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Free digital platforms are smartphone-compatible and permit self-directed curriculum development based on learners' interests and educational needs. We developed a free mobile vascular surgery handbook initiated, authored, and edited by surgical house officers and surveyed on the content and users.Using a free digital platform, house officers developed a vascular surgery handbook. Initiated by a single user for conference preparation and clinical care, the use expanded through sharing among residents. The handbook was then deployed at a second medical center, with free access granted to users after completing a survey. Handbook and content use were evaluated based on user ratings ≥4 on a Likert scale from 1 to 5, where 1 = "strongly disagree" and 5 = "completely agree." Domains assessed included handbook ease of use, content, and relevance to a variety of learning environments and goals (e.g., preparation for the operating room, rounds, clinic, teaching conferences, and examinations). Analytic methods included qualitative analysis, graphical evaluation, and categorical tests.The handbook is organized into sections, with each consisting of multiple pages and/or posts related to the section topic. Sections with the most content included lower extremity arterial disease, endovascular aneurysm repair/thoracic endovascular aortic repair, venous disease, anticoagulation, and anatomy/exposures. Fifty-four users participated in the evaluation phase, including different types of surgical residents (35%), medical students (30%), and anesthesia residents (22%). Sixty-nine percent of participants were in their position for2 years. The average age was 29.1 years, and 57% were women. Preferred learning styles among users at the time of enrollment primarily included question banks (52%), followed by slide-based lectures (15%) and "chalk talk" lectures (13%). Of the users who participated in the presurvey, 43 users participated in the postsurvey with a general agreement on the handbook being an easy-to-use resource that was useful for gaining overall knowledge and contained accurate information. Users generally agreed they would recommend the handbook to a colleague.References customized to user needs can be developed through crowdsourcing and published with free digital resources. These approaches allow mobile access to useful information during conferences and clinical care. House officers' self-perceived educational needs can be targeted for tailored educational initiatives.

Myeloid cells are critical for orchestrating regulated inflammation during wound healing. TLRs, particularly TLR4, and its downstream-signaling MyD88 pathway play an important role in regulating myeloid-mediated inflammation. Because an initial inflammatory phase is vital for tissue repair, we investigated the role of TLR4-regulated, myeloid-mediated inflammation in wound healing. In a cutaneous tissue injury murine model, we found that TLR4 expression is dynamic in wound myeloid cells during the course of normal wound healing. We identified that changes in myeloid TLR4 during tissue repair correlated with increased expression of the histone methyltransferase, mixed-lineage leukemia 1 (MLL1), which specifically trimethylates the histone 3 lysine 4 (H3K4me3) position of the TLR4 promoter. Furthermore, we used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine MLL1 drives Tlr4 expression during wound healing. To understand the critical role of myeloid-specific TLR4 signaling, we used mice deficient in Tlr4 (Tlr4−/−), Myd88 (Myd88−/−), and myeloid-specific Tlr4 (Tlr4f/fLyz2Cre+) to demonstrate delayed wound healing at early time points postinjury. Furthermore, in vivo wound myeloid cells isolated from Tlr4−/− and Myd88−/− wounds demonstrated decreased inflammatory cytokine production. Importantly, adoptive transfer of monocyte/macrophages from wild-type mice trafficked to wounds with restoration of normal healing and myeloid cell function in Tlr4-deficient mice. These results define a role for myeloid-specific, MyD88-dependent TLR4 signaling in the inflammatory response following cutaneous tissue injury and suggest that MLL1 regulates TLR4 expression in wound myeloid cells.

OBJECTIVE The purpose of this study was to measure the efficacy of a novel faculty and resident educational bundle focused on development of faculty-resident behaviors and entrustment in the operating room. SUMMARY BACKGROUND DATA As surgical training environments are orienting to entrustable professional activities (EPAs), successful transitions to this model will require significant faculty and resident development. Identifying an effective educational initiative which prepares faculty and residents for optimizing assessment, teaching, learning, and interacting in this model is critical. METHODS From September 2015 to June 2017, an experimental study was conducted in the Department of Surgery at the University of Michigan Health System (UMHS). Case observations took place across general, plastic, thoracic, and vascular surgical specialties. A total of 117 operating room observations were conducted during Phase I of the study and 108 operating room observations were conducted during Phase II following the educational intervention. Entrustment behaviors were rated for 56 faculty and 73 resident participants using OpTrust, a validated intraoperative entrustment instrument. RESULTS Multiple regression analysis showed a significant increase in faculty entrustment (Phase I = 2.32 vs Phase II = 2.56, P < 0.027) and resident entrustability (Phase I = 2.16 vs Phase II = 2.40, P < 0.029) scores following exposure to the educational intervention. CONCLUSIONS Our study shows improved intraoperative entrustment following implementation of faculty and resident development, indicating the efficacy of this innovative educational bundle. This represents a crucial component in the implementation of a competency-based assessment framework like EPAs.

