Objective: South Asians are at elevated diabetes risk, attributed to insulin resistance, insulin deficiency, and ectopic fat. The CHAriSmA study compared metabolic mechanisms in South Asian, White, and African American(AA) adolescents and young adults(AYA) to determine early diabetes risk in South Asians. Research Design and Methods: AYA 12-21y, BMI ≥23kg/m2 or ≥80%ile underwent MRI/MRS to quantify fat, OGTT with Minimal modeling to calculate insulin sensitivity(Si), AUC insulin secretory rate(AUC-ISR), and disposition index(DI), DXA, and glucose-potentiated arginine stimulation test. Results: South Asian AYA(n=53, age: median(IQR) 20.3y(18.9, 21.4)) compared to White(n=53, 19.1y(17.6, 20.8)) and AA(n=49, 18.8y(17.7, 20.5), p=0.02) of similar sex, puberty, and BMIZ had higher MRI visceral fat(p<0.001 vs. White, p=0.009 vs. AA) and MRS liver fat(p<0.001 vs. both). South Asians had lower Si(p=0.006) and higher AUC-ISR dynamic(p=0.003) vs. White, higher AUC-ISR total and static vs. both(p<0.001), and lower dynamic DI vs. AA(p=0.039). South Asian AYA had lower insulin clearance than White(p=0.027) and AA(p=0.007). First-pass hepatic insulin extraction was lower in AA than South Asian(p<0.0001) and White AYA(p=0.027). Group differences in Si, dynamic AUC-ISR, and dynamic DI lost significance when visceral or liver fat was added to models; but, higher total and static AUC-ISR in South Asians persisted. Conclusions: Compared to White and AA AYA, South Asians have higher visceral and liver fat. These findings, along with lower Si and dynamic DI, suggest elevated metabolic risk in South Asians, even at young ages. Higher total and static phase insulin secretion in South Asian AYA may precede insulin deficiency reported in adults.

ObjectiveTo evaluate the potential of targeted inflammatory proteins high mobility group box 1 (HMGB1), matrix metalloproteinase 9 (MMP-9) and interleukins (IL)-6, IL-8 and IL-10 as early biomarkers for post-traumatic epilepsy (PTE) prediction.MethodsIn this prospective, international study, adult patients with traumatic brain injury (TBI) and an anticipated high risk of PTE based on radiological and clinical findings were recruited from Level 1 trauma centers in the USA and Europe. Blood was collected on days 2 and 4 post-TBI. Patients were followed clinically for 24 months for PTE development. Serum levels of the inflammatory markers were assessed using commercially available ELISA and AlphaLISA kits and compared between patients who did and did not develop PTE, and between PTE and a subgroup of non-PTE patients matched for age, sex, and Glasgow Coma Scale using non-parametric tests.ResultsWe found no statistically significant differences in serum levels of the inflammatory markers between PTE patients (n = 13) and non-PTE patients (n = 73), neither at each timepoint nor in the change from day 2 to day 4. Exploring temporal changes within each group, we found a significant decrease in IL-6 level between the two timepoints in the total and matched non-PTE groups, but not in the PTE group. MMP-9 level decreased in both the PTE and the matched non-PTE groups, but not in the total non-PTE group.SignificanceBased on our findings, serum levels of HMGB1, MMP-9, IL-6, IL-8 and IL-10 measured at early time points after TBI may not serve as sensitive biomarkers of PTE. However, a faster decline in IL-6 levels in the non-PTE groups suggests a more rapid resolution of inflammation among patients who do not develop PTE, supporting the role of neuroinflammatory mechanisms in epileptogenesis. The potential of IL-6’s temporal profile as a biomarker of PTE warrants further exploration.

AbstractBackgroundOrnithine 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.MethodsWe 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.ResultsAmong 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.ConclusionsAnalysis 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.

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.

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.

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. (c) 2023 Society for Adolescent Health and Medicine. All rights reserved.

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.

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.

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.

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.

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.(c) 2022 Elsevier Inc. All rights reserved.

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.

