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The ultimate goal of our public health system is to reduce the incidence of disability and premature death. Evidence suggests that, by this standard, the USA falls behind most other developed countries largely as a function of disparities in health outcomes among significant portions of the US population. We present a framework for addressing these disparities that attributes them, not simply to differences in the behavioral and physical risk factors, but to social, environmental, and structural inequities such as poverty, discrimination, toxic physical setting, and the marketing of harmful products. These inequities result from de facto and instituted public policies. An analysis of the NIH research portfolio indicates a relative lack of investment in experimental evaluations of preventive interventions—especially studies targeting disadvantaged populations. Moreover, experimental research on reducing social inequities is almost entirely lacking. A line of research focusing on the drivers of inequities and their dissolution must include experimental evaluation of strategies for getting policies adopted that will reduce inequities. In conclusion, a summary is provided of the types of research that are needed and the challenges involved in conducting the experimental research that is essential for reducing inequities and disparities and, in turn, prolonging life.

Background: PRESENCE was a Phase 2 trial assessing mevidalen for symptomatic treatment of Lewy body dementia (LBD). Participants received daily doses (10, 30, or 75 mg) of mevidalen (LY3154207) or placebo for 12 weeks. Objective: To evaluate if frequent cognitive and motor tests using an iPad app and wrist-worn actigraphy to track activity and sleep could detect mevidalen treatment effects in LBD. Methods: Of 340 participants enrolled in PRESENCE, 238 wore actigraphy for three 2-week periods: pre-, during, and post-intervention. A subset of participants (n = 160) enrolled in a sub-study using an iPad trial app with 3 tests: digital symbol substitution (DSST), spatial working memory (SWM), and finger-tapping. Compliance was defined as daily test completion or watch-wearing ≥23 h/day. Change from baseline to week 12 (app) or week 8 (actigraphy) was used to assess treatment effects using Mixed Model Repeated Measures analysis. Pearson correlations between sensor-derived features and clinical endpoints were assessed. Results: Actigraphy and trial app compliance was > 90% and > 60%, respectively. At baseline, daytime sleep positively correlated with Epworth Sleepiness Scale score (p

BACKGROUND Mevidalen is a selective positive allosteric modulator (PAM) of the dopamine D1 receptor subtype. OBJECTIVE To assess the safety and efficacy of mevidalen for treatment of cognition in patients with Lewy body dementia (LBD). METHODS PRESENCE was a phase 2, 12-week study in participants with LBD (N = 344) randomly assigned (1:1:1:1) to daily doses of mevidalen (10, 30, or 75 mg) or placebo. The primary outcome measure was change from baseline on Cognitive Drug Research Continuity of Attention (CoA) composite score. Secondary outcomes included Alzheimer's Disease Assessment Scale-Cognitive Subscale 13 (ADAS-cog13 ), Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS), and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). Numerous safety measures were collected. RESULTS Mevidalen failed to meet primary or secondary cognition endpoints. Mevidalen resulted in significant, dose-dependent improvements of MDS-UPDRS total score (sum of Parts I-III, 10 mg P

The threats of climate change to human well-being are well-documented and are growing in number and intensity. Despite the international community investing heavily in technological innovation and policy initiatives to solve the problem, emissions continue to rise. Experts are recognizing that eliminating emissions cannot be achieved without modifying the human behavior of which emissions are a function. However, little attention has been allocated to expanding the use of strategies developed by the behavioral-science community to reduce emissions on large scales. One possible reason is that federal funding has not been arranged to select such research. Therefore, we conducted an analysis of six sources of information about federal funding to fight climate change (the Government Accountability Office, the National Science Foundation, the Environmental Protection Agency, the Department of Energy, the National Institutes of Health, and the Center for Disease Control) and examined the extent to which they are funding behavioral science research to reduce emissions. Our results show an appalling lack of funding for behavioral science research to reduce emissions, especially experimental evaluations of strategies for reducing them. Implications and recommendations for funding of future research are discussed.

Mevidalen (LY3154207) is a positive allosteric modulator of the dopamine D1 receptor that enhances the affinity of dopamine for the D1 receptor. The safety, tolerability, motor effects, and pharmacokinetics of mevidalen were studied in patients with Parkinson disease. Mevidalen or placebo was given once daily for 14 days to 2 cohorts of patients (cohort 1, 75 mg; cohort 2, titration from 15 to 75 mg). For both cohorts, the median time to maximum concentration for mevidalen plasma concentration was about 2 hours, the apparent steady-state clearance was 20-25 L/h, and mevidalen plasma concentrations were similar between the 1st and 14th administration in cohort 1, indicating minimal accumulation upon repeated dosing. Mevidalen was well tolerated, and most treatment-emergent adverse events were mild. Blood pressure and pulse rate increased when taking mevidalen, but there was considerable overlap with patients taking placebo, and vital signs normalized with repeated dosing. In the Movement Disorder Society-United Parkinson's Disease Rating Scale, all patients taking mevidalen showed a better motor examination sub-score on day 6 compared to only some patients in the placebo group. These data support examining mevidalen for symptomatic treatment of patients with Parkinson disease and Lewy body dementia.

