Are asymptomatic carriers of OTC deficiency always asymptomatic? A multicentric retrospective study of risk using the UCDC longitudinal study database.

BACKGROUND: Ornithine transcarbamylase deficiency (OTCD) due to an X-linked OTC mutation, is responsible for moderate to severe hyperammonemia (HA) with substantial morbidity and mortality. About 80% of females with OTCD remain apparently "asymptomatic" with limited studies of their clinical characteristics and long-term health vulnerabilities. Multimodal neuroimaging studies and executive function testing have shown that asymptomatic females exhibit limitations when stressed to perform at higher cognitive load and had reduced activation of the prefrontal cortex. This retrospective study aims to improve understanding of factors that might predict development of defined complications and serious illness in apparent asymptomatic females. A proband and her daughter are presented to highlight the utility of multimodal neuroimaging studies and to underscore that asymptomatic females with OTCD are not always asymptomatic. METHODS: We review data from 302 heterozygote females with OTCD enrolled in the Urea Cycle Disorders Consortium (UCDC) longitudinal natural history database. We apply multiple neuroimaging modalities in the workup of a proband and her daughter. RESULTS: Among the females in the database, 143 were noted as symptomatic at baseline (Sym). We focused on females who were asymptomatic (Asx, n = 111) and those who were asymptomatic initially upon enrollment in study but who later became symptomatic sometime during follow-up (Asx/Sym, n = 22). The majority of Asx (86%) and Asx/Sym (75%) subjects did not restrict protein at baseline, and ~38% of Asx and 33% of Asx/Sym subjects suffered from mild to severe neuropsychiatric conditions such as mood disorder and sleep problems. The risk of mild to severe HA sometime later in life for the Asx and Asx/Sym subjects as a combined group was ~4% (5/133), with ammonia ranging from 77 to 470 µM and at least half (2/4) of subjects requiring hospital admission and nitrogen scavenger therapy. For this combined group, the median age of first HA crisis was 50 years, whereas the median age of first symptom which included neuropsychiatric and/or behavioral symptoms was 17 years. The multimodal neuroimaging studies in female heterozygotes with OTCD also underscore that asymptomatic female heterozygotes with OTCD (e.g., proband) are not always asymptomatic. CONCLUSIONS: Analysis of Asx and Asx/Sym females with OTCD in this study suggests that future evidence-based management guidelines and/or a clinical risk score calculator for this cohort could be useful management tools to reduce morbidity and improve long-term quality of life.

Cardiac magnetic resonance haemodynamics in paediatric heart transplant patients: fick oximetry versus cardiac magnetic resonance phase contrast.

BACKGROUND: Lifetime radiation exposure for paediatric orthotopic heart transplant (OHT) patients is significant with cardiac catheterisation as the dominant source. Interventional cardiac magnetic resonance is utilised to obtain simultaneous, radiation-free haemodynamics and flow/function measurements. We sought to compare invasive haemodynamic measurements and radiation exposure in traditional cardiac catheterisation, to comprehensive interventional cardiac magnetic resonance. METHODS: Twenty-eight OHT patients who underwent 67 interventional cardiac magnetic resonance procedures at Children's National Hospital were identified. Both invasive oximetry with peripheral oxygen saturation (Fick) and cardiac magnetic resonance phase contrast measurements of pulmonary and systemic blood flow were performed. Systemic and pulmonary blood flow from the two modalities was compared using Bland-Altman, concordance analysis, and inter-reader correlation. A mixed model was implemented to account for confounding variables and repeat encounters. Radiation dosage data were collected for a contemporaneous cohort of orthotopic heart transplant patients undergoing standard, X-ray-guided catheterisation. RESULTS: Simultaneous cardiac magnetic resonance and Fick have poor agreement in our study based on Lin's correlation coefficient of 0.68 and 0.73 for pulmonary and systemic blood flow, respectively. Bland-Altman analysis demonstrated a consistent over estimation of cardiac magnetic resonance cardiac output by Fick. The average indexed dose area product for patients undergoing haemodynamics with endomyocardial biopsy was 0.73 (SD ±0.6) Gy*m2/kg. With coronary angiography added, the indexed dose area product was 14.6 (SD ± 7.8) Gy*m2/kg. CONCLUSIONS: Cardiac magnetic resonancemeasurements of cardiac output/index in paediatric orthotopic heart transplant patients have poor concordance with Fick estimates; however, cardiac magnetic resonance has good internal validity and inter-reader reliability. Radiation doses are small for haemodynamics with biopsy and increase exponentially with angiography, identifying a new target for cardiac magnetic resonance imaging.

