Caregiver-Reported Burden in RE-KINECT: Data From a Prospective Real-World Tardive Dyskinesia Screening Study.

BACKGROUND: RE-KINECT (NCT03062033), a real-world study of possible tardive dyskinesia (TD) in antipsychotic-treated patients, included a questionnaire to assess the effects of patients' abnormal involuntary movements on caregivers. AIMS: To capture the experiences of caregivers who assisted individuals with abnormal involuntary movements that were confirmed by clinicians as being consistent with TD. METHODS: Qualified (nonpaid) caregivers were invited to complete a questionnaire that included the following: caregivers' sociodemographic characteristics, their perceptions about the impact of abnormal involuntary movements on patients, and the impact of these movements on themselves (caregivers). RESULTS: Of the 41 participating caregivers, 25 (61.0%) were women, 20 (48.8%) were employed full time or part time, and 35 (85.4%) were family members or friends. Based on responses from caregivers who noticed patients' abnormal involuntary movements and were caring for individuals who also noticed those movements, 48.0% of patients had "a lot" of severity in ≥1 body region and 76.0% had abnormal involuntary movements in ≥2 regions. Caregiver ratings were significantly correlated with patient ratings (but not with clinician ratings) for maximum severity of abnormal involuntary movements and the number of affected regions (both p <.05). Based on their own judgments and perceptions, caregivers reported that the patient's movements had "some" or "a lot" of impact on their (caregiver's) ability to continue usual activities (50.0%), be productive (58.3%), socialize (55.6%), or take care of self (50.0%). CONCLUSIONS: Caregivers as well as patients are negatively affected by TD, and the impact of TD on caregivers' lives should be considered when determining treatment options.

Longitudinal Examination of Leisure-Time Physical Activity (LTPA), Participation, and Social Inclusion Upon Joining a Community-based LTPA Program for Adults With Physical Disabilities.

OBJECTIVE: First, to examine whether participants reported changes in (1) leisure-time physical activity (LTPA) participation and social inclusion variables and (2) well-being outcomes before and after joining a community-based LTPA program for adults with physical disabilities. Second, to explore the longitudinal relationship between LTPA and the other aforementioned outcomes. DESIGN: A double baseline longitudinal design with measurements at 4-6 weeks (baseline 1) and immediately (baseline 2) before and 2 and 4 months after joining the community-based LTPA program. SETTING: Community. PARTICIPANTS: Adults (N=43) with a physical disability who reported no cognitive impairment, were new members of the community-based LTPA program, and spoke English or French. INTERVENTIONS: A community-based physical activity program for adults with physical disabilities. Participants were provided an individualized exercise program and accessed the program at designated times during the week. MAIN OUTCOME MEASURES: Primary: LTPA (LTPA Questionnaire for People with Spinal Cord Injury), participation (Patient-Perceived Participation in Daily Activities Questionnaire), and social inclusion. Secondary: depression severity, self-esteem, resilience, and life satisfaction. RESULTS: After joining the program, participants reported an increase in total LTPA (meanbaseline2, 177.80±211.32; mean2months, 299.31±298.70; mean4months, 288.14±292.14), moderate-to-vigorous LTPA (meanbaseline2, 83.95±123.95; mean2months, 142.00±198.38; mean4months, 163.23±182.08), and participation in health (meanbaseline2, 6.24±1.16; mean2months, 6.58±1.25; mean4months, 6.97±0.82) and family-related activities (meanbaseline2, 12.18±2.43; mean2months, 12.60±2.30; mean4months, 13.47±2.01). A significant increase (ß=3.46, P<.001) in social inclusion before joining the program was followed by a decrease (ß=-1.09, P<.05) 4 months later. Improvements related to depression severity were noted (ßbaseline1-baseline2=-1.51, P<.05; ßbaseline2-4 months=-0.28, P>.05). CONCLUSIONS: The results support the role of a community-based LTPA program in increasing LTPA levels and enhancing participation in some activities among adults with physical disabilities.

RE-KINECT: A Prospective Study of the Presence and Healthcare Burden of Tardive Dyskinesia in Clinical Practice Settings.

