Citations

Abstract Activation of innate immunity in the brain is a prominent feature of Alzheimer's disease (AD). The present study investigated the regulation of innate immunity by young serum in a transgenic AD mouse model. We found that young serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Neutrophil depletion via Ly6G neutralizing antibodies mimicked the benefits of young serum on AD brain functions. Serum proteomic analysis of young serum revealed significant enrichment of the factors VEGF-A and CXCL1, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Intravenously injected VEGF-A reversed Aβ-induced decreases in Cdk5 and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration and thereby restored memory in APP/PS1 mice. Our data uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and provide a rationale for targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.

Abstract Purpose: Current endoscopy-based screening and surveillance programs have not been proven effective at decreasing esophageal adenocarcinoma (EAC) mortality, creating an unmet need for effective molecular tests for early detection of this highly lethal cancer. We conducted a genome-wide methylation screen to identify novel methylation markers that distinguish EAC and high-grade dysplasia (HGD) from normal squamous epithelium (SQ) or nondysplastic Barrett's esophagus (NDBE). Experimental Design: DNA methylation profiling of samples from SQ, NDBE, HGD, and EAC was performed using HM450 methylation arrays (Illumina) and reduced-representation bisulfate sequencing. Ultrasensitive methylation-specific droplet digital PCR and next-generation sequencing (NGS)-based bisulfite-sequencing assays were developed to detect the methylation level of candidate CpGs in independent esophageal biopsy and endoscopic brushing samples. Results: Five candidate methylation markers were significantly hypermethylated in HGD/EAC samples compared with SQ or NDBE (P < 0.01) in both esophageal biopsy and endoscopic brushing samples. In an independent set of brushing samples used to construct biomarker panels, a four-marker panel (model 1) demonstrated sensitivity of 85.0% and 90.8% for HGD and EACs respectively, with 84.2% and 97.9% specificity for NDBE and SQ respectively. In a validation set of brushing samples, the panel achieved sensitivity of 80% and 82.5% for HGD and EAC respectively, at specificity of 67.6% and 96.3% for NDBE and SQ samples. Conclusions: A novel DNA methylation marker panel differentiates HGD/EAC from SQ/NDBE. DNA-methylation–based molecular assays hold promise for the detection of HGD/EAC using esophageal brushing samples.

BACKGROUND: The American Board of Anesthesiology administers the APPLIED Examination as a part of initial certification, which as of 2018 includes 2 components—the Standardized Oral Examination (SOE) and the Objective Structured Clinical Examination (OSCE). The goal of this study is to investigate the measurement construct(s) of the APPLIED Examination to assess whether the SOE and the OSCE measure distinct constructs (ie, factors). METHODS: Exploratory item factor analysis of candidates’ performance ratings was used to determine the number of constructs, and confirmatory item factor analysis to estimate factor loadings within each construct and correlation(s) between the constructs. RESULTS: In exploratory item factor analysis, the log-likelihood ratio test and Akaike information criterion index favored the 3-factor model, with factors reflecting the SOE, OSCE Communication and Professionalism, and OSCE Technical Skills. The Bayesian information criterion index favored the 2-factor model, with factors reflecting the SOE and the OSCE. In confirmatory item factor analysis, both models suggest moderate correlation between the SOE factor and the OSCE factor; the correlation was 0.49 (95% confidence interval [CI], 0.42-0.55) for the 3-factor model and 0.61 (95% CI, 0.54-0.64) for the 2-factor model. The factor loadings were lower for Technical Skills stations of the OSCE (ranging from 0.11 to 0.25) compared with those of the SOE and Communication and Professionalism stations of the OSCE (ranging from 0.36 to 0.50). CONCLUSIONS: The analyses provide evidence that the SOE and the OSCE measure distinct constructs, supporting the rationale for administering both components of the APPLIED Examination for initial certification in anesthesiology.

