Access to innovative therapies in pediatric oncology: Report of the nationwide experience in Canada.

BACKGROUND: The need for new therapies to improve survival and outcomes in pediatric oncology along with the lack of approval and accessible clinical trials has led to "out-of-trial" use of innovative therapies. We conducted a retrospective analysis of requests for innovative anticancer therapy in Canadian pediatric oncology tertiary centers for patients less than 30 years old between 2013 and 2020. METHODS: Innovative therapies were defined as cancer-directed drugs used (a) off-label, (b) unlicensed drugs being used outside the context of a clinical trial, or (c) approved drugs with limited evidence in pediatrics. We excluded cytotoxic chemotherapy, cellular products, and cytokines. RESULTS: We retrieved data on 352 innovative therapy drug requests. Underlying diagnosis was primary CNS tumor 31%; extracranial solid tumor 37%, leukemia/lymphoma 22%, LCH 2%, and plexiform neurofibroma 6%. RAS/MAP kinase pathway inhibitors were the most frequently requested innovative therapies in 28% of all requests followed by multi-targeted tyrosine kinase inhibitors (17%), inhibitors of the PIK3CA-mTOR-AKT pathway (8%), immune checkpoints inhibitors (8%), and antibody drug conjugates (8%). In 112 out of 352 requests, innovative therapies were used in combination with another anticancer agent. 48% of requests were motivated by the presence of an actionable molecular target. Compassionate access accounted for 52% of all requests while public insurance was used in 27%. Mechanisms of funding varied between provinces. CONCLUSION: This real-world data collection illustrates an increasing use of "out-of-trial" innovative therapies in pediatric oncology. This new field of practice warrants further studies to understand the impact on patient trajectory and equity in access to innovative therapies.

Magnetization transfer saturation reveals subclinical optic nerve injury in pediatric-onset multiple sclerosis.

BACKGROUND: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON. OBJECTIVE: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity. METHODS: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models. RESULTS: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p = 0.0023), and in both in the ON (-0.62 nU, p < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p = 0.00071), with these being positively correlated (+0.57 nU, p = 0.00037). CONCLUSIONS: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Physical Activity and Sedentary Behavior Patterns Across Weekdays and Weekend Days in Youth With Multiple Sclerosis and Controls.

Background: This study quantified and compared weekday and weekend patterns of device-measured physical activity (PA) and sedentary behavior between youth with pediatric multiple sclerosis (MS) and controls for the purpose of informing future PA behavior change interventions. Methods: Participant data were obtained from 3 ongoing observational studies, and the sample included 40 participants with pediatric MS and 41 controls. Light PA (LPA), moderate to vigorous PA (MVPA), and sedentary behavior data were collected using activity monitors (ActiGraph LLC) over 1 week. The main analysis involved a 2-way mixed factor analysis of variance with group as a between-subjects factor (pediatric MS vs control) and day as a within-subjects factor (weekday vs weekend day). Results: There was no group by day interaction from the analysis of variance for percentage of activity monitor wear time spent in LPA, MVPA, or sedentary behavior. There was no effect of group for LPA, MVPA, or sedentary behavior. There was an effect of day of week on percentage of day spent in LPA, MVPA, and sedentary behavior. Conclusions: These results suggest that youth with pediatric MS and controls were less physically active and more sedentary on weekends than on weekdays, but there were no differences between groups in PA and sedentary behavior overall or by day of the week. Physical activity interventions may be more successful by initially targeting weekend day activity.

Progressive retinal changes in pediatric multiple sclerosis.