Background Optimizing intraoperative education is critical for development of autonomous residents. Faculty decisions concerning intraoperative entrustment determine the degree to which a resident gains intraoperative responsibility. Accordingly, residents exhibit entrustable behaviors that further faculty entrustment in the operating room. Little empiric evidence exists evaluating how the sex of a resident influences faculty-resident decisions of entrustment. Studies involving perception-based measurements of autonomy report inequities for women residents. We sought to assess faculty behaviors in entrustment in relation to resident sex using OpTrust, a third-party objective measurement tool. Methods From September 2015 to June 2017 at the University of Michigan, surgical cases were observed and entrustment behaviors were rated using OpTrust. Critical case sampling was used to generate variation in operation type, case difficulty, faculty-resident pairings, faculty experience, and the level of the resident's training. Independent sample t-tests were conducted to compare faculty entrustment scores, as well as resident entrustability scores. Results A total of 56 faculty and 73 residents were observed across 223 surgical cases from 4 surgical specialties: general, plastic, thoracic, and vascular. There was no difference in faculty entrustment or entrustability scores between women and men (2.54 vs 2.35, P = .117 and 2.32 vs 2.22, P = .393, respectively). Conclusion Using OpTrust scores, we found that a resident's sex does not appear to influence faculty entrustment in the OR. Faculty entrustment scores for women and men residents are similar across cases. This observation suggests that during the intraoperative interaction, faculty are not extending entrustment or opportunities for autonomy differently to women or men. Future research is needed to identify and measure perioperative elements that inform resident autonomy, which may contribute to inequities for women residents.

Background Changes in the surgical training landscape have sparked an interest in developing new educational models anchored on entrustment assessment. We sought to optimize the validated OpTrust entrustment assessment tool by comparing ratings from short-course video reviews to previously validated intraoperative assessments. Methods Entrustment assessment scores for video-based and 1-h (short-course) observations were compared to previously validated intraoperative assessment scores. Faculty and residents were surveyed for their perceptions related to operative observation. Results There was a strong association between entrustment scores when comparing in-person to video-based observations (R2 = 0.76–0.84, p 97%) felt observation did not negatively impact operative experience. Conclusions Assessment of entrustment behaviors using short-course video review provides a feasible approach to intraoperative assessment. This latest application of OpTrust allows for the tool to be incorporated into surgical training programs across a variety of environments.

Objective— Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that is critical for proper healing, however, in diabetes mellitus, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown. Approach and Results— Here, we characterized the kinetics and function of Ly6C Hi [Lin − (CD3 − CD19 − NK1.1 − Ter-119 − ) Ly6G − CD11b + ] and Ly6C Lo [Lin − (CD3 − CD19 − NK1.1 − Ter-119 − ) Ly6G − CD11b + ] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted tdTomato -labeled Ly6C Hi monocyte/macrophages, we show Ly6C Hi cells transition to a Ly6C Lo phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C Hi cells that fail transition to Ly6C Lo . The second wave of Ly6C Hi cells in diabetic wounds corresponded to a spike in MCP-1 (monocyte chemoattractant protein-1) and selective administration of anti-MCP-1 reversed the second Ly6C Hi influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq–based transcriptome profiling was performed on flow-sorted Ly6C Hi [Lin − Ly6G − CD11b + ] and Ly6C Lo [Lin − Ly6G − CD11b + ] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C Hi cells demonstrated differences in proinflammatory and profibrotic genes compared with controls. Conclusions— Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b + Ly6C Hi monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.

