Faculty Bibliography

AIM/OBJECTIVE:To assess the accuracy of consumer available wrist-based and hip-based activity trackers in quantitatively measuring ambulation in children with cerebral palsy (CP). METHOD/METHODS:Thirty-nine children (23 males, 16 females; mean age [SD] 9y 7mo [3y 5mo]; range 4-15y) with CP were fitted with trackers both on their wrist and hip. Each participant stood for 3 minutes, ambulated in a hallway, and sat for 3 minutes. The number of steps and distance were recorded on trackers and compared to manually counted steps and distance. Pearson correlation coefficients were determined for the number of steps during ambulation from each tracker and a manual count. Mean absolute error (MAE) and range of errors were calculated for steps during ambulation for each tracker and a manual count and for distance for each tracker and hallway distance. RESULTS:For the number of steps, a weak inverse relationship (r=-0.033) was found for the wrist-based tracker and a strong positive relationship (r=0.991) for the hip-based tracker. The MAE was 88 steps for the wrist-based and seven steps for the hip-based tracker. The MAE for distance was 0.06 miles for the wrist-based and 0.07 miles for the hip-based tracker. INTERPRETATION/CONCLUSIONS:Only the hip-based tracker provided an accurate step count; neither tracker was accurate for distance. Thus, ambulation of children with CP can be accurately quantified with readily available trackers.

BACKGROUND:We aim to describe and psychometrically validate the Rett Syndrome Motor Evaluation Scale, a 25-item ordinal scale examining (loco-)motor function across six sections: standing, sitting, transitions, walking, running, and walking up or downstairs. METHODS:We illustrate the process of item construction and validation, report findings and normative data obtained on a standardization sample of 60 patients with Rett syndrome. We investigate the validity and reliability of the scale and illustrate its psychometric properties using modern multivariate techniques of data analysis. RESULTS:Sixty patients with Rett syndrome were included (all female; mean age 12.45 (S.D. 8.75) years). The multidimensional latent structure of the scale was supported by the results of the confirmatory factor analysis. Rett Syndrome Motor Evaluation Scale showed strong internal consistency reliability as well as excellent inter-rater agreement. The Rett Syndrome Motor Evaluation Scale scores were not predicted by age, but were associated with disease severity, degree of spasticity, and hand dysfunction. We also identified three latent classes with different degrees of impairment. CONCLUSIONS:Rett Syndrome Motor Evaluation Scale is a new, valid, and reliable scale that can be introduced in clinical practice when assessing (loco-)motor function in Rett syndrome.

BACKGROUND:Less than 25% of stroke patients arrive to an emergency department within the 3-hour treatment window. OBJECTIVE:We evaluated the cost-effectiveness of a stroke preparedness behavioral intervention study (Stroke Warning Information and Faster Treatment [SWIFT]), a stroke intervention demonstrating capacity to decrease race-ethnic disparities in ED arrival times. METHODS:Using the literature and SWIFT outcomes for 2 interventions, enhanced educational (EE) materials, and interactive intervention (II), we assess the cost-effectiveness of SWIFT in 2 ways: (1) Markov model, and (2) cost-to-outcome ratio. The Markov model primary outcome was the cost per quality-adjusted life-year (QALY) gained using the cost-effectiveness threshold of $100 000/QALY. The primary cost-to-outcome endpoint was cost per additional patient with ED arrival <3 hours, stroke knowledge, and preparedness capacity. We assessed the ICER of II and EE versus standard care (SC) from a health sector and societal perspective using 2015 USD, a time horizon of 5 years, and a discount rate of 3%. RESULTS:The cost-effectiveness of the II and EE programs was, respectively, $227.35 and $74.63 per additional arrival <3 hours, $440.72 and $334.09 per additional person with stroke knowledge proficiency, and $655.70 and $811.77 per additional person with preparedness capacity. Using a societal perspective, the ICER for EE versus SC was $84 643 per QALY gained and the ICER for II versus EE was $59 058 per QALY gained. Incorporating fixed costs, EE and II would need to administered to 507 and 1693 or more patients, respectively, to achieve an ICER of $100 000/QALY. CONCLUSION/CONCLUSIONS:II was a cost-effective strategy compared with both EE and SC. Nevertheless, high initial fixed costs associated with II may limit its cost-effectiveness in settings with smaller patient populations.