PURPOSE/BACKGROUND: RE-KINECT (NCT03062033) was designed to assess the presence and impact of possible tardive dyskinesia (TD) in antipsychotic-treated outpatients. METHODS/PROCEDURES: The study included adults with 3 or more months of lifetime antipsychotic exposure and 1 or more psychiatric disorder. Based on clinician observation and assessment, patients were assigned to cohort 1 (without involuntary movements or with non-TD involuntary movements) or cohort 2 (with involuntary movements confirmed by clinician as possible TD). Baseline assessments included the following: patient characteristics; location/severity of involuntary movements; and impact of possible TD on health-related quality of life, including the EuroQoL 5-Dimensions 5-Level questionnaire. FINDINGS/RESULTS: Of 739 eligible patients, 204 (27.6%) had clinician-confirmed possible TD (cohort 2). Compared with cohort 1, patients in cohort 2 were significantly older (P < 0.0001), more likely to have schizophrenia or schizoaffective disorder (P < 0.0001) and longer lifetime exposure to antipsychotics (P < 0.0001), and less likely to be working or studying, based on clinician perception (P = 0.0010). Clinician- and patient-rated severity of possible TD movements was significantly correlated in each of 4 body regions (head/face, neck/trunk, upper extremities, lower extremities), for maximum severity in any region, and for total number of affected regions (P < 0.001 for all correlations). For the patient-rated EuroQoL 5-Dimensions 5-Level, the health state visual analog scale score was significantly lower (worse) in cohort 2 versus cohort 1 (66.8 vs 69.7; P = 0.0002), as was the utility index score (0.71 vs 0.76; P < 0.0175). IMPLICATIONS/CONCLUSIONS: Results from this real-world population indicate that TD occurs frequently and can significantly reduce quality of life in patients with a psychiatric disorder.

Maternal smoking during pregnancy and ADHD: a comprehensive clinical and neurocognitive characterization.

INTRODUCTION: Evidence from epidemiological studies has consistently shown an association between maternal smoking during pregnancy (MSDP) and attention-deficit/hyperactivity disorder (ADHD). The objective of this study is to test the hypothesis that children with ADHD exposed to MSDP show a distinctive clinical and neurocognitive profile when compared with unexposed children. METHODS: Four hundred and thirty-six children diagnosed with ADHD were stratified by exposure to MSDP and compared with regard to severity of illness, comorbidity, IQ, and executive function as assessed by a battery of neuropsychological tests. All comparisons were adjusted for socioeconomic status, ethnicity, mother's age at child's birth, and maternal alcohol consumption during pregnancy. RESULTS: Exposed children had more severe behavioral problems with greater externalizing symptoms and more conduct and oppositional defiant disorder items, lower verbal IQ, and a sluggish cognitive profile on the Continuous Performance Test (CPT). Linear regression analyses revealed a dose-response relationship between the average number of cigarettes smoked per day during pregnancy and verbal IQ, CPT omission errors T score and several other clinical variables. CONCLUSIONS: These results suggest that MSDP is associated with a more severe form of ADHD, characterized by more severe clinical manifestations and poorer neuropsychological performance. This phenotypic signature associated with MSDP may help to identify a more homogenous subgroup of children with ADHD.

Strategies to improve access to physical activity opportunities for people with physical disabilities.

Community-based physical activity opportunities have been shown to help adults with physical disabilities improve their participation in daily activities and reduce social isolation. Despite the known benefits, substantial barriers and challenges inhibit accessibility to these physical activity opportunities. To facilitate the co-construction of strategies to overcome accessibility issues pertaining to community-based physical activity opportunities. In total, 45 individuals with physical disabilities, patients at a rehabilitation hospital, staff members of disability organizations, staff of local or provincial government agencies/departments, kinesiologists, occupational therapists, graduate students, and peer mentors participated in one of four World Cafés held in their respective cities. World Café is a methodology for fostering collaborative, solution-focused conversation that aims to solve problems through collective intelligence. Participants were divided into groups of three to four people and invited to engage in evolving rounds of discussions responding to prompts about accessibility to physical activity in their communities. Transcripts were analyzed using content analysis. In total, 17 strategies were identified, addressing 5 areas: representation and visibility (e.g., prioritize hiring people with a disability), finances (e.g., reduce direct costs for participants), connection and social support (e.g., foster social networks that provide informational support), education and programming (e.g., enhance awareness of existing services and resources), and government programs and policies (e.g., enforce accessibility standards for indoor and outdoor spaces). The findings of this study provide strategies and practical applications for community programs and governments to consider for increasing access to physical activity opportunities for people with physical disabilities.

