Gender-based differences in letters of recommendation in applications for general surgery residency programs in Canada.

BACKGROUND: In Canada, residency programs do not have many objective measures for ranking candidates. Instead, ranking relies on subjective measures such as letters of reference, which can be affected by the genders of the writer and the applicant. Our study assesses letters of recommendation for a general surgery program in Canada to categorize differences in reference letters based on the genders of applicant and letter writer. METHODS: We assessed 215 reference letters from 51 general surgery candidates for systematic differences in the descriptors used for male and female applicants and differences based on male and female authorship. RESULTS: Female applicants were more often described as mature, pleasant and flexible. Male applicants were more often described as having initiative, completing research, earning awards and performing extracurricular activities. Female writers were more likely to highlight an applicant's interest, initiative, response to feedback, knowledge of their limits, flexibility, communication, achievement in research and awards, confidence and ability to be a good assistant. Significantly more female applicants had female letter writers, compared with male applicants. CONCLUSION: These differences may affect the acceptance of applicants based on their gender and the genders of people who recommend them. Future research is required to explore how these differences in how applicants are described may affect residency selection committees' perceptions and rankings of applicants.

High MHC-II expression in Epstein-Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation.

EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.

High Levels of Class I Major Histocompatibility Complex mRNA Are Present in Epstein-Barr Virus-Associated Gastric Adenocarcinomas.

Epstein-Barr virus (EBV) is responsible for approximately 9% of stomach adenocarcinomas. EBV-encoded microRNAs have been reported as reducing the function of the class I major histocompatibility complex (MHC-I) antigen presentation apparatus, which could allow infected cells to evade adaptive immune responses. Using data from nearly 400 human gastric carcinomas (GCs), we assessed the impact of EBV on MHC-I heavy and light chain mRNA levels, as well as multiple other components essential for antigen processing and presentation. Unexpectedly, mRNA levels of these genes were as high, or higher, in EBV-associated gastric carcinomas (EBVaGCs) compared to normal control tissues or other GC subtypes. This coordinated upregulation could have been a consequence of the higher intratumoral levels of interferon γ in EBVaGCs, which correlated with signatures of increased infiltration by T and natural killer (NK) cells. These results indicate that EBV-encoded products do not effectively reduce mRNA levels of the MHC-I antigen presentation apparatus in human GCs.

The Standardization of Outpatient Procedure (STOP) Narcotics: A Prospective Health Systems Intervention to Reduce Opioid Use in Ambulatory Breast Surgery.

BACKGROUND: During the past 15 years, opioid-related overdose death rates for women have increased 471%. Many surgeons provide opioid prescriptions well in excess of what patients actually use. This study assessed a health systems intervention to control pain adequately while reducing opioid prescriptions in ambulatory breast surgery. METHODS: This prospective non-inferiority study included women 18-75 years of age undergoing elective ambulatory general surgical breast procedures. Pre- and postintervention groups were compared, separated by implementation of a multi-pronged, opioid-sparing strategy consisting of patient education, health care provider education and perioperative multimodal analgesic strategies. The primary outcome was average pain during the first 7 postoperative days on a numeric rating scale of 0-10. The secondary outcomes included medication use and prescription renewals. RESULTS: The average pain during the first 7 postoperative days was non-inferior in the postintervention group despite a significant decrease in median oral morphine equivalents (OMEs) prescribed (2.0/10 [100 OMEs] pre-intervention vs 2.1/10 [50 OMEs] post-intervention; p = 0.40 [p < 0.001]). Only 39 (44%) of the 88 patients in the post-intervention group filled their rescue opioid prescription, and 8 (9%) of the 88 patients reported needing an opioid for additional pain not controlled with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) postoperatively. Prescription renewals did not change. CONCLUSION: A standardized pain care bundle was effective in minimizing and even eliminating opioid use after elective ambulatory breast surgery while adequately controlling postoperative pain. The Standardization of Outpatient Procedure Narcotics (STOP Narcotics) initiative decreases unnecessary and unused opioid medication and may decrease risk of persistent opioid use. This initiative provides a framework for future analgesia guidelines in ambulatory breast surgery.

Characterizing the Patient Experience of CS/HIPEC Through In-Depth Interviews with Patients: Identification of Key Concepts in the Development of a Patient-Centered Program.

