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PURPOSE OF REVIEW: Botulinum neurotoxin A (BoNT/A), or Botox, is a popular option for overactive bladder (OAB) and neurogenic bladder (NGB) with or without incontinence. This review aims to discuss the clinical outcomes of BoNT in adult and pediatric bladder conditions, and introduces the potential benefit of novel, engineered neurotoxins beyond BoNT/A. RECENT FINDINGS: A large volume of evidence supports the use of Botox for OAB (to reduce urgency, frequency and incontinence episodes), and for NGB (to decrease incontinence and improve bladder capacity and detrusor pressures). Botox is now also Food & Drug Administration (FDA)-approved for pediatric neurogenic detrusor overactivity. However, urinary retention, diminished response over time and treatment failures are prevalent issues with Botox. Modifying natural BoNTs or forming chimeric toxins are alternatives to BoNT/A that may have higher efficacy and lower side-effect profile. One example is BoNT/B(my-ww). This novel engineered toxin binds to a more commonly expressed synaptotagmin receptor, with potentially more potent paralytic effect and less capacity for systemic diffusion. SUMMARY: Novel engineered neurotoxins may be the next frontier in OAB and NGB therapy.

Botulinum neurotoxins (BoNTs) are the most potent toxins known and are also utilized to treat a wide range of disorders including muscle spasm, overactive bladder, and pain. BoNTs’ ability to target neurons determines their specificity, potency, and therapeutic efficacy. Homologous synaptic vesicle membrane proteins synaptotagmin-1 (Syt1) and synaptotagmin-2 (Syt2) have been identified as receptors for BoNT family members including BoNT/B, DC, and G, but their contributions at physiologically relevant toxin concentrations in vivo have yet to be validated and established. Here we generated two knockin mutant mouse models containing three designed point-mutations that specifically disrupt BoNT binding in endogenous Syt1 or Syt2, respectively. Utilizing digit abduction score assay by injecting toxins into the leg muscle, we found that Syt1 mutant mice showed similar sensitivity as the wild type mice, whereas Syt2 mutant mice showed reduced sensitivity to BoNT/B, DC, and G, demonstrating that Syt2 is the dominant receptor at skeletal neuromuscular junctions. We further developed an in vivo bladder injection assay for analyzing BoNT action on bladder tissues and demonstrated that Syt1 is the dominant toxin receptor in autonomic nerves controlling bladder tissues. These findings establish the critical role of protein receptors for the potency and specificity of BoNTs in vivo and demonstrate the differential contributions of Syt1 and Syt2 in two sets of clinically relevant target tissues., Author summary Establishing receptors that mediate binding and entry of toxins into host cells is fundamental to understanding the specificity of toxins. The in vivo contribution of candidate receptors can be difficult to elucidate if they are critical for survival. Such a limitation exists for botulinum neurotoxins (BoNTs), a family of bacterial toxins. They are potential bioterrorism agents and are also used to treat growing numbers of medical conditions. Previous studies identified synaptotagmin-1 (Syt1) and homologous synaptotagmin-2 (Syt2) as receptors for BoNT members including type B, G, and DC. However, as Syt1 and Syt2 are essential for survival of animals, there is no viable loss-of-function animal model to establish their role in vivo. Here we created and evaluated two mutant mouse lines containing designed point-mutations in endogenous Syt1 or Syt2, respectively, that specifically disrupt toxin binding. Using these tailor-made mouse models, we demonstrated that Syt2 is the dominant receptor for BoNT/B, DC, and G at skeletal muscle neuromuscular junctions, whereas Syt1 is the dominant receptor in autonomic nerves in bladder tissues. These findings validate the role of Syt1 and Syt2 as toxin receptors in animal models and reveal their differential contributions in two clinically relevant tissues.

