AOA Critical Issues Symposium: The Disruptive Physician: Bad Apple or Toxic Tree?

ABSTRACT: Disruptive physician behavior has become a common problem in medicine. Individuals who conduct themselves in a manner that could negatively affect patient care, or "disruptive physicians," frequently cause stress for patients and staff, are a headache for leadership, and can require expensive remediation. We suggest that rather than "bad apples," many disruptive physicians are the fruit of a "toxic tree." That is, many physicians only become disruptive as a response to their environment. It is important for leaders to accurately identify the root causes of disruptive behavior in order to address the problem. In general, it is important for leaders to act prospectively, to examine events from all perspectives, to promote wellness and communication, and to identify external or systemic causes. We also discuss additional considerations for when the physician who has been labeled "disruptive" is a member of an underrepresented group (in orthopaedic surgery, the underrepresented groups are women and racial minorities). As a conclusion, we offer a case example of how 1 institution established a system of physician wellness to enhance prevention efforts.

[WHAT IS "PHYSICAL MEDICINE" - THE FIELD OF PHYSICAL MEDICINE AND REHABILITATION IN ISRAEL?]

BACKGROUND: The field of Physical Medicine and Rehabilitation is as diverse and broad as any field in medicine. The two, seemingly different, fields developed separately and over time (as later presented) merged into one specialty. This resulted in an initial asymmetry of focus amongst training programs - and indeed countries. In Israel, although rehabilitation medicine is on par with the highest levels in the world, its partner, physical medicine (PM) has suffered to the extent that it is practically invisible in some of the training hospitals in our country. OBJECTIVES: We will define PM, explain why it is less developed in Israel, and present the methods being employed to rectify the training imbalance. METHODS: A systematic literature review was performed for prior descriptions and issues in PM in Israel. The search was conducted using four databases (PubMed, Google Scholar, ScienceDirect and the Cochrane Library). Searches were not limited by language or date, reflecting all available data. RESULTS: No articles were identified. This was anticipated as the field of PM is in the process of development in Israel. CONCLUSIONS: Whereas PM has been an official partner of rehabilitation medicine in Israel and prominently featured in academic syllabi, the reality has been otherwise. Our article delineates why this developed and the plans and methods on how it is changing, allowing Israel to be a world leader in all aspects of Physical Medicine and Rehabilitation.

Efficacy and Safety of Upadacitinib or Elsubrutinib Alone or in Combination for Patients With Systemic Lupus Erythematosus: A Phase 2 Randomized Controlled Trial.

OBJECTIVE: The 48-week, phase 2 SLEek study (NCT03978520) evaluated the efficacy and safety of upadacitinib (JAK inhibitor) and elsubrutinib (BTK inhibitor) alone or in combination (ABBV-599) in adults with moderately to severely active systemic lupus erythematosus (SLE). METHODS: Patients were randomized 1:1:1:1:1 to elsubrutinib 60 mg and upadacitinib 30 mg once daily (ABBV-599 high dose), elsubrutinib 60 mg and upadacitinib 15 mg once daily (ABBV-599 low dose), elsubrutinib 60 mg once daily (QD), upadacitinib 30 mg QD, or placebo QD. The primary endpoint was the proportion of patients achieving both Systemic Lupus Erythematosus Responder Index 4 (SRI-4) and glucocorticoid dose ≤10 mg QD at week 24. Additional assessments through week 48 included British Isles Lupus Assessment Group-Based Composite Lupus Assessment (BICLA) and Lupus Low Disease Activity State (LLDAS) responses, number of flares, time to first flare, and adverse events. RESULTS: The study enrolled 341 patients. The ABBV-599 low dose and elsubrutinib arms were discontinued after a planned interim analysis showed lack of efficacy (no safety concerns). More patients achieved the primary endpoint with upadacitinib (54.8%; P = 0.028) and ABBV-599 high dose (48.5%; P = 0.081) versus placebo (37.3%). SRI-4, BICLA, and LLDAS response rates were higher for both upadacitinib and ABBV-599 high dose versus placebo at weeks 24 and 48. Flares were reduced, and time to first flare through week 48 was substantially delayed with both upadacitinib and ABBV-599 high dose versus placebo. No new safety signals were observed beyond those previously reported for upadacitinib or elsubrutinib. CONCLUSION: Upadacitinib 30 mg alone or in combination with elsubrutinib (ABBV-599 high dose) demonstrated significant improvements in SLE disease activity and reduced flares and were well tolerated through 48 weeks.