We examined 2-year longitudinal change in clinical features and biomarkers in LRRK2 non-manifesting carriers (NMCs) versus healthy controls (HCs) enrolled in the Parkinson’s Progression Markers Initiative (PPMI). We analyzed 2-year longitudinal data from 176 LRRK2 G2019S NMCs and 185 HCs. All participants were assessed annually with comprehensive motor and non-motor scales, dopamine transporter (DAT) imaging, and biofluid biomarkers. The latter included cerebrospinal fluid (CSF) Abeta, total tau and phospho-tau; serum urate and neurofilament light chain (NfL); and urine bis(monoacylglycerol) phosphate (BMP). At baseline, LRRK2 G2019S NMCs had a mean (SD) age of 62 (7.7) years and were 56% female. 13% had DAT deficit (defined as

This article reflects on future directions within the field of contextual behavioral science (CBS), focusing on (1) refinement of the theory of CBS and implications for clinical practice; (2) methodological aspects, particularly the utility of individual-level analyses for understanding change processes and customized interventions; (3) how digital resources can be utilized to improve research and clinical interventions, including accessibility to empirically supported treatments; (4) how a systems-oriented approach can improve the ability to address complex problems in, for example, young individuals and their families; (5) why and how dissemination across cultural contexts is an important area of development; and (6) how CBS can be used at a societal level to promote public health, including policymaking and key research studies. It is hoped that directing attention to key challenges and opportunities will inspire other researchers, Finally, suggestions are offered on how to develop the field to gain further knowledge, improve methods, increase evidence, and, ultimately, promote health and well-being.

Background: Characterizing patients with Parkinson’s disease (PD) and cognitive impairment is important toward understanding their natural history. Objective: Understand clinical, treatment, and cost characteristics of patients with PD pre- and post-cognitive impairment (memory loss/mild cognitive impairment/dementia or dementia treatment) recognition. Methods: 2,711 patients with PD newly diagnosed with cognitive impairment (index) were identified using administrative claims data. They were matched (1:1) on age and gender to patients with PD and no cognitive impairment (controls). These two cohorts were compared on patient characteristics, healthcare resource utilization, and total median costs for 3 years pre- and post-index using Chi-square tests, t-tests, and Wilcoxon rank-sum tests. Logistic regression was used to identify factors predicting cognitive impairment. Results: Comorbidity indices for patients with cognitive impairment increased during the 6-year study period, especially after the index. Enrollment in Medicare Advantage Prescription Drug plans vs. commercial (OR = 1.60), dual Medicare/Medicaid eligibility (OR = 1.36), cerebrovascular disease (OR = 1.24), and PD medication use (OR = 1.46) were associated with a new cognitive impairment diagnosis (all p

There is no question that climate change threatens the very existence of the human species. Indeed, there is mounting evidence that the sixth mass extinction event is well and truly underway. Mitigating the threats imposed by a warming climate requires a dynamic and coordinated approach, including a strong international coalition embodied by the Paris Agreement, significant investment in technological innovations to redesign the way resource-intensive commodities are produced, and a renewed emphasis on shifting climate-relevant behavior toward more sustainable alternatives. The latter has been largely neglected by the international community and funding agencies. This article serves to identify the international context in which efforts to reduce emissions using behavioral science are embedded. We highlight some of the work of behavioral scientists to enhance pro-environmental behavior that will prove vital to large-scale efforts to reduce emissions. We propose a model for designing experimental evaluations of multisector community interventions to reduce emissions on large scales. Finally, we issue a call to action for behavioral scientists and community organizers to collaborate in a new age of behavioral science research to curb the climate crisis.

As the identification of Lewy body dementia (LBD) is often confirmed postmortem, there is a paucity of evidence on the progression of disease antemortem. This study aimed to comprehensively assess the course of LBD over time across cognitive, functional, and neuropsychiatric outcomes using real-world data.Adults with at least one visit to an Alzheimer's Disease Center with a diagnosis of mild cognitive impairment/dementia (index date), indication of LBD, and at least one follow-up visit were identified in the National Alzheimer's Coordinating Center database (September 2005-June 2020). Participant characteristics, medication use, comorbidities, and changes in outcomes were assessed over a 5-year follow-up period and stratified by disease severity based on the Clinical Dementia Rating (CDR®) Dementia Staging Instrument-Sum of Boxes (CDR-SB) score at index.A total of 2052 participants with LBD (mean age at index 73.4 years) were included (mild, 219; moderate, 988; severe, 845). Mean annualized increase over 5 years was 0.9 points for CDR-Global Score, 5.6 points for CDR-SB, 10.4 points for the Functional Activities Questionnaire, and 2.0 points for the Neuropsychiatric Inventory-Questionnaire. Disease progression was greater among participants with moderate and severe LBD at index compared with those with mild LBD.Participants with LBD experienced decline across all outcomes over time, and impairment increased with disease severity. Findings highlight the substantial clinical burden associated with LBD and the importance of earlier diagnosis and effective treatment. Further research is needed to understand the predictors of cognitive and functional decline in LBD which may help inform clinical trials.

Objective The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site‐centric therapeutic trials in Parkinson’s disease and generate novel insights. The value of this approach has never been more evident than during the current COVID‐19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow‐up of clinical trial participants, (2) compare changes in smartphone‐based assessments, online patient‐reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson’s disease disability and progression. Methods Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele‐Health Outcomes in Multiyear Extensions of Parkinson’s Disease trials (AT‐HOME PD), a two‐year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone‐based assessments of motor function and socialization, and patient‐reported outcomes online. Results From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study’s smartphone application and 161 (71%) have completed patient‐reported outcomes on the online platform. Interpretation It is feasible to conduct a large‐scale, international virtual observational study following the completion of participation in brick‐and‐mortar clinical trials in Parkinson’s disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow‐up of clinical trial participants and design of future clinical trials.