Determination of Glucose-Independent Racial Disparity in HbA1c for Youth With Type 1 Diabetes in the Era of Continuous Glucose Monitoring.

BACKGROUND: The magnitude and importance of higher HbA1c levels not due to mean blood glucose (MBG) in non-Hispanic black (B) versus non-Hispanic white (W) individuals is controversial. We sought to clarify the relationship of HbA1c with glucose data from continuous glucose monitoring (CGM) in a young biracial population. METHODS: Glycemic data of 33 B and 85 W, healthy youth with type 1 diabetes (age 14.7 ± 4.8 years, M/F = 51/67, duration of diabetes 5.4 ± 4.7 years) from a factory-calibrated CGM was compared with HbA1c. Hemoglobin glycation index (HGI) = assayed HbA1c - glucose management index (GMI). RESULTS: B patients had higher unadjusted levels of HbA1c, MBG, MBGSD, GMI, and HGI than W patients. Percent glucose time in range (TIR) and percent sensor use (PSU) were lower for B patients. Average HbA1c in B patients 8.3% was higher than 7.7% for W (P < .0001) after statistical adjustment for MBG, age, gender, insulin delivery method, and accounting for a race by PSU interaction effect. Higher HbA1c persisted in B patients when TIR was substituted for MBG. Predicted MBG was higher in B patients at any level of PSU. The 95th percentile for HGI was 0.47 in W patients, and 52% of B patients had HGI ≥ 0.5. Time below range was similar for both. CONCLUSIONS: Young B patients have clinically relevant higher average HbA1c at any given level of MBG or TIR than W patients, which may pose an additional risk for diabetes complications development. HGI ≥ 0.5 may be an easy way to identify high-risk patients.

Health-related quality of life in a systematically assessed cohort of children and adults with urea cycle disorders.

PURPOSE: Individuals with urea cycle disorders (UCDs) may develop recurrent hyperammonemia, episodic encephalopathy, and neurological sequelae which can impact Health-related Quality of Life (HRQoL). To date, there have been no systematic studies of HRQoL in people with UCDs. METHODS: We reviewed HRQoL and clinical data for 190 children and 203 adults enrolled in a multicenter UCD natural history study. Physical and psychosocial HRQoL in people with UCDs were compared to HRQoL in healthy people and people with phenylketonuria (PKU) and diabetes mellitus. We assessed relationships between HRQoL, UCD diagnosis, and disease severity. Finally, we calculated sample sizes required to detect changes in these HRQoL measures. RESULTS: Individuals with UCDs demonstrated worse physical and psychosocial HRQoL than their healthy peers and peers with PKU and diabetes. In children, HRQoL scores did not differ by diagnosis or severity. In adults, individuals with decreased severity had worse psychosocial HRQoL. Finally, we show that a large number of individuals would be required in clinical trials to detect differences in HRQoL in UCDs. CONCLUSION: Individuals with UCDs have worse HRQoL compared to healthy individuals and those with PKU and diabetes. Future work should focus on the impact of liver transplantation and other clinical variables on HRQoL in UCDs.

Firearm Deaths among Youth in the United States, 2007-2016.