Objectives To determine to what extent acute demyelinating episodes versus chronic degenerative phenomena drive retinal neuroaxonal damage in pediatric acquired demyelinating syndromes (ADS). Methods We acquired optical coherence tomography (OCT) data (follow-up range: 2 weeks - 5 years, at variable intervals from presentation) in pediatric participants who had multiple sclerosis (MS), monophasic ADS, or were healthy. Multivariable mixed effects models were used to assess the association of the number of demyelinating episodes (either optic neuritis [ON], or non-ON relapses) with changes in retinal nerve fiber layer (RNFL) or ganglion cell layer-inner plexiform layer (GCIPL) thickness. Results 64 OCT sans from 23 MS, and 33 scans from 12 monophasic ADS participants were compared with 68 scans from 62 healthy participants. The first ON episode had the biggest impact on RNFL or GCIPL thickness in monophasic ADS (RNFL: -7.9 µm, CI=5.5, p = 0.0056; GCIPL: -8.4 µm, CI=4.4, p = 0.0002) and MS (RNFL: -16 µm, CI = 3.7, p < 10-6; GCIPL: -15 µm, CI = 2.6, p < 10-6). Non-ON relapses were also associated with small but significant retinal thickness reductions in MS (RNFL: -2.6 µm/relapse, CI = 1.4, p = 0.0003; GCIPL: -2.8 µm/relapse, CI = 0.89, p < 10-6). MS participants showed progressive GCIPL thinning independent of acute demyelinating episodes (-2.7 µm/year, CI = 1.9, p = 0.0058). Conclusions We showed a prominent impact of early ON episodes on OCT measures of neuroaxonal structure in patients with ADS. We also demonstrated negative effects of non-ON relapses, and the presence of chronic retinal neurodegenerative changes, in youth with MS.

CanDIG: Federated network across Canada for multi-omic and health data discovery and analysis.

We present the Canadian Distributed Infrastructure for Genomics (CanDIG) platform, which enables federated querying and analysis of human genomics and linked biomedical data. CanDIG leverages the standards and frameworks of the Global Alliance for Genomics and Health (GA4GH) and currently hosts data for five pan-Canadian projects. We describe CanDIG's key design decisions and features as a guide for other federated data systems.

Rituximab in children with myelin oligodendrocyte glycoprotein antibody and relapsing neuroinflammatory disease.

The aim of this study was to evaluate tolerability of and response to rituximab in children with myelin oligodendrocyte glycoprotein (MOG) antibody-positive relapsing neuroinflammatory disease. This was an observational study of prospectively collected data on 12 consecutive children (eight females, four males; median age at onset 10y 6mo [interquartile range {IQR} 7y 2mo-12y 5mo], median follow-up 2y 1mo [IQR 1y 7mo-2y 6mo]) with central nervous system inflammation and persistent serum MOG immunoglobulin G positivity more than 12 weeks after clinical presentation. Patients received a standardized rituximab treatment protocol. MOG antibody testing was performed following standardized cell-based methods. Median clinical follow-up after rituximab induction was 2 years (IQR 1y 7mo-2y 10mo). The relapse rate in the first 12 months posttreatment was 0 (IQR 0-0). After rituximab, two patients relapsed during B-cell suppression and four showed clinical or radiological disease recurrences at B-cell reconstitution. Mild-to-moderate infusion related adverse events occurred in two patients. Leukopenia developed in seven patients and serum immunoglobulin suppression in five patients with no significant age effect on the risk of their development. None developed severe life-threatening events. Rituximab-induced B-cell suppression was associated with absence of relapses in 10 patients who were MOG-positive with recurrent disease. Rituximab was well tolerated. The most frequent adverse effects were hypogammaglobulinemia and leukopenia. We recommend monitoring of complete blood counts and immunoglobulins in this population. WHAT THIS PAPER ADDS: Rituximab appears to control disease in most anti-myelin oligodendrocyte glycoprotein-positive patients with relapsing neuroinflammatory disease. Rituximab was associated with transitory, mild-to-moderate infusion-related effects. Half of patients treated with rituximab developed leukopenia or hypogammaglobulinemia. No opportunistic infections were observed.

Early neuroaxonal injury is seen in the acute phase of pediatric optic neuritis.