The healing of cutaneous wounds is dependent on the progression through distinct, yet overlapping phases of wound healing, including hemostasis, inflammation, proliferation, and resolution/remodeling. The failure of these phases to occur in a timely, progressive fashion promotes pathologic wound healing. The macrophage (MΦ) has been demonstrated to play a critical role in the inflammatory phase of tissue repair, where its dynamic plasticity allows this cell to mediate both tissue-destructive and -reparative functions. The ability to understand and control both the initiation and the resolution of inflammation is critical for treating pathologic wound healing. There are now a host of studies demonstrating that metabolic and epigenetic regulation of gene transcription can influence MΦ plasticity in wounds. In this review, we highlight the molecular and epigenetic factors that influence MΦ polarization in both physiologic and pathologic wound healing, with particular attention to diabetic wounds.

Macrophages are critical for the initiation and resolution of the inflammatory phase of wound repair. In diabetes, macrophages display a prolonged inflammatory phenotype in late wound healing. Mixed-lineage leukemia-1 (MLL1) has been shown to direct gene expression by regulating nuclear factor-κB (NF-κB)–mediated inflammatory gene transcription. Thus, we hypothesized that MLL1 influences macrophage-mediated inflammation in wound repair. We used a myeloid-specific Mll1 knockout (Mll1f/fLyz2Cre+) to determine the function of MLL1 in wound healing. Mll1f/fLyz2Cre+ mice display delayed wound healing and decreased wound macrophage inflammatory cytokine production compared with control animals. Furthermore, wound macrophages from Mll1f/fLyz2Cre+ mice demonstrated decreased histone H3 lysine 4 trimethylation (H3K4me3) (activation mark) at NF-κB binding sites on inflammatory gene promoters. Of note, early wound macrophages from prediabetic mice displayed similarly decreased MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines compared with controls. Late wound macrophages from prediabetic mice demonstrated an increase in MLL1, H3K4me3 at inflammatory gene promoters, and inflammatory cytokines. Prediabetic macrophages treated with an MLL1 inhibitor demonstrated reduced inflammation. Finally, monocytes from patients with type 2 diabetes had increased Mll1 compared with control subjects without diabetes. These results define an important role for MLL1 in regulating macrophage-mediated inflammation in wound repair and identify a potential target for the treatment of chronic inflammation in diabetic wounds.

Functional popliteal artery entrapment syndrome can be difficult to diagnose, as the imaging modalities presently employed are designed to detect anatomic entrapment. We describe a novel imaging technique to aid in diagnosis in this cohort. A 22-year-old cyclist presented with exercise-limiting claudication. Magnetic resonance angiography with provocative maneuvers was nondiagnostic. Digital subtraction angiography revealed long-segment occlusion of the popliteal artery with plantar flexion; however, the specific site of compression remained unclear. Intravascular ultrasound allowed specific localization of compression and further confirmed the diagnosis. Thus, we report this as an adjunctive imaging modality to definitively diagnose functional popliteal artery entrapment syndrome and to assist in operative planning.

Macrophage (Mφ) plasticity, allowing the transition of Mφs from an inflammatory to a reparative phenotype, is critical for normal wound healing. In pathologic conditions, such as type 2 diabetes (T2D), wounds fail to heal due to impaired resolution of Mφ inflammation. Although the mechanisms responsible for the persistent inflammatory phenotype in T2D wounds are unknown, recent investigations have revealed that cellular metabolites can alter Mφ function providing a link between metabolism and innate immunity. Further, there is increasing evidence that epigenetic mechanisms control Mφ function. The purpose of this study was to investigate if altered Mφ metabolism in T2D induces epigenetic modifications resulting in derangements in Mφ inflammation and impaired wound healing. Using the murine diet induce obesity (DIO) wound model, we demonstrate that diabetic bone marrow derived macrophages (BMDM) and wound Mφs display a hyperinflammatory phenotype following injury with increased expression of toll-like receptor (TLR) 4 signaling and proinflammatory cytokines (IL-1β and TNFα). Given that histone methylation has previously been shown by our group to influence Mφ phenotype, we examined H3K4 trimethylation on the TLR4 promoter and found a significant increase in DIO BMDMs and wound Mφs. To evaluate the impact of Mφ metabolites on inflammation we performed a LC-MS metabolite expression analysis demonstrating significant upregulation of the methyl donor, S-adenosyl methionine (SAM), which participates in histone methylation, and its rate limiting enzyme, MAT2a, in diabetic BMDMs. In summary, these results suggest that increased levels of the metabolite SAM in diabetic Mφs contribute to an inflammatory Mφ phenotype via increased H3K4 methylation at the TLR4 promoter. Disclosure F.M. Davis: None. A.D. denDekker: None. A.S. Kimball: None. A. Boniakowski: None. A. Joshi: None. M. ElAzzouny: Employee; Self; Agilent Technologies. C. Burant: Stock/Shareholder; Self; Metabolic Solutions Development Company. K. Gallagher: None. Funding National Institutes of Health