To describe the trends in epidemiology, healthcare resource use (HCRU), and costs associated with Lewy body dementia (LBD), dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD) in the United States. This retrospective study used administrative claims data for Medicare fee-for-service (2010–2018) and commercially-insured beneficiaries (2010–2017). The annual prevalence and incidence were calculated among the Medicare beneficiaries by dividing the number of prevalent or incident LBD, DLB, and PDD patients by the total eligible population of that calendar year. Baseline patient characteristics, HCRU, and costs over time were described for Medicare and commercially insured patients with continuous health plan enrollment for ≥12 months before and ≥24 months after first cognitive impairment (CI) diagnosis. From 2010 to 2016, the incidence and prevalence rates of LBD among Medicare beneficiaries ranged from 0.21%–0.18% and 0.90%–0.83%, respectively. Of 9019 Medicare patients with LBD who met other inclusion criteria, 4796 (53.2%) had DLB and 4223 (46.8%) had PDD. The mean age was 78 years and the mean Charlson Comorbidity Index score was 1.6. On average, patients with LBD incurred $18,309 in medical costs during the 1-year pre-diagnosis and $29,174 and $22,814 at years 1 and 5 after diagnosis, respectively. The main cost drivers were inpatient and outpatient visits. Similar trends were observed for DLB and PDD as well as for commercially-insured patients. Our findings highlight the substantial epidemiological and economic burden across the LBD spectrum and underscore a high unmet need for effective treatments to improve patient outcomes.

Activation of the brain dopamine D1 receptor has attracted attention because of its promising role in neuropsychiatric diseases. Although efforts to develop D1 agonists have been challenging, a positive allosteric modulator (PAM), represents an attractive approach with potential better drug‐like properties. Phase 1 single‐ascending‐dose (SAD; NCT03616795) and multiple‐ascending‐dose (MAD; NCT02562768) studies with the D1PAM mevidalen (LY3154207) were conducted with healthy subjects. There were no treatment‐related serious adverse events (AEs) in these studies. In the SAD study, 25‐200 mg administered orally showed dose‐proportional pharmacokinetics (PK) and acute dose‐related increases in systolic blood pressure (SBP) and diastolic blood pressure DBP) and pulse rate at doses ≥ 75 mg. AE related to central activation were seen at doses ≥ 75 mg. At 25 and 75 mg, central penetration of mevidalen was confirmed by measurement of mevidalen in cerebrospinal fluid. In the MAD study, once‐daily doses of mevidalen at 15‐150 mg for 14 days showed dose‐proportional PK. Acute dose‐dependent increases in SBP, DBP, and PR were observed on initial administration, but with repeated dosing the effects diminished and returned toward baseline levels. Overall, these findings support further investigation of mevidalen as a potential treatment for a range of neuropsychiatric disorders.

Author(s): Schneider, Ruth B; Myers, Taylor L; Rowbotham, Helen M; Luff, Marie K; Amodeo, Katherine; Sharma, Saloni; Wilson, Renee; Jensen-Roberts, Stella; Auinger, Peggy; McDermott, Michael P; Alcalay, Roy N; Biglan, Kevin; Kinel, Daniel; Tanner, Caroline; Winter-Evans, Reni; Augustine, Erika F; Cannon, Paul; 23andMe Research Team; Holloway, Robert G; Dorsey, E Ray | Abstract: BackgroundThe rise of direct-to-consumer genetic testing has enabled many to learn of their possible increased risk for rare diseases, some of which may be suitable for gene-targeted therapies. However, recruiting a large and representative population for rare diseases or genetically defined sub-populations of common diseases is slow, difficult, and expensive.ObjectiveTo assess the feasibility of recruiting and retaining a cohort of individuals who carry a genetic mutation linked to Parkinson's disease (G2019S variant of LRRK2); to characterize this cohort relative to the characteristics of traditional, in-person studies; and to evaluate this model's ability to create an engaged study cohort interested in future clinical trials of gene-directed therapies.MethodsThis single-site,3-year national longitudinal observational study will recruit between 250 to 350 LRRK2 carriers without Parkinson's disease and approximately 50 with the condition. Participants must have undergone genetic testing by the personal genetics company, 23andMe, Inc., have knowledge of their carrier status, and consent to be contacted for research studies. All participants undergo standardized assessments, including video-based cognitive and motor examination, and complete patient-reported outcomes on an annual basis.Results263 individuals living in 33 states have enrolled. The cohort has a mean (SD) age of 56.0 (15.9) years, 59% are female, and 76% are of Ashkenazi Jewish descent. 233 have completed the baseline visit: 47 with self-reported Parkinson's disease and 186 without.ConclusionsThis study establishes a promising model for developing a geographically dispersed and well-characterized cohort ready for participation in future clinical trials of gene-directed therapies.

Despite significant progress in research on the treatment and prevention of psychological, behavioral, and health problems, the translation of this knowledge into population-wide benefit remains limited. This paper reviews the state of America's children and families, highlighting the influence of stressful contextual and social conditions on child and family well-being and the concentration of disadvantage in numerous neighborhoods and communities throughout the nation. It then briefly reviews the progress that has been made in pinpointing policies that can reduce stressful contextual conditions such as poverty, discrimination, and the marketing of unhealthful foods and substances. It also describes numerous family and school interventions that have proven benefit in preventing psychological and behavioral problems as diverse as tobacco, alcohol, and other drug use; depression; antisocial behavior; academic failure; obesity prevention; and early childbearing. We argue that progress in translating existing knowledge into widespread benefit will require a nationwide effort to intervene comprehensively in neighborhoods and communities of concentrated disadvantage. We present a strategic plan for how such an effort could be organized. The first step in this organizing would be the creation of a broad and diverse coalition of organizations concerned with advancing public health and well-being. Such a coalition could increase public support both for the policies needed to focus on these disadvantaged areas and the research needed to incrementally improve our ability to help these areas.

