Characterizing dysregulations via cell-cell communications in Alzheimer's brains using single-cell transcriptomes.

BACKGROUND: Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting 44 million people worldwide, leading to cognitive decline, memory loss, and significant impairment in daily functioning. The recent single-cell sequencing technology has revolutionized genetic and genomic resolution by enabling scientists to explore the diversity of gene expression patterns at the finest resolution. Most existing studies have solely focused on molecular perturbations within each cell, but cells live in microenvironments rather than in isolated entities. Here, we leveraged the large-scale and publicly available single-nucleus RNA sequencing in the human prefrontal cortex to investigate cell-to-cell communication in healthy brains and their perturbations in AD. We uniformly processed the snRNA-seq with strict QCs and labeled canonical cell types consistent with the definitions from the BRAIN Initiative Cell Census Network. From ligand and receptor gene expression, we built a high-confidence cell-to-cell communication network to investigate signaling differences between AD and healthy brains. RESULTS: Specifically, we first performed broad communication pattern analyses to highlight that biologically related cell types in normal brains rely on largely overlapping signaling networks and that the AD brain exhibits the irregular inter-mixing of cell types and signaling pathways. Secondly, we performed a more focused cell-type-centric analysis and found that excitatory neurons in AD have significantly increased their communications to inhibitory neurons, while inhibitory neurons and other non-neuronal cells globally decreased theirs to all cells. Then, we delved deeper with a signaling-centric view, showing that canonical signaling pathways CSF, TGFß, and CX3C are significantly dysregulated in their signaling to the cell type microglia/PVM and from endothelial to neuronal cells for the WNT pathway. Finally, after extracting 23 known AD risk genes, our intracellular communication analysis revealed a strong connection of extracellular ligand genes APP, APOE, and PSEN1 to intracellular AD risk genes TREM2, ABCA1, and APP in the communication from astrocytes and microglia to neurons. CONCLUSIONS: In summary, with the novel advances in single-cell sequencing technologies, we show that cellular signaling is regulated in a cell-type-specific manner and that improper regulation of extracellular signaling genes is linked to intracellular risk genes, giving the mechanistic intra- and inter-cellular picture of AD.

External Urethral Sphincter Botulinum Toxin Injection to Treat Pseudodysynergia in Patients With Cerebral Palsy.

OBJECTIVE: To evaluate urinary outcomes following cystoscopic external urinary sphincter onabotulinumtoxinA (BTX) injections in patients with cerebral palsy (CP). Adults with CP can suffer from bladder outlet obstruction and urinary retention due to a spastic external urethral sphincter ("pseudodysynergia"). We have used BTX injections into the sphincter to relieve the obstruction and allow patients to maintain spontaneous voiding rather than intermittent catheterization. METHODS: Patients were included in this retrospective cohort study if they had a diagnosis of CP, were at least 18 years of age, and underwent a urethral external sphincter BTX injection between 2016-2023. The procedure included 100 u or 200 u of BTX mixed in 4cc of saline. Primary outcomes were subjective, patient or caregiver reported changes in retention, lower urinary tract symptoms (LUTS), frequency of recurrent urinary tract infections (UTIs), and hydronephrosis or bladder stones/debris on ultrasound. RESULTS: Fifty patients were included; the majority were male (60%), lived at home with assistance (58%), and had a Gross Motor Function Classification System level of V (50%; ie, severe CP). The most common indications for BTX were retention (96%), LUTS (48%), hydronephrosis (18%), and recurrent UTIs (22%). Post-BTX improvement was seen in 67% of those with LUTS, 65% with retention, 67% with hydronephrosis, and 73% with recurrent UTIs. Most patients underwent repeat injections (60%). There were no significant complications associated with injections. CONCLUSION: External urethral sphincter BTX is a safe, effective option for treating pseudodysynergia in adults with CP.

Retrospective Multicenter Observational Study of Immediate Voiding at End of Urinary Sphincter Surgery (REMOVE).

