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Background and ObjectivesRepresentation of persons from marginalized racial and ethnic groups in Parkinson disease (PD) trials has been low, limiting the generalizability of therapeutic options for individuals with PD. Two large phase 3 randomized clinical trials sponsored by the National Institute of Neurological Disorders and Stroke (NINDS), STEADY-PD III and SURE-PD3, screened participants from overlapping Parkinson Study Group clinical sites under similar eligibility criteria but differed in participation by underrepresented minorities. The goal of this research is to compare recruitment strategies of PD participants belonging to marginalized racial and ethnic groups.MethodsA total of 998 participants with identified race and ethnicity consented to STEADY-PD III and SURE-PD3 from 86 clinical sites. Demographics, clinical trial characteristics, and recruitment strategies were compared. NINDS imposed a minority recruitment mandate on STEADY-PD III but not SURE-PD3.ResultsTen percent of participants who consented to STEADY-PD III self-identified as belonging to marginalized racial and ethnic groups compared to 6.5% in SURE-PD3 (difference = 3.9%, 95% confidence interval [CI] 0.4%–7.5%,pvalue = 0.034). This difference persisted after screening (10.1% of patients in STEADY-PD III vs 5.4% in SURE-PD 3, difference = 4.7%, 95% CI 0.6%–8.8%,pvalue = 0.038).DiscussionAlthough both trials targeted similar participants, STEADY-PD III was able to consent and recruit a higher percentage of patients from racial and ethnic marginalized groups. Possible reasons include differential incentives for achieving minority recruitment goals.Trial Registration InformationThis study used data from The Safety, Tolerability, and Efficacy Assessment of Isradipine for Parkinson Disease (STEADY-PD III;NCT02168842) and the Study of Urate Elevation in Parkinson’s Disease (SURE-PD3;NCT02642393).

The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behaviour disorder is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151 to 560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Arterial blowout syndrome has mostly been described in carotid arteries and has been attributed to factors associated with head and neck neoplasia, radical resection, and a history of irradiation. Only sporadic cases have been described in other arteries. Herein we present a case of the femoral artery blowout syndrome, six months after radical surgery of the vulva and radiation therapy.

This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.

Background This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses. Objectives A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms. Methods Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated. Conclusions Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society.

Background: Subtle gait deficits can be seen in people with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD), a prodromal stage of Parkinson’s disease (PD) and related alpha-synucleinopathies. It is unknown if the presence and level of REM sleep without atonia (RSWA, the electromyographic hallmark of RBD) is related to the severity of gait disturbances in people with PD. Objective: We hypothesized that gait disturbances in people with mild-to-moderate PD would be greater in participants with RSWA compared to those without RSWA and matched controls, and that gait impairment would correlate with measures of RSWA. Methods: Spatiotemporal characteristics of gait were obtained from 41 people with PD and 21 age-matched controls. Overnight sleep studies were used to quantify muscle activity during REM sleep and group participants with PD into those with RSWA (PD-RSWA+, n = 22) and normal REM sleep muscle tone (PD-RSWA-, n = 19). Gait characteristics were compared between groups and correlated to RSWA. Results: The PD-RSWA+ group demonstrated significantly reduced gait speed and step lengths and increased stance and double support times compared to controls, and decreased speed and cadence and increased stride velocity variability compared to PD-RSWA- group. Larger RSWA scores were correlated with worse gait impairment in the PD group. Conclusion: The presence and level of muscle tone during REM sleep is associated with the severity of gait disturbances in PD. Pathophysiological processes contributing to disordered gait may occur earlier and/or progress more rapidly in people with PD and RBD.

We find ourselves at our present crossroads with a well-traveled toolkit, perhaps too well worn but with aspirational hopes and dreams for the field of sleep neurotherapeutics. This volume is organized thematically into six topical domains that parallel the major subspecialty areas of contemporary clinical sleep neurology practice, as well as novel directions and opportunities. The issue begins with an overview of the central disorders of hypersomnolence, including narcolepsy, idiopathic hypersomnia and other hypersomnia disorders, and the related use of the entire broad range of stimulant and wake-promoting pharmacotherapies. Next, the range of behavioral therapies, application of light and light restriction and melatonin therapies, and hypnotic pharmacotherapies useful in insomnia and circadian sleep–wake rhythm disorders are reviewed, followed by an overview of treatment options for sleep-related breathing disorders including positive airway pressure and the novel approach of hypoglossal neurostimulation for obstructive sleep apnea. The parasomnias and sleep-related movement disorders, including NREM disorders of arousal, REM parasomnias (nightmares and isolated sleep paralysis and idiopathic/isolated REM sleep behavior disorder, and restless legs syndrome are then discussed, and the applications of sleep neurotherapeutics in sleep and neurological disease are reviewed, including neurodevelopmental, epileptic, autoimmune encephalopathies, and neurodegenerative diseases. Last, the novel directions and opportunities in sleep neurology offered by cannabinoid therapies and machine learning/artificial intelligence methodology conclude this comprehensive survey of contemporary sleep neurology. We hope that you find this volume to be a useful and inspirational support tool for the work that matters most, your care of all our sleep neurology patients in the clinics. Supplementary Information The online version contains supplementary material available at 10.1007/s13311-021-01032-7.