INTRODUCTION: The cytoreduction and hyperthermic intraperitoneal chemotherapy (CS/HIPEC) procedure is complex, involving lengthy preparation and recovery in a heterogeneous patient group. Understanding the patient experience is essential to improving interactions with health professionals that is critical to recovery. OBJECTIVE: This study sought to characterize the early recovery and return to quality of life (at 3 and 6-12 months post-surgery, respectively) in patients having undergone CS/HIPEC, through structured interviews. METHODS: Two sets of interviews were conducted among 20 CS/HIPEC patients. Interviews were uploaded into QSR NVivo 10 qualitative software (QSR International, Australia) and coded by two study personnel. Interview 1 focused on initial treatment decision making and postoperative hospitalization, while interview 2 focused on recovery, supports, and return to quality of life. RESULTS: Among the participants, 60% were female and the mean age was 57 years (range 31-71). Diagnoses included disseminated peritoneal adenomucinosis (n = 6), appendiceal adenocarcinoma (n = 4), colorectal adenocarcinoma (n = 6), goblet cell (n = 2), and mesothelioma (n = 2). The first interview identified common themes of perioperative psychosocial isolation, lack of direction, and the importance of an established support system. Patients requested printed and audiovisual materials focused on addressing expectations. The main findings from the second interview captured patient experiences with longer-term complications, as well as surveillance. CONCLUSION: Focused interviews with patients recently having undergone CS/HIPEC identified key issues that may be addressed in programs to improve the patient experience. These issues were distinctly different in relation to phase of recovery, and patient-centered programs designed with these factors in mind have the potential to enhance the recovery process.

Current Delivery of Hyperthermic Intraperitoneal Chemotherapy with Cytoreductive Surgery (CS/HIPEC) and Perioperative Practices: An International Survey of High-Volume Surgeons.

BACKGROUND: Cytoreductive surgery and heated intraperitoneal chemotherapy (CS/HIPEC) is performed for selected indications at a limited number of specialized centers worldwide. Currently there is no standardized approach to the perioperative care process. We sought to capture current practices in the perioperative management of patients who undergo CS/HIPEC at high-volume centers. METHODS: Surgeon members of the American Society of Peritoneal Surface Malignancies working at high-volume CS/HIPEC centers (>10 cases/year) were invited to complete an online survey. The survey included questions relating to preoperative preparation of patients, intraoperative practices, and postoperative care. RESULTS: Ninety-seven surgeons from five continents completed the survey (response rate 55%). The majority (80%) practiced in academic environments. Most respondents (68%) indicated that a formal preoperative preparatory pathway for CS/HIPEC surgery existed at their centers, but few (26%) had used enhanced recovery protocols in this group of patients. Whereas the intraoperative technical practices of the CS/HIPEC procedure were relatively consistent across respondents, there was little agreement on pre- and postoperative care practices, including use of mechanical bowel preparation, nutritional supplementation, methods of perioperative analgesia, timing of physical therapy and ambulation, nasogastric tube and Foley removal, intravenous fluids, blood transfusion parameters, and postoperative use of deep-vein thrombosis prophylaxis and antibiotics. CONCLUSIONS: Perioperative care practices for CS/HIPEC are widely variable nationally and internationally. Standardization of such practices offers an opportunity to incorporate evidence-based interventions and may enhance patient outcomes and improve care standards across all centers that offer this procedure.

Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model.

BACKGROUND: Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis, necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors in mouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, a caspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model. METHODS: Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniature swine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kg orally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitored for 1 month. Glucose tolerance and acute insulin release were determined at 1 month. RESULTS: There were no differences in islet procurement, isolation, or islet functional parameters between the two groups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolic reserve and acute insulin release for pigs in the treatment group. CONCLUSIONS: IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although this study has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justify early clinical trials of IDN6556 in islet transplantation.

Intra-abdominal adhesions: cellular mechanisms and strategies for prevention.

Postoperative intra-abdominal adhesions represent a serious clinical problem. In this review, we have focused on recent progress in the cellular and humoral mechanisms underpinning adhesion formation, and have reviewed strategies that interfere with these pathways as a means to prevent their occurrence. Current and previous English-language literature on the pathogenesis of adhesion formation was identified. As the burden of surgical disease in the world population increases, and the frequency of reoperation increases, prevention of adhesion formation has become a pressing goal in surgical research.

Sirolimus drug-eluting, hydrogel-impregnated polypropylene mesh reduces intra-abdominal adhesion formation in a mouse model.

