The publication quality of laboratory values in clinical studies in neonates.

BACKGROUND: There are no generally accepted age-appropriate reference ranges for laboratory values in neonates. This also matters for drug development. The International Neonatal Consortium (INC) is engaged to define actionable reference ranges of commonly used laboratory values in neonates. METHODS: A structured literature search was performed to identify standards or recommendations for publications that present neonatal laboratory data to assess the publication quality of laboratory values in neonates. Using a modified Delphi approach, an assessment and data extraction instrument to screen on completeness of information was developed. RESULTS: On 2908 hits, 281 papers were retained for full reading and 257 for data extraction. None of the papers reported a publication standard. Using the extraction instrument, most papers presented single country or unit findings. The median number of neonates was 120, with uncertainty on single or repeated measurements. Clinically meaningful information on age, sex, and medical conditions was commonly provided. Information on pharmacotherapy, equipment, analytical method, or laboratory location was rarely mentioned. CONCLUSIONS: Published information on laboratory values for neonates is sparse, not systematic, and incomplete. This undermines efforts to compare treatments, safety monitoring, or clinical management. Furthermore, there appears to be no standard yet to report laboratory values in neonates. IMPACT: There are no generally accepted age-appropriate reference ranges for laboratory values in neonates, leading to a significant knowledge gap, also for safety reporting and drug development in neonates. We performed a literature search to identify standards or recommendations for publications on neonatal laboratory data and to assess the publication quality of laboratory values in clinical studies involving neonates. Standards or recommendations for publications that present neonatal laboratory data were not identified, while published information on laboratory values for neonates is sparse, not systematic, and incomplete.

Mortality in infantile spasms: A hospital-based study.

OBJECTIVE: To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died. METHODS: This is a retrospective chart review of IS patients born between 2000 and 2011. We examined potential risk factors for mortality, including etiology, neurologic impairment, medication use, persistence of epileptic spasms, and comorbid systemic involvement (requirement for G-tube feedings, respiratory interventions). For patients who died, we describe cause of death and resuscitation status or end-of-life care measures. RESULTS: We identified 150 IS patients with median follow-up of 12 years. During the study period, 25 (17%) patients died, 13 before 5 years of age. Univariate analysis demonstrated that developmental delay, identifiable etiology, hormonal use for IS, persistence of epileptic spasms, polypharmacy with antiseizure medications, refractory epilepsy, respiratory system comorbidity, and the need for a G-tube were significant risk factors for mortality. In a multivariate analysis, mortality was predicted by persistence of epileptic spasms (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 1.11-16.67, P = .035) and significant respiratory system comorbidity (OR = 12.75, 95% CI = 2.88-56.32, P = .001). Mortality was epilepsy-related in one-third of patients who died with sudden unexpected death in epilepsy (SUDEP), accounting for 88% of epilepsy-related deaths. Most deaths before age 5 years were related to respiratory failure, and SUDEP was less common (17%) whereas SUDEP was more common (45%) with deaths after 5 years. For the majority (67%) of patients with early mortality, an end-of-life care plan was in place (based on documentation of resuscitation status, comfort measures, or decision not to escalate medical care). SIGNIFICANCE: Mortality at our single-center IS cohort was 17%, and persistence of epileptic spasms and comorbid respiratory system disorders were the most important determinants of mortality. Early deaths were related to neurological impairments/comorbidities. SUDEP was more common in children who died after 5 years of age than in those who died younger than 5 years.

High-grade ovarian serous carcinomas: Significant correlation of histologic patterns with IMP3 and E-Cadherin predicting disease recurrence and survival.

