Codon-Optimized and de novo-Synthesized E-Selectin/AAV2 Dose-Response Study for Vascular Regeneration Gene Therapy.

OBJECTIVE: This study focuses on dose-response investigation using a codon-optimized and de novo-synthesized E-Selectin/AAV2 (E-Sel/AAV2) vector in preparation for Investigational New Drug (IND)-enabling of subsequent clinical studies. BACKGROUND: Gene therapy is a potential solution for patients suffering from chronic limb-threatening ischemia (CLTI). Understanding the dose for effective gene delivery is crucial for future IND-enabling studies. METHODS: Expression of the codon-optimized E-Selectin gene was assessed by flow cytometry following in vitro cell transfection assay and RT-qPCR for murine limbs injected in vivo with AAV-m-E-Selectin (E-Sel/AAV2). Dose-response studies involved three cohorts of FVB/NJ mice (n=6/group) with escalating log doses of E-Selectin/AAV2 injected intramuscularly (IM) in divided aliquots, ranging from 2×109 VG to 2×1011 VG, into ischemic limbs created by left femoral artery/vein ligation/excision and administration of nitric oxide synthase inhibitor, L-NAME. Limb perfusion, extent of gangrene free limb, functional limb recovery and therapeutic angiogenesis were assessed. RESULTS: Codon-optimized E-Sel/AAV2 gene therapy exhibits superior expression level than WT E-Sel/AAV2 gene therapy both in vitro and in vivo. Mice treated with a high dose (2×1011 VG) of E-Sel/AAV2 showed significantly improved perfusion indices, lower Faber's scores, increased running stamina and neovascularization compared with lower doses tested with control groups, indicating a distinct dose-dependent response. No toxicity was detected in any of the animal groups studied. CONCLUSION: E-Sel/AAV2 Vascular Regeneration Gene Therapy (VRGT) holds promise for enhancing the recovery of ischemic hindlimb perfusion and function, with the effective dose identified in this study as 2×1011 VG aliquots injected IM.

Fibroblasts in Diabetic Foot Ulcers.

Fibroblasts are stromal cells ubiquitously distributed in the body of nearly every organ tissue. These cells were previously considered to be "passive cells", solely responsible for ensuring the turnover of the extracellular matrix (ECM). However, their versatility, including their ability to switch phenotypes in response to tissue injury and dynamic activity in the maintenance of tissue specific homeostasis and integrity have been recently revealed by the innovation of technological tools such as genetically modified mouse models and single cell analysis. These highly plastic and heterogeneous cells equipped with multifaceted functions including the regulation of angiogenesis, inflammation as well as their innate stemness characteristics, play a central role in the delicately regulated process of wound healing. Fibroblast dysregulation underlies many chronic conditions, including cardiovascular diseases, cancer, inflammatory diseases, and diabetes mellitus (DM), which represent the current major causes of morbidity and mortality worldwide. Diabetic foot ulcer (DFU), one of the most severe complications of DM affects 40 to 60 million people. Chronic non-healing DFU wounds expose patients to substantial sequelae including infections, gangrene, amputation, and death. A complete understanding of the pathophysiology of DFU and targeting pathways involved in the dysregulation of fibroblasts are required for the development of innovative new therapeutic treatments, critically needed for these patients.

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs.

OBJECTIVE: Here, we report a new method to increase the therapeutic potential of mesenchymal stem/stromal cells (MSCs) for ischemic wound healing. We tested biological effects of MSCs modified with E-selectin, a cell adhesion molecule capable of inducing postnatal neovascularization, on a translational murine model. BACKGROUND: Tissue loss significantly worsens the risk of extremity amputation for patients with chronic limb-threatening ischemia. MSC-based therapeutics hold major promise for wound healing and therapeutic angiogenesis, but unmodified MSCs demonstrate only modest benefits. METHODS: Bone marrow cells harvested from FVB/ROSA26Sor mTmG donor mice were transduced with E-selectin-green fluorescent protein (GFP)/AAV-DJ or GFP/AAV-DJ (control). Ischemic wounds were created via a 4 mm punch biopsy in the ipsilateral limb after femoral artery ligation in recipient FVB mice and subsequently injected with phosphate-buffered saline or 1×10 6 donor MSC GFP or MSC E-selectin-GFP . Wound closure was monitored daily for 7 postoperative days, and tissues were harvested for molecular and histologic analysis and immunofluorescence. Whole-body DiI perfusion and confocal microscopy were utilized to evaluate wound angiogenesis. RESULTS: Unmodified MSCs do not express E-selectin, and MSC E-selectin-GFP gain stronger MSC phenotype yet maintain trilineage differentiation and colony-forming capability. MSC E-selectin-GFP therapy accelerates wound healing compared with MSC GFP and phosphate-buffered saline treatment. Engrafted MSC E-selectin-GFP manifest stronger survival and viability in wounds at postoperative day 7. Ischemic wounds treated with MSC E-selectin-GFP exhibit more abundant collagen deposition and enhanced angiogenic response. CONCLUSIONS: We establish a novel method to potentiate regenerative and proangiogenic capability of MSCs by modification with E-selectin/adeno-associated virus. This innovative therapy carries the potential as a platform worthy of future clinical studies.