We sought to compare risk factors contributing to unintentional, homicide, and suicide firearm deaths in children. We conducted a retrospective review of the National Fatality Review Case Reporting System. We included all firearm deaths among children aged 0-18 years occurring from 2007 to 2016. Descriptive analyses were performed on demographic, psychosocial, and firearm characteristics and their relationship to unintentional, homicide, and suicide deaths. Regression analyses were used to compare factors contributing to unintentional vs. intentional deaths. There were 6148 firearm deaths during the study period. The mean age was 14 years (SD ± 4 years), of which 81% were male and 41% were non-Hispanic White. The most common manners of death were homicide (57%), suicide (36%), and unintentional (7%). Over one-third of firearms were stored unlocked. Homicide deaths had a higher likelihood of occurring outside of the home setting (aOR 3.2, 95% CI 2.4-4.4) compared with unintentional deaths. Suicide deaths had a higher likelihood of occurring in homes with firearms that were stored locked (aOR 4.2, 95% CI 2.1-8.9) compared with unintentional deaths. Each manner of firearm death presents a unique set of psychosocial circumstances and challenges for preventive strategies. Unsafe firearm storage practices remain a central theme in contributing to the increased risk of youth firearm deaths.

Relationship between longitudinal changes in neuropsychological outcome and disease biomarkers in urea cycle disorders.

BACKGROUND: Urea cycle disorders (UCDs) cause impaired conversion of waste nitrogen to urea leading to rise in glutamine and ammonia. Elevated ammonia and glutamine have been implicated in brain injury. This study assessed relationships between biomarkers of metabolic control and long-term changes in neuropsychological test scores in participants of the longitudinal study of UCDs. The hypothesis was that elevated ammonia and glutamine are associated with neuropsychological impairment. METHODS: Data from 146 participants who completed 2 neuropsychological assessments were analyzed. Neuropsychological tests that showed significant changes in scores over time were identified and associations between score change and interim metabolic biomarker levels were investigated. RESULTS: Participants showed a significant decrease in performance on visual motor integration (VMI) and verbal learning immediate-recall. A decrease in scores was associated with experiencing interim hyperammonemic events (HAE) and frequency of HAE. Outside of HAE there was a significant association between median ammonia levels ≥50µmol/L and impaired VMI. CONCLUSION: VMI and memory encoding are specifically affected in UCDs longitudinally, indicating that patients experience difficulties when required to integrate motor and visual functions and learn new information. Only ammonia biomarkers showed a significant association with impairment. Preventing HAE and controlling ammonia levels is key in UCD management. IMPACT: The Beery-Buktenica Developmental Test of Visual-Motor Integration (Beery VMI) and List A Trial 5 of the California Verbal Learning Test (CVLT) may be good longitudinal biomarkers of treatment outcome in urea cycle disorders (UCD). This is the first report of longitudinal biomarkers for treatment outcome in UCD. These two biomarkers of outcome may be useful for clinical trials assessing new treatments for UCD. These results will also inform educators how to design interventions directed at improving learning in individuals with UCDs.

Cardiometabolic risk in young adults with Down syndrome.

Studies regarding cardiometabolic risk (CMR) for individuals with Down syndrome (DS) conflict. Our previous research in youth with DS, aged 10-20 years, found increased prevalence of dyslipidemia and prediabetes compared to matched peers without DS. Herein, we compare CMR in young adults with DS, aged 18-35 years, to a similar population-based sample from the 2001-2018 National Health and Nutrition Examination Survey (NHANES). The group with DS had higher NonHDL-C (mean DS 131.9 mg/dL; NHANES 126.1 p < 0.001), lower HDL-C (DS 47.5 mg/dL; NHANES 52.2 p < 0.001), higher LDL-C (DS 109.3 mg/dL; NHANES 105.4 p < 0.001), higher triglycerides (DS 102.9 mg/dL; NHANES 86.9 p < 0.001), but lower fasting glucose (DS 85.8 mg/dL; NHANES 95.2 p < 0.0001), lower HOMA-IR (DS 2.17; NHANES 2.24 p = 0.0006), lower systolic (DS 109.7 mmHg; NHANES 114.6 p < 0.0001) and lower diastolic (DS 60.9 mmHg; NHANES 67.8 p < 0.0001) blood pressures. There was relationship of higher HDL-C, triglycerides, glucose, systolic, and diastolic blood pressure with increasing BMI in the NHANES cohort which was dampened in the group with DS. These results indicate that more information is needed to guide clinicians in screening for CMR in individuals with DS.

