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.

Outcomes Among Malnourished Patients With Crohn's Disease Undergoing Elective Ileocecectomy: A Nationwide Analysis.

BACKGROUND: Crohn's patients' nutritional status can be suboptimal given disease pathophysiology; the effect of a malnourished state prior to elective surgery on post-operative outcomes remains to be more clearly elucidated. This study aims to characterize the effect of malnutrition on post-operative outcomes and readmission patterns for Crohn's patients undergoing elective ileocecectomy using a nationally representative cohort. METHODS: The colectomy-targeted National Surgical Quality Improvement Program Database (2016-2020) was used to identify patients with Crohn's disease without systemic complications who underwent elective ileocecectomy; emergency surgeries were excluded. Malnourished status was defined as pre-operative hypoalbuminemia <3.5 g/dL, weight loss >10% in 6 months, or body mass index <18.5 kg/m2 prior to surgery. RESULTS: Of 1464 patients (56% female) who met inclusion criteria, 1137 (78%) were well-nourished and 327 (22%) were malnourished. Post-operatively, malnourished patients had more organ space surgical site infections (SSI) (9% vs 4% nourished groups, P < .001) and more bleeding events requiring transfusion (9% vs 3% nourished, P < .001). 30-day unplanned readmission was higher in the malnourished group (14% vs 9% nourished, P = .032). Index admission length of stay was significantly longer in the malnourished group (4 days [3-7 days] vs the nourished cohort: 4 days [3-5 days], P < .001). DISCUSSION: Poor nutritional status is associated with organ space infections and bleeding as well as longer hospitalizations and more readmissions in Crohn's patients undergoing elective ileocecectomy. A detailed nutritional risk profile and nutritional optimization is important prior to elective surgery.

Race-based outcomes of thoracic aortic aneurysms and dissections in the Global Registry for Endovascular Aortic Treatment.

OBJECTIVE: This study characterizes racial differences in presentation, as well as short- and long-term outcomes after endovascular treatment of thoracic aortic aneurysm (TAA) and type B aortic dissection (TBAD). METHODS: We queried the Gore Global Registry for Endovascular Aortic Treatment for thoracic endovascular aortic repairs (TEVARs) performed between 2010 and 2016 and followed through 2022. Pathologies represented were descending TAA, complicated TBAD, and uncomplicated TBAD. Using standard statistical tests, we compared overall and pathology-specific demographics, procedural factors, and outcomes among Black and White patients undergoing TEVAR. RESULTS: We identified 438 TEVAR cases, including 236 descending TAA, 121 complicated TBAD, and 74 uncomplicated TBAD. Overall, Black patients were younger and had a higher incidence of renal insufficiency (P = .001), whereas White patients had more chronic obstructive pulmonary disease (P = .003) and cardiac arrhythmias (P = .037). In patients treated for descending TAA, Black patients had increased device- and procedure-related complications (34.3% vs 17.4%; P = .014), conversion to open repair (2.9% vs 0%; P = .011) and type II endoleak (5.7% vs 1.0%; P = .040), but no differences in mortality, length of hospital stay, or major adverse cardiovascular events. Whereas outcomes of TEVAR for uncomplicated TBAD were comparable, Black patients more frequently presented with complicated TBAD than White patients (Black, 40.5% vs White, 24.8%; P = .008) and had subsequently greater reintervention rates (28.1% vs 12.4%; P = .012), all-cause mortality (hazard ratio, 4.28; 95% confidence interval, 1.74-10.5; P = .002) and aortic-related mortality (hazard ratio, 16.7; 95% confidence interval, 1.49-186; P = .022). CONCLUSIONS: Despite increased device- and procedure-related complications, similar short- and long-term outcomes are achieved in Black and White patients undergoing TEVAR for descending TAA and uncomplicated TBAD. However, Black patients are more likely to present with, require reintervention for, and suffer mortality from complicated TBAD.

