New and continuing physician-based outpatient mental health care among children and adolescents during the COVID-19 pandemic in Ontario, Canada: a population-based study.

Objective: To assess physician-based mental health care utilization during the COVID-19 pandemic among children and adolescents new to care and those already engaged with mental health services, and to evaluate differences by sociodemographic factors. Study design: We performed a population-based repeated cross-sectional study using linked health and administrative databases in Ontario, Canada among all children and adolescents 3-17 years. We examined outpatient visit rates per 1,000 population for mental health concerns for those new to care (no physician-based mental healthcare for ≥1 year) and those with continuing care needs (any physician-based mental healthcare <1 year) following onset of the pandemic. Results: Among ~2.5 million children and adolescents (48.7% female, mean age 10.1 ± 4.3 years), expected monthly mental health outpatient visits were 1.5/1,000 for those new to mental health care and 5.4/1,000 for those already engaged in care. Following onset of the pandemic, visit rates for both groups were above expected [adjusted rate ratio (aRR) 1.22, 95% CI 1.17, 1.27; aRR 1.10, 95% CI 1.07, 1.12] for new and continuing care, respectively. The greatest increase above expected was among females (new: aRR 1.33, 95% CI 1.25, 1.42; continuing: aRR 1.22 95% CI 1.17, 1.26) and adolescents ages 13-17 years (new: aRR 1.31, 95% CI 1.27, 1.34; continuing: aRR 1.15 95% CI 1.13, 1.17). Mood and anxiety concerns were prominent among those new to care. Conclusion: In the 18 months following onset of the pandemic, outpatient mental health care utilization increased for those with new and continuing care needs, especially among females and adolescents.

Self-harm among youth during the first 28 months of the COVID-19 pandemic in Ontario, Canada: a population-based study.

BACKGROUND: Youth have reported worsening mental health during the COVID-19 pandemic. We sought to evaluate rates of pediatric acute care visits for self-harm during the pandemic according to age, sex and mental health service use. METHODS: We conducted a population-based, repeated cross-sectional study using linked health administrative data sets to measure monthly rates of emergency department visits and hospital admissions for self-harm among youth aged 10-17 years between Jan. 1, 2017, and June 30, 2022, in Ontario, Canada. We modelled expected rates of acute care visits for self-harm after the pandemic onset based on prepandemic rates. We reported relative differences between observed and expected monthly rates overall and by age group (10-13 yr and 14-17 yr), sex and mental health service use (new and continuing). RESULTS: In this population of about 1.3 million children and adolescents, rates of acute care visits for self-harm during the pandemic were higher than expected for emergency department visits (0.27/1000 population v. 0.21/1000 population; adjusted rate ratio [RR] 1.29, 95% confidence interval [CI] 1.19-1.39) and hospital admissions (0.74/10 000 population v. 0.43/10 000 population, adjusted RR 1.72, 95% CI 1.46-2.03). This increase was primarily observed among females. Rates of emergency department visits and hospital admissions for self-harm were higher than expected for both those aged 10-13 years and those aged 14-17 years, as well as for both those new to the mental health system and those already engaged in care. INTERPRETATION: Rates of acute care visits for self-harm among children and adolescents were higher than expected during the first 2 and a half years of the COVID-19 pandemic, particularly among females. These findings support the need for accessible and intensive prevention efforts and mental health supports in this population.

Impact of remuneration, extrinsic and intrinsic incentives on interprofessional primary care teams: protocol for a rapid scoping review.

INTRODUCTION: Interprofessional teams and funding and payment provider arrangements are key attributes of high-performing primary care. Several Canadian jurisdictions have introduced team-based models with different payment models. Despite these investments, the evidence of impact is mixed. This has raised questions about whether team-based primary care models are being implemented to facilitate team collaboration and effectiveness. Thus, we present a protocol for a rapid scoping review to systematically map, synthesise and summarise the existing literature on the impact of provider remuneration mechanisms and extrinsic and intrinsic incentives in team-based primary care. This review will answer three research questions: (1) What is the impact of provider remuneration models on team, patient, provider and system outcomes in primary care?; (2) What extrinsic and intrinsic incentives have been used in interprofessional primary care teams?; and (3) What is the impact of extrinsic and intrinsic team-based incentives on team, patient, provider and system outcomes? METHODS AND ANALYSIS: We will conduct a rapid scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews guidelines. We will search electronic databases (Medline, Embase, CINAHL, PsycINFO, EconLit) and grey literature sources (Google Scholar, Google). This review will consider all empirical studies and full-text English-language articles published between 2000 and 2022. Reviewers will independently perform the literature search, data extraction and synthesis of included studies. The Mixed Methods Appraisal Tool will be used to appraise the quality of evidence. The literature will be synthesised, summarised and mapped to themes that answer the research question of this review. ETHICS AND DISSEMINATION: Ethics approval is not required. Findings from this study will be written for publication in an open-access peer-review journal and presented at national and international conferences. Knowledge users are part of the research team and will assist with disseminating findings to the public, clinicians, funders and professional associations.

