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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.

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.

To evaluate health care fragmentation in patients with stage II and III rectal cancers. Fragmentation of care among multiple hospitals may worsen outcomes for cancer patients. National Cancer Database was queried for adult patients who underwent radiation and surgery for locally advanced (stage II–III) rectal adenocarcinoma from 2006 to 2015. Fragmented care was defined as receiving radiation at a different hospital from surgery. Descriptive statistics characterized patients, and survival probability was plotted using the Kaplan-Meier method and a Cox proportional hazards model. A total of 37,081 patients underwent surgery and radiation for stage II–III rectal cancer from 2006 to 2015 (24,102 integrated care vs. 12,979 fragmented care). Patients who received fragmented care (hazard ratio [HR] 1.105; 95% CI 1.045–1.169) had a higher risk of mortality. Patients who received at least surgery (HR 0.84; 95% CI 0.77–0.92) at academic hospitals had a lower risk of mortality. Academic hospitals had a higher proportion of patients with fragmented care (38.0 vs. comprehensive community 32.8% vs. community 33.8%, p

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. Keywords: Carotid artery stenosis, Transcarotid artery revascularization (TCAR), Combined coronary artery disease

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.

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.

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.

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.

Peripheral artery disease (PAD) is nearly as common as coronary artery disease, but few effective treatments exist, and it is associated with significant morbidity and mortality. Although PAD studies have focused on the vascular response to ischemia, skeletal muscle cells play a critically important role in determining the phenotypic manifestation of PAD. Here, we demonstrate that genetic ablation of Pax7+muscle progenitor cells (MPCs, or satellite cells) in a murine model of hind limb ischemia (HLI) resulted in a complete absence of normal muscle regeneration following ischemic injury, despite a lack of morphological or physiological changes in resting muscle. Compared to ischemic muscle of control mice (Pax7WT), the ischemic limb of Pax7-deficient mice (Pax7Δ) was unable to generate significant force 7- or 28-days after HLI inex vivoforce measurement studies. A dramatic increase in adipose infiltration was observed 28 days after HLI in Pax7Δmice, which replaced functional muscle. To investigate the mechanism of this adipogenic change, mice with inhibition of fibro/adipogenic precursors (FAPs), another pool of MPCs, were subjected to HLI. Inhibition of FAPs decreased muscle adipose fat but increased fibrosis. MPCs cultured from mouse muscle tissue failed to form myotubesin vitrofollowing depletion of satellite cellsin vivo, and they displayed an increased propensity to differentiate into fat in adipogenic medium. Importantly, this phenotype was recapitulated in patients with critical limb ischemia (CLI), the most severe form of PAD. Skeletal muscle samples from CLI patients demonstrated an increase in adipose deposition in more ischemic regions of muscle, which corresponded with a decrease in the number of satellite cells in those regions. Collectively, these data demonstrate that Pax7+MPCs are required for normal muscle regeneration after ischemic injury, and they suggest that targeting muscle regeneration may be an important therapeutic approach to prevent muscle degeneration in PAD.

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.

Currently, there is a global emphasis on quality improvement in medicine based on medical error analysis. This has resulted in increased access to outcomes data collected through standardized reporting systems; however, there is a need for categorizing and discussing outcomes so that the data are used more effectively to build an error-tolerant system. An error taxonomy is a useful tool for any organization looking to classify this collated information in a meaningful way. Obesity surgery has long stood at the forefront of quality improvement and reporting, but similarly there is need for standardized methods of categorizing and therefore understanding error in the field. Herein, we present an overview of the literature analyzing the occurrence of medical error both from the perspective of the individual and the system. An example of a hierarchical method of error taxonomy is proposed that incorporates both personal and systematic approaches to error categorization. The continued importance of error reporting in enhancing our understanding of medical errors is demonstrated. Overall, establishing a robust taxonomy is critical for building a well-informed system that mitigates the potential for errors to produce harm. Incorporating this taxonomy into national regulations and institutional policies will continue to propel bariatric surgery as the leading safe, high-quality solution to obesity and its associated comorbidities.