Outcomes of Incidental Appendectomy During Ovarian Operations in a National Pediatric Cohort.

INTRODUCTION: The utility of incidental appendectomy (IA) during many ovarian operations has not been evaluated in the pediatric population. This study sought to compare outcomes after ovarian surgery with IA in the pediatric population. METHODS: Females (≤20 y old) undergoing ovarian surgeries (oophorectomy, detorsion and/or drainage) were identified from the Nationwide Readmissions Database (2016-2018). Those with appendicitis were excluded. A propensity score-matched analysis (PSMA) with 46 covariates (demographics, comorbidities, hospitalization factors, etc.) was performed between those receiving ovarian surgery with or without IA. RESULTS: There were 13,202 females (median age 17 [IQR 14-20] y old) who underwent oophorectomy (90%), detorsion (26%), and/or ovarian drainage (13%). There were more episodes of torsion in the PSMA cohort receiving ovarian surgery alone (17% versus 10% IA; P = 0.016), while other indications (ovarian mass, cyst) were similar. Open (66% versus 34% laparoscopic) IAs were more frequent. Length of stay (LOS) was longer for those undergoing IA (3 [2-4] versus 2 [2-4] days ovarian surgery alone; P < 0.001). There was a higher rate of postoperative GI complications in the IA cohort. Subgroup analysis of those undergoing laparoscopic operations demonstrated no difference in LOS or postoperative complications between patients undergoing IA or not. CONCLUSIONS: These data indicate that IA in pediatric ovarian operations is associated with longer LOS and higher GI postoperative complications. However, laparoscopic IA was not associated with higher cost, complications, LOS, or readmissions. This suggests that IA performed during ovarian surgeries in select patients may be cost-effective and worthy of future study.

Radical Resection of Pediatric Fibrosarcoma Is Not Associated With Survival Benefit: A Nationwide Database Analysis.

INTRODUCTION: Fibrosarcoma is one of the most common nonrhabdomyosarcoma soft tissue sarcomas in the pediatric population. Surgical resection is the cornerstone of treatment; however, optimal factors regarding the extent of fibrosarcoma resection in localized versus regional disease is poorly understood. METHODS: The Surveillance, Epidemiology, and End Results database was queried for patients who are 19 y old or younger with a diagnosis of fibrosarcoma from 1975 to 2016. Kaplan-Meier analyses were performed for disease-specific survival on clinical and pathologic variables. Multivariate analysis was performed based on significant predictors of disease-specific survival. RESULTS: There were 1290 patients (median age 13 [7-17] y) identified with fibrosarcoma. The overall survival rate at 20 y was 93%. Radical resection was performed on 22%, 40%, and 52% of patients with localized, regional, and distant Surveillance, Epidemiology, and End Results disease stage, respectively. Chemotherapy (P < 0.001), radiation (P < 0.001), histology (P < 0.001), and stage (P = 0.004) were significant predictors of increased mortality using univariate Kaplan-Meier analysis. Most patients (86%) with localized or regional stage who underwent radiation had fibrosarcomas of nondermatofibrosarcoma histology (P < 0.001). Dermatofibrosarcoma subtype comprised most radical resections (41%). Excluding distant stage, nondermatofibroma histology (hazard ratio 16.94, 95% confidence interval 3.77-76.01) and regional stage (hazard ratio 8.15, 95% confidence interval 2.93-22.69) were independent prognostic factors of mortality (both P < 0.001). Radical resection was not a significant independent prognostic indicator of survival. CONCLUSIONS: Nondermatofibrosarcoma subtype is independently associated with increased mortality. Although surgery remains the mainstay of treatment, the extent of resection is not a predictor of survival for patients with the localized and regional stage of disease.

