULTS: The supermarket and web-based intervention targeting nutrition (SuperWIN) for cardiovascular risk reduction trial is a randomized, controlled dietary intervention study. Adults identified from a primary care network with 1 or more risk factors were randomized at their preferred store to: (1) standard of care plus individualized, point- of-purchase nutrition education; (2) standard of care plus individualized, point- of-purchase nutrition education enhanced with online shopping technologies and training; or (3) standard of care alone. Educational sessions within each store's clinic and aisles, emphasized the dietary approaches to stop hypertension (DASH) diet. The primary assessment was an intention-to-treat comparison on the effects of the dietary interventions on mean change in DASH score (90-point range) from baseline to 3 months (post-intervention). Additional outcomes included blood pressure, lipids, weight, purchasing behavior, food literacy, and intervention feedback. Between April 2019 to February 2021, 267 participants were randomized (20 excluded due to coronavirus disease pandemic). Median age was 58 years, 69% were female, 64% had a college degree, 53% worked full-time, 64% were obese, 73% were treated with blood pressure and 42% with cholesterol medications, and most had low-to-moderate diet quality. CONCLUSION: The SuperWIN trial was designed to provide a rigorous evaluation of the efficacy of 2 novel, comprehensive, supermarket-based dietary intervention programs.

Elevated blood pressure in youth in pediatric weight management programs in the Pediatric Obesity Weight Evaluation Registry (POWER).

Blood pressure (BP) assessment and management are important aspects of care for youth with obesity. This study evaluates data of youth with obesity seeking care at 35 pediatric weight management (PWM) programs enrolled in the Pediatric Obesity Weight Evaluation Registry (POWER). Data obtained at a first clinical visit for youth aged 3-17 years were evaluated to: (1) assess prevalence of BP above the normal range (high BP); and (2) identify characteristics associated with having high BP status. Weight status was evaluated using percentage of the 95th percentile for body mass index (%BMIp95); %BMIp95 was used to group youth by obesity class (class 1, 100% to < 120% %BMIp95; class 2, 120% to < 140% %BMIp95; class 3, ≥140% %BMIp95; class 2 and class 3 are considered severe obesity). Logistic regression evaluated associations with high BP. Data of 7943 patients were analyzed. Patients were: mean 11.7 (SD 3.3) years; 54% female; 19% Black non-Hispanic, 32% Hispanic, 39% White non-Hispanic; mean %BMIp95 137% (SD 25). Overall, 48.9% had high BP at the baseline visit, including 60.0% of youth with class 3 obesity, 45.9% with class 2 obesity, and 37.7% with class 1 obesity. Having high BP was positively associated with severe obesity, older age (15-17 years), and being male. Nearly half of treatment-seeking youth with obesity presented for PWM care with high BP making assessment and management of BP a key area of focus for PWM programs.

Characteristics of paediatric weight management in the United States: Associations with program retention and BMI outcomes in the paediatric obesity weight evaluation registry (POWER).

OBJECTIVE: To describe characteristics of paediatric weight management (PWM) programs across the United States and evaluate associations with program-specific retention rates and body mass index (BMI) outcomes at 6 months. METHODS: A program profile survey was administered to 33 programs within the Paediatric Obesity Weight Evaluation Registry (POWER) to assess program staffing, services, and treatment format. Patient retention and percent of the 95th BMI percentile (%BMIp95) changes were assessed for each program. RESULTS: At 6 months program retention rates ranged from 15% to 74% (median: 41%), and program %BMIp95 changes ranged from -9.0 to +0.5 percentage points (median: -1.7). Percent of patients with ≥5 percentage-point decrease in %BMIp95 ranged from 17% to 71% across programs (median: 29%). No associations were detected between program characteristics and retention or %BMIp95 changes. CONCLUSIONS: Six-month patient retention and BMI outcomes vary substantially in PWM programs across the United States. Yet, no associations were found between PWM treatment factors and these program-level patient outcomes.

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial.

BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.

Elucidation of de novo small insertion/deletion biology with parent-of-origin phasing.

