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To determine whether objective parameters of sleep quality differ throughout recovery between children and adolescents who experienced an early return to school (RTS) and those who had a delayed RTS or did not return at all during the study period.Sleep parameters reflective of sleep quality were evaluated in participants' natural sleeping habitat throughout 9 weeks postinjury.Ninety-four children and adolescents (aged 5-18 years) with diagnosed concussion.Prospective cohort. Participants followed RTS protocols.Actigraphy-derived estimates of total sleep time (TST), sleep efficiency (SE), wake after sleep onset (WASO), average arousal length (AAL), and number of arousals (NOAs) per hour were assessed. The length of time from injury until RTS was determined for each participant. Participants were categorized into an early RTS or delayed RTS group based on their time to RTS.Both TST and SE were significantly greater in the early RTS group. WASO duration, AAL, and NOAs were significantly greater in the delayed RTS group. Differences between RTS groups were most apparent during weeks 1 to 5 postinjury.Participants who returned to school earlier had significantly better objective sleep quality than participants who experienced a delayed RTS. This study provides evidence in support of a relationship between sleep quality and time to RTS in children and adolescents with concussion. Considering early monitoring of sleep, education regarding sleep hygiene, and access to age-appropriate sleep interventions may be helpful in pediatric concussion recovery.

ObjectiveTo assess imaging utilization practices across clinical specialists in neurofibromatosis type 1 (NF1) for the evaluation of symptomatic and asymptomatic children and adults with or without plexiform neurofibromas (PN).MethodsAn institutional review board–exempt survey was administered to medical practitioners caring for individuals with NF1 at the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) meeting in September 2019. The survey included questions on respondent demographic data (9 questions), type of imaging obtained for asymptomatic (4 questions) and symptomatic (4 questions) people with and without PN, and utilization of diffusion-weighted imaging (2 questions).ResultsThirty practitioners participated in the survey. Most were academic neuro-oncologists at high-volume (>10 patients/week) NF1 centers. Of 30 respondents, 26 had access to whole-body MRI (WB-MRI). The most common approach to an asymptomatic person without PN was no imaging (adults: 57% [17/30]; children: 50% [15/30]), followed by a screening WB-MRI (adults: 20% [6/30]; children: 26.7% [8/30]). The most common approach to a person with symptoms or known PN was regional MRI (adults: 90% [27/30]; children: 93% [28/30]), followed by WB-MRI (adults: 20% [6/30]; children: 36.7% [11/30]). WB-MRI was most often obtained to evaluate a symptomatic child with PN (37% [11/30]).ConclusionsMore than 90% of practitioners indicated they would obtain a regional MRI in a symptomatic patient without known or visible PN. Otherwise, there was little consensus on imaging practices. Given the high prevalence of PN and risk of malignant conversion in this patient population, there is a need to define imaging-based guidelines for optimal clinical care and the design of future clinical trials.

PURPOSE Recurrent instability following a lateral patellar dislocation is a common indication for surgical intervention. Several surgical procedures are described in the literature to address recurrent patellar instability. Medial patellofemoral ligament (MPFL) reconstruction utilizing the quadriceps turndown technique attempts to restore medial stability. Results of the quadriceps turndown technique have previously only been reported in adult populations. The purpose of this study was to assess the safety, efficacy, and patient-reported outcomes following a quadriceps turndown MPFL reconstruction in the pediatric and adolescent population. METHODS Records of all patients who underwent MPFL reconstruction using a quadriceps turndown technique between 2011 and 2018 were reviewed for demographics, risk factors, complications, mechanism of injury, and concomitant procedures. Return to activities of daily living (ADLs), return to presurgery level of sport, length of bracing, and recurrent instability were assessed with the administration of the Kujala Anterior Knee Pain Score. All analyses were completed using IBM SPSS Statistics 26. RESULTS Thirty-six knees [14 female (39%), 22 male (61%)] from 34 patients met inclusion/exclusion criteria. The average follow-up length was 35.9±15.2 months. The average age was 16.3±1.8 years at the time of surgery. The average time for resumption of ADLs was 8.1±6.0 weeks after surgery. Ninety-four percent of patients returned to preinjury level of sport at an average of 23.6±12.0 weeks after surgery. Mean Kujala Anterior Knee Pain Score was 90.7±10.3. Female patients (P

