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BACKGROUND: In January 2016, as part of the Maintenance of Certification in Anesthesiology (MOCA) program, the American Board of Anesthesiology launched MOCA Minute, a web-based longitudinal assessment, to supplant the former cognitive examination. We investigated the association between participation and performance in MOCA Minute and disciplinary actions against medical licenses of anesthesiologists. METHODS: All anesthesiologists with time-limited certificates (ie, certified in 2000 or after) who were required to register for MOCA Minute in 2016 were followed up through December 31, 2016. The incidence of postcertification prejudicial license actions was compared between those who did and did not register and compared between registrants who did and did not meet the MOCA Minute performance standard. RESULTS: The cumulative incidence of license actions was 1.2% (245/20,006) in anesthesiologists required to register for MOCA Minute. Nonregistration was associated with a higher incidence of license actions (hazard ratio, 2.93 [95% confidence interval {CI}, 2.15–4.00]). For the 18,534 (92.6%) who registered, later registration (after June 30, 2016) was associated with a higher incidence of license actions. In 2016, 16,308 (88.0%) anesthesiologists met the MOCA Minute performance standard. Of those not meeting the standard (n = 2226), most (n = 2093, 94.0%) failed because they did not complete the required 120 questions. Not meeting the standard was associated with a higher incidence of license actions (hazard ratio, 1.92 [95% CI, 1.36–2.72]). CONCLUSIONS: Both timely participation and meeting performance standard in MOCA Minute are associated with a lower likelihood of being disciplined by a state medical board.

Cellular senescence defines an irreversible cell growth arrest state linked to loss of tissue function and aging in mammals. This transition from proliferation to senescence is typically characterized by increased expression of the cell-cycle inhibitor p16 INK4a and formation of senescence-associated heterochromatin foci (SAHF). SAHF formation depends on HIRA-mediated nucleosome assembly of histone H3.3, which is regulated by the serine/threonine protein kinase Pak2. However, it is unknown if Pak2 contributes to cellular senescence. Here, we show that depletion of Pak2 delayed oncogene-induced senescence in IMR90 human fibroblasts and oxidative stress–induced senescence of mouse embryonic fibroblasts (MEFs), whereas overexpression of Pak2 accelerated senescence of IMR90 cells. Importantly, depletion of Pak2 in BubR1 progeroid mice attenuated the onset of aging-associated phenotypes and extended life span. Pak2 is required for expression of genes involved in cellular senescence and regulated the deposition of newly synthesized H3.3 onto chromatin in senescent cells. Together, our results demonstrate that Pak2 is an important regulator of cellular senescence and organismal aging, in part through the regulation of gene expression and H3.3 nucleosome assembly.

AbstractIntroductionAutonomic modulation has been used as a therapy to control recurrent ventricular arrhythmia (VA). This study was to explore stellate ganglion block (SGB) effect on cardiac electrophysiologic properties and evaluate the long‐term outcome of cardiac sympathetic denervation (CSD) for patients with recurrent VA and structural heart disease (SHD).Materials and MethodsPatients who had recurrent VA due to SHD were enrolled prospectively. Electrophysiologic study and ventricular tachycardia (VT) induction were performed before and after left and right SGB. VA burden and long‐term outcomes were assessed for a separate patient group who underwent left or bilateral CSD for drug‐refractory VA due to SHD.ResultsElectrophysiologic study of nine patients showed that baseline mean (SD) corrected sinus node recovery time (cSNRT) increased from 320.4 (73.3) ms to 402.9 (114.2) ms after left and 482.4 (95.7) ms after bilateral SGB (P = .03). SGB did not significantly change P‐R, QRS, and Q‐T intervals and ventricular effective refractory period, nor did the inducibility of VA. Nineteen patients underwent left (n = 14) or bilateral (n = 5) CSD. CSD reduced VA burden and appropriate ICD therapies from a median (interquartile range) of 2.5 (0.4‐11.6) episodes weekly to 0.1 (0.0‐2.4) episodes weekly at 6‐month follow‐up (P = .002). Three‐year freedom from orthotopic heart transplant (OHT) and death was 52.6%. New York Heart Association functional class III/IV and VT rate less than 160 beats per minute were predictors of recurrent VA, OHT, and death.ConclusionSGB increased cSNRT without changing heart rate. CSD was more beneficial for patients with mild‐to‐moderate heart failure and faster VA.