This study is part of the Project PEERSolvers, which aims at conceptualization and designing an evidence-based intervention to promote young people’s capacities for constructive peer interaction and collaborative problem-solving. Previous research indicates that spontaneous peer interaction is often unproductive (Howe and Mercer, 2010). Thus, scholars (e.g. Dawes & Sams, 2004; Mercer et al., 2004; Wegerif & Scrimshaw, 1997) consider it is important to support young people to constructively participate in a dialogue during collaborative problem-solving. Although much is known about the process of peer dialogue (Howe & Abedin, 2013), the systematization of knowledge about characteristics of dialogue that make collaborative problem solving among peers productive or unproductive is lacking. Therefore, we will set out to determine such features in order to conceptualize the intervention model which will promote constructive dialogue and at the same time prevent the occurrence of undesirable ways of communication in teamwork. Furthermore, research findings suggest that adult scaffolding, especially teachers’ plays important role in building youngsters' capacities for constructive dialogue and that digital media could act as resources for effective collaborative problem-solving (e.g. Hathcock et al., 2015; Ratnasari et al., 2019; Sobko et al., 2020). Thus, we intend to systematically review the relevant body of literature not just to identify productive and unproductive dimensions of peer dialogue, but also to target adult scaffolding techniques and the role of digital media as the potential resources in collaborative problem-solving. (see also HYPOTHESES and STUDY TYPE).

This study is part of Project PEERSolvers, which aims at designing an evidence-based intervention to promote young people’s capacities for constructive peer interaction and collaborative problem solving. A major assumption of the Project is that group interaction and collaborative problem solving may be greatly enhanced if participants demonstrate the abilities, competencies and skills encompassed by the construct of emotional intelligence (EI; see e.g., Mayer & Salovey, 1997; Mestre et al., 2016). This assumption is based on prior research which has shown EI to contribute to the quality of social/interpersonal relations (Lopes et al., 2004, 2005; Song et al., 2010) and to play a significant role in teamwork (e.g., Cole et al., 2019; Farh et al., 2012). In the present study we intend to test this assumption and further examine the role of socio-emotional competencies in collaborative problem solving by systematically reviewing the relevant body of literature (see also HYPOTHESES and STUDY TYPE).

This study is part of Project PEERSolvers, which aims at designing an evidence-based intervention to develop young people’s capacities for constructive peer interaction and collaborative problem solving. Informed by several previous studies, the Project builds on the assumption that personality traits play a significant role in team processes and performance (e.g., Bell, 2007; Driskell et al., 2006; Morgeson et al., 2005; Peeters et al., 2006; van Vianen & De Dreu, 2001) and that team work may actually be facilitated by diversity in personality profiles (Hammer & Huszczo, 1996), especially if team members are taught to appreciate and take advantage of this diversity (Clinebell & Stecher, 2003). To establish a firm ground for designing the planned intervention, the present study will systematically review the evidence pertaining to the above assumptions and synthesize available findings on the role of personality differences in collaborative problem solving (see also HYPOTHESES and STUDY TYPE). Bell, S. T. (2007). Deep-Level composition variables as predictors of team performance: A meta-analysis. Journal of Applied Psychology, 92, 595–615. doi: https://doi.org/10.1037/0021-9010.92.3.595 Clinebell, S., & Stecher, M. (2003). Teaching teams to be teams: An exercise using the Myers-Briggs Type Indicator and the Five-Factor personality traits. Journal of Management Education, 27, 362–383. doi: https://doi.org/10.1177/1052562903027003006 Driskell, J. E., Goodwin, G. F., Salas, E., & O’Shea, P.G. (2006). What makes a good team player? Personality and team effectiveness. Group Dynamics Theory Research and Practice, 10, 249–271. doi: https://doi.org/10.1037/1089-2699.10.4.249 Hammer, A. L., & Huszczo, G. E. (1996). Teams. In A. L. Hammer (Eds.), MBTI applications: A decade of research on the Myers-Briggs Type Indicator (pp. 81–103). Palo Alto, CA: Consulting Psychologists Press, Inc. Morgeson, F. P., Reider, M. H., & Campion, M. A. (2005). Selecting individuals in team settings: The importance of social skills, personality characteristics, and teamwork knowledge. Personnel Psychology, 58, 583–611. doi: https://doi.org/10.1111/j.1744-6570.2005.655.x Peeters, M. A. G., Van Tuijl, H. F. J. M., Rutte, C. G., & Reymen, I. M. M. J. (2006). Personality and team performance: A meta-analysis. European Journal of Personality, 20, 377–396. doi: https://doi.org/10.1002/per.588 van Vianen, A. E. M., & De Dreu, C. K. W. (2001). Personality in teams: Its relationship to social cohesion, task cohesion, and team performance. European Journal of Work and Organizational Psychology, 10, 97-120. doi: https://doi.org/10.1080/13594320143000573

