Sexually transmitted infections and the vaginal microbiome after vaginoplasty.

PURPOSE OF THE REVIEW: Transgender and gender-diverse individuals (TGD) are at risk for sexually transmitted infections. Gender affirmation surgery is a cornerstone of care for many TGD individuals. For genital gender affirmation, the surgical creation of a vagina may be performed through a number of techniques. Those who have undergone vaginoplasty have unique anatomical and biopsychosocial considerations, which we discuss. RECENT FINDINGS: While sexually-transmitted infections including HPV, HSV, HIV, gonorrhea, and chlamydia, have been described in TGD individuals after vaginoplasty, the reports are very rare, and the provider should maintain an index of suspicion and maintain a broad differential for symptoms including neovaginal discharge. We discuss the association of the neovaginal microbiota composition with bacterial vaginosis, and how its modulation could potentially reduce bacterial vaginosis and sexually transmitted infection risk. SUMMARY: We examine the literature regarding sexually-transmitted infections following vaginoplasty, and the neovaginal microbiome and its similarities and differences relative to the natal vaginal microbiome.

Sacral neuromodulation device biofilm differs in the absence and presence of infection, harbors antibiotic resistance genes, and is reproducible in vitro.

INTRODUCTION/PURPOSE: Sacral neuromodulation (SNM) is effective therapy for overactive bladder refractory to oral therapies, and non-obstructive urinary retention. A subset of SNM devices is associated with infection requiring surgical removal. We sought to compare microbial compositions of explanted devices in the presence and absence of infection, by testing phase, and other clinical factors, and to investigate antibiotic resistance genes present in the biofilms. We analyzed resistance genes to antibiotics used in commercially-available anti-infective device coating/pouch formulations. We further sought to assess biofilm reconstitution by material type and microbial strain in vitro using a continuous-flow stir tank bioreactor, which mimics human tissue with an indwelling device. We hypothesized that SNM device biofilms would differ in composition by infection status, and genes encoding resistance to rifampin and minocycline would be frequently detected. MATERIALS/METHODS: Patients scheduled to undergo removal or revision of SNM devices were consented per IRB-approved protocol (IRB 20-415). Devices were swabbed intraoperatively upon exposure, with controls and precautions to reduce contamination of the surrounding field. Samples and controls were analyzed with next-generation sequencing and RT-PCR, metabolomics, and culture-based approaches. Associations between microbial diversity or microbial abundance, and clinical variables were then analyzed using t-tests and ANOVA. Reconstituted biofilm deposition in vitro using the bioreactor was compared by microbial strain and material type using plate-based assays and scanning electron microscopy. RESULTS: Thirty seven devices were analyzed, all of which harbored detectable microbiota. Proteobacteria, Firmicutes and Actinobacteriota were the most common phyla present overall. Beta-diversity differed in the presence versus absence of infection (p = 0.014). Total abundance, based on normalized microbial counts, differed by testing phase (p < 0.001), indication for placement (p = 0.02), diabetes mellitus (p < 0.001), cardiac disease (p = 0.008) and history of UTI (p = 0.008). Significant microbe-metabolite interaction networks were identified overall and in the absence of infection. 24% of biofilms harbored the tetA tetracycline/minocycline resistance gene and 53% harbored the rpoB rifampin resistance gene. Biofilm was reconstituted across tested strains and material types. Ceramic and titanium did not differ in biofilm deposition for any tested strain. CONCLUSIONS: All analyzed SNM devices harbored microbiota. Device biofilm composition differed in the presence and absence of infection and by testing phase. Antibiotic resistance genes including to rifampin and tetracycline/minocycline, which are used in commercially-available anti-infective pouches, were frequently detected. Isolated organisms from SNM devices demonstrated the ability to reconstitute biofilm formation in vitro. Biofilm deposition was similar between ceramic and titanium, materials used in commercially-available SNM device casings. The findings and techniques used in this study together provide the basis for the investigation of the next generation of device materials and coatings, which may employ novel alternatives to traditional antibiotics. Such alternatives might include bacterial competition, quorum-sensing modulation, or antiseptic application, which could reduce infection risk without significantly selecting for antibiotic resistance.

Bladder Compliance: How We Define It and Why It Is Important.