Background and ObjectivesTo recruit and characterize a national cohort of individuals who have a genetic variant (LRRK2 G2019S) that increases risk of Parkinson disease (PD), assess participant satisfaction with a decentralized, remote research model, and evaluate interest in future clinical trials.MethodsIn partnership with 23andMe, Inc., a personal genetics company, LRRK2 G2019S carriers with and without PD were recruited to participate in an ongoing 36-month decentralized, remote natural history study. We examined concordance between self-reported and clinician-determined PD diagnosis. We applied the Movement Disorder Society Prodromal Parkinson's Disease Criteria and asked investigators to identify concern for parkinsonism to distinguish participants with probable prodromal PD. We compared baseline characteristics of LRRK2 G2019S carriers with PD, with prodromal PD, and without PD.ResultsOver 15 months, we enrolled 277 LRRK2 G2019S carriers from 34 states. At baseline, 60 had self-reported PD (mean [SD] age 67.8 years [8.4], 98% White, 52% female, 80% Ashkenazi Jewish, and 67% with a family history of PD), and 217 did not (mean [SD] age 53.7 years [15.1], 95% White, 59% female, 73% Ashkenazi Jewish, and 57% with a family history of PD). Agreement between self-reported and clinician-determined PD status was excellent (κ = 0.94, 95% confidence interval 0.89–0.99). Twenty-four participants had prodromal PD; 9 met criteria for probable prodromal PD and investigators identified concern for parkinsonism in 20 cases. Compared with those without prodromal PD, participants with prodromal PD were older (63.9 years [9.0] vs 51.9 years [15.1], p < 0.001), had higher modified Movement Disorders Society-Unified Parkinson's Disease Rating Scale motor scores (5.7 [4.3] vs 0.8 [2.1], p < 0.001), and had higher Scale for Outcomes in PD for Autonomic Symptoms scores (11.5 [6.2] vs 6.9 [5.7], p = 0.002). Two-thirds of participants enrolled were new to research, 97% were satisfied with the overall study, and 94% of those without PD would participate in future preventive clinical trials.DiscussionAn entirely remote national cohort of LRRK2 G2019S carriers was recruited from a single site. This study will prospectively characterize a large LRRK2 G2019S cohort, refine a new model of clinical research, and engage new research participants willing to participate in future therapeutic trials.

In 2019, the Lewy Body Dementia Association formed an Industry Advisory Council to bring together a collaborative group of stakeholders with the goal of accelerating clinical research into Lewy body dementia treatments. At the second annual meeting of the Industry Advisory Council, held virtually on June 18, 2020, the key members presented ongoing and planned efforts toward the council’s goals. The meeting also featured a discussion about the effects of the COVID-19 pandemic on Lewy body dementia clinical research, lessons learned from that experience, and how those lessons can be applied to the design and conduct of future clinical trials. This report provides a brief summary of the meeting proceedings with a focus on efforts to improve and adapt future Lewy body dementia clinical research.

This article reviews the evidence regarding behavioral science approaches to the prevention of substance use disorders. Prevention science grew out of research on family and school-based interventions that were designed to treat common behavioral problems of children and adolescents. That research showed that the amelioration of problems such as aggressive behavior could prevent the development of later problems including substance use, depression, and academic failure. We begin by reviewing evidence regarding the risk factors that contribute to the development of substance use disorders, as well as the protective factors that can reduce their likelihood. We then describe a variety of family, school, and community prevention programs that have been shown to prevent youthful use and abuse of substances. We conclude by describing the progress that has been made in getting these programs widely and effectively implemented, and the challenges we face in getting to the point where most communities are achieving considerable success in prevent substance use and the other common and costly behavioral and psychological problems of children and adolescents.

Background The appropriate timing of dopaminergic treatment initiation in Parkinson's disease (PD) remains a matter of debate. The primary objective of this study was to determine whether earlier initiation of treatment was associated with less worsening of total UPDRS scores over 48 months. Methods We performed a secondary analysis of data from the CALM-PD (Comparison of the Agonist Pramipexole With Levodopa on Motor Complications of Parkinson's Disease) trial to examine the associations between years since diagnosis and 48-month changes in total and component UPDRS scores, Parkinson's Disease Quality of Life Scale (PDQUALIF) score, and the EuroQol-5D visual analogue scale (VAS) score. Results There were no associations between years since PD diagnosis and 48-month changes in total UPDRS, component UPDRS scores, PDQUALIF score, or EuroQol-5D VAS score. Conclusion Earlier treatment was not associated with improved long-term outcomes in this secondary analysis. Prospective studies are required to determine the appropriate timing of initiation of dopaminergic treatment to inform clinical practice.