Violent Injury as a Predictor of Subsequent Assault-Related Emergency Department Visits Among Adolescents.

PURPOSE: To measure the risk of a subsequent assault-related emergency department (ED) visit in assault injured adolescents as compared to those who initially presented for non-assault related injuries. METHODS: This was a historical cohort study of youth (ages 10-18 years) seen at two pediatric EDs between 2016 and 2019. Participants were included if their visit had an International Classification of Diseases-10 code for assaultive injury or accidental injury (motor vehicle collisions (MVC) and sports injuries). We calculated the rate of a subsequent ED visit for an assault-related injury, and then used survival analysis to compare time to subsequent ED visit with an assault-related injury between study and comparison groups. RESULTS: A total of 6125 adolescents met inclusion criteria (Assault: n = 2782, 45.4%; MVC: n = 1834, 29.9%; Sports n = 1509, 24.6%). The overall rate per 100 person years of a subsequent assault-related ED visit was 5.6 (n = 344). Patients who initially presented with an assault-related injury had an increased adjusted relative risk (aRR) of return for a subsequent ED visit for an assault-related injury when compared to MVC patients (aRR 17.6 [95% CI: 9.6, 32.2]). Kaplan-Meier time to event analysis found that patients in the assault injury group have a higher probability of a subsequent ED visit for an assault-related injury compared to patients in the MVC injury group (adjusted hazard ratio (aHR): 17.7 [95% CI: 9.67, 32.42]). DISCUSSION: Adolescents injured by assault are more likely to return to the ED for a subsequent assault-related injury compared to adolescents who initially present with non-assault-related injuries.

Can HbA1c Alone Be Safely Used to Guide Insulin Therapy in African Youth with Type 1 Diabetes?

Introduction: The relationship of HbA1c versus the mean blood glucose (MBG) is an important guide for diabetes management but may differ between ethnic groups. In Africa, the patient's glucose information is limited or unavailable and the management is largely guided by HbA1c. We sought to determine if the reference data derived from the non-African populations led to an appropriate estimation of MBG from HbA1c for the East African patients. Methods: We examined the relationship of HbA1c versus MBG obtained by the continuous glucose monitoring in a group of East African youth having type 1 diabetes in Kenya and Uganda (n = 54) compared with the data obtained from A1c-derived average glucose (ADAG) and glucose management indicator (GMI) studies. A self-identified White (European heritage) population of youth (n = 89) with type 1 diabetes, 3-18 years old, living in New Orleans, LA, USA metropolitan area (NOLA), was studied using CGM as an additional reference. Results: The regression equation for the African cohort was MBG (mg/dL) = 32.0 + 16.73 × HbA1c (%), r = 0.55, p < 0.0001. In general, the use of the non-African references considerably overestimated MBG from HbA1c for the East African population. For example, an HbA1c = 9% (74.9 mmol/mol) corresponded to an MBG = 183 mg/dL (10.1 mmol/L) in the East African group, but 212 mg/dL (11.7 mmol/L) using ADAG, 237 mg/dL (13.1 mmol/L) using GMI and 249 mg/dL (13.8 mmol/L) using NOLA reference. The reported occurrence of serious hypoglycemia among the African patients in the year prior to the study was 21%. A reference table of HbA1c versus MBG from the East African patients was generated. Conclusions: The use of non-African-derived reference data to estimate MBG from HbA1c generally led to the overestimation of MBG in the East African patients. This may put the East African and other African patients at higher risk for hypoglycemia when the management is primarily based on achieving target HbA1c in the absence of the corresponding glucose data.

