A Deep Intronic PKHD1 Variant Identified by SpliceAI in a Deceased Neonate With Autosomal Recessive Polycystic Kidney Disease.

The etiologies of newborn deaths in neonatal intensive care units usually remain unknown, even after genetic testing. Whole-genome sequencing, combined with artificial intelligence-based methods for predicting the effects of non-coding variants, provide an avenue for resolving these deaths. Using one such method, SpliceAI, we identified a maternally inherited deep intronic PKHD1 splice variant (chr6:52030169T>C), in trans with a pathogenic missense variant (p.Thr36Met), in a newborn who died of autosomal recessive polycystic kidney disease at age 2 days. We validated the deep intronic variant's impact in maternal urine-derived cells expressing PKHD1. Reverse transcription polymerase chain reaction followed by Sanger sequencing showed that the variant causes inclusion of 147bp of the canonical intron between exons 29 and 30 of PKHD1 into the mRNA, including a premature stop codon. Allele-specific expression analysis at a heterozygous site in the mother showed that the mutant allele completely suppresses canonical splicing. In an unrelated healthy control, there was no evidence of transcripts including the novel splice junction. We returned a diagnostic report to the parents, who underwent in vitro embryo selection.

NeoTalk: Communication Skills Training for Neonatal Clinicians.

BACKGROUND: Despite proven benefit, pediatric subspecialists often have not been offered formal serious illness communication skills training. We sought to: 1) develop and evaluate the impact of a communication skills course, based on the VitalTalk framework, on Neonatal Intensive Care Unit (NICU) clinicians; 2) evaluate provider comfort with key serious illness communication skills and frequency of use of those skills, before and after "NeoTalk" and; 3) explore differences and similarities between adult and pediatric serious illness communication skills courses. METHODS: We developed a NICU specific communication skills course and surveyed course participants to evaluate comfort with key communication skills before and after course participation, and frequency of use of key skills before and 2 months after our course. Wilcoxon signed rank tests and Kruskal-Wallis tests were performed to compare participant responses across time points. RESULTS: 34 providers completed NeoTalk training. Complete pre- and post-course data was available for 29 participants. Participants reported increased comfort with skills including 'sharing difficult news' (P = .018), and 'responding to emotion' (P = .002). Participants did not report increased frequency in using target skills 2 months after training. CONCLUSIONS: A multi-disciplinary cohort of NICU providers endorsed increased confidence in key communication skills but not increased skill application 2-months post-course completion. While a single course can successfully teach skills, additional exposure may be necessary to build new communication habits. Our experience developing NeoTalk helped elucidate some of the ways in which conversations about seriously ill infants may be different from conversations about seriously ill adults.

Real-Time Ultrasound Guidance for Umbilical Venous Cannulation in Neonates With Congenital Heart Disease.

OBJECTIVES: Umbilical venous cannulation is the favored approach to perinatal central access worldwide but has a failure rate of 25-50% and the insertion technique has not evolved in decades. Improving the success of this procedure would have broad implications, particularly where peripherally inserted central catheters are not easily obtained and in neonates with congenital heart disease, in whom umbilical access facilitates administration of inotropes and blood products while sparing vessels essential for later cardiac interventions. We sought to use real-time, point-of-care ultrasound to achieve central umbilical venous access in patients for whom conventional, blind placement techniques had failed. DESIGN: Multicenter case series, March 2019-May 2021. SETTING: Cardiac and neonatal ICUs at three tertiary care children's hospitals. PATIENTS: We identified 32 neonates with congenital heart disease, who had failed umbilical venous cannulation using traditional, blind techniques. INTERVENTIONS: Real-time ultrasound guidance and liver pressure were used to replace malpositioned catheters and achieve successful placement at the inferior cavoatrial junction. MEASUREMENTS AND MAIN RESULTS: In 32 patients with failed prior umbilical venous catheter placement, real-time ultrasound guidance was used to successfully "rescue" the line and achieve central position in 23 (72%). Twenty of 25 attempts (80%) performed in the first 48 hours of life were successful, and three of seven attempts (43%) performed later. Twenty-four patients (75%) were on prostaglandin infusion at the time of the procedure. We did not identify an association between patient weight or gestational age and successful placement. CONCLUSIONS: Ultrasound guidance has become standard of care for percutaneous central venous access but is a new and emerging technique for umbilical vessel catheterization. In this early experience, we report that point-of-care ultrasound, together with liver pressure, can be used to markedly improve success of placement. This represents a significant advance in this core neonatal procedure.