Background Longitudinal contact between faculty and residents facilitates greater faculty entrustment. The purpose of this study is to assess the relationship between faculty familiarity with residents and faculty entrustment. Materials and methods Researchers observed and rated entrustment behaviors using OpTrust, September 2015–June 2017 at Michigan Medicine. Faculty familiarity with resident was measured on a 1–4 scale (1 = not familiar, 4 = extremely familiar). ANOVA and Sidak adjusted multiple comparisons were used to assess the relationship between faculty familiarity and faculty entrustment. Results 56 faculty and 73 residents were observed across 225 surgical cases. Faculty entrustment scores increased to 2.48 when resident familiarity was reported as “slightly familiar”. Faculty entrustment scores for “moderately familiar” increased to 2.57. Faculty entrustment scores for “extremely familiar” increased to 2.84. Conclusions We found a positive relationship between faculty familiarity and entrustment. These findings support greater continuity in faculty/resident relationships. Longitudinal contact allows learners to be granted progressive entrustment. Summary This study demonstrates a positive relationship between faculty familiarity with residents and an increase in intraoperative entrustment. These findings support greater continuity in faculty/resident relationships.

Objective The natural history of type II endoleak (T2EL) after endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA) remains elusive; as such, treatment guidelines are ill defined. The purpose of this study was to better delineate the natural history of T2EL after EVAR for rAAA in an effort to determine the need for reintervention and optimal surveillance. Methods A retrospective record review was conducted of all patients undergoing EVAR for rAAA in two large tertiary care academic vascular centers. Patient demographics, comorbidities, anatomic variables, and operative details were analyzed. Primary outcomes included the presence of T2EL, reintervention, delayed rupture, and aneurysm-related death. Results EVAR was used to treat rAAA in 56 patients between 2000 and 2013. Mean follow-up of this cohort was 634 days. Completion arteriogram demonstrated T2ELs in 12 patients (21%), and an additional four T2ELs (7%) were found by postoperative computed tomography angiogram that were not identified on the completion angiogram. Body mass index was the only statistically significant variable associated with the development of T2EL ( P = .03). Preoperative warfarin use, aortic thrombus burden, and device type did not correlate with T2EL development. Iliolumbar vessels supplied 75% (n = 12) of T2ELs. Of the 14 patients with T2ELs who underwent serial imaging postoperatively, six (43%) sealed spontaneously. Five patients (36%) underwent reintervention for T2EL by way of coil embolization—four in which treatment was initiated by attending preference. One patient was treated for ongoing anemia in the immediate postoperative period. There was no sac expansion, delayed rupture, or graft explantation. Conclusions T2ELs after EVAR for rAAA are common and appear to be associated with a benign natural history if left untreated. Although many will spontaneously seal early in the postoperative period, those that remain patent do not appear to increase the risk for sac expansion or delayed rupture or affect patient survival. As such, a conservative approach to treatment of T2ELs in rAAA may be warranted.

