Cariprazine as a maintenance therapy in the prevention of mood episodes in adults with bipolar I disorder.

INTRODUCTION: Cariprazine treats acute manic and depressive episodes in bipolar I disorder (BP-I), but its efficacy in preventing relapse of mood episode remains unknown. METHODS: In this phase 3b, double-blind, placebo-controlled study, patients with BP-I with acute manic or depressive episodes (each with/without mixed features), were treated with cariprazine 3.0 mg/day during a 16-week open-label treatment period; those who achieved stable remission within 8 weeks and remained stable for at least another 8 weeks were randomized to receive cariprazine 1.5 or 3.0 mg per day or placebo in the double-blind treatment period for up to 39 weeks. The primary efficacy endpoint was time to relapse of any mood episode. Adverse events (AEs) were assessed. RESULTS: Patients (440/896) enrolled in the open-label treatment period achieved stability criteria and were randomized to receive cariprazine 3.0 mg/day (n = 148), cariprazine 1.5 mg/day (n = 147), or placebo (n = 145) in the double-blind treatment period. Relapse rates were 17.9%, 16.8%, and 19.7% in the cariprazine 3.0 mg/day, cariprazine 1.5 mg/day, and placebo groups, respectively. Neither dose of cariprazine was more effective than placebo on the primary outcome (3.0 mg/day: HR = 0.89, [95% CI: 0.5, 1.5]; 1.5 mg/day: HR = 0.83, 95% CI [0.5, 1.4]). The most frequently reported AEs (≥5%) were akathisia, headache, insomnia, and nausea in the open-label treatment period and increased weight and insomnia in the double-blind treatment period. In the open-label and double-blind treatment periods, 7.5% and 1.6% of patients experienced an AE leading to discontinuation. CONCLUSION: Cariprazine was not superior to placebo in the prevention of relapses in this study. Relapse rates were unusually low in the placebo group. Cariprazine was well-tolerated.

Parsing the toxicity paradox: Composition and duration of exposure alter predicted oil spill effects by orders of magnitude.

Oil spilled into an aquatic environment produces oil droplet and dissolved component concentrations and compositions that are highly variable in space and time. Toxic effects on aquatic biota vary with sensitivity of the organism, concentration, composition, environmental conditions, and frequency and duration of exposure to the mixture of oil-derived dissolved compounds. For a range of spill (surface, subsea, blowout) and oil types under different environmental conditions, modeling of oil transport, fate, and organism behavior was used to quantify expected exposures over time for planktonic, motile, and stationary organisms. Different toxicity models were applied to these exposure time histories to characterize the influential roles of composition, concentration, and duration of exposure on aquatic toxicity. Misrepresenting these roles and exposures can affect results by orders of magnitude. Well-characterized laboratory studies for <24-hour exposures are needed to improve toxicity predictions of the typically short-term exposures that characterize spills.

AOA Critical Issues: A Culture of Safety Across All Orthopaedic Professional Endeavors.

ABSTRACT: Medical professionals strive for a culture of safety in which error is anticipated, systems are designed to catch an error before it causes harm, and each event is an opportunity for specific clinicians and the system they work in to improve. A culture of safety is based on behavioral ethics, which recognizes that the automatic functions of the human mind can lead good people to misstep, and it incorporates tools such as checklists that embody critical thinking in order to help limit missteps and associated harm. Although the discussion surrounding a culture of safety often focuses on patient care, the social contract between physicians and society involves expectations that physicians will use their expertise to promote the public good in all of their professional endeavors. For example, lapses in professional conduct in the management of conflicts of interest and in ethical marketing have led to restrictions in physician self-regulation. Orthopaedic surgeons can cultivate a culture of safety and a growth mindset across all aspects of the profession, including media coverage of musculoskeletal illness, surgeon participation in informational media (e.g., podcasts and blogs), the marketing of oneself or one's practice, practice patterns and variations, academic discourse, expert legal testimony, the development and implementation of policy and law, and commercial ventures. Systems that anticipate the human potential for missteps; create tools, tactics, and structures to limit missteps and associated harm; and support surgeons and their teams in all professional endeavors can contribute to the effective and fulfilling promotion of the public good.

