Skeletal muscle regeneration failure in ischemic-damaged limbs is associated with pro-inflammatory macrophages and premature differentiation of satellite cells.

BACKGROUND: Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell-cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI. METHODS: We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell-cell signaling interactions and differentiation trajectories. RESULTS: Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries. CONCLUSIONS: Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

Pro-inflammatory macrophages impair skeletal muscle regeneration in ischemic-damaged limbs by inducing precocious differentiation of satellite cells.

Chronic limb-threatening ischemia (CLTI), representing the end-stage of peripheral arterial disease (PAD), is associated with a one-year limb amputation rate of ∻15-20% and significant mortality. A key characteristic of CLTI is the failure of the innate regenerative capacity of skeletal muscle, though the underlying mechanisms remain unclear. Here, single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients demonstrated that ischemic-damaged tissue is enriched with pro-inflammatory macrophages. Comparable results were also observed in a murine CLTI model. Importantly, integrated analyses of both human and murine data revealed premature differentiation of muscle satellite cells (MuSCs) in damaged tissue and indications of defects in intercellular signaling communication between MuSCs and their inflammatory niche. Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and murine models, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

Muscle progenitor cells are required for skeletal muscle regeneration and prevention of adipogenesis after limb ischemia.

Skeletal muscle injury in peripheral artery disease (PAD) has been attributed to vascular insufficiency, however evidence has demonstrated that muscle cell responses play a role in determining outcomes in limb ischemia. Here, we demonstrate that genetic ablation of Pax7+ muscle progenitor cells (MPCs) in a model of hindlimb ischemia (HLI) inhibited muscle regeneration following ischemic injury, despite a lack of morphological or physiological changes in resting muscle. Compared to control mice (Pax7WT), the ischemic limb of Pax7-deficient mice (Pax7Δ) was unable to generate significant force 7 or 28 days after HLI. A significant increase in adipose was observed in the ischemic limb 28 days after HLI in Pax7Δ mice, which replaced functional muscle. Adipogenesis in Pax7Δ mice corresponded with a significant increase in PDGFRα+ fibro/adipogenic progenitors (FAPs). Inhibition of FAPs with batimastat decreased muscle adipose but increased fibrosis. In vitro, Pax7Δ MPCs failed to form myotubes but displayed increased adipogenesis. Skeletal muscle from patients with critical limb threatening ischemia displayed increased adipose in more ischemic regions of muscle, which corresponded with fewer satellite cells. Collectively, these data demonstrate that Pax7+ MPCs are required for muscle regeneration after ischemia and suggest that muscle regeneration may be an important therapeutic target in PAD.

Radiofrequency Identification Track for Tray Optimization: An Instrument Utilization Pilot Study in Surgical Oncology.

BACKGROUND: Surgical instrument tray reduction attempts to minimize intraoperative inefficiency and processing costs. Previous reduction methods relied on trained observers manually recording instrument use (i.e. human ethnography), and surgeon and/or staff recall, which are imprecise and inherently limited. We aimed to determine the feasibility of radiofrequency identification (RFID)-based intraoperative instrument tracking as an effective means of instrument reduction. METHODS: Instrument trays were tagged with unique RFID tags. A RFID reader tracked instruments passing near RFID antennas during 15 breast operations performed by a single surgeon; ethnography was performed concurrently. Instruments without recorded use were eliminated, and 10 additional cases were performed utilizing the reduced tray. Logistic regression was used to estimate odds of instrument use across cases. Cohen's Kappa estimated agreement between RFID and ethnography. RESULTS: Over 15 cases, 37 unique instruments were used (median 23 instruments/case). A mean 0.64 (median = 0, range = 0-3) new instruments were added per case; odds of instrument use did not change between cases (OR = 1.02, 95%CI 1.00-1.05). Over 15 cases, all instruments marked as used by ethnography were recorded by RFID tracking; 7 RFID-tracked instruments were never recorded by ethnography. Tray size was reduced 40%. None of the 25 eliminated instruments were required in 10 subsequent cases. Cohen's Kappa comparing RFID data and ethnography over all cases was 0.82 (95%CI 0.79-0.86), indicating near perfect agreement between methodologies. CONCLUSIONS: Intraoperative RFID instrument tracking is a feasible, data-driven method for surgical tray reduction. Overall, RFID tracking represents a scalable, systematic, and efficient method of optimizing instrument supply across procedures.

Examining the Effect of Travel Distance to Pediatric Cancer Centers and Rurality on Survival and Treatment Experiences: A Systematic Review.

Accessing pediatric cancer treatment remains problematic for rural families or those living at increased distances from specialized centers. Rural adult cancer patients or those living far removed from treatment may present with later stage disease, receive different treatments than their closer counterparts, and experience worsened survival. While the financial and psychosocial strain of increased travel is well documented, effects of travel distance on similar outcomes for pediatric cancer patients remain ill-defined. We conducted a systematic review to synthesize literature examining the effect of travel distance and/or rurality (as a proxy for distance) on pediatric cancer treatment experiences and survival outcomes. Included studies examined travel distance to specialized centers or rural status for patients above 21 years of age. Studies were excluded if they focused on financial or quality of life outcomes. We analyzed 24 studies covering myriad malignancies and outcomes, including location of care, clinical trial participation, and likelihood of receiving specialized treatments such as stem cell transplants or proton beam therapy. Most were retrospective, and 9 were conducted outside the United States. While some studies suggest rural patients may experience worsened survival and those traveling furthest may experience shorter hospitalization times/rates, the available evidence does not uniformly assert negative effects of increased distance.

