Advancements in surgical education: exploring animal and simulation models in fetal and neonatal surgery training.

Introduction: Surgical education is undergoing a transformation, moving away from traditional models towards more modern approaches that integrate experiential and didactic methods. This shift is particularly pertinent in the realm of fetal and neonatal surgery, where specialized training is crucial. Historical training methods, such as cadaveric dissection, have been prevalent for centuries, but newer innovations, including animal and non-animal simulation models, are gaining prominence. This manuscript aims to explore the use of both animal and non-animal models in surgical education, with a specific focus on fetal and neonatal surgery. Animal models: The use of animal models in surgical training has a long history, dating back to Halsted's introduction in 1889. These models, often utilizing large animals like swine and dogs, offer valuable insights into fetal and neonatal surgeries. They allow for the study of long-term outcomes and the simulation of various diseases and anomalies, providing essential training experiences not readily available in human surgeries. However, there are notable limitations, including anatomical and physiological differences from humans, ethical considerations, and substantial infrastructure and maintenance costs. Simulation models: Simulation-based training offers several benefits, including standardized and safe learning environments without risks to real patients. Bench models, using synthetic materials or non-living animal tissue, provide cost-effective options for skills development. Virtual reality and 3-D printing technologies further enhance simulation experiences, allowing for the replication of complex clinical scenarios and patient-specific anatomies. While these models offer significant advantages, they lack the complexity of biological systems found in animal models. Conclusion: In conclusion, both animal and non-animal simulation models play crucial roles in enhancing surgical education, particularly in fetal and neonatal surgery. While advancements in non-animal technologies are important for ethical reasons, the continued necessity of animal models in certain areas should be acknowledged. By responsibly integrating these models into training programs, surgical education can be further enriched while upholding ethical standards and ensuring optimal patient outcomes.

A Role for Genitourinary Reconstruction in Locally Advanced Bilateral Wilm's Tumor.

Wilm's tumor, an embryonal tumor that develops from remnants of the immature kidney, is the most common primary malignant renal tumor of childhood and accounts for approximately 6%-7% of all childhood cancers. Here, we present a case of a 10-year-old female with stage IV Wilm's tumor involving the bilateral kidneys. She ultimately required complex genitourinary reconstruction via a transureteroureterostomy following extensive oncologic resection. This case highlights the critical role of Urologists at an early stage in cases requiring complex genitourinary reconstruction.

A study on etiology of incontinence in double knockout mouse model.

INTRODUCTION AND OBJECTIVE: Stress urinary incontinence is of concern in both pediatric and adult population. Double mutant GLI family zinc finger Gli2+/-; Gli3Δ699/+ murine model of stress incontinence has been recently developed as a reliable model which does not require surgical manipulation to create incontinence and is shown to survive to adulthood. The aim of this study was to establish the etiology of incontinence in the double mutant Gli2+/-; Gli3Δ699/+ mice. STUDY DESIGN: We used 13 cluster of differentiation 1 (CD-1) mice (7-9 weeks) for demonstration of histology of the bladder and urethra. There were 3 Wild Gli2+/- females, 2 Wild Gli2+/- males, 4 Gli2+/-;Gli3Δ699/+ females and 4 Gli2+/-;Gli3Δ699/+ males. The Wild Gli2+/- mice served as the control group and Gli2+/-;Gli3Δ699/+ mice served as the test group. Additionally, eight 16.5 days mice (2 each of Wild Gli2+/- females, Wild Gli2+/- males, double knockout (DKO) Gli2+/-;Gli3Δ699/+ females and Gli2+/-;Gli3Δ699/+ males) were used to assess the histology of the spinal cord. The gross appearance of bladder and urethra was studied using ink injection assays. Immunohistochemistry was done for smooth muscle actin and cytokeratin. RESULTS: Gross and histologic appearance confirmed the previously reported widening of bladder outlet and hypoplasia of smooth muscles in female urethra and also established them in the male urethra of Gli2+/-;Gli3Δ699/+ mice compared to Gli2+/- mice. The double knockout mice were smaller than the Gli2 mice (5.2 vs 6.1 cm, p = 0.002). Immunohistochemistry demonstrated epithelial hyperplasia and smooth muscle hypoplasia. Additionally, there was prostatic hypoplasia in the Gli2+/-;Gli3Δ699/+ male mice. The spinal cord length for body size appeared comparable between the Gli2+/- and Gli2+/-;Gli3Δ699/+ mice but histological evaluation revealed abnormal development of the caudal end of the vertebral body with premature termination of the spinal cord (Figure). DISCUSSION: The histological changes in the bladder neck and urethra were consistent to those previously reported. While previous report described the findings in female mice only, we confirmed that these findings are also present in males as well as prostatic hypoplasia, a possible additional factor leading to stress incontinence. The most important finding in the present study however, was the detection of premature termination of spinal cord in the DKO Gli2+/-; Gli3Δ699/+ mice which has not been reported previously and is likely a major contributor to incontinence in this model. CONCLUSION: The incontinence in male as well as female Gli2+/-; Gli3Δ699/+ mice is due to both myogenic and neurogenic involvement. These double knockout mice are a valuable model of stress incontinence related to neurogenic bladder due to low outlet resistance.