Nationwide Outcomes After Thoracoscopic Versus Open Resection of Congenital Pulmonary Airway Malformations in Newborns.

Purpose: Elective resection of congenital pulmonary airway malformations (CPAM) has been debated for decades and varies significantly between individual surgeons. However, few studies have compared outcomes and costs associated with thoracoscopic and open thoracotomy approaches on a national level. This study sought to compare nationwide outcomes and resource utilization in infants undergoing elective lung resection for CPAM. Materials and Methods: The Nationwide Readmission Database was queried from 2010 to 2014 for newborns who underwent elective surgical resection of CPAM. Patients were stratified by operative approach (thoracoscopic versus open). Demographics, hospital characteristics, and outcomes were analyzed using standard statistical tests. Results: A total of 1716 newborns with CPAM were identified. Elective readmission for pulmonary resection was performed in 12% (n = 198), with 63% of resections completed at a different hospital than the newborn stay. Most resections were thoracoscopic (75%), compared to only 25% via thoracotomy. Infants treated with thoracoscopic resection were more often male (78% versus 62% open, P = .040) and were older at the time of resection. Patients who had an open thoracotomy experienced a higher rate of serious complications (40% versus 10% thoracoscopic, P < .001), including postoperative hemorrhage, tension pneumothorax, and pulmonary collapse. Readmission costs were higher for infants treated via thoracotomy (P < .001). Conclusion: Thoracoscopic lung resection for CPAM is associated with lower cost and fewer postoperative complications than thoracotomy. Most resections are performed at different hospitals than the place of birth, which may affect long-term outcomes from single institutional studies. These findings may be used to address costs and improve future evaluations of elective CPAM resections.

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.

E-Selectin/AAV Gene Therapy Promotes Myogenesis and Skeletal Muscle Recovery in a Mouse Hindlimb Ischemia Model.

The response to ischemia in peripheral artery disease (PAD) depends on compensatory neovascularization and coordination of tissue regeneration. Identifying novel mechanisms regulating these processes is critical to the development of nonsurgical treatments for PAD. E-selectin is an adhesion molecule that mediates cell recruitment during neovascularization. Therapeutic priming of ischemic limb tissues with intramuscular E-selectin gene therapy promotes angiogenesis and reduces tissue loss in a murine hindlimb gangrene model. In this study, we evaluated the effects of E-selectin gene therapy on skeletal muscle recovery, specifically focusing on exercise performance and myofiber regeneration. C57BL/6J mice were treated with intramuscular E-selectin/adeno-associated virus serotype 2/2 gene therapy (E-sel/AAV) or LacZ/AAV2/2 (LacZ/AAV) as control and then subjected to femoral artery coagulation. Recovery of hindlimb perfusion was assessed by laser Doppler perfusion imaging and muscle function by treadmill exhaustion and grip strength testing. After three postoperative weeks, hindlimb muscle was harvested for immunofluorescence analysis. At all postoperative time points, mice treated with E-sel/AAV had improved hindlimb perfusion and exercise capacity. E-sel/AAV gene therapy also increased the coexpression of MyoD and Ki-67 in skeletal muscle progenitors and the proportion of Myh7+ myofibers. Altogether, our findings demonstrate that in addition to improving reperfusion, intramuscular E-sel/AAV gene therapy enhances the regeneration of ischemic skeletal muscle with a corresponding benefit on exercise performance. These results suggest a potential role for E-sel/AAV gene therapy as a nonsurgical adjunct in patients with life-limiting PAD.

Effect of Body Mass Index on Early Outcomes of Endovascular Abdominal Aortic Aneurysm Repair.