Outcomes of Gastrostomy Tubes in Newborns With Congenital Heart Disease and Comparison of Techniques.

INTRODUCTION: Gastrostomy tube (GT) placement for enteral access is one of the most common procedures for infants with numerous conditions such as congenital heart disease (CHD). Discrepancies in the literature exist regarding outcomes of newborns with CHD undergoing GT placement. This study sought to characterize postoperative outcomes and readmission complications in this patient population. METHODS: The Nationwide Readmission Database was queried from 2010 to 2014 for all newborns who underwent GT placement during their index hospitalization. Newborns with or without CHD other than an isolated atrial or ventricular septal defect were compared using standard statistical tests. A propensity score-matched analysis was performed among newborns with or without CHD using > 100 covariates. RESULTS: Seven thousand seven hundred thirty six patients underwent GT placement. Newborns with CHD (27%) more frequently underwent open GT (59% versus 55%) and less frequently underwent laparoscopic (17% versus 19%) or percutaneous (24% versus 26%) GT placement compared to those without CHD, P = 0.043. GT-related complications on index admission were similar between groups (7% versus 7%, P = 0.770). Newborns with CHD had higher overall readmission rates (39% versus 31%), more GT-related readmission complications (7% versus 3%), and higher readmission costs ($35,787 versus $20,073) compared to newborns without CHD, all P < 0.001. Laparoscopic GT was associated with the lowest rate of GT-related complications (0%) and overall readmission rates (27%) compared to open or percutaneous endoscopic gastrostomy (all P < 0.001). CONCLUSIONS: Compared to newborns without CHD, newborns with CHD had higher rates of overall readmissions, readmission costs, and GT-related complications on readmission. The laparoscopic GT approach was underused despite fewer complications and readmissions.

National burden of pediatric abusive injuries: patterns vary by age.

PURPOSE: Child abuse is often unrecognized by healthcare practitioners. This study sought to characterize pediatric abuse injury patterns and associated mortality rates in a nationwide cohort. METHODS: The Kids' Inpatient Database (1997-2012) was queried for patients < 18 years old with a diagnosis of child abuse (utilizing ICD-9 codes for abusive head trauma [AHT], neglect, physical, emotional, sexual, and other abuse). Demographic factors, mortality, and injury patterns were compared with demographic factors using standard statistical tests. RESULTS: > 39,000 children were hospitalized for abuse from 1997 to 2012. The majority were Caucasian (36%), male (51%) and < 4 years old (70%). Most sustained physical abuse (53%), followed by AHT (14%), sexual (9%) and emotional abuse (2%). Multiple injuries were sustained by 44% of patients. Mortality was 4% (n = 1476). Burns (2%) and intrathoracic (2%) injuries had the highest mortality compared to other injuries (21% and 19%, respectively; both P < 0.001). Emotional abuse (5%) and neglect (1%) were highest in those ≥ 13 years old (both P  = 0.001). CONCLUSION: Physical injuries are less common in adolescents (13-18 years) hospitalized for abuse. However, they are more likely to report emotional abuse and neglect, which has not been compared in previous studies. Intrathoracic injuries and AHT are associated with significant mortality.

Nationwide outcomes of incidental appendectomy during cholecystectomy versus cholecystectomy alone in children: a propensity score-matched analysis.

BACKGROUND: The utility of incidental appendectomy, appendectomy during another index surgery in the absence of appendicitis, has not been evaluated in the pediatric population during cholecystectomy. This study sought to compare nationwide outcomes after cholecystectomy with incidental appendectomy in children. METHODS: Patients ≤ 18 years old who underwent cholecystectomy from 2010-2014 were identified from the Nationwide Readmissions Database. A propensity score-matched analysis (PSMA) with > 40 covariates including demographics, comorbidities, and hospitalization factors was performed between those receiving cholecystectomy alone versus incidental appendectomy at the time of cholecystectomy. RESULTS: 34,390 patients underwent cholecystectomy (median age 15 [13-17] years). Laparoscopic (92%) approach was utilized most frequently, with 2% requiring conversion to open cholecystectomy. PSMA demonstrated a higher frequency of perforation or laceration of adjacent organs occurring in those receiving cholecystectomy alone during index admission. No significant differences in readmissions within 30 days or the calendar year were detected. Those undergoing cholecystectomy alone had higher overall readmission costs ($11,783 [$4942-$39,836] vs. $6,100 [$2358-$19,719] cholecystectomy with appendectomy; p = 0.010). CONCLUSION: This nationwide PSMA indicates that incidental appendectomy in pediatric cholecystectomies is not associated with higher postoperative complications, cost, or readmissions. This suggests that incidental appendectomy during cholecystectomy is safe, cost-effective, and worthy of future study. LEVEL OF EVIDENCE: Level III.