Genetic alterations of Keap1 confers chemotherapeutic resistance through functional activation of Nrf2 and Notch pathway in head and neck squamous cell carcinoma.

Keap1 mutations regulate Nrf2 activity and lead to chemoresistance in cancers. Yet the underlying molecular mechanisms of chemoresistance are poorly explored. By focusing and genotyping head and neck squamous cell carcinoma (HNSCC) that had available pathologic and clinical data, we provide evidence that Keap1 displays frequent alterations (17%) in HNSCC. Functional loss of Keap1 results in significant activation of Nrf2 and promotes cancer cell growth, proliferation, and elevated cancer stem cell (CSCs) self-renewal efficiency and resistance to oxidative stress. Furthermore, decreased Keap1 activity in these cells increased nuclear accumulation of Nrf2 and activation of the Notch pathway, causing enhanced transcriptional alterations of antioxidants, xenobiotic metabolism enzymes, and resistance to chemotherapeutic treatment. Limiting the Nrf2 activity by either Keap1 complementation or by Nrf2 silencing increased the sensitivity to chemotherapy in Keap1-mutated cells and repressed the CSC self-renewal activity. Our findings suggest that Keap1 mutations define a distinct disease phenotype and the Keap1-Nrf2 pathway is one of the leading molecular mechanisms for clinical chemotherapeutic resistance. Targeting this pathway may provide a potential and attractive personalized treatment strategy for overcoming chemotherapeutic resistance conferred by Keap1 mutations.

Decline in Respiratory Functions in Hospitalized SARS-CoV-2 Infected Cancer Patients Following Cytotoxic Chemotherapy-An Additional Risk for Post-chemotherapy Complications.

Background: Patients recovering from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection demonstrate impaired lung function and those requiring chemotherapy after recovering from SARS-CoV-2 infection have yet to be explored. In this study, we sought to investigate the possible pulmonary functional changes during and after administering chemotherapy in patients with prior SARS-CoV-2 infection. Methods: In this study, a total of 37 SARS-CoV-2 infected patients with cancer who were discharged from hospital and received subsequent cytotoxic chemotherapy were enrolled and prospectively followed-up. The following parameters were prospectively measured before (P1), after first chemotherapy cycle (P2), and 10 weeks after the end of chemotherapy (P3), to assess their impact on respiratory complications in terms of diffusion capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1-s (FEV1), forced vital capacity (FVC), 6-min walking distance (6MWD) test and levels of key inflammatory markers. Results: All patients completed at least 2 cycles of chemotherapy without showing overt respiratory complications. Six patients (16%) complained about dyspnea during chemotherapy or at follow-up period. DLCO was significantly impaired during follow-up period [from P1 78 to P3 60% of predicted values; interquartile range (IQR) 55-89] and in 32 of 37 (86% of patients) from P1 to P2 (65% of predictive value; IQR 58-70; p < 0.001). Several patients experienced post-chemotherapy respiratory complications. As expected, all patients from control groups showed persistent improved pulmonary functions. Conclusion: The risk of pulmonary impairments due to cytotoxic chemotherapy in prior SARS-CoV-2 infected patients is linked to the loss of DLCO. Accordingly, we recommend that for patients with cancer requiring chemotherapy after recovering from prior SARS-CoV-2 infection, pulmonary tests to be performed routinely before and during chemotherapy treatment to monitor the pulmonary performance.

Impact of native nephrectomy on hypertension outcomes in pediatric kidney transplant recipients: a 10-year institutional experience.