Reward & Reminder has been a component of community-based preventive efforts against sales of substances (e.g., tobacco) to youth. To date, there has not been a randomized trial of Reward & Reminder as a stand-alone prevention program targeting youth access to alcohol. In this study, we addressed that gap. Data were collected as part of a randomized trial of a school- and community-based prevention program. Our analysis included 23 vendors in control communities and 33 vendors in intervention communities. We visited each vendor at least two times, and vendors in intervention communities received the Reward & Reminder protocol. Using McNemar’s Test, which evaluates the degree to which the outlets in each condition moved to a different cell in the contingency table from the first visit to the second (i.e., from yes to no or vice versa), we found that the control outlets did not change (all p values were non-significant). In contrast, the test results for the intervention outlets were significantly more likely to ask for ID (p < .05) and significantly less willing to sell alcohol to young-looking project confederates (p < .05); Asked for Age did not change. We conclude that Reward & Reminder could assist in preventing underage access to alcohol.

Cross-sectional, longitudinal, and experimental studies have found a link between youth exposure to cigarette marketing and youth initiation of smoking. These decisive research findings led to regulations of cigarette marketing to youth-including no television or radio ads, prohibitions on the use of cartoons, bans on transit and billboard advertisements, and disallowing tobacco brand sponsorships of sporting events or concerts. Similar products that may cause more harm than benefits include alcohol, electronic cigarettes, and opioids. We review the evidence linking problematic use of these products with exposure to marketing and discuss standards for assessing the potential harmfulness of marketing. We next address how public health agencies might apply regulatory principles to these harmful products similar to those applied to cigarette advertising, in the advancement of public health.

Dopamine (DA) plays a key role in several central functions including cognition, motor activity, and wakefulness. Although efforts to develop dopamine receptor 1 (D1) agonists have been challenging, a positive allosteric modulator represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the dopamine receptor 1 positive allosteric modulator (D1PAM) mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al., 2021). Herein, we describe the effects of mevidalen on sleep and wakefulness in humanized dopamine receptor 1 (hD1) mice and in sleep-deprived healthy male volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent [3-100 mg/kg, orally (PO)] fashion when measured during the light (zeitgeber time 5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice after prior sleep deprivation and delayed sleep onset by 5.5- and 15.2-fold compared with vehicle-treated animals, after the 20 and 60 mg/kg PO doses, respectively, when compared with vehicle-treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, and 75 mg) separated from placebo at the first 2-hour postdose time point with a circadian effect at the 6-hour postdose time point. Sleep wakefulness should be considered a translational biomarker for the dopamine receptor 1 positive allosteric modulator mechanism. SIGNIFICANCE STATEMENT: This is the first translational study describing the effects of a selective dopamine receptor 1 positive allosteric modulator (D1PAM) on sleep and wakefulness in the human dopamine receptor 1 mouse and in sleep-deprived healthy male volunteers. In both species, drug exposure correlated with sleep latency, supporting the use of sleep-wake activity as a translational central biomarker for D1PAM. Wake-promoting effects of D1PAMs may offer therapeutic opportunities in several conditions, including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders.

Background This paper describes the development and psychometric evaluation of a behavioral assessment instrument primarily intended for use with workgroups in any type of organization. The instrument was developed based on the Nurturing Environments framework which describes four domains important for health, well-being, and productivity; minimizing toxic social interactions, teaching and reinforcing prosocial behaviors, limiting opportunities for problem behaviors, and promoting psychological flexibility. The instrument is freely available to use and adapt under a CC-BY license and intended as a tool that is easy for any group to use and interpret to identify key behaviors to improve their psychosocial work environment. Methods Questionnaire data of perceived frequency of behaviors relevant to nurturance were collected from nine different organizations in Sweden. Data were analyzed using confirmatory factor analysis, Rasch analysis, and correlations to investigate relationships with relevant workplace measures. Results The results indicate that the 23-item instrument is usefully divided in two factors, which can be described as risk and protective factors. Toxic social behaviors make up the risk factor, while the protective factor includes prosocial behavior, behaviors that limit problems, and psychological flexibility. Rasch analysis showed that the response categories work as intended for all items, item fit is satisfactory, and there was no significant differential item functioning across age or gender. Targeting indicates that measurement precision is skewed towards lower levels of both factors, while item thresholds are distributed over the range of participant abilities, particularly for the protective factor. A Rasch score table is available for ordinal to interval data transformation. Conclusions This initial analysis shows promising results, while more data is needed to investigate group-level measurement properties and validation against concrete longitudinal outcomes. We provide recommendations for how to work in practice with a group based on their assessment data, and how to optimize the measurement precision further. By using a two-dimensional assessment with ratings of both frequency and perceived importance of behaviors the instrument can help facilitate a participatory group development process. The Group Nurturance Inventory is freely available to use and adapt for both commercial and non-commercial use and could help promote transparent assessment practices in organizational and group development.

Background: There is rising interest in remote clinical trial assessments, particularly in the setting of the COVID-19 pandemic. Objective: To demonstrate the feasibility, reliability, and value of remote visits in a phase III clinical trial of individuals with Parkinson’s disease. Methods: We invited individuals with Parkinson’s disease enrolled in a phase III clinical trial (STEADY-PD III) to enroll in a sub-study of remote video-based visits. Participants completed three remote visits over one year within four weeks of an in-person visit and completed assessments performed during the remote visit. We evaluated the ability to complete scheduled assessments remotely; agreement between remote and in-person outcome measures; and opinions of remote visits. Results: We enrolled 40 participants (mean (SD) age 64.3 (10.4), 29% women), and 38 (95%) completed all remote visits. There was excellent correlation (ICC 0.81–0.87) between remote and in-person patient-reported outcomes, and moderate correlation (ICC 0.43–0.51) between remote and in-person motor assessments. On average, remote visits took around one quarter of the time of in-person visits (54 vs 190 minutes). Nearly all participants liked remote visits, and three-quarters said they would be more likely to participate in future trials if some visits could be conducted remotely. Conclusion: Remote visits are feasible and reliable in a phase III clinical trial of individuals with early, untreated Parkinson’s disease. These visits are shorter, reduce participant burden, and enable safe conduct of research visits, which is especially important in the COVID-19 pandemic.

