Factors contributing to telemedicine efficacy in pediatric urology.

INTRODUCTION: Despite swift implementation of telemedicine with the coronavirus disease 2019 pandemic, there is a paucity of research on its use for management of pediatric urology patients. Specifically, there is limited knowledge and inconsistent data on the effectiveness of telemedicine for various pediatric urologic conditions. Our aim was to evaluate the efficacy of pediatric urological care provided via video visits (VVs) at a large tertiary care children's hospital. MATERIAL AND METHODS: We performed a prospective assessment of pediatric urology patients younger than 21 years who had a VV between 5/18/2022 and 5/17/2023. New patients with a testicular diagnosis were not eligible for VVs. After entering the diagnosis and submitting billing using a modifier for telemedicine, clinicians were mandated to select whether the VV allowed for: complete case management (CCM), suboptimal case management (SCM), or incomplete case management (ICM) requiring an in-person visit. Case management categorizations were analyzed according to patient pathology, visit type (i.e., new or established), and patient-centered variables including age, sex, race, insurance type, need for an interpreter, and distress score [a proxy for socioeconomic status]. RESULTS: During the one-year period, there were 3267 telemedicine patients with a median age of 9 years (IQR 3-13) and 57.0% were male. Most VVs (89.3%) were established encounters. Almost 12% of telemedicine patients had external organ pathology (EOP, e.g., phimosis), 43.0% had internal organ pathology (IOP, e.g., hydronephrosis), and 45.1% had functional urological pathology (FUP, e.g., dysfunctional voiding). Clinicians deemed 96.9%, 2.7%, and 0.5% of VVs as having CCM, SCM or ICM, respectively. Telemedicine patients with IOP or FUP were more likely to have CCM, than those with EOP (98.5% and 97.8% vs 87.1%, p < 0.0001). On multivariable analysis, patient age, pathology, and visit type were predictive of VV efficacy. DISCUSSION: Now that telemedicine use has slowed, it is necessary to evaluate and establish its optimal role in pediatric urology. Factors associated with VV efficacy included older patient age, internal organ or functional urological pathology, and established encounters. The long-term success of telemedicine requires suitable patient selection. CONCLUSIONS: Telemedicine is quite effective for the management of a wide variety of pediatric urology patients. Continued evaluation of telemedicine, including multi-institutional investigation and corroboration, is necessary for the development of evidence-based best practice guidelines regarding appropriate, safe, and effective integration of telemedicine that drives pediatric urological care forward to meet the demands of the future.

Temperature-responsive silk-elastinlike protein polymer enhancement of intravesical drug delivery of a therapeutic glycosaminoglycan for treatment of interstitial cystitis/painful bladder syndrome.

Interstitial cystitis (IC), also known as painful bladder syndrome, is a debilitating chronic condition with many patients failing to respond to current treatment options. Rapid clearance, mucosal coating, and tight epithelium create strong natural barriers that reduce the effectiveness of many pharmacological interventions in the bladder. Intravesical drug delivery (IDD) is the administration of therapeutic compounds or devices to the urinary bladder via a urethral catheter. Previous work in improving IDD for IC has focused on the sustained delivery of analgesics within the bladder and other small molecule drugs which do not address underlying inflammation and bladder damage. Therapeutic glycosaminoglycans (GAG) function by restoring the mucosal barrier within the bladder, promoting healing responses, and preventing irritating solutes from reaching the bladder wall. There is an unmet medical need for a therapy that provides both acute relief of symptoms while alleviating underlying physiological sources of inflammation and promoting healing within the urothelium. Semi-synthetic glycosaminoglycan ethers (SAGE) are an emerging class of therapeutic GAG with intrinsic anti-inflammatory and analgesic properties. To reduce SAGE clearance and enhance its accumulation in the bladder, we developed a silk-elastinlike protein polymer (SELP) based system to enhance SAGE IDD. We evaluated in vitro release kinetics, rheological properties, impact on bladder function, pain response, and bladder inflammation and compared their effectiveness to other temperature-responsive polymers including Poloxamer 407 and poly(lactic-co-glycolic acid)-poly(ethylene glycol). SAGE delivered via SELP-enhanced intravesical delivery substantially improved SAGE accumulation in the urothelium, provided a sustained analgesic effect 24 h after administration, and reduced inflammation.

IL-33 mast cell axis is central in LL-37 induced bladder inflammation and pain in a murine interstitial cystitis model.

Interstitial cystitis (IC), also known as painful bladder syndrome (PBS), is a debilitating chronic condition that afflicts over 3 million women above the age of 18 in the U.S., and most patients fail to respond to current treatment options. Mast cells have previously been implicated as both a diagnostic and prognostic marker in IC/PBS. Patients with IC/PBS have been shown to have elevated levels of IL-33, a cytokine released in response to tissue insult, in their urine. We hypothesize that mast cell-mediated inflammation induced from IL-33 may play an important role in initiating pain and inflammation in IC/PBS. A human cathelicidin, LL-37, which is found at elevated levels in IC/PBS patients, was used to induce an IC/PBS-like state of inflammation and bladder pain in mast cell deficient C-kit (-/-) and wild type C57Bl/6 (WT) mice. Inflammation was quantified using myeloperoxidase (MPO) expression in bladder tissues measured via ELISA. Response rate to suprapubic stimulation from von Frey filaments was used to assess the relative pain and discomfort. Both types of mice increased IL-33 expression in response to LL-37 exposure. However, mast cell deficient mice demonstrated significantly lower levels of inflammation (p < 0.001) and reduced pain response (p < 0.001) compared to WT mice. These findings implicate an IL-33-mast cell dependent axis with a potential etiology of pain and inflammation in IC/PBS. Future therapeutics aimed at targeting the IL-33 - mast cell axis could potentially serve as useful targets for treating IC/PBS.