BACKGROUND: This study compares the presentation, management, and outcomes of patients undergoing endovascular abdominal aortic aneurysm repair (EVAR), based on their weight status as defined by their body mass index (BMI). METHODS: Patients with primary EVAR for ruptured and intact abdominal aortic aneurysm (AAA) were identified in the National Surgical Quality Improvement Program database (2016-2019). Patients were categorized by weight status (underweight: BMI < 18.5 kg/m2, normal weight: 18.5-24.9 kg/m2, overweight: 25-29.9 kg/m2, Obese I: 30-34.9 kg/m2, Obese II: 35-39.9 kg/m2, Obese III: > 40 kg/m2). Preoperative characteristics and 30-day outcomes were compared. RESULTS: Of 3,941 patients, 4.8% were underweight, 24.1% normal weight, 37.6% overweight, and 22.5% with Obese I, 7.8% Obese II, and 3.3% Obese III status. Underweight patients presented with larger (6.0 [5.4-7.2] cm) and more frequently ruptured (25.0%) aneurysms than normal weight patients (5.5 [5.1-6.2] cm and 4.3%, P < 0.001 for both). Pooled 30-day mortality was worse for underweight (8.5%) compared to all other weight status (1.1-3.0%, P < 0.001), but risk-adjusted analysis demonstrated that aneurysm rupture (odds ratio [OR] 15.9, 95% confidence interval [CI] 8.98-28.0) and not underweight status (OR 1.75, 95% CI 0.73-4.18) accounted for increased mortality in this population. Obese III status was associated with prolonged operative time and respiratory complications after ruptured AAA, but not 30-day mortality (OR 0.82, 95% CI 0.25-2.62). CONCLUSIONS: Patients at either extreme of the BMI range had the worst outcomes after EVAR. Underweight patients represented only 4.8% of all EVARs, but 21% of mortalities, largely attributed to higher incidence of ruptured AAA at presentation. Severe obesity, on the other hand, was associated with prolonged operative time and respiratory complications after EVAR for ruptured AAA. BMI, as an independent factor, was however not predictive of mortality for EVAR.

Comparison of upper gastrointestinal series and symptom questionnaires with intraoperative diagnosis of hiatal hernia during sleeve gastrectomy.

BACKGROUND: Hiatal hernias are common in bariatric surgery patients, but the utility of preoperative hiatal hernia diagnosis prior to sleeve gastrectomy (SG) is debated. OBJECTIVE: This study compared preoperative and intraoperative hiatal hernia detection rates in patients undergoing laparoscopic SG. SETTING: University hospital, United States. METHODS: As part of a randomized trial evaluating the role of routine crural inspection during SG, an initial cohort was prospectively studied to assess the correlation between preoperative upper gastrointestinal (UGI) series, reflux and dysphagia symptoms, and intraoperative hiatal hernia diagnosis. Preoperatively, patients completed the Gastroesophageal Reflux Disease Questionnaire (GerdQ), the Brief Esophageal Dysphagia Questionnaire (BEDQ), and a UGI series. Intraoperatively, patients with an anteriorly visible defect underwent hiatal hernia repair followed by SG. All others were randomized to standalone SG or posterior crural inspection with repair of any hiatal hernia identified prior to SG. RESULTS: Between November 2019 and June 2020, 100 patients (72 female patients) were enrolled. Preoperative UGI series identified hiatal hernia in 28% (26 of 93) of patients. Intraoperatively, hiatal hernia was diagnosed during initial inspection in 35 patients. Diagnosis was associated with older age, lower body mass index, and Black race but did not correlate with GerdQ or BEDQ. Using the standard conservative approach, compared with intraoperative diagnosis, sensitivity and specificity of the UGI series were 35.3% and 80.7%, respectively. Hiatal hernia was identified in an additional 34% (10 of 29) of patients randomized to posterior crural inspection. CONCLUSION: Hiatal hernias are highly prevalent in SG patients. However, GerdQ, BEDQ, and a UGI series unreliably identify hiatal hernia in the preoperative setting and should not influence intraoperative evaluation of the hiatus during SG.

Nationwide management of perforated pediatric appendicitis: Interval versus same-admission appendectomy.