BACKGROUND: Thinning of the retinal nerve fiber layer (RNFL) and ganglion cell/inner plexiform layer (GCIPL) occur in the chronic phase after optic neuritis (ON) in children and reflect neuroaxonal injury. The objective of this study was to describe changes in RNFL and GCIPL thickness in the acute phase following pediatric ON. METHODS: Data were collected prospectively from consecutive children presenting with ON as part of an incident acquired demyelinating event. Children with a final diagnosis of multiple sclerosis (n = 9, 10 ON-affected eyes) or monophasic demyelination (n = 16, 25 ON-affected eyes) who underwent spectral-domain optical coherence tomography (OCT) testing within 30 days of symptom onset were included. Standardized visual assessment was performed at presentation and 6-18 months follow-up. OCT measures were compared to those of healthy controls (n = 25, 50 eyes). RESULTS: Median (interquartile range [IQR]) global RNFL thickness was increased in ON-affected eyes (155 µm [114-199 µm]) compared to control eyes (104 µm [98.5-107.5 µm]; p < 0.0001). Compared to controls, fellow eyes demonstrated a reduced temporal quadrant RNFL thickness (59 µm [53-72 µm] versus 71.5 µm [65-81 µm]; p = 0.013) and lower GCIPL thickness (80.5 µm [74-88 µm] versus 87 µm [85-89 µm]; p = 0.003). The ON-affected eyes of children with monophasic demyelination demonstrated a greater global RNFL thickness (183.5 µm [146.5-206 µm]) compared to the ON-affected eyes of children with multiple sclerosis (108.5 µm [95-124 µm]; p = 0.01). OCT measures at presentation did not predict low-contrast visual acuity nor color vision at 6-18 months follow-up. CONCLUSION: Children with multiple sclerosis show less RNFL swelling in their ON-affected eyes at onset compared to children with monophasic demyelination. Lower GCIPL and temporal RNFL thickness in the clinically unaffected eyes of those children with unilateral ON suggests the presence of pre-existing neuroaxonal injury in children presenting with a first episode of ON. This finding may be driven by the subset of children with multiple sclerosis.

Benefits of Physical Activity for Depression and Fatigue in Multiple Sclerosis: A Longitudinal Analysis.

OBJECTIVES: To examine the longitudinal relationship between physical activity and fatigue and depression among youth with demyelinating conditions. STUDY DESIGN: From September 2013 to March 2017, we performed a longitudinal study of consecutive youth diagnosed at their first visit with pediatric onset multiple sclerosis (POMS) or monophasic acquired demyelinating syndromes (mono-ADS) at a neuroinflammatory disorders clinic in a tertiary children's hospital. Fatigue was determined at each visit by the Pediatric Quality of Life Multidimensional Fatigue Scale, depressive symptoms by the Center of Epidemiologic Studies Depression Children Rating Scale, and physical activity level by the Godin Leisure Time Exercise Questionnaire. Mixed linear models were used to examine the associations of moderate-to-vigorous physical activity (MVPA) with fatigue and depression over time, adjusting for age, time from incident demyelination, sex, number of relapses, relapse within 30 days, and disability. RESULTS: In 182 patients (48 POMS, age 15 ± 1.7 years, 35 female; and 134 mono-ADS, age 12 ± 3.6 years 67 female) with 538 visits (mean follow-up 3.6 ± 2.7 years and 4.2 ± 3.3 years, respectively), a trajectory of increased fatigue over time was observed in POMS (2.28 points/year, P = .008) and mono-ADS (1.33 points/year, P = .007) patients. Youth with POMS had more depressive symptoms (estimate = 11.4 points, P < .002) than mono-ADS. Depressive symptoms increased over time in female patients with POMS (estimate = 1.4 points/year, P < .02). MVPA was associated with lower depression (-0.09, P < .001) and general fatigue (0.13, P = .02) over time in POMS. CONCLUSIONS: Youth with POMS who have higher levels of MVPA demonstrate lesser depressive symptoms and lower fatigue over time. Our results may inform future interventions to manage mood and fatigue in POMS.