This paper describes the culture and components of the PAX Good Behavior Game and offers it as one model for how to enhance the well-being of populations through the diffusion of nurturing practices into several venues of society. The PAX components, also known as evidence-based kernels, are proposed to be useful in classrooms, families, organizations, criminal justice, and in improving public discussion and government. Kernels affect behavior in the short- and long-term through combinations of antecedents, reinforcers, relational networks, and physiological effects. Identifying common strategies, tools, and clear targets of change is suggested as a way to work towards evolving freely available evidence-based tools that can be combined to improve social conditions in multiple contexts. This work was in part supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Grant # R01 AA021726). Open Access funding provided by OsloMet - Oslo Metropolitan University.

The COVID-19 pandemic has brought about significant stress and anxiety for many parents around the world. Psychological flexibility and self-care are fundamental aspects of psychological health (Kashdan & Rottenberg, 2010). For parents, shaping these processes may help promote family nurturance, support children’s prosocial behavior, and provide effective and consistent use of evidence-based parenting “kernels”. The goal of this article is to provide practitioners with evidence-based tools that will support psychological flexibility, self-care, and positive parenting behaviors in caregivers during COVID-19 and beyond.

Parents managing their home environments during government ordered stay-at-home periods are likely to need new skills for occupying their children’s time with activities which promote health and emotional well-being. Moreover, parents and children know they need help managing these circumstances. Perhaps for the first time, behavior analysts hold the reinforcers for increasing parental involvement in effective child-rearing practices. In fact, behavior analysts can help parents enlist their children in managing the household by framing their behavior in terms of hidden superpowers. In the current paper, we argue that behavior analysts have a range of tools to offer which are grounded in evidence-based principles, strategies, and kernels, or essential units of behavioral influence. When combined into scheduled daily practices and invoked by children taught to see their use of the tools as nothing short of heroic, these practices function as vaccinations that inoculate families against toxic and unsafe behaviors.

In this study, we tested the effects of cooperative learning on students' prosocial behavior. Cooperative learning is a small-group instructional technique that establishes positive interdependence among students and, unlike most current school-based programs, does not mandate a formal curriculum. Given the emphasis in cooperative learning on peer reinforcement for positive and helpful behavior during learning activities, we hypothesized that cooperative learning would promote higher levels of prosocial behavior, and that these effects would be mediated by peer relatedness. Using a sample of 1,890 students (47.1% female, 75.2% White) from a cluster randomized trial of 15 middle schools, we found that cooperative learning significantly enhanced prosocial behavior across two years. Mediation was only partial, however, suggesting that additional mechanisms were at work, such as changes to social norms or teacher behavior. Given that cooperative learning has been shown to enhance student engagement and academic achievement in prior research, we argue that cooperative learning should be a central component of teacher training and professional development.

Huntington’s disease is an autosomal dominant, progressive neurodegenerative disease characterized by multiple movement disorders, psychiatric disturbances, and cognitive decline. The pathogenic mechanism is expansion of a trinucleotide repeat region of the interesting transcript 15 gene that produces excess polyglutamine residues in its protein product, huntingtin, which in turn aggregate and are suspected to induce cellular dysfunction via aberrant bioenergetics and mitochondrial dysfunction. This progressive decline at the cellular level appears to be quite early and specific in the striatum, particularly medium spiny neurons, with eventual cortical dysfunction and more diffuse basal ganglia involvement. Treatment centers on suppression of hyperkinetic movements, stabilization of psychiatric disturbances, including depression, irritability, and anxiety, and tailoring of lifestyle to promote safety and maximal activity. A variety of new genetically based therapies are being developed and tested that may substantially alter the treatment landscape.

BackgroundThe Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.MethodsThis cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.FindingsBetween Jan 1, 2014, and Jan 1, 2019, the study enrolled 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson’s disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.

This paper examines the misalignment between modern human society and certain male phenotypes, a misalignment that has been highlighted and explored in great detail in the work of Tom Dishion. We begin by briefly enumerating the ongoing developmental difficulties of many boys and young men and how these difficulties affect them and those around them. We then suggest that the qualities that have been advantageous for men and their families in our earlier evolution but that are often no longer functional in modern society are a source of these problems. Finally, we provide a brief review of prevention programs that can contribute to preventing this type of problematic development and eliciting more prosocial behavior from at-risk boys and men. We conclude with an overview of research and policy priorities that could contribute to reducing the proportion of boys and young men who experience developmental difficulties in making their way in the world.