PURPOSE: Although conservative management followed by readmission for interval appendectomy is commonly used to manage perforated appendicitis, many studies are limited to individual or noncompeting pediatric hospitals. This study sought to compare national outcomes following interval or same-admission appendectomy in children with perforated appendicitis. METHODS: The Nationwide Readmission Database was queried (2010-2014) for patients <18 years old with perforated appendicitis who underwent appendectomy using ICD9-CM Diagnosis codes. A propensity score-matched analysis (PSMA) utilizing 33 covariates between those with (Interval Appendectomy) and without a prior admission (Same-Admission Appendectomy) was performed to examine postoperative outcomes. RESULTS: There were 63,627 pediatric patients with perforated appendicitis. 1014 (1%) had a prior admission for perforated appendicitis within one calendar year undergoing interval appendectomy compared to 62,613 (99%) Same-Admission appendectomy patients. The Interval Appendectomy group was more likely to receive a laparoscopic (87% vs. 78% same-admission) than open (13% vs. 22% same-admission; p < 0.001) operation. Patients receiving interval appendectomy were more likely to have their laparoscopic procedure converted to open (5% vs. 3%) and receive more concomitant procedures. PSMA demonstrated a higher rate of small bowel obstruction in those receiving Same-Admission appendectomy while all other complications were similar. Although those receiving Interval Appendectomy had a shorter index length of stay (LOS) and lower admission costs, they incurred an additional $8044 [$5341-$13,190] from their prior admission. CONCLUSION: Patients treated with interval appendectomy experienced more concomitant procedures and incurred higher combined hospitalization costs while still having a similar postoperative complication profile compared to those receiving same-admission appendectomy for perforated appendicitis. LEVEL OF EVIDENCE: III. TYPE OF STUDY: Retrospective Comparative Study.

Outcomes of laparoscopic versus open resection of pediatric choledochal cyst.

BACKGROUND: Untreated pediatric choledochal cyst (CC) is associated with complications including cholangitis, pancreatitis, and risk of malignancy. Therefore, CC is typically treated by surgical excision with biliary reconstruction. Both open and laparoscopic (lap) surgical approaches are regularly used, but outcomes have not been compared on a national level. METHODS: The Nationwide Readmissions Database was used to identify pediatric patients (age 0-21 years, excluding newborns) with choledochal cyst from 2016 to 2018 based on ICD-10 codes. Patients were stratified by operative approach (open vs. lap). Demographics, operative management, and complications were compared using standard statistical tests. Results were weighted for national estimates. RESULTS: Choledochal cyst excision was performed in 577 children (75% female) via lap (28%) and open (72%) surgical approaches. Patients undergoing an open resection experienced longer index hospital length of stay (LOS), higher total cost, and more complications. Anastomotic technique differed by approach, with Roux-en-Y hepaticojejunostomy (RYHJ) more often utilized with open cases (86% vs. 29%) and hepaticoduodenostomy (HD) more common with laparoscopic procedures (71% vs. 15%), both p < 0.001. There was no significant difference in post-operative cholangitis or mortality. CONCLUSIONS: Although utilized less frequently than an open approach, laparoscopic choledochal cyst resection is safe in pediatric patients and is associated with shorter LOS, lower costs, and fewer complications. HD anastomosis is more commonly performed during laparoscopic procedures, whereas RYHJ more commonly used with the open approach. While HD is associated with more short-term gastrointestinal dysfunction than RYHJ, the latter is more commonly associated with sepsis, wound infection, and respiratory dysfunction. LEVEL OF EVIDENCE: Level III: Retrospective Comparative Study.

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.

Racial disparities in presentation and outcomes for endovascular abdominal aortic aneurysm repair.

