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Abstract The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex. RAGE is highly expressed only in the lung at readily measurable levels but increases quickly at sites of inflammation, largely on inflammatory and epithelial cells. It is found either as a membrane-bound or soluble protein that is markedly upregulated by stress in epithelial cells, thereby regulating their metabolism and enhancing their central barrier functionality. Activation and upregulation of RAGE by its ligands leads to enhanced survival. Perpetual signaling through RAGE-induced survival pathways in the setting of limited nutrients or oxygenation results in enhanced autophagy, diminished apoptosis, and (with ATP depletion) necrosis. This results in chronic inflammation and in many instances is the setting in which epithelial malignancies arise. RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress. Understanding the molecular structure and function of it and its ligands in the setting of inflammation is critically important in understanding the role of this receptor in tumor biology.

Think about 6 loved ones of reproductive age in your life. Now imagine that 1 of these 6 individuals is suffering from infertility. Perhaps they feel alone and isolated, unable to discuss their heartbreak with their closest friends, family, and support network. Suffering in silence. In this editorial, we discuss the infertility journey through the lens of the patients, the providers, and the scientists who struggle with infertility each and every day. Our goal is to open a dialogue surrounding infertility, with an emphasis on dismantling the longstanding societal barriers to acknowledging male infertility as a disease. Through education, communication, compassion, and advocacy, together we can all begin to break the deafening silence of male infertility., Competing Interests: Declaration of Competing Interest Jake Anderson: Owner, FertilityIQ. The other authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: A manufacturer's benefit verification database was evaluated to ascertain United States health plan insurance coverage for implantable penile prostheses for erectile dysfunction., Methods: All-payer and employer-sponsored health plan benefit verification databases were queried to determine implantable penile prosthesis approval status. For the all-payer analysis, data by payer were available and presented for 2019-2021 to assess approval status varied by payer and over time. For the employer-sponsored health plan analysis, data by payer were available from 2018-2021., Results: Benefit verification records for the all-payer database were available for 3,167 patients in 2019, 3,016 in 2020, and 2,837 in 2021. Insurance type was preferred provider organization (27.5%), Medicare Advantage (26.9%), Medicare (15.9%), or point-of-service (10.5%). Most patients were approved or verified for implantable penile prosthesis coverage (79.4% in 2019, 79.6% in 2020, and 78.4% in 2021). Coverage was most extensive for government-based insurance (Medicare 98.7%, Medicare Advantage 97.1%, Tricare 100%, and Veterans Affairs 80.0%) but was also favorable for commercial insurance (75.0%). The most common reason for lack of coverage was employer exclusion; the proportion of patients with no coverage due to exclusion increased from 13.5% in 2019 to 17.5% in 2021. Analyses of the employer-sponsored health plan database (n=3,083 patients) showed that 63.1% of patients were approved or verified for coverage and 34.2% did not have coverage due to health plan exclusions., Conclusions: Approximately 80% of patients had implantable penile prosthesis coverage. Employer exclusion was the most common reason for lagging coverage; rates of employer exclusion increased 29.3% from 2019-2021.

