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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.

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.

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

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.

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 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.

Author(s): Chahine, Lana M; Siderowf, Andrew; Barnes, Janel; Seedorff, Nicholas; Caspell-Garcia, Chelsea; Simuni, Tanya; Coffey, Christopher S; Galasko, Douglas; Mollenhauer, Brit; Arnedo, Vanessa; Daegele, Nichole; Frasier, Mark; Tanner, Caroline; Kieburtz, Karl; Marek, Kenneth; The Parkinson’s Progression Markers Initiative | Abstract: BackgroundImproved prediction of Parkinson's disease (PD) progression is needed to support clinical decision-making and to accelerate research trials.ObjectivesTo examine whether baseline measures and their 1-year change predict longer-term progression in early PD.MethodsParkinson's Progression Markers Initiative study data were used. Participants had disease duration ≤2 years, abnormal dopamine transporter (DAT) imaging, and were untreated with PD medications. Baseline and 1-year change in clinical, cerebrospinal fluid (CSF), and imaging measures were evaluated as candidate predictors of longer-term (up to 5 years) change in Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) score and DAT specific binding ratios (SBR) using linear mixed-effects models.ResultsAmong 413 PD participants, median follow-up was 5 years. Change in MDS-UPDRS from year-2 to last follow-up was associated with disease duration (β= 0.351; 95% CI = 0.146, 0.555), male gender (β= 3.090; 95% CI = 0.310, 5.869), and baseline (β= -0.199; 95% CI = -0.315, -0.082) and 1-year change (β= 0.540; 95% CI = 0.423, 0.658) in MDS-UPDRS; predictors in the model accounted for 17.6% of the variance in outcome. Predictors of percent change in mean SBR from year-2 to last follow-up included baseline rapid eye movement sleep behavior disorder score (β= -0.6229; 95% CI = -1.2910, 0.0452), baseline (β= 7.232; 95% CI = 2.268, 12.195) and 1-year change (β= 45.918; 95% CI = 35.994,55.843) in mean striatum SBR, and 1-year change in autonomic symptom score (β= -0.325;95% CI = -0.695, 0.045); predictors in the model accounted for 44.1% of the variance.ConclusionsBaseline clinical, CSF, and imaging measures in early PD predicted change in MDS-UPDRS and dopamine-transporter binding, but the predictive value of the models was low. Adding the short-term change of possible predictors improved the predictive value, especially for modeling change in dopamine-transporter binding.

Background: The Unified Huntington’s Disease Rating Scale (UHDRS) is the principal means of assessing motor impairment in Huntington disease but is subjective and generally limited to in-clinic assessments. Objective: To evaluate the feasibility and ability of wearable sensors to measure motor impairment in individuals with Huntington disease in the clinic and at home. Methods: Participants with Huntington disease and controls were asked to wear five accelerometer-based sensors attached to the chest and each limb for standardized, in-clinic assessments and for one day at home. A secondchest sensor was worn for six additional days at home. Gait measures were compared between controls, participants with Huntington disease, and participants with Huntington disease grouped by UHDRS total motor score using Cohen’s d values. Results: Fifteen individuals with Huntington disease and five controls completed the study. Sensor data were successfully captured from 18 of the 20 participants at home. In the clinic, the standard deviation of step time (timebetween consecutive steps) was increased in Huntington disease (p

Background: Progressive 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. Objectives: To 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. Methods: Multicenter 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. Results: The 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. Conclusion: The 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.

Type II translational research tends to emphasize getting evidence-based programs implemented in real world settings. To fully realize the aspirations of prevention scientists, we need a broader strategy for translating knowledge about human wellbeing into population-wide improvements in wellbeing. Far-reaching changes must occur in policies and cultural practices that affect the quality of family, school, workplace, and community environments. This paper describes a broad cultural movement, not unlike the tobacco control movement, that can make nurturing environments a fundamental priority of public policy and daily life, thereby enhancing human wellbeing far beyond anything achieved thus far.

In Huntington's disease, 60% of the variance in onset age is not explained by the huntingtin gene mutation. Huntington's disease onset was earlier in caffeine users.The objective of this study was to assess the relationship of lifestyle factors with motor phenoconversion among persons at risk for Huntington's disease.The associations of motor phenoconversion and exposure to selected lifestyle and health factors were examined using Cox proportional hazards analyses adjusted for age, gender, and repeat length.Of 247 participants, 36 (14.6%) phenoconverted. Mean follow-up was 4.2 years. Greater caffeinated soda use was associated with an increased hazard of phenoconversion: moderate use hazard ratio 2.26 (95% confidence interval 0.59-8.71), high use hazard ratio 4.05 (95% confidence interval 1.18-13.96).Huntington's disease onset was earlier among consumers of caffeinated soda, but not other caffeinated beverages. This finding may be spurious or not related to caffeine. © 2018 International Parkinson and Movement Disorder Society.

Background In Huntington disease (HD), cognitive changes due to disease-progression or treatment are potentially confounded by "practice effects" (PE)--performance improvement from prior exposure to test materials. Objective A practice run-in ("dual baseline") was used in an HD cognitive trial to determine if PE could be minimized and evaluate performance trajectories over multiple visits. Methods Non-depressed adults (N = 36) with mild to moderate HD-related cognitive deficits participated in a clinical trial to examine the efficacy of citalopram to enhance cognition. Cognitive tests were administered at three visits (2 weeks separating each visit), before active treatment randomization. Some tests were also administered at screening. Therefore 3-4 pre-treatment repetitions were available. We examined test improvement using repeated-measures ANOVAs with planned pairwise comparisons. Results Despite the practice run-in and use of alternate test forms, results indicated ongoing improvements over at least three test sessions on all three UHDRS cognitive tests. Trails A and B showed improvements between the third and fourth session, which suggests that one pre-baseline visit may not be effective in reducing practice on this important and commonly used test. Conclusions Overall, 7 out of 13 variables showed some degree of short-term PE, even after multiple sessions and alternate forms. Tests assessing processing speed and memory may be particularly confounded by ongoing PE across at least 2-3 sessions. Practice run-in periods and alternate forms may help minimize the impact of such effects in HD clinical trials but awareness of which tests are most susceptible to PE is important in clinical trial design.