The mechanisms underlying de novo insertion/deletion (indel) genesis, such as polymerase slippage, have been hypothesized but not well characterized in the human genome. We implemented two methodological improvements, which were leveraged to dissect indel mutagenesis. We assigned de novo variants to parent-of-origin (i.e., phasing) with low-coverage long-read whole-genome sequencing, achieving better phasing compared to short-read sequencing (medians of 84% and 23%, respectively). We then wrote an application programming interface to classify indels into three subtypes according to sequence context. Across three cohorts with different phasing methods (Ntrios = 540, all cohorts), we observed that one de novo indel subtype, change in copy count (CCC), was significantly correlated with father's (p = 7.1 × 10-4 ) but not mother's (p = .45) age at conception. We replicated this effect in three cohorts without de novo phasing (ppaternal = 1.9 × 10-9 , pmaternal = .61; Ntrios = 3,391, all cohorts). Although this is consistent with polymerase slippage during spermatogenesis, the percentage of variance explained by paternal age was low, and we did not observe an association with replication timing. These results suggest that spermatogenesis-specific events have a minor role in CCC indel mutagenesis, one not observed for other indel subtypes nor for maternal age in general. These results have implications for indel modeling in evolution and disease.

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial.

Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept-based CNIA/ESW regimens with a tacrolimus-based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti-thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease-calculated eGFR of <45 mL/min/1.73 m2 at 12 months. Results are reported by treatment group (alemtuzumab/belatacept, rATG/belatacept, and rATG/tacrolimus). Superiority was not observed at 1 year for the primary endpoint (9/107 [8.4%], 15/104 [14.4%], and 14/105 [13.3%], respectively; P = NS) for either belatacept-based regimen. Differences were not observed for secondary endpoints (death, death-censored graft loss, or estimated glomerular filtration rates < 45 mL/min/1.73 m2 ). Differences were observed in biopsy-proved acute cellular rejection (10.3%, 18.3%, and 1.9%, respectively) (P < .001), but not in antibody-mediated rejection, mixed acute rejection, or de novo donor-specific anti-HLA antibodies. Neurologic and electrolyte abnormality adverse events were less frequent under belatacept. Belatacept-based CNIA/ESW regimens did not prove to be superior for the primary or secondary endpoints. Belatacept-treated patients demonstrated an increase in biopsy-proved acute cellular rejection and reduced neurologic and metabolic adverse events. These results demonstrate that simultaneous CNIA/ESW is feasible without excessive acute rejection.

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry.

OBJECTIVE: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. DATA SOURCE: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. STUDY DESIGN: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. PRINCIPAL FINDINGS: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. CONCLUSIONS: A quality improvement based approach to data quality monitoring and improvement is feasible and effective.

Health Outcomes of Youth in Clinical Pediatric Weight Management Programs in POWER.

OBJECTIVE: To describe treatment outcomes of children and adolescents enrolled in the Pediatric Obesity Weight Evaluation Registry, a consortium of multicomponent pediatric weight management programs in the US. STUDY DESIGN: This multicenter prospective observational cohort study, established in 2013, includes youth (2-18 years of age) with obesity enrolled from 31 Pediatric Obesity Weight Evaluation Registry (POWER) sites over a 2-year period and followed up to 12 months. Weight status was evaluated by the percentage of the 95th percentile for body mass index (%BMIp95). Associations of weight status outcomes with patient characteristics and program exposure were analyzed with multivariable mixed effects modeling. RESULTS: We included 6454 children and adolescents (median age, 11 years; IQR, 9-14 years; 53% white, 32% Hispanic; 73% with severe obesity) who were enrolled in POWER. Median changes in %BMIp95 for this cohort were -1.88 (IQR, -5.8 to 1.4), -2.50 (IQR, -7.4 to 1.8), -2.86 (IQR, -8.7 to 1.9), at 4-6, 7-9, and 10-12 of months follow-up, respectively (all P < .05). Older age (≥12 years), greater severity of obesity, and Hispanic race/ethnicity were associated with better improvement in %BMIp95. A 5-percentage point decrease in %BMIp95 was associated with improvement in cardiometabolic risk factors. CONCLUSIONS: Overall, treatment in pediatric weight management programs is associated with a modest median decrease in BMI as measured by change in %BMIp95. Further studies are needed to confirm these findings, as well as to identify additional strategies to enhance the effectiveness of these multicomponent interventions for youth with severe obesity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02121132.