Objective: To add to the literature which has reported higher attrition rates amongst General Surgery residents who identify as female or underrepresented in medicine (URM), we aimed to determine how these factors contribute to attrition within Urology. We hypothesized that women and URM Urology residents will similarly have higher attrition rates., Methods: The Association of American Medical Colleges surveyed residents to obtain matriculation and attrition status from 2001 to 2016. Data included demographics, medical school type, and specialty. A multivariable logistic regression model was performed to identify predictors of attrition amongst Urology residents., Results: In our sample of 4321 Urology residents, 22.5% were female, 9.9% were URM, 25.8% were older than 30 years, 2.5% were Doctor of Osteopathic Medicine graduates and 4.7% were International Medical Graduates. On multivariable analysis, being female (Odds ratio [OR] = 2.3, P < .001) was associated with increased residency attrition when compared to male residents. Additionally, residents who matriculated between 30 and 39 years old (OR = 1.9, P < .001) or ≥40 years old (OR = 10.7, P < .001) had an increased risk of residency attrition when compared to residents who matriculated between 26 and 29 years old. Attrition rates for URM trainees have recently increased., Conclusion: Women, older, and URM Urology residents experience higher rates of attrition compared to their peers. It is essential to identify trainees with a higher likelihood of attrition to determine system-level changes to combat departures from training programs. Our study highlights the need to foster more inclusive training environments and change institutional cultures to diversify the surgical workforce., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: We aimed to assess safety and efficacy of incobotulinumtoxinA for the treatment of neurogenic detrusor overactivity (NDO)., Methods: We identified patients with NDO confirmed on urodynamics (UDS) and reported urgency incontinence (UI) in those who received intravesical incobotulinumtoxin A injection for neurogenic bladder between November 2013 and May 2017. Parameters studied were daytime frequency, daily incontinence episodes, daily pad use, clean intermittent catheterization (CIC) volumes, symptom scores (UDI6, IIQ7, PGII), and complications., Results: We examined 17 male patients who met inclusion criteria and underwent incobotulinumtoxinA injection. Mean age was 61.2±15.4 years. Fourteen patients (82%) were taking oral antimuscarinics prior to the incobotulinumtoxin A injection. There were improvements in the following parameters: average daily pads (4.5 to 3.3, p=0.465), daily urinary frequency (9.4 to 4.6, p=0.048), daily incontinent episodes (2.5 to 0.4, p=0.033), CIC volumes (400 to 550 mL, p=0.356), hours in between CIC (3.6 to 5.2, p=0.127), and the validated questionnaires UDI6 (30.6 to 7.4, p=0.543) and IIQ7 (52.4 to 6.8, p=0.029). There were no documented symptomatic urinary tract infections (UTIs) within 30 days of injection or reports of de novo urinary retention. Nine of 17 patients (53%) reported being dry at their first postoperative visit., Conclusions: In this preliminary pilot study of a small cohort of males with NDO and UI, significant improvements were seen following incobotulinumtoxinA injection in daily frequency, incontinence episodes, hours in between CIC, and quality of life. Larger-scale and long-term studies are required to confirm these results, but initial findings are promising for wider use of this formulation.

Purpose: Hysterectomy (Hys) is the most common non-urologic surgery associated with iatrogenic genitourinary (GU) injury. We present the largest known population-based evaluation of GU injury related to benign Hys., Methods: The New York Statewide Planning and Research Cooperative System (SPARCS) was queried by ICD-9 and CPT codes. SPARCS for women from 1995 to 2014, who underwent laparoscopic or robotic Hys (minimally invasive surgery = MIS), abdominal Hys (AH), and vaginal Hys (VH) for benign diagnoses. Bladder and ureteral repairs were captured based on the procedure codes. Codes for ureteroneocystotomy (UNC) were compared to any other ureteral repairs, to elucidate injury patterns. Statistical analysis was conducted using Chi squared test, ANOVA, Mann-Whitney test and Poisson Regression and multivariable analysis were performed., Results: 516,340 women underwent Hys for a benign etiology. 69% were AH, 25% VH, and 6% were MIS. 7490 patients (1.45%) had a concomitant GU injury. Compared to VH, MIS and AH were associated with greater odds of bladder and ureteral injury (p < 0.001). MIS and AH, compared to VH, were associated with reduced odds of UNC compared to complex reconstruction (OR 0.27, p < 0.001 and OR 0.12, p < 0.00, respectively). The injured cohort had higher total mean charges ($29,889 vs $15,808) and length of hospitalization (6.32 vs 3.56 days) (p < 0.001)., Conclusions: Bladder and ureteral injuries during hysterectomy are uncommon in contemporary practice and are lower than historical rates. GU injury increases hospitalization cost. VH is associated with the lowest rate of GU injury, and thus appears to be a valuable approach, when feasible.