Background: Remote, non-invasive and objective tests that can be used to support expert diagnosis for Parkinson's disease (PD) are lacking. Methods: Participants underwent baseline in-clinic assessments, including the Unified Parkinson's Disease Rating Scale (UPDRS), and were provided smartphones with an Android operating system that contained a smartphone application that assessed voice, posture, gait, finger tapping, and response time. Participants then took the smart phones home to perform the five tasks four times a day for a month. Once a week participants had a remote (telemedicine) visit with a Parkinson disease specialist in which a modified (excluding assessments of rigidity and balance) UPDRS performed. Using statistical analyses of the five tasks recorded using the smartphone from 10 individuals with PD and 10 controls, we sought to: (1) discriminate whether the participant had PD and (2) predict the modified motor portion of the UPDRS. Results: Twenty participants performed an average of 2.7 tests per day (68.9% adherence) for the study duration (average of 34.4 days) in a home and community setting. The analyses of the five tasks differed between those with Parkinson disease and those without. In discriminating participants with PD from controls, the mean sensitivity was 96.2% (SD 2%) and mean specificity was 96.9% (SD 1.9%). The mean error in predicting the modified motor component of the UPDRS (range 11-34) was 1.26 UPDRS points (SD 0.16). Conclusion: Measuring PD symptoms via a smartphone is feasible and has potential value as a diagnostic support tool.

Objective:To determine whether providing remote neurologic care into the homes of people with Parkinson disease (PD) is feasible, beneficial, and valuable.Methods:In a 1-year randomized controlled trial, we compared usual care to usual care supplemented by 4 virtual visits via video conferencing from a remote specialist into patients' homes. Primary outcome measures were feasibility, as measured by the proportion who completed at least one virtual visit and the proportion of virtual visits completed on time; and efficacy, as measured by the change in the Parkinson's Disease Questionnaire–39, a quality of life scale. Secondary outcomes included quality of care, caregiver burden, and time and travel savings.Results:A total of 927 individuals indicated interest, 210 were enrolled, and 195 were randomized. Participants had recently seen a specialist (73%) and were largely college-educated (73%) and white (96%). Ninety-five (98% of the intervention group) completed at least one virtual visit, and 91% of 388 virtual visits were completed. Quality of life did not improve in those receiving virtual house calls (0.3 points worse on a 100-point scale; 95% confidence interval [CI] −2.0 to 2.7 points; p = 0.78) nor did quality of care or caregiver burden. Each virtual house call saved patients a median of 88 minutes (95% CI 70–120; p < 0.0001) and 38 miles per visit (95% CI 36–56; p < 0.0001).Conclusions:Providing remote neurologic care directly into the homes of people with PD was feasible and was neither more nor less efficacious than usual in-person care. Virtual house calls generated great interest and provided substantial convenience.ClinicalTrials.gov identifier:NCT02038959.Classification of evidence:This study provides Class III evidence that for patients with PD, virtual house calls from a neurologist are feasible and do not significantly change quality of life compared to in-person visits. The study is rated Class III because it was not possible to mask patients to visit type.

Background Virtual visits through web-based video conferencing can increase access to specialty care for individuals with Huntington disease (HD) and facilitate research participation. Objective To determine the feasibility of conducting virtual visits directly into the homes of individuals with HD, to assess the reliability of conducting remote versus in-person motor assessments, and to determine the test-retest reliability of conducting motor assessments remotely. Methods Individuals with mild to moderate HD underwent baseline in-person clinic assessments and completed a HD care survey. Participants were randomized to receive three virtual visits from one of two physicians over four months that included a modified Unified Huntington's Disease Rating Scale motor examination (excluding rigidity and balance assessments) via web-based video conferencing. Intraclass coefficients (ICC) were calculated to determine the level of agreement between remote and in-person assessments. Participants also completed a survey on their interest in telemedicine. Results Thirteen individuals underwent baseline assessments, eleven (85%) participants completed at least one virtual visit, and 27 (82%) of 33 total virtual visits were completed. Remote motor scores demonstrated good reliability (ICC = 0.78; n = 11) compared to in-person motor scores. Test-retest reliability of motor scores conducted remotely was excellent (ICC = 0.90; n = 11). Participants expressed moderate future interest in using virtual visits to participate in research and to receive care. Conclusion In this pilot study, virtual visits into the home were feasible and reliable for conducting motor assessments in HD. Larger scale studies need to confirm and generalize these findings to a broader population of participants.

BACKGROUND "Practice effects" (PE), or performance improvements due to prior exposure to testing, are known to confound cognitive test results, particularly when short intervals occur between two test sessions. OBJECTIVE We examined two subsamples with short or long re-test intervals from a recent clinical trial. METHODS Thirty-four non-depressed adults with mild Huntington Disease (HD) participated. Three cognitive tests were administered at screening and again at baseline, before active treatment randomization. Half the sample had a 24-hour retest interval while the other half was >6-days. RESULTS The two groups differed on demographic/clinical factors (age, Total Motor Score and Total Functional Capacity). After controlling for age and motor score, PE differences were found on three of the five UHDRS cognitive tests: the longer interval group showed larger PE on Symbol-Digit Modalities and Stroop color, while the rapid interval group had larger PE on Stroop interference. Controlling for screening cognitive performance yielded similar results. CONCLUSIONS Length of interval between screening and baseline visits and level of disease severity may influence stability of UHDRS cognitive test results in clinical trials in HD.

