Canagliflozin impedes ischemic hind-limb recovery in the setting of diabetes.

There is a reported increased incidence of lower extremity amputations in individuals with diabetes who are treated with canagliflozin (an SGLT2 receptor inhibitor). It is unclear whether this is an unintended consequence of therapy, or whether canagliflozin can affect peripheral limb perfusion in the setting of underling arterial malperfusion. To evaluate this we explored the effect of canagliflozin on tissue recovery following unilateral hind-limb ischemia (HLI). Adult wildtype (+/+) and diabetic (db/db) mice were maintained on 8 weeks of a regular chow diet, or a chow diet containing canagliflozin (200 mg/kg). Following HLI, hind-limb appearance, function, and Doppler perfusion were serially evaluated. Gastrocnemius muscle fiber size and microvessel density were also evaluated 21 days following HLI. We observed that db/db that received a diet containing canagliflozin had significantly worse hind-limb function and appearance scores compared to both db/db mice that received a regular diet and +/+ mice that received a canagliflozin diet. At post-HLI day 21, db/db mice that received a canagliflozin diet also had decreased Doppler perfusion, gastrocnemius muscle fiber size, and microvessel density compared to +/+ mice that received a canagliflozin diet. These findings indicate that canagliflozin appears to impede ischemic peripheral tissue recovery and warrant further clinical investigation in individuals with diabetes and a history of peripheral artery disease.

Defects in vein valve PROX1/FOXC2 antithrombotic pathway in endothelial cells drive the hypercoagulable state induced by trauma and critical illness.

OBJECTIVES: Deep venous thrombosis (DVT) causes significant morbidity and mortality after trauma. Recently, we have shown that blood flow patterns at vein valves induce oscillatory stress genes, which maintain an anticoagulant endothelial phenotype that inhibits spontaneous clotting at vein valves and sinuses, is lost in the presence of DVT in human pathological samples, and is dependent on expression of the transcription factor FOXC2. We describe an assay, modifying our mouse multiple injury system, which shows evidence of clinically relevant microthrombosis and hypercoagulability applicable to the study of spontaneous DVT in trauma without requiring direct vascular injury or ligation. Finally, we investigated whether these model findings are relevant to a human model of critical illness by examining gene expression changes by quantitative polymerase chain reaction and immunofluorescence in veins collected from critically ill. METHODS: C57/Bl6 mice were subjected to a modified mouse multiple injury model with liver crush injury, crush and pseudofracture of a single lower extremity, and 15% total blood volume hemorrhage. Serum was assayed for d-dimer at 2, 6, 24, and 48 hours after injury by enzyme-linked immunosorbent assay. For the thrombin clotting assay, veins of the leg were exposed, 100 µL of 1 mM rhodamine (6 g) was injected retro-orbitally, and 450 µg/mL thrombin was then applied to the surface of the vein with examination of real-time clot formation via in vivo immunofluorescence microscopy. Images were then examined for percentage area of clot coverage of visible mouse saphenous and common femoral vein. Vein valve specific knockout of FOXC2 was induced with tamoxifen treatment in PROX1 Ert2Cre FOXC2 fl/fl mice as previously described. Animals were then subjected to a modified mouse multiple injury model with liver crush injury, crush and pseudofracture of a single lower extremity, and 15% total blood volume hemorrhage. Twenty-four hours after injury, we examined the valve phenotype in naive versus multiple injury animals, with and without loss of the FOXC2 gene from the vein valve (FOXC2 del ) via the thrombin assay. Images were then examined for proximity of clot formation to the valve present at the junction of the mouse saphenous, tibial, and superficial femoral vein and presence of spontaneous microthrombi present in the veins before exposure to thrombin. Human vein samples were obtained from excess tissue preserved after harvest for elective cardiac surgery and from organ donors after organ procurement. Sections were submitted for paraffin embedding and then assayed by immunofluorescence for PROX1, FOXC2, thrombomodulin, endothelial protein C receptor, and von Willebrand's factor. All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee, and all human studies reviewed and approved by the institutional review board. RESULTS: After mouse multiple injuries, enzyme-linked immunosorbent assay for d-dimer showed evidence of products of fibrin breakdown consistent with formation of clot related to injury, fibrinolysis, and/or microthrombosis. The thrombin clotting assay demonstrated higher percentage area of vein covered with clot when exposed to thrombin in the multiple injury animals compared with uninjured (45% vs. 27% p = 0.0002) consistent with a phenotype of hypercoagulable state after trauma in our model system. Unmanipulated FoxC2 knockout mice manifest increased clotting at the vein valve as compared with unmanipulated wild type animals. After multiple injuries, wild type mice manifest increase clotting at the vein after thrombin exposure ( p = 0.0033), and equivalent to that of valvular knockout of FoxC2 (FoxC2del), recapitulating the phenotype seen in FoxC2 knockout animals. The combination of multiple injuries and FoxC2 knockout resulted in spontaneous microthrombi in 50% of the animals, a phenotype not observed with either multiple injuries or FoxC2 deficiency alone (χ 2 , p = 0.017). Finally, human vein samples demonstrated the protective vein valve phenotype of increased FOXC2 and PROX1 and showed decreased expression in the critically ill organ donor population by immunofluorescence imaging in organ donor samples. CONCLUSION: We have established a novel model of posttrauma hypercoagulation that does not require direct restriction of venous flow or direct injury to the vessel endothelium to assay for hypercoagulability and can generate spontaneous microthrombosis when combined with valve-specific FOXC2 knockout. We find that multiple injuries induce a procoagulant phenotype that recapitulates the valvular hypercoagulability seen in FOXC2 knockout and, in critically ill human specimens, find evidence for loss of oscillatory shear stress-induced gene expression of FOXC2 and PROX1 in the valvular endothelium consistent with potential loss of DVT-protective valvular phenotype.