Surgeon Implicit Association of Women With Supportive Roles in Medicine.

BACKGROUND: In a previous study, we documented patient implicit bias that surgeons are men. As a next step, we tested the implicit bias of surgeons that women in medicine have leading (chair, surgeon) or supporting roles (medical assistant, physician assistant). QUESTIONS/PURPOSE: (1) What is the relationship between the implicit associations and expressed beliefs of surgeons regarding women as leaders in medicine? (2) Are there factors associated with surgeon implicit association and explicit preference regarding the roles of women in medicine? METHODS: A total of 102 musculoskeletal surgeon members of the Science of Variation Group (88 men and 12 women) completed an implicit association test (IAT) of implicit bias regarding sex and lead/support roles in medicine and a questionnaire that addressed respondent demographics and explicit preference regarding women's roles. The IAT consisted of seven rounds with five rounds used for teaching and two rounds for evaluation. RESULTS: On average, there was an implicit association of women with supportive roles (D-score: -48; SD 4.7; P < 0.001). The mean explicit preference was for women in leadership roles (median: 73; interquartile ranges: 23 to 128; P < 0.001). There was a correlation between greater explicit preference for women in a leading role and greater implicit bias toward women in a supporting role (ρ = 0.40; P < 0.001). Women surgeons and shoulder and elbow specialists had less implicit bias that women have supporting roles. CONCLUSION: The observation that musculoskeletal surgeons have an explicit preference for women in leading roles in medicine but an implicit bias that they have supporting roles-more so among men surgeons-documents the gap between expressed opinions and ingrained mental processing that is the legacy of the traditional "roles" of women in medicine and surgery. To resolve this gap, we will need to be intentional about promotion of and emersion in experiences where the leader is a woman. LEVEL OF EVIDENCE: III.

Efficacy of cariprazine in patients with bipolar depression and higher or lower levels of baseline anxiety: a pooled post hoc analysis.

Post hoc analyses evaluated cariprazine, a dopamine D 3 -preferring D 3 /D 2 receptor partial agonist, in patients with bipolar I depression and high baseline anxiety. Data were pooled from two phase 3, randomized, double-blind, placebo-controlled studies in adults with bipolar I disorder and a major depressive episode (NCT02670538, NCT02670551). Cariprazine 1.5 and 3 mg/d were evaluated in patient subgroups with higher and lower baseline anxiety. In patients with higher baseline anxiety, significant differences for cariprazine 1.5 mg/d versus placebo were observed on change in Montgomery-Åsberg Rating Scale (MADRS) total score, Hamilton Anxiety Rating Scale (HAM-A) total score and subscale scores, and rates of MADRS remission ( P < 0.05 all); nonsignificant numerical improvements were observed for cariprazine 3 mg/d versus placebo. In patients with lower anxiety, differences versus placebo were significant for HAM-A (cariprazine 3 mg/d) and MADRS (cariprazine 1.5 and 3 mg/d) total score changes ( P < 0.05 all). Rates of treatment-emergent mania were low and similar for cariprazine and placebo. Cariprazine 1.5 mg/d had consistent effects on anxiety and depression symptoms in patients with bipolar I depression and higher baseline anxiety; tolerability was favorable. Given few proven treatments for this common comorbidity, these preliminary results are promising.

Multi-dimensional task recognition for human-robot teaming: literature review.

Human-robot teams collaborating to achieve tasks under various conditions, especially in unstructured, dynamic environments will require robots to adapt autonomously to a human teammate's state. An important element of such adaptation is the robot's ability to infer the human teammate's tasks. Environmentally embedded sensors (e.g., motion capture and cameras) are infeasible in such environments for task recognition, but wearable sensors are a viable task recognition alternative. Human-robot teams will perform a wide variety of composite and atomic tasks, involving multiple activity components (i.e., gross motor, fine-grained motor, tactile, visual, cognitive, speech and auditory) that may occur concurrently. A robot's ability to recognize the human's composite, concurrent tasks is a key requirement for realizing successful teaming. Over a hundred task recognition algorithms across multiple activity components are evaluated based on six criteria: sensitivity, suitability, generalizability, composite factor, concurrency and anomaly awareness. The majority of the reviewed task recognition algorithms are not viable for human-robot teams in unstructured, dynamic environments, as they only detect tasks from a subset of activity components, incorporate non-wearable sensors, and rarely detect composite, concurrent tasks across multiple activity components.