To determine if the addition of video coaching to an obstetrics and gynecology resident laparoscopic simulation curriculum improves acquisition of suturing skills.Randomized controlled trial (Canadian Task Force classification I).Academic teaching hospital with a residency program in obstetrics and gynecology.Twenty obstetrics and gynecology residents undergoing a 4-week laparoscopic simulation curriculum were video recorded weekly performing a suturing task on a validated vaginal cuff model.Residents were randomized to standard simulation curriculum or standard curriculum plus weekly video coaching by an expert laparoscopic surgeon. Primary outcome measure was comparison of weekly Global Operative Assessment of Laparoscopic Skills plus Vaginal Cuff Metrics (GOALS+) scores of the suturing task.Baseline GOALS+ scores did not differ across training groups (p = .406), although "senior" (postgraduate years 3 and 4) residents initially had significantly higher GOALS+ scores than "junior" (postgraduate years 1 and 2) residents (p .001). GOALS+ scores significantly improved from week 1 to week 2 in the intervention group compared with the control group (p .05). Junior coached residents had significantly higher GOALS+ scores at week 2 (mean, 28.06; standard deviation, 3.10) compared with the junior control residents (mean, 20.75; standard deviation, 6.38; p .04). Over the 4-week period all residents showed significant improvement (p = .005), with novice residents improving more than experienced residents (p = .001). The junior coached residents exhibited a significant difference between weeks 1 and 2 when compared with the junior residents undergoing the standard curriculum.Video coaching during laparoscopic simulation training has the greatest impact early in junior learners' skill acquisition, thus providing another tool for simulation training curricula.

This study explored the relationship of experiential avoidance (eg, the tendency to avoid, suppress, or otherwise control internal experiences even when doing so causes behavioral harm) to alcohol use disorders and alcohol-related problems.Cross-sectional data were collected from 240 undergraduate college students in their first year in college between December 2009 and April 2010.Participants completed a diagnostic interview and online self-report survey.Students with a history of alcohol abuse or dependence had significantly higher levels of experiential avoidance relative to students with no alcohol use disorder diagnosis. A hierarchical linear regression analysis found that experiential avoidance significantly predicted alcohol-related problems, even after controlling for gender and psychological distress. Furthermore, experiential avoidance mediated the relationship of psychological distress to alcohol-related problems.These findings suggest that experiential avoidance may play a role in problematic alcohol use among college students.

Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P .001), cognitive (P .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [-0.05 to 0.11]), cognitive (-0.54 [-0.67 to -0.40] vs 0.22 [0.12 to 0.32]), and functional (-0.08 [-0.09 to -0.06] vs -0.01 [-0.02 to 0]) measures compared with those without expansion (P .001 for all); behavioral domain scores did not diverge significantly between groups.Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Living in poverty and living in areas of concentrated poverty pose multiple risks for child development and for overall health and wellbeing. Poverty is a major risk factor for several mental, emotional, and behavioral disorders, as well as for other developmental challenges and physical health problems. In this paper, the Promise Neighborhoods Research Consortium describes a science-based framework for the promotion of child health and development within distressed high-poverty neighborhoods. We lay out a model of child and adolescent developmental outcomes, and integrate knowledge of potent and malleable influences to define a comprehensive intervention framework to bring about a significant increase in the proportion of young people in high-poverty neighborhoods who will develop successfully. Based on a synthesis of research from diverse fields, we designed the Creating Nurturing Environments framework to guide community-wide efforts to improve child outcomes and reduce health and educational inequalities.