Background and ObjectivesNeurofibromatosis type 1 (NF1)-associated cognitive impairments carry significant lifelong morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of mitogen-activated protein kinase inhibitor (MEKi) treatment.MethodsFifty-nine patients with NF1 aged 5–27 years on an MEKi clinical trial treating plexiform neurofibroma underwent pretreatment and follow-up cognitive assessments over 48 weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were the primary outcomes. Group-level (paired t tests) and individual-level analyses (Reliable Change Index, RCI) were used.ResultsAnalysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: t(58) = 3.03, p = 0.004, d = 0.24; 48-week Metacognition Index: t(39) = 2.70, p = 0.01, d = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ2 = 11.95, p = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate (p > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ2 = 8.36, p = 0.004, OR = 4.6, and 48-week χ2 = 9.34, p = 0.004, OR = 5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than nonimpaired patients (24 weeks 46% vs 8%; χ2 = 9.54, p = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ2 = 7.50, p = 0.02, OR = 9.0).DiscussionOur data show no evidence of neurotoxicity in 48 weeks of treatment with an MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.

Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%–50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R 10 ) or forced expiratory volume in 1 or 0.75 seconds (FEV 1 or FEV 0.75 ) as primary pulmonary endpoints. The group defined minimum changes in AHI, R 10 , and FEV 1 or FEV 0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.

Background To date, there are few studies that examine the perspectives of older survivors of childhood brain tumors who are living with their families in terms of their sense of self and their role in their families. Objective The aim of this study was to describe how adolescent and young adult survivors of childhood brain tumors describe their health-related quality of life, that is, their physical, emotional, and social functioning. Methods This qualitative descriptive study included a purposive sample of 41 adolescent and young adult survivors of a childhood brain tumor who live with their families. Home interviews were conducted using a semistructured interview guide. Directed content analytic techniques were used to analyze data using health-related quality of life as a framework. Results This group of brain tumor survivors described their everyday lives in terms of their physical health, neurocognitive functioning, emotional health, social functioning, and self-care abilities. Overall, survivors struggle for normalcy in the face of changed functioning due to their cancer and the (late) effects of their treatment. Conclusions Neurocognitive issues seemed most compelling in the narratives. The importance of families went beyond the resources, structure, and support for functioning. Their families provided the recognition that they were important beings and their existence mattered to someone. Implications for practice The value and complexity of care coordination were highlighted by the multifaceted needs of the survivors. Advocacy for appropriate and timely educational, vocational, and social support is critical as part of comprehensive cancer survivorship care.

Two children without neurofibromatosis type 1 presented with unilateral decreased vision and MRI revealing optic nerve tumors. In the first case, chemotherapy was initiated empirically for presumed optic pathway glioma, but the lesion increased in size with associated clinical worsening, raising concern for a possible alternate diagnosis. Biopsy of the involved optic nerve resulted in worsening of vision due to a branch retinal artery occlusion and showed a grade I pilocytic astrocytoma. In the second case, sudden symptom onset and rapid tumor growth prompted an optic nerve biopsy, resulting in vision loss due to a central retinal artery occlusion and revealing grade I pilocytic astrocytoma. In both cases, tissue diagnosis did not alter the course of management. Instead, biopsy was associated with additional vision loss, highlighting the risk of biopsy in children with isolated optic nerve tumors and imaging that is most consistent with an optic pathway glioma.

