Phase I study of liver depot gene therapy in late-onset Pompe disease.

Gene therapy with an adeno-associated virus serotype 8 (AAV8) vector (AAV8-LSPhGAA) could eliminate the need for enzyme replacement therapy (ERT) by creating a liver depot for acid α-glucosidase (GAA) production. We report initial safety and bioactivity of the first dose (1.6 × 1012 vector genomes/kg) cohort (n = 3) in a 52-week open-label, single-dose, dose-escalation study (NCT03533673) in patients with late-onset Pompe disease (LOPD). Subjects discontinued biweekly ERT after week 26 based on the detection of elevated serum GAA activity and the absence of clinically significant declines per protocol. Prednisone (60 mg/day) was administered as immunoprophylaxis through week 4, followed by an 11-week taper. All subjects demonstrated sustained serum GAA activities from 101% to 235% of baseline trough activity 2 weeks following the preceding ERT dose. There were no treatment-related serious adverse events. No subject had anti-capsid T cell responses that decreased transgene expression. Muscle biopsy at week 24 revealed unchanged muscle glycogen content in two of three subjects. At week 52, muscle GAA activity for the cohort was significantly increased (p < 0.05). Overall, these initial data support the safety and bioactivity of AAV8-LSPhGAA, the safety of withdrawing ERT, successful immunoprophylaxis, and justify continued clinical development of AAV8-LSPhGAA therapy in Pompe disease.

Use of Electronic Health Records to Identify Exposure-Response Relationships in Critically Ill Children: An Example of Midazolam and Delirium.

Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children <18 years of age hospitalized in the pediatric intensive care unit at Duke University; these children were administered midazolam during mechanical ventilation and had ≥1 Cornell Assessment of Pediatric Delirium (CAPD) score. We used individual-level data extracted from the EHR and a previously published population pharmacokinetic (PK) model developed in critically ill children to simulate plasma concentrations at the time of CAPD scores in 1,000 representative datasets. We used multilevel repeated measures models, with clustering at patient and simulation levels, to evaluate the associations between measures of drug exposure (e.g., concentration and area under concentration time curve) and delirium scores. We included 61 children, median age 1.5 years (range = 0.1-16.3), with 181 CAPD assessments. We identified similarities between simulated Empirical Bayesian parameter estimates from the EHR cohort and those from the PK model population. We identified a stronger association between drug concentration at the time of score and CAPD scores (coefficient 1.78; 95% confidence interval: 1.66-1.90) compared with cumulative dose per kilogram and CAPD scores (coefficient -0.01; 95% confidence interval: -0.01 to -0.01). EHR and PK models can be leveraged to investigate exposure-response relationships in critically ill children.

Health Disparities in the Treatment of Supraventricular Tachycardia in Pediatric Patients.

Supraventricular tachycardia (SVT) is a common pediatric arrhythmia. The objective of this investigation was to investigate the existence and degree of the health disparities in the treatment of pediatric patients with supraventricular tachycardia based on sociodemographic factors. This was retrospective cohort study at a large academic medical center including children ages 5-18 years old diagnosed with SVT. Patients with congenital heart disease and myocarditis were excluded. Initial treatment and ultimate treatment with either medical management or ablation were determined. The odds of having an ablation procedure were determined based on patient age, sex, race, ethnicity, and insurance status. There was a larger portion of non-White patients (p = 0.033) within the cohort that did not receive an ablation during the study period. Patients that were younger, female, American Indian/Alaskan Native, unknown race, and had missing insurance information were less likely to receive ablation therapy during the study period. In this single center, regional evaluation, we demonstrated that disparities in the treatment of pediatric SVT are present based on multiple patient sociodemographic factors. This study adds evidence to the presence of inequities in health care delivery across pediatric populations.

First-in-Human Studies of MW01-6-189WH, a Brain-Penetrant, Antineuroinflammatory Small-Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Studies in Healthy Adult Volunteers.

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury.

