Citations

Abstract Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Abstract Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer’s disease based on inferred underlying histopathology. Parkinson’s disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington’s disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned—more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers—we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.

LINKED CONTENTThis article is linked to Grover et al and Elwing & Sayuk papers. To view these articles, visit https://doi.org/10.1111/apt.16591 and https://doi.org/10.1111/apt.16603

Background: Diversity within the healthcare workforce is essential to improve quality of care, although evaluation of diversity within surgical training remains limited. This study analyzed diversity in recruitment of residents into surgical subspecialties at a large academic medical institution and national trends. Methods: A 21-year cross-sectional study of medical school graduates accepted into all surgical subspecialty training programs was performed. The institutional cohort was divided into two groups (1997–2006, 2007–2017). Subspecialty acceptance rates were determined between 2011 and 2018. Data on candidate demographics including gender, race, ethnicity, citizenship, and origin of medical education at a single institution and nationally were extracted. Results: Two thousand found hundred seventy-two residents were included in this study. From 1997 to 2018, female acceptances increased from 21.1% to 29.7% (p < 0.01), non-White increased from 27.9% to 31.8% (p = 0.01), and international medical graduates decreased from 28.8% to 25.5% (p = 0.02). There was no significant change in accepted Hispanic and Non-US candidates. Female subspecialty rates for subspecialties increased nationally and was comparable to our cohort, except in general surgery. Hispanic subspecialty acceptance rates were less than 10% and Black/African American acceptance rates remained less than 5% across subspecialties nationally and at our institution. Conclusion: Diversity in surgical training has modestly progressed over the last two decades, but the degree of positive change has not been universal and highlights the critical need for improvement and action. Continued institution driven and collaborative strategies are essential to promote diversity in recruitment across all surgical specialties that has implications on our future workforce and surgical leadership.

Purpose To determine whether elbow torque was associated with anatomic adaptations of the medial elbow following a season of competitive pitching. Methods Pitchers from 3 collegiate baseball teams were recruited during the preseason for participation. Before the season, pitchers were recorded throwing 5 “game‐speed” fastball pitches from a standard distance off a mound while wearing a wearable sensor baseball compression sleeve that calculates elbow torque, arm speed, arm slot, and arm rotation. Participants subsequently underwent dynamic ultrasound imaging of the medial elbow, including measurements of the ulnar collateral ligament (UCL) and ulnohumeral joint space to assess elbow laxity. Following a full season of competitive pitching, all testing was repeated, and statistical analysis comparing preseason to postseason sonographic findings was performed. Results Twenty‐eight collegiate pitchers underwent preseason sonographic and kinematic testing. Nineteen pitchers were available for postseason testing. The average age (standard deviation) and playing experience was 19.9 (1.2) and 14.7 (1.5) years. Compared with preseason, there were significant increases in postseason UCL thickness (1.92 ± 0.09 vs 1.56 ± 0.09 mm, P < .01) and elbow laxity (1.77 ± 0.23 vs 1.15 ± 0.22 mm, P = .028) after a season of pitching. No significant changes in pitching kinematic measurements were observed between preseason and postseason testing. Preseason pitching kinematic measurements were significantly associated with increased UCL thickness (arm slot: beta estimate –0.03 ± 0.01, P = .011) and reduction in elbow laxity (elbow torque: beta estimate –0.03 ± 0.01, P = .04) after a season of pitching. Pitchers with increased body weight and arm length demonstrated reduced medial elbow torque during pitching ( P < .05). Conclusions After a season of competitive pitching, adaptive changes of the medial elbow were demonstrated on dynamic ultrasound. However, the influence of pitching kinematic measurements on these adaptations are of small magnitude and unknown clinical significance. Although wearable sensor technology may have value in trending individual pitcher kinematics, no discrete threshold appears to predict the development of adaptive changes at the elbow. Level of Evidence Level II, prospective observational study.

The Wilderness Medical Society convened an expert panel to develop evidence-based guidelines for the prevention and management of tick-borne illness (TBI). Recommendations are graded based on quality of supporting evidence according to criteria put forth by the American College of Chest Physicians. The guidelines include a brief review of the clinical presentation, epidemiology, prevention, and management of TBI in the United States, with a primary focus on interventions that are appropriate for resource-limited settings. Strong recommendations are provided for the use of DEET, picaridin, and permethrin; tick checks; washing and drying clothing at high temperatures; mechanical tick removal within 36 h of attachment; single-dose doxycycline for high-risk Lyme disease exposures versus “watchful waiting;” evacuation from backcountry settings for symptomatic tick exposures; and TBI education programs. Weak recommendations are provided for the use of light-colored clothing; insect repellents other than DEET, picaridin, and permethrin; and showering after exposure to tick habitat. Weak recommendations are also provided against passive methods of tick removal, including the use of systemic and local treatments. There was insufficient evidence to support the use of long-sleeved clothing and the avoidance of tick habitat such as long grasses and leaf litter. Although there was sound evidence supporting Lyme disease vaccination, a grade was not offered as the vaccine is not currently available for use in the United States.