PURPOSE: Patients may remain catheterized after artificial urinary sphincter surgery to prevent urinary retention, despite a lack of evidence to support this practice. Our study aims to evaluate the feasibility of outpatient, catheter-free continence surgery using a multi-institutional database. We hypothesize that between catheterized controls and patients without a catheter, there would be no difference in the rate of urinary retention or postoperative complications. MATERIALS AND METHODS: We conducted a retrospective review of patients undergoing first-time artificial urinary sphincter placement from 2009-2021. Patients were stratified by postoperative catheter status into either no-catheter (leaving the procedure without a catheter) or catheter (postoperative indwelling catheter for ∼24 hours). The primary outcome, urinary retention, was defined as catheterization due to subjective voiding difficulty or documented postvoid residual over 250 mL. RESULTS: Our study identified 302 catheter and 123 no-catheter patients. Twenty (6.6%) catheter and 9 (7.3%) no-catheter patients developed urinary retention (P = .8). On multivariable analysis, controlling for age, cuff size, radiation history and surgeon, there was no statistically significant association between omitting a catheter and urinary retention (OR: 0.45, 95% CI: 0.13-1.58; P = .2). Furthermore, at 30 months follow-up, Kaplan-Meier survival analysis revealed that device survival was 70% (95% CI: 62%-76%) vs 69% (95% CI: 48%-82%) for the catheter and no-catheter group, respectively. CONCLUSIONS: In our multi-institutional cohort, overall retention rates were low (7%) in groups with a catheter and without. Obviating postoperative catheterization facilitates outpatient incontinence surgery without altering reoperation over medium-term follow-up.

Complex ureteral stricture from chronic schistosomiasis requiring ileal ureter interposition: a case report.

Background: Schistosomiasis is most notably associated with squamous cell carcinoma of the bladder, and it is estimated that approximately 10% of people infected will develop a urologic complication. Ureteral pathology is rare and has only been described in a handful of case reports. Increasing awareness of this condition is needed given a recent increase in sub-Saharan immigrant population in the United States (US), as prompt recognition is key to providing optimal care. Case Description: A 40-year-old Kenyan immigrant presented to the emergency department with left-sided flank pain and was found to have left hydronephrosis and three mid-ureteral calcifications. He underwent ureteroscopy where the left ureter appeared blind-ending just proximal to the iliac vessels. A percutaneous nephrostomy tube was placed, and renal pelvis urine was analyzed for mycobacterium tuberculosis and acid fast bacilli which were negative. Antegrade ureteroscopy demonstrated a second, proximal ureteral stricture with a pinpoint lumen. Antegrade and retrograde pyelography revealed a 3 cm mid-ureteral stricture with no contrast passage. Given the stricture length, multifocality, and unclear pathology, we opted to perform ureterectomy with ileal interposition. Final pathology revealed schistosomiasis with calcifications. The patient received two doses of Praizquantel and his stent was removed 6 weeks postoperatively. He is doing well without complications. Conclusions: There is a wide range of urologic complications caused by schistosomiasis infection, and this case highlights an extreme case. Although many patients will present with a fixed urologic complaint, they remain at risk for additional urologic pathology in the future without antihelminthic therapy. This highlights the need for an accurate diagnosis and a high index of suspicion for at-risk populations.

Multi-institutional review of non-hypospadiac penile urethral stricture management and outcomes.