OBJECTIVE: To assess the role native nephrectomy (NN) in hypertension-related outcomes for pediatric patients undergoing renal transplantation (RT). METHODS: Renal transplants (RT) performed at our institution between 2006 and 2015 were reviewed. RT recipients who underwent NN were compared to those who did not. Primary outcomes were hypertension-related: use/number of medications pre-/post-transplant and hypertension-related readmissions. Secondary outcomes were 1-year outcomes of: readmissions, eGFR, Clavien-Dindo classification ≥ 3 complications, and graft loss. RESULTS: 135 patients were evaluated. 24 underwent NN (Group 1) and 111 did not (Group 2). Baseline characteristics were similar between Groups 1 and 2. The majority of NN indications were hypertension (10/39 kidneys) and proteinuria (12/39 kidneys). There were no differences in use/number of anti-hypertensive medications pre- or post-transplant. However, between Group 2 and subgroup of patients who underwent NN for hypertension, a significant difference was seen in medication use/numbers but not post-transplant. Number of readmissions due to hypertension was similar (7.2% vs. 12.5%). The only difference in secondary outcomes was higher readmission rates with bacterial infections for group 1 (45.8% vs. 23.4%, p = 0.041). CONCLUSION: NN, when offered to patients at higher risk of post-RT hypertension, may allow high-risk patients to achieve similar hypertension outcomes as those at lower risk.

Serious and Fatal Complications after Neonatal Circumcision.

Neonatal circumcision (NNC) is the most frequently performed surgical procedure worldwide and is generally considered safe in Western societies. Deaths attributed to NNC are seldom reported and are mostly explained by lack of adherence to medical standards. We reviewed our emergency department database for circumcision-related emergency admissions. During 2000-2013, 19 previously healthy neonates were admitted for acute complications after circumcision. Four were admitted for bleeding, with hemophilia identified in two cases and von Willebrand disease in one. Eight boys required emergency surgery, three for severe bleeding. Four boys with amputation of the glans underwent immediate surgical reconstruction. One infant was taken to the operating room to remove an obstructing Plastibell ring. Seven boys were admitted to the intensive care unit with severe bleeding or sepsis, three of whom ultimately progressed to hemorrhagic or septic shock. Two of these children died of their complications. We estimate that the annual incidence of severe complications requiring hospitalization after NNC in the Greater Toronto Area was approximately 0.01%, and the incidence of fatalities over the 14-yr review period was approximately 0.0012%. Our results indicate that the risk of serious complications and death as a result of NNC is greater than generally assumed.

Risk of urinary tract infection in patients with hydroureter: An analysis from the Society of Fetal Urology Prenatal Hydronephrosis Registry.

BACKGROUND: Prenatal hydronephrosis is one of the most common anomalies detected on prenatal ultrasonography. Patients with prenatal hydronephrosis and ureteral dilation are at increased risk of urinary tract infection (UTI) and continuous antibiotic prophylaxis (CAP) is recommended. However, current guidelines do not define the minimum ureteral diameter that would be considered a dilated ureter in these patients. OBJECTIVE: We evaluate the definition of clinically relevant hydroureter, its association with UTI, and the impact of CAP. STUDY DESIGN: Patients with prenatal hydronephrosis from seven centers were enrolled into the Society for Fetal Urology Prenatal Hydronephrosis Registry from 2008 to 2020. Patients with ureteral measurement on ultrasound were included. Patients with ureterocele, ectopic ureter, neurogenic bladder, posterior urethral valves, horseshoe or solitary kidney, known ureteropelvic junction obstruction, or follow-up less than one month were excluded. Primary outcome was UTI. Analyses were performed using Cox regression. RESULTS: Of the 1406 patients enrolled in the registry, 237 were included. Seventy-six percent were male, ureteral diameter ranged from 1 to 34 mm, and median follow-up was 2.2 years. Patients with ureters 7 mm or greater had nearly three times the risk of UTI adjusting for sex, circumcision status, antibiotic prophylaxis and hydronephrosis grade (HR = 2.7, 95% CI: 1.1-6.5, p = 0.03; Figure). In patients who underwent voiding cystourethrogram (VCUG; 200/237), ureteral dilation of 7 mm or more identified patients at increased UTI risk controlling for sex, circumcision status, vesicoureteral reflux and hydronephrosis grade (HR = 2.3, 95% CI: 0.97-5.6, p = 0.06). CAP was significantly protective against UTI (HR = 0.50 (95% CI: 0.28-0.87), p = 0.01). Among patients who underwent VCUG and did not have vesicoureteral reflux, ureteral dilation 7 mm or greater corresponded with higher UTI risk compared to ureteral diameter less than 7 mm on multivariable analysis (HR = 4.6, 95% CI: 1.1-19.5, p = 0.04). CONCLUSIONS: This is the first prospectively collected, multicenter study to demonstrate that hydroureter 7 mm or greater identifies a high-risk group for UTI who benefit from antibiotic prophylaxis. In contrast, patients with prenatal hydronephrosis and non-refluxing hydroureter less than 7 mm may be managed more conservatively.

The utility of native ureter in the management of ureteral complications in children after renal transplantation.