Microvascular Angiopathic Consequences of COVID-19.

The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world. The disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which first appeared in Wuhan, China in December, 2019. Ever increasing data is continuing to emerge about the impact of COVID-19 on cardiovascular tissue and other organ system. Clinical features associated with COVID-19 suggest that endothelial cell dysfunction and microvascular thrombosis are to a large extent contributing to resultant multi-organ complications. This review is aimed at highlighting the critical aspects associated with COVID-19 and its presumed microvascular angiopathic consequences on the cardiovascular system leading to multi-organ dysfunction.

Bringing surgeons together across the world: diagnosis and management of acute appendicitis.

INTRODUCTION: Despite appendicitis being one of the most common surgical emergencies in the pediatric population, there is still a great deal of debate among pediatric surgeons regarding the workup and treatment. MATERIALS AND METHODS: In an interactive Web symposium consisting of 130 pediatric surgeons from various regions of the world, questions about diagnosis and management of appendicitis were displayed on the screen. The audience was asked to respond to the poll questions. The questions asked to the participants pertained to an example case of a 12-year-old boy presenting to the emergency department with the classic history and exam for appendicitis. RESULTS: The total number of respondents varied between 30 and 37, giving response rates of 23%-28%. Sixty-six percent of respondents would not order imaging. Thirty-one percent said that they would order ultrasound. No participant would order a computed tomography scan, whereas 5% would order some other form. Ninety-five percent of respondents said that they would treat the patient operatively. The majority (89%) of the participants felt comfortable waiting until morning to operate on the patient if the patient arrived at 11 p.m. Fifty-seven percent stated that they would use a three-port laparoscopic approach, and 38% would use a single port, whereas 5% would use an open surgical approach. The majority (34%) reported being able to visualize the appendix as the greatest benefit to using laparoscopy. Fifty-seven percent would give the patient one additional dose of antibiotics and then discharge him 24 hours later following treatment for acute, nonperforated appendicitis. Twenty percent of respondents would give no further antibiotics and would discharge the patient from the recovery room or soon after. Sixteen percent would not give any additional antibiotics and would discharge him 24 hours postoperatively, whereas 6% would give one additional dose of antibiotics and discharge him soon after. CONCLUSIONS: The use of virtual broadcasts affords a unique opportunity to surgeons around the world to share and learn from each other.