AIMS We aimed to describe the effectiveness of Onabotulinumtoxin A (Botox) in children with neurogenic bladder (NGB) unresponsive to medical therapy to determine urodynamic parameters predictive of success. METHODS Children receiving Botox for refractory NGB, between 2008 and 2019, from a single academic center, were included in this study. Botox success was defined as improvement of incontinence and/or urodynamic parameters. RESULTS Of 34 patients who received Botox, 13 (38.2%) had a positive response from their first injection, with improvement in capacity by a median of 35% of expected capacity for age compared to only a 9% increase in those who did not respond clinically. When patients were divided into groups by baseline urodynamic parameters, high-pressure (Pdetmax > 20 cm H2 O) patients had significantly greater improvement in compliance compared with low-pressure patients (p = 0.017). Low compliance patients (

Introduction: Inferior vena cava (IVC) thrombosis occurs in

INTRODUCTION AND OBJECTIVE:Inferior vena cava (IVC) thrombosis occurs in less than 10% of patients with renal cell carcinoma (RCC). Up to 25% of these cases will require IVC interruption or resecti...

INTRODUCTION AND OBJECTIVE:RPLND is a cornerstone of management in advanced testis cancer. Robotic RPLND (R-RPLND) may be associated with reduced morbidity and length of stay compared to traditiona...

INTRODUCTION AND OBJECTIVES:A 2010 AUA survey of empiric medical therapy (EMT) for male infertility found that 25% of urologists would treat infertile males with testosterone (T) while pursuing a p...

Summary Introduction/background Metachronous contralateral inguinal hernias (MCH) occur in approximately 10% of pediatric patients following unilateral inguinal hernia repairs (UIHR). Laparoscopic evaluation of the contralateral internal ring is a method of identifying high-risk individuals for prophylactic contralateral exploration and repair. Objective The objective of this study was to assess variation in utilization of diagnostic laparoscopy, and report costs associated with the evaluation of a contralateral patent processus vaginalis during hernia repair in pediatric hospitals. Study design The Pediatric Health Information System database was searched to identify outpatient surgical encounters for pediatric patients with a diagnosis of inguinal hernia during a 1-year period (2014). Records were identified that contained diagnostic codes for unilateral or bilateral inguinal hernia in combination with a procedure code for open hernia repair with or without diagnostic laparoscopy. Results After exclusions there were 3952 hernia repairs performed at 30 hospitals; median age was 4 years (IQR 1–7), 78.8% were male, and 64.9% Caucasian. Three-quarters (76.7%) had UIHR, 8.6% had unilateral repairs with laparoscopy (UIHRL), 12.2% had bilateral inguinal hernia repairs (BIHR), and 2.4% had bilateral repairs with laparoscopy (BIHRL). Where laparoscopy was used, 78% resulted in a unilateral repair and 22% in a bilateral procedure. The percent of patients undergoing laparoscopy varied from 0 to 57% among hospitals, and 0–100% among surgeons. Pediatric surgeons were more than three times more likely to perform a diagnostic laparoscopy compared with pediatric urologists. Median adjusted costs were $2298 (IQR 1659–2955) for UIHR, $2713 (IQR 1873–3409) for UIHRL, $2752 (IQR 2230–3411) for BIHR, and $2783 (IQR 2233–3453) for BIHRL. Median costs varied over two-fold among hospitals ($1310–4434), and over four-fold among surgeons ($948–5040). Discussion Data suggested that Conclusions Variation existed in the use of laparoscopy during inguinal hernia repairs and associated costs within the current sample from children's hospitals in the United States. The additional costs of laparoscopic evaluation must be considered against the clinical utility and therapeutic consequences of identifying individuals with a higher risk of metachronous contralateral inguinal hernia. Summary Table . Characteristics of population and proportion, and cost of hernia repairs with and without diagnostic laparoscopy. Characteristic Total (n = 3.952) Hernia without laparoscopy (n = 3.515) Hernia with diagnostic laparoscopy (n = 437) Laterality: Unilateral 3375 (85.4) 3033 (86.3) 342 (78.3) Bilateral 577 (14.6) 482 (13.7) 95 (21.7) Age, years: Median (IQR) 4 (1–7) 4 (1–7) 2 (0–5) 665 (16.8) 542 (15.4) 123 (28.1) 1–2 917 (23.2) 815 (23.2) 102 (23.3) 3–5 1034 (26.2) 925 (26.3) 109 (24.9) 6–11 869 (22.0) 784 (22.3) 85 (19.5) 12–18 467 (11.8) 449 (12.8) 18 (4.1) Gender: Male 3115 (78.8) 2807 (79.9) 308 (70.5) Female 837 (21.2) 708 (20.1) 129 (29.5) Race/Ethnicity: Caucasian 2565 (64.9) 2264 (64.4) 301 (68.9) Black 658 (16.6) 586 (16.7) 72 (16.5) Other 587 (14.9) 543 (15.4) 44 (10.1) Missing 142 (3.6) 122 (3.5) 20 (4.6) Hispanic 592 (15.0) 544 (15.5) 48 (11.0) Payer type: Public 1849 (46.8) 1658 (47.2) 191 (43.7) Private 1934 (48.9) 1697 (48.3) 237 (54.2) Self/other 169 (4.3) 160 (4.5) 9 (2.1) Surgeon type: Pediatric surgeon 2766 (70.0) 2387 (67.9) 379 (86.7) Pediatric urologist 1186 (30.0) 1128 (32.1) 58 (13.3) Adjusted cost: $2395 ($1735–3071) $2363 ($1718–3024) $2735 ($1990–3425) Table given as median (IQR) or n (%).