Towards a novel clinical outcome assessment for systemic lupus erythematosus: first outcomes of an international taskforce.

Systemic lupus erythematosus (SLE) is a disease of high unmet therapeutic need. The challenge of accurately measuring clinically meaningful responses to treatment has hindered progress towards positive outcomes in SLE trials, impeding the approval of potential new therapies. Current primary end points used in SLE trials are based on legacy disease activity measures that were neither specifically designed for the clinical trial context, nor developed according to contemporary recommendations for clinical outcome assessments (COAs), such as that substantial patient input should be incorporated into their design. The Treatment Response Measure for SLE (TRM-SLE) Taskforce is a global collaboration of SLE clinician-academics, patients and patient representatives, industry partners and regulatory experts, established to realize the goal of developing a new COA for SLE clinical trials. The aim of this project is a novel COA designed specifically to measure treatment effects that are clinically meaningful to patients and clinicians, and intended for implementation in a trial end point that supports regulatory approval of novel therapeutic agents in SLE. This Consensus Statement reports the first outcomes of the TRM-SLE project, including a structured process for TRM-SLE development.

The Effects of Brief Guided Imagery on Patients Suffering From Chronic Back Pain: An A-B Design Study.

BACKGROUND: Guided imagery (GI) is a non-pharmacological method used to reduce pain, stress, and anxiety. AIMS: This study aimed to evaluate the impact of brief GI on symptoms of chronic back pain in adults treated in the Rheumatology clinic. DESIGN: A-B design study. SETTINGS & PARTICIPANTS: A sample of 35 women with chronic back pain were recruited at the Rheumatology Outpatient Clinic of Barzilai Medical Center in Ashkelon, Israel. METHODS: All subjects completed questionnaires at recruitment (T1), and after 8-10 weeks, they completed questionnaires again before the first intervention (T2). The intervention included five brief GI group meetings every 2-3 weeks, one hour each (3-5 subjects per group). Participants learned 6 GI exercises and were asked to practice brief guided imagery exercises at least once daily. Then, questionnaires were completed the third time (T3). OUTCOME MEASURES: MOQ - Modified Oswestry Low Back Pain Disability Questionnaire, STAI - State-Trait Anxiety Inventory, FABQ - Fear-Avoidance Beliefs Questionnaire, NPRS - Numerical Pain Rating Scale (average pain over the last week). RESULTS: Compared with the period without intervention, NPRS (Δ = 2.53, standard error [SE] = 0.43, p < .001), STAI (Δ = 8.41, SE = 1.95, p < .001), and MOQ (Δ = 0.06, SE = 0.02, p = .019) reported significantly lower levels after brief guided imagery training. However, no statistically significant change was found in FABQ. CONCLUSIONS: The brief guided imagery intervention may help alleviate chronic back pain, help decrease anxiety, and improve daily activity in women who suffer from chronic low back pain.

Long-Term Efficacy and Safety of Upadacitinib in Patients with Rheumatoid Arthritis: Final Results from the BALANCE-EXTEND Open-Label Extension Study.