Adherence in Youth With Multiple Sclerosis: A Qualitative Assessment of Habit Formation, Barriers, and Facilitators.

Rates of medication nonadherence in youth with multiple sclerosis (MS) range from 10% to 60%. Qualitative studies of adherence can provide insight into children's own perspectives about barriers and facilitators to their adherence and inform future interventions. This qualitative longitudinal descriptive study included children with MS ( n = 28) participating in a randomized controlled trial focused on medication adherence ( clinicaltrials.gov : NCT02234713). Following established methods, three independent reviewers coded transcripts of motivational interviewing (MI) sessions (three interviews per subject, performed monthly over a 3-month period) for relevant themes. They were subsequently categorized using inductive content analysis. Youth described medication adherence as being dependent on the ability to build and maintain healthy habits related to medication use, including embodiment of these habits. Barriers and facilitators included remembering/forgetting, experiences with fatigue, and experiences with medication. These themes were maintained through the second and third interviews. Future research focus on barriers and facilitators to habit maintenance in this population.

Physical activity and dentate gyrus volume in pediatric acquired demyelinating syndromes.

OBJECTIVE: To assess the association between daily moderate-to-vigorous physical activity (MVPA) and dentate gyrus volume (DGv) in pediatric patients with acquired demyelinating syndromes (ADSs) of the CNS. METHODS: Cross-sectional analysis of accelerometry (7 days) and research protocol MRI data from 12 pediatric MS and 18 children with monophasic ADS (monoADS). Total brain and DGv were quantified using standardized methods. The association of daily minutes of MVPA with normalized DGv (nDGv) was assessed using multivariable generalized linear models. RESULTS: Median (interquartile range) MVPA was lower in MS patients [9.5 (14)] and exhibited less variation than in monoADS patients [24.5 (47)]. nDGv did not differ significantly between groups [mean nDGv (SD) [cm3]: MS 0.34 (0.1); monoADS 0.4 (0.1); p = 0.100]. In the monoADS group, every 1-minute increase in MVPA was associated with a 2.4-mm3 increase in nDGv (p = 0.0017), an association that was independent of age at incident demyelination, time from incident demyelination, sex, and brain white matter T2 lesion volume. No significant association was found between MVPA and nDGv (-2.6 mm3/min, p = 0.16) in the MS group. CONCLUSIONS: Higher MVPA associates with greater nDGv in children who have recovered from monophasic demyelination. Larger studies are required to determine whether MVPA can promote regional brain development, or limit tissue damage, in youth with MS.

Evaluation of an Ophthalmoscopy Simulator to Teach Funduscopy Skills to Pediatric Residents.

BACKGROUND: Medical school and residency training in ophthalmoscopic evaluation is limited, reducing diagnostic accuracy. We sought to evaluate the efficacy of self-study using an ophthalmoscopy simulator to improve the technical motor skills involved in direct funduscopy in postgraduate pediatric residents. METHODS: In this randomized-controlled study, 17 pediatric residents (postgraduate years 1-3) were randomized to control (n=8) or intervention (n=9) groups. Participants were asked to correctly identify the funduscopic findings presented to them on an ophthalmoscopy simulator after being trained on its use. Each participant was asked to review 20 images of the fundus, and then record their multiple-choice response on a scantron sheet listing all possible funduscopic pathologies. Pre- and post-intervention testing was performed. Survey data assessing exposure to funduscopy skills during undergraduate and postgraduate training and overall experience with the simulator were collected. RESULTS: Most (65% [11/17]) participants reported minimal or no formal teaching in ophthalmology during their undergraduate medical studies. Average pre-intervention score (of 20) was 10.24±1.75 (51%) for the entire group, with no statistically significant difference between average pre-score in the control (10.63±1.77) versus intervention (9.89±1.76, p=0.405) groups. Intervention subjects experienced a statistically significant improvement in scores (9.89±1.76 vs. 12.78±2.05, p=0.006 [95% confidence interval 4.80-0.98]), but control subjects did not. CONCLUSIONS: A single session with an ophthalmoscopy simulator can improve diagnostic accuracy in postgraduate pediatric trainees. Use of ophthalmoscopy simulation represents a novel addition to traditional learning methods for postgraduate pediatric residents that can help trainees to improve their confidence and accuracy in performing this challenging examination.