Most high-grade serous carcinomas (HGSC) of the ovary are advanced stage tumors with early recurrences. However, some tumors do not recur and have a better survival. We identified such cases of HGSC and compared those with the cases that recurred and assessed the relationship between patterns of invasion (intracystic, IC; micropapillary, MP; nonpapillary, NP) with IMP3 and E-Cadherin expression, and evaluated their predictive role in recurrence and survival. The study comprised of seventeen tumors recurred within 18 months of follow-up and 14 cases that did not recur with a minimum follow-up of 49 months. 73% tumors with predominantly MP pattern recurred, while only 27% of non-recurrent tumors showed this pattern. In contrast, predominant NP and IC patterns were seen in 71% of the non-recurrent and in 35% of recurrent tumors. 67.7% tumors expressed IMP3 and all cases expressed E-Cadherin. The tumors with a higher percentage of destructive invasion showed higher IMP3 positivity and greater chances of recurrence, whereas tumors with higher percentage of pushing invasion showed lower IMP3 positivity and lesser chances of recurrence (p = 0.02). IMP3-negative tumors had lower odds of recurrence than IMP3-positive ones (p = 0.01). The patients with negative IMP3 staining had a significantly higher OS than those with IMP3 positive tumors (p = 0.01), regardless of the histologic patterns. Also, reduction in E-Cadherin staining in the metastatic site led to poor DFS (p = 0.016) and OS (p = 0.006). IMP3 may serve as a useful prognostic marker that can stratify patients of advanced stage, high-grade serous carcinomas into two distinct subsets: majority with early recurrence with an infiltrative pattern of invasion and IMP3 positivity particularly in the MP areas; and a smaller subset that do not show early recurrence having pushing borders and are IMP3 negative. Also, E-Cadherin showed significant decrease in expression in the metastatic site of the recurrent cases.

Early Trends in Bronchoscopic Lung Volume Reduction: A Systematic Review and Meta-analysis of Efficacy Parameters.

INTRODUCTION: The goal of our systematic review and meta-analysis is to examine the therapeutic effectiveness of bronchoscopic lung volume reduction (BLVR), and to compare it with medical management and lung volume reduction surgery. METHODS: Variables of interest were absolute change in FEV1, 6MWT, and SGRQ. Meta-analysis was performed for the BLVR modalities with ≥3 trials. Of the 18 shortlisted publications, only valves (four trials; n = 159) and coils (six trials; n = 194) qualified for meta-analysis. To avoid redundant reporting for valves, only the data for intact fissure subjects were analyzed. Outcome data are presented as the mean difference from baseline with 95% confidence interval at 6-months follow-up. RESULTS: For BLVR using valves, the pooled mean difference (PMD) for FEV1 was 0.146 L (95% CI 0.111-0.181; p < 0.001), 6MWT was 45.225 meters (95% CI 26.954-63.495; p < 0.001), and SGRQ was -8.825 points (95% CI -14.824 to -2.825; p = 0.004). All the PMDs were statistically significant and higher than their respective minimal clinically important difference (MCID). For BLVR using coils, the PMD for FEV1 was 0.080 L (95% CI 0.057-0.104; p < 0.001), 6MWT was 45.320 meters (95% CI 28.040-62.600; p < 0.001), and SGRQ was -10.570 points (95% CI -13.299 to -7.841; p < 0.001). All three variables showed statistically significant PMDs but that for FEV1 was smaller than the MCID. Data from BLVR modalities with <3 major publications are reviewed in the discussion section. CONCLUSIONS: BLVR offers early promise in the palliation of advanced emphysema. Better characterization of patients to identify phenotypes that will derive sustained benefit is needed.

Sulforaphane treatment of autism spectrum disorder (ASD).