A randomized, controlled trial of an innovative, multimedia instructional program for acquiring auditory skill in identifying pediatric heart murmurs.

Objective: To create a brief, acceptable, innovative method for self-paced learning to enhance recognition of pediatric heart murmurs by medical students, and to demonstrate this method's effectiveness in a randomized, controlled trial. Materials and methods: A curriculum of six 10-min online learning modules was designed to enable deliberate practice of pediatric cardiac auscultation, using recordings of patients' heart murmurs. Principles of andragogy and multimedia learning were applied to optimize acquisition of this skill. A pretest and posttest, given 4 weeks apart, were created using additional recordings and administered to 87 3rd-year medical students during their pediatric clerkship. They were randomized to have access to the modules after the pretest or after the posttest, and asked to use at least the first 2 of the modules. Results: 47 subjects comprised the Intervention group, and 40 subjects the Control group. On our primary outcome, distinguishing innocent from pathological with at least moderate confidence, the posttest scores were significantly higher for the Intervention group (60.5%) than for the Control group (20.0%). For our secondary outcomes, the 2 groups also differed significantly in the ability to distinguish innocent from pathological murmurs, and in identifying the actual diagnosis. On all 3 outcomes, those Intervention group subjects who accessed 4-6 modules scored higher than those who accessed 0-3 modules, who in turn scored higher than the Control group. Summary: Applying current principles of adult learning, we have created a teaching program for medical students to learn to recognize common pediatric murmurs. Its effectiveness was demonstrated in a randomized, controlled trial. The program results in a meaningful gain in this skill from 1 h of self-paced training with high acceptance to learners.

Mini thoracic CT adequately determines Haller index and decreases radiation exposure in children with pectus excavatum.

INTRODUCTION: The preoperative assessment of Pectus Excavatum (PE) is resource intensive. CT chest for the purpose of calculating a Haller index (HI) remains a central component and is necessary for third-party reimbursment for surgical correction. With the goal of minimizing radiation exposure, a strategy was introduced to perform a mini-Thoracic CT (mini-CT) for the calculation of HI. OPERATIVE TECHNIQUE: The mini-CT was performed as follows: a radio-opaque marker (ROM) was placed at the clinical deepest point of the deformity. The CT was then columnated to scan 3 cm above and 3 cm below the ROM. HI was calculated according to previously described technique. Seven children with PE who underwent mini-CT were age and weight matched to 7 children with PE who underwent standard low dose CT chest during the same time period. Radiation doses were evaluated using dose length product (DLP) and effective dose (mSv) between the two groups. Significance of differences was determined using the students t-test. The DLP of mini-CT compared to chest-CT was 17.9 vs 48.9,mGycm respectively. (p< 0.001) The mSv of the mini-CT compared to chest-CT was 0.32 vs 0.88, sMV respectively. (p<0.001) Both DLP and mSv were reduced by 63% in children who received a mini-CT. All children obtained insurance authorization and underwent uncomplicated Nuss repair. CONCLUSION: For children with pectus excavatum deformities the mini-Thoracic CT is an effective method to calculate the HI. Compard to the conventional low dose chest CT, the mini-CT strategy significantly reduces radiation exposure to the child by 63% with no impact on third-party authorizations or Nuss repair.

Racial and Ethnic Disparities in Pediatric Mental Health-Related Emergency Department Visits.