Sociodemographic Differences in Physician-Based Mental Health and Virtual Care Utilization and Uptake of Virtual Care Among Children and Adolescents During the COVID-19 Pandemic in Ontario, Canada: A Population-Based Study.

OBJECTIVE: We sought to evaluate the relationship between social determinants of health and physician-based mental healthcare utilization and virtual care use among children and adolescents in Ontario, Canada, during the COVID-19 pandemic. METHODS: This population-based repeated cross-sectional study of children and adolescents (3-17 years; N = 2.5 million) used linked health and demographic administrative data in Ontario, Canada (2017-2021). Multivariable Poisson regressions with generalized estimating equations compared rates of outpatient physician-based mental healthcare use during the first year of the COVID-19 pandemic with expected rates based on pre-COVID patterns. Analyses were conducted by socioeconomic status (material deprivation quintiles of the Ontario Marginalization index), urban/rural region of residence, and immigration status. RESULTS: Overall, pediatric physician-based mental healthcare visits were 5% lower than expected (rate ratio [RR] = 0.95, 95% confidence interval [CI], 0.92 to 0.98) among those living in the most deprived areas in the first year of the pandemic, compared with the least deprived with 4% higher than expected rates (RR = 1.04, 95% CI, 1.02 to 1.06). There were no differences in overall observed and expected visit rates by region of residence. Immigrants had 14% to 26% higher visit rates compared with expected from July 2020 to February 2021, whereas refugees had similarly observed and expected rates. Virtual care use was approximately 65% among refugees, compared with 70% for all strata. CONCLUSION: During the first year of the pandemic, pediatric physician-based mental healthcare utilization was higher among immigrants and lower than expected among those with lower socioeconomic status. Refugees had the lowest use of virtual care. Further work is needed to understand whether these differences reflect issues in access to care or the need to help inform ongoing pandemic recovery planning.

Utilization of Physician-Based Mental Health Care Services Among Children and Adolescents Before and During the COVID-19 Pandemic in Ontario, Canada.

IMPORTANCE: Public health measures to reduce the spread of COVID-19 have heightened distress among children and adolescents and contributed to a shift in delivery of mental health care services. OBJECTIVES: To measure and compare physician-based outpatient mental health care utilization before and during the COVID-19 pandemic and quantify the extent of uptake of virtual care delivery. DESIGN, SETTING, AND PARTICIPANTS: Population-based repeated cross-sectional study using linked health and administrative databases in Ontario, Canada. All individuals aged 3 to 17 years residing in Ontario from January 1, 2017, to February 28, 2021. EXPOSURES: Pre-COVID-19 period from January 1, 2017, to February 29, 2020, and post-COVID-19 onset from March 1, 2020, to February 28, 2021. MAIN OUTCOMES AND MEASURES: Physician-based outpatient weekly visit rates per 1000 population for mental health diagnoses overall and stratified by age group, sex, and mental health diagnostic grouping and proportion of virtual visits. Poisson generalized estimating equations were used to model 3-year pre-COVID-19 trends and forecast expected trends post-COVID-19 onset and estimate the change in visit rates before and after the onset of COVID-19. The weekly proportions of virtual visits were calculated. RESULTS: In a population of almost 2.5 million children and adolescents (48.7% female; mean [SD] age, 10.1 [4.3] years), the weekly rate of mental health outpatient visits was 6.9 per 1000 population. Following the pandemic onset, visit rates declined rapidly to below expected (adjusted relative rate [aRR], 0.81; 95% CI, 0.79-0.82) in April 2020 followed by a growth to above expected (aRR, 1.07; 95% CI, 1.04-1.09) by July 2020 and sustained at 10% to 15% above expected as of February 2021. Adolescent female individuals had the greatest increase in visit rates relative to expected by the end of the study (aRR, 1.26; 95% CI, 1.25-1.28). Virtual care accounted for 5.0 visits per 1000 population (72.5%) of mental health visits over the study period, with a peak of 5.3 visits per 1000 population (90.1%) (April 2020) and leveling off to approximately 70% in the latter months. CONCLUSIONS AND RELEVANCE: Physician-based outpatient mental health care in Ontario increased during the pandemic, accompanied by a large, rapid shift to virtual care. There was a disproportionate increase in use of mental health care services among adolescent female individuals. System-level planning to address the increasing capacity needs and to monitor quality of care with such large shifts is warranted.