Contemporary Trends in Laparoscopy and Ovarian Sparing Surgery for Ovarian Torsion in the Pediatric Population.

PURPOSE: Although total oophorectomy (TO) was historically performed in cases of nonviable-appearing ovaries, considerable evidence has demonstrated equivalent outcomes after ovarian sparing surgery (OSS) as well as long-term fertility preservation benefits. This study sought to compare outcomes of OSS and TO for patients with ovarian torsion. METHODS: Females <21 years old admitted for ovarian torsion were identified from the Nationwide Readmissions Database (2016-2018) and stratified by OSS or TO. Propensity score-matched analysis (PSMA) utilizing >50 covariates (demographics, medical comorbidities, ovarian diagnoses, etc.) was constructed between those receiving TO and OSS. RESULTS: There were 3,161 females (median 15 [12-18] years) with ovarian torsion, and concomitant pathologies included cysts (42%), benign masses (25%), and malignant masses (<1%). Open approaches were more common (52% vs. 48% laparoscopic), and ovarian resection (OSS or TO) was performed in 87% (39% OSS and 48% TO). OSS was more commonly performed with laparoscopic detorsions (60% vs. 40% TO), while TO was more frequent in open operations (59% vs. 41% TO; both p < 0.001). No differences in overall readmissions (7% OSS vs. 8% TO) or readmissions for recurrent torsion (<1% overall) and ovarian masses (<1%) were observed (both groups <1%; p = 0.612). After PSMA, laparoscopy was still utilized less frequently with TO (39% vs. 53%; p < 0.001) despite similar rates of malignant masses. CONCLUSIONS: Overall, these data offer additional support for the current practice guidelines that give preference to OSS as the primary method of treatment for pediatric ovarian torsion in the majority of cases. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective Comparative Study.

Uncovering Risk Factors and Outcomes of Pulmonary Embolism in a Nationwide Cohort of Hospitalized Children.

PURPOSE: The incidence of pulmonary embolism (PE) in hospitalized children has increased in recent years. This study sought to characterize factors and outcomes associated with PE using a national pediatric cohort. METHODS: The Nationwide Readmissions Database was queried (2016-2018) for patients (<18 years) with a diagnosis of PE. Index and prior hospitalizations (PHs) within 1 year were analyzed. A binary logistic regression utilizing 37 covariates (demographics, procedures, comorbidities, etc.) was constructed to examine a primary outcome of in-hospital mortality. RESULTS: 3440 patients were identified (57% female) with the majority >12 years old (77%). One-third had a known deep vein thrombosis (69% lower and 31% upper extremity). Nineteen percent underwent central venous catheter (CVC) placement. Twenty-one percent had a PH within 1 year. Nine percent underwent an operation with the majority being cardiothoracic (5%). Overall mortality was 5%. Neurocranial surgery, cardiothoracic surgery, and CVC placement were associated with the highest odds of inpatient mortality after logistic regression. CONCLUSION: Pediatric patients with PE have a high rate of PHs, CVC placement, and inpatient operations, which may be associated with higher mortality. This information can be utilized to improve screening measures and clinical suspicion for PE in hospitalized children.

Using intent to get ahead of pediatric cranial firearm injuries.