Improvements in health information technology have made aggregate multipayer pharmacy claims data increasingly available through the electronic health record (EHR). The objective of this study was to assess the current awareness, utilization, and impact of pharmacy history data available in the EHR on primary care provider (PCP) decision making. A 14-question survey was distributed to all PCPs in a large medical practice. Of the 55/72 responding PCPs, 47 (85.5%) were aware of the EHR medication history function, and 36 (65.5%) had used it previously. Respondents indicated the medication history could be most useful when considering prescribing a narcotic (33/36, 92%) and when addressing nonadherence concerns (28/35, 80%). Barriers included delays in data loading and the time pressures of clinical practice. Access to aggregate multipayer pharmacy history data has the potential to affect medication reconciliation, yet future implementation should focus on making these data complete and easily available in routine practice.

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

Acute lymphoblastic leukaemia (ALL) has a marked propensity to metastasize to the central nervous system (CNS). In contrast to brain metastases from solid tumours, metastases of ALL seldom involve the parenchyma but are isolated to the leptomeninges, which is an infrequent site for carcinomatous invasion. Although metastasis to the CNS occurs across all subtypes of ALL, a unifying mechanism for invasion has not yet been determined. Here we show that ALL cells in the circulation are unable to breach the blood–brain barrier in mice; instead, they migrate into the CNS along vessels that pass directly between vertebral or calvarial bone marrow and the subarachnoid space. The basement membrane of these bridging vessels is enriched in laminin, which is known to coordinate pathfinding of neuronal progenitor cells in the CNS. The laminin receptor α6 integrin is expressed in most cases of ALL. We found that α6 integrin–laminin interactions mediated the migration of ALL cells towards the cerebrospinal fluid in vitro. Mice with ALL xenografts were treated with either a PI3Kδ inhibitor, which decreased α6 integrin expression on ALL cells, or specific α6 integrin-neutralizing antibodies and showed significant reductions in ALL transit along bridging vessels, blast counts in the cerebrospinal fluid and CNS disease symptoms despite minimally decreased bone marrow disease burden. Our data suggest that α6 integrin expression, which is common in ALL, allows cells to use neural migratory pathways to invade the CNS.

Breast cancer metastatic relapse can occur years after therapy, indicating that disseminated breast cancer cells (BCCs) have a prolonged dormant phase before becoming proliferative. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating BCCs to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Using real-time in vivo microscopy of bone marrow (BM) in a breast cancer xenograft model, we show that dormant and proliferating BCCs occupy distinct areas, with dormant BCCs predominantly found in E-selectin- and stromal cell-derived factor 1 (SDF-1)-rich perisinusoidal vascular regions. We use highly specific inhibitors of E-selectin and C-X-C chemokine receptor type 4 (CXCR4) (SDF-1 receptor) to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Whereas E-selectin interactions are critical for allowing BCC entry into the BM, the SDF-1/CXCR4 interaction anchors BCCs to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation. Homing studies with primary BCCs also demonstrate that E-selectin regulates their entry into bone through the sinusoidal niche, and immunohistochemical staining of patient BMs shows dormant micrometastatic disease adjacent to SDF-1(+) vasculature. These findings shed light on how BCCs traffic within the host, and suggest that simultaneous blockade of CXCR4 and E-selectin in patients could molecularly excise dormant micrometastases from the protective BM environment, preventing their emergence as relapsed disease.