Bladder compliance is the relationship between detrusor pressure and bladder storage volume. We discuss the definition of compliance, how it may be accurately measured, and its clinical relevance. Specifically, we discuss the association between low compliance and upper urinary tract deterioration. We discuss medical and surgical therapies that have been demonstrated to improve compliance and reduce upper tract risk. Finally, we propose a model, which not only considers compliance but also differential pressure between the bladder and ureters, and how this may also be an accurate predictor of upper tract deterioration. We call for further investigation to test this model.

An exploratory study investigating the impact of the bladder tumor microbiome on Bacillus Calmette Guerin (BCG) response in non-muscle invasive bladder cancer.

PURPOSE: Intravesical Bacillus Calmette-Guerin (BCG) is standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC). The effect of the bladder microbiome on response to BCG is unclear. We sought to characterize the microbiome of bladder tumors in BCG-responders and non-responders and identify potential mechanisms that drive treatment response. MATERIALS AND METHODS: Patients with archival pre-treatment biopsy samples (2012-2018) were identified retrospectively. Prospectively, urine and fresh tumor samples were collected from individuals with high-risk NMIBC (2020-2023). BCG response was defined as tumor-free 2 years from induction therapy. Extracted DNA was sequenced for 16S rRNA and shotgun metagenomics. Primary outcomes were species richness (α-diversity) and microbial composition (ß-diversity). Paired t-tests were performed for α-diversity (Observed species/Margalef). Statistical analysis for ß-diversity (weighted and unweighted UniFrac distances, weighted Bray-Curtis dissimilarity) were conducted through Permanova, with 999 permutations. RESULTS: Microbial species richness (P < 0.001) and composition (P = 0.001) differed between BCG responders and non-responders. Lactobacillus spp. were significantly enriched in BCG-responders. Shotgun metagenomics identified possible mechanistic pathways such as assimilatory sulfate reduction. CONCLUSION: A compositional difference exists in the tumor microbiome of BCG responders and non-responders with Lactobacillus having increased abundance in BCG responders.

Surgical Management and Oncologic Outcomes of Renal Cell Carcinoma and Inferior Vena Caval Thrombi With Aggressive Histologic Variants.

OBJECTIVE: To characterize the surgical management, perioperative, and cancer-specific outcomes, and the influence of aggressive histologic variants (AHV) on operative management among patients with renal cell carcinoma (RCC) and inferior vena cava (IVC) thrombus. RCC with rhabdoid and/or sarcomatoid differentiation, which we defined as AHV, portends a worse prognosis. AHV can be associated with a desmoplastic reaction which may complicate resection. METHODS: We reviewed patients undergoing radical nephrectomy and IVC thrombectomy between 1990 and 2020. Comparative statistics were employed as appropriate. Survival analysis was performed according to the Kaplan-Meier method, and intergroup analysis performed with log-rank statistics. Multivariable cox proportional hazards regression was used to assess the effect of AHV, age, thrombus level, vena cavectomy, metastases, and medical comorbidities on recurrence and overall survival (OS). RESULTS: Ninety-four of 403 (23.3%) patients had AHV, including 43 (46%) rhabdoid, 39 (41%) sarcomatoid, and 12 (13%) with both. AHV were more likely to present with advanced disease; however, increased perioperative complications or decreased OS were not observed. Median (IQR) survival was 16.7 (4.8-47) months without AHV and 12.6 (4-29) months with AHV (P = .157). Sarcomatoid differentiation was independently associated with worse OS (HR = 2.016, CI 1.38-2.95, P <.001), whereas rhabdoid alone or with sarcomatoid demonstrated similar OS (P = 0.063). CONCLUSION: RCC and IVC thrombus with AHV are more likely to present with metastatic disease, and sarcomatoid differentiation is associated with a worse OS. Resection of tumors with and without AHV have similar perioperative complications, suggesting that surgery can be safely accomplished in patients with RCC and IVC thrombus with AHV.

Penile prostheses harbor biofilms driven by individual variability and manufacturer even in the absence of clinical infection.