OBJECTIVE: In the present study, we used a national database to identify racial differences in the presentation and outcomes for patients undergoing endovascular abdominal aortic aneurysm (AAA) repair (EVAR) and identified areas for improving their care. METHODS: We queried the EVAR-targeted National Surgical Quality Improvement Program database (2016-2019) to identify patients who had undergone EVAR for both ruptured and nonruptured AAAs. The patients were categorized according to race (White, Black, and Asian). Patients with a history of abdominal aortic surgery or an indication other than AAAs were excluded. The data was analyzed using the χ2 and Kruskal-Wallis tests, presented as frequencies and percentages or median and interquartile range (IQR) for categorical and continuous variables, respectively. RESULTS: We identified 3629 patients (16.6% female), including 3312 White (91.3%), 248 Black (6.8%), and 69 Asian (1.9%) patients. Black patients were more frequently women (27.0%) compared with White patients (15.9%) and were younger (median age, 71 years; IQR, 64-77 years) than White (median age, 73 years; IQR, 67-79 years) and Asian (median age, 76 years; IQR, 67-81 years) patients (P < .001 for both). The incidence of smoking, congestive heart failure, and dialysis dependency was highest for Black patients, and the incidence of obesity was lowest for Asian patients. The AAAs in Black patients extended more frequently beyond the aortic bifurcation (P = .047). In Asian patients, the internal iliac arteries were more involved (P = .040). For Black patients, 29.8% of the EVARs were performed in a nonelective setting compared with 20.2% for the White and 15.9% for the Asian patients (P < .001). The aneurysm diameter, nonruptured symptomatic rate, and rupture rate were similar across the groups (P = .807). The operative time was prolonged for Black (median, 128 minutes; IQR, 96-177 minutes) compared with White (median, 114 minutes; IQR, 84-162 minutes) patients (P < .001). Postoperatively, Black patients were more likely to require blood transfusion (16.5%) and had prolonged length of hospital stay (median, 2 days; IQR, 1-4 days) compared with White (10.0%; median, 1 day; IQR, 1-3 days) and Asian (4.3%; median, 1 day; IQR, 1-3 days) patients (P = .001 and P < .001, respectively). Black patients also had a higher 30-day readmission rate (P = .038). On multivariate analysis, Black race was an independent factor for length of stay >1 day after both elective and nonelective EVAR and 30-day readmission for elective EVAR, but not 30-day mortality after elective and nonelective EVAR. CONCLUSIONS: In the present nationwide sample of EVAR cases, Black patients were more often women and younger. Despite similar rates of symptomatic and ruptured AAAs at presentation and 30-day mortality, Black patients more often presented and were treated during the same nonelective admission; they also had associated increased length of hospital stay and readmission. These findings signal a missed opportunity to diagnose, optimize, and treat this particular group of patients in an elective setting.

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.

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.

E-Selectin/AAV2/2 Gene Therapy Alters Angiogenesis and Inflammatory Gene Profiles in Mouse Gangrene Model.

For patients with chronic limb-threatening ischemia and limited revascularization options, alternate means for therapeutic angiogenesis and limb salvage are needed. E-selectin is a cell adhesion molecule that is critical for inflammation and neovascularization in areas of wound healing and ischemia. Here, we tested the efficacy of modifying ischemic limb tissue by intramuscular administration of E-selectin/AAV2/2 (adeno-associated virus serotype 2/2) to modulate angiogenic and inflammatory responses in a murine hindlimb gangrene model. Limb appearance, reperfusion, and functional recovery were assessed for 3 weeks after induction of ischemia. Mice receiving E-selectin/AAV2/2 gene therapy had reduced gangrene severity, increased limb and footpad perfusion, enhanced recruitment of endothelial progenitor cells, and improved performance on treadmill testing compared to control group. Histologically, E-selectin/AAV2/2 gene therapy was associated with increased vascularity and preserved myofiber integrity. E-selectin/AAV2/2 gene therapy also upregulated a panel of pro-angiogenic genes yet downregulated another group of genes associated with the inflammatory response. This novel gene therapy did not induce adverse effects on coagulability, or hematologic, hepatic, and renal function. Our findings highlight the potential of E-selectin/AAV2/2 gene therapy for improving limb perfusion and function in patients with chronic limb-threatening ischemia.

Outcomes and role of shunting during carotid endarterectomy for symptomatic patients.