Correction to: Impact of an electronic monitoring device and behavioural feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial.

The clinicaltrials.gov identifying number for the article titled "Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial" is NCT02234713 (https://clinicaltrials.gov/ct2/show/NCT02234713).

Risk factors for non-adherence to disease-modifying therapy in pediatric multiple sclerosis.

BACKGROUND: Adherence to disease-modifying therapies (DMTs) in pediatric multiple sclerosis (MS) is not well understood. We examined the prevalence and risk factors for poor adherence in pediatric MS. METHODS: This cross-sectional study recruited youth with MS from 12 North American pediatric MS clinics. In addition to pharmacy-refill data, patients and parents completed self-report measures of adherence and quality of life. Additionally, patients completed measures of self-efficacy and well-being. Factor analysis and linear regression methods were used. RESULTS: A total of 66 youth (mean age, 15.7 years) received MS DMTs (33% oral, 66% injectable). Estimates of poor adherence (i.e. missing >20% of doses) varied by source: pharmacy 7%, parent 14%, and patient 41%. Factor analysis yielded two composites: adherence summary and parental involvement in adherence. Regressions revealed that patients with better self-reported physical functioning were more adherent. Parents were more likely to be involved in adherence when their child had worse parent-reported PedsQL School Functioning and lower MS Self-Efficacy Control. Oral DMTs were associated with lesser parental involvement in adherence. CONCLUSION: Rates of non-adherence varied by information source. Better self-reported physical functioning was the strongest predictor of adherence. Parental involvement in adherence was associated with worse PedsQL School Functioning and lower MS Self-Efficacy-measured confidence in controlling MS.

Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial.

PURPOSE: To report the results of a randomized controlled trial using an electronic monitoring device (EM) plus a motivational interviewing (MI) intervention to enhance adherence to disease-modifying therapies (DMT) in pediatric MS. METHODS: Fifty-two youth with MS (16.03 ± 2.2 years) were randomized to receive either MI (n = 25) (target intervention) or a MS medication video (n = 27) (attention control). Primary endpoint was change in adherence. Secondary outcomes included changes in quality of life, well-being and self-efficacy. Random effects modeling and Cohen's effect size computation evaluated intervention impact. RESULTS: Longitudinal random effect models revealed that the MI group decreased their EM adherence (GroupxTime interaction = -0.19), while increasing frequency of parental DMT reminder (26.01)/administration (11.69). We found decreased EM use in the MI group at 6 months (Cohen's d = -0.61), but increased pharmacy refill adherence (d = 0.23). Parental reminders about medication increased in MI subjects vs controls (d = 0.59 at 3 months; d = 0.70 at 6 months). We found increases in self-reported adherence (d = 0.21) at 3 but not 6 months, fewer barriers to adherence at three (d = -0.58) and six months (d = -0.31), better physical (d = 0.23 at 3 months; d = 0.45 at 6 months), emotional (d = 0.25 at 3 months) and self-efficacy function (d = 0.55 at 3 months; 0.48 at 6 months), but worse well-being, including self-acceptance (d = -0.53 at 6 months) and environmental mastery (d = -0.42 at 3 and 6 months) in intervention as compared to control patients. CONCLUSIONS: Participants receiving MI + EM experienced worsening on objective measures of adherence and increased parental involvement, but improved on some self- and parent-reported measures. MI participants reported improvements in quality of life and self-efficacy, but worsened well-being.