Protocol of a Multicenter Prospective Trial of Office-Based Carpal Tunnel Release With Ultrasound Guidance (ROBUST).

Background Carpal tunnel release (CTR) is a common surgical procedure for patients with severe or refractory carpal tunnel syndrome (CTS) symptoms. Historically, CTR procedures have been performed in a hospital or an ambulatory surgery center (ASC). However, due to advancements in techniques, greater patient demand, and concerns about growing healthcare costs, there is a distinct trend toward performing CTR procedures in an office-based setting. Several small studies with limited follow-up duration have demonstrated the feasibility of CTR with ultrasound guidance (CTR-US) when performed in an office-based setting. The objective of this study is to evaluate the safety and effectiveness of office-based CTR-US in a large cohort of patients (n=140) with symptomatic CTS followed for two years post-treatment. Design and methods ROBUST is a prospective multicenter observational study in which 140 subjects at up to 12 sites in the United States will be treated with CTR-US in an office-based setting. The primary endpoint of the study is the change in the Boston Carpal Tunnel Questionnaire Symptom Severity Scale score. Secondary endpoints include time to return to normal daily activities, time to return to work among employed subjects, change in the Boston Carpal Tunnel Questionnaire Functional Status Scale score, change in the Michigan Hand Questionnaire overall and domain scores, change in the Numeric Pain Scale score, change in the EuroQoL-5 Dimension 5-Level score, global satisfaction scores, and the incidence of device or procedure-related adverse events. The primary analysis of study endpoints will occur three months post-treatment. Patient follow-up in this study will continue for two years. Conclusions A central institutional review board approved the study protocol, and a data safety monitoring board will provide study oversight. The authors plan to report study results at medical conferences and in peer-reviewed medical journals. The outcomes of ROBUST will provide physicians, patients, and payors with important safety and effectiveness data regarding the clinical utility of CTR-US when performed in an office setting.

Adjunctive Cariprazine for the Treatment of Patients With Major Depressive Disorder: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study.

OBJECTIVE: The purpose of this study was to investigate the efficacy of cariprazine, a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist, as adjunctive therapy for patients with major depressive disorder and nonresponse to at least one antidepressant monotherapy. METHODS: In this double-blind placebo-controlled study, adults with major depressive disorder and inadequate response to antidepressants alone were randomized in a 1:1:1 ratio to placebo, cariprazine at 1.5 mg/day, or cariprazine at 3.0 mg/day. The primary outcome was change from baseline to week 6 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). Least-squares mean differences were estimated in the modified intent-to-treat (mITT) population using a mixed-effects model for repeated measures with adjustment for multiple comparisons. RESULTS: The mITT population comprised 751 patients (placebo: N=249; cariprazine 1.5 mg/day: N=250; cariprazine 3.0 mg/day: N=252). At week 6, the mean reduction from baseline in MADRS total score was significantly greater with cariprazine 1.5 mg/day than with placebo (-14.1 vs. -11.5) but not with cariprazine 3.0 mg/day (-13.1). Significant differences between the cariprazine 1.5 mg/day and placebo groups were also observed at weeks 2 and 4. Meeting the MADRS response criteria was significantly more likely among patients receiving cariprazine 1.5 mg/day than placebo (44.0% vs. 34.9%); remission rates were not significantly different among groups. Common treatment-emergent adverse events (≥5% in either cariprazine group and twice the placebo rate) were akathisia and nausea. CONCLUSIONS: Adjunctive cariprazine at 1.5 mg/day demonstrated efficacy in reducing depressive symptoms in adults with major depressive disorder and inadequate response to antidepressants alone. Cariprazine was generally well tolerated, with a safety profile that was consistent with previous findings.