BACKGROUND: Ureteral complications after renal transplantation in children are a major source of morbidity. Management is complex and variable. METHODS: With IRB approval, health records were retrospectively reviewed of patients who: were <18 years, underwent kidney transplant between 1997 and 2017, had at least 2 years of follow-up, and underwent interventions due to post-transplant ureteral complications. RESULTS: Of 136 patients, seventeen (13%) required ureteral intervention due to stricture (n = 3), reflux (n = 12), or both (n = 2). Transplant occurred at median 10.5 years (3.1-14.7). Reconstruction occurred at median 10 months (7-15) after transplant. Pre-existing bladder pathology was present in 6 (35%) patients. Four of five patients with strictures had at least one endoscopic balloon dilation. Ultimate management included reimplantation, ureteroureterostomy of native to transplant ureter, pyeloureterostomy to native ureter, multiple endoscopic interventions followed by a Boari flap, or multiple failed endoscopic interventions. Fourteen patients with VUR underwent reimplantation (n = 5), ureteroureterostomy of native to transplant ureter (n = 4), pyeloureterostomy to native ureter (n = 4), and one underwent endoscopic injection with Deflux of the transplant ureter. Only one patient had a non-functioning graft due to ureteral complication. All patients were alive at follow-up (median 17 years [12-19]). CONCLUSIONS: Transplant ureteral reflux and stricture are significant complications following pediatric renal transplantation and may require surgical management. In our population, reflux or stricture requiring ureteral reconstruction occurred in 10% and 4%, respectively. Endoscopic interventions were rarely successful. Native ureters were used for ureteral reconstruction in more than two thirds of patients should be considered in management of ureteral complications.

Time to event analysis for post-hypospadias repair complications: a single-surgeon experience.

OBJECTIVE: The optimal follow-up duration and frequency following hypospadias repair is unclear within the pediatric urology community. This analysis aims to delineate the time to various complications following primary hypospadias repairs. MATERIALS AND METHODS: A retrospective review of a single-surgeon hypospadias database over 2001-2017 was performed. The primary outcome of the study was determining the significant factors leading to complications over time. As a secondary outcome, subgroup analysis was performed to determine whether there was a significant difference in time to detecting voiding-related complications (fistula, stricture/stenosis, and diverticulum) based on age. RESULTS: Eight hundred and thirty-two patients were identified. The complication rates for distal, midshaft, and proximal hypospadias were 17.9% (112/625), 36.7% (40/109), and 55.1% (49/89), respectively (p < 0.0001). Survival analysis using Kaplan-Meier curves showed significance in three variables for time to complication: hypospadias severity (p < 0.0001), technique (p < 0.0001), and penile curvature > 30° (p < 0.0001). Cox-regression analysis showed that hypospadias severity and penile curvature were significantly contributing to the model (p < 0.0001, p = 0.044). Patients with proximal hypospadias and penile curvature developed complications earlier than other patients, with approximately 95% of complications occurring within 2 years. CONCLUSIONS: Complications from repair of proximal hypospadias with curvature > 30° are likely to occur within 2 years of surgery. Surgeons may consider more frequent follow-up within the first 2 years of surgery to detect these complications.

Utility of pre-transplant lower urinary tract investigation in pediatric renal transplant population after referral: A 16-year institutional experience.

To evaluate the clinical utility of pre-renal transplant LUT investigations in pediatric populations after their referral for transplant evaluation based on the etiology of their ESRD. A 16 year retrospective review of patients undergoing RT performed at our institution was performed. Patients were stratified into two groups: Group 1-non-urologic and Group 2-urologic etiology for ESRD. Baseline characteristics, pre-transplant LUT investigations, and urologic interventions were assessed. One-year clinical outcomes were compared between those with and without LUT investigations following referral for renal transplantation (RT). 227 patients and 97 patients were identified for Groups 1 and 2, respectively. 19% of Group 1 and 73% of Group 2 had VCUG, while 1% and 13%, respectively, had UDS ordered following referral for RT. In both groups, >50% of VCUG and UDS were ordered without specific clinical concerns. These had low likelihood of prompting interventions, both pre-transplant (Group 1-VCUG 0%, UDS 0%; Group 2-VCUG 0%, UDS 8%) or post-transplant (Group 1-0%, Group 2-5%). In both groups, LUT investigation following referral for RT did not lead to differences in 1 year outcomes assessed. In anticipation of pediatric RT, LUT investigations ordered without clinical indications did not provide information that altered management prior to transplantation.

Do post-operative phone calls enhance family satisfaction and outcomes after outpatient pediatric urological surgeries? A prospective study.