OBJECTIVES: To test the hypotheses that (1) rates of mental health-related concerns presenting to pediatric emergency departments (ED) have increased (2) rates are increasing more in minority than nonminority youth. METHODS: We performed a 5-year retrospective cohort study of youth with mental health-related ED visits using the Pediatric Health Information System. We calculated rates of mental health-related visits, in aggregate and by race/ethnicity. The Poisson model was used to generate incidence rate ratios of unique mental health-related visits each year using census data as the population denominator. RESULTS: There were 242,036 mental health-related visits that met the inclusion criteria, representing 160,656 unique patients. Approximately 7% of unique patients had 3 or more mental health-related visits, differing by race/ethnicity (8.75% non-Hispanic [NH]-Black vs 7.01% NH-White; adjusted odds ratio 1.14 [1.03, 1.26]). Overall, there were 42.8 mental health-related ED visits per 100,000 US children. The NH-Black children had higher rates of visits per 100,000 children compared with NH-Whites (66.1 vs 41.5; adjusted relative risk, 1.54 [1.50-1.59]). Mental health-related visits increased from 2012 to 2016 (33.31 [32.92-33.70] to 49.94 [49.46-50.41]). Every racial/ethnic group experienced an increase in rate of presentation over the study period; Hispanics experienced a significantly larger increase compared with NH-White children (P < 0.05). CONCLUSIONS: Mental health-related ED visits among children are increasing overall, disproportionally affecting minority children. The NH-Black children have the highest visit rates, and rates among Hispanics are increasing at a significantly higher rate when compared with NH-Whites. These results indicate need for increased capacity of EDs to manage mental health-related complaints, especially among minority populations.

Randomized and non-randomized designs for causal inference with longitudinal data in rare disorders.

In the United States, approximately 7000 rare diseases affect 30 million patients, and only 10% of these diseases have existing therapies. Sound study design and causal inference methods are essential to demonstrate the therapeutic efficacy, safety, and effectiveness of new therapies. In the rare diseases setting, several factors challenge the use of typical parallel control designs: the small patient population size, genotypic and phenotypic diversity, and the complexity and incomplete understanding of the disorder's progression. Repeated measures, when spaced appropriately relative to disease progression and exploited in design and analysis, can increase study power and reduce variability in treatment effect estimation. This paper reviews these longitudinal designs and draws the parallel between some new and existing randomized studies in rare diseases and their less well-known controlled observational study designs. We show that self-controlled randomized crossover and N-of-1 designs have similar considerations as the observational case series and case-crossover designs. Also, randomized sequential designs have similar considerations to longitudinal cohort studies using sequential matching or weighting to control confounding. We discuss design and analysis considerations for valid causal inference and illustrate them with examples of analyses in multiple rare disorders, including urea cycle disorder and cystic fibrosis.

Suicidality Risk of Newer Antiseizure Medications: A Meta-analysis.

Importance: Most antiseizure medications (ASMs) carry a US Food and Drug Administration-mandated class label warning of increased suicidality risk, based on a meta-analysis comparing suicidality between individuals treated with medications vs placebo in randomized clinical trials done before 2008. ASMs approved since then carry this warning although they were not similarly studied. Objective: To review all placebo-controlled phase 2 and 3 studies of 10 ASMs approved since 2008 to evaluate the risk of suicidality of these drugs compared with placebo. Data Sources: Primary publications and secondary safety analyses in PubMed of all phase 2 and 3 randomized placebo-controlled epilepsy trials of ASMs approved since 2008, using keywords epilepsy, antiepileptic drugs, seizures, suicidality, suicidal ideation, and the names of individual drugs. Study Selection: All phase 2 and 3 randomized clinical trials of adjunctive treatment of drug-resistant epilepsy and their secondary safety analyses. Data Extraction and Synthesis: Articles were reviewed for frequency of suicidality (ideation, attempts, and completed suicides). Mode of suicidality ascertainment included treatment-emergent adverse event reports, Standardized Medical Dictionary for Regulatory Activities queries for events in prespecified categories including suicidal ideation and behavior, prospective collection of suicidality data as a prespecified safety outcome using the Columbia-Suicide Severity Rating Scale, and retrospective evaluation by blinded review using the Columbia-Classification Algorithm of Suicide Assessment. A meta-analysis compared risk for drugs vs placebo of each outcome for all drugs overall and by individual drugs and trials. Main Outcomes and Measures: Suicidality (total and by ideation), attempts, and completed suicides. Results: Excluding studies that did not evaluate suicidality (everolimus and fenfluramine) or did not evaluate it prospectively (lacosamide, ezogabine, and clobazam), 5 drugs were analyzed: eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Suicidality was evaluated in 17 randomized clinical trials of these drugs, involving 5996 patients, of whom 4000 patients were treated with ASMs and 1996 with placebo. There was no evidence of increased risk of suicidal ideation (drugs vs placebo overall risk ratio, 0.75; 95% CI, 0.35-1.60) or attempt (risk ratio, 0.75; 95% CI, 0.30-1.87) overall or for any individual drug. Suicidal ideation occurred in 12 of 4000 patients treated with ASMs (0.30%) vs 7 of 1996 patients treated with placebo (0.35%) (P = .74). Three patients treated with ASMs and no patients treated with placebo attempted suicide (P = .22). There were no completed suicides. Conclusions and Relevance: There is no current evidence that the 5 ASMs evaluated in this study increase suicidality in epilepsy and merit a suicidality class warning.