OBJECTIVE: Shunt placement during carotid endarterectomy (CEA) has often been advocated to protect the ischemic penumbra in patients with symptomatic carotid stenosis. In the present study, we assessed the effect of shunt placement during CEA on postoperative stroke risk in symptomatic patients. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database (2016-2019) for CEA cases with complete CEA procedure-targeted data available. Symptomatic patients were identified as those with a preoperative diagnosis of stroke on presentation (DS), transient ischemic attack, amaurosis fugax, or temporary monocular blindness. The DS patients were further analyzed according to the severity of their stroke using the modified Rankin scale scores. To better assess the effect of shunt placement on the stroke rate, we compared cases of CEA with the patch angioplasty technique stratified by the use of an intraoperative shunt. Patients who had undergone carotid eversion or primary closure were excluded. The baseline demographics and perioperative outcomes were compared using the χ2 and Mann-Whitney U tests. Multivariate analysis was performed to identify the independent risk factors for postoperative stroke and cranial nerve injury. RESULTS: We identified 4652 cases of CEA with patch angioplasty in symptomatic patients, including 1889 with (40.6%) and 2763 without (59.4%) shunt placement. The distribution of age, race, and sex was similar for both procedures. Compared with patients without a shunt, those with a shunt had significantly higher rates of emergency surgery (9.1% vs 7.0%; P = .010), nonelective surgery (40.3% vs 37.2%; P = .035), general anesthesia (97.0% vs 86.3%; P < .001), and bleeding disorders (27.2% vs 22.7%; P < .001). The 30-day incidence of postoperative stroke was similar between the patients with (3.2%) and without (2.6%) shunt placement (P = .219). Additionally, a subgroup analysis failed to show any benefit from shunt placement on the incidence of postoperative stroke, regardless of the preoperative symptoms or neurologic disability. In contrast, shunt placement was associated with an increased rate of cranial nerve injury (4.1% vs 2.4%; P = .001). Multivariate analysis revealed that nonelective surgery (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.36-2.91; P < .001) and DS (vs transient ischemic attack, amaurosis fugax, or temporary monocular blindness; OR, 1.64; 95% CI, 1.12-2.41; P = .012) were predictive of 30-day postoperative stroke. After adjusting for confounders, shunt placement had no effect on stroke risk at 30 days but remained an independent risk factor for cranial nerve injury (adjusted OR, 1.87; 95% CI, 1.32-2.64; P < .001). CONCLUSIONS: For symptomatic patients undergoing CEA with patch angioplasty, shunt placement was associated with an increased risk of cranial nerve injury without a reduction in postoperative stroke risk.

High-Resolution Three-Dimensional Imaging of the Footpad Vasculature in a Murine Hindlimb Gangrene Model.

Peripheral arterial disease (PAD) is a significant cause of morbidity resulting from chronic exposure to atherosclerotic risk factors. Patients suffering from its most severe form, chronic limb-threatening ischemia (CLTI), face substantial impairments to daily living, including chronic pain, limited walking distance without pain, and nonhealing wounds. Preclinical models have been developed in various animals to study PAD, but mouse hindlimb ischemia remains the most widely used. There can be significant variation in response to ischemic insult in these models depending on the mouse strain used and the site, number, and means of arterial disruption. This protocol describes a unique method combining femoral artery and vein electrocoagulation with the administration of a nitric oxide synthase (NOS) inhibitor to reliably induce footpad gangrene in Friend Virus B (FVB) mice that resembles the tissue loss of CLTI. While traditional means of assessing reperfusion such as laser Doppler perfusion imaging (LDPI) are still recommended, intracardiac perfusion of the lipophilic dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) is used to label the vasculature. Subsequent whole-mount confocal laser scanning microscopy allows for high-resolution, three-dimensional (3D) reconstruction of footpad vascular networks that complements traditional means of assessing reperfusion in hindlimb ischemia models.

Therapeutic angiogenesis in Buerger's disease: reviewing the treatment landscape.