OBJECTIVES: Penile urethral stricture disease not associated with hypospadias is rare, and there is a wide range of commonly used surgical repair techniques for this disease. We sought to compile a multi-institutional database of patients who had surgical correction of strictures in the penile urethra not limited to the meatus, and who had no history of hypospadias, for analysis using the Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology classification system. METHODS: A retrospective database from 13 institutions was compiled of patients who had undergone surgical correction of Trauma and Urologic Reconstructive Network of Surgeons length, urethral segment and etiology urethral stricture segments S2b/S2c and excluding E5, with a minimum follow-up time of 4 months. Failure was defined as cystoscopically confirmed recurrence of a stricture measuring less than 16-Fr. RESULTS: We analyzed 222 patients with a median age of 57 years and a follow-up of 49 months. The overall surgical success rate was 80.2%. On multivariate analysis, the two variables identified that were predictive of surgical success were stricture length ≤2 cm as well as use of a buccal mucosa graft as compared to use of a fasciocutaneous flap, which had success rates of 83% and 52%, respectively (P = 0.0004). No statistically significant differences were found based on incisional approach or surgical technique, nor were outcomes different based on etiology or preoperative patient demographics. CONCLUSIONS: Surgical repair of penile urethral strictures of non-hypospadiac origin have a favorable overall success rate, at 80.2%. Regardless of incisional approach or surgical technique, all operations appear to have similar outcomes other than repairs using fasciocutaneous flap, which were statistically less successful than those using buccal mucosa graft.

A Systematic Review of Randomized Controlled Trials Comparing Buccal Mucosal Graft Harvest Site Non-Closure versus Closure in Patients Undergoing Urethral Reconstruction.

PURPOSE: To assess the effects of buccal mucosal graft site non-closure versus closure on postoperative oral morbidity for male undergoing augmentation urethroplasty for urethral stricture. MATERIALS AND METHODS: We included randomized controlled trials. Inclusion criteria were male over the age of 18 with urethral stricture disease requiring reconstruction with buccal mucosal graft harvest. Primary outcomes of the review were postoperative oral pain, need for secondary oral procedures and cosmetic defects. RESULTS: We included 5 studies with 346 randomized patients with urethral strictures, of whom 260 completed the trials. In terms of primary outcomes, non-closure graft site may reduce oral pain on postoperative day #1 (standard mean difference [SMD] 0.24 lower; 95% confidence interval [CI] 0.61 lower to 0.12 higher; low certainty evidence [CoE]) but we are uncertain how this impacts pain on postoperative days 3 to 6 (SMD 0.35; 95% CI 0.12 to 0.81 higher; very low CoE). We are also very uncertain as to how it affects the need for secondary oral procedures (risk ratio [RR] 0.22; 95% CI 0.01 to 4.28; very low CoE). Non-closure may increase the risk of cosmetic defects (RR 2.40; 95% CI 0.93 to 6.22; low CoE). CONCLUSIONS: This review describes the trade-off for buccal mucosal graft site non-closure versus closure for various patient-important outcomes; decision-making will likely hinge on the relative value individual patients and surgeons place on them. The supporting evidence was rated as low and very low, thereby signaling substantial underlying uncertainty and the need for better trials.

Testicular rupture following rubber bullet trauma case report.

Following civil unrest during 2020, physicians began to notice a variety of injuries resulting from crowd control weapons. While prior research emphasized ocular trauma, genitourinary complications of injuries have yet to be investigated. A previously healthy 27-year-old male presented to the emergency department due to sudden onset of severe left testicular pain following rubber bullet trauma. Physical exam showed extreme tenderness, abrasion, contusion, and edema of the left testicle with normal right testicle. Doppler ultrasound showed minimal blood flow to the superior pole with irregularity of the tunica albuginea. Surgery confirmed testicular rupture with a large tunical violation and extruded spermatic tubules. The testicle was thoroughly irrigated, non-viable tubules were debrided, and intraoperative ultrasound confirmed restoration of blood flow. Patient was discharged and instructed to follow-up should he face any fertility concerns in the future. Current crowd control guidelines state projectiles should be aimed at the lower abdomen or extremities; however, projectiles can cause testicular trauma which may lead to hypogonadism, infection, and psychological impact. Until there are changes to methods of crowd control, attendees should consider the use of athletic cups.

Multicenter urethroplasty outcomes for urethral stricture disease for patients with neurogenic bladder or bladder dysfunction requiring clean intermittent catheterization.