Autism spectrum disorder (ASD), characterized by both impaired communication and social interaction, and by stereotypic behavior, affects about 1 in 68, predominantly males. The medico-economic burdens of ASD are enormous, and no recognized treatment targets the core features of ASD. In a placebo-controlled, double-blind, randomized trial, young men (aged 13-27) with moderate to severe ASD received the phytochemical sulforaphane (n = 29)--derived from broccoli sprout extracts--or indistinguishable placebo (n = 15). The effects on behavior of daily oral doses of sulforaphane (50-150 µmol) for 18 wk, followed by 4 wk without treatment, were quantified by three widely accepted behavioral measures completed by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC), Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement Scale (CGI-I). Initial scores for ABC and SRS were closely matched for participants assigned to placebo and sulforaphane. After 18 wk, participants receiving placebo experienced minimal change (<3.3%), whereas those receiving sulforaphane showed substantial declines (improvement of behavior): 34% for ABC (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a significantly greater number of participants receiving sulforaphane had improvement in social interaction, abnormal behavior, and verbal communication (P = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales rose toward pretreatment levels. Dietary sulforaphane, of recognized low toxicity, was selected for its capacity to reverse abnormalities that have been associated with ASD, including oxidative stress and lower antioxidant capacity, depressed glutathione synthesis, reduced mitochondrial function and oxidative phosphorylation, increased lipid peroxidation, and neuroinflammmation.

Evaluating the safety and efficacy of felbamate in the context of a black box warning: A single center experience.

INTRODUCTION: Felbamate was approved in 1993 to treat partial seizures with and without secondary generalization in adults and in Lennox-Gastaut Syndrome in children. Its use was later restricted when rare but fatal cases of aplastic anemia and hepatic failure were identified. METHODS: This single center analysis retrospectively evaluated the safety and efficacy of felbamate in a cohort of children, adolescents, and adults with epilepsy. RESULTS: A chart review identified 103 patients taking felbamate. The range of felbamate dose was 300-4500 mg (mean: 1800 ± 900 mg). The duration of therapy ranged from 1 month to 20 years (mean duration: 35 ± 45 months). Eighteen (17.5%) subjects experienced adverse events including insomnia, nausea, vomiting, decreased appetite, weight loss, gastric discomfort, diarrhea, mood and behavioral problems, high blood pressure, headache, and elevated liver enzymes. Out of these, 6 (5.9%) patients discontinued the therapy. No hepatic failure or agranulocytosis was observed. Fifty-nine (57.72%) patients achieved ≥ 50% reduction in seizure frequency, and 30 (29.12%) patients achieved seizure freedom. CONCLUSIONS: These findings suggest that felbamate is safe, well tolerated, and effective in treatment of various types of epilepsy syndromes.

Safety and efficacy of perampanel in children and adults with various epilepsy syndromes: A single-center postmarketing study.

INTRODUCTION: Perampanel is an AMPA receptor antagonist recently approved for the treatment of partial and generalized epilepsies with tonic-clonic seizures as an add-on therapy. METHODS: This single-center postmarketing study retrospectively evaluated the efficacy of perampanel in patients with partial onset and other seizure types, with a special emphasis on its efficacy, safety, and tolerability. RESULTS: Review of medical records revealed that adequate data were available on 101 patients taking perampanel. Fifty-seven patients were female. Sixteen patients were of pediatric age range. The average dose of perampanel was 6.5mg, and average treatment duration was 8.2months. After treatment, median seizure frequency reduction was 50% overall, 50% in children, and 33% in adults; 44% in primary generalized, 38% in secondarily generalized, and 33% in partial seizures. Responder rate (50% seizure frequency reduction) was 51% overall, 63% in children, and 49% in adults; 60% in partial seizures, 43% in secondarily generalized tonic-clonic seizures, 53% in primary generalized tonic-clonic seizures, and 56% in other seizure types. Seizure freedom was attained in 6% of cases. Most common adverse events were sleepiness/fatigue (35%), behavioral problems (30%), and dizziness (22%). Adverse events were correlated with dosage. Average dose was 7.3mg in patients with adverse events vs. 5.5mg in those without adverse events. Patients who developed fatigue, cognitive decline, headaches, and weight gain were more likely to discontinue perampanel than those patients who experienced coordination issues and behavioral problems. CONCLUSIONS: These findings suggest that perampanel is safe, well-tolerated, and effective in treatment of various types of adult and pediatric epilepsy syndromes. Fatigue, cognitive decline, headache and weight gain were the main causes of perampanel discontinuation.