Test-retest variability for quantitative two-dimensional and Doppler measurements in the fetus.

OBJECTIVES: Echocardiography is used to quantitatively characterize cardiovascular function in fetuses with cardiac abnormalities and inform decisions for fetal or perinatal interventions. It is clinically important to understand the reproducibility of these measures, particularly between testers. While studies have reported intra-observer variability and inter-observer variability, little is known about test-retest variability for these measures. We hypothesized that even in a high volume echocardiography laboratory, quantitative measurements will demonstrate higher test-retest variability compared with inter-observer variability and intra-observer variability of the same measurements. METHODS: Prospective study of uncomplicated, singleton pregnancies to evaluate fetal measures of cardiovascular function obtained by echocardiography. One sonographer obtained predefined variables, and then, a second sonographer obtained the same variables 15 minutes after the first sonographer. Separate data acquisitions were obtained by the two sonographers to evaluate test-retest variability. Intra-observer variability and inter-observer variability were also evaluated. RESULTS: Thirty fetuses between 17- and 36-week gestation were enrolled. Time-based variables had the best intra-observer agreement and inter-observer agreement (1.2%-7.4%), while 2D (7.5%-10%), M-mode (4.9%-10.1%), and velocity-time integral (VTI; 2.6%-13.8%) measurements had poorer agreement. For all variables, test-retest agreement was worse (3%-32.1%), particularly for measurement of myocardial performance index (MPI; 19.7%-21.1%), cardiac output estimation (27.2%-27.9%), and VTI-based indices (14.7%-32.1%). CONCLUSIONS: In a laboratory highly experienced in quantitative fetal echocardiography, intra-observer agreement and inter-observer agreement are good for most quantitative parameters. However, test-retest agreement is fair or poor for several variables, notably the MPI, cardiac output estimation, and VTI-based indices. Understanding how these measures vary between separate acquisitions is important for clinical interpretation and decision making.

Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values.

The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.

Fetal somatic growth trajectory differs by type of congenital heart disease.

BackgroundThe growth trajectories of common measurements, including estimated fetal weight (EFW), head circumference (HC), and abdominal circumference (AC), in fetuses with congenital heart disease (CHD) have not been described for different cardiac lesions. We hypothesized that (i) fetuses with CHD have differential growth in utero, and (ii) different categories of CHD demonstrate different in utero growth curves.MethodsWe performed a retrospective observational cohort study of pregnancies with known fetal CHD seen from January 2000 to June 2013. For analysis, the infants were divided into single ventricle (SV), biventricular conotruncal, d-transposition of great arteries (d-TGA), biventricular septal defects (SD; including atrial, ventricular, and atrioventricular SD), and all others (Other).ResultsA total of 194 newborns met inclusion criteria. There was significant differential growth of EFW in all CHD types, except d-TGA, starting with low z-scores before 25 weeks gestation, improving toward normal around 30-32 weeks gestation, and then again differential growth with advancing gestation. SV and SD groups had significant differential growth of HC starting early in gestation and linearly progressing negative z-scores with advancing gestation.ConclusionWe observed differences in the fetal growth curves throughout gestation for the major categories of CHD, including significant differential growth in even "simple" CHD, such as SD.

Bioequivalence between innovator and generic tacrolimus in liver and kidney transplant recipients: A randomized, crossover clinical trial.