Introduction Individuals with cervical dystonia (CD) often report difficulty with balance and an altered perception of vertical. Previous studies have suggested a decreased proprioceptive response to stretch of neck muscle spindles in these patients, and impaired dynamic balance changes in individuals with tremor. Methods Participants with CD were divided into three groups based on severity of tremor and dystonic position on the Toronto Western Spasmodic Torticollis Rating Scale 2 (TWSTRS2). Unaffected controls completed assessments including Fukuda, modified Romberg, and subjective visual vertical tests. Participants with CD completed the same assessments at baseline and 4 to 6 weeks following botulinum toxin treatment. Results CD participants with marked tremor and deviation had more difficulty perceiving what was vertical as demonstrated by a greater degree off midline on the subjective visual vertical test, compared to individuals with marked tremor with minimal deviation and controls, though this was not significant after adjustment for multiple comparisons. Individuals with CD also had more difficulty maintaining balance on a compliant surface with eyes closed compared to controls on the modified Romberg test. TWSTRS2 motor severity score was significantly associated with degrees off midline on the subjective visual vertical test at baseline for CD participants, but not after botulinum toxin treatment. Conclusions Individuals with more severe tremor and dystonic posture appear to have an altered perception of vertical associated with CD severity and that may improve following botulinum toxin treatment. Modified Romberg testing suggests that visual cues may also be important to compensate for tremor and dystonic positions found in CD.

Background and Introduction: Delivering care through telemedicine directly into the patient's home is increasingly feasible, valuable, and beneficial. However, qualitative data on how patients' and physicians' perceive these virtual house calls are lacking. We conducted a qualitative analysis of perceptions of these visits for Parkinson's disease to (1) determine how patients and physicians perceive virtual visits and (2) identify components contributing to positive and negative perceptions.Qualitative survey data were collected from patients and physicians during a 12-month randomized controlled trial of virtual house calls for Parkinson's disease. Data from 149 cases were analyzed using case-based qualitative content analysis and quantitative sentiment analysis techniques.Positive and negative perceptions of virtual visits were driven by three themes: (1) personal benefits of the virtual visit, (2) perceived quality of care, and (3) perceived quality of interpersonal engagement. In general, participants who identified greater personal benefit, high quality of care, and good interpersonal engagement perceived visits positively. Technical problems with the software were commonly mentioned. The sentiment analysis for patients was strongly favorable (+2.5) and moderately favorable for physicians (+0.8). Physician scores were lowest (-0.3) for the ability to perform a detailed motor examination remotely.Patients and providers generally view telemedicine favorably, but individual experiences are dependent on technical issues.Satisfaction with and effectiveness of remote care will likely increase as common technical problems are resolved.

This paper reviews research suggesting that the prevention of intergenerational poverty will be enhanced if we add evidence-based family and school prevention programs to existing efforts to reduce poverty in order to address the adverse social environments that often accompany poverty. Government policies such as the Earned Income Tax Credit can reduce family poverty, but simply improving the economic stability of the family will not necessarily prevent the development of child and adolescent problems such as academic failure, antisocial behavior, drug abuse, and depression, all of which can undermine future economic wellbeing. We briefly review the evidence linking family poverty to adverse social environments, which can have deleterious effects on children's psychological, behavioral, neurological, and physical development. We then document the value of evidence-based family- and school-based prevention programs in effectively addressing these behavioral, emotional, cognitive, and neurophysiological factors that can put children at risk for continued poverty in adulthood. We also describe three family-based prevention programs that have been found to have a direct effect on families' future economic wellbeing. The evidence indicates that widely disseminating effective and efficient family- and school-based prevention programs can help to address both poverty itself and the effects of adverse social environments, making future poverty less likely. We conclude with specific recommendations for federal and state policymakers, researchers, and practitioners.

Background Challenges in clinical trial recruitment threaten the successful development of improved therapies. This is particularly true in Parkinson's disease (PD) studies of disease modification where the population of interest is difficult to find and study design is more complex. Objective This paper seeks to understand how STEADY PD III, a National Institute of Neurological Disorders and Stroke (NINDS) funded phase 3 trial evaluating the efficacy of isradipine as a disease modifying agent for PD, was able to recruit their full target population 6 months ahead of schedule. Methods STEADY PD III aimed to enroll 336 individuals with early stage idiopathic PD within 18 months using 57 sites across the United States and Canada. The study included a 10% NIH minority recruitment goal. Eligible participants agreed to be followed for up to 36 months, complete 12 in-person visits and 4 telephone visits. A Recruitment Committee of key stakeholders was critical in the development of a comprehensive recruitment strategy involving: multi-modal outreach, protocol modifications and comprehensive site selection and activation. Efforts to increase site-specific minority recruitment strategies were encouraged through additional funding. Results A total of 336 individuals, including 34 minorities, were enrolled within 12 months - 6 months ahead of the projected timeline. Quantitative analysis of recruitment activity questionnaires found that of the sites that completed them (n = 54), (20.4%) met goals, (24.1%) exceeded goals, and (55.6%) fell below projected goals. Referral sources completed at time of screening indicate top four study referral sources as: site personnel (53.8%); neurologists (24%); Fox Trial Finder (10.2%); and communications from The Michael J. Fox Foundation (3.9%). Conclusions STEADY PD III serves as an important example of methods that can be used to increase clinical trial recruitment. This research highlights a continued need to improve site infrastructure and dedicate more resources to increased participation of minorities in clinical research.