Severity of manifestations in tuberous sclerosis complex in relation to genotype.

OBJECTIVE: Patients with tuberous sclerosis complex (TSC) commonly present with significant neurologic deficits, including seizures, autism, and intellectual disability. Previous evidence suggests that the TSC2 mutation genotype may be associated with a more severe disease phenotype. This study evaluates the association of the TSC1 and TSC2 genotype with patient and disease characteristics in a retrospective review of a large TSC Natural History Database consisting of 919 patients with TSC. METHODS: Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics. RESULTS: As compared to patients with the TSC1 mutation, patients with the TSC2 mutation were younger (p = 0.02), more likely to have partial epilepsy (odds ratio (OR) 1.74, p = 0.0015), complex partial seizures (OR 2.03, p = 0.02), infantile spasms (IS) (OR 1.67, p = 0.01), subependymal giant-cell astrocytomas (SEGAs) (OR 1.64, p = 0.01), and intellectual disability (OR 2.90, p = 0.0002). SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. Our findings confirm and supplement existing literature that TSC2 mutation is likely to be associated with a more severe, earlier presenting TSC phenotype, including infantile spasms.

Genotype/phenotype in tuberous sclerosis complex: associations with clinical and radiologic manifestations.

OBJECTIVES: Patients with tuberous sclerosis complex (TSC) frequently have autism spectrum disorders and neuropsychiatric disorders. Subependymal giant cell astrocytomas (SEGAs) have been reported to occur in 5-20% of patients with TSC; however, the relationship between SEGAs and neuropsychiatric disorders in TSC remains unknown. We utilized a large multicenter database to study associations between SEGAs and neuropsychiatric disorders in patients with TSC. METHODS: Associations between the presence of SEGAs and neuropsychiatric disorders were examined in a retrospective review of 916 patients enrolled in the TSC Natural History Database Project (Tuberous Sclerosis Alliance). RESULTS: Among the 916 TSC patients, 226 had SEGAs (25%) and 155 had autism spectrum disorder (ASD) (17%). Compared to patients without SEGAs, patients with SEGAs were 1.83 (95% confidence interval [CI] 1.26-2.66) times more likely to have ASD. No significant relationship was found between SEGAs and intellectual disability, attention-deficit/hyperactive disorder, or major depressive disorder. SIGNIFICANCE: The clinical presentation of TSC is highly variable and not well understood. These data show that SEGAs are associated with ASD in patients with TSC, suggesting that the pathologic changes leading to SEGA formation may also predispose patients to ASD.

Risk factors for recurrence and prognosis of low-grade endometrial adenocarcinoma; vaginal versus other sites.

Endometrial adenocarcinoma is the most common gynecologic cancer in the United States. The prognosis is generally favorable, however, a significant number of patients do develop local or distant recurrence. The most common site of recurrence is vaginal. Our aim was to better characterize patients with vaginal recurrence of low-grade endometrioid adenocarcinoma with respect to associated tumor parameters and clinical outcome. We compiled 255 cases of low-grade (FIGO Grade I or II) endometrioid adenocarcinoma on hysterectomy specimens with lymph node dissection. A total of 113 cases with positive lymph nodes or recurrent disease were included in our study group. Seventy-three cases (13 Grade 1, 60 Grade 2) developed extravaginal recurrence and 40 cases (7 Grade 1, 33 Grade 2) developed vaginal recurrence. We evaluated numerous tumor parameters including: percentage myoinvasion, presence of microcystic, elongated, and fragmented pattern of myoinvasion, lymphovascular space invasion, and cervical involvement. Clinical follow-up showed that 30% (34/113) of all patients with recurrent disease died as a result of their disease during our follow-up period, including 31 (42.5%) with extravaginal recurrence and 3 (7.5%) with primary vaginal recurrence (P=0.001). The 3 patients with vaginal recurrence developed subsequent extravaginal recurrence before death. Vaginal recurrence patients show increased cervical involvement by tumor, but lack other risk factors associated with recurrent disease at other sites. There were no deaths among patients with isolated vaginal recurrence, suggesting that vaginal recurrence is not a marker of aggressive tumor biology.