Huntington disease (HD) is a progressive, fatal, autosomal dominant neurodegenerative disease that primarily affects movement, cognition, and psychiatric functions. Diagnosis of HD is based on the presence of unequivocal motor signs of HD, in conjunction with a positive genetic test for the HD CAG expansion or a confirmed family history of HD. Most people with the HD gene appear healthy throughout their youth and early adulthood, and then gradually develop signs and symptoms of HD, often leading to a diagnosis in middle age. The age of diagnosis varies in accordance with the number of CAG repeats on the expanded allele, although there is also substantial individual variability not accounted for by this genetic factor (Andrew et al., 1993; Gusella, MacDonald, Ambrose, & Duyao, 1993). A growing community of researchers is directing efforts at finding treatments to delay onset or slow the progression of early pathological changes in an attempt to reduce the tremendous personal and social costs of HD. Finding effective therapeutic or preventive treatments for HD depends critically on the ability to reliably and sensitively measure clinical signs of disease. Cognitive measures have excellent potential both for identifying individuals beginning to show subtle signs prior to the diagnosis of HD who might be suitable for clinical trials, and as sensitive outcome measures in HD trials. Cognition is an important target for therapeutic trials because even subtle cognitive changes can affect functional abilities like work performance, driving, and financial management. Cognition is actively studied in the HD prodrome, with more than 150 empirical reports of neurocognitive function published since the genetic mutation for HD was identified in 1993. In early studies, the evidence of cognitive dysfunction was inconsistent. But more recent, adequately powered studies have revealed that people with the HD prodrome have poorer performance on measures of attention, working memory, processing speed, psychomotor functions, episodic memory, emotion processing, sensory-perceptual functions, and executive functions (Johnson et al., 2007; Kirkwood et al., 2000; Paulsen et al., 2006a; Paulsen et al., 2008; Paulsen et al., 2001; Pirogovsky et al., 2007; e.g., Stout et al., 2007). The use of cognitive measures in clinical trials requires a substantial knowledge base, indicating when in the HD prodrome cognitive changes can be reliably detected, and which measures show adequate sensitivity. The PREDICT-HD study was designed to address these questions. PREDICT-HD is a 31-site international study of potential clinical and biological markers of HD in individuals with the CAG-expansion for HD, but who did not meet criteria based on motor impairment for diagnosis at the time of enrolment. The PREDICT-HD cohort is large, with more than 700 non-diagnosed CAG-expanded (prodromal) participants. For each participant, age-conditioned estimates of time to onset of motor disease were derived using a survival analysis regression equation based on CAG repeat length (Langbehn et al., 2004). Estimated time to motor disease onset in the sample varies from 5 to 25 years. The size and diversity of this sample makes it possible to stratify participants based on their estimated proximities to diagnosis, allowing an estimation of when, in the extended period leading up to HD diagnosis, cognitive signs can be detected, and which cognitive measures appear to have the most promise for detecting change in longitudinal studies. We report findings based on three stratified prodromal HD groups, a far from diagnosis group (FAR) estimated to be more than 15 years from diagnosis, a middle group, estimated to be between 9 and 15 years from diagnosis (MID), and a near diagnosis group, estimated to be less than 9 years from diagnosis (NEAR). For each of these groups compared to controls, we computed effect sizes for individual cognitive measures, allowing a direct comparison of all the tasks in our cognitive assessment. This allows a determination of which tasks are most adversely affected during the HD prodrome, and an upper-limit estimate of how early in the prodromal phase significant effects could be detected (Paulsen et al., 2008). Additionally, we examined the associations between cognitive findings and results of the clinical motor examination, which also reveals subtle signs prior to diagnosis (Biglan et al., 2009). Thus, this study provides a comprehensive depiction of the cognitive prodrome for HD.

Relatively little is known about patient satisfaction with Parkinson's disease (PD) care and the use of support groups in the United States. We surveyed members of the Muhammad Ali Parkinson's Disease Registry to assess satisfaction with medical care and to evaluate support group use. Satisfaction was measured on a 5-point Likert scale, with high satisfaction defined as a four or five. We used multiple logistic regression to identify factors associated with high satisfaction and support group use. The response rate was 38% (726 of 1923). Most (57%) expressed high satisfaction with PD care. Individuals were most satisfied with the time their provider spent with them (61%) and PD education (56%) but least satisfied with prognostic information (35%) and information about non-drug interventions (28%). Patients seeing a PD specialist were three times more satisfied with their care than those seeing a general neurologist (OR = 3.00, 95% CI: 1.92-4.71; P < 0.0001). Support group use is common, and 61% of survey respondents had attended one at any point. Caucasian race (OR = 2.85, 95% CI: 1.45-5.61), PD duration (OR = 1.05 per year, CI: 1.01-1.10), and PD specialist care (OR = 1.80, CI: 1.16-2.77) were associated with greater support group attendance. Overall, 49% reported high satisfaction with their support group. The greatest concerns were specific needs not being addressed (15%) and insufficient expertise within the group (14%). Most individuals with Parkinson's disease expressed high levels of satisfaction, especially with specialist care. Specialty care and improved education, in the clinic or through support groups, may enhance satisfaction and health care quality.

Idiopathic Parkinson's disease (PD) and progressive supranuclear palsy (PSP) are distinct clinicopathological entities characterized by α-synuclein and tau pathology, respectively. They have occasionally been reported to co-exist in the same patient. We describe a rare case of a 73-year-old Caucasian woman diagnosed as idiopathic PD 5 years before her death yet at autopsy had not only PD, but also PSP. Although this patient fulfilled clinical criteria for idiopathic PD and did not have supranuclear ophthalmoplegia, she had several atypical features, including early postural instability with falls, early dysphagia, and a relatively rapid course. In conclusion, this case and a literature review highlight the co-existence of synuclein and tau pathology in the same patient and demonstrate that multiple diagnoses may exist in patients presenting with parkinsonism. The clinical heterogeneity seen in parkinsonism may reflect the occurrence of combined pathology.

We conducted a randomized, controlled pilot trial to evaluate the feasibility of providing subspecialty care via telemedicine for patients with Parkinson's disease residing in a remote community located approximately 130 miles from an academic movement disorders clinic. Study participants were randomized to receive telemedicine care with a movement disorder specialist at the University of Rochester or to receive their usual care. Participants in the telemedicine group received three telemedicine visits over six months. Feasibility, as measured by the completion of telemedicine visits, was the primary outcome measure. Secondary measures were quality of life, patient satisfaction, and clinical outcomes. Ten participants residing in the community were randomized to receive telemedicine care (n = 6) or their usual care (n = 4). Four nursing home patients were assigned to telemedicine. Those receiving telemedicine completed 97% (29 of 30) of their telemedicine visits as scheduled. At the study's conclusion, 13 of 14 study participants opted to receive specialty care via telemedicine. Compared with usual care, those randomized to telemedicine had significant improvements in quality of life (3.4 point improvement vs. 10.3 point worsening on the Parkinson's Disease Questionnaire 39; P = 0.04) and motor performance (0.3 point improvement vs. 6.5 point worsening on the Unified Parkinson's Disease Rating Scale, motor subscale; P = 0.03). Relative to baseline, nursing home patients experienced trends toward improvement in quality of life and patient satisfaction. Providing subspecialty care via telemedicine for individuals with Parkinson's disease living remotely is feasible.