BACKGROUND: Our objective is to better comprehend treatment considerations for urethral stricture disease (USD) in patients requiring long-term clean intermittent catheterization (CIC). Patient characteristics, surgical outcomes and complications are unknown in this population. METHODS: Six members of the Trauma and Urologic Reconstruction Network of Surgeons (TURNS) participated in a prospective (2009 to present) and retrospective (prior to 2009) database recording patient demographics, surgical approach and outcomes. We included all patients undergoing urethroplasty who perform CIC. Descriptive statistics were used to analyze results. RESULTS: A total of 37 patients with 39 strictures were included. Bladder dysfunction was characterized as detrusor failure in 35% and neurogenic etiology in 65%. Median stricture length was 3 cm (IQR: 1.5-5.5) with 28% repaired with dorsal onlay buccal mucosal graft, 26% excision and primary anastomosis, 8% dorsal inlay, 8% ventral and dorsal, 8% flap based 8% non-transecting and 15% other. Functional success was 90%: 4 patients required DVIU or dilation due to recurrence, with 2 of those ultimately requiring repeat urethroplasty. 86% of patients returned to CIC; no patients reported new pad use for urinary leakage after urethroplasty. During a median follow-up period of 3.1 years (IQR: 1.0-5.3), no patients underwent urinary diversion. CONCLUSIONS: Urethroplasty is suitable, safe and effective for patients dependent on CIC suffering from USD. The effect of continual CIC on long-term outcomes remains uncertain.

Detection of the SARS-CoV-2 spike protein in saliva with Shrinky-Dink© electrodes.

Using the children's toy, Shrinky-Dink©, we present an aptamer-based electrochemical (E-AB) assay that recognizes the spike protein of SARS-CoV-2 in saliva for viral infection detection. The low-cost electrodes are implementable at population scale and demonstrate detection down to 1 ag mL-1 of the S1 subunit of the spike protein.

The Management of Complications of Feminizing Gender Affirming Genital Surgery.

Penile inversion vaginoplasty is the most common technique used for gender affirming genital surgery in the treatment of gender dysphoria among transwomen. As vaginoplasty becomes more widely available, the management of associated complications has become its own field. There is a relative dearth of literature on surgery for complications following vaginoplasty. This review illustrates surgical technique and management options for patient reported complaints and complications following vaginoplasty. The goal of this manuscript is 2-fold (1) to introduce community surgeons to common postoperative issues they may encounter and (2) provide a systematic operative approach to complications for reconstructive surgeons who see transgender patients regularly.

Technique and Outcomes of Hand-Assist Laparoscopic Continent Cutaneous Ileocecocystoplasty.

BACKGROUND: Continent cutaneous ileocecocystoplasty (CCIC) involves reconfiguring the ileocecal segment for use as a bladder augment and continent catheterizable channel. CCIC requires release of the hepatic flexure of the colon, which necessitates a longer midline laparotomy than would be required for a standard bladder augmentation. This is associated with high rates of ventral and parastomal hernias. OBJECTIVES: To describe the technique of hand-assist laparoscopic CCIC and to compare outcomes to open CCIC. MATERIALS AND METHODS: We found pure laparoscopic colon mobilization difficult due to significant colonic distension in patients with neurogenic bladder and bowel. We modified our approach to hand-assisted laparoscopic mobilization for better retraction of the bowel. A 12-mm camera port is placed through the umbilicus, which later serves as the stoma site, and a 5-mm assist port is placed a handbreadth cephalad to the 12-mm port. A Pfannenstiel incision is made for use as the hand port. After colonic mobilization is completed the remainder of the procedure is performed in an open fashion through the Pfannenstiel incision. The primary outcome was 90-day Clavien grade 2 or greater complications. Secondary outcomes included revision rates, wound infection, urinary continence, operative time, and length of stay. Data was analyzed using Mann-Whitney U test and Fisher's exact test. RESULTS: Thirty-two laparoscopic and 21 open procedures were reviewed. Those who underwent open procedures were more likely to have undergone prior catheterizable channel or bladder augmentation (7 vs 1, P < .01). There were fewer 90-day complications in the laparoscopic group (18.8% vs 47.6%, P = .03). There was no difference in operative time, hospital length of stay, wound infections, need for subsequent channel revision, or long-term continence between groups. CONCLUSION: Hand-assist laparoscopic CCIC offers a minimally invasive alternative to open CCIC with fewer short-term complications and comparable long-term outcomes.