BACKGROUND: A temporary decrease in anesthesiology residency graduates that occurred around the turn of the millennium may have workforce implications. The aims of this study are to describe, between 2005 and 2015, (1) demographic changes in the workforce of physicians trained as anesthesiologists; (2) national and state densities of these physicians, as well as temporal changes in the densities; and (3) retention of medical licenses by mid- and later-career anesthesiologists. METHODS: Using records from the American Board of Anesthesiology and state medical and osteopathic boards, the numbers of licensed physicians aged 30–59 years who had completed Accreditation Council for Graduate Medical Education–accredited anesthesiology residency training were calculated cross-sectionally for 2005, 2010, and 2015. Demographic trends were then described. Census data were used to calculate national and state densities of licensed physicians. Individual longitudinal data were used to describe retention of medical licenses among older physicians. RESULTS: The number of licensed physicians trained as anesthesiologists aged 30–59 years increased from 32,644 in 2005 to 36,543 in 2010 and 36,624 in 2015, representing a national density of 1.10, 1.18, and 1.14 per 10,000 population in those years, respectively. The density of anesthesiologists among states ranged from 0.37 to 3.10 per 10,000 population. The age distribution differed across the years. For example, anesthesiologists aged 40–49 years predominated in 2005 (47%), but by 2015, only 31% of anesthesiologists were aged 40–49 years. The proportion of female anesthesiologists grew from 22% in 2005, to 24% in 2010, and to 28% in 2015, particularly among early-career anesthesiologists. For anesthesiologists with licenses in 2005, the number who still had active licenses in 2015 decreased by 9.6% for those aged 45–49 years, by 14.1% for those aged 50–54 years, and by 19.7% for those aged 55–59 years. CONCLUSIONS: The temporary decrease in anesthesiology residency graduates around the turn of the 21st century decreased the proportion of anesthesiologists who were midcareer as of 2015. This may affect the future availability of senior leaders as well as the future overall workforce in the specialty as older anesthesiologists retire. National efforts to plan for workforce needs should recognize the geographical variability in the distribution of anesthesiologists.

Abstract The key functional molecules involved in inflammatory bowel disease (IBD) and IBD-induced colorectal tumorigenesis remain unclear. In this study, we found that the apoptosis repressor with caspase recruitment domain (ARC) protein plays critical roles in IBD. ARC-deficient mice exhibited substantially higher susceptibility to dextran sulfate sodium (DSS)-induced IBD compared with wild-type mice. The inflammatory burden induced in ARC-deficient conditions was inversely correlated with CCL5 and CXCL5 levels in immune cells, especially CD4-positive T cells. Pathologically, ARC expression in immune cells was significantly decreased in clinical biopsy specimens from patients with IBD compared with normal subjects. In addition, ARC levels inversely correlated with CCL5 and CXCL5 levels in human biopsy specimens. ARC interacted with TNF receptor associated factor (TRAF) 6, regulating ubiquitination of TRAF6, which was associated with NF-κB signaling. Importantly, we identified a novel ubiquitination site at lysine 461, which was critical in the function of ARC in IBD. ARC played a critical role in IBD and IBD-associated colon cancer in a bone marrow transplantation model and azoxymethane/DSS-induced colitis cancer mouse models. Overall, these findings reveal that ARC is critically involved in the maintenance of intestinal homeostasis and protection against IBD through its ubiquitination of TRAF6 and subsequent modulation of NF-κB activation in T cells. Significance: This study uncovers a crucial role of ARC in the immune system and IBD, giving rise to a novel strategy for IBD and IBD-associated colon cancer therapy.