Advantages of respiratory monitoring during video-EEG evaluation to differentiate epileptic seizures from other events.

Differentiating between epileptic seizures (ES) and seizure-like nonepileptic events (SLNE) is often difficult using descriptions of seizure semiology. Cardiopulmonary dysfunction is frequent in ES but has not been objectively examined in relation to SLNE. Our purpose was to compare cardiopulmonary dysfunction between ES and SLNE. We prospectively recorded cardiopulmonary function using pulse oximetry, EKG, and respiratory inductance plethysmography (RIP) in 52 ES and 22 SLNE. Comparison of cardiopulmonary complications between ES and SLNE was done using two-sample T-tests and logistic regression. Ictal bradypnea and preictal bradycardia were more frequent in ES than SLNE (p<0.05). Desaturation was found in 57% of ES and in 0% of SLNE (p<0.0001). Oxygen saturation nadir was significantly lower in ES vs. SLNE (p<0.0001). Ictal apnea was present in 31% ES and 9% SLNE (p=0.06). Preictal, ictal, and postictal tachycardia did not significantly differ between ES and SLNE (p>1.0). Cardiorespiratory dysfunction, specifically bradypnea, apnea, preictal bradycardia, and oxygen desaturation, is more frequently seen in ES than in SLNE. Tachycardia was not discriminant between ES and SLNE.

Cardiopulmonary complications during pediatric seizures: a prelude to understanding SUDEP.

PURPOSE: Sudden unexpected death in epilepsy (SUDEP) is an important, unexplained cause of death in epilepsy. Role of cardiopulmonary abnormalities in the pathophysiology of SUDEP is unclear in the pediatric population. Our objective was to assess cardiopulmonary abnormalities during epileptic seizures in children, with the long-term goal of identifying potential mechanisms of SUDEP. METHODS: We prospectively recorded cardiopulmonary functions using pulse-oximetry, electrocardiography (ECG), and respiratory inductance plethysmography (RIP). Logistic regression was used to evaluate association of cardiorespiratory findings with seizure characteristics and demographics. KEY FINDINGS: We recorded 101 seizures in 26 children (average age 3.9 years). RIP provided analyzable data in 78% and pulse-oximetry in 63% seizures. Ictal central apnea was more prevalent in patients with younger age (p = 0.01), temporal lobe (p < 0.001), left-sided (p < 0.01), symptomatic generalized (p = 0.01), longer duration seizures (p < 0.0002), desaturation (p < 0.0001), ictal bradycardia (p < 0.05), and more antiepileptic drugs (AEDs; p < 0.01), and was less prevalent in frontal lobe seizures (p < 0.01). Ictal bradypnea was more prevalent in left-sided (p < 0.05), symptomatic generalized seizures (p < 0.01), and in brain magnetic resonance imaging (MRI) lesions (p < 0.1). Ictal tachypnea was more prevalent in older-age (p = 0.01), female gender (p = 0.05), frontal lobe (p < 0.05), right-sided seizures (p < 0.001), fewer AEDs (p < 0.01), and less prevalent in lesional (p < 0.05) and symptomatic generalized seizures (p < 0.05). Ictal bradycardia was more prevalent in male patients (p < 0.05) longer duration seizures (p < 0.05), desaturation (p = 0.001), and more AEDs (p < 0.05), and was less prevalent in frontal lobe seizures (p = 0.01). Ictal and postictal bradycardia were directly associated (p < 0.05). Desaturation was more prevalent in longer-duration seizures (p < 0.0001), ictal apnea (p < 0.0001), ictal bradycardia (p = 0.001), and more AEDs (p = 0.001). SIGNIFICANCE: Potentially life-threatening cardiopulmonary abnormalities such as bradycardia, apnea, and hypoxemia in pediatric epileptic seizures are associated with predictable patient and seizure characteristics, including seizure subtype and duration.