INTRODUCTION: This study assesses whether post-operative check-in phone calls (POPC) performed within 48 h of outpatient pediatric urological surgeries by a non-medical professional (NMP) would increase patient/family satisfaction and minimize extraneous resource use by increasing email/telephone communication, while reducing emergency department (ED) visits within 30 days of that procedure. METHODS: Families of patients undergoing ambulatory pediatric urology surgeries were enrolled over 8 weeks. Group 1 did not receive POPC. Group 2 received a POPC within 48 h of their operation by a NMP. Both groups received a phone-call survey 2 weeks after surgery to assess families' perioperative satisfaction. RESULTS: In total, 74 families were enrolled (Group 1 = 44, Group 2 = 31). The response rates to phone surveys for Groups 1 and 2 were 59.1% and 77.4%, respectively. POPC did not improve perioperative satisfaction, nor did it significantly promote the use of nursing email/telephone communication (19.2% vs. 4.2%, p = 0.128) or reduce ED visits (15.4% vs. 0.0%, p = 0.111). However, all families in Group 2 thought POPC was timed appropriately and 79.1% perceived it to be helpful in reducing post-operative anxiety. CONCLUSION: POPC by a NMP within 48 h of surgery may not affect perioperative satisfaction of families of patients undergoing same-day pediatric urology surgery but may have an impact in reducing post-operative anxiety.

Chemotherapeutic resistance of head and neck squamous cell carcinoma is mediated by EpCAM induction driven by IL-6/p62 associated Nrf2-antioxidant pathway activation.

Overexpression of epithelial cell adhesion molecule (EpCAM) has been associated with chemotherapeutic resistance, leads to aggressive tumor behavior, and results in an adverse clinical outcome. The molecular mechanism by which EpCAM enrichment is linked to therapeutic resistance via Nrf2, a key regulator of antioxidant genes is unknown. We have investigated the link between EpCAM and the Nrf2 pathway in light of therapeutic resistance using head and neck squamous cell carcinoma (HNSCC) patient tumor samples and cell lines. We report that EpCAM was highly expressed in Nrf2-positive and HPV-negative HNSCC cells. In addition, cisplatin-resistant tumor cells consisted of a higher proportion of EpCAMhigh cells compared to the cisplatin sensitive counterpart. EpCAMhigh populations exhibited resistance to cisplatin, a higher efficiency in colony formation, sphere growth and invasion capacity, and demonstrated reduced reactive oxygen species (ROS) activity. Furthermore, Nrf2 expression was significantly higher in EpCAMhigh populations. Mechanistically, expression of Nrf2 and its target genes were most prominently observed in EpCAMhigh populations. Silencing of EpCAM expression resulted in the attenuation of expressions of Nrf2 and SOD1 concomitant with a reduction of Sox2 expression. On the other hand, silencing of Nrf2 expression rendered EpCAMhigh populations sensitive to cisplatin treatment accompanied by the inhibition of colony formation, sphere formation, and invasion efficiency and increased ROS activity. The molecular mechanistic link between EpCAM expression and activation of Nrf2 was found to be a concerted interaction of interleukin-6 (IL-6) and p62. Silencing of p62 expression in EpCAMhigh populations resulted in the attenuation of Nrf2 pathway activation suggesting that Nrf2 pathway activation promoted resistance to cisplatin in EpCAMhigh populations. We propose that therapeutic targeting the Nrf2-EpCAM axis might be an excellent approach to modulate stress resistance and thereby survival of HNSCC patients enriched in EpCAMhigh populations.

Comparative outcome analysis of pediatric kidney transplant in posterior urethral valves children with or without pretransplant Mitrofanoff procedure.

BACKGROUND: Urinary diversion using catheterizable channel among posterior urethral valve (PUV) patients may help to alleviate the functional concerns of the bladder on the allograft. Herein, we review our series of PUV patients undergoing renal transplants at a single institution to determine outcomes between those with and without pretransplant Mitrofanoff. METHODS: PUV cases in our transplant database from 2000 to 2017 were identified. Data collected included clinical demographics, presentation of PUV, bladder function, implementation of dialysis and donor type. Post-transplant variables included graft function, and bladder function including incontinence and UTI development. Comparison between with vs without pretransplant Mitrofanoff patient groups was performed using Fisher's exact and t test analysis. RESULTS: Overall, 22 cases were analyzed. The majority (77%) had a prenatal diagnosis of PUV, and 23% had a symptomatic presentation. Pretransplant Mitrofanoffs were performed in 40.9% of cases. The overall age at transplant was 10 ± 5 years. Five percent experienced post-transplant incontinence and 23% UTIs. No difference between groups was noted in variables including age at transplant, the timing of PUV diagnosis. Mitrofanoff group patients had more symptomatic febrile UTIs than those without Mitrofanoff (67% vs 15%; P = .03); however, there was no difference in post-transplant UTI development. Furthermore, the Mitrofanoff group seems to have later onset of dialysis or need for transplant (age at the start of dialysis 36 ± 56 vs 156 ± 25 months, P < .001). CONCLUSION: Our study suggests that patients with early PUV diagnoses who develop symptomatic UTI may benefit from early creation of a Mitrofanoff cathetherizable channel, which is associated with delayed ESRD progression and need for dialysis.