Spina bifida (SB) patients afflicted with myelomeningocele typically possess a neurogenic urinary bladder and exhibit varying degrees of bladder dysfunction. Although surgical intervention in the form of enterocystoplasty is the current standard of care in which to remedy the neurogenic bladder, it is still a stop-gap measure and is associated with many complications due to the use of bowel as a source of replacement tissue. Contemporary bladder tissue engineering strategies lack the ability to reform bladder smooth muscle, vasculature, and promote peripheral nerve tissue growth when using autologous populations of cells. Within the context of this study, we demonstrate the role of two specific populations of bone marrow (BM) stem/progenitor cells used in combination with a synthetic elastomeric scaffold that provides a unique and alternative means to current bladder regeneration approaches. In vitro differentiation, gene expression, and proliferation are similar among donor mesenchymal stem cells (MSCs), whereas poly(1,8-octanediol-cocitrate) scaffolds seeded with SB BM MSCs perform analogously to control counterparts with regard to bladder smooth muscle wall formation in vivo. SB CD34 + hematopoietic stem/progenitor cells cotransplanted with donor-matched MSCs cause a dramatic increase in tissue vascularization as well as an induction of peripheral nerve growth in grafted areas compared with samples not seeded with hematopoietic stem/progenitor cells. Finally, MSC/CD34 + grafts provided the impetus for rapid urothelium regeneration. Data suggest that autologous BM stem/progenitor cells may be used as alternate, nonpathogenic cell sources for SB patient-specific bladder tissue regeneration in lieu of current enterocystoplasty procedures and have implications for other bladder regenerative therapies.

Background The prevalence of type 2 diabetes (T2D) is increasing worldwide and creating a significant burden on health systems, highlighting the need for the development of innovative therapeutic approaches to overcome immune dysfunction, which is likely a key factor in the development of insulin resistance in T2D. It suggests that immune modulation may be a useful tool in treating the disease. Methods In an open-label, phase 1/phase 2 study, patients (N = 36) with long-standing T2D were divided into three groups (Group A, oral medications, n = 18; Group B, oral medications + insulin injections, n = 11; Group C having impaired β-cell function with oral medications + insulin injections, n = 7). All patients received one treatment with the Stem Cell Educator therapy in which a patient’s blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, briefly co-cultures them with adherent cord blood-derived multipotent stem cells (CB-SCs), and returns the educated autologous cells to the patient’s circulation. Results Clinical findings indicate that T2D patients achieve improved metabolic control and reduced inflammation markers after receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C) in Group A and B was significantly reduced from 8.61% ± 1.12 at baseline to 7.25% ± 0.58 at 12 weeks (P = 2.62E-06), and 7.33% ± 1.02 at one year post-treatment (P = 0.0002). Homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that insulin sensitivity was improved post-treatment. Notably, the islet beta-cell function in Group C subjects was markedly recovered, as demonstrated by the restoration of C-peptide levels. Mechanistic studies revealed that Stem Cell Educator therapy reverses immune dysfunctions through immune modulation on monocytes and balancing Th1/Th2/Th3 cytokine production. Conclusions Clinical data from the current phase 1/phase 2 study demonstrate that Stem Cell Educator therapy is a safe approach that produces lasting improvement in metabolic control for individuals with moderate or severe T2D who receive a single treatment. In addition, this approach does not appear to have the safety and ethical concerns associated with conventional stem cell-based approaches. Trial registration ClinicalTrials.gov number, NCT01415726