Sirolimus is an inhibitor of mammalian target of rapamycin, which exhibits large interindividual pharmacokinetic variability. We report sirolimus pharmacokinetic data collected as part of a concentration-controlled multicenter phase II clinical trial in pediatric patients with neurofibromatosis type 1. The purpose of this study was to explore the effect of growth on age-dependent changes in sirolimus clearance with a focus on cytochrome P450 3A (CYP3A) subfamily mediated metabolism.Predose blood samples were obtained at steady state from 18 patients with neurofibromatosis type 1. Sirolimus and its 5 CYP3A-dependent primary metabolites were quantified by HPLC-UV/MS. Concentration ratios of metabolites to sirolimus (metabolic ratio) were calculated as an index of metabolite formation.Metabolic ratios of the main metabolites, 16-O-demethylsirolimus (16-O-DM) and 24-hydroxysirolimus (24OH), were significantly correlated with sirolimus clearance, whereas this was not the case for the other 3 metabolites (25-hydroxysirolimus, 46-hydroxysirolimus, and 39-O-demethylsirolimus). The ratios for the 16-O-DM and 24OH metabolites were lower in children than adults. No significant difference in allometrically scaled metabolic ratios of 16-O-DM and 24OH was observed between children and adults.This study suggests that the age-dependent changes in sirolimus clearance can be explained by size-related increases in CYP3A metabolic capacity, most likely due to liver and intestinal growth. These findings will help facilitate the development of age-appropriate dosing algorithms for sirolimus in infants and children.

The goal of the Response Evaluation in Neurofibromatosis and Schwannomatosis Visual Outcomes Committee is to define the best functional outcome measures for future neurofibromatosis type 1 (NF1)-associated optic pathway glioma (OPG) clinical trials.The committee considered the components of vision, other ophthalmologic parameters affected by OPG, potential biomarkers of visual function, and quality of life measures to arrive at consensus-based, evidence-driven recommendations for objective and measurable functional endpoints for OPG trials.Visual acuity (VA) assessments using consistent quantitative testing methods are recommended as the main functional outcome measure for NF1-OPG clinical trials. Teller acuity cards are recommended for use as the primary VA endpoint, and HOTV as a secondary endpoint once subjects are old enough to complete it. The optic disc should be assessed for pallor, as this appears to be a contributory variable that may affect the interpretation of VA change over time. Given the importance of capturing patient-reported outcomes in clinical trials, evaluating visual quality of life using the Children's Visual Function Questionnaire as a secondary endpoint is also proposed.The use of these key functional endpoints will be essential for evaluating the efficacy of future OPG clinical trials.

Objective: Neurofibromatosis (NF)-related benign tumors such as plexiform neurofibromas (PN) and vestibular schwannomas (VS) can cause substantial morbidity. Clinical trials directed at these tumors have become available. Due to differences in disease manifestations and the natural history of NF-related tumors, response criteria used for solid cancers (1-dimensional/RECIST [Response Evaluation Criteria in Solid Tumors] and bidimensional/World Health Organization) have limited applicability. No standardized response criteria for benign NF tumors exist. The goal of the Tumor Measurement Working Group of the REiNS (Response Evaluation in Neurofibromatosis and Schwannomatosis) committee is to propose consensus guidelines for the evaluation of imaging response in clinical trials for NF tumors. Methods: Currently used imaging endpoints, designs of NF clinical trials, and knowledge of the natural history of NF-related tumors, in particular PN and VS, were reviewed. Consensus recommendations for response evaluation for future studies were developed based on this review and the expertise of group members. Results: MRI with volumetric analysis is recommended to sensitively and reproducibly evaluate changes in tumor size in clinical trials. Volumetric analysis requires adherence to specific imaging recommendations. A 20% volume change was chosen to indicate a decrease or increase in tumor size. Use of these criteria in future trials will enable meaningful comparison of results across studies. Conclusions: The proposed imaging response evaluation guidelines, along with validated clinical outcome measures, will maximize the ability to identify potentially active agents for patients with NF and benign tumors.