OBJECTIVE: Pediatric firearm injuries (PFI) are a public health crisis. Little is known about how injury intent may influence the outcome of pediatric cranial firearm injuries (PCFI). The current study sought to compare demographics and outcomes of PCFI based on intent of injury. METHODS: The Nationwide Readmission Database (2010-2014) was queried to identify patients <18 years old with PCFI. Demographics and outcomes were compared by injury intent (assault, self-inflicted, unintentional), and results were weighted for national estimates to create a population-based cohort study. RESULTS: There were 1,365 cases of PCFI identified for an incidence of 11% of all PFI. The majority of patients were male (83 %), >13 years (81 %), and had an injury severity score >15 (79 %). Overall PCFI mortality was 43 %, compared to 6 % for all PFI. Assault was the most common intent (51 %), followed by self-inflicted (25 %), and unintentional (24 %). Assault was more likely to occur in patients from low-income households (61 % vs. 31 % self-inflicted vs. 42 % unintentional), p < 0.001. Unintentional injuries occurred in those <13 years old (40 % vs. 12 % assault vs. 16 % self-inflicted) and more often resulted in facial fracture (19 % vs. 11 % vs. 13 %), all p < 0.001. Readmission rate within the year was 21 %. The majority (56 %) of readmissions were unplanned, and the rate was highest for assault (77 % vs. <1 % self-inflicted vs. 44 % unintentional, p < 0.001). CONCLUSIONS: PCFI are associated with significant morbidity and mortality. Demographics and outcomes vary by intent of injury; knowledge of these patterns can direct future interventions to reduce injuries and impact outcomes.

Directing Cell Delivery to Murine Atherosclerotic Aortic Lesions via Targeting Inflamed Circulatory Interface using Nanocarriers.

Stem cell therapy holds significant potential for many inflammatory diseases and regenerative medicine applications. However, delivery of therapeutic cells to specific disease sites after systemic administration without indiscriminate trafficking to other non-target tissues is a major limitation of current cell therapies. Here, we describe a novel nanocarrier-directed targeted cell delivery system that enables cell surface coating with dendrimer nanocarriers containing adhesion moieties to serve as a global positioning system "GPS" to guide circulating cells to targeted lesions and mediate the anchoring of cells at the inflammation site. By exploiting cell surface ligands/receptors selectively and/or molecular moieties that are highly expressed on activated endothelium in pathologic disease states, nanocarrier-coated cells containing the counterpart binding receptors/ligands can be enabled to specifically traffic to and dock at vasculature within target lesions. We demonstrate the efficacy of the I-domain fragment of LFA-1 ( id LFA-1) complexed to modified nanocarriers to facilitate homing of mesenchymal stem cells (MSCs) to inflamed luminal endothelial cells on which ICAM-1 is highly expressed in a murine model of aortic atherosclerosis. Our method can overcome challenges imposed by the high velocity and dynamic circulatory flow of the aorta to successfully deliver MSCs to atherosclerotic regions and allow for docking of the potentially therapeutic and immunomodulating cells. This targeted cell-delivery platform can be tailored for selective systemic delivery of various types of therapeutic cells to different disease areas.

Outcomes After Pectus Excavatum Repair: Center Volume Matters.

PURPOSE: Pectus excavatum (Pectus) repair may be offered for those with significant cardiopulmonary compromise or severe cosmetic defects. The influence of hospital center volume on postoperative outcomes in children is unknown. This study aimed to investigate the outcomes of children undergoing Pectus repair, stratified by hospital surgical volume. METHODS: The Nationwide Readmission Database was queried (2016-2020) for patients with Pectus (Q67.6). Patients were stratified into those who received repair at high-volume centers (HVCs; ≥20 repairs annually) versus low-volume centers (LVCs; <20 repairs annually). Demographics and outcomes were analyzed using standard statistical tests. RESULTS: A total of 9414 patients with Pectus underwent repair during the study period, with 69% treated at HVCs and 31% at LVCs. Patients at LVCs experienced higher rates of complications during index admission, including pneumothorax (23% vs. 15%), chest tube placement (5% vs. 2%), and overall perioperative complications (28% vs. 24%) compared to those treated at HVCs, all p < 0.001. Patients treated at LVCs had higher readmission rates within 30 days (3.8% vs. 2.8% HVCs) and overall readmission (6.8% vs. 4.7% HVCs), both p < 0.010. Among readmitted patients (n = 547), the most frequent complications during readmission for those initially treated at LVCs included pneumothorax/hemothorax (21% vs. 8%), bar dislodgment (21% vs. 12%), and electrolyte disorders (15% vs. 9%) compared to those treated at HVCs. CONCLUSION: Pediatric Pectus repair performed at high-volume centers was associated with fewer index complications and readmissions compared to lower-volume centers. Patients and surgeons should consider this hospital volume-outcome relationship. TYPE OF STUDY: Retrospective Comparative. LEVEL OF EVIDENCE: III.

Management and Outcomes of Pediatric Lymphatic Malformations: A Systematic Review From the APSA Outcomes and Evidence-Based Practice Committee.

