Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology.

Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.

Improving On-Time Starts for Pediatric Cardiac MRI.

PURPOSE: Delayed start times for cardiac MRI examinations have resulted in longer patient fasts, extended wait times, and poor synchronization of anesthesia induction and contrast administration. The aim of this work was to improve on-time start rates from an initial baseline of 10%. METHODS: A multidisciplinary team comprising members of the cardiac and radiology services used the Realizing Improvement Through Team Empowerment methodology to target the root causes of the delays and enhance workflow. The main factors identified as contributing to examination delays were late patient arrival, variations in patient preparation time, unavailability of equipment, and inefficient scheduling processes. RESULTS: The implementation of various interventions, such as the use of standardized appointment scripts, ensuring timely patient preparation, and ensuring the availability of equipment when required, resulted in an increase in on-time start rates for cardiac MRI examinations to 34%. CONCLUSIONS: The study's systematic approach proved to be valuable in both understanding and resolving the identified problems. Through the continuous application of plan-do-study-act cycles, the authors effectively pinpointed obstacles and tested multiple potential measures to overcome them. This approach made it possible to comprehend the issue and to implement targeted interventions to address it.

Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia.

Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl-CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5'-deoxy-adenosylcobalamin. It is characterized by life-threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte-targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut-type (N = 91), cblB-type (15), and cblA-type MMA (17), as well as from an Italian cohort of mut-type (N = 19) and cblB-type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin-2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.

Severity modeling of propionic acidemia using clinical and laboratory biomarkers.

PURPOSE: To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. METHODS: Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. RESULTS: Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. CONCLUSION: Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.

1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA).

PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.

Developing Leadership Competencies in Midlevel Nurse Leaders: An Innovative Approach.

A pediatric teaching hospital developed a comprehensive leadership training program for midlevel nurse leaders with varying levels of management knowledge and experience. Content was based on American Organization for Nursing Leadership nurse manager competencies and data from a comprehensive needs assessment. Learners identified differentiating between leadership and management, influencing behavior, managing change, and communication as areas of increased confidence. This program is applicable to any hospital with multiple midlevel nurse leaders new to the role.

Chronic kidney disease in propionic acidemia.

PURPOSE: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. METHODS: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342). RESULTS: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. CONCLUSION: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.

Characterization of tracheal intubation process of care and safety outcomes in a tertiary pediatric intensive care unit.

OBJECTIVE: To characterize tracheal intubation process of care and safety outcomes in a large tertiary pediatric intensive care unit using a pediatric adaptation of the National Emergency Airway Registry. Variances in process of care and safety outcome of intubation in the pediatric intensive care unit have not been described. We hypothesize that tracheal intubation is a common but high-risk procedure and that the novel pediatric adaptation of the National Emergency Airway Registry is a feasible tool to capture variances in process of care and outcomes. DESIGN: Prospective descriptive study. SETTING: A single 45-bed tertiary noncardiac pediatric intensive care unit in a large university-affiliated children's hospital. PATIENTS: Critically ill children who required intubation in the pediatric intensive care unit. INTERVENTIONS: Airway management data were prospectively collected for all initial airway management from July 2007 through September 2008 using the National Emergency Airway Registry tool tailored for pediatric application with explicit operational definitions. MEASUREMENT AND MAIN RESULTS: One hundred ninety-seven initial intubation encounters were reported (averaging one every 2.3 days). The first course intubation method was oral intubation in 181 (91.9%) and nasal in 16 (9.1%). Unwanted tracheal intubation-associated events were frequently reported (n = 38 [19.3%]), but severe tracheal intubation-associated events were rare (n = 6 [3.0%]). Esophageal intubation with immediate recognition was the most common tracheal intubation-associated event (n = 22). Desaturation <80% was reported in 51 of 183 (27.7%) and more than two intubation attempts in 30 of 196 (15.3%), both associated with occurrence of a tracheal intubation-associated event (p < .001, p = .001, respectively). Interestingly, patient age, history of difficult airway, and first attempt by resident were not associated with tracheal intubation-associated events. CONCLUSIONS: Unwanted tracheal intubation-associated events occurred frequently, but severe tracheal intubation-associated events were rare. Our novel registry can be used to describe the pediatric intensive care unit tracheal intubation procedural process of care and safety outcomes.