BACKGROUND: Culture-based studies have shown that penile prostheses harbor biofilms in the presence and absence of infection, but these findings have not been adequately validated using contemporary microbiome analytic techniques. AIM: The study sought to characterize microbial biofilms of indwelling penile prosthesis devices according to patient factors, device components, manufacturer, and infection status. METHODS: Upon penile prostheses surgical explantation, device biofilms were extracted, sonicated, and characterized using shotgun metagenomics and culture-based approaches. Device components were also analyzed using scanning electron microscopy. OUTCOMES: Outcomes included the presence or absence of biofilms, alpha and beta diversity, specific microbes identified and the presence of biofilm, and antibiotic resistance genes on each prosthesis component. RESULTS: The average age of participants from whom devices were explanted was 61 ± 11 years, and 9 (45%) of 20 had a diagnosis of diabetes mellitus. Seventeen devices were noninfected, and 3 were associated with clinical infection. Mean device indwelling time prior to explant was 5.1 ± 5.1 years. All analyzed components from 20 devices had detectable microbial biofilms, both in the presence and absence of infection. Scanning electron microscopy corroborated the presence of biofilms across device components. Significant differences between viruses, prokaryotes, and metabolic pathways were identified between individual patients, device manufacturers, and infection status. Mobiluncus curtisii was enriched in manufacturer A device biofilms relative to manufacturer B device biofilms. Bordetella bronchialis, Methylomicrobium alcaliphilum, Pseudoxanthomonas suwonensis, and Porphyrobacter sp. were enriched in manufacturer B devices relative to manufacturer A devices. The most abundant bacterial phyla were the Proteobacteria, Actinobacteria, and Firmicutes. Glycogenesis, the process of glycogen synthesis, was among the predominant metabolic pathways detected across device components. Beta diversity of bacteria, viruses, protozoa, and pathways did not differ among device components. CLINICAL IMPLICATIONS: All components of all penile prostheses removed from infected and noninfected patients have biofilms. The significance of biofilms on noninfected devices remains unknown and merits further investigation. STRENGTHS AND LIMITATIONS: Strengths include the multipronged approach to characterize biofilms and being the first study to include all components of penile prostheses in tandem. Limitations include the relatively few number of infected devices in the series, a relatively small subset of devices included in shotgun metagenomics analysis, and the lack of anaerobic and other expanded conditions for culture. CONCLUSION: Penile prosthesis biofilms are apparent in the presence and absence of infection, and the composition of biofilms was driven primarily by device manufacturer, individual variability, and infection, while being less impacted by device component.

Microbe-metabolite interaction networks, antibiotic resistance, and in vitro reconstitution of the penile prosthesis biofilm support a paradigm shift from infection to colonization.

To understand differences between asymptomatic colonized and infected states of indwelling medical devices, we sought to determine penile prosthesis biofilm composition, microbe-metabolite interaction networks, and association with clinical factors. Patients scheduled for penile prosthesis removal/revision were included. Samples from swabbed devices and controls underwent next-generation sequencing, metabolomics, and culture-based assessments. Biofilm formation from device isolates was reconstituted in a continuous-flow stir tank bioreactor. 93% of 27 analyzed devices harbored demonstrable biofilm. Seven genera including Faecalibaculum and Jeotgalicoccus were more abundant in infected than uninfected device biofilms (p < 0.001). Smokers and those with diabetes mellitus or cardiac disease had lower total normalized microbial counts than those without the conditions (p < 0.001). We identified microbe-metabolite interaction networks enriched in devices explanted for infection and pain. Biofilm formation was recapitulated on medical device materials including silicone, PTFE, polyurethane, and titanium in vitro to facilitate further mechanistic studies. Nearly all penile prosthesis devices harbor biofilms. Staphylococcus and Escherichia, the most common causative organisms of prosthesis infection, had similar abundance irrespective of infection status. A series of other uncommon genera and metabolites were differentially abundant, suggesting a complex microbe-metabolite pattern-rather than a single organism-is responsible for the transition from asymptomatic to infected or painful states.

Urinalysis Exhibits Excellent Predictive Capacity for the Absence of Urinary Tract Infection.