The reporting quality of randomized controlled trials and experimental animal studies for urethroplasty.

OBJECTIVES: To assess the reporting quality of randomized controlled trials and experimental animal studies examining urethroplasty in reconstructive urological surgery literature. METHODS: We performed a comprehensive literature search to identify all urethroplasty-related RCTs examining humans as well as animal models. We used the Consolidated Standards of Reporting Trials (CONSORT) and the Animals in Research: Reporting in vivo Experiments (ARRIVE) guidelines to assess reporting quality. Two reviewers performed data abstraction independently and in duplicate. We then generated descriptive statistics including CONSORT (0-25) and ARRIVE (0-20) summary scores using the median and interquartile range. RESULTS: Twenty studies were ultimately included; 14 randomized controlled trials and 6 experimental animal studies. All studies were two-armed, parallel group studies. Median sample sizes (and interquartile range) of the human and animal studies were 48.5 (31.8-53.8) and 18 (15.3-27.5), respectively. The median CONSORT and ARRIVE scores were 10.0 (8.75-12.63) and 7.97 (6.79-8.64), respectively. Human randomized controlled trials did not consistently report the method of allocation concealment (6/14; 42.9%), blinding (2/14; 14.3%), or discuss the generalizability of the results (6/14; 42.9%). Animal studies infrequently reported why a given animal model was used (1/6; 16.7%), how they were allocated to groups (0/6; 0%) or what the experimental primary and secondary outcomes were (0/6; 0%). CONCLUSIONS: Urethroplasty literature is marked by a paucity of both randomized controlled trials and experimental design animal studies. The existing studies are inconsistently reported and are therefore of uncertain methodological quality.

Detection of the SARS-CoV-2 spike protein in saliva with Shrinky-Dink© electrodes.

Using the children's toy, Shrinky-Dink ©, we present an aptamer-based electrochemical (E-AB) assay that recognizes the spike protein of SARS-CoV-2 in saliva for viral infection detection. The low-cost electrodes are implementable at population scale and demonstrate detection down to 0.1 fg mL -1 of the S1 subunit of the spike protein.

Contemporary multicenter outcomes of continent cutaneous ileocecocystoplasty in the adult population over a 10-year period: A Neurogenic Bladder Research Group study.

AIMS: Evidence is sparse on the long-term outcomes of continent cutaneous ileocecocystoplasty (CCIC). We hypothesized that obesity, laparoscopic/robotic approach, and concomitant surgeries would affect morbidity after CCIC and aimed to evaluate the outcomes of CCIC in adults in a multicenter contemporary study. METHODS: We retrospectively reviewed the charts of adult patients from sites in the Neurogenic Bladder Research Group undergoing CCIC (2007-2017) who had at least 6 months of follow-up. We evaluated patient demographics, surgical details, 90-day complications, and follow-up surgeries. the Mann-Whitney U test was used to compare continuous variables and χ² and Fisher's Exact tests were used to compare categorical variables. RESULTS: We included 114 patients with a median age of 41 years. The median postoperative length of stay was 8 days. At 3 months postoperatively, major complications occurred in 18 (15.8%), and 24 patients (21.1%) were readmitted. During a median follow-up of 40 months, 48 patients (42.1%) underwent 80 additional related surgeries. Twenty-three patients (20.2%) underwent at least one channel revision, most often due to obstruction (15, 13.2%) or incontinence (4, 3.5%). Of the channel revisions, 10 (8.8%) were major and 14 (12.3%) were minor. Eleven patients (9.6%) abandoned the catheterizable channel during the follow-up period. Obesity and laparoscopic/robotic surgical approach did not affect outcomes, though concomitant surgery was associated with a higher rate of follow-up surgeries. CONCLUSIONS: In this contemporary multicenter series evaluating CCIC, we found that the short-term major complication rate was low, but many patients require follow-up surgeries, mostly related to the catheterizable channel.