OBJECTIVES/OBJECTIVE:The objective of this study was to compare safety and efficacy of patent foramen ovale (PFO) closure compared with medical therapy in patients with cryptogenic stroke (CS). BACKGROUND:The role of PFO closure in preventing recurrent stroke in patients with prior CS has been controversial. METHODS:We searched PubMed, EMBASE, the Cochrane Central Register of Controlled trials, and the clinical trial registry maintained at clinicaltrials.gov for randomized control trials that compared device closure with medical management and reported on subsequent stroke and adverse events. Event rates were compared using a forest plot of relative risk using a random-effects model assuming interstudy heterogeneity. RESULTS: = 27%, P = 0.002). The presence/absence of atrial septal aneurysm (P = 0.52) had no effect on the outcome. CONCLUSION/CONCLUSIONS:PFO closure is associated with a significant reduction in the risk of stroke compared to medical management. However, it causes an increased risk of atrial fibrillation.

BACKGROUND: There is no effective therapy for patients (pts) with IDH-mutant gliomas that progress after RT and chemotherapy. At time of progression, these tumors have often transformed to glioblastoma (GBM) and have increased numbers of somatic mutations, i.e. have a ?hypermutator phenotype?. We hypothesized that there is synergistic efficacy of Avelumab (anti-PD-L1) combined with HFRT in pts with secondarily trans- formed IDH-mutant GBMs. Safety-lead-in results will be presented.
METHOD(S): This is a phase II, open-label, single-arm, multicenter study of Avelumab with HFRT in adults with transformed IDH-mutant GBM who previously received RT and TMZ and/or PCV. All pts received Avelumab 10 mg/kg IV followed at Day 8 by HFRT (25 Gy in 5 daily 5-Gy fractions) and then Avelumab 10 mg/kg IV every 2 weeks. A 3 + 3 design was used for a 6-patient safety-lead-in cohort. Adverse events were recorded according to CTCAE.
RESULT(S): Six pts (F=4, M=2) with a median age= 45.5 yrs (range 31.5-54.4 yrs) were enrolled in the safety-lead-in cohort. No DLT was observed. Grade >= 3 AEs included increased cerebral edema (3 pts), hyponatremia (1 pt) and worsening hemiparesis (3 pts). Grade <= 2 AEs included nausea, hypothyroidism, lymphopenia, thrombocytopenia, transaminase elevation, and fever/chills. Median follow-up time was 8.9 mo. Best treatment response was SD in 1 patient. At time of last follow-up all pts have discontinued treatment for PD. Median PFS was 4.2 mo (range 1.4-5.7). Median OS was 10.1 (range 6.8-21+) mo. 4 pts (67%) died, 2 pts remain alive in follow-up at 6.9 and 21.6 months after treatment initiation. The study was closed after the safety lead-in completed enrollment due to slow accrual.
CONCLUSION(S): Avelumab combined with HFRT was tolerable without dose-limiting toxicity in this safety-lead-in cohort of adult patients with transformed IDH-mutant GBM. Further studies are necessary to determine efficacy of this treatment regimen

H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27Mmutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor's IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3-3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8-29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported