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background This repeated cross-sectional survey study was conducted to determine the prevalence of, and factors associated with, burnout, distress, and depression among anesthesiology residents and first-year graduates. We hypothesized that heavy workload and student debt burden were associated with a higher risk of physician burnout, distress, and depression, and that perception of having adequate workplace resources, work–life balance, and social support were associated with a lower risk. Methods Physicians beginning U.S. anesthesiology residency between 2013 and 2016 were invited to take online surveys annually from their clinical anesthesia year 1 to 1 yr after residency graduation. The Maslach Burnout Inventory, the Physician Well-Being Index, and the Harvard Department of Psychiatry/National Depression Screening Day Scale were used to measure burnout, distress, and depression, respectively. Logistic regression analyses were conducted to examine whether self-reported demographics, personal, and professional factors were associated with the risk of burnout, distress, and depression. Results The response rate was 36% (5,295 of 14,529). The prevalence of burnout, distress, and depression was 51% (2,531 of 4,966), 32% (1,575 of 4,941), and 12% (565 of 4,840), respectively. Factors associated with a lower risk of all three outcomes included respondents’ perceived workplace resource availability, (odds ratio = 0.51 [95% CI, 0.45 to 0.57] for burnout; 0.51 [95% CI, 0.45 to 0.56] for distress; 0.52 [95% CI, 0.45 to 0.60] for depression) and perceived ability to maintain work–life balance (0.61 [95% CI, 0.56 to 0.67] for burnout; 0.50 [95% CI, 0.46 to 0.55] for distress; 0.58 [95% CI, 0.51 to 0.65] for depression). A greater number of hours worked per week and a higher amount of student debt were associated with a higher risk of distress and depression, but not burnout. Conclusions Burnout, distress, and depression are notable among anesthesiology residents. Perceived institutional support, work–life balance, strength of social support, workload, and student debt impact physician well-being.

This study compared anesthesiology residency graduates’ written certification examination performance before and after the American Board of Anesthesiology (ABA) introduced the staged examination system. After equating test scores using common test items, the first 2 cohorts (2013, 2014) in the staged system scored 7.1 points and 8.3 points higher than the 2011 baseline cohort in the former examination system. The 2013 and 2014 cohorts’ pass rates (94.2% and 95.9%) were also higher than the 2011 and 2012 cohorts (91.9% and 92.6%) if a common standard had been applied. The staged examination system may be associated with improved knowledge of anesthesiology graduates.

e21039 Background: Tumor-infiltrating neutrophils (TINs) and their myeloid precursors play an important role in cancer biology. While activated neutrophils have been shown to kill tumor cells, there is growing evidence that neutrophils may also support tumor progression by impairing T cell-dependent anti-tumor immunity. We hypothesized that low TINs would be associated with better responses to immunotherapy (IO). Methods: Pretreatment biopsies from 15 metastatic melanoma (MM) pts treated with anti-CTL4 and anti-PD-1 therapy from 2012-17 were collected and stained with myeloperoxidase (MPO). Slides were scanned at 40x magnification on the Aperio ScanScope AT Turbo brightfield instrument (Leica Biosystems) at a resolution of 0.25 microns per pixel. To indicate the region of analysis, the digital pen tool was used to trace a minimum 85% of tumor. Ten fixed-sized boxes were placed on the hottest staining region in a second annotation layer on the image. The boxes equaled 1mm2 in total area. If the tumor tracing had an area of 1mm2, or less, boxes were not placed on the image. The selected tissue was analyzed using an Aperio imaging quatification algorithm . The number of 3+ cells were considered positive for neutrophils and used in subsequent calculations. Quality control review was performed on a subset of cases by Anatomic Pathologists. Response to therapy was assessed using the Response Evaluation Criteria In Solid Tumors (RECIST). Overall survival (OS) was calculated using the Kaplan Meier method. Results: The median number of treatment lines before the biopsy was 1 (range 0-2). The treatment immediately following the biopsy consisted of ipilimumab (n = 10, 66.6%), pembrolizumab (n = 4, 26.6%), ipilimumab/nivolumab (n = 1, 6.6%). The median number of neutrophils in the biopsy hotspot was 92/mm2 (range 6-219) for the entire cohort. For patients achieving PR and CR after 4 cycles of therapy, the median neutrophils were 36/mm2 (IQ 14-78) while the median was 106/mm2 (IQ 60-138) for patients who had progressive disease,( p = 0.04). There was no correlation between the numbers of neutrophils in the biopsy with the absolute neutrophil count in the peripheral blood (R value: 0.012). Conclusions: Decreased TINs are significantly associated with better responses to IO in MM pts. Measurements of TINs may help to select patients who are likely to benefit from anti-CTL4 and anti-PD-1 therapy. Additionally, exploration of whether combining therapies that decrease neutrophils intratumorally should be explored.