Competency in Tubularized Incised Plate Repair for Distal Hypospadias: Cumulative Sum Learning Curve Analysis of a Single Surgeon Experience.

PURPOSE: We sought to determine the number of cases to achieve competency and proficiency in tubularized incised plate technique for distal hypospadias repair using cumulative sum analysis. MATERIALS AND METHODS: From 2001 to 2015 we reviewed all distal tubularized incised plate repairs performed by a single surgeon since independent practice. Data for 450 consecutive cases included age, meatal location, presence of curvature, operative time, occurrence of complications and followup duration. A cumulative sum analysis cohort chart was used to determine trends in complication rate and operative time during the evaluation period. In order to account for surgical experience with time, the highest peak, plateau, and down trends in operative time and complication rate were identified on the plot and set as the transition points between learning (phase 1), competence (phase 2) and proficiency (phase 3). RESULTS: Based on the cumulative sum analysis learning curve, the competence phase with plateau of operative time and complication rate commences beyond the 127th case, and the proficiency phase with notable decline in operative time and complication rate was noted beyond the 234th case. When comparing case characteristics and surgical outcomes between phases and learning curve, the proficiency phase involved younger patients and more severe degree of distal hypospadias being repaired using the tubularized incised plate approach with fewer complications related to meatal stenosis and fewer cosmetic complications. CONCLUSIONS: In our study competency in distal hypospadias tubularized incised plate repair was reached beyond the 127th case, while proficiency was attained beyond the 234th case.

Widespread expression of Sonic hedgehog (Shh) and Nrf2 in patients treated with cisplatin predicts outcome in resected tumors and are potential therapeutic targets for HPV-negative head and neck cancer.

BACKGROUND: Sonic hedgehog (Shh) and Nrf2 play a critical role in chemotherapeutic resistance. These two genes have been found to be dysregulated in head and neck squamous cell carcinomas (HNSCC). The purpose of this study was to analyze the expression, function and clinical prognostic relationship of Shh and Nrf2 in HNSCC in the context of therapeutic resistance and cancer stem cells (CSCs). METHODS: We analyzed a cohort of patients with HNSCC to identify potential therapeutic biomarkers correlating with overall survival (OS) as well as disease-free survival (DFS) from our own data and validated these results using The Cancer Genome Atlas dataset. Expression of Shh and Nrf2 was knocked down by siRNA and cell growth, sphere growth and chemotherapeutic resistance were evaluated. RESULTS: Widespread abundant expression of Shh and Nrf2 proteins were associated with shorter OS and DFS. The combination of Shh and Nrf2 expression levels was found to be a significant predictor of patient DFS. The tumor stromal index was correlated with Shh expression and inversely associated with shorter OS and DFS. Inhibition of Shh by siRNA or cyclopamine resulted in the attenuation of resistant CSC self-renewal, invasion, clonogenic growth and re-sensitization to the chemotherapeutic agents. Concomitant upregulation of Shh and Nrf2 proved to be an independent predictor of poor OS and DFS in patients with HNSCC. CONCLUSIONS: These findings suggest that Shh and Nrf2 could serve as therapeutic targets as well as promising dual prognostic therapeutic biomarkers for HNSCC.

Turning a new "page": ways to decrease the number of pages after hours without compromising patient care

Background: Pages to house staff after hours, especially overnight, lead to interrupted sleep and fatigue the next day. Although some pages are urgent, others may not need an immediate response. In this study we aimed to identify unwarranted pages and to establish ways to reduce them. Methods: Over 2 months, all pages to the Department of Pediatric Urology at the Hospital for Sick Children in Toronto, Canada, during call hours were documented, including the assessment of the responding physicians of their medical necessity. After analyzing the reasons for inappropriate pages, we took several steps to try to reduce them without impairing patient care. One year later, pages were tracked again to evaluate the efficacy of our interventions. Results: In the initial measurement period, no calls from parents and approximately 50% of the in-hospital pages (15 of 36 pages from the wards, 27 of 49 pages from the emergency department, 17 of 31 pages requesting consultations, and 8 of 8 pages from the inhouse pharmacy and outside pharmacies) were considered medically urgent. The reasons for unwarranted pages were inconsistent parent teaching, lack of adequate triaging and prioritizing on the ward and lack of awareness of the structure of the on-call provisions among different services in the hospital. Several steps were taken to streamline the teaching of parents and nurses, standardize information, provide alternative means of communication within the hospital and restrict parents' access by phone to the urologist on call. One year later, the number of pages had decreased by 70%. Conclusion: Although physician coverage throughout the day and night is necessary for high-quality and safe patient care, communication with on-call physicians should be only for appropriate reasons. The provision of consistent teaching and alternative communication channels can improve patient care as well as decrease the number of after-hour pages.

