Postoperative Ultrasound as a Predictor of Newborn Function and Ambulation after Open Fetal Myelomeningocele Repair.

OBJECTIVE: Function of the lower extremities after prenatal myelomeningocele (MMC) repair is best assessed with ambulatory function at 30-36 months of age, but parents often ask about function before this milestone. Lower extremity movement can be assessed by ultrasound (US) and at the newborn exam (NE), but correlation between US, NE, and ambulation is not firmly established. METHODS: This was a retrospective correlation study of fetuses that underwent open prenatal MMC repair at SSM Cardinal Glennon Fetal Care Institute, St. Louis, MO, between January 2011 and June 2017. Movement at the ankles, knees, and hips was assessed by US after open repair on postoperative days (PODs) 0-5 and at 32 weeks gestation. NE was performed by physical therapy or neurosurgery within the first month of life, and pediatric follow-up between 30 and 36 months of age was obtained to document ambulation. RESULTS: Forty-two fetuses were included. Joint movement seen on US varied by POD: it was present on POD 1 in 7% of fetuses and 62% by POD 5. Degree of ventriculomegaly, lesion level, and lesion length did not have a significant effect on US, NE, or ambulation. Knee movement on POD 3 correlated with knee movement at NE (k = 0.58, p < 0.01), but only later knee movement correlated with ambulation (k = 0.28-0.46, p = 0.01). Hip movement at 32 weeks was the only single joint assessment that correlated with NE and ambulation (k = 0.45 and 0.46, p = 0.03 and 0.01, respectively). CONCLUSION: Lower extremity movement increases between POD 1 and POD 5 in fetuses after open fetal MMC repair. Knee and hip movement on US at 32 weeks correlates with ambulation at 30-36 months. These data may inform counseling, and direct therapy and spark prospective investigations.

A Functional Assay for Sick Sinus Syndrome Genetic Variants.

BACKGROUND/AIMS: Congenital Sick Sinus Syndrome (SSS) is a disorder associated with sudden cardiac death due to severe bradycardia and prolonged pauses. Mutations in HCN4, the gene encoding inward Na+/K+ current (If), have been described as a cause of congenital SSS. The objective of this study is to develop an SSS model in embryonic zebrafish, and use zebrafish as a moderate-throughput assay to functionally characterize HCN4 variants. METHODS: To determine the function of hcn4 in zebrafish, embryos were either bathed in the If -specific blocker (ZD-7288), or endogenous hcn4 expression was knocked down using splice-blocking morpholinos. To assess whether the zebrafish model discriminates benign from pathogenic variants, we tested four HCN4 mutations known to cause human SSS and four variants of unknown significance (VUS). RESULTS: Pharmacological blockade and knockdown of hcn4 in zebrafish phenocopied human SSS, displaying bradycardia and cardiac pauses in intact embryos and explanted hearts. The zebrafish assay correctly identified all disease-causing variants. Of the VUS, the assay predicted 2 as benign and 2 as hypomorphic variants. CONCLUSIONS: We conclude that our embryonic zebrafish assay is a novel and effective tool to functionally characterize human HCN4 variants, which can be translated into important clinical prognostic information.

Multi-electrolyte disturbance and supplementation in severely malnourished hospitalized adolescents with restrictive eating disorders.

BACKGROUND: This study describes the prevalence of hypophosphatemia, hypokalemia, and/or hypomagnesemia and resulting electrolyte supplementation during refeeding in severely malnourished youths hospitalized for restrictive eating disorders. METHODS: Hospitalized patients between 11-26y (N = 81) at < 75% treatment goal weight (TGW) were assessed through retrospective chart review. Outcomes were compared between participants < 70% TGW and those 70-75% TGW. Nutritional rehabilitation started at 1750 kcals/day and advanced by 500 kcal every other day until target intake was achieved. Associations between %TGW on admission; hypophosphatemia, hypokalemia, and/or hypomagnesemia; and electrolyte supplementation were examined. RESULTS: Of the 24 (29.6%) participants with hypophosphatemia, hypokalemia, and/or hypomagnesemia, 7 (8.6%) received supplementation; the remainder corrected without supplementation. Participants < 70% TGW did not differ from those 70-75% TGW on rates of these conditions or need for supplementation. CONCLUSIONS: Hospital-based nutritional rehabilitation did not confer increased rates of hypophosphatemia, hypokalemia, and/or hypomagnesemia or need for electrolyte supplementation in patients < 70% TGW compared to those 70-75% TGW. While additional research is needed to establish clinical practice guidelines on electrolyte management in this population, our findings suggest that nutritional rehabilitation may be reasonably undertaken without prophylactic electrolyte supplementation, even in patients < 70% TGW.

Identifying safe management methods for nutritional rehabilitation among severely malnourished hospitalized adolescents and young adults with restrictive eating disorders can expedite discharge planning and improve treatment outcomes. In contrast to past studies on inpatient nutritional rehabilitation, this study describes the prevalence and management of multiple-electrolyte disturbance (hypophosphatemia, hypokalemia, and/or hypomagnesemia) during refeeding among hospitalized severely malnourished youths with restrictive eating disorders. We found that in this population, with experienced, close medical supervision, nutritional rehabilitation may be reasonably undertaken without prophylactic electrolyte supplementation, even in patients < 70% goal treatment weight. These findings can inform hospital-based refeeding protocols for adolescents and young adults with restrictive eating disorders, where the practice around prophylactic supplementation is variable.

The Failed Bidirectional Glenn Shunt: Risk Factors for Poor Outcomes and the Role of Early Reoperation.

Background: Bidirectional Glenn shunt (BDG) failure carries high morbidity and mortality but the clinical factors associated with failure and the optimal management strategy are understudied. Methods: A total of 217 patients undergoing BDG at our institution between 1989 and 2020 were retrospectively reviewed and categorized as success or failure. Failure was defined as the need for reoperation (BDG takedown, reoperation for correction of cardiac defect, and/or transplantation) at any time postoperatively; operative mortality (death attributable to BDG malfunction occurring during the index hospitalization for BDG or within 30 days of discharge); or late mortality (death directly attributable to BDG malfunction occurring prior to Fontan or next-stage palliation). Univariate and binary logistic regression analyses were performed. Results: BDG failure occurred in 14 (6.5%) patients. Univariate predictors were: hypoplastic left heart syndrome (P = .037), right ventricular (RV) dominance (P = .010), greater pre-BDG pulmonary vascular resistance (PVR) (P = .012), concomitant atrioventricular valve repair (P = .020), prolonged pleural drainage (P = .001), intensive care unit (P<.001) and hospital (P = .002) stays, and extracorporeal membrane oxygenation (ECMO) requirement (P<.001). Multivariate predictors were: RV dominance (P = .002), greater PVR (P = .041), ICU (P<.001) and hospital (P = .020) stays, and need for ECMO (P<.001). As many as 10 of 14 (71%) patients with BDG failure died. Reoperation was performed for 10 patients with BDG failure. Five reoperation patients survived until discharge, with four patients alive at last follow-up (mean 7.9 years). Survivors underwent reoperation earlier than nonsurvivors (36 vs. 94 days). Conclusions: BDG failure carries high mortality, but preoperative predictors and postoperative indicators of failure exist. Early BDG takedown and insertion of aorta-pulmonary shunt may allow survival.

The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele.

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.