Recommendations for improving the reporting and communication of aquatic toxicity studies for oil spill planning, response, and environmental assessment.

Standardized oil toxicity testing is important to ensure comparability of study results, and to generate information to support oil spill planning, response, and environmental assessments. Outcomes from toxicity tests are useful in the development, improvement and validation of effects models, and new or revised knowledge could be integrated into existing databases and related tools. To foster transparency, facilitate repeatability and maximize use and impact, outcomes from toxicity tests need to be clearly reported and communicated. This work is part of a series of reviews to support the modernization of the "Chemical Response to Oil Spills: Ecological Effects Research Forum" protocols focusing on technological advances and best toxicity testing practices. Thus, the primary motivation of the present work is to provide guidance and encourage detailed documentation of aquatic toxicity studies. Specific recommendations are provided regarding key reporting elements (i.e., experimental design, test substance and properties, test species and response endpoints, media preparation, exposure conditions, chemical characterization, reporting metric corresponding to the response endpoint, data quality standards, and statistical methods, and raw data), which along with a proposed checklist can be used to assess the completeness of reporting elements or to guide study conduct. When preparing journal publications, authors are encouraged to take advantage of the Supplementary Material section to enhance dissemination and access to key data and information that can be used by multiple end-users, including decision-makers, scientific support staff and modelers. Improving reporting, science communication, and access to critical information enable users to assess the reliability and relevance of study outcomes and increase incorporation of results gleaned from toxicity testing into tools and applications that support oil spill response decisions. Furthermore, improved reporting could be beneficial for audiences outside the oil spill response community, including peer reviewers, journal editors, aquatic toxicologists, researchers in other disciplines, and the public.

Integrating Mental and Social Health in Orthopaedic Practice: The Time Is Now.

Tremendous advances have been made in understanding the intimate relationships between physical, emotional, and social health. There is now a substantial body of evidence demonstrating that mental health and social health may have as much influence on patients' symptom intensity and level of capability-the key metrics of success in orthopaedic care-as pathophysiology. But as a specialty the focus remains mostly on biomedical management (which focuses on structural damage and technical solutions), rather than taking a biopsychosocial approach, which involves screening, measurement, and decision making that prioritizes mental and social health concerns. Failure to do so means orthopaedic surgeons fall short in delivering whole-person care. It is important to highlight the biopsychosocial model of health and healthcare; describe the evidence for mental and social health in orthopaedic practice; outline strategies to identify, measure, and manage psychological and social concerns; and provide frameworks to implement comprehensive models of orthopaedic care that promise to benefit patients, populations, and health systems.

Optimizing Outcomes By Optimizing Bone Health.

Orthopaedic surgeons have long been aware of the importance of metabolic bone health for fracture healing; however, recent attention has focused on optimization of bone health before elective surgery and also regarding pathways to ensure patients have appropriate evaluation and treatment for bone health issues. It is important to describe issues of importance to fragility fracture care and prevention and optimization of outcomes before elective or fracture surgery. To address the challenge of who has the time, expertise, and appropriate patient contact to identify and treat patients at risk of bone metabolic issues, one model for a suggested pathway to ensure these patients are identified and treated is outlined.

Nerve Conditions of the Upper Limb: How Not to Miss or Mismanage.

There are several issues associated with nerve compression syndromes of the upper limb; ultrasonography is a useful diagnostic tool. The orthopaedic surgeon should know how to evaluate and treat patients who do not obtain expected relief following carpal or cubital tunnel release, and also be knowledgeable about the workup and evaluation of patients with conditions of debatable pathology and treatment, such as radial tunnel syndrome or pronator syndrome. Recent studies on suprascapular neuropathy include discussions about the pathophysiology and etiology of the condition, its natural history, and who might benefit from surgery.

Predicting task performance for intelligent human-machine interactions.