This paper reports relationships between methamphetamine use and behaviors and social influences using data from a population-based survey of 8th- and 11th-grade students in Oregon for the 2001-2003 school years. We analyze methamphetamine use within a general problem behavior framework to identify malleable correlates of behavior for future prevention interventions. We specifically test two models of methamphetamine use employing logistic regression analysis: one comprised of behaviors and traits of the individual students and another focusing on peer and parental influences. This study finds adolescent methamphetamine use related to several problem behaviors. However, the specific problems vary by grade and are moderated by gender. Findings indicate the need for tailored interventions targeting gender/grade-specific behaviors or problems such as antisocial activities, risky sex, and depression, as well as social influences such as peers engaging in antisocial behaviors or using drugs and parents favoring drug use or poorly monitoring or setting limits for their children.

Objective: The objective of the Predict-HD study is to use genetic, neurobiological and refined clinical markers to understand the early progression of Huntington’s disease (HD), prior to the point of traditional diagnosis, in persons with a known gene mutation. Here we estimate the approximate onset and initial course of various measurable aspects of HD relative to the time of eventual diagnosis. Methods: We studied 438 participants who were positive for the HD gene mutation, but did not yet meet the diagnostic criteria for HD and had no functional decline. Predictability of baseline cognitive, motor, psychiatric and imaging measures was modelled non-linearly using estimated time until diagnosis (based on CAG repeat length and current age) as the predictor. Results: Estimated time to diagnosis was related to most clinical and neuroimaging markers. The patterns of association suggested the commencement of detectable changes one to two decades prior to the predicted time of clinical diagnosis. The patterns were highly robust and consistent, despite the varied types of markers and diverse measurement methodologies. Conclusions: These findings from the Predict-HD study suggest the approximate time scale of measurable disease development, and suggest candidate disease markers for use in preventive HD trials.

The objective of this study was to examine the relationship between CAG repeat length (CAGn) and clinical progression in patients with Huntington's disease (HD). There are conflicting reports about the relationship between CAGn and clinical progression of HD. We conducted an analysis of data from the Coenzyme Q10 and Remacemide Evaluation in Huntington's Disease (CARE-HD) clinical trial. We modeled progression over 30 months on the Unified Huntington's Disease Rating Scale (UHDRS) and supplemental neuropsychological and behavioral tests using multiple linear regression. Mean subject age was 47.9 +/- 10.5 years and mean CAGn was 45.0 +/- 4.1. Multiple linear regression revealed statistically significant associations between CAGn and worsening on several motor, cognitive, and functional outcomes, but not behavioral outcomes. Many effects were clinically important; 10 additional CAG repeats were associated with an 81% increase in progression on the Independence Scale. These associations were not observed in the absence of age adjustment. Age at the time of assessment confounds the association between CAGn and progression. Adjusting for age shows that longer CAGn is associated with greater clinical progression of HD. This finding may account for the variable results from previous studies examining CAGn and progression. Adjusting for CAGn may be important for clinical trials.

In a randomized controlled trial, we evaluated the effect on tobacco use onset among middle school students of Family Communications (FC) activities designed to mobilize parental influences against tobacco use and Youth Anti-tobacco Activities (YAT) designed to market anti-tobacco norms to adolescents. We conducted a simple, two-condition experimental design in which 40 middle schools, with a prevalence of tobacco use at or above the Oregon median, received, by random assignment, either the intervention or no intervention. State, county, and local prevention coordinators around Oregon served as liaisons to schools. To generate interest, staff made presentations to these groups and distributed marketing packets at several conferences. Dependent variables were indices of smoking prevalence and use of smokeless tobacco (ST) in the prior month. Additionally, we created an intervention manual so that other communities could replicate this study. The findings suggest that efforts to influence parents to discourage their children's tobacco use and efforts to market an anti-tobacco perspective to teens are effective in preventing smoking. The impact of YAT is consistent with experimental and nonexperimental evaluations of media campaigns to influence young people not to smoke.

The objective of this analysis was to identify variables that predict the initiation of smoking among adolescents, and the development of susceptibility to smoking, over a 2-year period. We assessed variables that might predict later smoking among nonsmoking students in grades 7 and 9 and assessed their smoking status 2 years later, when they were in grades 9 and 11, thus receiving data from 4,130 students at two time points. Initiation of weekly smoking over the 2 years was associated with having a parent, sibling, or close friend who smokes; low school grades; higher levels of deviant behavior; susceptibility to smoking; use of smokeless tobacco; and for 7th graders, perception of higher levels of normative smoking. Susceptibility, defined as not being able to rule out the idea of smoking a year after the survey, was identified as a strong predictor of smoking and a valuable intermediary measure. We also assessed factors associated with the prediction of susceptibility 2 years post-test. Susceptibility to smoking was associated with deviant behavior, low grades, lower parental monitoring, relaxed parental attitude toward youth smoking, ease of access to tobacco, and lower exposure to anti-tobacco messages. This study provides support for the idea that susceptibility to smoking could be a useful outcome variable for tobacco research, as an intermediary to the initiation of smoking. In addition, evidence indicates that theoretically manipulable variables, including access to tobacco and exposure to anti-tobacco information, have the potential to influence susceptibility to smoking over a time.