Cortical stimulation mapping for localization of visual and auditory language in pediatric epilepsy patients.

OBJECTIVE: To determine resection margins near eloquent tissue, electrical cortical stimulation (ECS) mapping is often used with visual naming tasks. In recent years, auditory naming tasks have been found to provide a more comprehensive map. Differences in modality-specific language sites have been found in adult patients, but there is a paucity of research on ECS language studies in pediatric patients. The goals of this study were to evaluate word-finding distinctions between visual and auditory modalities and identify which cortical subregions most often contain critical language function in a pediatric population. METHODS: Twenty-one pediatric patients with epilepsy or temporal lobe pathology underwent ECS mapping using visual (n = 21) and auditory (n = 14) tasks. Fisher's exact test was used to determine whether the frequency of errors in the stimulated trials was greater than the patient's baseline error rate for each tested modality and subregion. RESULTS: While the medial superior temporal gyrus was a common language site for both visual and auditory language (43.8% and 46.2% of patients, respectively), other subregions showed significant differences between modalities, and there was significant variability between patients. Visual language was more likely to be located in the anterior temporal lobe than was auditory language. The pediatric patients exhibited fewer parietal language sites and a larger range of sites overall than did adult patients in previously published studies. CONCLUSIONS: There was no single area critical for language in more than 50% of patients tested in either modality for which more than 1 patient was tested (n > 1), affirming that language function is plastic in the setting of dominant-hemisphere pathology. The high rates of language function throughout the left frontal, temporal, and anterior parietal regions with few areas of overlap between modalities suggest that ECS mapping with both visual and auditory testing is necessary to obtain a comprehensive language map prior to epileptic focus or tumor resection.

Patterns of phlebotomy blood loss and transfusions in extremely low birth weight infants.

OBJECTIVE: Characterize frequency and volume of blood draws and transfusions in extremely low birth weight infants in the first 10 weeks of life. STUDY DESIGN: We included infants with a birth weight <1000 g born 23 0/7-29 6/7 weeks gestational age (GA) and with a length of stay ≥10 weeks, admitted between 2014 and 2016 to a single neonatal intensive care unit. RESULTS: Of 54 infants, median (25th, 75th percentile) GA and birth weight were 25 weeks (24, 26) and 665 g (587, 822), respectively. Median number of blood draws per infant decreased from 57 (49, 65) in week 1 to 12 (8, 22) in week 10. Median volume of blood extracted was 83 mL (70, 97), and median number of blood transfusions was 8 (5, 10). CONCLUSIONS: This cohort experienced a high number and volume of blood draws. Draw frequency and transfusions decreased over the first 10 weeks of life.

Agreement of an echocardiogram-based diagnosis of pulmonary hypertension in infants at risk for bronchopulmonary dysplasia among masked reviewers.

OBJECTIVE: To evaluate the agreement of an echocardiogram-based pulmonary hypertension diagnosis in premature infants at risk for bronchopulmonary dysplasia (BPD). STUDY DESIGN: Echocardiograms from infants born ≤28 weeks post menstrual age were retrospectively reviewed with a standardized reading protocol by three pediatric cardiologists masked to patient's clinical history to determine the presence of pulmonary hypertension. RESULTS: A total of 483 echocardiograms from 49 unique patients were each reviewed by three pediatric cardiologists. Overall there was an 82.9% agreement on the presence of pulmonary hypertension among the three readers (95% CI: 78.4%, 85.4%) with a modified Fleiss' kappa of 0.759 (95% CI: 0.711, 0.801). Percent agreement between rereads was 92.4%, and modified Fleiss' kappa was 0.847 (95% CI: 0.750, 0.931). CONCLUSIONS: Using a standardized reading protocol and echocardiogram-based definition of pulmonary hypertension, there is high inter- and intra-rater agreement for the diagnosis of pulmonary hypertension in at-risk premature infants, suggesting echocardiography can be successfully used for clinical and research monitoring of pulmonary hypertension in infants.