Pharmacokinetics of rotigotine transdermal system in adolescents with idiopathic restless legs syndrome (Willis-Ekbom disease).

OBJECTIVE: To investigate the pharmacokinetics (PK) of rotigotine transdermal system in adolescents with moderate-to-severe idiopathic restless legs syndrome (RLS). METHODS: This multicenter, open-label, dose-escalation study enrolled patients ≥13 to <18 years of age. Rotigotine transdermal patches were applied daily and up-titrated weekly: 0.5, 1, 2, 3 mg/24 h. Blood samples were collected on the final day of each dose step. Primary PK variables were the apparent total body clearance (CL/f; L/h) and volume of distribution at steady state (VSS/f; L) of unconjugated rotigotine for each dose step, calculated for the PK per-protocol set (PKPPS). Other PK, safety, and efficacy variables (International RLS Study Group Rating Scale [IRLS]; Clinical Global Impressions Item 1 [CGI-1]) were assessed. RESULTS: Of 24 patients who received rotigotine, 23 completed all dose steps and 17 formed the PKPPS. Least-squares mean (95% confidence interval) CL/f and VSS/f values were broadly similar across all dose steps (CL/f: 0.5 mg/24 h: 676.86 [408.50-1121.51]; 1 mg/24 h: 671.72 [459.11-982.80]; 2 mg/24 h: 937.56 [658.50-1334.89]; 3 mg/24 h: 1088.77 [723.47-1638.53]; VSS/f: 5403.16 [2850.67-10,241.17]; 6220.79 [3842.05-10,072.28]; 7114.01 [4547.88-11,128.07]; 6037.92 [3598.36-10,131.41]). Among 23 patients with efficacy data, mean IRLS and CGI-1 scores improved at each dosage level. Adverse events reported by ≥3 patients were nausea (seven) and application site reactions (four). CONCLUSIONS: Key PK properties of rotigotine in adolescent patients with moderate-to-severe idiopathic RLS were comparable to those previously observed in adults. Rotigotine improved RLS symptoms and was well tolerated. ClinicalTrials.gov: NCT01495793.

Phosphorylation of pRb: mechanism for RB pathway inactivation in MYCN-amplified retinoblastoma.

A small, but unique subgroup of retinoblastoma has been identified with no detectable mutation in the retinoblastoma gene (RB1) and with high levels of MYCN gene amplification. This manuscript investigated alternate pathways of inactivating pRb, the encoded protein in these tumors. We analyzed the mutation status of the RB1 gene and MYCN copy number in a series of 245 unilateral retinoblastomas, and the phosphorylation status of pRb in a subset of five tumors using immunohistochemistry. There were 203 tumors with two mutations in RB1 (RB1-/- , 83%), 29 with one (RB1+/- , 12%) and 13 with no detectable mutations (RB1+/+ , 5%). Eighteen tumors carried MYCN amplification between 29 and 110 copies: 12 had two (RB1-/- ) or one RB1 (RB1+/- ) mutations, while six had no mutations (RB1+/+ ). Immunohistochemical staining of tumor sections with antibodies against pRb and phosphorylated Rb (ppRb) displayed high levels of pRb and ppRb in both RB1+/+ and RB1+/- tumors with MYCN amplification compared to no expression of these proteins in a classic RB1-/- , MYCN-low tumor. These results establish that high MYCN amplification can be present in retinoblastoma with or without coding sequence mutations in the RB1 gene. The functional state of pRb is inferred to be inactive due to phosphorylation of pRb in the MYCN-amplified retinoblastoma without coding sequence mutations. This makes inactivation of RB1 by gene mutation or its protein product, pRb, by protein phosphorylation, a necessary condition for initiating retinoblastoma tumorigenesis, independent of MYCN amplification.

Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome: An RCT.