INTRODUCTION: Upadacitinib (UPA) is an oral, selective Janus kinase inhibitor that has demonstrated favorable efficacy with an acceptable safety profile across a global, phase 3 program in rheumatoid arthritis (RA). This phase 2 open-label extension investigated the efficacy and safety of UPA through 6 years of treatment. METHODS: Patients from two phase 2b trials (BALANCE-1 and -2) enrolled in BALANCE-EXTEND (NCT02049138) and received open-label UPA 6 mg twice daily (BID). Dose increases to 12 mg BID were required for patients with < 20% improvement in swollen or tender joint counts at weeks 6 or 12 and permitted for those not achieving Clinical Disease Activity Index (CDAI) low disease activity (LDA; CDAI 2.8 to ≤ 10). Dose reduction to UPA 6 mg BID was permitted only for safety or tolerability reasons. After January 2017, the 6/12 mg BID doses were replaced by 15/30 mg once-daily extended-release equivalents. Efficacy and safety were monitored up to 6 years of UPA treatment; outcomes included rates of achievement of LDA or remission. Data were analyzed for patients who received the lower UPA dose throughout; titrated up to the higher UPA dose from weeks 6 or 12; or titrated to the higher UPA dose and back down. RESULTS: Overall, 493 patients entered BALANCE-EXTEND ('Never titrated', n = 306; 'Titrated up', n = 149; 'Titrated up and down', n = 38), and 223 patients (45%) completed the 6-year study. Total cumulative exposure was 1863 patient-years. Rates of LDA and remission were maintained through 6 years. Overall, 87%/70%/73% of patients in the 'Never titrated'/'Titrated up'/'Titrated up and down' groups achieved CDAI LDA at week 312, while the respective rates of Disease Activity Score 28 with C-reactive protein meeting LDA and remission criteria were 85%/69%/70% and 72%/46%/63%. Improvements in patient-reported outcomes were similar among the three groups. No new safety signals were identified. CONCLUSIONS: In this open-label extension of two phase 2 studies, UPA demonstrated sustained efficacy and an acceptable safety profile through 6 years of treatment in patients who completed the study. These data support a favorable long-term benefit-risk profile of UPA in patients with RA. TRIAL REGISTRATION: Trial registration number: NCT02049138.

Evaluation of response to 13-valent conjugated pneumococcal vaccination in patients with rheumatoid arthritis receiving upadacitinib: results from a phase 2 open-label extension study.

OBJECTIVE: To assess the immunogenicity of pneumococcal 13-valent conjugate vaccination (PCV-13) in patients with rheumatoid arthritis receiving upadacitinib and background methotrexate (MTX). METHODS: Eligible patients from the phase 2 open-label extension trial BALANCE-EXTEND (NCT02049138) receiving stable dosing of upadacitinib 15 mg or 30 mg once daily plus background MTX were given PCV-13. Antibody titres were collected prevaccination and 4 and 12 weeks postvaccination. The primary endpoint was the proportion of patients with satisfactory humoral response to PCV-13, defined as a ≥2-fold increase in ≥6 of 12 pneumococcal antigens at 4 weeks postvaccination. RESULTS: Of 111 patients (upadacitinib 15 mg, N=87; 30 mg, N=24), 85.6% were women, 97.3% used concomitant MTX and 44.1% used oral corticosteroids. At 4 weeks, 67.5% (95% CI 57.4 to 77.5) of patients receiving upadacitinib 15 mg and 56.5% (36.3 to 76.8) receiving 30 mg had a satisfactory PCV-13 response. Responses were similar in patients who used or did not use concomitant corticosteroids. No deaths or serious adverse events were reported. CONCLUSIONS: Approximately two-thirds of patients receiving upadacitinib 15 mg once daily achieved a satisfactory humoral response to PCV-13 despite receiving concomitant MTX. Concomitant corticosteroid use did not negatively affect PCV-13 response.

Ethical Issues in Medical Rehabilitation: The Dilemma of Who to Admit.

ABSTRACT: Ethical allocation of scare medical resources is a ubiquitous challenge in many, if not all, medical specialties. The field of physical medicine and rehabilitation is no exception and presents its own unique dilemmas. We report on a small inpatient rehabilitation unit at a large university medical center with a large catchment area representing a vast range of socioeconomic classes. The decision of whom to admit is a constant challenge. We review the existing literature regarding ethical considerations in rehabilitation department admission criteria and attempt to analyze criteria used to admit patients to a general physical medicine and rehabilitation ward. Finally, we discuss our medical center approach to the ethical dilemma of admission priority. A systemic search was conducted in six sources (PubMed, Google Scholar, ScienceDirect, Cochrane Library, LILACS, Embase). Searches were limited to English language articles with no date restriction, reflecting all available data. A reviewer applied the inclusion criteria to identify relevant articles.This review highlights a number of important ethical issues in evaluation and selection criteria that may assist clinicians in improving selection procedures and standardizing access to inpatient rehabilitation. Further high-quality empirical studies and reviews of ethical admission practice with regard to rehabilitation acceptance are required.