Mentoring relationships have been encouraged for medical students interested in surgical specialties. We investigated the role of mentoring relationships of integrated vascular surgery residents, while in medical school. We hypothesized that mentoring relationships between medical students and vascular surgeons would have a positive effect on match outcome in the integrated vascular surgery residency match.We used an online survey that respondents completed on a smartphone, tablet, or computer. This was created with Qualtrics Software. The survey was circulated to all North American Integrated Vascular Surgery residents, with the support of the Association of Program Directors in Vascular Surgery Recruitment Committee and the Society for Vascular Surgery Resident/Student Outreach Committee. Questions were posed either as Likert Scale or as multiple choice. Data were analyzed in Stata.Response rate (67 total responses of 241 polled residents) was 28%. Earlier postgraduate year residents were more likely to have had vascular surgeon mentors (P = 0.033). There was no association between having a mentor and match rank; however, those with vascular surgeon mentors matched higher on their rank list (P = 0.022). 50% of respondents indicated that mentoring was influential in the choice of integrated residency. Respondents with nonvascular surgeon mentors were more likely to answer negatively regarding their mentor's knowledge about other integrated (P 0.0001) and traditional programs (P 0.0001) while residents with a vascular surgeon mentor were more likely to respond positively to this question (P 0.0001). Regarding the effectiveness of mentorship, 81% indicated their mentor was accessible, 92% responded that their mentor demonstrated professional integrity, and 76% responded that their mentor prioritized their success.Integrated vascular surgery residents were generally positive about their medical school mentors. Our data indicate that surgical mentorship in medical school is effective, both in influencing medical students to choose the vascular surgery specialty and in improving match rank-vascular surgeons were more knowledgeable and mentees with vascular surgeon mentors tended to be more successful in the match.

To determine the association between intraoperative entrustment and personality alignment.For surgical residents, achieving operative autonomy has become increasingly difficult. The impact of faculty-resident operative interactions in accomplishing this goal is not well understood. We hypothesized that if operative dyads (faculty and resident) had personality alignment or congruency, then resident entrustment in the operating room would increase.We completed a retrospective analysis of 63 operations performed from September 2015 to August 2016. Operations were scored using OpTrust, a validated tool that assesses progressive entrustment of responsibility to surgical residents in the operating room. All dyads were classified as having congruent or incongruent personality alignment as measured by promotion or prevention orientation using the regulatory focus questionnaire. The association between personality congruence and OpTrust scores was identified using multivariable linear regression.A total of 35 congruent dyads and 28 incongruent dyads were identified. Congruent dyads had a higher percentage of "very difficult" cases (33.3 vs. 7.4%, P = 0.017), female residents (37.1 vs. 14.3%, P = 0.042) and faculty with fewer years of experience (10.4 vs. 14.8%, P = 0.028) than incongruent dyads. In addition to post-graduate year level, dyad congruency was independently associated with a 0.88 increase (95% CI [0.27-1.49], P = 0.006) in OpTrust scores (overall range 2-8), after adjusting for case difficulty, faculty experience, and post-graduate year.Congruent operative dyads are associated with increased operative entrustment as demonstrated by increased OpTrust scores. Developing awareness and strategies for addressing incongruence in personality in the operative dyad is needed.

Wound healing in diabetes is impaired due to failed resolution of inflammation. Macrophages play a significant role in the establishment of a regulated inflammatory response during wounding. Macrophage function is dictated by metabolism, which alters gene expression. Recent studies suggest that a fatty acid binding protein, FABP4, may control macrophage function in diabetes by altering metabolism. Thus, we examined whether FABP4 controls macrophage function and hence inflammation in diabetic wound healing. To investigate this, C57BL/6 mice were fed either a normal (12% saturated fat) diet or a high-fat (60% saturated fat) diet (HFD) for 12 weeks to induce physiologic “pre-diabetes.” Wounds were created and CD3-CD19-NK1.1-CD11b+ cells (macrophages) were isolated each day following injury and FABP4 expression was quantified by qPCR and Western blot. We found that HFD wound macrophages demonstrated a significant increase in FABP4 gene expression and protein production on day 3 post-injury compared with controls. To determine if FABP4 alters inflammatory gene expression in wound macrophages, we isolated wound macrophages with an FABP4 inhibitor, treated them, and analyzed for IL-1β and TNFα expression. IL1β and TNFα gene expression were significantly reduced (P Chromatin immunoprecipitation (ChIP) analysis of the FABP4 promoter in wound macrophages revealed a significant increase in H3K4 trimethylation, an activating mark, on the FABP4 promoter in diabetic wound macrophages suggesting that epigenetic regulation may play an important role in the differential expression of FABP4 in diabetic wounds. In conclusion, FABP4 appears to be upregulated in diabetic wound macrophages and contributes to increased macrophage inflammation. Modulation of FABP4 or its expression may help resolve inflammation in diabetic wounds and promote healing.