OBJECTIVE: This double-blind, placebo-controlled, interventional trial was conducted to investigate the effects of rotigotine patch on periodic limb movement (PLM)-associated nocturnal systolic blood pressure (SBP) elevations. METHODS: Patients with moderate to severe restless legs syndrome (RLS) were randomized to rotigotine (optimal dose [1-3 mg/24 h]) or placebo. Continuous beat-to-beat blood pressure (BP) assessments were performed during polysomnography at baseline and at the end of 4-week maintenance. Primary outcome was change in number of PLM-associated SBP elevations (defined as slope of linear regression ≥2.5 mm Hg/beat-to-beat interval over 5 consecutive heartbeats [≥10 mm Hg]). Additional outcomes were total SBP elevations, PLM-associated and total diastolic BP (DBP) elevations, periodic limb movements index (PLMI), and PLM in sleep arousal index (PLMSAI). RESULTS: Of 81 randomized patients, 66 (37 rotigotine, 29 placebo) were included in efficacy assessments. PLM-associated SBP elevations were significantly reduced with rotigotine vs placebo (least squares mean treatment difference [95% confidence interval (CI)] -160.34 [-213.23 to -107.45]; p < 0.0001). Rotigotine-treated patients also had greater reduction vs placebo in total SBP elevations (-161.13 [-264.47 to -57.79]; p = 0.0028), PLM-associated elevations (-88.45 [-126.12 to -50.78]; p < 0.0001), and total DBP elevations (-93.81 [-168.45 to -19.16]; p = 0.0146), PLMI (-32.77 [-44.73 to -20.80]; p < 0.0001), and PLMSAI (-7.10 [-11.93 to -2.26]; p = 0.0047). Adverse events included nausea (rotigotine 23%; placebo 8%), headache (18% each), nasopharyngitis (18%; 8%), and fatigue (13%; 15%). CONCLUSIONS: Further investigation is required to determine whether reductions in nocturnal BP elevations observed with rotigotine might modify cardiovascular risk. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with moderate to severe RLS, rotigotine at optimal dose (1-3 mg/24 h) reduced PLM-associated nocturnal SBP elevations.

Effects of rotigotine on daytime symptoms in patients with primary restless legs syndrome: a randomized, placebo-controlled study.

OBJECTIVE: This 12 week double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01569464) was conducted to evaluate the effects of rotigotine transdermal patch on daytime symptoms in patients with idiopathic restless legs syndrome (RLS). METHODS: Adult patients with moderate-to-severe RLS were randomized to rotigotine (optimal dose: 1-3 mg/24 h) or placebo. A modified four-assessment version (4:00 pm, 6:00 pm, 8:00 pm, and 10:00 pm) of the Multiple Suggested Immobilization Test (m-SIT) was performed at baseline and end of 4 week maintenance (EoM). Primary study outcomes were change from baseline to EoM in International Restless Legs Syndrome Rating Scale (IRLS) and in average of means for the m-SIT Discomfort Scale (m-SIT-DS) (combined average of mean values from each of the individual assessments). Secondary outcomes included average of means of Periodic Limb Movement during Wakefulness Index (PLMWI; PLM/hour) for the combination of m-SIT. RESULTS: A total of 150 patients were randomized and 137 (rotigotine: 92/101 [91.1%]; placebo: 45/49 [91.8%]) completed maintenance. All 150 randomized patients were assessed for efficacy. At EoM, mean change in IRLS was -14.9 ± 9.3 with rotigotine vs. -12.7 ± 7.6 with placebo (ANCOVA, LS mean treatment difference [95% CI]: -0.27 [-2.96, 2.42]; p = 0.8451). Changes in average of means of m-SIT-DS values of each individual SIT were comparable with rotigotine (-2.68 ± 2.31) vs. placebo (-2.62 ± 2.61) (ANCOVA, LS mean treatment difference [95% CI]: 0.07 [-0.61, 0.75]; p = 0.8336) and comparable reductions in PLMWI were observed in both treatment groups (8.34 [-8.50, 25.17]; p = 0.3290). Rotigotine was generally well tolerated. Application site reactions (rotigotine: 20 patients [19.8%]; placebo: 4 [8.2%]) and nausea (16 [15.8%]; 3 [6.1%]) were the most common AEs. CONCLUSIONS: Rotigotine was beneficial in improving overall RLS symptom severity (assessed by IRLS) and RLS symptom severity at various times of the day (m-SIT-DS); however, superiority to placebo was not established.

Post Hoc Analysis of Data from Two Clinical Trials Evaluating the Minimal Clinically Important Change in International Restless Legs Syndrome Sum Score in Patients with Restless Legs Syndrome (Willis-Ekbom Disease).