Objective: To determine whether severe recurrent headache is a risk factor for neurovascular events in children who received radiation for brain tumors. Methods: This is a retrospective cohort study of children with brain tumors who received cranial irradiation at a large tertiary care center, aged 0–21 years at diagnosis, with initial treatment between January 1, 1993 and December 31, 2002, and 2 or more follow-up visits. Patients were considered to have severe recurrent headache if this appeared as a complaint on 2 or more visits. Headaches attributed to tumor progression, shunt malfunction, or infection, or appearing at the end of life, were excluded. Medical records were reviewed for events of stroke or TIA. Results: Of 265 subjects followed for a median of 6.0 years (interquartile range 1.7–9.2 years), stroke or TIA occurred in 7/37 (19%) with severe headaches compared to 6/228 (3%) without these symptoms (hazard ratio 5.3, 95% confidence interval 1.8–15.9, p = 0.003). Adjusting for multiple variables did not remove the significance of this risk. Median time to first neurovascular event for the entire cohort was 4.9 years (interquartile range 1.7–5.5 years). Conclusions: Severe recurrent headache appears to be a risk factor or predictor for subsequent cerebral ischemia in pediatric brain tumor survivors treated with radiation. This finding has clinical implications for both monitoring survivors and targeting a specific population for primary stroke prevention.

Childhood optic pathway gliomas (OPGs) are low-grade neoplasms intrinsic to the optic nerve, optic chiasm, tracts, and radiations. The management of OPGs is still a highly controversial topic among neuro-ophthalmologists.Authors' personal experience and literature review.This review describes our current understanding of the behavior of OPGs and discusses advances in their imaging, evaluation, and management. Patients with OPGs that progress are typically treated with chemotherapy using carboplatin and vincristine; however, newer approaches to therapy are being explored.Although chemotherapy is the mainstay of treatment when indicated, multicenter collaborative studies involving oncologists and neuro-ophthalmologists, both retrospective and prospective, are still needed to establish evidence-based guidelines for the management of children with OPGs.

The mangled extremity is a complex and multifaceted traumatic orthopaedic injury. This injury results in damage to bone, nerve, soft tissue, and/or vascular structures, and often requires multiple surgeries. The treatment decision between limb salvage and amputation is complicated, but must be made. A systematic approach to the evaluation and medical decision-making process can help an orthopaedic provider to make an informed medical decision. This article will provide a detailed overview of the evaluation, medical decision-making, and treatment of the mangled extremity.

Endotoxin (ET) induces neutrophil sequestration in hepatic sinusoids, the activation of proinflammatory transcription factors (nuclear factor KB [NF-kappaB]) with up-regulation of adhesion molecules on sinusoidal endothelial cells and hepatocytes. However, if galactosamine (Gal) is co-administered with ET, neutrophils transmigrate and attack parenchymal cells. This suggests that a signal from parenchymal cells triggers neutrophil transmigration. In this study, we tested the hypothesis that parenchymal cell apoptosis may induce neutrophil transendothelial migration in the Gal/ET model. Treatment of C3Heb/FeJ mice with 700 mg/kg Gal and 100 microg/kg ET induced tumor necrosis factor alpha (TNF-alpha) formation (13.25 +/- 0.75 ng/mL) and hepatic NF-kappaB activation at 90 minutes; the generation of the C-X-C chemokine KC (2.86 +/- 0.30 ng/mL at 5 hours); sinusoidal neutrophil sequestration (380 +/- 21 polymorphonuclear leukocytes/50 high-power fields) and apoptosis (925% +/- 29% increase of DNA fragmentation; and a 45-fold increase of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells) at 6 hours, followed by transmigration of neutrophils and development of substantial necrosis (38% +/- 3% of hepatocytes; alanine transaminase [ALT]: 1,500 +/- 300 U/L) at 7 hours. Administration of uridine (1,000 mg/kg) did not reduce plasma levels of TNF-alpha and KC, NF-kappaB activation, or polymorphonuclear leukocyte sequestration, but attenuated apoptosis by 90% to 94%. In these livers, neutrophils did not transmigrate and liver injury was prevented (necrosis: < 5%; ALT: 40 +/- 3 U/L). However, massive apoptosis and liver injury initiated by the anti-Fas antibody, Jo2, did not recruit neutrophils into the liver. We conclude that excessive parenchymal cell apoptosis represents an important signal for transmigration of primed neutrophils sequestered in sinusoids during endotoxemia in vivo. However, apoptosis per se does not cause neutrophil sequestration in the liver vasculature.

