Staphylococcus aureus alpha toxin activates Notch in vascular cells.

Staphylococcus aureus infection is one of the leading causes of morbidity in hospitalized patients in the United States, an effect compounded by increasing antibiotic resistance. The secreted agent hemolysin alpha toxin (Hla) requires the receptor A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10) to mediate its toxic effects. We hypothesized that these effects are in part regulated by Notch signaling, for which ADAM10 activation is essential. Notch proteins function in developmental and pathological angiogenesis via the modulation of key pathways in endothelial and perivascular cells. Thus, we hypothesized that Hla would activate Notch in vascular cells. Human umbilical vein endothelial cells were treated with recombinant Hla (rHla), Hla-H35L (genetically inactivated Hla), or Hank's solution (HBSS), and probed by different methods. Luciferase assays showed that Hla (0.01 µg/mL) increased Notch activation by 1.75 ± 0.5-fold as compared to HBSS controls (p < 0.05), whereas Hla-H35L had no effect. Immunocytochemistry and Western blotting confirmed these findings and revealed that ADAM10 and γ-secretase are required for Notch activation after inhibitor and siRNA assays. Retinal EC in mice engineered to express yellow fluorescent protein (YFP) upon Notch activation demonstrated significantly greater YFP intensity after Hla injection than controls. Aortic rings from Notch reporter mice embedded in matrix and incubated with rHla or Hla-H35L demonstrate increased Notch activation occurs at tip cells during sprouting. These mice also had higher skin YFP intensity and area of expression after subcutaneous inoculation of S. aureus expressing Hla than a strain lacking Hla in both EC and pericytes assessed by microscopy. Human liver displayed strikingly higher Notch expression in EC and pericytes during S. aureus infection by immunohistochemistry than tissues from uninfected patients. In sum, our results demonstrate that the S. aureus toxin Hla can potently activate Notch in vascular cells, an effect which may contribute to the pathobiology of infection with this microorganism.

Pediatric lymphatic malformations: evolving understanding and therapeutic options.

Multimodal treatment of lymphatic malformations continues to expand as new information about the biology and genetics of these lesions is discovered, along with knowledge gained from clinical practice. A patient-centered approach, ideally provided by a multidisciplinary medical and surgical team, should guide timing and modality of treatment. Current treatment options include observation, surgery, sclerotherapy, radiofrequency ablation, and laser therapy. New medical and surgical therapies are emerging, and include sildenafil, propranolol, sirolimus, and vascularized lymph node transfer. The primary focus of management is to support and optimize these patients' quality of life. Researchers continue to study lymphatic malformations with the goal of increasing therapeutic options and developing effective clinical pathways for these complicated lesions.

Management of lymphatic malformations in children.

PURPOSE OF REVIEW: To review the literature on lymphatic malformations and to provide current opinion about the management of these lesions. RECENT FINDINGS: Current treatment options include nonoperative management, surgery, sclerotherapy, radiofrequency ablation, and laser therapy. New therapies are emerging, including sildenafil, propranolol, sirolimus, and vascularized lymph node transfer. The primary focus of management centers on the patient's quality of life. SUMMARY: Multimodal treatment of lymphatic malformations continues to expand as new information about the biology and genetics of these lesions is discovered, in addition to knowledge gained from clinical practice. A patient-centered approach should guide timing and modality of treatment. Continued study of lymphatic malformations will increase and solidify a treatment algorithm for these complicated lesions.

Acute kidney injury post-abdominal surgery in infants: implications for prevention and management.