This paper studied the beliefs about mathematics, mathematics assessment, and written and oral mathematics assessment in post-secondary education from the mathematics professors’ perspectives. Seven mathematics professors and instructors were interviewed and asked to explain how they perceive mathematics and mathematics assessment and how they compare the oral exam to the written exam. Four out of seven mathematics professors and instructors were educated in Poland, Romania, Bosnia, and Ukraine, and they are currently teaching mathematics at a university in Canada. The other three professors were educated in Canada, Germany, and the United States, and they are currently teaching at a university in Germany. Five participants had previously experienced an oral examination in mathematics, while the other two had never been exposed to an oral examination in mathematics throughout their schooling. The results showed that similar beliefs about mathematics and mathematics assessment result in different beliefs about written and oral mathematics assessment.

International audience; BackgroundExcessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide.ObjectiveThe aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS.MethodsThe method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score.ResultsBoth doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: −1.4 [−2.49; −0.31], P = 0.012) but did not change significantly with the 200/18 dosage.ConclusionsTHN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society

Introduction/Objective. Spinal anesthesia is often used for hip endoprosthesis surgery. Significant surgical stress response consisting of hormonal, metabolic and inflammatory changes can be initiated by the hip replacement surgery. Intrathecal opioids, as adjuvants to local anesthetics, make spinal block sufficient even with lower doses of the local anesthetics, and the incidence of the side effects reduce to minimum. Methods. This study included 162 patients of either sex, American Society of Anesthesiology classification (ASA) 1?2, scheduled for total hip arthroplasty. The patients had spinal anesthesia with 10 mg of 0.5% bupivacaine with 20 ?g (Group I), or 25 ?g (Group II) or 30 ?g fentanyl intrathecally (Group III). Results. Mean time to achieve maximum motor and sensory blockade was with no significant difference among the groups. Time of motor block duration was shorter in the Group III. Four hours after the operation, patients in the Group I had significantly higher cortisol serum levels. Blood glucose levels were with no significant difference among the groups. Levels of CRP increased remarkably postoperatively in the Group I. Incidence of hypotension, bradycardia, nausea and vomiting was significantly higher in the Group III. Pruritus and shevering were not recorded among the groups. The first time an analgetic was needed postoperatively was the longest in the Group III. Conclusion. The dose of 10 mg of bupivacaine combined with 25 ?g fentanyl was the optimal option to achieve hemodynamic stability, sufficient sensory and motor blockade, and reduce the stress response and incidence of the opioids side effects such as vomiting, nausea, pruritus etc.

Introduction Individuals with idiopathic rapid eye movement sleep behavior disorder (iRBD) are at high risk for a clinical diagnosis of an α‐synucleinopathy (aSN). They could serve as a key population for disease‐modifying trials. Abnormal dopamine transporter (DAT) imaging is a strong candidate biomarker for risk of aSN diagnosis in iRBD. Our primary objective was to identify a quantitative measure of DAT imaging that predicts diagnosis of clinically‐defined aSN in iRBD. Methods The sample included individuals with iRBD, early Parkinson’s Disease (PD), and healthy controls (HC) enrolled in the Parkinson Progression Marker Initiative, a longitudinal, observational, international, multicenter study. The iRBD cohort was enriched with individuals with abnormal DAT binding at baseline. Motor and nonmotor measures were compared across groups. DAT specific binding ratios (SBR) were used to calculate the percent of expected DAT binding for age and sex using normative data from HCs. Receiver operative characteristic analyses identified a baseline DAT binding cutoff that distinguishes iRBD participants diagnosed with an aSN in follow‐up versus those not diagnosed. Results The sample included 38 with iRBD, 205 with PD, and 92 HC who underwent DAT‐SPECT at baseline. Over 4.7 years of mean follow‐up, 14 (36.84%) with iRBD were clinically diagnosed with aSN. Risk of aSN diagnosis was significantly elevated among those with baseline putamen SBR ≤ 48% of that expected for age and sex, relative to those above this cutoff (hazard ratio = 17.8 [95%CI: 3.79–83.3], P = 0.0003). Conclusion We demonstrate the utility of DAT SBR to identify individuals with iRBD with increased short‐term risk of an aSN diagnosis.