ASL expression in ALDH1A1+ neurons in the substantia nigra metabolically contributes to neurodegenerative phenotype.

Argininosuccinate lyase (ASL) is essential for the NO-dependent regulation of tyrosine hydroxylase (TH) and thus for catecholamine production. Using a conditional mouse model with loss of ASL in catecholamine neurons, we demonstrate that ASL is expressed in dopaminergic neurons in the substantia nigra pars compacta, including the ALDH1A1 + subpopulation that is pivotal for the pathogenesis of Parkinson disease (PD). Neuronal loss of ASL results in catecholamine deficiency, in accumulation and formation of tyrosine aggregates, in elevation of α-synuclein, and phenotypically in motor and cognitive deficits. NO supplementation rescues the formation of aggregates as well as the motor deficiencies. Our data point to a potential metabolic link between accumulations of tyrosine and seeding of pathological aggregates in neurons as initiators for the pathological processes involved in neurodegeneration. Hence, interventions in tyrosine metabolism via regulation of NO levels may be therapeutic beneficial for the treatment of catecholamine-related neurodegenerative disorders.

Ovarian tissue cryopreservation in young females with cancer and its impact on ovarian follicle density.

BACKGROUND: Cancer therapy in young females results in irreversible damage to their ovaries potentially leading to premature ovarian failure (POF) and infertility. Ovarian follicle density (FD) serves as a key predictor of reproductive potential for a woman. FD is significantly reduced after cryopreservation in adult women with cancer. FD in young females with cancer has not been investigated. The specific aim of this study was to assess the efficacy of ovarian tissue cyropreservation (OTC) in young females with cancer by evaluating its impact on FD. METHODS: An IRB approved prospective human and animal trial enrolled girls (ages 6-18 years) with cancer at high risk for POF from July 1, 2012 through June 30, 2018. All participants underwent pre-operative ultrasounds evaluating their ovaries.  Following a normal ultrasound, each patient underwent a left ovarian tissue harvest prior to cancer therapy. The ovarian tissue was sectioned for use in pathologic analysis, fertility preservation and xenotransplantation before and after cryopreservation. Comparative statistical analyses of the means of FD before and after cryopreservation were implemented using mixed regression modeling that accounted for the correlation among samples from the same patient and differences in age. RESULTS: Six girls were enrolled (mean, 12 years; median, 13 years, range, 6-17 years). Pathologic analysis was carried out in all viable grafts and ovarian follicle densities were determined. Mean ovarian follicle density (+/- SEM) before cryopreservation was 50.5 +/- 4.26 follicles/mm2 and after cryopreservation was 44.1 +/- 4.25 follicles/mm2, p < 0.001. Following cryopreservation, on average the ovarian tissue retained 89.0.% of the FD of paired fresh samples (95% CI 82.8%, 95.2%). CONCLUSIONS: FD in young females with cancer is significantly reduced following OTC. However, the degree of reduction may be less than that reported in adult women. This is the first study in adolescent girls to provide histologic evidence of preservation of ovarian follicle density and potential efficacy of the ovarian tissue cryopreservation strategy.  By providing this evidence base, the potential benefit to young females with cancer and their family may be prognostically and clinically significant.