Adults living with physical disabilities experience numerous benefits (e.g., greater social connection and ability to complete everyday tasks) from participation in community-based physical activities. Despite the known benefits of physical activity for adults with physical disabilities, accessibility to community-based physical activity opportunities remain limited in Canada. The purpose of this study was to facilitate conversations among members of the disability and physical activity communities and co-develop strategies to improve access to community-based physical activity opportunities. In total, 45 participants in 3 Canadian cities were divided into small groups to engage in evolving rounds of discussions responding to access to physical activity in their communities. Altogether, 17 strategies targeting 5 areas related to accessibility were developed. The five areas included representation and visibility (e.g., prioritize hiring people with a disability), finances (e.g., reduce direct costs for participants), connection and social support (e.g., foster social networks that provide informational support), education and programming (e.g., enhance awareness of existing services and resources), and government programs and policies (e.g., enforce accessibility standards for indoor and outdoor spaces). The findings of this study provide practical strategies that community organizations and governments can implement to improve access to community-based physical activity opportunities for people with physical disabilities.

Impact of possible tardive dyskinesia on physical wellness and social functioning: results from the real-world RE-KINECT study.

BACKGROUND: Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with antipsychotic use. Data from RE-KINECT, a real-world study of antipsychotic-treated outpatients, were analyzed to assess the effects of possible TD on patient health and social functioning. METHODS: Analyses were conducted in Cohort 1 (patients with no abnormal involuntary movements) and Cohort 2 (patients with possible TD per clinician judgment). Assessments included: EuroQoL's EQ-5D-5L utility (health); Sheehan Disability Scale (SDS) total score (social functioning); patient- and clinician-rated severity of possible TD ("none", "some", "a lot"); and patient-rated impact of possible TD ("none", "some", "a lot"). Regression models were used to analyze the following: associations between higher (worse) severity/impact scores and lower (worse) EQ-5D-5L utility (indicated by negative regression coefficients); and associations between higher (worse) severity/impact scores and higher (worse) SDS total score (indicated by positive regression coefficients). RESULTS: In Cohort 2 patients who were aware of their abnormal movements, patient-rated TD impact was highly and significantly associated with EQ-5D-5L utility (regression coefficient: - 0.023, P < 0.001) and SDS total score (1.027, P < 0.001). Patient-rated severity was also significantly associated with EQ-5D-5L utility (- 0.028, P < 0.05). Clinician-rated severity was moderately associated with both EQ-5D-5L and SDS, but these associations were not statistically significant. CONCLUSIONS: Patients were consistent in evaluating the impacts of possible TD on their lives, whether based on subjective ratings ("none", "some", "a lot") or standardized instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD.

Indirect Treatment Comparison of Inotuzumab Ozogamicin Versus Blinatumomab for Relapsed or Refractory Acute Lymphoblastic Leukemia.

INTRODUCTION: No head-to-head studies have compared inotuzumab ozogamicin (InO) and blinatumomab (Blina) for the treatment of adults with relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL). Indirect treatment comparisons (ITCs), namely network meta-analysis (NMA), anchored matching-adjusted indirect comparison (MAIC), and simulated treatment comparison (STC), were conducted to compare the relative efficacy of these therapies. METHODS: Patient-level data from a study that evaluated InO with standard of care (SoC) chemotherapy (INO-VATE-ALL) and published data from a study that evaluated Blina with SoC chemotherapy (TOWER) were used in the analyses. Endpoints evaluated included remission rate defined as complete remission or complete remission with incomplete hematologic recovery (CR/CRi), hematopoietic stem cell transplantation (HSCT), overall survival (OS), and event-free survival (EFS). For each outcome, treatment-effect modifiers were adjusted for in the anchored MAIC and STC analyses. RESULTS: Analyses showed statistically significant higher rates of remission and HSCT with InO compared to Blina irrespective of the ITC method used or measure of the effect (i.e., odds ratio [OR] or rate difference). The treatment effects derived from the MAIC and STC analyses were consistent and stronger than those estimated from the NMA. A trend favoring InO was detected for EFS. The ITC results for OS suggest no difference between InO and Blina. CONCLUSION: Results from these ITCs indicated a statistically significant advantage for InO over Blina for rates of remission and HSCT in adults with relapsed or refractory B cell precursor ALL. It was not possible to fully adjust for all treatment-effect modifiers, and the similarity in chemotherapy regimens used in the SoC comparator arms of the INO-VATE-ALL and TOWER studies is worthy of further exploration. Both studies, however, used chemotherapy regimens that have a low response rate; therefore, no significant differences in efficacy outcomes are expected between SoC arms. FUNDING: Pfizer Inc, New York, NY. Plain language summary available for this article.