Comparison of cardiorespiratory and EEG abnormalities with seizures in adults and children.

Cardiopulmonary dysfunction and postictal generalized EEG suppression (PGES) are proposed as possible risk factors for the occurrence of SUDEP. The evolution of cardiorespiratory abnormalities with seizures has not been systematically studied for any age-related findings. Additionally, not many studies have looked into the possible effect of age-related brain maturation on PGES. The purpose of this study was to compare these SUDEP risk factors in adults versus children. We prospectively recorded cardiopulmonary abnormalities during seizures using pulse oximetry, EKG, and respiratory inductance plethysmography. Linear and logistic regression models adjusting for multiple seizures in a single patient were used to compare the cardiorespiratory and EEG findings between adults and children. We recorded 101 seizures in 26 children and 55 seizures in 22 adults. Ictal central apnea and bradycardia occurred more often in children than in adults (p=0.02 and p=0.008, respectively), while ictal tachycardia occurred more often in adults (p=0.001) than in children. Postictal generalized EEG suppression of longer duration occurred more often in adults (p=0.003) than in children. Minimum O2 saturation and seizure duration/generalization/lateralization did not significantly differ between adults and children (p>0.1). Children had more frontal lobe seizures, and adults had more temporal lobe seizures recorded (p=0.01). There may be an age-related effect on cardiorespiratory and EEG abnormalities associated with seizures, with higher rates of apnea and bradycardia in children and a much higher prevalence of PGES of longer duration in adults. This may indicate why, despite lower rates of cardiopulmonary dysfunction, adults die more frequently from SUDEP than children.

Sleep in Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder.

SLEEP IN AUTISM SPECTRUM DISORDER AND ATTENTION DEFICIT HYPERACTIVITY DISORDER: Kanwaljit Singh, Andrew W. Zimmerman Seminars in Pediatric Neurology Volume 22, Issue 2, June 2015, Pages 113-125 Sleep problems are common in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Sleep problems in these disorders may not only worsen daytime behaviors and core symptoms of ASD and ADHD but also contribute to parental stress levels. Therefore, the presence of sleep problems in ASD and ADHD requires prompt attention and management. This article is presented in 2 sections, one each for ASD and ADHD. First, a detailed literature review about the burden and prevalence of different types of sleep disorders is presented, followed by the pathophysiology and etiology of the sleep problems and evaluation and management of sleep disorders in ASD and ADHD.

The neonatal adverse event severity scale: current status, a stakeholders' assessment, and future perspectives.

To support informed decisions on drug registration and prescription, clinical trials need tools to assess the efficacy and safety signals related to a given therapeutic intervention. Standardized assessment facilitates reproducibility of results. Furthermore, it enables weighted comparison between different interventions, instrumental to facilitate shared decisions. When focused on adverse events in clinical trials, tools are needed to assess seriousness, causality and severity. As part of such a toolbox, the international Neonatal Consortium (INC) developed a first version of the neonatal adverse event severity scale (NAESS). This version underwent subsequent validation in retro-and prospective trials to assess its applicability and impact on the inter-observer variability. Regulators, sponsors and academic researchers also reported on the use of the NAESS in regulatory documents, trial protocols and study reports. In this paper, we aim to report on the trajectory, current status and impact of the NAESS score, on how stakeholders within INC assess its relevance, and on perspectives to further develop this tool.

Evaluating a web-based self-management program for employees with hypertension and prehypertension: a randomized clinical trial.