OBJECTIVE: To assess predictive value of urinalysis for negative urine culture and absence of urinary tract infection, re-evaluate the microbial growth threshold for positive urine culture result, and describe antimicrobial resistance features. Urine culture is associated with 27% of U.S. hospitalizations, and unnecessary antibiotic prescription is a main antibiotic resistance contributor. METHODS: Urinalyses with urine culture from women ages 18-49 from 2013 to 2020 were studied. Clinically diagnosed urinary tract infection (CUTI) was defined as (1) uropathogen growth, (2) documented diagnosis of urinary tract infection, and (3) antibiotic prescription. Sensitivity, specificity, and diagnostic predictive values were used to assess urinalysis performance in predicting isolation of a uropathogen by culture and in detection of CUTI. RESULTS: Total 12,252 urinalyses were included. Forty-one percent of urinalyses were associated with positive urine culture and 1287 (10.5%) with CUTI. Negative urinalysis exhibited high predictive accuracy for negative urine culture (specificity 90.3%, PPV 87.3%) and absence of CUTI (specificity 92.2%, PPV 97.4%). Twenty-four percent of patients not meeting the CUTI definition were still prescribed antibiotics. Twenty-two percent of cultures associated with CUTI exhibited growth less than 100,000 CFU/mL. Escherichia coli was implemented as causing 70% of CUTIs, and 4.2% of these produced an extended spectrum beta-lactamase. CONCLUSION: Negative urinalysis exhibits high predictive accuracy for absence of CUTI. A reporting threshold of 10,000 CFU/mL is more clinically appropriate than a 100,000 CFU/mL cutpoint. Reflex culture based on urinalysis results could complement clinical judgement and improve laboratory and antibiotic stewardship in premenopausal women.

Neuro-Urology: Call for Universal, Resource-Independent Guidance.

Neurogenic lower urinary tract dysfunction (NLUTD), the abnormal function of the lower urinary tract in the context of neurological pathology, has been the subject of multiple efforts worldwide for the development of clinical practice guidelines. These guidelines are based on the same body of evidence, and are therefore subject to the same gaps. For example, sexual and bowel dysfunction in the context of NLUTD, optimal renal function assessment in those who are non-ambulatory or with low muscle mass, optimal upper tract surveillance timing, and modification of diagnostic and treatment modalities for low-resource nations and communities are inadequately addressed. In addition, many aspects of the conclusions and final recommendations of the guidelines are similar. This duplicative work represents a large expenditure of time and effort, which we believe could be focused instead on evidence gaps. Here, we call for a global unified approach to create a single, resource-independent, comprehensive guidance on NLUTD, neurogenic sexual, and neurogenic bowel dysfunction. Targeted research addressing the evidence gaps should be called for and pursued. This will allow for focus to shift to filling the gaps in the evidence for future guidelines.

Ureteral Stents Harbor Complex Biofilms With Rich Microbiome-Metabolite Interactions.

PURPOSE: We sought to determine microbe-metabolite composition and interactions within indwelling ureteral stent biofilms, determine their association with patient factors including infection, and reconstitute biofilm formation on relevant surface materials in vitro. MATERIALS AND METHODS: Upon ureteral stent removal from patients, proximal and distal ends were swabbed. Samples were analyzed by 16S next-generation sequencing and metabolomics. A continuous-flow stir-tank bioreactor was used to reconstitute and quantify in vitro biofilm formation from stent-isolated bacteria on stent-related materials including silicone, polytetrafluoroethylene, polyurethane, polycarbonate, and titanium. Diversity, relative abundance, and association with clinical factors were analyzed with ANOVA and Bonferroni t-tests or PERMANOVA. Biofilm deposition by microbial strain and device material type were analyzed using plate counts and scanning electron microscopy following bioreactor incubation. RESULTS: All 73 samples from 37 ureteral stents harbored microbiota. Specific genera were more abundant in samples from stents wherein there was antibiotic exposure during indwelling time (Escherichia/Shigella, Pseudomonas, Staphylococcus, Ureaplasma) and in those associated with infection (Escherichia/Shigella, Ureaplasma). The enriched interaction subnetwork in stent-associated infection included Ureaplasma and metabolite 9-methyl-7-bromoeudistomin. Strains identified as clinically relevant and central to interaction networks all reconstituted biofilm in vitro, with differential formation by strain (Enterococcus faecalis most) and material type (titanium least). CONCLUSIONS: Ureteral stent biofilms exhibit patterns unique to stent-associated infection and antibiotic exposure during indwelling time. Microbes isolated from stents reconstituted biofilm formation in vitro. This work provides a platform to test novel materials, evaluate new coatings for anti-biofilm properties, and explore commensal strain use for bacterial interference against pathogens.

Biofilms on Indwelling Artificial Urinary Sphincter Devices Harbor Complex Microbe-Metabolite Interaction Networks and Reconstitute Differentially In Vitro by Material Type.