Purpose: We evaluated the impact of varicocele grade on the response to varicocelectomy or spermatic vein embolization., Materials and Methods: We systematically reviewed the published English language literature to identify studies on changes in semen quality and pregnancy outcomes after varicocele treatment, stratified by varicocele grade. Descriptive statistics and continuous random effects models were used to study the impact of varicocele grade and the surgical approach on the response to treatment. Result heterogeneity among studies was analyzed using the I 2 statistic. Quality assessment of nonrandomized studies was done with the Newcastle-Ottawa Scale. Publication bias was analyzed using funnel plots and the Egger test., Results: We identified 20 studies describing the outcome of varicocele treatment stratified by varicocele grade in a total of 2,001 infertile men with varicocele. A microsurgical approach (inguinal, subinguinal and/or Palomo) was used in 11 of the 20 studies (55%). Varicocele treatment was associated with improvements in sperm concentration and overall motility in patients with all grades of varicocele. Semen quality improvements were directly related to varicocele grade. The mean sperm concentration improvement in men with grades 1, 2, 2-3 and 3 varicoceles were 5.5, 8.9, 12.7 and 16.0 million sperm per ml, respectively. The mean improvement in the percent of overall motility in men with grades 1, 2, 2-3 and 3 varicoceles was 9.6%, 10.6%, 10.8% and 17.7%, respectively. Pregnancy outcomes were assessed but could not be analyzed systematically due to the lack of adequate published data., Conclusions: Mean improvements in the sperm concentration and the percent of overall motility after treatment of grade 1 varicocele were statistically significant but small in magnitude. In contrast, mean improvements in the sperm concentration and the percent of overall motility after treatment of grade 2-3 varicoceles were greater and highly likely to be clinically significant. Incorporating varicocele grade into shared decision making discussions with affected couples may improve the ability to select patients who are the best candidates for treatment.

Objective: To evaluate the quality of web-based information on ablative therapies for prostate cancer., Methods: The 2 most common search engines (Google and Bing) were queried for the following terms: "prostate cancer" + "HIFU" and "cryotherapy," respectively. The top 50 websites for each were obtained. Websites were characterized and analyzed regarding their accuracy and completeness of information using criteria determined a priori. Academic papers were excluded., Results: Of "HIFU" search results, 17% were advertisements, 13% and 29% were academic and private practice websites, respectively. Erroneous information on oncological efficacy was presented in 15% and 41% of academic and private practice websites, respectively. Criteria for treatment were mentioned in 31% and 66% of academic and private practice websites, respectively. Of "cryotherapy" search results, 18% were advertisements, 15% academic sites, and 11% private practices. Erroneous information was presented in 73% of both academic and private practice websites. Criteria for treatment were mentioned in 27% and 18% of these sites, respectively. Seventy eight percent and 75% of HIFU and cryotherapy sites, respectively, mentioned general side effects., Conclusion: There is substantial inaccurate and incomplete information on the Internet regarding ablative treatments for prostate cancer from academic and private practice websites. Selection criteria are uncommonly discussed. More attention to accuracy of information is needed to ensure patients are not misled about the data behind these treatments., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Critical care is often an integral part of rescue for patients with surgical complications. We sought to understand critical care characteristics predictive of failure-to-rescue (FTR) performance at the hospital level., Methods: Using 2009 to 2011 FTR data from Hospital Compare, we identified 144 outlier hospitals with significantly better/worse performance than the national average. We surveyed intensive care unit (ICU) directors and nurse managers regarding physical structures, patient composition, staffing, care protocols, and rapid response teams (RRTs). Hospitals were compared using descriptive statistics and logistic regression., Results: Of 67 hospitals completing the survey, 56.1% were low performing, and 43.9% were high performing. Responders were more likely to be teaching hospitals (40.9% vs 25.0%; P=.05) but were similar to nonresponders in terms of size, region, ownership, and FTR performance. Poor performers were more likely to serve higher proportions of Medicaid patients (68.4% vs 20.7%; P<.0001) and be level 1 trauma centers (55.9% vs 25.9%; P=.02). After controlling for these 2 characteristics, an intensivist on the RRT (adjusted odds ratio, 4.27; confidence interval, 1.45-23.02; P=.005) and an internist on staff in the ICU (adjusted odds ratio, 2.13; P=.04) were predictors of high performance., Conclusions: Intensivists on the RRT and internists in the ICU may represent discrete organizational strategies for improving patient rescue. Hospitals with high Medicaid burden fare poorly on the FTR metric., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Cancer vaccination may be our best and most benign option for preventing or treating metastatic cancer. However, breakthroughs are hampered by immune suppression in the tumor microenvironment. In this study, we analyzed whether cyclic diguanylate (c-di-GMP), a ligand for stimulator of interferon genes (STING), could overcome immune suppression and improve vaccination against metastatic breast cancer. Mice with metastatic breast cancer (4T1 model) were therapeutically immunized with an attenuated Listeria monocytogenes (LM)-based vaccine, expressing tumor-associated antigen Mage-b (LM-Mb), followed by multiple low doses of c-di-GMP (0.2 μmol/L). This treatment resulted in a striking and near elimination of all metastases. Experiments revealed that c-di-GMP targets myeloid-derived suppressor cells (MDSC) and tumor cells. Low doses of c-di-GMP significantly increased the production of IL12 by MDSCs, in correlation with improved T-cell responses to Mage-b, whereas a high dose of c-di-GMP (range, 0.3-3 mmol/L) activated caspase-3 in the 4T1 tumor cells and killed the tumor cells directly. On the basis of these results, we tested one administration of high-dose c-di-GMP (3 mmol/L) followed by repeated administrations of low-dose c-di-GMP (0.2 μmol/L) in the 4T1 model, and found equal efficacy compared with the combination of LM-Mb and c-di-GMP. This finding correlated with a mechanism of improved CD8 T-cell responses to tumor-associated antigens (TAA) Mage-b and Survivin, most likely through cross-presentation of these TAAs from c-di-GMP-killed 4T1 tumor cells, and through c-di-GMP-activated TAA-specific T cells. Our results demonstrate that activation of STING-dependent pathways by c-di-GMP is highly attractive for cancer immunotherapy., (©2014 American Association for Cancer Research.)