STUDY OBJECTIVES: Determine the minimal clinically important change (MCIC), a measure determining the minimum change in scale score perceived as clinically beneficial, for the international restless legs syndrome (IRLS) and restless legs syndrome 6-item questionnaire (RLS-6) in patients with moderate to severe restless legs syndrome (RLS/Willis-Ekbom disease) treated with the rotigotine transdermal system. METHODS: This post hoc analysis analyzed data from two 6-mo randomized, double-blind, placebo-controlled studies (SP790 [NCT00136045]; SP792 [NCT00135993]) individually and as a pooled analysis in rotigotine-treated patients, with baseline and end of maintenance IRLS and Clinical Global Impressions of change (CGI Item 2) scores available for analysis. An anchor-based approach and receiver operating characteristic (ROC) curves were used to determine the MCIC for the IRLS and RLS-6. We specifically compared "much improved vs minimally improved," "much improved/very much improved vs minimally improved or worse," and "minimally improved or better vs no change or worse" on the CGI-2 using the full analysis set (data as observed). RESULTS: The MCIC IRLS cut-off scores for SP790 and SP792 were similar. Using the pooled SP790+SP792 analysis, the MCIC total IRLS cut-off score (sensitivity, specificity) for "much improved vs minimally improved" was -9 (0.69, 0.66), for "much improved/very much improved vs minimally improved or worse" was -11 (0.81, 0.84), and for "minimally improved or better vs no change or worse" was -9 (0.79, 0.88). MCIC ROC cut-offs were also calculated for each RLS-6 item. CONCLUSIONS: In patients with RLS, the MCIC values derived in the current analysis provide a basis for defining meaningful clinical improvement based on changes in the IRLS and RLS-6 following treatment with rotigotine.

Mutation spectrum of RB1 gene in unilateral retinoblastoma cases from Tunisia and correlations with clinical features.

Retinoblastoma, an embryonic neoplasm of retinal origin, is the most common primary intraocular malignancy in children. Somatic inactivation of both alleles of the RB1 tumor suppressor gene in a retinal progenitor cell through diverse mechanisms including genetic and epigenetic modifications, is the crucial event in initiation of tumorigenesis in most cases of isolated unilateral retinoblastoma. We analyzed DNA from tumor tissue and from peripheral blood to determine the RB1 mutation status and seek correlations with clinical features of 37 unrelated cases of Tunisian origin with sporadic retinoblastoma. All cases were unilateral except one who presented with bilateral disease, in whom no germline coding sequence alteration was identified. A multi-step mutation scanning protocol identified bi-allelic inactivation of RB1 gene in 30 (81%) of the samples tested. A total of 7 novel mutations were identified. There were three tumors without any detectable mutation while a subset contained multiple mutations in RB1 gene. The latter group included tumors collected after treatment with chemotherapy. There were seven individuals with germline mutations and all presented with advanced stage of tumor. There was no difference in age of onset of RB based on the germline mutation status. Thus 20% of the individuals with sporadic unilateral RB in this series carried germline mutations and indicate the importance of genetic testing all children with sporadic retinoblastoma. These findings help to characterize the spectrum of mutations present in the Tunisian population and can improve genetic diagnosis of retinoblastoma.

Rotigotine transdermal system: developing continuous dopaminergic delivery to treat Parkinson's disease and restless legs syndrome.

Rotigotine is a nonergoline dopamine receptor agonist with structural similarity to dopamine. Rotigotine binds to the D1 through D5 dopamine receptors, having several times more affinity than dopamine does to the D2 and D3 receptors. Although rotigotine was demonstrated to restore locomotor activity in animal models of Parkinson's disease (PD), the rapid metabolism of rotigotine limited the development of an orally administered formulation. Rotigotine's high lipid solubility and extended duration of action when applied to the skin in experimental models of PD suggested that rotigotine was a candidate for transdermal application. The constant transdermal delivery of rotigotine over 24 h is hypothesized to approximate continuous agonist-receptor stimulation, which conceptually more closely mimics physiologic striatal dopamine receptor function. Randomized clinical studies have demonstrated rotigotine's efficacy, safety, and tolerability in patients with early- and advanced-stage PD, including improvements in motor symptoms and off-time. Although the etiology is unknown, restless legs syndrome (RLS) is thought to involve dopaminergic dysregulation. Randomized clinical studies also have demonstrated the efficacy of rotigotine in improving the symptoms of moderate-to-severe primary RLS. This review examines rotigotine's developmental history for transdermal administration leading to its approval for the treatment of early- and advanced-stage PD and moderate-to-severe primary RLS.

Rotigotine transdermal system and evaluation of pain in patients with Parkinson's disease: a post hoc analysis of the RECOVER study.