Catechol-o-methyltransferase gene and executive function in children with ADHD.

OBJECTIVE: To examine the association between functional haplotypes in the catechol-o-methyltransferase (COMT) gene and ADHD diagnosis, and executive function (EF) in children with ADHD. METHOD: COMT single nucleotide polymorphism (SNPs; rs6269, rs4633, rs4818, and rs4680) were genotyped in 445 ADHD children. EF was assessed using Wisconsin Card Sorting Test (WCST), Tower of London, and self-ordered pointing task. COMT haplotypes were tested for association using family-based association testing (fBAT) and quantitative trait analyses. RESULTS: fBAT analysis showed no association between COMT alleles/haplotypes and ADHD diagnosis and EF parameters. Using ANCOVA in the Caucasian only sample, significant associations between COMT haplotypes, and WCST indices were observed. However, after correction for multipletesting, the only significant effect observed was between rs6269 and the number of categories completed (a measure of concept formation ability) on the WCST, F(1,285) = 8.92, p = .003. CONCLUSION: These results tentatively implicate COMT gene in modulating EF in children with ADHD.

Association of diabetes with anxiety: a systematic review and meta-analysis.

OBJECTIVES: Anxiety has been shown to be associated with poor outcomes in people with diabetes. However, there has been little research which has specifically examined whether diabetes mellitus is associated with an increased likelihood of co-morbid anxiety. The aim of this systematic review and meta-analysis was to determine whether people with diabetes are more likely to have anxiety disorders or elevated anxiety symptoms than people who do not have diabetes. METHODS: A systematic review was performed by three independent reviewers who searched for articles that examined the association between anxiety and diabetes in adults 16 or older. Those studies that met eligibility criteria were put forward for meta-analysis using a random-effects model. RESULTS: A total of twelve studies with data for 12,626 people with diabetes were eligible for inclusion in the systematic review and meta-analysis. Significant and positive associations were found for diabetes with both anxiety disorders, 1.20 (1.10-1.31), and elevated anxiety symptoms, 1.48 (1.02-1.93). The pooled OR for all studies that assessed anxiety was 1.25 (1.10-1.39). CONCLUSIONS: Results from this meta-analysis provide support that diabetes is associated with an increased likelihood of having anxiety disorders and elevated anxiety symptoms.

Self-rated health: a predictor for the three year incidence of major depression in individuals with Type II diabetes.

BACKGROUND: To determine whether self-rated health was a predictor for the three year incidence of major depression in people with Type II diabetes. METHODS: Data was collected as part a population-based telephone survey of adults with diabetes, in Québec, Canada (2008-2011). Adults with Type II diabetes who did not have major depression at baseline were assessed at three follow-up interviews conducted 12, 24 and 36 months after baseline. Depression was assessed using the Patient Health Questionnaire (PHQ-9). Self-rated health status was determined by asking participants to rate their health on a scale from excellent to poor. RESULTS: The sample consisted of 1265 adults with Type II diabetes who did not have major depression at baseline. 36% of individuals who had developed major depression at follow up rated their health as fair or poor at baseline compared to 14.4% of those who had not developed major depression. Logistic regression analyses indicated fair or poor self-rated health at baseline to be predictive of a twofold increased risk for major depression at follow-up, even after adjusting for socio-demographic characteristics, lifestyle-related behaviors, disability and diabetes characteristics (OR=2.05, 95% CI 1.20-3.48). LIMITATIONS: We have focused on current depression (last two weeks) and we have used a questionnaire (PHQ-9) rather than a clinical interview for the assessment of depression. CONCLUSIONS: Self-rated health status might be a predictor for developing major depression in people with diabetes in addition to well established risk factors.

Self-rated diabetes control in a Canadian population with type 2 diabetes: associations with health behaviours and outcomes.