Success of cancer vaccination is strongly hampered by immune suppression in the tumor microenvironment (TME). Interleukin (IL)-6 is particularly and highly produced by triple-negative breast cancer (TNBC) cells, and has been considered as an important contributor to immune suppression in the TME. Therefore, we hypothesized that IL-6 reduction may improve efficacy of vaccination against TNBC cancer through improved T-cell responses. To prove this hypothesis, we investigated the effect of curcumin, an inhibitor of IL-6 production, on vaccination of a highly attenuated Listeria monocytogenes (Listeria(at)), encoding tumor-associated antigens (TAA) Mage-b in a TNBC model 4T1. Two therapeutic vaccination strategies with Listeria(at)-Mage-b and curcumin were tested. The first immunization strategy involved all Listeria(at)-Mage-b vaccinations and curcumin after tumor development. As curcumin has been consumed all over the world, the second immunization strategy involved curcumin before and all therapeutic vaccinations with Listeria(at)-Mage-b after tumor development. Here, we demonstrate that curcumin significantly improves therapeutic efficacy of Listeria(at)-Mage-b with both immunization strategies particularly against metastases in a TNBC model (4T1). The combination therapy was slightly but significantly more effective against the metastases when curcumin was administered before compared to after tumor development. With curcumin before tumor development in the combination therapy, the production of IL-6 was significantly decreased and IL-12 increased by myeloid-derived suppressor cells (MDSC), in correlation with improved CD4 and CD8 T-cell responses in blood. Our study suggests that curcumin improves the efficacy of Listeria(at)-Mage-b vaccine against metastases in TNBC model 4T1 through reversal of tumor-induced immune suppression.

The Receptor for Advanced Glycation Endproducts [RAGE] is an evolutionarily recent member of the immunoglobulin super-family, encoded in the Class III region of the major histocompatability complex. RAGE is highly expressed only in the lung at readily measurable levels but increases quickly at sites of inflammation, largely on inflammatory and epithelial cells. It is found either as a membrane-bound or soluble protein that is markedly upregulated by stress in epithelial cells, thereby regulating their metabolism and enhancing their central barrier functionality. Activation and upregulation of RAGE by its ligands leads to enhanced survival. Perpetual signaling through RAGE-induced survival pathways in the setting of limited nutrients or oxygenation results in enhanced autophagy, diminished apoptosis, and (with ATP depletion) necrosis. This results in chronic inflammation and in many instances is the setting in which epithelial malignancies arise. RAGE and its isoforms sit in a pivotal role, regulating metabolism, inflammation, and epithelial survival in the setting of stress. Understanding the molecular structure and function of it and its ligands in the setting of inflammation is critically important in understanding the role of this receptor in tumor biology.

5-Fluoroanthranilic acid (FAA)-resistant mutants were selected in homothallic diploids of three Saccharomyces species, taking care to isolate mutants of independent origin. Mutations were assigned to complementation groups by interspecific complementation with S. cerevisiae tester strains. In all three species, trp3, trp4 and trp5 mutants were recovered. trp1 mutants were also recovered if the selection was imposed on a haploid strain. Thus, FAA selection may be more generally applicable than was previously described., ((c) 2007 John Wiley & Sons, Ltd.)