Bladder pain in an LL-37 interstitial cystitis and painful bladder syndrome model.

Our goal was to evaluate the pain response in an LL-37 induced murine model for interstitial cystitis/painful bladder syndrome (IC/PBS). In particular, we sought to characterize the dose dependence, time-course, and relationship of LL-37 induced bladder inflammation and pain. The IC/PBS model was induced in C57Bl/6 mice by instilling 50 µL of LL-37, an immunomodulatory human cathelicidin (anti-microbial peptide), in the bladder for 1 hr. Pain responses were measured using von Frey filaments (0.04 gm to 4.0 gm) before and after LL-37 instillation. Inflammation was evaluated using tissue myeloperoxidase (MPO) assay, gross inspection, and microscopic histologic examination. The dose response experiment demonstrated a graded pain response, with higher concentrations of LL-37 challenge yielding higher pain responses across all stimuli tested. Statistical significance was seen when comparing 1.0 gm von Frey filament results at 320 µM (68 ± 8% response) vs. 0 µM (38 ± 6% response). Interestingly, pain responses did not attenuate across time but increased significantly after 5 (p=0.0012) and 7 days (p=0.0096). Comparison with MPO data suggested that pain responses could be independent of inflammation. We demonstrated within our LL-37 induced IC/PBS model pain occurs in a dose-dependent fashion, pain responses persist beyond the initial point of insult, and our dose response and time course experiments demonstrated that pain was independent of inflammation.

Combination of Extracorporeal Shockwave Lithotripsy and Ureteroscopy for Large Staghorn Calculi in a Pediatric Patient: Case Report.

Background: Extracorporeal shockwave lithotripsy (SWL) is a procedure commonly performed to treat nephrolithiasis, with promising results in pediatric patients. However, increasing renal calculi size is directly related to worsening stone-free rates. There are few reports in the literature of >2-cm staghorn calculi that expound on the exact mechanism of treatment in the pediatric population. Case Presentation: We present a case report of a 3-year-old boy who presented with a large 3-cm staghorn calculi effectively treated with one session of SWL followed by a planned staged ureteroscopy for definitive treatment. Conclusion: Despite the numerous studies limiting the use of SWL to treat stones <2 cm, if used in softer composition stones, coupled with the larger focal volume involved with smaller patients, SWL when used in combination with adjunctive ureteroscopy is a safe and effective treatment option.

Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis.

Radiation-induced proctitis (RIP) is the most common clinical adverse effect for patients receiving radiotherapy as part of the standard course of treatment for ovarian, prostate, colon, and bladder cancers. RIP limits radiation dosage, interrupts treatment, and lowers patients' quality of life. A prophylactic treatment that protects the gastrointestinal tract from deleterious effects of radiotherapy will significantly improve patient quality of life and may allow for higher and more regular doses of radiation therapy. Semi-synthetic glycosaminoglycan (GAG), generated from the sulfation of hyaluronic acid, are anti-inflammatory but have difficulty achieving therapeutic levels in many tissues. To enhance the delivery of GAG, we created an in situ gelling rectal delivery system using silk-elastinlike protein polymers (SELPs). Using solutions of SELP 815K (which contains 6 repeats of blocks comprised of 8 silk-like units, 15 elastin-like units, and 1 lysine-substituted elastin-like unit) with GAG GM-0111, we created an injectable delivery platform that transitioned in <5min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30min and enhanced the accumulation of GAG in the rectum compared to traditional enema-based delivery. Using a murine model of radiation-induced proctitis, the prophylactic delivery of a single dose of GAG from a SELP matrix administered prior to irradiation significantly reduced radiation-induced pain after 3, 7, and 21days by 53±4%, 47±10%, and 12±6%, respectively. Matrix-mediated delivery of GAG by SELP represents an innovative method for more effective treatment of RIP and promises to improve quality of life of cancer patients by allowing higher radiotherapy doses with improved safety.

Topical cathelicidin (LL-37) an innate immune peptide induces acute olfactory epithelium inflammation in a mouse model.

BACKGROUND: Cathelicidin (LL-37) is an endogenous innate immune peptide that is elevated in patients with chronic rhinosinusitis (CRS). The role of LL-37 in olfactory epithelium (OE) inflammation remains unknown. We hypothesized that: (1) LL-37 topically delivered would elicit profound OE inflammation; and (2) LL-37 induced inflammation is associated with increased infiltration of neutrophils and mast cells. METHODS: To test our hypothesis we challenged C57BL/6 mice intranasally with increasing concentrations of LL-37. At 24 hours tissues were examined histologically and scored for inflammatory cell infiltrate, edema, and secretory hyperplasia. In separate experiments, fluorescently conjugated LL-37 was instilled and tissues were examined at 0.5 and 24 hours. To test our last hypothesis, we performed tissue myeloperoxidase (MPO) assays for neutrophil activity and immunohistochemistry for tryptase to determine the mean number of mast cells per mm(2) . RESULTS: LL-37 caused increased inflammatory cell infiltrate, edema, and secretory cell hyperplasia of the sinonasal mucosa, with higher LL-37 concentrations yielding significantly more inflammatory changes (p < 0.01). Fluorescent LL-37 demonstrated global sinonasal epithelial binding and tissue distribution. Further, higher concentrations of LL-37 led to significantly greater MPO levels with dose-dependent increases in mast cell infiltration (p < 0.01). CONCLUSION: LL-37 has dramatic inflammatory effects in the OE mucosa that is dose-dependent. The observed inflammatory changes in the olfactory mucosa were associated with the infiltration of both neutrophils and mast cells. Our biologic model represents a new model to further investigate the role of LL-37 in OE inflammation.