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.

A Small Number of Surgeons Perform the Large Majority of Uncommon Nerve Decompression Procedures.

BACKGROUND: Notable surgeon-to-surgeon variation in rates of uncommon surgery can reflect appropriate concentration of expertise with technically difficult or risky procedures that address problematic impairment due to objective pathophysiology. Examples include vascularized tissue transfer or transplantation to address complex tissue loss and release of bony elbow ankylosis. Perhaps more problematic is notable variation in straightforward, discretionary surgeries intended to alleviate pain, offered in the absence of objectively measurable pathophysiology, and without experimental evidence of benefit over placebo and other nonspecific effects. Evidence of concentration of this type of surgery in the hands of a few surgeons might point to inordinate influence of surgeon opinions on patient behavior. A study of variation in operations for upper extremity peripheral mononeuropathy has the potential to uncover potentially problematic variation. There are billing codes specific to common surgeries that can benefit patients with objectively verifiable neuropathies. And there are billing codes that represent less common nerve decompression surgeries that in many cases are offered in the absence of both objective evidence of pathophysiology as well as experimental evidence that surgery alleviates pain better than simulated surgery. QUESTIONS/PURPOSES: We asked the following questions: (1) Among surgeons who billed a mean of at least 10 carpal tunnel releases (CTRs) per year in patients with Medicare insurance in the United States, how many also performed at least one less common peripheral nerve release and cubital tunnel release (CubTR) per year? (2) Among surgeons who billed a mean of at least one less common peripheral nerve release or CubTR on average per year, what is the median and range of the number of less common peripheral nerve releases and CubTRs and the relative proportion of these compared with CTRs per year? (3) Are there any differences in gender, specialty, and number of CTRs and CubTRs between surgeons who performed at least one less common nerve decompression and surgeons who, on average, performed none? METHODS: Using the Medicare Physician & Other Practitioners - by Provider and Service database, we identified surgeons who perform a minimum of 10 CTRs per year. Because this database has all surgeries billed to Medicare performed in any setting by individual surgeons, it is well suited to the study of surgeon-specific operative rates among Medicare patients. Among 7259 clinicians who billed one or more nerve procedure to Medicare between January 2013 and December 2019, we excluded 120 nonsurgical clinicians, 47 podiatrists, and 1561 clinicians who billed procedures as an organization. Among the remaining 5531 surgeons, 5439 performed at least 10 CTRs on average per year, which we considered representative of surgeons who include nerve decompression surgery as a part of their practice. Among these 5439 surgeons, we calculated the mean number of CTRs, CubTRs, and less common peripheral nerve releases (including decompression of a digital nerve, nerve in hand or wrist, ulnar nerve at the wrist, brachial plexus, and unspecified nerve) per year between 2013 and 2019. Decompression of the median nerve at the carpal tunnel, the ulnar nerve at the cubital tunnel, and, much less frequently, the ulnar nerve at the wrist typically addresses measurable neuropathy. The other nerve releases are often performed for illnesses characterized by pain that are defined, in part, by the absence of experimentally verifiable pathophysiology such as radial tunnel and pronator (or lacertus) syndromes. We counted the number of surgeons who billed an average of at least one less common peripheral nerve release and CubTR per year; the median and range of the number of less common nerve releases and CubTRs and their relative proportion among those subsets of surgeons; and differences in the number of surgeons who performed one or none less common surgery by gender, specialty, and volume of CTR/CubTR surgery. RESULTS: Of 5439 surgeons who performed a mean of at least 10 CTRs per year, 2% (93) performed a mean of at least one less common peripheral nerve release per year among patients on Medicare, 14% (775) at least one CubTR, and 1% (47) performed both. Surgeons who performed a mean of at least one less common peripheral nerve release per year performed a median (IQR) of 7 (3 to 17) per year (with a maximum of 153 per year), representing approximately one less common peripheral nerve release for every five CTRs. Sixty-five percent (4076 of 6272) of all less common nerve procedures were performed by the top 20 billing surgeons. Gender was not associated with doing one or more uncommon nerve releases (women 1% [6 of 413], men 2% [87 of 5026]; p = 0.84), but specialty was, with plastic surgeons leading (6% [20 of 340] compared with 1% [73 of 5087] for other types of surgeons; p < 0.001). CONCLUSION: The observation that a relatively small number of surgeons perform a large majority of the surgery for nerve syndromes conceptualized as accounting for arm pain suggests that most surgeons are cautious about ascribing pain to conceptual nerve compression syndromes and offering surgery. CLINICAL RELEVANCE: An approach to surgical care founded on ethical principles regards this type of notable variation as a signal of inordinate influence of surgeon opinion on patient behavior, suggesting that professional conduct may be supported by safeguards such as checklists that help guide patients to choices consistent with their values unclouded by surgeon beliefs, false hope, and common misconceptions.