Inhibition of structural joint damage progression with upadacitinib in rheumatoid arthritis: 1-year outcomes from the SELECT phase 3 program.

OBJECTIVES: To evaluate the inhibition of progression of structural joint damage through week 48 in patients with moderately to severely active RA receiving upadacitinib as monotherapy or in combination with MTX. METHODS: Radiographic progression was assessed in two phase 3 randomized controlled trials. MTX-naïve patients were randomized to upadacitinib 15 or 30 mg once daily or MTX monotherapy (SELECT-EARLY, n = 945), while MTX inadequate responders (IRs) were randomized to upadacitinib 15 mg once daily or adalimumab 40 mg every other week or placebo added to background MTX (SELECT-COMPARE, n = 1629). The mean changes from baseline in modified total Sharp score (mTSS), joint space narrowing and erosion scores were determined. Data were analysed both by linear extrapolation for missing data imputation and treatment switching and as observed. RESULTS: In patients naïve or with limited exposure to MTX (SELECT-EARLY), mean changes from baseline to week 48 in mTSS were 0.03 for upadacitinib 15 mg, 0.14 for upadacitinib 30 mg and 1.00 for MTX based on linear extrapolation (P < 0.001 for both upadacitinib doses vs MTX). Among patients with an inadequate response to MTX (SELECT-COMPARE), the mean change from baseline in mTSS was significantly reduced in the upadacitinib 15 mg plus MTX group vs placebo plus MTX (0.28 vs 1.73; P < 0.001). The mean change from baseline in the adalimumab plus MTX group was 0.39. CONCLUSION: Upadacitinib monotherapy or in combination with background MTX was effective in inhibiting the progression of structural joint damage through week 48 in MTX-naïve and MTX-IR patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT02706873 and NCT02629159.

Personality Predicts the Efficacy of a Physician Leadership Development Program.

It is imperative for health care organizations to foster leadership skills in their workforce. Leadership development programs offer a potential mechanism to achieve this goal. These development programs are likely not equally effective for all participants. This study evaluates the efficacy of one such program and determines personality predictors of its efficacy. Before and after a 12-month leadership development program, 28 physicians from various disciplines completed self-reported measures of leadership knowledge across 3 domains. At baseline, participants also provided personality data across the Big-5 factors of personality as well as 2 narrow facets (learning-goal orientation and preference for collaboration). Results suggest that leadership development programs can increase knowledge across leadership domains. Extraversion and conscientiousness predict changes in knowledge. Learning-goal-orientation and preference for collaboration personality facets provide incremental predictive power. Leadership development programs can improve self-rated knowledge across a range of leadership domains and is differentially effective for people based on their personalities.

Safety and efficacy of elsubrutinib or upadacitinib alone or in combination (ABBV-599) in patients with rheumatoid arthritis and inadequate response or intolerance to biological therapies: a multicentre, double-blind, randomised, controlled, phase 2 trial.