Purpose To investigate the causes and characteristics of glaucoma in children following cataract surgery. Methods Twenty-four patients (37 eyes) with uncomplicated congenital cataracts who developed glaucoma after cataract surgery were studied retrospectively. Variables included cataract morphology, surgical techniques, post-operative complications, time to the onset of glaucoma, gonioscopic findings, presence of microcornea and the histopathologic characteristics of the filtration angle (in one case). Results There was a bimodal onset of glaucoma after cataract surgery. Early-onset glaucoma occurred at a mean age of 6 months in 15 eyes and delayed-onset glaucoma at a mean age of 12 years in 22 eyes. Early-onset glaucoma was significantly (p=0.018) more likely to be due to angle closure than delayed-onset glaucoma. With delayed-onset glaucoma, the filtration angle was open in 86% of eyes and significantly (p=0.006) more eyes in the delayed-onset group had microcornea. Medical treatment was sufficient to control intraocular pressure in the delayed-onset group while the early-onset group required surgical treatment (P

Remote assessments of individuals with a neurological disease via telemedicine have the potential to reduce some of the burdens associated with clinical care and research participation. We aim to evaluate the feasibility of conducting the Montreal Cognitive Assessment remotely in individuals with movement disorders. A pilot study derived from two telemedicine trials was conducted. In total, 17 individuals with movement disorders (8 with Parkinson disease and 9 with Huntington disease) had Montreal Cognitive Assessment examinations evaluated in-person and remotely via web-based video conferencing to primarily determine feasibility and potential barriers in its remote administration. Administering the Montreal Cognitive Assessment remotely in a sample of movement disorder patients with mild cognitive impairment is feasible, with only minor common complications associated with technology, including delayed sound and corrupted imaging for participants with low connection speeds. The Montreal Cognitive Assessment has the potential to be used in remote assessments of patients and research participants with movement disorders.

The authors calculated binary indicators of seven positive and 23 negative behaviours for 22,898 8th and 15,828 11th grade students who participated in the Oregon Healthy Teens Survey across two school years. Relationships among these variables, using both the Jaccard measure of co-occurrence and the relative risk for each member of each variable pair, given exposure to the other, showed strong inter-relationships within, but not between, the sets of behaviours. The likelihood of negative behaviours given negative behaviours was much stronger than the likelihood of positive behaviours given positive behaviours. Positive behaviours provided little protection against the likelihood of negative behaviors.

Objective: To examine the relation between rates of sales of tobacco to minors and youth smoking prevalence. Design: Repeated annual cross sectional surveys. Setting: Seventy five communities in Oregon. Participants: A random sample of students in grades 8 and 11 (ages 13 and 17 years) and retail outlets in each participating community. Main outcome measures: Thirty day and daily smoking prevalence. Results: The rate of illegal merchant sales in the communities was related to the smoking rate for 11th graders in those communities, but not for 8th graders. For every 10% increase in illegal sales rates there was an estimated 0.8% increase in 11th grade 30 day smoking prevalence and a 0.4% increase in daily smoking. Communities with lower illegal merchant sales rates had expanded use of social sources and reduced use of commercial sources by 11th graders, with the opposite pattern seen in 8th graders. Conclusions: There appears to be a relatively small positive linear relation between the community rate of sales to minors and 11th grade youth smoking prevalence in those communities. Youth adjust their tobacco sources depending on the level of commercial availability.

The purpose of the research presented in this article was to characterize restless legs syndrome (RLS) in a headache population and correlate treatment induced risks with dopamine blockers. Fifty patients with severe headache who were admitted to an outpatient infusion center were enrolled. The diagnosis of RLS was established using the International Restless Legs Syndrome Study Group criteria. Patients were screened for baseline akathisia using an akathisia scale and reexamined for akathisia after receiving intravenous infusion with one of four dopamine receptor blocking agents as treatment for their headaches. A change from baseline to post-infusion assessment of two points on a global assessment of akathisia was considered positive for drug-induced akathisia. Our results indicated that 41 (82%) of patients had episodic or chronic migraine. The rest had new daily persistent headache, cluster, or posttraumatic headache. Seventeen subjects (34%) met the criteria for RLS. Nineteen (38%) of the subjects developed drug-induced akathisia. Thirteen (76.5%) of the subjects with RLS developed akathisia compared with only 6 of the 33 (18.2%) without RLS (PFinally, we concluded that headache patients with RLS are at a greatly increased risk of developing drug-induced akathisia when treated with intravenous dopamine receptor blocking agents.

The purpose of this study was to investigate the long-term outcome of high hypermetropic refractive errors in childhood. We retrospectively reviewed data from the clinical records of 164 children with spherical equivalent (SE) hypermetropic refractive errors in three medical centers collected over 29 years. Refractive errors between +1.00 and +3.00 diopter (D) on initial examination were classified as mild hypermetropia and those +5.00D or greater were classified as high hypermetropia. The four variables studied were, age, refractive error, strabismus, and gender. The rate of reduction in hypermetropic refractive error was calculated over time in years. We identified subgroups according to age, gender, and initial refractive error. Seventy-eight children with high hypermetropia and 86 children with mild hypermetropia were studied. High hypermetropia was detected at a mean age of 3.3 years, while mild hypermetropia was detected at a mean 4 years of age. The mean follow-up was 6.6 years for high hypermetropia and 6.4 years for mild hypermetropia. Over the follow-up period, children in all subgroups tended to reduce their refractive errors. The reduction in refraction power was small for both mild and high hypermetropic refractive errors. Amblyopia in the high hypermetropia group was more common and more refractory to treatment. Most children with hypermetropia of less than +3.00D experience a reduction in hyperopic refractive error over time and will outgrow any need for corrective lenses. Children with hyperopia greater than +5.00D will not experience a significant reduction in the power of the refractive error.