The majority of children and adults who experience relapse of acute lymphoblastic leukemia (ALL) will die from the disease. The presence of leukemic blasts within the cerebrospinal fluid (CSF) is an important predictor of disease recurrence in both the bone marrow (BM) and central nervous system (CNS), a frequent site of disease involvement. In the absence of intrathecal chemotherapy or craniospinal irradiation, 30%‒50% of patients will in fact develop CNS disease. All patients therefore receive CNS prophylaxis. High-risk patients require intensive CNS-directed treatment that causes toxic side effects and can impact cognitive development in children. Patients who develop recurrence in the CNS have limited treatment options and an extremely poor prognosis. The enzyme PI3K plays an important role in many biological effects including cell proliferation, migration, and apoptosis. The d isoform of PI3K is specifically expressed in immune cells. The PI3Kd inhibitor idelalisib is approved for use in combination with rituximab for the treatment of chronic lymphocytic leukemia (CLL). However, little is known about the efficacy of PI3Kd inhibition in ALL. Here, the PI3Kd inhibitor GS-649443, a potent and specific in vivo tool compound, was evaluated in a xenograft mouse model. The in vivo effects of GS-649443 were investigated in a Nalm-6 pre-B ALL SCID model. At approximately 40 days postengraftment, untreated mice all developed symptoms of CNS involvement and displayed hind limb paralysis. Hind limb paralysis is the clinical endpoint for sacrifice, occurring prior to death from progressive BM disease. Mice were treated with GS-649443 by oral gavage beginning on postengraftment day 1 and continuing until the development of clinical symptoms requiring sacrifice (hind limb paralysis, weight loss >20%, respiratory or other distress). Only 17% of GS-649443‒treated mice developed hind limb paralysis at their clinical endpoint, while 100% of vehicle-treated mice showed hind limb paralysis. In addition, mice treated with GS-649443 or vehicle control were paired. When either mouse in a treatment pair reached a clinical endpoint, both were sacrificed so disease burden in individual organs could be compared at matched time points. There was no difference in tumor burden or leukemic cell apoptotic rate in the BM of treated vs vehicle control groups. In contrast, there was a significant decrease in the number of leukemic blasts harvested from the CSF of treated mice (Fig. 1). Consistent with the inhibition of CNS disease progression, GS-649443 significantly prolonged the survival of treated mice (Fig. 2). While compromised blood-brain barrier in leukemic mice may allow therapeutic targeting of CNS disease, it is unknown whether GS-649443 enters the CNS in healthy rodents. Given the well-described effects of idelalisib on CLL cell migration, we hypothesized that PI3Kd blockade impacts disease in this ALL model by impairing leukemia migration into the CNS. To investigate the in vitro effect of GS-649443 on ALL cell migration, transwell migration assays with SDF-1 as chemoattractant were performed. Both GS-649443 and idelalisib suppressed migration of Nalm-6 and primary human ALL cells toward SDF-1. Lastly, the effects of GS-649443 in combination with conventional chemotherapy were examined. GS-649443 alone did not cause significant cytotoxicity of Nalm-6 in vitro, however, treatment with GS-649443 after cytarabine significantly increased apoptosis. Leukemic mice (20 days post-engraftment) were then treated with cytarabine (days 1‒5) in combination with GS-649443 or cytarabine alone (days 1‒7) for 1 cycle. In contrast to the single-agent study, significant decreases in the number of leukemic blasts harvested from both the BM and CSF of treated mice were observed, suggesting that PI3Kd inhibition sensitized ALL cells to cytarabine chemotherapy (Fig. 3). This decrease in residual disease after combination therapy led to significantly prolonged survival in GS-649443‒treated mice (Fig. 4). Taken together, this study provides evidence that PI3Kd inhibition prevents ALL progression in the CNS. In addition, GS-649443 and conventional chemotherapy appear to synergize to decrease residual BM disease. The potential for PI3Kd inhibition to improve chemotherapy response and impede development of CNS disease in ALL warrants further investigation in a translational clinical study. Disclosures Yao: Gilead Sciences, Inc.: Research Funding. Price:Gilead Sciences, Inc.: Research Funding. Olivere:Gilead Sciences, Inc.: Research Funding. Warner:Gilead Sciences, Inc.: Research Funding. Tannheimer:Gilead Sciences: Employment. Sipkins:Gilead Sciences, Inc.: Research Funding.