Thromboangiitis obliterans, also known as Buerger's disease, is a rare inflammatory vasculitis that predominantly develops in smokers and characteristically affects the small- and medium-sized peripheral arteries and veins. Patients typically present with extremity claudication, but symptoms may progress to rest pain and tissue loss, especially in those unable to abstain from tobacco use. Unfortunately, traditional medical treatments are largely ineffective and due to the small caliber of affected vessels and lack of suitable distal targets or venous conduits, endovascular and open surgical approaches are often not possible. Eventually, a significant number of patients require major amputation. For these reasons, much research effort has been made in developing techniques of therapeutic angiogenesis to improve limb perfusion, both for atherosclerotic peripheral arterial disease and the smaller subset of patients with critical limb ischemia due to Buerger's disease. Neovascularization in response to ischemia relies on a complex interplay between the local tissue microenvironment and circulating stem and progenitor cells. To date, studies of therapeutic angiogenesis have therefore focused on exploiting known angiogenic factors and stem cells to induce neovascularization in ischemic tissues. This review summarizes the available clinical data regarding the safety and efficacy of various angiogenic therapies, notably injection of naked DNA plasmids, viral gene constructs, and cell-based preparations, and describes techniques for potentiating in vivo efficacy of gene- and cell-based therapies as well as ongoing developments in exosome-based cell-free approaches for therapeutic angiogenesis. Plain Language Title and Summary: A review of available and emerging treatments for improving blood flow and wound healing in patients with Buerger's disease, a rare disorder of blood vessels Buerger's disease is a rare disorder of the small- and medium-sized blood vessels in the arms and legs that almost exclusively develops in young smokers. Buerger's disease causes inflammation in arteries and veins, which leads to blockage of these vessels and reduces blood flow to and from the extremities. Decreased blood flow to the arms and legs can lead to development of nonhealing wounds and infection for which some patients may eventually require amputation. Unfortunately, traditional medical and surgical treatments are not effective in Buerger's disease, so other methods for improving blood flow are needed for these patients. There are several different ways to stimulate new blood vessel formation, both in humans and animal models. The most common treatments involve injection of DNA or viruses that express genes related to blood vessel formation or, alternatively, stem cell-based treatments that help regenerate blood vessels and repair wound tissue. This review explores how safe and effective these various treatments are and describes recent research developments that may lead to better therapies for patients with Buerger's disease and other vascular disorders.

Nationwide Outcomes and Readmission After Pediatric Laparoscopic and Open Fundoplication.

Purpose: Fundoplications are a common operation in the pediatric population. This study aims to explore outcomes comparing laparoscopic versus open operative techniques. Methods: From 2010 to 2014 the Nationwide Readmissions Database was used to identify patients aged 0-18 years who underwent a fundoplication. Propensity score matched analysis was performed based on 87 covariates. Demographics, hospital factors, readmissions, and complications were compared by surgical technique (laparoscopic versus open). Results: There were 4411 patients (47% female) who underwent fundoplication via laparoscopic (69%) versus open (31%) technique. Gastrostomy tubes were placed in 75% of patients also undergoing fundoplication. Newborn made up 64% of the cohort, with 47% of newborns having cardiac anomalies and 96% being premature. Open fundoplications were more likely to be performed in newborns (72% versus 61%) and those in the lowest income quartile compared to laparoscopic (41% versus 31% P < .001), both P < .001. The readmission rate was 20% within 30 days and 38% within the year, with 15% admitted to a different hospital. Only 14% of readmissions were elective. Open fundoplication was associated with more unplanned readmissions (94% versus 84%), conversion to gastrojejunostomy tube (11% versus 5%) along with major (5% versus 3%) and minor (8% versus 2%) complications compared to the laparoscopic approach, all P < 0.001. Conclusion: The majority of fundoplications are being performed in newborns and are being done laparoscopically, which are associated with lower complication and postoperative readmission rates compared to open fundoplications.