Human-machine teams are deployed in a diverse range of task environments and paradigms that may have high failure costs (e.g., nuclear power plants). It is critical that the machine team member can interact with the human effectively without reducing task performance. These interactions may be used to manage the human's workload state intelligently, as the overall workload is related to task performance. Intelligent human-machine teaming systems rely on a facet of the human's state to determine how interaction occurs, but typically only consider the human's state at the current time step. Future task performance predictions may be leveraged to determine if adaptations need to occur in order to prevent future performance degradation. An individualized task performance prediction algorithm that relies on a multi-faceted human workload estimate is shown to predict a supervisor's task performance accurately. The analysis varies the prediction time frame (from 0 to 300 s) and compares results to a generalized algorithm.

Treatment patterns among children and adolescents with attention-deficit/hyperactivity disorder in the United States - a retrospective claims analysis.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder affecting approximately 10.0% of children and 6.5% of adolescents in the United States (US). A comprehensive assessment of the current treatment landscape is warranted to highlight potential unmet needs of children and adolescents with ADHD. Therefore, this study described treatment patterns and healthcare costs among commercially insured children and adolescents with ADHD in the US. METHODS: Children and adolescents with ADHD initiating pharmacological treatment indicated for ADHD were identified from IBM MarketScan Commercial Database (2014-2018). A treatment sequence algorithm was used to examine treatment patterns, including discontinuation (≥ 180 days following the last day of supply of any ADHD treatment), switch, add-on, and drop (discontinuation of an agent in combination therapy), during the 12-month study period following the index date (i.e., first observed ADHD treatment). Total adjusted annual healthcare costs were compared between patients with and without treatment changes. RESULTS: Among 49,756 children and 29,093 adolescents included, mean age was 9 and 15 years, respectively, and 31% and 38% were female. As the first treatment regimen observed, 92% of both children and adolescents initiated a stimulant and 11% initiated combination therapy. Over half of the population had a treatment change over 12 months-59% of children and 68% of adolescents. Treatment discontinuation over 12 months was common in both populations-21% of children and 36% of adolescents discontinued treatment. Healthcare costs increased with the number of treatment changes observed; children and adolescents with treatment changes (i.e., 1, 2, or ≥ 3) incurred an incremental annual cost of up to $1,443 and $2,705, respectively, compared to those without a treatment change (p < 0.001). Costs were largely driven by outpatient visits. CONCLUSIONS: Over a 12-month period, treatment changes were commonly observed and were associated with excess costs, highlighting the unmet treatment needs of children and adolescents with ADHD in the US.

Reasons for treatment changes in adults with attention-deficit/hyperactivity disorder: a chart review study.

BACKGROUND: Adults with attention-deficit hyperactivity disorder (ADHD) often cycle through multiple treatments for reasons that are not well documented. This study analyzed the reasons underlying treatment changes among adults treated for ADHD in a real-world setting. METHODS: Data were collected via an online reporting form completed by eligible physicians between October and November 2020. Data for adult patients in the United States who were diagnosed with ADHD and initiated a treatment regimen within 1 to 5 years of chart abstraction were obtained. Reason for a treatment change was described for a randomly selected regimen episode, which spanned from treatment initiation until the earliest among treatment add-on/switch or discontinuation, death, or date of chart abstraction. The overall rate of ADHD/treatment-related complications were also described. Physician satisfaction with current treatment options for adult ADHD and opinions on areas for improvement were assessed. RESULTS: Data on 320 patients were reported by 152 physicians specializing in psychiatry (40.1%), pediatrics (25.0%), family medicine (21.7%), and internal medicine (13.2%). Patients had a mean age of 29.3 years; most were diagnosed with ADHD as adults (57.5%) and within the previous 5 years (56.5%). Selected treatment regimens included stimulants (79.1%), nonstimulants (14.7%), and combination therapy (5.6%) for an average duration of 1.9 years. Among patients with treatment discontinuation (N = 59), the most common reasons for discontinuation were suboptimal symptom management (55.9%), occurrence of ADHD/treatment-related complications (25.4%), and patient attitude/dislike of medication (25.4%). The main reasons for other key treatment changes were inadequate/suboptimal management of symptoms and cost considerations. Over 40% of patients had ≥ 1 documented ADHD/treatment-related complication, irrespective of whether they led to a treatment change. One in 5 physicians (19.8%) were very dissatisfied, moderately dissatisfied, or neither satisfied nor dissatisfied with current treatment options for ADHD in adults; the top 3 suggested improvements were lower risk of abuse (71.7%), longer effect duration (65.1%), and fewer ADHD/treatment-related complications (61.2%). CONCLUSIONS: The top reasons for treatment changes among adults with ADHD are lack of efficacy and ADHD/treatment-related complications, highlighting the importance of developing more effective and safer treatments to alleviate the burden of ADHD.