BACKGROUND: Web-based self-management programs offer a novel approach for self-insured employers seeking to improve and maintain employee health. METHODS: We conducted a 6-month prospective, cluster-randomized controlled trial designed to evaluate whether worksite access to an automated, web-based, self-management program resulted in better blood pressure control. The trial was conducted at 6 EMC Corporation worksites in Massachusetts, each of which had at least 600 employees; 404 EMC employees with pre-hypertension or hypertension participated. Participants at 3 worksites received a home blood pressure cuff that uploaded readings to a Web site where they could view trends and read automated rules-based messages. Participants at 3 worksites received access to an onsite blood pressure cuff. Primary outcome measure was change in systolic blood pressure. Secondary outcome measures were change in diastolic blood pressure, proportion of participants achieving significant changes in systolic and diastolic blood pressure, and subject satisfaction. RESULTS: Although the mean change in systolic blood pressure was not significantly different between intervention and control groups (-1.69 vs. -0.86 mm HG, respectively, P = .49) the change in diastolic blood pressure between groups was significant. (-1.08 vs. = 1.47 mm HG, respectively, P < .001). Significantly more intervention participants experienced a >10-mm Hg decrease in systolic blood pressure or >5-mm Hg decrease in diastolic blood pressure compared to controls (22% vs 17%, P = .02 and 29% vs 16%, P = .03, respectively). Intervention participants were twice as likely to report starting a new medication (P = .02) and more likely to report improved communication with their doctor (P = .02). CONCLUSIONS: Participation in an automated online self-management program resulted in improved blood pressure among employees with prehypertension or hypertension.

Landscape analysis for a neonatal disease progression model of bronchopulmonary dysplasia: Leveraging clinical trial experience and real-world data.

The 21st Century Cures Act requires FDA to expand its use of real-world evidence (RWE) to support approval of previously approved drugs for new disease indications and post-marketing study requirements. To address this need in neonates, the FDA and the Critical Path Institute (C-Path) established the International Neonatal Consortium (INC) to advance regulatory science and expedite neonatal drug development. FDA recently provided funding for INC to generate RWE to support regulatory decision making in neonatal drug development. One study is focused on developing a validated definition of bronchopulmonary dysplasia (BPD) in neonates. BPD is difficult to diagnose with diverse disease trajectories and few viable treatment options. Despite intense research efforts, limited understanding of the underlying disease pathobiology and disease projection continues in the context of a computable phenotype. It will be important to determine if: 1) a large, multisource aggregation of real-world data (RWD) will allow identification of validated risk factors and surrogate endpoints for BPD, and 2) the inclusion of these simulations will identify risk factors and surrogate endpoints for studies to prevent or treat BPD and its related long-term complications. The overall goal is to develop qualified, fit-for-purpose disease progression models which facilitate credible trial simulations while quantitatively capturing mechanistic relationships relevant for disease progression and the development of future treatments. The extent to which neonatal RWD can inform these models is unknown and its appropriateness cannot be guaranteed. A component of this approach is the critical evaluation of the various RWD sources for context-of use (COU)-driven models. The present manuscript defines a landscape of the data including targeted literature searches and solicitation of neonatal RWD sources from international stakeholders; analysis plans to develop a family of models of BPD in neonates, leveraging previous clinical trial experience and real-world patient data is also described.

Length of Stay in Pediatric Neurology Hospital Admissions.