Cerebral monitoring during transcarotid artery revascularization with flow reversal via transcranial doppler ultrasound examination.

OBJECTIVE: Transcarotid artery revascularization (TCAR) is a hybrid technique for carotid artery revascularization that relies on proximal carotid occlusion with flow reversal for distal embolic protection. The hemodynamic response of the intracranial circulation to flow reversal is unknown. In addition, the rate and pattern of cerebral embolization during flow reversal has yet to be investigated. The aim of this study was to characterize cerebral hemodynamic and embolization patterns during TCAR. METHODS: A single-institution retrospective study of patients with carotid artery stenosis undergoing TCAR with intraoperative transcranial Doppler (TCD) monitoring of the middle cerebral artery (MCA) was performed. Primary outcomes included changes in MCA velocity and MCA embolic signals observed throughout TCAR. RESULTS: Eleven patients underwent TCAR with TCD monitoring of the ipsilateral MCA. The average MCA velocity at baseline was 50.6 ± 16.4 cm/s. MCA flow decreased significantly upon initiation of flow reversal (50.5 ± 16.4 cm/s vs 19.1 ± 18.4 cm/s; P = .02). The reinitiation of antegrade flow resulted in a significant increase in the number of embolic events compared with baseline (P = .003), and embolic events were observed in two patients during flow reversal. CONCLUSIONS: TCD monitoring of patients undergoing TCAR revealed that the initiation of flow reversal results in a decrement in ipsilateral MCA velocity. Furthermore, embolic events can occur during flow reversal and are significantly associated with the reinitiation of antegrade flow in the internal carotid artery. However, both of these hemodynamic events were well-tolerated in our cohort. These findings suggest that TCAR remains a safe neuroprotective strategy for carotid revascularization.

Implementation of a Surgical Oncology Disparities Curriculum for Preclinical Medical Students.

BACKGROUND: Underinsured and uninsured surgical-oncology patients are at higher risk of perioperative morbidity and mortality. Curricular innovation is needed to train medical students to work with this vulnerable population. We describe the implementation of and early educational outcomes from a student-initiated pilot program aimed at improving medical student insight into health disparities in surgery. MATERIALS/METHODS: First-year medical students participated in a dual didactic and perioperative-liaison experience over a 10-month period. Didactic sessions included surgical-skills training and faculty-led lectures on financial toxicity and management of surgical-oncology patients. Students were partnered with uninsured and Medicaid patients receiving surgical-oncology care and worked with these patients by providing appointment reminders, clarifying perioperative instructions, and accompanying patients to surgery and clinic appointments. Students' interest in surgery and self-reported comfort in 15 Association of American Medical Colleges core competencies were assessed with preparticipation and postparticipation surveys using a 5-point Likert scale. RESULTS: Twenty-four first-year students were paired with 14 surgical-oncology patients during the 2017-2018 academic year. Sixteen students (66.7%) completed both preprogram and postprogram surveys. Five students (31.3%) became "More Interested" in surgery, whereas 11 (68.8%) reported "Similar Interest or No Change." Half of the students (n = 8) felt more prepared for their surgery clerkship after participating. Median self-reported comfort improved in 7/15 competencies including Oral Communication and Ethical Responsibility. All students reported being "Somewhat" or "Extremely Satisfied" with the program. CONCLUSIONS: We demonstrate that an innovative program to expose preclinical medical students to challenges faced by financially and socially vulnerable surgical-oncology patients is feasible and may increase students' clinical preparedness and interest in surgery.

Safety and Feasibility of Simultaneous Transcarotid Revascularization With Flow Reversal and Coronary Artery Bypass Grafting for Concomitant Carotid Artery Stenosis and Coronary Artery Disease.

OBJECTIVE: The management of patients with combined severe carotid artery and coronary artery disease (CAD) is controversial. Transcarotid stenting with flow reversal (TCAR) is a novel hybrid technique for carotid revascularization. We sought to investigate the safety and feasibility of simultaneous TCAR and coronary artery bypass grafting (CABG) for concomitant carotid and CAD. METHODS: A single-institution, retrospective study of patients with critical carotid artery stenosis and symptomatic CAD who underwent simultaneous TCAR-CABG was completed. The primary outcomes were technical success, perioperative stroke, death, and hemorrhage. RESULTS: Four patients underwent TCAR-CABG. All patients were male with a mean age of 64. Technical success was achieved in all cases. There were no perioperative strokes or deaths. There were no reexplorations for hemorrhage. CONCLUSIONS: Transcarotid stenting with flow reversal-CABG is a technically feasible hybrid approach for simultaneous carotid and coronary revascularization. It should be part of the vascular surgeon's armamentarium for coexisting carotid and coronary disease. Further research focused on patient selection and perioperative antiplatelet management is warranted prior to the widespread adoption of this technique.