In 2018, the American Board of Anesthesiology (ABA) became the first US medical specialty certifying board to incorporate an Objective Structured Clinical Examination (OSCE) into its initial certification examination system. Previously, the ABA’s staged examination system consisted of 2 written examinations (the BASIC and ADVANCED examinations) and the Standardized Oral Examination (SOE). The OSCE and the existing SOE are now 2 separate components of the APPLIED Examination. This report presents the results of the first-year OSCE administration. A total of 1410 candidates took both the OSCE and the SOE in 2018. Candidate performance approximated a normal distribution for both the OSCE and the SOE, and was not associated with the timing of the examination, including day of the week, morning versus afternoon session, and order of the OSCE and the SOE. Practice-based Learning and Improvement was the most difficult station, while Application of Ultrasonography was the least difficult. The correlation coefficient between SOE and OSCE scores was 0.35 ([95% confidence interval {CI}, 0.30–0.39]; P < .001). Scores for the written ADVANCED Examination were modestly correlated with scores for the SOE ( r = 0.29 [95% CI, 0.25–0.34]; P < .001) and the OSCE ( r = 0.15 [95% CI, 0.10–0.20]; P < .001). Most of the candidates who failed the SOE passed the OSCE, and most of the candidates who failed the OSCE passed the SOE. Of the 1410 candidates, 77 (5.5%) failed the OSCE, 155 (11.0%) failed the SOE, and 25 (1.8%) failed both. Thus, 207 (14.7%) failed at least 1 component of the APPLIED Examination. Adding an OSCE to a board certification examination system is feasible. Preliminary evidence indicates that the OSCE measures aspects of candidate abilities distinct from those measured by other examinations used for initial board certification.

e14507 Background: Regorafenib, an oral multikinase inhibitor of VEGFR2/3, PDGFRb, KIT, FGFR, RET, RAF and TIE2, is efficacious in refractory mCRC but its mechanism of action is unclear and predictive biomarkers are lacking. Methods: We assessed tumor and circulatory biomarkers in a phase 2 study of regorafenib in refractory mCRC patients. Regorafenib was administered orally at 160mg/d for 3 out of 4 weeks. Post cycle 2 response was assessed by RECIST 1.1. Subjects were scheduled for FDG PET-CT scans (pre + D15) and paired core needle tumor biopsies for IHC analysis (pre + D21) in cycle 1. Archival tumor mutations were evaluated using Sequenom MassARRAY OncoCarta Panel V1.0 assay. Results: 35 patients were treated; 49% received > 4 prior therapies and 43% had prior bevacizumab. Median PFS was 3.45 mths (95% CI: 3.40-3.49), ORR was 3% and disease control rate [DCR] (PR + SD at 8 wks) was 57%. Early PET responses (EORTC criteria) were seen in 49%, but did not predict for DCR (p=1.0). Fatigue, hand foot skin reaction (HFSR), voice change and diarrhea occurred in > 30% of subjects. Grade 3-5 toxicities occurred in 46%, the commonest being HFSR and rash (17% each). Median relative dose intensity was 92%; 43% required > 1 dose reduction, 60% required > 1 dose interruption. KRAS (29%), BRAF (9%), EGFR (9%), NRAS (6%) KIT (3%), PIK3CA (3%), PDGFRA (3%) and CDK (3%) mutations were detected in archival tumors. None predicted for ORR or DCR; PFS was identical in KRAS mutant vs wt patients (3.45 mths, p=0.39) and similar in BRAF mutant vs wt patients (3.48 vs 3.45 mths, p=0.10). The patient with the longest PFS (12.6 mths) had a BRAF mutation. Amongst the 10 paired tumor samples available, IHC markers upregulated in >50% cases were pMEK, pERK, pJun and pJNK, whilst those downregulated/ unchanged in >50% were pKIT, pVEGFR2, CD31 [vascular endothelial cells (ECs)] and podoplanin (lymphatic ECs). The greatest change was observed in podoplanin expression, corresponding to a 60% reduction in lymphatic vessel density. Conclusions: FDG-PET responses in cycle 1 did not predict for regorafenib clinical benefit in mCRC patients. Targeting lymphatic/vascular ECs in the tumor microenvironment may be a more significant antitumor mechanism of regorafenib than MAP kinase pathway inhibition. Clinical trial information: NCT01189903.

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.