OBJECTIVE: To describe inpatient length of stay patterns, identify key drivers related to prolonged length of stay, and evaluate the relationship between length of stay and readmission in pediatric neurology. METHODS: This was a retrospective review of patients <19 years old admitted with a principal neurologic diagnosis to our hospital between January 2017 and July 2019. Scheduled admissions and hospital admissions lasting >30 days were excluded from analysis. Length of stay was obtained in addition to demographic characteristics, principal discharge diagnosis, multispecialty care, use of multiple antiseizure medications, inpatient hospital costs (ie, claims paid), and pediatric intensive care unit (ICU) admission for unplanned admissions and 7- and 30-day readmissions. RESULTS: There were a total of 1579 unplanned admissions. The most common reasons for admission were seizure (n = 942), headache (n = 161), other neurologic diagnosis (n = 121), and psychiatric disorders/functional neurologic disorder (n = 60). Children admitted to the hospital for a neurologic condition have an average length of stay of 2.8±5.0 days for unplanned admissions, 4.5±7.4 days for 7-day readmissions, and 5.2±7.5 days for 30-day readmissions. Average inpatient hospital costs were $44 075±56 976 for unplanned admissions, $60 361±71 427 for 7-day readmissions, and $55 434±56 442 for 30-day readmissions. Prolonged length of stay and increased hospital costs were associated with pediatric ICU admission, multispecialty care, 7- and 30-day readmission, multiple antiseizure medications, and psychiatric disorders / functional neurologic disorders. CONCLUSIONS: Pediatric ICU admission, multispecialty care, readmission, multiple antiseizure medications, and psychiatric disorder / functional neurologic disorder prolong length of stay and increase hospital costs.

Randomized controlled trial of sulforaphane and metabolite discovery in children with Autism Spectrum Disorder.

BACKGROUND: Sulforaphane (SF), an isothiocyanate in broccoli, has potential benefits relevant to autism spectrum disorder (ASD) through its effects on several metabolic and immunologic pathways. Previous clinical trials of oral SF demonstrated positive clinical effects on behavior in young men and changes in urinary metabolomics in children with ASD. METHODS: We conducted a 15-week randomized parallel double-blind placebo-controlled clinical trial with 15-week open-label treatment and 6-week no-treatment extensions in 57 children, ages 3-12 years, with ASD over 36 weeks. Twenty-eight were assigned SF and 29 received placebo (PL). Clinical effects, safety and tolerability of SF were measured as were biomarkers to elucidate mechanisms of action of SF in ASD. RESULTS: Data from 22 children taking SF and 23 on PL were analyzed. Treatment effects on the primary outcome measure, the Ohio Autism Clinical Impressions Scale (OACIS), in the general level of autism were not significant between SF and PL groups at 7 and 15 weeks. The effect sizes on the OACIS were non-statistically significant but positive, suggesting a possible trend toward greater improvement in those on treatment with SF (Cohen's d 0.21; 95% CI - 0.46, 0.88 and 0.10; 95% CI - 0.52, 0.72, respectively). Both groups improved in all subscales when on SF during the open-label phase. Caregiver ratings on secondary outcome measures improved significantly on the Aberrant Behavior Checklist (ABC) at 15 weeks (Cohen's d - 0.96; 95% CI - 1.73, - 0.15), but not on the Social Responsiveness Scale-2 (SRS-2). Ratings on the ABC and SRS-2 improved with a non-randomized analysis of the length of exposure to SF, compared to the pre-treatment baseline (p < 0.001). There were significant changes with SF compared to PL in biomarkers of glutathione redox status, mitochondrial respiration, inflammatory markers and heat shock proteins. Clinical laboratory studies confirmed product safety. SF was very well tolerated and side effects of treatment, none serious, included rare insomnia, irritability and intolerance of the taste and smell. LIMITATIONS: The sample size was limited to 45 children with ASD and we did not impute missing data. We were unable to document significant changes in clinical assessments during clinical visits in those taking SF compared to PL. The clinical results were confounded by placebo effects during the open-label phase. CONCLUSIONS: SF led to small yet non-statistically significant changes in the total and all subscale scores of the primary outcome measure, while for secondary outcome measures, caregivers' assessments of children taking SF showed statistically significant improvements compared to those taking PL on the ABC but not the SRS-2. Clinical effects of SF were less notable in children compared to our previous trial of a SF-rich preparation in young men with ASD. Several of the effects of SF on biomarkers correlated to clinical improvements. SF was very well tolerated and safe and effective based on our secondary clinical measures. TRIAL REGISTRATION: This study was prospectively registered at clinicaltrials.gov (NCT02561481) on September 28, 2015. Funding was provided by the U.S. Department of Defense.