BACKGROUND: Pain is a troublesome non-motor symptom of Parkinson's disease (PD). The RECOVER (Randomized Evaluation of the 24-hour Coverage: Efficacy of Rotigotine; Clintrials.gov: NCT00474058) study demonstrated significant improvements in early-morning motor function (UPDRS III) and sleep disturbances (PDSS-2) with rotigotine transdermal system. Improvements were also reported on a Likert pain scale (measuring any type of pain). This post hoc analysis of RECOVER further evaluates the effect of rotigotine on pain, and whether improvements in pain may be attributable to benefits in motor function or sleep disturbance. METHODS: PD patients with unsatisfactory early-morning motor impairment were randomized to optimal-dose (up to 16 mg/24 h) rotigotine or placebo, maintained for 4 weeks. Pain was assessed in the early-morning using an 11-point Likert pain scale (rated average severity of pain (of any type) over the preceding 12 hours from 0 [no pain] to 10 [worst pain ever experienced]). Post hoc analyses for patients reporting 'any' pain (pain score ≥1) at baseline, and subgroups reporting 'mild' (score 1-3), and 'moderate-to-severe' pain (score ≥4) were performed. Likert pain scale change from baseline in rotigotine-treated patients was further analyzed based on a UPDRS III/PDSS-2 responder analysis (a responder defined as showing a ≥30% reduction in early morning UPDRS III total score or PDSS-2 total score). As post hoc analyses, all p values presented are exploratory. RESULTS: Of 267 patients with Likert pain data (178 rotigotine, 89 placebo), 187 (70%) reported 'any' pain; of these 87 (33%) reported 'mild', and 100 (37%) 'moderate-to-severe' pain. Change from baseline pain scores decreased with rotigotine compared with placebo in patients with 'any' pain (-0.88 [95% CI: -1.56, -0.19], p = 0.013), and in the subgroup with 'moderate-to-severe' pain (-1.38 [-2.44, -0.31], p = 0.012). UPDRS III or PDSS-2 responders showed greater improvement in pain than non-responders. CONCLUSIONS: The results from this post hoc analysis of the RECOVER study suggest that pain was improved in patients with PD treated with rotigotine; this may be partly attributable to benefits in motor function and sleep disturbances. Prospective studies are warranted to investigate this potential benefit and the clinical relevance of these findings.

Associations between severity of motor function and nonmotor symptoms in Parkinson's disease: a post hoc analysis of the RECOVER Study.

BACKGROUND: RECOVER (NCT00474058), a double-blind, placebo-controlled trial in patients with Parkinson's disease (PD) and unsatisfactory early-morning motor symptom control, demonstrated significant improvements with rotigotine in early-morning motor function (Unified Parkinson's Disease Rating Scale [UPDRS] III), and nocturnal sleep disturbances (modified Parkinson's Disease Sleep Scale [PDSS-2]), and improvements in nonmotor symptoms (NMS; Non-Motor Symptom Scale [NMSS]). METHODS: Post hoc analyses investigated the correlation between motor symptom and NMS severity in PD by evaluating associations between UPDRS III and both NMSS and PDSS-2 scores. Categories were defined for UPDRS III, NMSS, and PDSS-2 total scores; analyses were conducted for the full analysis set (n = 267). RESULTS: There was a trend toward increasing PDSS-2 and NMSS total and domain scores with increasing UPDRS III category at baseline and end of maintenance (EoM). Pearson correlation coefficients between UPDRS III and both NMSS and PDSS-2 total and domain scores were r = 0.12-0.44 (r(2) = 0.01-0.19) at baseline, r = 0.05-0.38 (r(2) = 0.00-0.14) at EoM, and r = -0.02-0.36 (r(2) = 0.00-0.13) for change from baseline to EoM. CONCLUSION: There was only a small correlation between severity of early-morning motor symptoms and overall burden of NMS and nocturnal sleep disturbances in RECOVER, suggesting that motor symptoms and NMS originate, at least partly, from distinct pathophysiological pathways.

Enhanced sensitivity for detection of low-level germline mosaic RB1 mutations in sporadic retinoblastoma cases using deep semiconductor sequencing.