BACKGROUND: Although the generic drug approval process has a long-term successful track record, concerns remain for approval of narrow therapeutic index generic immunosuppressants, such as tacrolimus, in transplant recipients. Several professional transplant societies and publications have generated skepticism of the generic approval process. Three major areas of concern are that the pharmacokinetic properties of generic products and the innovator (that is, "brand") product in healthy volunteers may not reflect those in transplant recipients, bioequivalence between generic and innovator may not ensure bioequivalence between generics, and high-risk patients may have specific bioequivalence concerns. Such concerns have been fueled by anecdotal observations and retrospective and uncontrolled published studies, while well-designed, controlled prospective studies testing the validity of the regulatory bioequivalence testing approach for narrow therapeutic index immunosuppressants in transplant recipients have been lacking. Thus, the present study prospectively assesses bioequivalence between innovator tacrolimus and 2 generics in individuals with a kidney or liver transplant. METHODS AND FINDINGS: From December 2013 through October 2014, a prospective, replicate dosing, partially blinded, randomized, 3-treatment, 6-period crossover bioequivalence study was conducted at the University of Cincinnati in individuals with a kidney (n = 35) or liver transplant (n = 36). Abbreviated New Drug Applications (ANDA) data that included manufacturing and healthy individual pharmacokinetic data for all generics were evaluated to select the 2 most disparate generics from innovator, and these were named Generic Hi and Generic Lo. During the 8-week study period, pharmacokinetic studies assessed the bioequivalence of Generic Hi and Generic Lo with the Innovator tacrolimus and with each other. Bioequivalence of the major tacrolimus metabolite was also assessed. All products fell within the US Food and Drug Administration (FDA) average bioequivalence (ABE) acceptance criteria of a 90% confidence interval contained within the confidence limits of 80.00% and 125.00%. Within-subject variability was similar for the area under the curve (AUC) (range 12.11-15.81) and the concentration maximum (Cmax) (range 17.96-24.72) for all products. The within-subject variability was utilized to calculate the scaled average bioequivalence (SCABE) 90% confidence interval. The calculated SCABE 90% confidence interval was 84.65%-118.13% and 80.00%-125.00% for AUC and Cmax, respectively. The more stringent SCABE acceptance criteria were met for all product comparisons for AUC and Cmax in both individuals with a kidney transplant and those with a liver transplant. European Medicines Agency (EMA) acceptance criteria for narrow therapeutic index drugs were also met, with the only exception being in the case of Brand versus Generic Lo, in which the upper limits of the 90% confidence intervals were 111.30% (kidney) and 112.12% (liver). These were only slightly above the upper EMA acceptance criteria limit for an AUC of 111.11%. SCABE criteria were also met for the major tacrolimus metabolite 13-O-desmethyl tacrolimus for AUC, but it failed the EMA criterion. No acute rejections, no differences in renal function in all individuals, and no differences in liver function were observed in individuals with a liver transplant using the Tukey honest significant difference (HSD) test for multiple comparisons. Fifty-two percent and 65% of all individuals with a kidney or liver transplant, respectively, reported an adverse event. The Exact McNemar test for paired categorical data with adjustments for multiple comparisons was used to compare adverse event rates among the products. No statistically significant differences among any pairs of products were found for any adverse event code or for adverse events overall. Limitations of this study include that the observations were made under strictly controlled conditions that did not allow for the impact of nonadherence or feeding on the possible pharmacokinetic differences. Generic Hi and Lo were selected based upon bioequivalence data in healthy volunteers because no pharmacokinetic data in recipients were available for all products. The safety data should be interpreted in light of the small number of participants and the short observation periods. Lastly, only the 1 mg tacrolimus strength was utilized in this study. CONCLUSIONS: Using an innovative, controlled bioequivalence study design, we observed equivalence between tacrolimus innovator and 2 generic products as well as between 2 generic products in individuals after kidney or liver transplantation following current FDA bioequivalence metrics. These results support the position that bioequivalence for the narrow therapeutic index drug tacrolimus translates from healthy volunteers to individuals receiving a kidney or liver transplant and provides evidence that generic products that are bioequivalent with the innovator product are also bioequivalent to each other. TRIAL REGISTRATION: ClinicalTrials.gov NCT01889758.

Impaired cerebral autoregulation in preoperative newborn infants with congenital heart disease.