Background: Most antiseizure medications (ASMs) carry an FDA-mandated class label warning of increased suicidality risk. This is based on an FDA meta-analysis comparing suicidality between ASM and placebo (PBO)-treated subjects in PBO-controlled randomized clinical trials (RCTs) done up to 2007. New ASMs approved since then carry this warning although they were not similarly evaluated. We review all PBO-controlled phase 2 and 3 studies of 10 ASMs approved since 2008 to compare suicidality between actively vs PBO-treated patients.Methods: We reviewed primary publications and secondary safety analyses of all phase 2 and 3 RCTs in patients with treatment-resistant epilepsy for ASMs approved since 2008 for the frequency of suicidality (ideation, attempts and completed suicides).A meta-analysis compared risk for ASM vs PBO of each outcome for all drugs overall and by individual ASMs and trials.Findings: Excluding RCTs of ASMs which did not evaluate suicidality (everolimus, fenfluramine),or did not evaluate it prospectively (lacosamide, ezogabine, clobazam) we analyzed five ASMs, eslicarbazepine, perampanel, brivaracetam, cannabidiol and cenobamate. Suicidality was evaluated in 17 RCTs of these five ASMs, involving 5996 patients,4,000 actively-treated and 1996 PBO-treated. Twelve of 4000 (0.3%) ASM-treated patients had suicidal ideation, compared with 7/1996 (0.35%) of PBO-treated patients (p=0.75).Three actively treated and no PBO-treated patients attempted suicide (p=0.22).There were no completed suicides. There was no evidence of increased risk of suicidal ideation (ASM versus PBO overall RR=0.75, 95% CI 0.35,1.60) or suicide attempt (RR=0.75, 95% CI 0.30,1.87) overall or for any individual drug. Risk ratios of suicidal ideation for individual drugs vs PBO were 0.76, 0.47, 0.88 and 1.22,respectively,for eslicarbazepine, perampanel, brivaracetam and cenobamate. No suicidalities were reported with cannabidiol.Interpretation: Newer antiseizure medications do not increase suicidality in epilepsy patients. The ASM suicidality class warning is not warranted. Suicidality risk should be evaluated for each medication using validated methods in prospective studies. Labeling should be based on data from such studies and individualized for each new ASM.Funding Statement: None.Declaration of Interests: PK receives grant support from CURE/department of defense. He has received consulting or speaker fees from, or been on advisory boards of Abbot, Aquestive, Eisai, Greenwich Pharmaceuticals, Neurelis, SK Life Science, Sunovion and UCB Pharma. He is on the Medical Advisory Board of Alliance-Stratus, is on Scentific Advisory Board of OB Pharma, and is the CEO of PrevEp, LLC. Orrin Devinsky receives grant support from NINDS, NIMH, MURI, CDC and NSF. He has equity and/or compensation from the following companies: Tilray, Receptor Life Sciences, Qstate Biosciences, Tevard Biosciences, Regel Biosciences, Script Biosciences, Empatica, Engage, Papa & Barkley, Rettco, SilverSpike, and California Cannabis Enterprises (CCE). He has received consulting fees from Eisai and Zogenix. J. French receives NYU salary support from the Epilepsy Foundation and for consulting work and/or attending Scientific Advisory Boards on behalf of the Epilepsy Study Consortium for Aeonian/Aeovian, Anavex, Arvelle Therapeutics, Inc., Athenen Therapeutics/Carnot Pharma, Axovant, Biogen, BioXcel Therapeutics, Blackfynn, Cerebral Therapeutics, Cerevel, Crossject, CuroNZ, Eisai, Eliem Therapeutics, Encoded Therapeutics, Engage Therapeutics, Engrail, Epiminder, Epitel, Fortress Biotech, Greenwich Biosciences, GW Pharma, Ionis, Janssen Pharmaceutica, Knopp Biosciences, Lundbeck, Marinus, Mend NeuroscienceMerck, NeuCyte, Inc., Neurocrine, Otsuka Pharmaceutical Development, Ovid Therapeutics Inc., Passage Bio, Pfizer, Praxis, Redpin, Sage, SK Life Sciences, Sofinnova, Stoke, Sunovion, Supernus, Takeda, UCB Inc., Xenon, Xeris, Zogenix. J. French has also received research grants from Biogen, Cavion, Eisai, Engage, GW Pharma, Lundbeck, Neurelis, Ovid, Pfizer, SK Life Sciences, Sunovion, UCB, Xenon and Zogenix as well as grants from the Epilepsy Research Foundation, Epilepsy Study Consortium, and NINDS. She is on the editorial board of Lancet Neurology and Neurology Today. She is Chief Medical/Innovation Officer for the Epilepsy Foundation for which NYU receives salary support. She has received travel reimbursement related to research, advisory meetings, or presentation of results at scientific meetings from the Epilepsy Study Consortium, the Epilepsy Foundation, Arvelle Therapeutics, Inc., Biogen, Cerevel, Engage, Lundbeck, NeuCyte, Inc., Otsuka, Sage, UCB, Xenon, Zogenix. Cynthia Harden is employed by Xenon Pharmaceuticals Inc.Gregory Krauss has worked as an investigator for Cerevel Therapeutics, Eisai Labs, EpiWatch, Inc. SK Life Sciences, UCB Pharma, and as a consultant for Arvelle Therapeutics, NeuroCyte, Inc. Pled Pharma, and SK Life Science. He is a director of and owns equity in EpiWatch, Inc.Robert McCarter receives grant support from CHF/O’Malley Foundation and from NIH, and receives research support from Johns Hopkins University.Michael Sperling receives research grant and contracts from NIH, UCB Pharma, SK Life Sciences, Takeda, Neurelis, Engage Therapeutics, Medtronic, Eisai, Cavion, Cerevel, and Xenon. He has consulted for the Medtronic and the Epilepsy Study Consortium. He has received speaker fees from Eisai, Medscape, NeurologyLive, UCB Pharma, Projects in Knowledge.

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.

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-8(th)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.

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/mm(2) and after cryopreservation was 44.1 +/- 4.25 follicles/mm(2), 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. (c) 2021 Elsevier Inc. All rights reserved.