Contexte: Les appels au personnel interne par téléavertisseur, surtout la nuit, perturbent le sommeil et entraînent de la fatigue le lendemain. Même si certains de ces appels sont urgents, d'autres ne nécessitent pas de réponse immédiate. Avec cette étude nous avons voulu identifier les appels par téléavertisseur qui sont injustifiés et trouver des façons d'en réduire le nombre. Méthodes: Sur une période 2 mois, nous avons documenté tous les appels par téléavertisseur adressés durant les heures de garde au service d'urologie pédiatrique de l'Hôpital SickKids de Toronto, au Canada, et demandé aux médecins y ayant répondu d'en évaluer le bien-fondé au plan médical. Après avoir analysé les raisons des appels jugés injustifiés, nous avons adopté plusieurs mesures pour en réduire le nombre sans compromettre les soins. Un an plus tard, nous avons de nouveau comptabilisé les appels par téléavertisseur pour mesurer l'efficacité de nos interventions. Résultats: Durant la période de mesure initiale, aucun appel des parents n'a été considéré médicalement urgent, tout comme environ 50 % des appels provenant de l'hôpital même (15 appels sur 36 des unités de soins, 27 appels sur 49 du service des urgences, 17 appels sur 31 pour des demandes de consultation et 8 appels sur 8 de la pharmacie de l'hôpital ou de pharmacies de l'extérieur). Les raisons des appels injustifiés étaient entre autres incohérence dans l'enseignement aux parents, triage et priorisation inadéquats à l'unité de soin et méconnaissance des différents services de l'hôpital quant à la structure et au fonctionnement du système de garde. Plusieurs mesures ont été prises pour simplifier l'enseignement aux parents et au personnel infirmier, standardiser l'information, fournir d'autres moyens de communication dans l'hôpital même et restreindre l'accès des parents à l'urologue de garde par téléphone. Un an plus tard, le nombre d'appels avait diminué de 70 %. Conclusion: Même si les médecins doivent être joignables jour et nuit pour assurer la qualité des soins et la sécurité des patients, les raisons de communiquer avec eux doivent être appropriées. Le rappel des consignes et le recours à d'autres canaux de communication peuvent améliorer les soins aux patients et réduire le nombre d'appels le soir et la nuit.

Increased hand digit length ratio (2D:4D) is associated with increased severity of hypospadias in pre-pubertal boys.

INTRODUCTION: Hypospadias is a common congenital male disorder, with much research focusing on prenatal androgen exposure as a causative factor. Whilst digit length ratios were apparent in sexual dimorphism since the nineteenth century, their role in hypospadias remains unknown. The objective of our study was to determine the correlation between digit length (2D:4D) ratio, hypospadias severity, and anogenital distance. METHODS: Pre-pubertal boys (<3 years old) seen intra/postoperatively following hypospadias repair (June 2018-January 2019 inc.) were included. These were age-matched to non-hypospadias controls. Anthropomorphic measurements of digit lengths, penile/glans width, and anogenital distance were measured using digital calipers. RESULTS: Data measurements were collected for 105 boys with hypospadias (60 distal; 45 proximal) and 55 controls. There were significant differences in 2D:4D ratios in each hand (p < 0.001), as well as individual digits (p < 0.001), and a reduced anogenital distance (p < 0.001), when comparing the proximal group with distal or control groups. There were no significant differences in glans width, or between term- and preterm births. CONCLUSIONS: This study is the first to demonstrate increased 2D:4D ratios with proximal hypospadias, which also correlate with a shortened anogenital distance. This may provide a non-invasive, potentially antenatal, anthropomorphic measurement, as an indirect indicator of aberrant urogenital development.

The impact of sex hormones on genital wound healing in mice: a comparative study.