BACKGROUND: Significant variation in management strategies for lymphatic malformations (LMs) in children persists. The goal of this systematic review is to summarize outcomes for medical therapy, sclerotherapy, and surgery, and to provide evidence-based recommendations regarding the treatment. METHODS: Three questions regarding LM management were generated according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Publicly available databases were queried to identify articles published from January 1, 1990, to December 31, 2021. A consensus statement of recommendations was generated in response to each question. RESULTS: The initial search identified 9326 abstracts, each reviewed by two authors. A total of 600 abstracts met selection criteria for full manuscript review with 202 subsequently utilized for extraction of data. Medical therapy, such as sirolimus, can be used as an adjunct with percutaneous treatments or surgery, or for extensive LM. Sclerotherapy can achieve partial or complete response in over 90% of patients and is most effective for macrocystic lesions. Depending on the size, extent, and location of the malformation, surgery can be considered. CONCLUSION: Evidence supporting best practices for the safety and effectiveness of management for LMs is currently of moderate quality. Many patients benefit from multi-modal treatment determined by the extent and type of LM. A multidisciplinary approach is recommended to determine the optimal individualized treatment for each patient.

Methods and Limitations of Augmenting Mesenchymal Stem Cells for Therapeutic Applications.

Significance: Given their capacity for self-renewal, multilineage differentiation, and immunomodulatory potential, mesenchymal stem cells (MSCs) represent a promising modality of clinical therapy for both regenerative medicine and immune diseases. In this study, we review the key approaches and popular methods utilized to boost potency and modify functions of MSCs for clinical purposes as well as their associated limitations. Recent Advances: Several major domains of cell modification strategies are currently employed by investigators to overcome these deficits and augment the therapeutic potential of MSCs. Priming MSCs with soluble factors or pharmacologic agents as well as manipulating oxygen availability in culture have been demonstrated to be effective biochemical methods to augment MSC potential. Distinct genetic and epigenetic methods have emerged in recent years to modify the genetic expression of target proteins and factors thereby modulating MSCs capacity for differentiation, migration, and proliferation. Physical methods utilizing three-dimensional culture methods and alternative cell delivery systems and scaffolds can be used to recapitulate the native MSC niche and augment their engraftment and viability for in vivo models. Critical Issues: Unmodified MSCs have demonstrated only modest benefits in many preclinical and clinical studies due to issues with cell engraftment, viability, heterogeneity, and immunocompatibility between donor and recipient. Furthermore, unmodified MSCs can have low inherent therapeutic potential for which intensive research over the past few decades has been dedicated to improving cell functionality and potency.

Small Intestinal Perforation Secondary to Necrotizing Enteritis-An Under-Recognized Complication of Crohn's Disease.

Small bowel perforation is an uncommon but severe event in the natural history of Crohn's disease with fewer than 100 cases reported. We review Crohn's disease cases with necrotizing enteritis and share a case of a 26-year-old female who presented with a recurrent episode of small intestinal perforation. A PubMed literature review of case reports and series was conducted using keywords and combinations of "Crohn's disease," "small intestine perforation," "small bowel perforation," "free perforation," "regional enteritis," and "necrotizing enteritis." Data extracted included demographic data, pre- or postoperative steroid administration, medical or surgical management, and case fatality. Nineteen reports from 1935 to 2021 qualified for inclusion. There were 43 patients: 20 males and 23 females with a mean age of 36 ± 15 years old. 75 total perforations were described: 56 ileal (74.6%), 15 jejunal (20.0%), 2 cecal (2.7%), and 1 small intestine non-specified (2.7%). 38 of 43 patients were managed surgically by primary repair (11), ostomy creation (21), or an anastomosis (11). Of 11 case fatalities, medical management alone was associated with higher mortality (5/5; 100% mortality) compared to those treated surgically (6/38; 15.8% mortality; P < .001). Patient sex, disease history, acute abdomen, and pre- or postoperative steroid use did not significantly correlate with mortality. Jejunal perforation was significantly (P = .028) associated with event mortality while ileal was not (P = .45). Although uncommon, necrotizing enteritis should be considered in Crohn's patients who present with small intestinal perforation. These cases often require urgent surgical intervention and may progress to fulminant sepsis and fatality if not adequately treated.

Targeted cell delivery of mesenchymal stem cell therapy for cardiovascular disease applications: a review of preclinical advancements.