Macrophage (Mϕ) plasticity, allowing for transition of Mϕs from an inflammatory to a reparative phenotype, is critical for normal wound healing. In pathologic conditions, such as type 2 diabetes (T2D), wounds fail to heal due to impaired resolution of inflammation. The mechanism(s) responsible for the persistent inflammatory phenotype in T2D wounds are unclear. Prior studies have shown that the Toll-like receptor (TLR) 4 pathway regulates Mϕ-mediated inflammation in tissues. Growing evidence indicates that TLR4 is a versatile receptor binding a spectrum of ligands including non-microbial ligands such as saturated fatty acids (SFAs). Given the excess SFAs in T2D, the purpose of this study was to examine the role of the SFA palmitate on TLR4 signaling and Mϕ phenotype in diabetic wound healing. We have previously shown that Mϕs isolated from wounds in a murine model of glucose intolerance (diet-induced obesity; DIO) maintained on a 60% high fat diet (HFD) for 12-18 weeks, display increased levels of inflammatory cytokines (IL-1β, IL-12, and TNFα) at both a gene expression and protein level. In the current study, we found that blood monocytes and wound Mϕs from DIO mice display increased TLR4 receptors compared to control blood and wounds. To determine if altered metabolites in the diabetic environment impact Mϕ phenotype, bone marrow derived macrophages (BMDMs) were incubated in serum isolated from DIO or control mice. BMDMs incubated with DIO serum displayed a hyperinflammatory response following LPS stimulation. Further, stimulation with the metabolite palmitate produced significantly increased IL-1β expression in DIO BMDMs compared to controls suggesting that DIO BMDMs are programmed toward an inflammatory response. To determine the mechanism, we examined several epigenetic enzymes known to affect Mϕ polarization and found that palmitate stimulated expression of JMJD3, a histone demethylase, which increases inflammatory gene expression. In conclusion, these studies suggest that the diabetic milieu, specifically increased levels of the SFA palmitate, induces expression of the epigenetic enzyme, JMJD3, in Mϕs and this regulates inflammatory gene expression and cell function.

Faculty entrustment decisions affect resident entrustability behaviors and surgical autonomy. The relationship between entrustability and autonomy is not well understood. This pilot study explores that relationship.108 case observations were completed. Entrustment behaviors were rated using OpTrust. Residents completed a Zwisch self-assessment to measure surgical autonomy. Resident perceived autonomy was collected for 67 cases used for this pilot study.Full entrustability was observed in 5 of the 108 observed cases. Residents in our study did not report full autonomy. Spearman's rank correlation coefficient identified that resident entrustability was positively correlated with perceived resident autonomy (ρ = 0.66, p 0.05). Ordinal logistic regression assessed the relationship between resident entrustability and autonomy. The relationship persisted while controlling for PGY level, gender, and case complexity (OR = 8.42, SEM = 4.54, p 0.000).Resident entrustability is positively associated with perceived autonomy, yet full entrustability is not translating to the perception of full autonomy for residents.

Diabetic foot ulcerations (DFU) affect 25% of patients with diabetes mellitus during their lifetime and constitute a major health problem as they are often recalcitrant to healing due to a constellation of both intrinsic and extrinsic factors. The purpose of this review is to (1) detail the current mechanistic understanding of DFU formation and (2) highlight future therapeutic targets. From a molecular perspective, DFUs exhibit a chronic inflammatory predisposition. In addition, increased local hypoxic conditions and impaired cellular responses to hypoxia are pathogenic factors that contribute to delayed wound healing. Finally, recent evidence suggests a role for epigenetic alterations, including microRNAs, in delayed DFU healing due to the complex interplay between genes and the environment. In this regard, notable progress has been made in the molecular and genetic understanding of DFU formation. However, further studies are needed to translate preclinical investigations into clinical therapies.

OBJECTIVE To understand statewide variation in preoperative cardiology consultation prior to major vascular surgery and to determine whether consultation was associated with differences in perioperative myocardial infarction (poMI). SUMMARY BACKGROUND DATA Medical consultation prior to major vascular surgery is obtained to reduce perioperative risk. Despite perceived benefit of preoperative consultation, evidence is lacking specifically for major vascular surgery on the effect of preoperative cardiac consultation. METHODS Patient and clinical data were obtained from a statewide vascular surgery registry between January 2012 and December 2014. Patients were risk stratified by revised cardiac risk index category and compared poMI between patients who did or did not receive a preoperative cardiology consultation. We then used logistic regression analysis to compare the rate of poMI across hospitals grouped into quartiles by rate of preoperative cardiology consultation. RESULTS Our study population comprised 5191 patients undergoing open peripheral arterial bypass (n = 3037), open abdominal aortic aneurysm repair (n = 332), or endovascular aneurysm repair (n = 1822) at 29 hospitals. At the patient level, after risk-stratification by revised cardiac risk index category, there was no association between cardiac consultation and poMI. At the hospital level, preoperative cardiac consultation varied substantially between hospitals (6.9%-87.5%, P 66%) had a reduction in poMI (OR, 0.52; confidence interval: 0.28-0.98; P