Background: Clinician rating scales and patient-reported outcomes are the principal means of assessing motor symptoms in Parkinson disease and Huntington disease. However, these assessments are subjective and generally limited to episodic in-person visits. Wearable sensors can objectively and continuously measure motor features and could be valuable in clinical research and care. Methods: We recruited participants with Parkinson disease, Huntington disease, and prodromal Huntington disease (individuals who carry the genetic marker but do not yet exhibit symptoms of the disease), and controls to wear 5 accelerometer-based sensors on their chest and limbs for standardized in-clinic assessments and for 2 days at home. The study’s aims were to assess the feasibility of use of wearable sensors, to determine the activity (lying, sitting, standing, walking) of participants, and to survey participants on their experience. Results: Fifty-six individuals (16 with Parkinson disease, 15 with Huntington disease, 5 with prodromal Huntington disease, and 20 controls) were enrolled in the study. Data were successfully obtained from 99.3% (278/280) of sensors dispatched. On average, individuals with Huntington disease spent over 50% of the total time lying down, substantially more than individuals with prodromal Huntington disease (33%, p = 0.003), Parkinson disease (38%, p = 0.01), and controls (34%; p < 0.001). Most (86%) participants were “willing” or “very willing” to wear the sensors again. Conclusions: Among individuals with movement disorders, the use of wearable sensors in clinic and at home was feasible and well-received. These sensors can identify statistically significant differences in activity profiles between individuals with movement disorders and those without. In addition, continuous, objective monitoring can reveal disease characteristics not observed in clinic.

Summary Disparities in access to health care, particularly specialist care, exist worldwide. As the prevalence of chronic neurological disorders increases with ageing populations, access to neurologist care is likely to worsen in many regions if there are no changes to models of care. Telemedicine—defined here as the use of real-time, synchronous videoconferencing to deliver medical care—could be used to improve access to neurologist care for patients with a range of chronic neurological disorders. In Parkinson's disease, several studies have shown the feasibility and potential benefits of telemedicine-delivered care. Further research is needed to establish whether telemedicine can deliver on the promise of improved access to neurologist care and whether telemedicine-delivered care is comparable to in-person care in terms of clinical outcomes. Many barriers to widespread implementation of telemedicine services remain to be addressed, including reimbursement, legal considerations, and technological issues.

Introduction: The integration of remote specialists into local care teams has not been widely evaluated. Methods: Therefore, we surveyed clinicians whose patients with Parkinson's disease had participated in a national randomized controlled trial of video visits to determine (1) whether clinicians received recommendations from remote specialists; (2) whether those recommendations were implemented; (3) what barriers to specialty care local clinicians perceived; and (4) whether they would recommend video visits. Results: Of 183 clinicians surveyed, 89 (49%) responded. Less than half received the recommendations of remote specialists, but they implemented most of the recommendations they received and found them to be beneficial. Conclusion: The greatest perceived barrier among respondents was distance from patient to specialist, and 40% of local clinicians would recommend video visits. As telemedicine grows, improved communication between remote specialists and local clinicians is likely needed.

This paper argues that diverse disciplines within the human sciences have converged in identifying the conditions that human beings need to thrive and the programs, policies, and practices that are needed to foster well-being. In the interest of promoting this view, we suggest that this convergence might usefully be labeled “The Nurture Consilience.” We review evidence from evolutionary biology, developmental, clinical, and social psychology, as well as public health and prevention science indicating that, for evolutionary reasons, coercive environments promote a “fast” life strategy that favors limited self-regulation, immediate gratification, and early childbearing. However, this trajectory can be prevented through programs, practices, and policies that (a) minimize toxic social and biological conditions, (b) limit opportunities and influences for problem behavior, (c) richly reinforce prosocial behavior, and (d) promote psychological flexibility. The recognition of these facts has prompted research on the adoption, implementation, and maintenance of evidence-based interventions. To fully realize the fruits of this consilience, it is necessary to reform every sector of society. We review evidence that free-market advocacy has promoted the view that if individuals simply pursue their own economic well-being it will benefit everyone, and trace how that view led business, health care, education, criminal justice, and government to adopt practices that have benefited a small segment of the population but harmed the majority. We argue that the first step in reforming each sector of society would be to promote the value of ensuring everyone's well-being. The second step will be to create contingencies that select beneficial practices and minimizes harmful ones., Highlights • Describes coercive and nurturing environments and their impact on health. • Reviews interdisciplinary evidence to identify consilience on targets of change. • Advocates prosocial values and reformed contingencies in all sectors of society. • Documents how most psychological and behavioral problems can be prevented.

BACKGROUND There is limited understanding of the feasibility of conducting long-term research among undiagnosed (pre-symptomatic) adults at risk to develop Huntington disease (HD), while protecting their emotional well-being and safety. OBJECTIVE To assess pre-specified events pertaining to emotional well-being, safety, and feasibility among healthy consenting adults at risk for developing HD who have chosen not to undergo genetic testing. METHODS PHAROS research participants prospectively reported the occurrence of events pertaining to psychological distress (psychiatric evaluations, depression, suicidality) and feasibility (maintaining confidentiality, study attrition). PHAROS enrolled 1001 participants. RESULTS Events pertaining to psychological distress were reported by 35% of participants. The most common events included heightened suicide risk (26%), new onset depression (12%), and new mental health evaluation (9%); all occurred significantly more frequently among participants with expanded trinucleotide CAG repeats (≥37). Five deaths occurred, none related to suicide. Forty-one percent of participants reported self-disclosure of their HD at-risk status, and 15% reported that someone else (usually a family member) had done so. Confidentiality of CAG test results was maintained by investigators. The withdrawal rate was largely uniform over the study period and did not differ significantly by gender or CAG status. CONCLUSIONS The potentially vulnerable research participants in PHAROS showed good emotional tolerability and safety. Individual CAG data were not disclosed, and confidentiality about disclosure of at-risk HD status was well maintained by others (family, friends, etc.). Long-term research participation of adults at risk for HD who choose not to undergo pre-symptomatic DNA testing is well tolerated, safe and feasible.

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.