Interferon-Stimulated Gene Expression as a Preferred Biomarker for Disease Activity in Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome (AGS) is an early-onset, genetic disease characterized by recurrent fever, multifocal lesions of the brain, and systemic autoimmunity. We report on 3 AGS patients, 2 siblings with an RNASEH2A gene mutation and 1 patient with a SAMHD1 gene mutation. Serial analysis of peripheral blood from all 3 AGS patients showed consistently elevated expression of the interferon-stimulated genes (ISGs): ISG15, RSAD2, and IFI27, not observed in unaffected family members. Enumeration of circulating white blood cells and platelets and examination of C-reactive protein showed no significant deviation from the normal range for Patient 2 with the RNASEH2A mutation and Patient 3 with the SAMHD1 mutation, even when Patient 2 had magnetic resonance imaging abnormalities and ongoing febrile episodes. Erythrocyte sedimentation rates fluctuated within the normal range for Patient 2, with some elevation, yet, were in the normal range during the second febrile episode when there were accompanying neurological abnormalities. These preliminary data suggest that ISG expression may be a more specific indicator of disease activity in comparison to standard inflammatory markers.

Physical activity in pediatric onset multiple sclerosis: Validating a questionnaire for clinical practice and research.

BACKGROUND: Knowledge regarding physical activity (PA) and its benefits in pediatric onset multiple sclerosis (POMS) is growing and suggests high levels of inactivity. The utility of a validated screening tool for clinical settings is unknown. This study evaluated the Godin Leisure-Time Exercise Questionnaire (GLTEQ) as a measure of PA in POMS. METHODS: POMS patients (n=27) and healthy controls (n=45) wore an accelerometer over a 7-day period and then completed the GLTEQ. RESULTS: The GLTEQ captured expected group differences in PA for vigorous, moderate, and moderate-to-vigorous physical activity (MVPA), confirmed by accelerometry. There was a large, positive correlation between GLTEQ and accelerometry scores for vigorous PA in POMS (r=0.736, p=0.001), and a nearly significant and moderate, positive correlation between MVPA scores (r=0.319, p=.053). CONCLUSION: We provide evidence that supports the validity of GLTEQ scores as measures of vigorous and MVPA in POMS. Researchers and clinicians might adopt this scale for measuring PA.

Physical Activity and Its Correlates in Youth with Multiple Sclerosis.

OBJECTIVES: To investigate physical activity levels in youth with multiple sclerosis and monophasic acquired demyelinating syndromes ([mono-ADS], ie, children without relapsing disease) compared with healthy controls and to determine factors that contribute to engagement in physical activity. We hypothesized that greater physical activity goal setting and physical activity self-efficacy would be associated with greater levels of vigorous physical activity in youth with multiple sclerosis. STUDY DESIGN: A total of 68 consecutive patients (27 multiple sclerosis, 41 mono-ADS) and 37 healthy controls completed fatigue, depression, Physical Activity Self-Efficacy Scale, perceived disability, Exercise Goal-Setting scale, and physical activity questionnaires, and wore an accelerometer for 7 days. All patients had no ambulatory limitations (Expanded Disability Status Scale, scores all <4). RESULTS: Youth with multiple sclerosis engaged in fewer minutes per day of vigorous (P = .009) and moderate and vigorous physical activity (P = .048) than did patients with mono-ADS and healthy controls. A lower proportion of the group with multiple sclerosis (63%) reported participating in any strenuous physical activity than the mono-ADS (85%) and healthy control (89%) groups (P = .020). When we adjusted for age and sex, the Physical Activity Self-Efficacy Scale and Exercise Goal-Setting scale were associated positively with vigorous physical activity in the group with multiple sclerosis. Fatigue and depression did not predict physical activity or accelerometry metrics. CONCLUSIONS: Youth with multiple sclerosis participate in less physical activity than their counterparts with mono-ADS and healthy controls. Physical activity self-efficacy and exercise goal setting serve as potentially modifiable correlates of physical activity, and are measures suited to future interventions aimed to increase physical activity in youth with multiple sclerosis.

Physical activity and pediatric multiple sclerosis: Developing a research agenda.