Cardiovascular diseases (CVD) continue to be the leading cause of morbidity and mortality globally and claim the lives of over 17 million people annually. Current management of CVD includes risk factor modification and preventative strategies including dietary and lifestyle changes, smoking cessation, medical management of hypertension and cholesterol lipid levels, and even surgical revascularization procedures if needed. Although these strategies have shown therapeutic efficacy in reducing major adverse cardiovascular events such as heart attack, stroke, symptoms of chronic limb-threatening ischemia (CLTI), and major limb amputation significant compliance by patients and caregivers is required and off-target effects from systemic medications can still result in organ dysfunction. Stem cell therapy holds major potential for CVD applications but is limited by the low quantities of cells that are able to traffic to and engraft at diseased tissue sites. New preclinical investigations have been undertaken to modify mesenchymal stem cells (MSCs) to achieve targeted cell delivery after systemic administration. Although previous reviews have focused broadly on the modification of MSCs for numerous local or intracoronary administration strategies, here we review recent preclinical advances related to overcoming challenges imposed by the high velocity and dynamic flow of the circulatory system to specifically deliver MSCs to ischemic cardiac and peripheral tissue sites. Many of these technologies can also be applied for the targeted delivery of other types of therapeutic cells for treating various diseases.

Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies.

Progressive peripheral arterial disease (PAD) can result in chronic limb-threatening ischemia (CLTI) characterized by clinical complications including rest pain, gangrene and tissue loss. These complications can propagate even more precipitously in the setting of common concomitant diseases in patients with CLTI such as diabetes mellitus (DM). CLTI ulcers are cutaneous, non-healing wounds that persist due to the reduced perfusion and dysfunctional neovascularization associated with severe PAD. Existing therapies for CLTI are primarily limited to anatomic revascularization and medical management of contributing factors such as atherosclerosis and glycemic control. However, many patients fail these treatment strategies and are considered "no-option," thereby requiring extremity amputation, particularly if non-healing wounds become infected or fulminant gangrene develops. Given the high economic burden imposed on patients, decreased quality of life, and poor survival of no-option CLTI patients, regenerative therapies aimed at neovascularization to improve wound healing and limb salvage hold significant promise. Cell-based therapy, specifically utilizing mesenchymal stem/stromal cells (MSCs), is one such regenerative strategy to stimulate therapeutic angiogenesis and tissue regeneration. Although previous reviews have focused primarily on revascularization outcomes after MSC treatments of CLTI with less attention given to their effects on wound healing, here we review advances in pre-clinical and clinical studies related to specific effects of MSC-based therapeutics upon ischemic non-healing wounds associated with CLTI.

Effects of Recorded versus Live Teleconference Didactic Lectures on Medical Student Performance in the Surgery Clerkship.

OBJECTIVE: Due to the COVID-19 pandemic, numerous institutions converted medical education didactics to electronic formats including both live teleconference didactics and recorded faculty lectures. This study aims to compare the effect of recorded versus live teleconference didactic lectures on medical student examination scores during the surgery clerkship. DESIGN: Medical students completing the Surgery Clerkship received a weekly series of didactic lectures taught by faculty via a teleconference (2020-2021 academic year) or recorded format (2021-2022 academic year). Performance outcomes included weekly quizzes, National Board of Medical Examiners (NBME) Surgery Shelf Exam, and clerkship Objective Structured Clinical Examination (OSCE) scores. SETTING: University of Miami Miller School of Medicine. PARTICIPANTS: All second- (MS2) and third-year (MS3) medical students completing the Surgery Clerkship over two academic years (n = 312). RESULTS: Students who received live teleconference lectures (n = 156) demonstrated higher average scores on weekly quizzes (89%) and the NBME shelf exam (76%) compared to those receiving recorded lectures (n = 156; 71% quiz, 70% shelf exam), both p < 0.001. There was a significant association with performance in the highest quartile (Q1) of weekly quiz scores and receiving live lectures (40% vs. recorded lectures 1%, p < 0.001). Comparing only MS3 students, mean weekly quiz scores and Q1 achievement were significantly higher (both p < 0.001) in the teleconference cohort with no significant difference in NBME shelf exam performance (p = 0.971). No difference in OSCE performance was observed between groups. CONCLUSION: These results suggest that synchronous teleconferences may be more effective than recorded lectures for achieving institutional learning objectives on the surgery clerkship without any negative impact on NBME shelf exam or clinical evaluation parameters. This information should be used to inform future institutional clerkship design and educational initiatives.