Macrophages play a critical role in the establishment of a regulated inflammatory response following tissue injury. Following injury, CCR2(+) monocytes are recruited from peripheral blood to wound tissue, and direct the initiation and resolution of inflammation that is essential for tissue repair. In pathologic states where chronic inflammation prevents healing, macrophages fail to transition to a reparative phenotype. Using a murine model of cutaneous wound healing, we found that CCR2-deficient mice (CCR2(−/−)) demonstrate significantly impaired wound healing at all time points post-injury. Flow cytometry analysis of wounds from CCR2(−/−) and wild type mice revealed a significant decrease in inflammatory, Ly6C(Hi) recruited monocyte/macrophages in CCR2(−/−) wounds. We further show that wound macrophage inflammatory cytokine production is decreased in CCR2(−/−) wounds. Adoptive transfer of mT/mG monocyte/macrophages into CCR2(+/+) and CCR2(−/−) mice demonstrated that labeled cells on days 2 and 4 traveled to wounds in both CCR2(+/+) and CCR2(−/−) mice. Further, adoptive transfer of monocyte/macrophages from wild type mice restored normal healing, likely through a restored inflammatory response in the CCR2-deficient mice. Taken together, these data suggest that CCR2 plays a critical role in the recruitment and inflammatory response following injury, and that wound repair may be therapeutically manipulated through modulation of CCR2.

OBJECTIVE: Wound monocyte-derived macrophage plasticity controls the initiation and resolution of inflammation that are critical for proper healing, however, in diabetes, the resolution of inflammation fails to occur. In diabetic wounds, the kinetics of blood-monocyte recruitment and the mechanisms that control in vivo monocyte/macrophage differentiation remain unknown. APPROACH AND RESULTS: Here, we characterized the kinetics and function of Ly6C(Hi)[Lin(−) (CD3(−)CD19(−)NK1.1(−)Ter-119(−))Ly6G(−)CD11b(+)] and Ly6C(Lo)[Lin(−) (CD3(−)CD19(−)NK1.1(−)Ter-119(−))Ly6G(−)CD11b(+)] monocyte/macrophage subsets in normal and diabetic wounds. Using flow-sorted tdTomato-labeled Ly6C(Hi) monocyte/macrophages, we show Ly6C(Hi) cells transition to a Ly6C(Lo)- phenotype in normal wounds, whereas in diabetic wounds, there is a late, second influx of Ly6C(Hi) cells that fail transition to Ly6C(Lo). The second wave of Ly6C(Hi) cells in diabetic wounds corresponded to a spike in MCP-1 and selective administration of anti-MCP-1 reversed the second Ly6C(Hi) influx and improved wound healing. To examine the in vivo phenotype of wound monocyte/macrophages, RNA-seq-based transcriptome profiling was performed on flow-sorted Ly6C(Hi)[Lin(−)Ly6G(−)CD11b(+)] and Ly6C(Lo)[Lin(−)Ly6G(−)CD11b(+)] cells from normal and diabetic wounds. Gene transcriptome profiling of diabetic wound Ly6C(Hi) cells demonstrated differences in pro-inflammatory and pro-fibrotic genes compared to controls. CONCLUSIONS: Collectively, these data identify kinetic and functional differences in diabetic wound monocyte/macrophages and demonstrate that selective targeting of CD11b(+)Ly6C(Hi) monocyte/macrophages is a viable therapeutic strategy for inflammation in diabetic wounds.