BACKGROUND: Prosthetic mesh is used frequently in abdominal wall hernia reconstruction but is prone to postoperative adhesion formation. Complications resulting from intra-abdominal adhesions represent a considerable clinical and cost burden. We, herein, investigate the antiproliferative and antiadhesiogenic properties of sirolimus and hydrogel-impregnated, drug-eluting mesh to decrease such complications in a mouse model of abdominal wall hernia repair. METHODS: A 1 × 1cm(2) polypropylene mesh from 1 of 3 groups (group 1, plain control; group 2, hydrogel [2% agarose]; and group 3, hydrogel + 10 mcg sirolimus) was implanted operatively into the peritoneal cavity of BALB/c mice and followed for up to 4 weeks. Adhesions were scored by percent surface area of mesh (range, 0-100%), severity (range, 0-3), and tenacity (range, 0-4). Representative samples were assessed by scanning electron microscopy. RESULTS: Mesh impregnated with the combination of hydrogel and sirolimus led to a significant decrease in adhesion formation. The percent surface area of adhesional attachment to mesh was decreased from 100.0 ± 0% in the plain mesh control group versus 18 ± 8% (P < .001) in the combined impregnated mesh group. Similarly, adhesion severity scores were decreased from a score of 2.9 ± 0.1 (plain mesh) versus 1.4 ± 0.1 (sirolimus/hydrogel-impregnated mesh) (P < .001). Scores for tenacity were also decreased markedly from 3.5 ± 0.2 (plain mesh) versus 1.5 ± 0.1 (sirolimus/hydrogel-impregnated mesh (P < .001). CONCLUSION: Creation of a sirolimus drug-eluting and hydrogel-impregnated polypropylene mesh resulted in marked decrease of adhesion formation in this mouse model, was well tolerated without side effects, and has potential for clinical application.

The caspase inhibitor IDN-6556 (PF3491390) improves marginal mass engraftment after islet transplantation in mice.

BACKGROUND: Islet transplantation has become a viable option for selected type 1 diabetic patients; however, a significant portion need to return to exogenous insulin. The predominant factors include impaired islet engraftment and early islet loss. Caspase inhibition is a potent way to improve islet engraftment, but all tested compounds so far have not been clinically relevant. IDN-6556 (PF3491390) has already been used clinically and can be delivered orally with high portal vein concentrations. METHODS: Mice were given a marginal mass islet graft of either mouse or human islets and treated with either IDN-6556 (10 or 20 mg/kg ip bid) or vehicle and followed for diabetes reversal. At 1 month post-transplant, mice were subjected to a glucose tolerance test and an assessment of graft mass. In separate experiments, human islets were cultured with IDN-6556 or vehicle to assess for islet survival and viability. RESULTS: In both syngeneic mouse islets and human islets transplanted into immunodeficient mice, IDN-6556 (20 mg/kg) given for 7 days post-transplant led to a significantly enhanced rate of diabetes reversal as compared to vehicle. In addition, mice receiving caspase inhibitor displayed improved glucose tolerance and graft survival at the 1-month point. We also found protective effects in vitro for islet viability and marked reduction in apoptosis in vivo. CONCLUSION: Taken together, these results demonstrate the effectiveness of caspase inhibition with IDN-6556 on islet transplantation and in particular islet engraftment and survival.

Histopaque provides optimal mouse islet purification kinetics: comparison study with Ficoll, iodixanol and dextran.

Islet transplantation has become a very promising treatment for type 1 diabetes. To facilitate further clinical improvements in this exciting field, rodent islets are used to evaluate new strategies and modifications. One method to purify islets is on a density gradient, although the optimal gradient component can be debated. N=6 separate mouse islet isolations were used and the resulting islets were separated and purified on either a Ficoll, Histopaque, Dextran or Iodixanol gradient. Islets were assessed for recovery, viability, purity and in vitro functionality. Aliquots were transplanted into diabetic mice to assess in vivo functionality and survival. There was no difference in the number of islets recovered across groups nor in the size of recovered islets. Use of a Ficoll or Histopaque gradient led to the most pure and viable islets in comparison to Dextran and Iodixanol. Functionally, islets isolated on a Ficoll gradient had the highest glucose-stimulated insulin release in vitro while performing equally to Histopaque and Dextran gradients in vivo. Using a Ficoll gradient, however, comes at a higher monetary cost. We recommend using a Histopaque gradient, which led to the isolation of viable and functional islets with a reduced cost as compared to a Ficoll gradient.