OBJECTIVES: To characterize cerebral autoregulation (CA) in preoperative newborn infants with congenital heart disease (CHD). METHODS: This was a prospective, pilot study of term newborns with CHD who required intensive care. Continuous mean arterial blood pressure (MAP), cerebral tissue oxygen saturation (SCTO2) via near-infrared spectroscopy, and arterial oxygen saturation (SaO2) were collected. Significant low-frequency coherence between MAP and SCTO2 was used to define impaired CA in 20-minute epochs. Cerebral fractional tissue oxygen extraction (FTOE) = (SaO2 - SCTO2)/SaO2 was calculated. Spearman's and rank bi-serial correlations and logistic linear models accounting for multiple measures were used to identify associations with impaired CA and coherence. RESULTS: Twenty-four term neonates were evaluated for 23.4 ± 1.8 hours starting the first day of life. Periods of SaO2 variability >5% were excluded, leaving 63 ± 10 epochs per subject, 1515 total for analysis. All subjects demonstrated periods of abnormal CA, mean 15.3% ± 12.8% of time studied. Significant associations with impaired CA per epoch included greater FTOE (P = .02) and lack of sedation (P = .02), and associations with coherence included greater FTOE (P = .03), lack of sedation (P = .03), lower MAP (P = .006), and lower hemoglobin (P = .02). CONCLUSIONS: Term newborns with CHD display time-varying CA abnormalities. Associations seen between abnormal CA and greater FTOE, lack of sedation, and lower hemoglobin suggest that impaired oxygen delivery and increased cerebral metabolic demand may overwhelm autoregulatory capacity in these infants. Further studies are needed to determine the significance of impaired CA in this population.

Utility of Echocardiography in the Assessment of Left Ventricular Diastolic Function and Restrictive Physiology in Children and Young Adults with Restrictive Cardiomyopathy: A Comparative Echocardiography-Catheterization Study.

The aim of the study is to determine the utility of echocardiography in the assessment of diastolic function in children and young adults with restrictive cardiomyopathy (RCM). RCM is a rare disease with high mortality requiring frequent surveillance. Accurate, noninvasive echocardiographic measures of diastolic function may reduce the need for invasive catheterization. Single-center, prospective, observational study of pediatric and young adult RCM patients undergoing assessment of diastolic parameters by simultaneous transthoracic echocardiogram (TTE) and invasive catheterization. Twenty-one studies in 15 subjects [median (IQR) = 13.8 years (7.0-19.2), 60% female] were acquired with median left ventricular end-diastolic pressure (LVEDP) 21 (IQR 18-25) mmHg. TTE parameters of diastolic function, including pulmonary vein A wave duration (r s  = 0.79) and indexed left atrial volume (r s  = 0.49), demonstrated significant positive correlation, while mitral valve A (r s  = -0.44), lateral e' (r s  = -0.61) and lateral a' (r s  = -0.61) velocities showed significant negative correlation with LVEDP. Lateral a' velocity (≤0.042 m/s) and pulmonary vein A wave duration (≥156 m/s) both had sensitivity and specificity ≥80% for LVEDP ≥ 20 mmHg. In pediatric and young adult patients with RCM, lateral a' velocity and pulmonary vein A wave duration predicted elevated LVEDP with high sensitivity and specificity; however, due to technical limitations the latter was reliably measured in 12/21 patients. These noninvasive parameters may have utility in identifying patients that require further assessment with invasive testing. These findings require validation in a multicenter prospective cohort prior to widespread clinical implementation.

Creating a multi-center rare disease consortium - the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR).

 Eosinophilic gastrointestinal disorders (EGIDs) affect various segments of the gastrointestinal tract. Since these disorders are rare, collaboration is essential to enroll subjects in clinical studies and study the broader population. The Rare Diseases Clinical Research Network (RDCRN), a program of the National Center for Advancing Translational Sciences (NCATS), funded the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) in 2014 to advance the field of EGIDs. CEGIR facilitates collaboration among various centers, subspecialties, patients, professional organizations and patient-advocacy groups and includes 14 clinical sites. It has successfully initiated two large multi-center clinical studies looking to refine EGID diagnoses and management. Several pilot studies are underway that focus on various aspects of EGIDs including novel therapeutic interventions, diagnostic and monitoring methods, and the role of the microbiome in pathogenesis. CEGIR currently nurtures five physician-scholars through a career training development program and has published more than 40 manuscripts since its inception. This review focuses on CEGIR's operating model and progress and how it facilitates a framework for exchange of ideas and stimulates research and innovation. This consortium provides a model for progress on other potential clinical areas.