Three-quarters of children with multiple sclerosis (MS) experience fatigue or depression, and progressive neurocognitive decline may be seen as early as two years after MS diagnosis. Furthermore, a higher magnetic resonance imaging disease burden is seen in pediatric-onset MS compared with adult-onset MS. To date, limited knowledge exists regarding behavioral methods for managing symptoms and disease progression in pediatric MS. To that end, this paper builds an evidence-based argument for the possible symptomatic and disease-modifying effects of exercise and physical activity in pediatric MS. This will be accomplished through: (a) a review of pediatric MS and its consequences; (b) a brief overview of physical activity and its consequences in children and adults with MS; and (c) a selective review of research on the neurological benefits of physical activity in pediatric populations. This topical review concludes with a list of 10 questions to guide future research on physical activity and pediatric MS. The objective of this paper is the provision of a research interest, focus and agenda involving pediatric MS and its lifelong management though exercise and physical activity behavior. Such an agenda is critical as the effects and maintenance of physical activity and exercise track across the lifespan, particularly when developed in the early stages of life.

Lower physical activity is associated with higher disease burden in pediatric multiple sclerosis.

OBJECTIVE: To evaluate the association between physical activity (PA) and multiple sclerosis (MS) disease activity, depression, and fatigue in a cohort of children with MS and monophasic acquired demyelinating syndrome (mono-ADS). METHODS: In this cross-sectional study of consecutive patients attending a specialized pediatric MS clinic, we administered the PedsQL Multidimensional Fatigue Scale, Center for Epidemiological Studies Depression Scale, and Godin Leisure-Time Exercise Questionnaire. Quantitative MRI analysis was performed to obtain whole brain and T2 lesion volume in a subset of participants (n = 60). RESULTS: A total of 110 patients (79 mono-ADS; 31 MS; 5-18 years; M:F 1:1.2) were included. Patients with MS reported less strenuous (33.21 ± 31.88 metabolic equivalents [METs] vs 15.97 ± 22.73 METs, p = 0.002) and total (44.48 ± 39.35 METs vs 67.28 ± 59.65 METs; p = 0.0291) PA than those with mono-ADS. Patients with MS who reported greater amounts of moderate PA METs had fewer sleep/rest fatigue symptoms (r = -0.4). Participation in strenuous PA was associated with smaller T2 lesion volumes (r = -0.66) and lower annualized relapse rate (r = -0.66). No associations were found between total brain volume and participation in PA. CONCLUSIONS: Children with MS are less physically active than children with mono-ADS. Reasons for this are unclear, but may be related to ongoing disease activity, perceived limitations, or symptoms such as depression or fatigue. Children with MS reporting higher levels of strenuous PA had lower T2 lesion volumes and lower relapse rates, suggesting a potential protective effect of strenuous PA in this population. Further longitudinal studies are needed to establish the relationship of PA to MS symptoms and disease activity in this population.

Understanding early organogenesis using a simplified in situ hybridization protocol in Xenopus.

Organogenesis is the study of how organs are specified and then acquire their specific shape and functions during development. The Xenopuslaevis embryo is very useful for studying organogenesis because their large size makes them very suitable for identifying organs at the earliest steps in organogenesis. At this time, the primary method used for identifying a specific organ or primordium is whole mount in situ hybridization with labeled antisense RNA probes specific to a gene that is expressed in the organ of interest. In addition, it is relatively easy to manipulate genes or signaling pathways in Xenopus and in situ hybridization allows one to then assay for changes in the presence or morphology of a target organ. Whole mount in situ hybridization is a multi-day protocol with many steps involved. Here we provide a simplified protocol with reduced numbers of steps and reagents used that works well for routine assays. In situ hybridization robots have greatly facilitated the process and we detail how and when we utilize that technology in the process. Once an in situ hybridization is complete, capturing the best image of the result can be frustrating. We provide advice on how to optimize imaging of in situ hybridization results. Although the protocol describes assessing organogenesis in Xenopus laevis, the same basic protocol can almost certainly be adapted to Xenopus tropicalis and other model systems.