Firearms Injuries Involving Young Children in the United States During the COVID-19 Pandemic.

OBJECTIVES: Increased rates of firearm ownership, school closures, and a suspected decrease in supervision during the coronavirus disease 2019 (COVID-19) pandemic place young children at increased risk of firearm injuries. We measured trends in firearm injuries in children and inflicted by children discharging a firearm during the pandemic and correlated these changes with a rise in firearm acquisition. METHODS: In this cross-sectional study with an interrupted time series analysis, we used multiyear data from the Gun Violence Archive. We compared trends in (1) firearm injuries in children younger than 12 years old and (2) firearm injuries inflicted by children younger than 12 years old during the pre-COVID-19 period (March to August in the years 2016-2019) and during the first 6 months of the COVID-19 pandemic (March 2020 to August 2020). Linear regression models were developed to evaluate the relationship between firearm injuries and new firearm acquisitions. RESULTS: There was an increased risk of (1) firearm injuries in young children (relative risk = 1.90; 95% confidence interval 1.58 to 2.29) and (2) firearm injuries inflicted by young children (relative risk = 1.43; 95% confidence interval 1.14 to 1.80) during the first 6 months of the COVID-19 pandemic as compared to the pre-COVID-19 study period. These increased incidents correlate with an increase in new firearm ownership (P < .03). CONCLUSIONS: There has been a surge in firearm injuries in young children and inflicted by young children during the first 6 months of the COVID-19 pandemic. There is an urgent and critical need for enactment of interventions aimed at preventing firearm injuries and deaths involving children.

Outcomes from a pilot patient-centered hospital-to-home transition program for children hospitalized with asthma.

OBJECTIVE: To evaluate a multi-component hospital-to-home (H2H) transition program for children hospitalized with an asthma exacerbation. METHODS: A pilot prospective randomized clinical trial of guideline-based asthma care with and without a patient-centered multi-component H2H program among children enrolled in K-8th grade on Medicaid hospitalized for an asthma exacerbation. H2H program includes 5 components: medications in-hand at discharge, school-based asthma therapy (SBAT) for controller medications, referral for home trigger assessments, communication with the primary care provider (PCP), and patient navigator support. Primary outcomes included feasibility and acceptability. Secondary outcomes included healthcare utilization, asthma morbidity, and caregiver quality of life. RESULTS: A total of 32 children were enrolled and randomized. Feasibility outcomes in the intervention group included: medications in-hand at discharge (100%); SBAT for controller medication initiated (100%); home visit referrals made (100%) and home visits completed within 4 weeks of discharge (44%); PCP communication (100%); patient navigator communication at 3 days (81.3%) and 14 days (46.7%). Acceptability outcomes in the intervention group included: 87.5% of families continued SBAT, and 87.5% of families reported it was extremely helpful to have the home visit referral. Adjusting for baseline differences in age, asthma severity and control, there was no significant difference in healthcare utilization outcomes. CONCLUSION: These pilot data suggest that comprehensive care coordination initiated during the inpatient stay is feasible and acceptable. A larger trial is justified to determine if the intervention may reduce healthcare utilization for urban, minority children with asthma.

Autonomic nervous system maturation in the premature extrauterine milieu.

BACKGROUND: In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation. METHODS: We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) < 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30-33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks). RESULTS: One hundred infants, median (Q1-Q3) birth GA of 31.9 (28.7-33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities. CONCLUSION: Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA. IMPACT: Heart rate variability can evaluate the maturation of the autonomic nervous system. Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu. The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages. Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU. Modern NICU advances appear to support autonomic development in the preterm infant.