BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.ObjectiveTo perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.MethodsThe study was conducted by 42 investigators across 31 academic medical centres.ResultsWe identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion.ConclusionsIn TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

Objectives The optimal intranasal volume of administration (VOA) for achieving timely and effective sedation in children is unclear. We aimed to compare clinical outcomes relevant to procedural sedation associated with using escalating VOA to administer intranasal midazolam. Methods We conducted a randomized, single-blinded, three-arm, superiority clinical trial. Children 1 to 7 years old undergoing laceration repair requiring 0.5 mg/kg intranasal midazolam (5 mg/mL) were block-randomized to receive midazolam using one of three VOA: 0.2mL, 0.5mL, or 1mL. Procedures were videotaped, with outcome assessors blinded to VOA. Primary outcome was time to onset of minimal sedation (i.e. score of 1 on the University of Michigan Sedation Scale). Secondary outcomes included procedural distress; time to procedure start; deepest level of sedation achieved; adverse events; and clinician and caregiver satisfaction. Results Ninety-nine children were enrolled; 96 were analyzed for the primary outcome and secondary outcomes, except for the outcome of procedural distress, for which only 90 were analyzed. Time to onset of minimal sedation for each escalating VOA was 4.7 (95% CI 3.8, 5.4), 4.3 (95% CI 3.9, 4.9) and 5.2 (95% CI 4.6, 7) minutes, respectively. There were no differences in secondary outcomes except for clinician satisfaction with ease of administration: fewer clinicians were satisfied when using a VOA of 0.2mL. Conclusions There was a slightly shorter time to onset of minimal sedation when using a VOA of 0.5mL compared to 1mL, but all three VOA produced comparable clinical outcomes. Fewer clinicians were satisfied with ease of administration using a VOA of 0.2mL.

Preprocedural US by did not improve the rates of first-attempt success when compared with palpation method. Our results suggest that US is feasible and well accepted, with a perceptible impact on care.

No CV deaths through day 180 were observed in patients with hsTnT levels ≤0.014 μg/l despite high N-terminal pro-brain natriuretic peptide levels. Low baseline hsTnT may identify patients with acute heart failure at very low risk for CV mortality.

Patients with CDH are at increased risk for having a weight <5th percentile at 1 year of age. A history of ECMO and PAH are independently associated with an increased requirement for tube feedings at 1 year of age. Close nutritional monitoring and counseling should be considered in all of the patients with CDH, particularly those with a history of ECMO or PAH.