Minimally invasive surgery for pediatric trauma-a multicenter review.

INTRODUCTION: The published experience with minimally invasive techniques to treat injured children is currently small. In this multicenter case series, we aimed to characterize the contemporary role of minimally invasive surgery (MIS) in pediatric trauma. MATERIALS AND METHODS: After obtaining Institutional Review Board approval at six pediatric regional trauma centers in the United States, a retrospective review was conducted on children who have undergone thoracoscopy or laparoscopy for the management of trauma over the past 13 years. RESULTS: There were 200 patients with a mean age of 9.6 ± 4.2 years, and 73% were male. Laparoscopy was performed for 187 (94%) and thoracoscopy for 8 (4%), whereas 5 (2%) patients had both, for a total of 205 MIS procedures. Conversion to open surgery occurred in 36% (n=73). Median operative time was 77 (range, 16-369) minutes. Of the 132 procedures completed without conversion, 81 (61%) were diagnostic, whereas the remaining were therapeutic, including the repair of bowel injuries (n=20), distal pancreatectomy (n=5), splenectomy (n=2), repair of traumatic abdominal wall hernias (n=2), evacuation of hemothorax (n=3), and other thoracoscopic or laparoscopic interventions (n=19). Procedures that required conversion were most commonly for bowel injury (n=56). Patients with peritonitis were most likely to require conversion to an open procedure (77.4%). Mean time to a regular diet was 4.2 ± 8.6 days, and mean hospital stay was 6.3 ± 6.5 days. Postoperative complications occurred in 19 patients, long-term sequelae in 10 patients, and permanent disability in 2 patients. There were no deaths or missed injuries. CONCLUSIONS: In the stable pediatric trauma patient, laparoscopy and thoracoscopy can be performed safely and effectively for both diagnostic and therapeutic purposes.

What is "telemedicine" and what does it mean for a pediatric surgeon?

Telemedicine is a broad term and has recently become a household term in the medical field. However, there are many interpretations as to what the term "telemedicine" means. There are many facets to telemedicine and here we describe all of the elements of telemedicine, a glossary of terms, and how they relate to pediatric surgery.

Transcontinental telementoring with pediatric surgeons: proof of concept and technical considerations.

PURPOSE: To evaluate different technologies that can facilitate telementoring in a variety of pediatric surgical procedures. MATERIALS AND METHODS: Two different telementoring technologies were used to provide two-way audio and visual communication between experienced pediatric surgeon mentors located in another city and less experienced trainees performing a surgical procedure. The first technology consisted of store-bought equipment that connected the operating room laparoscope to a Skype™ (Microsoft, Redmond, WA) connection (used in 1 case), whereas the second was a proprietary telementoring robot, Karl Storz Endoscopy-America, Inc. VisitOR1(®) (Karl Storz GmbH & Co. KG, Tuttlingen, Germany) (used in 5 cases). The procedures included a video-assisted thoracic surgery lower lobectomy, a temporary and two permanent gastric stimulator placements, and two laparoscopic inguinal hernia repairs and were performed by pediatric surgeons (3 cases), a pediatric gastroenterologist (1 case), and a general surgeon (2 cases) under the guidance of pediatric surgeon mentors. RESULTS: All procedures were completed successfully in a time-efficient manner, without loss of transmission and without complications. Although the Skype technology was less costly, it lacked telestrator capacity and was not adequately secure. The VisitOR1 telementoring robot enabled high-resolution video communication, had telestrator capacity, and allowed pointing during the procedure. The mentors assisted with trocar placement, modifying the surgical technique, identifying planes of dissection, and indicating locations of device and suture placement. CONCLUSIONS: Telementoring is a useful adjunct in the field of pediatric surgery that can aid in the transfer of surgical skills remotely and shorten the time to implementation of new surgical techniques into practice. Optimal telementoring technology should have a secure wireless connection, high video resolution, and minimal bandwidth latency.