INTRODUCTION AND OBJECTIVE: The effects estrogen and testosterone have on penile wound healing are still uncertain. This study evaluated the effects of these hormones on the wound healing process of penile and non-penile skin in wild-type (Mus musculus species) 4-5-week-old mice. METHODOLOGY: Seventy wild-type Mus musculus species were randomly assigned to four groups control (n = 17), 1-week post-operative topical estrogen (n = 18), 1-week pre-operative testosterone (n = 17), and immediate post-operative testosterone (n = 18). Incisions were made on the ventrum of the penis and dorsal neck skin. On post-operative day 3, 7, and 14, incision sites were harvested. Evaluation was performed grossly for postsurgical penile edema and histologically for inflammatory cell concentration, presence of fibrinopurulent materials and distribution of collagen-fibroblastic cells. Each treatment group was compared at the three post-operative time points using the Fisher-Freeman--Halton exact test. CD34 and androgen receptor immunohistostaining was performed for between-group differences to assess microvascular density or vasodilatation and androgen receptor upregulation. RESULTS: In this study, the experiment noted significant penile edema on post-operative day 7 in the testosterone groups, whereas less edema in the estrogen group (P = 0.010; Figure). On histologic evaluation of the penile wounds, a significantly increased inflammatory cell concentration was noted for both pre-operative and post-operative testosterone groups on post-operative day 14 (P = 0.023). The estrogen group revealed significantly increased fibrinopurulent material on the 3rd and 7th post-operative days (P = 0.045 and P = 0.005, respectively). No significant between-group differences in the collagen-fibroblastic distribution were noted over the three-time phases. On histologic evaluation of the skin wounds, no significant differences were noted between the groups for inflammatory cell concentration and presence of fibrinopurulent materials. However, compared with the testosterone treatment groups, a significant higher collagen-fibroblast distribution was noted in the estrogen groups on post-operative day 3 and 14 (P = 0.001 and P = 0.044, respectively). CONCLUSION: Sex hormones, when given peri-operatively, may affect the wound healing process in mice. Testosterone appears to stimulate a prolonged inflammatory effect on penile wounds. Conversely, estrogen induces a fibrinopurulent congregation early in the penile wound healing process. For general skin healing, estrogen induces earlier collagen and fibroblast distribution, whereas testosterone has a delayed effect. The findings of this study should be further investigated in larger animal model with longer follow-up period.

Impact of previous abdominal surgery on the outcome of laparoscopy-assisted open appendicovesicostomy (Mitrofanoff) creation in children: a comparative study.

INTRODUCTION AND OBJECTIVE: For patients who require self-intermittent catheterization, a continent catheterizable stoma is a viable option. This patient population often has had previous abdominal surgery (PAS), a risk factor for complicated laparoscopic procedures. Therefore, the authors aim to determine whether PAS has an impact on the peri-operative outcomes of the laparoscopic-assisted Mitrofanoff procedure in children. MATERIALS AND METHODS: A research ethics board-approved retrospective review was performed to assess peri-operative outcomes among pediatric patients who underwent laparoscopic-assisted Mitrofanoff procedures in the authors institution from May 2000 to March 2016. Patients with no PAS were compared with those with intraperitoneal PAS. Demographic/baseline characteristics and peri-operative outcomes such as operative time, estimated blood loss, hospital stay, unanticipated additional operations, stomal stenosis, and urinary continence were compared. To ensure there is no confounding based on PAS characteristics, subgroups were created to compare the recency (PAS <1 year ago) and extent (ventriculoperitoneal (VP) shunt vs non-VP shunt PAS) to assess their peri-operative outcomes. Fisher's exact test and Mann-Whitney U test were used to determine statistical significance. RESULTS: Thirty-four patients (15 no PAS and 19 PAS) were included in the analysis. No significant difference in demographics and baseline characteristics was noted between the patient groups. The median age was 6.5 years (interquartile range [IQR] 4.8-14.0) and 9.9 years (4.2-14.3), respectively (NS). Peri-operative outcomes of operative time, estimated blood loss, and hospital stay were similar between the PAS and no PAS groups. There was no statistical difference in complications requiring surgical intervention (n = 3, 20.0%; n = 9, 47.4%). The median follow-up period was 25.9 (IQR 7.7-47.2) months and 28.0 (IQR 13.0-53.0) months, respectively (NS). Patients with VP shunts as their only PAS had higher estimated blood loss compared with no PAS group (50 [IQR 25-150], 25 [IQR 25-50], respectively) but without other differences in peri-operative outcomes. DISCUSSION: Findings support the use of a minimally invasive approach in this patient population as it is feasible, comparable, and safe but with careful consideration for risk factors that may predispose PAS patients to postsurgical complications requiring intervention. Although limited by small sample size, this study provides valuable insight into performing laparoscopic operations in children who have undergone prior surgeries and invites future studies to compare the outcomes between patients undergoing open, pure laparoscopic, and robotic-assisted laparoscopic Mitrofanoff procedures for children with PAS. CONCLUSION: Laparoscopic-assisted Mitrofanoff creation may be safely performed in children with PAS.