Efficacy, Safety, and Tolerability of Centanafadine Sustained-Release Tablets in Adults With Attention-Deficit/Hyperactivity Disorder: Results of 2 Phase 3, Randomized, Double-blind, Multicenter, Placebo-Controlled Trials.

PURPOSE/BACKGROUND: Centanafadine is an inhibitor of norepinephrine, dopamine, and serotonin reuptake transporters under investigation for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS/PROCEDURES: Two phase 3 randomized, double-blind, placebo-controlled, parallel-group studies of 200 mg/d or 400 mg/d centanafadine sustained-release tablets versus placebo included adults (18-55 years of age) with a diagnosis of ADHD. The primary and key secondary efficacy endpoints were the change from baseline at day 42 in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score and the Clinical Global Impression-Severity of Illness Scale, respectively. FINDINGS/RESULTS: Subjects randomized in study 1 (centanafadine 200 mg/d, n = 149; centanafadine 400 mg/d, n = 149; placebo, n = 148) and study 2 (centanafadine 200 mg/d, n = 145; centanafadine 400 mg/d, n = 143; placebo, n = 142) had moderate to severe ADHD (mean AISRS total score, 38.7 [SD, 6.8] across both studies). At day 42, statistically significant least-squares mean differences in AISRS total score were observed in favor of centanafadine versus placebo in study 1 (200 mg/d: -3.16, P = 0.019; 400 mg/d: -2.74, P = 0.039) and study 2 (200 mg/d: -4.01, P = 0.002; 400 mg/d: -4.47, P = 0.001). Effect sizes versus placebo were -0.28 for 200 mg/d and -0.24 for 400 mg/d in study 1 and -0.37 for 200 mg/d and -0.40 for 400 mg/d in study 2. The overall rate of treatment-emergent adverse events (TEAEs) was low, but there was a small increase in TEAE occurrence with increasing dose. Incidences of serious TEAEs and abuse potential-related AEs were low. IMPLICATIONS/CONCLUSIONS: These are the first large-scale studies to demonstrate the efficacy and safety profiles of 200 mg/d and 400 mg/d centanafadine in adults with ADHD.

Surgical management of osteoarthritis of the hand and wrist.

Osteoarthritis of the hand and wrist is common; varying disease manifestations and a spectrum of symptoms make it imperative to approach treatment strategies in an individualized fashion. In this review, attention is focused upon site specific diagnoses and indications for various surgical treatment strategies.

Surgical management of osteoarthritis in the shoulder and elbow.

Interesting recent trends are apparent in the setting of shoulder and elbow pathology. There is an increase in utilization of shoulder arthroplasty for osteoarthritis and post traumatic arthritis. At the same time, there remain limited options for osteoarthritis of the elbow particularly in the young and or active patient. This manuscript details surgical options for osteoarthritis at the elbow and shoulder.

Tips and Tricks in the Management of Distal Radius Fractures.

Distal radius fractures are common. Volar plating is a valuable approach for many fractures. There are also difficult fractures that require careful attention to the exposure and technique for successful volar plating. Classic approaches, such as external fixation with additional percutaneous reduction and pinning or bone graft and fragment-specific fixation, remain valuable especially when volar plating is not applicable. The main objectives are to review the intricacies of volar plating and the use of external fixation with distal radius fractures. This also includes an understanding of the associated injuries that are present with these fractures and the expected outcome of these injuries relative to the distal radius fracture. First, the challenges with volar locked plating as well as many tips and tricks to help with reduction and stabilization of these fractures are reviewed. Second, the benefits and tips and tricks of external fixation are discussed. Finally, the management of common combined injuries with distal radius fractures is reviewed.