Frequency of patient-reported UTIs is associated with poor quality of life after spinal cord injury: a prospective observational study.

STUDY DESIGN: Cross-sectional survey of the Neurogenic Bladder Research Group (NBRG) registry; a multicenter prospective observation study. OBJECTIVES: To assess how patient-reported urinary tract infections (PRUTIs) in spinal cord injury (SCI) affect quality of life (QOL). SETTING: Multiple United States hospitals. METHODS: 1479 participants with SCI were asked about neurogenic bladder-related QOL. Eligibility: age ≥ 18 years with acquired SCI. PRUTI frequency over the last year was classified as 0, 1-3, 4-6, or >6. Four UTI QOL domains were assessed: (1) UTIs limited daily activities, (2) UTIs caused increased muscle spasms, (3) UTIs would not go away, and (4) UTIs made me avoid going out. Multivariable regression identified variables associated with poor QOL. RESULTS: PRUTI frequency was 0 in 388 patients (26%), 1-3 in 677 (46%), 4-6 in 223 (15%), and more than 6 in 190 (13%). Increasing PRUTI rate was independently associated with worse QOL for all four questions. Compared with those with 0 PRUTIs, participants reporting >6 were more likely to limit daily activities (OR 9.0 [95% CI 8.1-21.2] p < 0.0001), experience increased muscle spasms (OR 12.4 [95% CI 7.5-20.6] p < 0.0001), perceive a UTI would not go away (OR 30.1 [95% CI 15.0-60.4] p < 0.0001), and avoid going out because of UTIs (OR 7.2 [95% CI 4.2-12.4] p < 0.0001). CONCLUSIONS: An increasing rate of PRUTIs is independently associated with worse QOL. Thorough evaluation and treatment may improve QOL in this population.

Presentation and Management Patterns of Lower Urinary Tract Symptoms in Adults Due to Rare Inherited Neuromuscular Diseases.

OBJECTIVE: To describe the urologic sequalae of several rare congenital neuromuscular diseases. METHODS: We retrospectively reviewed medical records at Gillette Specialty Healthcare (2014-2018) of patients presenting to urology clinic with lower urinary tract symptoms and select rare congenital diseases: muscular dystrophy, spinal muscular atrophy, and Rett syndrome. RESULTS: Muscular dystrophies (n = 19) are X-linked myogenic disorders characterized by progressive muscle wasting and weakness. Men present to the urologist at variable ages, typically with complaints of functional incontinence and normal cystometrograms; we manage them with oral anticholinergic medications, condom catheter, or suprapubic catheter. Spinal muscular atrophy (n = 6) is a rare autosomal recessive disease characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem leading to progressive muscle weakness and atrophy. Patients typically present with nephrolithiasis and urinary retention in late adolescence/early adulthood, but timing varies. Filling cystometrograms have been normal. We allow passive retention with intermittent catheterization and creation of catheterizable channels, when indicated. Rett syndrome (n = 5) is a rare, noninheritable genetic condition affecting females characterized by a brief period of normal development followed by loss of speech and purposeful hand use; there are characteristic behaviors. Patients present in early adulthood with complaints of urinary retention. We manage retention with permissive retention or sphincter chemodenervation. CONCLUSION: Several congenital neuromuscular conditions can cause lower urinary tract symptoms when these individuals become adults. We have discussed the clinical characteristics and management of select neurogenic and myogenic bladder conditions seen in adults with congenital conditions.