Acute kidney injury (AKI) is common in critically ill infants and is associated with long-term sequelae including hypertension and chronic kidney disease. The etiology of AKI in infants is multifactorial. There is robust literature highlighting the risk of AKI after cardiothoracic surgery in infants. However, risk factors and outcomes for AKI in infants after abdominal surgery remains limited. This article reviews the epidemiology and association of abdominal surgery with postoperative AKI and suggests methods for AKI management and prevention. Postoperative AKI may result from hemodynamic shifts, hypoxia, exposure to nephrotoxic medications, and inflammation. Infants in the intensive care unit after intraabdominal surgeries have a unique set of risk factors that predispose them to AKI development. Prematurity, sepsis, prolonged operation time, emergent nature of the procedure, and diagnosis of necrotizing enterocolitis increase risk of AKI after intrabdominal surgeries. Prevention, early diagnosis, and management of AKI post-abdominal surgery is imperative to clinical practice. Close monitoring of urine output, serum creatinine, and fluid status is necessary in infants after abdominal surgery. A recent study suggests elevated levels of a urinary biomarker, neutrophil gelatinase-associated lipocalin (NGAL), 24 h after an abdominal procedure may improve early prediction of AKI. Identification of risk factors, avoidance of nephrotoxic medications, careful fluid balance, early detection of AKI, and maintenance of hemodynamic stability is imperative to potentially prevent and/or mitigate AKI.

Limiting hospital resources for acute appendicitis in children: Lessons learned from the U.S. epicenter of the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic resulted in the suspension of nonemergent surgeries throughout New York. Our tertiary care children's hospital pivoted towards a brief trial of intravenous (IV) antibiotic therapy in all patients in order to limit operating room (OR) utilization and avoid prolonged hospital stays. We describe our pandemic-based strategy for non-operative management (NOM) of appendicitis but with a limited duration of IV antibiotics. METHODS: We performed a retrospective study of children treated for acute appendicitis at our center from 3/31/2020 to 5/3/2020 during the peak of the New York pandemic. We compared appendicitis volume to similar months in prior years. We evaluated failure of NOM, length of stay, and compared characteristics of children we successfully treated with our expanded NOM protocol to previously published inclusion criteria for NOM. RESULTS: 45.5% of children (25/55) with acute appendicitis underwent NOM. Of the 30 who underwent surgery, 13 had complicated appendicitis while 17 had simple appendicitis. Three patients were COVID-positive, although none had respiratory symptoms. The majority of patients presenting with acute appendicitis (78.2%) did not meet previously published criteria for NOM. CONCLUSIONS: We treated a similar volume of children with acute appendicitis during the pandemic compared to prior years. We applied non-operative management to nearly half our patients, even as we expanded inclusion criteria for NOM to reduce OR utilization, but limited the duration of the antibiotic trial to avoid prolonged hospital stays. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: IV.

Unstable Lumbar Spine Osteomyelitis Caused by Trans-Foraminal Migration of Laparoscopic Adjustable Gastric Band Connection Tubing: A Case Report.

Background: Disconnection of the tubing between the port and LAGB is a well-known complication in general surgery and accounts for up to 17% of LAGB complications. Typically, when this complication occurs patients present with abdominal or pelvic complaints. A complication of spinal infection due to trans-foraminal migration has not been previously reported. The aim of this study is to highlight an unusual infection of the thoracolumbar spine due to laparoscopic adjustable gastric band (LAGB) intragastric erosion, and migration into the lumbar spine causing epidural abscesses, discitis, and osteomyelitis. This case underscores the importance of a thorough surgical history, complete imaging, and multi-disciplinary approach in management of complex spine infections. Methods: We report a case of LAGB tubing migration into the spinal canal through the left L2/L3 neural foramen resulting in symptomatic epidural abscesses and osteomyelitis. Results: Although dislodgement and migration of LAGB tubing has been reported previously, this is the first report of trans-foraminal migration and erosion of lumbar vertebrae, causing osteomyelitis of the spine and epidural abscess formation, subsequent instability and neurologic deficit requiring urgent operative intervention. Conclusions: Dislodgement and migration of LAGB tubing is a known complication. While it most commonly leads to abdominal and pelvic sequelae, in rare circumstances it may acutely affect the spine. Careful history, imaging, and multidisciplinary approach are paramount for the successful management.Level of Evidence: V.