The effect of the free radical scavenger dimethyl sulfoxide (DMSO) on activation of the nuclear transcription factor kappa B (NF-kappa B) was investigated in an experimental model of endotoxin-induced liver failure. In galactosamine-sensitized C3Heb/FeJ mice, DMSO (10 mL/kg) effectively inhibited endotoxin-induced hepatic NF-kappa B activation, suppressed TNF-alpha levels in plasma by 86%, attenuated intercellular adhesion molecule-1 (ICAM-1) mRNA formation, blocked hepatic neutrophil accumulation by 79%, and reduced liver injury by 80%. In galactosamine-sensitized mice treated with 20 micrograms/kg murine TNF-alpha, DMSO moderately reduced hepatic NF-kappa B and decreased ICAM-1 mRNA formation and liver injury by 83%, but had no significant effect on hepatic neutrophil accumulation. Thus, DMSO was able to inhibit, at least in part, two critical NF-kappa B-dependent steps in the pathophysiology, i.e., TNF-alpha formation and ICAM-1 gene transcription. Our data suggest the involvement of redox-sensitive events in the signal transduction pathway of NF-kappa B activation in the liver. Inhibition of NF-kappa B activation correlates with the reduced activation of proinflammatory genes in vivo and the subsequent attenuation of inflammatory liver injury. Thus, antioxidants that are NF-kappa B inhibitors may have therapeutic potential in endotoxin shock and sepsis.

Basement membrane–degrading metalloproteinases (gelatinases) appear necessary for vascular smooth muscle cell migration and proliferation in culture and for intimal migration of cells after balloon injury to the rat carotid artery. We investigated in the present study the secretion of gelatinases from pig carotid artery tissue after balloon injury. Segments of injured artery and segments proximal and distal to the area of injury were removed 3, 7, and 21 days after balloon dilatation. Medial explants from these segments were then cultured for 3 days, and the serum-free conditioned media were subjected to gelatin zymography. Production of 72- and 95-kD gelatinases was quantified by densitometry. Balloon-injured segments secreted significantly more 72- and 95-kD gelatinase than did paired distal segments at all time points. Release of both gelatinase activities was increased at 3 and 7 days relative to segments from uninjured arteries but declined again by 21 days after balloon injury. Similar results were found for gelatinase levels in extracts of arterial tissue. Consistent with the protein secretion data, in situ hybridization demonstrated that the mRNAs for both gelatinases were upregulated after balloon injury. Expression was prominent in medial smooth muscle cells, particularly around foci of necrosis, and in neointimal cells 3 and 7 days after balloon injury; 72-kD gelatinase mRNA persisted after 21 days and was prominent in regrown endothelial cells. The upregulation of gelatinase activity paralleled the time course of smooth muscle cell migration and proliferation in this model. We conclude that increased gelatinase production occurs in response to balloon injury and may play a role in permitting migration and proliferation of vascular smooth muscle cells.

The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mg/kg Salmonella enteritidis endotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50% hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate superoxide by 65% and attenuated liver injury by 73% at 4 h and 58-69% at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11/CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90-95% at 24 h. The antioxidant Trolox and the iron-chelator deferoxamine attenuated liver injury by 71 and 80%, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis.

The association of diet with low density lipoprotein cholesterol (LDL-C) and total triglycerides, as well as with total and very low density lipoprotein cholesterol (VLDL-C), was investigated in a random sample of 4374 white participants aged 20 to 59 years seen by the Lipid Research Clinic Prevalence Study. Carbohydrate and total calories were negatively associated with LDL-C. There was also a statistically significant positive association of LDL-C with the percentage of total calories from fat. These three findings are generally consistent with what other cross-sectional studies have reported for the relation of diet with total cholesterol levels. The only diet variables significantly related to triglyceride levels in both men and women were the percentage of calories from fats, particularly polyunsaturated fatty acids (PFA), the P/S ratio, and the number of grams of PFA per day, all of which were inversely associated with the level of this lipid.