Background Tetrabenazine, a treatment for chorea in Huntington disease, carries a boxed warning due to safety, especially related to suicidality. Objective To compare the frequency of depressed mood and suicidality among a closely monitored cohort of individuals with Huntington disease who were exposed and not exposed to tetrabenazine. Methods A longitudinal prospective study involving 1360 individuals with HD evaluated at 48 research centers in Australia, Canada, and the United States was examined for frequency of depressed mood that triggered a risk assessment, suicidal thoughts, suicide attempts, and completed suicide among individuals with prior, new, and no exposure to tetrabenazine.. Seventy-seven individuals were on tetrabenazine at study enrollment (prior exposure), 64 individuals were exposed to tetrabenazine during the study's course (new exposure), and 1219 individuals had no exposure to tetrabenazine. Results The hazard ratio for depressed mood among those with prior exposure to tetrabenazine compared to no exposure was 0.9 (95% CI, 0.5-1.6) and for those with new exposure compared to no exposure was 1.2 (95% CI, 0.8-1.9). One individual (1.3%) with prior exposure, one individual (1.6%) with new exposure, and 35 individuals (2.9%) with no exposure to tetrabenazine reported suicidal thoughts. The hazard ratio for suicidal ideation among those with prior exposure to tetrabenazine compared to no exposure was 0.5 (95% CI, 0.1-3.8) and for those with new exposure to tetrabenazine compared to no exposure was 0.6 (95% CI, 0.1-4.4). Among individuals with prior or new exposure to tetrabenazine, no suicide attempts or suicides occurred. Among those with no exposure to tetrabenazine 17 suicide attempts (1.4%) and four suicides (0.3%) occurred. Conclusions In a large observational study with close clinical supervision, tetrabenazine treatment was not associated with an increased risk of depressed mood, suicidal ideation, suicide attempts, or suicide.

We analyzed plasma 8OHdG concentrations in 20 individuals enrolled in the Pre-2CARE study before and after treatment with CoQ. Treatment resulted in a mean reduction in 8OHdG of 2.9 ± 2.9 pg/ml for the cohort (p = 0.0003) and 3.0 ± 2.6 pg/ml, for the HD group (p = 0.002). Baseline 8OHdG levels were not different between individuals with HD and controls (19.3 ± 3.2 pg/ml vs. 19.5 ± 4.7 pg/ml, p = 0.87) though baseline CoQ levels were elevated in HD compared with controls (p < 0.001). CoQ treatment reduces plasma 8OHdG and this reduction may serve as a marker of pharmacologic activity of CoQ in HD.

Importance Optimizing assessments of rate of progression in Parkinson disease (PD) is important in designing clinical trials, especially of potential disease-modifying agents. Objective To examine the value of measures of impairment, disability, and quality of life in assessing progression in early PD. Design, Setting, and Participants Inception cohort analysis of data from 413 patients with early, untreated PD who were enrolled in 2 multicenter, randomized, double-blind clinical trials. Interventions Participants were randomly assigned to 1 of 5 treatments (67 received creatine, 66 received minocycline, 71 received coenzyme Q10, 71 received GPI-1485, and 138 received placebo). We assessed the association between the rates of change in measures of impairment, disability, and quality of life and time to initiation of symptomatic treatment. Main Outcomes and Measures Time between baseline assessment and need for the initiation of symptomatic pharmaceutical treatment for PD was the primary indicator of disease progression. Results After adjusting for baseline confounding variables with regard to the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II score, the UPDRS Part III score, the modified Rankin Scale score, level of education, and treatment group, we assessed the rate of change for the following measurements: the UPDRS Part II score; the UPDRS Part III score; the Schwab and England Independence Scale score (which measures activities of daily living); the Total Functional Capacity scale; the 39-item Parkinson’s Disease Questionnaire, summary index, and activities of daily living subscale; and version 2 of the 12-item Short Form Health Survey Physical Summary and Mental Summary. Variables reaching the statistical threshold in univariate analysis were entered into a multivariable Cox proportional hazards model using time to symptomatic treatment as the dependent variable. More rapid change (ie, worsening) in the UPDRS Part II score (hazard ratio, 1.15 [95% CI, 1.08-1.22] for 1 scale unit change per 6 months), the UPDRS Part III score (hazard ratio, 1.09 [95% CI, 1.06-1.13] for 1 scale unit change per 6 months), and the Schwab and England Independence Scale score (hazard ratio, 1.29 [95% CI, 1.12-1.48] for 5 percentage point change per 6 months) was associated with earlier need for symptomatic therapy. Conclusions and Relevance In early PD, the UPDRS Part II score and Part III score and the Schwab and England Independence Scale score can be used to measure disease progression, whereas the 39-item Parkinson’s Disease Questionnaire and summary index, Total Functional Capacity scale, and the 12-item Short Form Health Survey Physical Summary and Mental Summary are not sensitive to change. Trial Registration clinicaltrials.gov Identifiers:NCT00063193andNCT00076492