Perfusion-guided sonopermeation of neuroblastoma: a novel strategy for monitoring and predicting liposomal doxorubicin uptake in vivo.

Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, and imposes significant morbidity and mortality in this population. The aggressive chemoradiotherapy required to treat high-risk NB results in survival of less than 50%, yet is associated with significant long-term adverse effects in survivors. Boosting efficacy and reducing morbidity are therefore key goals of treatment for affected children. We hypothesize that these may be achieved by developing strategies that both focus and limit toxic therapies to the region of the tumor. One such strategy is the use of targeted image-guided drug delivery (IGDD), which is growing in popularity in personalized therapy to simultaneously improve on-target drug deposition and assess drug pharmacodynamics in individual patients. IGDD strategies can utilize a variety of imaging modalities and methods of actively targeting pharmaceutical drugs, however in vivo imaging in combination with focused ultrasound is one of the most promising approaches already being deployed for clinical applications. Over the last two decades, IGDD using focused ultrasound with "microbubble" ultrasound contrast agents (UCAs) has been increasingly explored as a method of targeting a wide variety of diseases, including cancer. This technique, known as sonopermeation, mechanically augments vascular permeability, enabling increased penetration of drugs into target tissue. However, to date, methods of monitoring the vascular bioeffects of sonopermeation in vivo are lacking. UCAs are excellent vascular probes in contrast-enhanced ultrasound (CEUS) imaging, and are thus uniquely suited for monitoring the effects of sonopermeation in tumors. Methods: To monitor the therapeutic efficacy of sonopermeation in vivo, we developed a novel system using 2D and 3D quantitative contrast-enhanced ultrasound imaging (qCEUS). 3D tumor volume and contrast enhancement was used to evaluate changes in blood volume during sonopermeation. 2D qCEUS-derived time-intensity curves (TICs) were used to assess reperfusion rates following sonopermeation therapy. Intratumoral doxorubicin (and liposome) uptake in NB was evalauted ex vivo along with associated vascular changes. Results: In this study, we demonstrate that combining focused ultrasound therapy with UCAs can significantly enhance chemotherapeutic payload to NB in an orthotopic xenograft model, by improving delivery and tumoral uptake of long-circulating liposomal doxorubicin (L-DOX) nanoparticles. qCEUS imaging suggests that changes in flow rates are highly sensitive to sonopermeation and could be used to monitor the efficacy of treatment in vivo. Additionally, initial tumor perfusion may be a good predictor of drug uptake during sonopermeation. Following sonopermeation treatment, vascular biomarkers show increased permeability due to reduced pericyte coverage and rapid onset of doxorubicin-induced apoptosis of NB cells but without damage to blood vessels. Conclusion: Our results suggest that significant L-DOX uptake can occur by increasing tumor vascular permeability with microbubble sonopermeation without otherwise damaging the vasculature, as confirmed by in vivo qCEUS imaging and ex vivo analysis. The use of qCEUS imaging to monitor sonopermeation efficiency and predict drug uptake could potentially provide real-time feedback to clinicians for determining treatment efficacy in tumors, leading to better and more efficient personalized therapies. Finally, we demonstrate how the IGDD strategy outlined in this study could be implemented in human patients using a single case study.

Segmental resection for the treatment of congenital pulmonary malformations.