Sporadic retinoblastoma (RB) is caused by de novo mutations in the RB1 gene. Often, these mutations are present as mosaic mutations that cannot be detected by Sanger sequencing. Next-generation deep sequencing allows unambiguous detection of the mosaic mutations in lymphocyte DNA. Deep sequencing of the RB1 gene on lymphocyte DNA from 20 bilateral and 70 unilateral RB cases was performed, where Sanger sequencing excluded the presence of mutations. The individual exons of the RB1 gene from each sample were amplified, pooled, ligated to barcoded adapters, and sequenced using semiconductor sequencing on an Ion Torrent Personal Genome Machine. Six low-level mosaic mutations were identified in bilateral RB and four in unilateral RB cases. The incidence of low-level mosaic mutation was estimated to be 30% and 6%, respectively, in sporadic bilateral and unilateral RB cases, previously classified as mutation negative. The frequency of point mutations detectable in lymphocyte DNA increased from 96% to 97% for bilateral RB and from 13% to 18% for unilateral RB. The use of deep sequencing technology increased the sensitivity of the detection of low-level germline mosaic mutations in the RB1 gene. This finding has significant implications for improved clinical diagnosis, genetic counseling, surveillance, and management of RB.

Relation of the International Restless Legs Syndrome Study Group rating scale with the Clinical Global Impression severity scale, the restless legs syndrome 6-item questionnaire, and the restless legs syndrome-quality of life questionnaire.

BACKGROUND: The SP790 study (ClinicalTrials.gov, NCT00136045) showed benefits of rotigotine over placebo in improving symptom severity of restless legs syndrome (RLS), also known as Willis-Ekbom disease, on the International Restless Legs Syndrome Study Group rating scale (IRLS), Clinical Global Impression item 1 (CGI-1), RLS 6-item questionnaire (RLS-6), and the RLS-quality of life questionnaire (RLS-QoL) in patients with moderate to severe idiopathic RLS. To provide clinical context for the IRLS and to guide the choice of assessment scales for RLS studies, our post hoc analysis of SP790 data evaluated associations between the IRLS and the CGI-1, IRLS and RLS-6, and the IRLS and RLS-QoL. METHODS: Scale associations were analyzed at baseline and at the end of maintenance (EoM) using data from the safety set (rotigotine and placebo groups combined [n=458]). Changes from baseline to EoM in IRLS score vs comparator scale scores also were analyzed. RESULTS: There was a trend towards increasing IRLS severity category with increasing CGI-1, RLS-6, and RLS-QoL score. Pearson product moment correlation coefficients showed correlations between IRLS and comparator scale scores at baseline and EoM as well as correlations for change from baseline to EoM. CONCLUSION: Correlations between the IRLS and comparator scales were substantial. These data indicate that the IRLS is clinically meaningful. The IRLS and CGI-1 are generally sufficient to evaluate the overall severity and impact of RLS symptoms in clinical trials.

Compliance with pharmacotherapy and direct healthcare costs in patients with Parkinson's disease: a retrospective claims database analysis.

BACKGROUND: Parkinson's disease (PD) is a progressive neurological disorder for which, at present, there is no cure. Current therapy is largely based on the use of dopamine agonists and dopamine replacement therapy, designed to control the signs and symptoms of the disease. The majority of current treatments are administered in tablet form and can involve multiple daily doses, which may contribute to sub-optimal compliance. Previous studies with small groups of patients suggest that non-compliance with treatment can result in poor response to therapy and may ultimately increase direct and indirect healthcare costs. OBJECTIVE: To determine the extent of non-compliance within the general PD population in the USA as well as the patient characteristics and healthcare costs associated with compliance and non-compliance. METHODS: A retrospective analysis from a managed care perspective was conducted using data from the USA PharMetrics patient-centric claims database. PharMetrics claims data were complete from 31 December 2005 to 31 December 2009. Patients were included if they had at least two diagnoses for PD between 31 December 2005 and 31 December 2008, were older than 18 years of age, were continuously enrolled for at least 12 months after the date of the most recent PD diagnosis, and had no missing or invalid data. The follow-up period was the most recent 12-month block of continuous enrollment that occurred between 2006 and 2009. Patients were required to have at least one PD-related prescription within the follow-up period. The medication possession ratio (MPR) was used to categorise patients as compliant or non-compliant. Direct all-cause annual healthcare costs for patients with PD were estimated for each patient, and regression analyses were conducted to determine predictors for non-compliance. RESULTS: A total of 15,846 patients were included, of whom 46 % were considered to be non-compliant with their prescribed medication (MPR <0.8). Predictors of non-compliance included prescription of a medication administered in multiple daily doses (p < 0.0001), a period of <2 years since the initial PD diagnosis (p = 0.0002), a diagnosis of gastrointestinal disorder (p < 0.0001), and a diagnosis of depression (p < 0.0001). Non-compliance was also found to be related to age, with a lower odds of non-compliance in patients aged 41-80 years than in patients aged ≥81 years (p < 0.05). Although total drug mean costs were higher for compliant patients than non-compliant patients (driven mainly by the cost of PD-related medications), the mean costs associated with emergency room and inpatient visits were higher for patients non-compliant with their prescribed medication. Overall, the total all-cause annual healthcare mean cost was lower for compliant ($77,499) than for non-compliant patients ($84,949; p < 0.0001). CONCLUSION: Non-compliance is prevalent within the general USA PD population and is associated with a recent PD diagnosis, certain comorbidities, and multiple daily treatment dosing. Non-compliance may increase the burden on the healthcare system because of greater resource usage compared with the compliant population. Treatments that require fewer daily doses may have the potential to improve compliance, which in turn could reduce the economic burden associated with PD.