This paper updates guidelines for effective treatments of children with specific types of acquired brain injury (ABI) published in 2007 with more recent evidence. A systematic search was conducted for articles published from 2006 to 2017. Full manuscripts describing treatments of children (post-birth to 18) with acquired brain injury were included if study was published in peer-reviewed journals and written in English. Two independent reviewers and a third, if conflicts existed, evaluated the methodological quality of studies with an Individual Study Review Form and a Joanna Briggs Institute (JBI) Critical Appraisal Checklist. Strength of study characteristics was used in development of practice guidelines. Fifty-six peer-reviewed articles, including 27 Class I studies, were included in the final analysis. Established guidelines for writing practice recommendations were used and 22 practice recommendations were written with details of potential treatment limitations. There was strong evidence for family/caregiver-focused interventions, as well as direct interventions to improve attention, memory, executive functioning, and emotional/behavioural functioning. A majority of the practice standards and guidelines provided evidence for the use of technology in delivery of interventions, representing an important trend in the field.Abbreviations: ABI = acquired brain injury, ACRM = American Congress of Rehabilitation Medicine, ACT = Acceptance and Commitment Therapy, Amat-c = Amsterdam Memory and Attention Training for Children, BRIEF = Behaviour Rating Inventory of Executive Function, BRIEF-MI = The Behaviour Rating Inventory of Executive Function Metacognitive Index, CAPS = Counselor Assisted Problem-solving, CBT = cognitive behaviour therapy, COPM = Canadian Occupational Performance Measure, CO-OP = Cognitive Orientation to daily Occupational Performance, CRP = Cognitive Remediation Program, EBR = Evidence-Based Review, FPS = Family Problem-solving, IRC = Internet Resource Comparison, JBI = Joanna Briggs Institute, mTBI = mild traumatic brain injury, SSTP = Stepping Stones Triple P, SMART = Strategic Memory Advanced Reasoning Training, TBI = traumatic brain injury, TOPS = Teen Online Problem-solving, TOPS-TO = Teen Online Problem-solving-Teens Only, WM = Working Memory.

In rodents, waking firing patterns replay in NREM sleep during hippocampal sharpwave-ripples (HC-SWR), correlated with neocortical graphoelements (NC-GE). NC-GE include theta-bursts, spindles, downstates and upstates. In humans, consolidation during sleep is correlated with scalp-recorded spindles and down-upstates, but HC-SWR cannot be recorded non-invasively. Here we show in humans of both sexes that HC-SWR are highly correlated with NC-GE during NREM, with significantly more related HC-SWR/NC-GE for downstates or upstates than theta-bursts or spindles, in N2 than N3, in posterior than anterior HC, in frontal than occipital cortex, and ipsilaterally than contralaterally. The preferences interacted, e.g. frontal spindles co-occurred frequently with posterior HC-SWR in N2. These preferred GE, stages and locations for HC-SWR/NC-GE interactions may index selective consolidation activity, although that was not tested in this study. SWR recorded in different HC regions seldom co-occurred, and were related to GE in different cortical areas, showing that HC-NC interact in multiple transient, widespread but discrete, networks. NC-GE tend to occur with consistent temporal relationships to HC-SWR, and to each other. Cortical theta-bursts usually precede HC-SWR, where they may help define cortical input triggering HC-SWR firing. HC-SWR often follow cortical downstate onsets, surrounded by locally-decreased broadband power, suggesting a mechanism synchronizing cortical, thalamic and hippocampal activities. Widespread cortical upstates and spindles follow HC-SWR, consistent with the hypothesized contribution by hippocampal firing during HC-SWR to cortical firing-patterns during upstates and spindles. Overall, our results describe how hippocampal and cortical oscillations are coordinated in humans during events that are critical for memory consolidation in rodents.SIGNIFICANCE STATEMENTHippocampal sharpwave-ripples, essential for memory consolidation, mark when hippocampal neurons replay waking firing patterns. In rodents, cortical sleep waves coordinate the transfer of temporary hippocampal to permanent cortical memories, but their relationship with human HC-SWR remains unclear. We show that human hippocampal sharpwave-ripples co-occur with all varieties of cortical sleep waves, in all cortical regions, and in all stages of Non-REM sleep but with overall preferences for each of these. We found that sharpwave-ripples in different parts of the hippocampus usually occurred independently of each other, and preferentially interacted with different cortical areas. We found that sharpwave-ripples typically occur after certain types of cortical waves, and before others, suggesting how the cortico-hippocampo-cortical interaction may be organized in time and space.