Does change in thoracic impedance measured via defibrillator electrode pads accurately detect ventilation breaths in children?

INTRODUCTION: Resuscitation guidelines recommend rescue ventilations consist of tidal volumes 7-10 ml/kg. Changes in thoracic impedance (ΔTI) measured using defibrillator electrode pads to detect and guide rescue ventilations have not been studied in children. AIM: We hypothesized that ΔTI measured via standard anterior-apical (AA) position can accurately detect ventilations with volume > 7 ml/kg in children. We also compared standard AA position with alternative anterior-posterior (AP) position. METHODS: IRB-approved, prospective, observational study of sedated, subjects (6 months to 17 years) on conventional mechanical ventilation. Thoracic impedance (TI) was obtained via Philips MRx defibrillator with standard electrode pads for 5 min each in AA and AP positions. Ventilations were simultaneously measured by pneumotachometer (Novametrix CO(2)SMO Plus). RESULTS: Twenty-eight subjects (median 4 years, IQR 1.7-9 years; median 16.3 kg, IQR 10.5-39 kg) were enrolled. Data were available for 21 episodes in AA position and 22 episodes in AP position, with paired AA and AP data available for 18. For ventilations with volume < 7 ml/kg, the defibrillator algorithm detected 80.0% for both AA and AP (p=0.99). For ventilations ≥ 7 ml/kg, detection was 95.1% for AA and 95.7% for AP (p=0.38). CONCLUSIONS: Changes in thoracic impedance obtained via defibrillator pads can accurately detect ventilations above 7 ml/kg in stable, mechanically ventilated children, corresponding to rescue ventilations recommended during CPR. Both AA and AP pad positions were less sensitive to detect smaller volumes (< 7 ml/kg) than higher volumes (≥ 7 ml/kg), suggesting that shallow ventilations during CPR might be missed. There were no differences in impedance measurements between standard AA pad position and commonly used alternative AP pad position.

Effect of residual leaning force on intrathoracic pressure during mechanical ventilation in children.

AIM: Determine the effect of residual leaning force on intrathoracic pressure (ITP) in healthy children receiving mechanical ventilation. We hypothesized that application of significant residual leaning force (2.5kg or 20% of subject body weight) would be associated with a clinically important change in ITP. METHODS: IRB-approved pilot study of healthy, anesthetized, paralyzed mechanically ventilated children (6 months to 7 years). Peak endotracheal pressure (ETP), a surrogate of ITP, was continuously measured before and during serial incremental increases in sternal force from 10% to 25% of the subject's body weight. A delta ETP of >or=2.0cmH(2)O was considered clinically significant. RESULTS: 13 healthy, anesthetized, paralyzed mechanically ventilated children (age: 26+/-24m, range: 6.5-87m; weight: 13+/-5kg, range: 7.4-24.8kg) were enrolled. Peak ETP increased from baseline for all force applications (10% body weight: mean difference of 0.8cmH(2)O, p<0.01; 15% body weight: mean difference of 1.1cmH(2)O, p<0.01; 20% body weight: mean difference of 1.5cmH(2)O, p<0.01; 25% body weight: mean difference of 1.89cmH(2)O, p<0.01). Residual leaning force of >or=2.5kg was associated with a 2.0cmH(2)O change in peak ETP (odds ratio 7.5; CI(95) 1.5-37.7; p=0.014) while sternal force >or=20% body weight was not (odds ratio 2.4; CI(95) 0.6-9.2; p=0.2). CONCLUSION: In healthy anesthetized children, changes in ETP were detectable at residual leaning forces as low as 10% of subject body weight. Residual leaning force of 2.5kg was associated with increases in ETP >or=2.0cmH(2)O.