9535 Background: A broad understanding of baseline immunity is needed in order to predict responses to PD-1 blockade. We previously reported in a preclinical model that elevated Th1 signature cytokines are present after successful therapy with PD-1 blockade. In this study we evaluated serum cytokines as biomarkers of response in a cohort of patients with metastatic melanoma undergoing anti-PD1 therapy. Methods: 27 pts diagnosed with metastatic melanoma (MM) received anti-PD-1 therapy and had peripheral blood collected prior to anti-PD-1 therapy start and 12 weeks after; 55 proinflammatory-related serum cytokines were analyzed at both times using the Meso Scale Discovery (MSD) assay. At week 12, we identified 15 pts who had radiographic complete or partial response (TR) and 12 had progressive disease (PD) using RECIST criteria. Spearman rank correlation coefficients (rho) were used to assess association between pre-treatment serum cytokine levels. For each cytokine, differences in pretreatment serum levels and the ratio of the 12 week to pre-treatment serum levels between TR and PD groups were assessed using Wilcoxon rank sum tests. Results: Pretreatment serum IL-12p40 and MIP3a (CCL20) were moderately correlated (rho=0.3944). Pretreatment IL-12p40 and was found to be significantly higher (p=0.0025) in the TR group (median=48.5; 25th to 75th percentile [IQR]:25.3-63.8) relative to the PD group (median=17.3; IQR: 8.6-30.3). Pretreatment MIP3a was also found to be significantly higher (p=0.0359) in the TR group (median=1.72; IQR: 1.41-2.65) relative to the PD group (median=1.33; IQR: 1.09-1.98). The 12th week pretreatment IL-12p40 ratio (median=1.98; IQR: 1.4-11.3) in the TR group was greater than that (median=0.64; IQR: 0.23-1.61) in the PD group (p=0.0029); we identified that baseline serum levels >15pg/ml of IL12p40 prior to immunotherapy were associated with significantly prolonged event free survival (p=0.001). Conclusions: Measurements of IL-12p40 and MIP-3a levels before immunotherapy may help to select patients who are likely to benefit from anti-PD1 therapy. Additionally, exploration of combination therapies that increase IL-12P40 and MIP3 prior or during immunotherapy should be undertaken.

Background: Functional tricuspid regurgitation (FTR) is common in heart failure with reduced ejection fraction and mostly consequent to pulmonary hypertension. However, the intrinsic clinical implications of FTR are not fully understood. Methods: The cohort of all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B-C and ejection fraction<50%, with FTR grading and systolic pulmonary artery pressure estimation by Doppler echocardiography was identified and outcomes were analyzed. Patients with pacemakers/defibrillators, organic valve disease, or previous valve surgery were excluded. The primary outcome measure was overall mortality (censored at implantation of a defibrillator, ventricular assist device, or cardiac transplantation), adjusting for clinical and echocardiographic associates with mortality and major comorbidities. Results: Among 13 026 patients meeting inclusion criteria, FTR was detected in 88% (N=11 507: 33% trivial, 32% mild, 17% moderate, and 6% severe), aged 68±14 years, 35% women, ejection fraction 36±10%, systolic pulmonary artery pressure 41±14 mm Hg with 20% atrial fibrillation. Covariates independently associated with FTR included elevated systolic pulmonary artery pressure, older age, female sex, lower ejection fraction, mitral regurgitation, and atrial fibrillation (all P <0.0001). FTR was independently associated with more dyspnea, impaired kidney function, and lower cardiac output ( P <0.003 for all). For long-term outcome, higher FTR degree compared with trivial tricuspid regurgitation was independently associated with higher mortality (adjusted hazard ratios 1.09 [1.01-1.17] for mild FTR, 1.21 [1.11-1.33] for moderate FTR and 1.57 [1.39-1.78] for severe FTR); hence, 5-year survival was substantially lower with increasing severity of functional FTR, 68±1% for trivial FTR, 58±2% for mild FTR, 45±2% for moderate FTR, and 34±4% for severe FTR. Conclusions: In this large cohort of patients with heart failure with reduced ejection fraction, FTR was common and independently associated with pulmonary hypertension, atrial fibrillation, and more severe heart failure presentation. Long-term, higher FTR severity is associated with considerably worse survival, independently of baseline characteristics. Given these untoward outcomes associated with FTR in patients with heart failure with reduced ejection fraction, clinical trials should be directed at testing FTR treatment.

AbstractAnaplastic large cell lymphomas (ALCLs) represent a relatively common group of T-cell non-Hodgkin lymphomas (T-NHLs) that are unified by similar pathologic features but demonstrate marked genetic heterogeneity. ALCLs are broadly classified as being anaplastic lymphoma kinase (ALK)+ or ALK−, based on the presence or absence of ALK rearrangements. Exome sequencing of 62 T-NHLs identified a previously unreported recurrent mutation in the musculin gene, MSCE116K, exclusively in ALK− ALCLs. Additional sequencing for a total of 238 T-NHLs confirmed the specificity of MSCE116K for ALK− ALCL and further demonstrated that 14 of 15 mutated cases (93%) had coexisting DUSP22 rearrangements. Musculin is a basic helix-loop-helix (bHLH) transcription factor that heterodimerizes with other bHLH proteins to regulate lymphocyte development. The E116K mutation localized to the DNA binding domain of musculin and permitted formation of musculin–bHLH heterodimers but prevented their binding to authentic target sequence. Functional analysis showed MSCE116K acted in a dominant-negative fashion, reversing wild-type musculin-induced repression of MYC and cell cycle inhibition. Chromatin immunoprecipitation–sequencing and transcriptome analysis identified the cell cycle regulatory gene E2F2 as a direct transcriptional target of musculin. MSCE116K reversed E2F2-induced cell cycle arrest and promoted expression of the CD30–IRF4–MYC axis, whereas its expression was reciprocally induced by binding of IRF4 to the MSC promoter. Finally, ALCL cells expressing MSCE116K were preferentially targeted by the BET inhibitor JQ1. These findings identify a novel recurrent MSC mutation as a key driver of the CD30–IRF4–MYC axis and cell cycle progression in a unique subset of ALCLs.