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.

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.

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.

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.

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.

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.

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.

The Use and Effectiveness of an Online Diagnostic Support System for Blood Film Interpretation: Comparative Observational Study.

BACKGROUND: The recognition and interpretation of abnormal blood cell morphology is often the first step in diagnosing underlying serious systemic illness or leukemia. Supporting the staff who interpret blood film morphology is therefore essential for a safe laboratory service. This paper describes an open-access, web-based decision support tool, developed by the authors to support morphological diagnosis, arising from earlier studies identifying mechanisms of error in blood film reporting. The effectiveness of this intervention was assessed using the unique resource offered by the online digital morphology Continuing Professional Development scheme (DM scheme) offered by the UK National External Quality Assessment Service for Haematology, with more than 3000 registered users. This allowed the effectiveness of decision support to be tested within a defined user group, each of whom viewed and interpreted the morphology of identical digital blood films. OBJECTIVE: The primary objective of the study was to test the effectiveness of the decision support system in supporting users to identify and interpret abnormal morphological features. The secondary objective was to determine the pattern and frequency of use of the system for different case types, and to determine how users perceived the support in terms of their confidence in decision-making. METHODS: This was a comparative study of identical blood films evaluated either with or without decision support. Selected earlier cases from the DM scheme were rereleased as new cases but with decision support made available; this allowed a comparison of data sets for identical cases with or without decision support. To address the primary objectives, the study used quantitative evaluation and statistical comparisons of the identification and interpretation of morphological features between the two different case releases. To address the secondary objective, the use of decision support was assessed using web analytical tools, while a questionnaire was used to assess user perceptions of the system. RESULTS: Cases evaluated with the aid of decision support had significantly improved accuracy of identification for relevant morphological features (mean improvement 9.8%) and the interpretation of those features (mean improvement 11%). The improvement was particularly significant for cases with higher complexity or for rarer diagnoses. Analysis of website usage demonstrated a high frequency of access for web pages relevant to each case (mean 9298 for each case, range 2661-24,276). Users reported that the decision support website increased their confidence for feature identification (4.8/5) and interpretation (4.3/5), both within the context of training (4.6/5) and also in their wider laboratory practice (4.4/5). CONCLUSIONS: The findings of this study demonstrate that directed online decision support for blood morphology evaluation improves accuracy and confidence in the context of educational evaluation of digital films, with effectiveness potentially extending to wider laboratory use.

Editorial Commentary: Elbow Arthroscopy Is a Safe Procedure. Sure.

Elbow arthroscopy is a procedure that is of great potential use and yet also of grave potential risks. To balance the risk-versus-reward consideration, one must be aware of the potential complications associated with this procedure, weigh them against the potential advantages, and understand one's own skills and familiarity with the procedure. There is no doubt that elbow arthroscopy has changed and even revolutionized our management of pathology about the elbow; however, one must bear in mind that this comes at a risk of complications that cannot be reduced to zero.

Hand and Wrist Problems That Can Be Deceptive: Avoiding Snakes in the Grass.

In this chapter, the authors describe hand conditions that can be "bad actors" and provide specific clues to identify these problems, and strategies to assess and successfully treat them. We will review pediatric and adult hand fractures, fractures of the distal radius, and trigger digits.

Scapholunate Ligament Injury: Management Strategies From Occult Injury to Arthritis.

This chapter will explore scapholunate ligament injuries with a focus on injury recognition, diagnosis, the natural history, and options for treatment. Treatment is based upon injury factors, patient factors, and surgeon preference. The classification systems in common use will be discussed, and treatment options will be explored, including nonsurgical, arthroscopic, repair, reconstruction, pain relieving measures, and salvage procedures.

Ethics and Professionalism: The Role of Self-Regulation and Peer Review in Maintaining Hand Surgery's Standards.

The practice of hand surgery is bound by the need for each of us to maintain our profession's high standards by fulfilling our peers' and society's expectations regarding ethical and professional behavior. Our profession is self-regulated by local, state, and national organizations, which provide expectations and standards for practice. This manuscript reviews the resources available from such organizations to foster standards of practice.