ObjectiveTo test the relationship between clinically relevant types of GBA mutations (none, risk variants, mild mutations, severe mutations) and β-glucocerebrosidase activity in patients with Parkinson disease (PD) in cross-sectional and longitudinal case-control studies.MethodsA total of 481 participants from the Harvard Biomarkers Study (HBS) and the NIH Parkinson's Disease Biomarkers Program (PDBP) were analyzed, including 47 patients with PD carrying GBA variants (GBA-PD), 247 without a GBA variant (idiopathic PD), and 187 healthy controls. Longitudinal analysis comprised 195 participants with 548 longitudinal measurements over a median follow-up period of 2.0 years (interquartile range, 1–2 years).Resultsβ-Glucocerebrosidase activity was low in blood of patients with GBA-PD compared to healthy controls and patients with idiopathic PD, respectively, in HBS (p < 0.001) and PDBP (p < 0.05) in multivariate analyses adjusting for age, sex, blood storage time, and batch. Enzyme activity in patients with idiopathic PD was unchanged. Innovative enzymatic quantitative trait locus (xQTL) analysis revealed a negative linear association between residual β-glucocerebrosidase activity and mutation type with p < 0.0001. For each increment in the severity of mutation type, a reduction of mean β-glucocerebrosidase activity by 0.85 μmol/L/h (95% confidence interval, −1.17, −0.54) was predicted. In a first longitudinal analysis, increasing mutation severity types were prospectively associated with steeper declines in β-glucocerebrosidase activity during a median 2 years of follow-up (p = 0.02).ConclusionsResidual activity of the β-glucocerebrosidase enzyme measured in blood inversely correlates with clinical severity types of GBA mutations in PD. β-Glucocerebrosidase activity is a quantitative endophenotype that can be monitored noninvasively and targeted therapeutically.

Introduction In 2010, The Michael J. Fox Foundation launched the Parkinson’s Progression Markers Initiative (PPMI) to study how Parkinson’s disease (PD) starts and changes over time. Volunteers participate in clinic, online or both. PPMI is now prioritizing recruitment of individuals with possible or probable REM sleep behavior disorder (RBD) without a PD diagnosis (goal of 500 in clinic). As 30% of people with RBD and smell loss receive a PD diagnosis within four years, RBD may provide a model to understand the evolution of the prodromal phase of PD. This presentation will describe diverse recruitment strategies utilized since 2020 to enroll individuals with RBD, to inform best practices for engaging this population in research. Methods A key strategy for identifying individuals with possible RBD was the dissemination of educational content on the disorder and its connection to PD. Materials emphasized that not everyone with RBD develops PD but that, in some people, RBD is an early symptom of the disease. Educational materials and messages (with associated calls to actions) were shared via webinars, print and online publications, emails, animated videos, radio, TV, and paid social media ads. Materials included scientific, participant and influencer spokespeople and were targeted to both individuals with RBD and bed partners. PPMI study sites sought referrals from sleep physicians. Results More than 535 individuals with a self-reported diagnosis of RBD (without PD) have enrolled in the online PPMI platform (59.4% male, 68.1% aged ≥60). Nearly 185 have been screened for site enrollment; 111 are contributing data at a study site. Foundation-led emails (16.1%) and paid social media ads (9.3%) were highest drivers to online enrollments. The most common referral sources to a PPMI RBD information and screening phone line were email (38%), social media (19%), and family/friend referral (19%). Approximately one-fourth of clinic enrollments were from physician referrals. Conclusion Multi-modal recruitment strategies, linked to tailored educational content, are critical for enrollment of individuals with RBD in clinical research studies including, but not limited to, those investigating and aiming to prevent other neurologic disorders. Support (if any) PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research.

Fosmetpantotenate; Randomized controlled trial Fosmetpantotenato; Ensayo controlado aleatorizado Fosmetpantotenat; Assaig controlat aleatoritzat Background Pantothenate kinase–associated neurodegeneration (PKAN) currently has no approved treatments. Objectives The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. Methods This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. Results Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was −0.09 (−1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. Conclusions Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. The FORT trial was supported by Retrophin, Inc.