BACKGROUND: ABBV-599 is a novel fixed-dose combination of the Bruton's tyrosine kinase (BTK) inhibitor elsubrutinib and the Janus kinase (JAK) inhibitor upadacitinib under investigation for the treatment of autoimmune diseases. We aimed to determine whether ABBV-599 could increase the treatment response for patients with active rheumatoid arthritis compared with inhibiting either pathway alone, while maintaining an acceptable safety profile. METHODS: We conducted a multicentre, double-blind, parallel-group, dose-exploratory, randomised, controlled, phase 2 trial at 75 community sites in eight countries in Europe and North America. We enrolled patients who were 18 years or older with rheumatoid arthritis and inadequate response or intolerance to biological disease-modifying antirheumatic drugs. Eligible patients were randomly assigned (3:2:2:2:2:1) via interactive response technology to receive daily, orally administered ABBV-599 (ie, upadacitinib 15 mg plus elsubrutinib 60 mg), elsubrutinib 60 mg, elsubrutinib 20 mg, elsubrutinib 5 mg, upadacitinib 15 mg, or placebo. Randomisation was stratified by the number of previous biological disease-modifying antirheumatic drugs. The investigator, study site personnel, and patients were masked throughout the study. The primary endpoint was change from baseline in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) at week 12 for all patients who received a study drug. Pharmacokinetics and safety were also assessed. This study is registered with ClinicalTrials.gov, number NCT03682705. FINDINGS: Between Oct 8, 2018, and March 26, 2020, 242 patients were randomly assigned to receive ABBV-599 (n=62), elsubrutinib 60 mg (n=41), elsubrutinib 20 mg (n=39), elsubrutinib 5 mg (n=41), upadacitinib 15 mg (n=40), or placebo (n=19). Of the 242 patients, 204 (84%) were female, 38 (16%) were male, and 220 (91%) were White; the mean age at baseline was 58·0 years (SD 11·3). Compared with placebo, the least squares mean changes from baseline in DAS28-CRP were -1·44 (90% CI -2·03 to -0·85; p<0·0001) for ABBV-599, -0·40 (-1·03 to 0·23; p=0·29) for elsubrutinib 60 mg, -0·20 (-0·85 to 0·44; p=0·61) for elsubrutinib 20 mg, -0·21 (-0·84 to 0·41; p=0·57) for elsubrutinib 5 mg, and -1·75 (-2·38 to -1·13; p<0·0001) for upadacitinib. No significant improvements in efficacy measures for elsubrutinib alone (any dose) versus placebo were detected, despite adequate plasma exposure and target engagement. Treatment-emergent adverse events were observed in 113 (47%) of 242 patients, with similar proportions for all groups. INTERPRETATION: Significant improvements in disease activity metrics of rheumatoid arthritis with ABBV-599 were driven by the JAK inhibitor upadacitinib with no discernible effect by the BTK inhibitor elsubrutinib. FUNDING: AbbVie.

Data-Based Self-awareness as the Foundation for Effective Leadership.

The AONL Nurse Executive Fellowship supports nurses who are new to an executive role in developing critical executive competencies. Participants engage in an in-depth specialized assessment process to help them understand themselves and the impact on their leadership. Learnings from the 1st 2 cohorts of fellowship participants provide insight into challenges faced by new executives and how self-awareness can improve performance to address those challenges.

Congenital tooth-bearing tumor of the eyelid leading to lacrimal system obstruction.

PURPOSE: We present an unusual case of a congenital lesion presenting with concomitant chronic dacryocystitis. The clinical presentation, examination, management, and histopathology are reviewed. OBSERVATIONS: A healthy male infant born at 37 weeks gestation presented with an isolated painless 5mm congenital mass of the left medial lower eyelid. Parents also reported episodic epiphora and discharge from the left eye. A surgical excision of the mass revealed an underlying dacryocystitis and the presence of a formed tooth. A dacryocystorhinostomy was performed together with a repair of the soft tissue defect. Histopathology revealed components of disorganized epithelial and mesenchymal tissues including a tooth, skeletal muscle, fat, fibrous tissue, nonkeratinized epithelium, and myelinated nerves. A diagnosis of an odontogenic choristoma of the eyelid was made. Furthermore, a lacrimal sac culture was positive for oxacillin-susceptible Staphylococcus aureus with pathological evidence of chronic dacryocystitis. CONCLUSIONS AND IMPORTANCE: Odontogenic choristoma is a very rare finding in the periocular region with only a few cases reported in the literature. Awareness of clinical findings from this case may allow for a more accurate clinical diagnosis and understanding of the embryologic mechanisms underpinning eyelid and nasolacrimal development. Timely management of this condition is critical to ensure normal oculofacial development and prevent future complications.