Differential calcium dependence of axonal versus somatodendritic dopamine release, with characteristics of both in the ventral tegmental area.

Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) exhibit somatodendritic release of DA. Previous studies indicate a difference between the Ca(2+) dependence of somatodendritic DA release in the SNc and that of axonal DA release in dorsal striatum. Here, we evaluated the Ca(2+) dependence of DA release in the VTA and nucleus accumbens (NAc) shell for comparison with that in the SNc and dorsal striatum. Release of DA was elicited by single-pulse stimulation in guinea-pig brain slices and monitored with subsecond resolution using carbon-fiber microelectrodes and fast-scan cyclic voltammetry. In dorsal striatum and NAc, DA release was not detectable at extracellular Ca(2+) concentrations ([Ca(2+)](o)) below 1 mM; however, a progressive increase in evoked extracellular DA concentration ([DA](o)) was seen with [Ca(2+)](o) ≥ 1.5 mM. By contrast, in SNc and VTA, robust increases in [DA](o) could be elicited in 0.25 mM [Ca(2+)](o) that were ∼60% of those seen in 1.5 mM [Ca(2+)](o). In SNc, a plateau in single-pulse evoked [DA](o) was seen at [Ca(2+)](o) ≥ 1.5 mM, mirroring the release plateau reported previously for pulse-train stimulation in SNc. In VTA, however, evoked [DA](o) increased progressively throughout the range of [Ca(2+)](o) tested (up to 3.0 mM). These functional data are consistent with the microanatomy of the VTA, which includes DA axon collaterals as well as DA somata and dendrites. Differences between axonal and somatodendritic release data were quantified using Hill analysis, which showed that the Ca(2+) dependence of axonal DA release is low affinity with high Ca(2+) cooperativity, whereas somatodendritic release is high affinity with low cooperativity. Moreover, this analysis revealed the dual nature of DA release in the VTA, with both somatodendritic and axonal contributions.

Bacteriology of blood, wound, and sputum cultures from non-US casualties treated in a combat support hospital in Iraq.

A review of culture results from non-US casualties in Iraq revealed gram-negative bacteria were the most commonly isolated pathogens. Cultures of respiratory fluid yielded positive results earlier than cultures of wound or blood samples and potentially serve as an earlier marker of future infections. Continued aggressive infection control for non-US casualties is needed.

Community meetings for emergency research community consultation.

OBJECTIVE: To survey attendees at community meetings for an emergency research protocol and determine whether these meetings aid participants' understanding and decision to support the proposed emergency research. DESIGN: Postmeeting questionnaire. SETTING: Three community meetings for the PolyHeme study in San Antonio area. SUBJECTS: One hundred fifty community meeting attendees. INTERVENTIONS: PolyHeme research team representatives made a study presentation concerning exception to informed consent regulations. In addition, institutional review board (IRB) members attended these meetings and made a separate presentation about the IRB approval of research and the exception to informed consent in emergency research. The IRB members requested attendees to voluntarily complete an additional Community Consultation Survey assessing demographics, community meeting satisfaction, and impact of the community meeting on their attitudes toward emergency research studies. MEASUREMENTS AND MAIN RESULTS: Feedback to the PolyHeme investigators with their validation questions indicated that 35% of the respondents objected to research without prior consent, but 82% gave approval for the study in the local community; 137 attendees completed the additional Community Consultation Survey. The average score on the adequacy of information provided about the PolyHeme study was 0.58 on a 5-point Likert scale (-2 to +2). Adequacy of IRB background information on human subjects research received an average score of 0.56, and the overall clarity of the information on community consultation was 0.91. Although 80% of respondents felt there was a potential benefit from PolyHeme, <67% would either want to participate or enroll their family members with or without prior consent. CONCLUSIONS: The majority of community meeting attendees understand basic concepts and regulations of emergency research without prior consent. Despite an 82% concurrence with the study in their community, approximately 30% of persons would not willingly choose to participate in emergency research or provide consent for their family members despite knowledge about the process.