Synthesis and biological activity of a CXCR4-targeting bis(cyclam) lipid.

A bis(cyclam)-capped cholesterol lipid designed to bind C-X-C chemokine receptor type 4 (CXCR4) was synthesised in good overall yield from 4-methoxyphenol through a seven step synthetic route, which also provided a bis(cyclam) intermediate bearing an octaethyleneglycol-primary amine that can be easily derivatised. This bis(cyclam)-capped cholesterol lipid was water soluble and self-assembled into micellar and non-micellar aggregates in water at concentrations above 8 µM. The bioactivity of the bis(cyclam)-capped cholesterol lipid was assessed using primary chronic lymphocytic leukaemia (CLL) cells, first with a competition binding assay then with a chemotaxis assay along a C-X-C motif chemokine ligand 12 (CXCL12) concentration gradient. At 20 µM, the bis(cyclam)-capped cholesterol lipid was as effective as the commercial drug AMD3100 for preventing the migration of CLL cells, despite a lower affinity for CXCR4 than AMD3100.

Forearm Instability: Anatomy, Biomechanics, and Treatment Options.

The forearm unit consists of the radius and ulna, a complex and interrelated set of joints (distal radioulnar joint, proximal radioulnar joint) and the soft tissue stabilizers between the 3 bones. Distally, this is represented by the triangular fibrocartilage complex at the wrist, proximally by the annular ligament at the elbow, and in the forearm by the interosseous membrane. Disruptions in any of these structures may lead to forearm instability, with consequences at each of the remaining structures.

Where Are the Women in Orthopaedic Surgery?

BACKGROUND: Although women account for approximately half of the medical students in the United States, they represent only 13% of orthopaedic surgery residents and 4% of members of the American Academy of Orthopaedic Surgeons (AAOS). Furthermore, a smaller relative percentage of women pursue careers in orthopaedic surgery than in any other subspecialty. Formal investigations regarding the gender discrepancy in choice of orthopaedic surgery are lacking. QUESTIONS/PURPOSES: (1) What reasons do women orthopaedic surgeons cite for why they chose this specialty? (2) What perceptions do women orthopaedic surgeons think might deter other women from pursuing this field? (3) What role does early exposure to orthopaedics and mentorship play in this choice? (4) What professional and personal choices do women in orthopaedics make, and how might this inform students who are choosing a career path? METHODS: A 21-question survey was emailed to all active, candidate, and resident members of the Ruth Jackson Orthopaedic Society (RJOS, n = 556). RJOS is the oldest surgical women's organization incorporated in the United States. An independent orthopaedic specialty society, RJOS supports leadership training, mentorship, grant opportunities, and advocacy for its members and promotes sex-related musculoskeletal research. Although not all women in orthopaedic practice or training belong to RJOS, it is estimated that 42% of women AAOS fellows are RJOS members. Questions were formulated to determine demographics, practice patterns, and lifestyle choices of women who chose orthopaedic surgery as a specialty. Specifically, we evaluated the respondents' decisions about their careers and their opinions of why more women do not choose this field. For the purpose of this analysis, the influences and dissuaders were divided into three major categories: personal attributes, experience/exposure, and work/life considerations. RESULTS: The most common reasons cited for having chosen orthopaedic surgery were enjoyment of manual tasks (165 of 232 [71%]), professional satisfaction (125 of 232 [54%]), and intellectual stimulation (123 of 232 [53%]). The most common reasons indicated for why women might not choose orthopaedics included perceived inability to have a good work/life balance (182 of 232 [78%]), perception that too much physical strength is required (171 of 232 [74%]), and lack of strong mentorship in medical school or earlier (161 of 232 [69%]). Respondents frequently (29 of 45 [64%]) commented that their role models, mentors, and early exposure to musculoskeletal medicine were influential, but far fewer (62 of 231 [27%]) acknowledged these in their top five influences than they did the more "internal" motivators. CONCLUSIONS: To our knowledge, this is the largest study of women orthopaedic surgeons regarding factors influencing their professional and personal choices. Our data suggest that the relatively few women currently practicing orthopaedics were attracted to the field because of their individual personal affinity for its nature despite the lack of role models and exposure. The latter factors may impact the continued paucity of women pursuing this field. Programs designed to improve mentorship and increase early exposure to orthopaedics and orthopaedic surgeons may increase personal interest in the field and will be important to attract a diverse group of trainees to our specialty in the future.