AIMS: Diabetes control is a multifaceted process involving successful adherence to a self-care regimen as indicated by improved health outcomes. The aim of this study was to ascertain the construct validity of self-reported diabetes control in a population-based survey. METHODS: This study assessed 1848 participants with type 2 diabetes who took part in the Montreal Diabetes Health and Wellbeing Study in Quebec, Canada. Participants were administered the diabetes complications index as well as sociodemographic and health questions. RESULTS: Fair/poor diabetes control was associated with being less likely to check blood glucose weekly, being less likely to drink alcohol, being more likely to report being physically inactive, reporting fair/poor eating habits, being obese and having 1 or more diabetes complications. When all variables were included in a regression model the two variables most strongly associated with poor fair/poor diabetes control were reporting fair/poor eating habits (odds ratio 1.36, 95% CI 1.00-1.85) and having 2 or more diabetes complications (odds ratio 1.60, 95% CI 1.06-2.40). CONCLUSIONS: Results from this study indicate that self-rated diabetes control has associations with diabetes-specific self-care behaviours and outcomes, and is a general indicator of self-care and diabetes-related complications in a population-based survey.

A randomized study of the effects of food on the pharmacokinetics of once-daily extended-release hydromorphone in healthy volunteers.

This randomized, open-label, crossover study investigated the influence of food on the pharmacokinetics of extended-release hydromorphone in 30 healthy volunteers. Participants received extended-release hydromorphone 16 mg in the fasted state and immediately after a high-fat breakfast. In addition, the pharmacokinetics of a 16-mg dose of extended-release hydromorphone and a 16-mg daily dose (4 mg qid) of immediate-release hydromorphone in the fasted state were compared. Treatments were separated by washout periods of 7 to 14 days. Naltrexone was given throughout each treatment period to block the opioid effects of hydromorphone. The 90% confidence intervals (CIs) of the ratios of geometric means for maximum plasma concentrations (C(max)) and area under the plasma concentration-time curve (AUC) for extended-release hydromorphone in the fed and fasted states were within the bioequivalence criteria range of 80% to 125%. In the fasted state, the 90% CIs of the ratios of AUC geometric means for extended-release hydromorphone and immediate-release hydromorphone were also within the bioequivalence range. Both hydromorphone treatments were well tolerated. This study shows that the bioavailability of extended-release hydromorphone is not affected by food and that the bioavailability of extended-release hydromorphone under fasting conditions is comparable with that of the immediate-release formulation when administered at the same total daily dose.

Steady-state pharmacokinetics of extended-release hydromorphone (OROS hydromorphone): a randomized study in healthy volunteers.

The steady-state pharmacokinetics of an extended-release formulation of hydromorphone, OROS hydromorphone, was investigated in a randomized, open-label, crossover study in healthy volunteers. Participants were randomly assigned to receive 16 mg of OROS hydromorphone once daily and 4 mg of immediate-release hydromorphone four times daily for five consecutive days. The two treatments were separated by a washout period of 7-14 days. Naltrexone was given throughout both treatment periods to block the opioid effects of hydromorphone. Steady-state hydromorphone concentrations were statistically analyzed using Helmert contrasts to determine when steady state was reached. A total of 30 participants were enrolled, of whom 29 completed both treatment periods. The two treatments produced comparable steady-state plasma drug concentrations, but peak-to-trough fluctuations were smaller with OROS hydromorphone (61 percent vs 172 percent) in comparison with immediate release hydromorphone. Overall systemic exposure to hydromorphone was similar between the two formulations. The ratio of the geometric means between the two formulations for the area under the concentration-time curves at steady state was 105.2 percent with a 90% confidence interval (CI) of 99.8-110.8 (geometric mean: 102.7 percent; 90% CI: 97.6-108.2 after correcting for measured drug content), which was within the bioequivalence range (80-125 percent). The analysis of Helmert contrasts showed that steady state conditions were attained by day 4. Both treatments were well tolerated. This study shows that OROS hydromorphone maintains steady-state plasma drug concentrations within the same range as immediate-release hydromorphone at the same total daily dose, with less fluctuation.

Obtaining the apex of the unitarity triangle from B-->piK decays.

We present a method of obtaining the apex of the unitarity triangle from measurements of B-->piK decay rates alone. Electroweak penguin amplitudes are included, and are related to tree operators. Discrete ambiguities are removed by comparing solutions with independent experimental data. The theoretical uncertainty in this method is about 10%.