PURPOSE: The purpose of this study was to compare clinical outcomes of segmental resection to lobectomy as increasing antenatal diagnosis of congenital pulmonary malformations has led to a shift in surgical management. METHODS: A retrospective institutional review for patients undergoing surgical excision of congenital pulmonary malformations was performed. RESULTS: Sixty-two patients with congenital pulmonary malformations were reviewed between 2001 and 2012. Forty-five were included for analysis. Malformations were subdivided into two groups, including congenital lobar emphysema (CLE) (n=11, 24%) and intrapulmonary (IP) lesions (n=34, 76%). Nineteen (56%) IP patients underwent segmental resection, and 15 (79%) were performed thoracoscopically without conversion to thoracotomy. None of these patients had recurrent disease. Lobectomy was performed in 11 (100%) CLE and 15 (44%) IP patients, and the majority were by thoracotomy. Median hospital stay was longer for the lobectomy group at 7days when compared to the segmentectomy group at 2days (p<0.001). There was not a difference in complication rate (21% vs. 19%, p=1.000) or in median number of chest tube days (2 vs. 3days, p=0.079) for segmentectomy versus lobectomy patients. CONCLUSIONS: Segmental resections of congenital pulmonary malformations can be performed safely while conserving healthy lung tissue.

Morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions: analysis of the American College of Surgeons National Surgical Quality Improvement Program data.

IMPORTANCE: Splenectomy is a commonly performed operation; however, data from large series regarding operative outcomes to help guide decision making and informed consent are lacking. OBJECTIVE: To evaluate clinical and pathologic variables associated with morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions in the United States. DESIGN, SETTING, AND PARTICIPANTS: A review of the American College of Surgeons National Surgical Quality Improvement Program data for elective splenectomy between January 1, 2005, and December 31, 2011, was performed, and 1715 eligible individuals were identified. INTERVENTION: Elective splenectomy for hematologic conditions. MAIN OUTCOMES AND MEASURES: Complications and operative mortality were evaluated for the entire cohort and compared between patients with benign vs malignant diseases. Multivariable logistic regression was used to evaluate factors predictive of operative complications and death. RESULTS: Splenectomy was performed in 1344 patients (78.4%) for benign disease and in 371 patients (21.6%) for malignant disease. Two hundred ninety-one patients (17.0%) had a complication, and operative mortality occurred in 27 patients (mortality rate, 1.6%). Patients treated for malignant disease had a higher rate of overall complications (27.2%) compared with patients treated for benign disease (14.1%) (P < .001). Several variables were independent predictors of complications, including malignant disease (vs benign) (Odds Ratio [OR], 1.86; 95% CI, 1.23-2.80; P = .003), independent performance status (vs dependent) (OR, 0.33; 95% CI, 0.07-1.52; P = .02), and increasing albumin level (OR, 0.75; 95% CI, 0.66-0.86; P < .001). Increasing age (OR, 1.03; 95% CI, 1.00-1.06; P = .05) was an independent predictor of mortality while increasing albumin level (OR, 0.63; 95% CI, 0.46-0.86; P = .003) predicted lower risk of operative death. From these data, a patient older than 60 years with a low preoperative albumin level has a predicted probability for operative death as high as 10.0%. CONCLUSIONS AND RELEVANCE: Preoperative performance and nutritional status are significant risk factors for complications and mortality following elective splenectomy. Although operative mortality continues to decrease over time, specific preoperative variables may help with patient selection before elective splenectomy for certain patients.

Postoperative pain assessment and analgesic administration in Native American patients undergoing laparoscopic cholecystectomy.

Ethnic disparities in pain assessment and analgesic administration following surgery have received little attention in the surgery literature. We noted that our Native American patients were less likely than others to complain of pain. A retrospective chart review of 21 Native American patients and a control group who underwent outpatient, elective laparoscopic cholecystectomy was performed. Native American patients had a statistically lower numeric pain score (mean, 6.5; 95% CI, 3.6-9.4) than non-Native American patients (mean, 8.1; 95% CI, 6.3-9.9; t38 = 2.63; P < .05). Native American patients also received less postsurgical analgesic (mean, 7.4; 95% CI, 4.0-10.8) than non-Native American patients (mean, 11.2; 95% CI, 7.2-15.2; t38 = 3.07; P < .01). Medical staff attending Native American patients should be aware that response to some scales to assess pain may not reflect accurately the degree of pain experienced.