Simultaneous transcarotid artery revascularization with flow reversal and coronary artery bypass grafting: A novel hybrid technique.

Optimal management of concomitant coronary artery disease and carotid artery stenosis remains unknown. Current treatment strategies for patients with significant dual disease burden include simultaneous carotid endarterectomy and coronary artery bypass grafting (CABG) or staged carotid endarterectomy and CABG. Herein we present the case of a patient with severe coronary artery disease and carotid artery stenosis and discuss a novel hybrid approach to management of concomitant coronary and carotid disease using transcarotid artery revascularization with flow reversal before CABG.

Health Career Academy: Addition of a Surgical Case-Based Learning Curriculum Captures the Interest of High School Students.

OBJECTIVE: The Health Career Academy (HCA) is a national program which provides a structure to introduce underserved high school students to healthcare careers. Utilizing the HCA framework, we adapted the curriculum to emphasize surgical cases and invited physicians to enrich the learning experience. DESIGN, SETTING, AND PARTICIPANTS: Medical students adapted a surgical case-based learning (CBL) curriculum at a local high school serving students from a primarily ethnic minority and low-income community (61% Black, 20% Hispanic; 58% free or reduced lunch). Each grade level received a minimum of ten, 90-minute CBL sessions. Expert faculty lecturers supplemented lessons. Medical student volunteers and 10th and 11th grade students completed postsemester surveys. RESULTS: Over four semesters, HCA held 44 sessions, with 81 students graduating from the program. A total of 66% of sessions featured at least one faculty volunteer. A total of 36 students in 10th and 11th grade and 15 medical student volunteers completed postparticipation surveys. A total of 46.2% of 11th grade students previously participated in the 10th grade curriculum. On a scale of 1 to 4, students rated HCA highly in its overview of career options (mean 3.61, [SD 0.5]) and instilling understanding of patient care (3.78 [0.42]). Students enjoyed learning about career paths (3.61 [0.50]) and health topics (3.83 [0.39]). Of 10th and 11th grade students, 100% considered a healthcare career, with 34.8% of 10th and 61.5% of 11th grade students expressing interest in pursuing a surgical specialty. After volunteering, medical students felt like better educators (4.47 [0.64]) and were more likely to pursue teaching roles (4.2 [0.86]). CONCLUSIONS: The Duke HCA chapter implemented the HCA program featuring CBL sessions emphasizing surgical cases. This program engaged minority students and potentially contributed to student interest in surgical careers. It helped to prepare medical students for future teaching roles. An interactive, surgery-focused program may increase the number of minority youth interested in pursuing health careers.

Routine postprocedure ultrasound increases rate of detection of femoral arterial thrombosis in infants after cardiac catheterization.

OBJECTIVES: To examine the effect of implementing postcatheterization ultrasound (US) on femoral arterial thrombosis detection rates and factors associated with thrombosis in infants. BACKGROUND: Although femoral arterial thrombosis is an uncommon complication of cardiac catheterization, it can cause limb threatening complications. Previous studies assessing the utility of postprocedure US to detect thrombosis in infants have utilized US as an adjunct to standard clinical detection methods, are small scale, or include small cohorts of infants within older populations. METHODS: We reviewed institutional records of patients 0-12 months undergoing catheterization from 2007 to 2016. Demographics and procedural data were compared between the thrombosis and non-thrombosis group. Pre- and post-US groups were compared for detected thrombosis rate. Using univariate and multivariable analyses, we identified factors associated with thrombosis. RESULTS: In total, 270 patients underwent 509 catheterizations, with 40 (7.9%) documented thromboses. The rate of thrombus detection in patients younger than 6 months increased from 8.3% to 23.4% (P = 0.006) after implementing routine US. On multivariable analysis, lower weight (P < 0.001), larger arterial sheath size (P < 0.001), and longer procedure duration (P = 0.003) were independently associated with higher odds of thrombosis. CONCLUSIONS: Higher rates of femoral arterial thrombosis detection were observed since implementing an US screening program. Further studies are needed to evaluate age-related changes in hemostasis in this population and how advanced screening methods and anticoagulation protocols may help improve short-term and long-term sequelae of femoral arterial thrombosis.

The business of educating the next generation of surgeons.

Surgical education community needs to be informed about how education is funded and how it is threatened. In order to explore these issues the Association of Surgical Education convened a panel with significant experience in managing surgery departments to discuss the business of surgical education. They specifically addressed methods to recognize and reward faculty, educate residents on safety, quality and cost, and increase departmental revenue. This information is important in the current educational environment where there is an increased need for institutions to find alternate revenue streams to sustain graduate medical education. It is also important to find additional revenue streams to fund new residency slots to accommodate the greater number medical students who have been admitted to medical schools in response to meet the projected shortage of physicians.