Importance Understanding the natural history of Huntington disease will inform patients and clinicians on the disease course and researchers on the design of clinical trials. Objective To determine the longitudinal change in clinical features among individuals with Huntington disease compared with controls. Design, Setting, and Participants Prospective, longitudinal cohort study at 44 research sites in Australia (n = 2), Canada (n = 4), and the United States (n = 38). Three hundred thirty-four individuals with clinically manifest Huntington disease who had at least 3 years of annually accrued longitudinal data and 142 controls consisting of caregivers and spouses who had no genetic risk of Huntington disease. Main Outcomes and Measures Change in movement, cognition, behavior, and function as measured by the Unified Huntington’s Disease Rating Scale, the Mini-Mental State Examination, and vital signs. Results Total motor score worsened by 3.0 points (95% CI, 2.5-3.4) per year and chorea worsened by 0.3 point per year (95% CI, 0.1-0.5). Cognition declined by 0.7 point (95% CI, 0.6-0.8) per year on the Mini-Mental State Examination. Behavior, as measured by the product of frequency and severity score on the Unified Huntington’s Disease Rating Scale, worsened by 0.6 point per year (95% CI, 0.0-1.2). Total functional capacity declined by 0.6 point per year (95% CI, 0.5-0.7). Compared with controls, baseline body mass index was lower in those with Huntington disease (25.8 vs 28.8; P P Conclusions and Relevance Over 3 years, the cardinal features of Huntington disease all declined in a monotonic manner. These data quantify the natural history of the disease and may inform the design of trials aimed at reducing its burden. Trial Registration clinicaltrials.gov Identifier:NCT00313495

Objective To investigate the visual acuity and binocular function results achieved in children who had monocular cataracts removed before 8 years of age. Design Retrospective, noncomparative case series. Participants Clinical records of 171 patients who underwent a unilateral cataract removal between January 1986 and 1996 were reviewed retrospectively. Seventy-four eyes were included in the study: 19 congenital, 11 developmental, 19 posterior lenticonus, 19 traumatic, and 6 complicated cataracts. Patients with less than 2 years of follow-up; eyes with cataracts resulting from retinoblastoma; prematurity; and those associated with dense corneal scars, lens dislocation, and persistent hyperplastic primary vitreous were excluded. Intervention Visual acuity was measured by means of age-appropriate tests such as the fixation pattern, Allen object recognition cards, isolated optotypes with the Sheridan Gardiner test, and Snellen letters. Sensory fusion was assessed with the Worth 4-dot test, and stereo acuity was assessed with the Titmus stereo test. Main outcome measures Cataracts were classified regarding type, extent, age at onset, duration of the opacity, age at surgery, method of removal, development of secondary membrane , form of optical rehabilitation, and presence of strabismus. Visual acuity levels between 6/6 and 6/12 were considered "good." Fusion of the Worth 4-dot test at distance and near, and presence of stereo acuity of 100 seconds of arc or better were considered "good" binocular function. Multiple logistic regression analysis was used to define factors that correlated with achieving good visual outcome. Results Visual acuity was 6/12 or better in 27 (36.5%) eyes. However, good binocular function was achieved in only 11 of these 27 patients. Results of univariate analysis showed that later age at onset of cataract and absence of strabismus were significant for good visual acuity and binocular function. The presence of strabismus increases the risk of not achieving good visual acuity by 5.45-fold. Conclusions Good visual acuity and binocular function can be achieved after removal of monocular cataracts in visually immature children. Patients with strabismus at presentation or during the follow-up period have the least chance of achieving a good sensory result.

OBJECTIVE—Experimental evaluation of comprehensive community wide programme to prevent adolescent tobacco use. DESIGN—Eight pairs of small Oregon communities (population 1700 to 13 500) were randomly assigned to receive a school based prevention programme or the school based programme plus a community programme. Effects were assessed through five annual surveys (time 1-5) of seventh and ninth grade (ages 12-15 years) students. INTERVENTION—The community programme included: (a) media advocacy, (b) youth anti-tobacco activities, (c) family communications about tobacco use, and (d) reduction of youth access to tobacco. MAIN OUTCOME MEASURE—The prevalence of self reported smoking and smokeless tobacco use in the week before assessment. RESULTS—The community programme had significant effects on the prevalence of weekly cigarette use at times 2 and 5 and the effect approached significance at time 4. An effect on the slope of prevalence across time points was evident only when time 2 data points were eliminated from the analysis. The intervention affected the prevalence of smokeless tobacco among grade 9 boys at time 2. There were also significant effects on the slope of alcohol use among ninth graders and the quadratic slope of marijuana for all students. CONCLUSION—The results suggest that comprehensive community wide interventions can improve on the preventive effect of school based tobacco prevention programmes and that effective tobacco prevention may prevent other substance use. Keywords: smokeless tobacco; primary prevention; intervention studies; adolescent behaviour; community interventions

Epidemiological research shows some ethnic-group differences in the prevalence of substance use. This approach does not address the question of whether there are ethnic-group differences in the models that are needed to understand the development of substance use. For this question we need to understand the relations between psychological constructs and their trajectories over time. In this paper we describe some approaches to studying ethnic-group differences in the predictors of substance use that illustrate probing for mediators, multisample analyses of structural models, and an experimental trial of a preventive intervention. Our studies found some ethnic-group differences in the structure of constructs and the relations between variables, but many similarities. The challenge for researchers is using appropriate research methods for studying ethnicity, uncovering the basis for ethnic-group differences when they occur, knowing when statistical differences are meaningful, and acknowledging when developmental models are comparable.

The psychometric properties of the Parenting Scale (Arnold, O'Leary, Wolff, and Acker, 1993), a 30-item instrument originally developed to assess the discipline practices of parents of preschool children, were examined for parents of middle school students. Subjects were 298 parents of middle school student identified as at-risk for problem behavior. An exploratory factor analysis identified two factors labeled 'Overreactivity' and 'Laxness', closely resembling two of the factors found by Arnold et al., but each of these factors contained only six items. Confirmatory factor analyses, using data from the first two assessments, replicated this factor structure. The factors were significantly correlated with measures of parents' behavior, with scales from the child Behavior Checklist and Parent Daily Reports, and with the Beck Depression Inventory. The Laxness factor was less robust than the Overreactivity factor.