Macrophages are essential immune cells necessary for regulated inflammation during wound healing. Recent studies have identified that Notch plays a role in macrophage-mediated inflammation. Thus, we investigated the role of Notch signaling on wound macrophage phenotype and function during normal and diabetic wound healing. We found that Notch receptor and ligand expression are dynamic in wound macrophages during normal healing. Mice with a myeloid-specific Notch signaling defect (DNMAMLfloxedLyz2Cre+ ) demonstrated delayed early healing (days 1-3) and wound macrophages had decreased inflammatory gene expression. In our physiologic murine model of type 2 diabetes (T2D), Notch receptor expression was significantly increased in wound macrophages on day 6, following the initial inflammatory phase of wound healing, corresponding to increased inflammatory cytokine expression. This increase in Notch1 and Notch2 was also observed in human monocytes from patients with T2D. Further, in prediabetic mice with a genetic Notch signaling defect (DNMAMLfloxedLyz2Cre+ on a high-fat diet), improved wound healing was seen at late time points (days 6-7). These findings suggest that Notch is critical for the early inflammatory phase of wound healing and directs production of macrophage-dependent inflammatory mediators. These results identify that canonical Notch signaling is important in directing macrophage function in wound repair and define a translational target for the treatment of non-healing diabetic wounds.

Objectives The relationship between preoperative medical consultations and postoperative complications has not been extensively studied. Thus, we investigated the impact of preoperative consultation on postoperative morbidity following elective abdominal aortic aneurysm repair. Methods A retrospective review was conducted on 469 patients (mean age 72 years, 20% female) who underwent elective abdominal aortic aneurysm repair from June 2007 to July 2014. Data elements included detailed medical history, preoperative cardiology consultation, and postoperative complications. Primary outcomes included 30-day morbidity, consult-specific morbidity, and mortality. A bivariate probit regression model accounting for the endogeneity of binary preoperative medical consult and patient variability was estimated with a maximum likelihood function. Results Eighty patients had preoperative medical consults (85% cardiology); thus, our analysis focuses on the effect of cardiac-related preoperative consults. Hyperlipidemia, increased aneurysm size, and increased revised cardiac risk index increased likelihood of referral to cardiology preoperatively. Surgery type (endovascular versus open repair) was not significant in development of postoperative complications when controlling for revised cardiac risk index ( p = 0.295). After controlling for patient comorbidities, there was no difference in postoperative cardiac-related complications between patients who did and did not undergo cardiology consultation preoperatively ( p = 0.386). Conclusions When controlling for patient disease severity using revised cardiac risk index risk stratification, preoperative cardiology consultation is not associated with postoperative cardiac morbidity.

Aneurysmal disease of the internal iliac vein is rare, with no standard indication for or accepted modality of treatment. Here we report an instance of unilateral, primary left internal iliac venous aneurysm and associated pelvic venous insufficiency. Following extensive workup for alternative causes, the aneurysm and left gonadal vein were coil embolized with good effect.

Macrophage (Mϕ) plasticity is essential for the repair and remodeling of wounds. However, under pathologic conditions such as type 2 diabetes (T2D), Mϕs exist in a chronic inflammatory state that drives continued tissue destruction and results in impaired wound healing. We have previously shown that Mϕs isolated from wounds in a murine model that mimics physiologic development of T2D (diet-induced obese mice; DIO) display increased levels of inflammatory cytokines at both a gene expression and protein level. Although the underlying mechanisms remain unclear, we and others have shown that Mϕ phenotype can be controlled by epigenetic modifications that alter gene expression. Our recent work provides evidence that the diabetic milieu alters gene expression and sets an “epigenetic signature” in myeloid cells that result in an exaggerated inflammatory phenotype and delayed wound healing in a murine model. Further, our recent work has found that the histone acetyl transferase, Males absent on the first (MOF), responsible for acetylation of lysine 16 on histone H4 (H4K16), was critical for expression of genes involved in fatty acid metabolism. In the present study, we find that wound Mϕs from DIO mice have increased expression of MOF at day 5, when Mϕs shift from a pro-inflammatory to an anti-inflammatory state within wound tissue. This change in MOF was accompanied by increased expression of components of MOF regulatory complexes, MSL1/2 and KANSL1. Our findings reveal a previously unreported role for MOF in promoting a pro-inflammatory state in innate immune cells. Moreover, our data suggest that the diabetic milieu promotes increased expression of MOF which, in turn, may contribute to maintaining the persistent inflammatory state in wound Mϕs.