Coordination-Driven Self-Assembly of Cyclometalated Iridium Squares Using Linear Aromatic Diisocyanides.

Here, we demonstrate facile [4 + 4] coordination-driven self-assembly of cyclometalated iridium(III) using linear aryldiisocyanide bridging ligands (BLs). A family of nine new [Ir(C^N)2(µ-BL)]44+ coordination cages is described, where C^N is the cyclometalating ligand-2-phenylpyridine (ppy), 2-phenylbenzothiazole (bt), or 1-phenylisoquinoline (piq)-and BL is the diisocyanide BL, with varying spacer lengths between the isocyanide binding sites. These supramolecular coordination compounds are prepared via a one-pot synthesis, with isolated yields of 40-83%. 1H NMR spectroscopy confirms the selective isolation of a single product, which is affirmed to be the M4L4 square by high-resolution mass spectrometry. Detailed photophysical studies were carried out to reveal the nature of the luminescent triplet states in these complexes. In most cases, phosphorescence arises from the [Ir(C^N)2]+ nodes, with the emission color determined by the cyclometalating ligand. However, in two cases, the lowest-energy triplet state resides on the aromatic core of the BL, and weak phosphorescence from that state is observed. This work shows that aromatic diisocyanide ligands enable coordination-driven assembly of inert iridium(III) nodes under mild conditions, producing supramolecular coordination complexes with desirable photophysical properties.

Efficient inhibition of O-glycan biosynthesis using the hexosamine analog Ac5GalNTGc.

There is a critical need to develop small-molecule inhibitors of mucin-type O-linked glycosylation. The best-known reagent currently is benzyl-GalNAc, but it is effective only at millimolar concentrations. This article demonstrates that Ac5GalNTGc, a peracetylated C-2 sulfhydryl-substituted GalNAc, fulfills this unmet need. When added to cultured leukocytes, breast cells, and prostate cells, Ac5GalNTGc increased cell-surface VVA binding by ∼10-fold, indicating truncation of O-glycan biosynthesis. Cytometry, mass spectrometry, and western blot analysis of HL-60 promyelocytes demonstrated that 50-80 µM Ac5GalNTGc prevented elaboration of 30%-60% of the O-glycans beyond the Tn-antigen (GalNAcα1-Ser/Thr) stage. The effect of the compound on N-glycans and glycosphingolipids was small. Glycan inhibition induced by Ac5GalNTGc resulted in 50%-80% reduction in leukocyte sialyl-Lewis X expression and L-/P-selectin-mediated rolling under flow conditions. Ac5GalNTGc was pharmacologically active in mouse. It reduced neutrophil infiltration to sites of inflammation by ∼60%. Overall, Ac5GalNTGc may find diverse applications as a potent inhibitor of O-glycosylation.

Mass spectrometry imaging of blast overpressure induced modulation of GABA/glutamate levels in the central auditory neuraxis of Chinchilla.

Acoustic trauma damages inner ear neural structures including cochlear hair cells which result in hearing loss and neurotransmitter imbalances within the synapses of the central auditory pathway. Disruption of GABA/glutamate levels underlies, tinnitus, a phantom perception of sound that persists post-exposure to blast noise which may manifest in tandem with acute/chronic loss of hearing. Many putative theories explain tinnitus physiology based on indirect and direct assays in animal models and humans, although there is no comprehensive evidence to explain the phenomenon. Here, GABA/glutamate levels were imaged and quantified in a blast overpressure model of chinchillas using Fourier transform ion cyclotron resonance mass spectrometry imaging. The direct measurement from whole-brain sections identified the relative levels of GABA/glutamate in the central auditory neuraxis centers including the cochlear nucleus, inferior colliculus, and auditory cortex. These preliminary results provide insight on the homeostasis of GABA/glutamate within whole-brain sections of chinchilla for investigation of the pathomechanism of blast-induced tinnitus.