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Introduction The management of chronic scrotal pain is long and varied, with historical treatment algorithms typically ending with orchiectomy. Microsurgical denervation of the spermatic cord (MDSC) is a testicle-sparing option for patients who have failed conservative treatment options and over its forty-year history has seen many technical refinements. Objectives To review the history and development of MDSC and discuss the outcomes of different surgical techniques. Methods A literature review using PubMed and Google Scholar was conducted to identify studies pertaining to surgical treatment of CSP, MDSC, and outcomes. Search terms included “chronic,” “scrotal pain,” “orchialgia,” “spermatic cord,” “denervation,” and “microsurgery.” Results We included 21 case reports and series since the first seminal paper describing MDSC technique in 1978. Additional studies that challenged existing conventions or described novel techniques are also discussed. The current standard procedure utilizes a subinguinal incision and a surgical microscope. Open, robotic, and laparoscopic approaches to MDSC have been described, but access to minimally invasive instruments may be limited outside of developed nations. Pain reduction following preoperative spermatic cord predicts success of MDSC. Methods for identifying and preserving the testicular and deferential arteries vary depending on surgeon preference but appear to have comparable outcomes. Future developments in MDSC involve targeted denervation, minimizing collateral thermal injury, and alternative techniques to visualize arterial supply. Conclusion For patients suffering from CSP, MDSC is a well-studied technique that may offer appropriately selected patients’ relief. Future investigation comparing targeted vs full MDSC as well as in vivo study of new techniques are needed to continue to improve outcomes.

Pressure injuries are a significant problem following spinal cord injury (SCI). High interface pressures while lying on a spine board during emergency transport appear to play a major role in their formation. The aim of the present study was to assess the interface pressures and sensing area between the body and the standard spine board (SSB) and a proof of concept spine board prototype (P-5). Twenty-one able-bodied subjects were assessed on each board. Interface pressures and sensing area were recorded every minute over 15 min. The mean peak pressure was higher on the SSB at the head, scapulothoracic (S-T), sacroiliac (S-I), and heels (227.6 mmHg, 148.9 mmHg, 360.3 mmHg, and 179.3 mmHg) compared to P-5 (51.9 mmHg, 60.1 mmHg, 66.8 mmHg, and 60.2 mmHg). The peak pressure index (PPI) at the head, S-T and S-I was higher on the SSB (100.2 mmHg, 101.6 mmHg, and 270.6 mmHg) compared to P-5 (41.6 mmHg, 51.9 mmHg and 58.7 mmHg). An analysis using pairwise comparisons for repeated measures showed that interface pressures (p < .05) and PPI (p < .001) were reduced at all locations. Modifications of a spine board incorporated in P-5 can dramatically reduce interface pressures and reduce pressure injury formation.

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.

Objective To better understand the interplay of socioeconomic and demographic traits on bladder cancer outcomes utilizing the Ohio state cancer registry, Ohio Cancer Incidence Surveillance System (OCISS). Methods We obtained demographic, clinical and outcome data on 47,182 bladder cancer cases diagnosed from 1996 to 2016 from OCISS. Multivariable Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between sex, race and poverty and survival, adjusting age, stage, and primary treatment. Results Within the OCISS database, there were 47,182 patients with a diagnosis of bladder cancer identified, with females representing 12,056 (26%) of the population. There were a total of 9255(35.2%) deaths due to bladder cancer, with median follow-up time of 4.4 years. After adjusting for confounding variables, women were statistically significantly less likely to die from any cause (HR: 0.94, 95% CI: 0.91-0.96), compared with men, but more likely to die from bladder cancer (HR: 1.21, 95% CI: 1.15-1.27). We also found that after adjusting for confounding variables, including sex and poverty, black race was statistically significantly associated with a higher risk of overall (HR: 1.12, 95% CI: 1.06-1.18) and bladder cancer-specific mortality (HR: 1.25, 95% CI: 1.15-1.36). Conclusion Using the OCISS database, female gender, self-reported black race, and neighborhood poverty level were associated with worse bladder cancer-specific survival. By recognizing these disparities, we can prospectively address risk factors in efforts to improve survival among these patient populations.

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.

Transvaginal bladder-neck closure is a definitive surgical option for urethral erosion due chronic bladder catheterization in patients with neurogenic bladder. Surgeons who perform female pelvic reconstructive surgery have limited exposure to this procedure in their training. The purpose of this video is to demonstrate a transvaginal bladder-neck closure due to urethral erosion in a patient with neurogenic bladder due to persistent neuropathy from Guillain-Barre syndrome managed with prolonged catheter drainage. We used a live-action surgical demonstration to describe transvaginal bladder-neck closure with urinary diversion. This video provides a step-by-step approach to transvaginal bladder-neck closure as treatment for urethral erosion from chronic catheterization. This video can be used to educate and train those performing female pelvic reconstructive surgery. Surgeons who perform female pelvic surgery should be familiar with the complications of chronic Foley catheterization and treatment options that include transvaginal bladder-neck closure. This video may be used to facilitate reproducibility and comprehension of this procedure.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor

Therapies that suppress RIPK1 kinase activity are emerging as promising therapeutic agents for the treatment of multiple inflammatory disorders. The ability to directly measure drug binding of a RIPK1 inhibitor to its target is critical for providing insight into pharmacokinetics, pharmacodynamics, safety and clinical efficacy, especially for a first‐in‐class small‐molecule inhibitor where the mechanism has yet to be explored. Here, we report a novel method for measuring drug binding to RIPK1 protein in cells and tissues. This TEAR1 (Target Engagement Assessment for RIPK 1) assay is a pair of immunoassays developed on the principle of competition, whereby a first molecule (ie, drug) prevents the binding of a second molecule (ie, antibody) to the target protein. Using the TEAR1 assay, we have validated the direct binding of specific RIPK1 inhibitors in cells, blood and tissues following treatment with benzoxazepinone (BOAz) RIPK1 inhibitors. The TEAR1 assay is a valuable tool for facilitating the clinical development of the lead RIPK1 clinical candidate compound, GSK2982772, as a first‐in‐class RIPK1 inhibitor for the treatment of inflammatory disease.