The artificial urinary sphincter (AUS) is an effective treatment option for incontinence due to intrinsic sphincteric deficiency in the context of neurogenic lower urinary tract dysfunction, or stress urinary incontinence following radical prostatectomy. A subset of AUS devices develops infection and requires explant. We sought to characterize biofilm composition of the AUS device to inform prevention and treatment strategies. Indwelling AUS devices were swabbed for biofilm at surgical removal or revision. Samples and controls were subjected to next-generation sequencing and metabolomics. Biofilm formation of microbial strains isolated from AUS devices was reconstituted in a bioreactor mimicking subcutaneous tissue with a medical device present. Mean patient age was 73 (SD 10.2). All eighteen artificial urinary sphincter devices harbored microbial biofilms. Central genera in the overall microbe−metabolite interaction network were Staphylococcus (2620 metabolites), Escherichia/Shigella (2101), and Methylobacterium-Methylorubrum (674). An rpoB mutation associated with rifampin resistance was detected in 8 of 15 (53%) biofilms. Staphylococcus warneri formed greater biofilm on polyurethane than on any other material type (p < 0.01). The results of this investigation, wherein we comprehensively characterized the composition of AUS device biofilms, provide the framework for future identification and rational development of inhibitors and preventive strategies against device-associated infection.

Estimated Glomerular Filtration Rate Using Cystatin C is a More Sensitive Marker for Kidney Dysfunction in Nonweight-bearing Individuals.

PURPOSE: Individuals with neuromuscular disorders and neurogenic lower urinary tract dysfunction are commonly nonweight-bearing with lower lean muscle mass than the general population. We sought to compare estimated glomerular filtration rate equations that include creatinine, cystatin C, or both, in nonweight-bearing individuals and matched ambulatory controls. MATERIALS AND METHODS: Records were reviewed for individuals with serum creatinine (Cr) and cystatin C (Cys) and diagnosis consistent with nonweight-bearing status, and matched ambulatory controls. The 2021 CKD-EPI (Chronic Kidney Disease-Epidemiology Collaboration) race agnostic equations were used to calculate estimated glomerular filtration rate. Renal function was compared by equation in the overall cohorts and in a patient subset with imaging and/or urinalysis evidence of renal dysfunction. RESULTS: Nonweight-bearing (n = 102) and control populations (n = 204) had similar demographics. In the nonweight-bearing population, estimated glomerular filtration rate differed when calculated using CKD-EPICr, CKD-EPICr+Cys, and CKD-EPICys (107, 93, 80 mL/min/1.73 m2, respectively, P < .001). The differences in estimated glomerular filtration rate were greater in the nonweight-bearing relative to the control group regardless of CKD-EPI equation pairs compared (P < .001). In the patient subset with imaging and/or proteinuria evidence of renal dysfunction, the nonweight-bearing population again had different estimated glomerular filtration rate when calculated using CKD-EPICr, CKD-EPICr+Cys, and CKD-EPICys (P < .001). Fifty-eight percent of nonweight-bearing individuals with evidence of renal dysfunction on imaging or urinalysis were reclassified into a lower estimated glomerular filtration rate category when using estimated glomerular filtration rateCys relative to estimated glomerular filtration rateCr. CONCLUSIONS: Estimated glomerular filtration rate equations containing serum creatinine, cystatin C, or both, validated in mostly ambulatory populations, are not equivalently accurate in estimating kidney function in nonweight-bearing individuals. Comparison of these equations against gold standard glomerular filtration rate measurement is needed to determine which most closely approximates true glomerular filtration rate.

Analysis of Native Kidney Function Recovery With Renal Scintigraphy Following Simultaneous Liver-Kidney Transplantation.

BACKGROUND: Patients undergoing simultaneous liver-kidney transplantation (SLK) have impaired native kidney function. The relative contribution of allograft versus native function after SLK is unknown. We sought to characterize the return of native kidney function following SLK. METHODS: Following SLK, patients underwent technetium-99 m-mercaptoacetyltriglycine renal scintigraphy following serum creatinine nadir. Kidney contributions to estimated glomerular filtration rate (eGFR) were determined. Patients with native kidney function at serum creatinine nadir contributing eGFR ≥30 versus <30 mL/min/1.73 m 2 were compared, and multiple linear regression analysis for native eGFR improvement was performed. RESULTS: Thirty-one patients were included in this analysis. Average native kidney contribution to overall kidney function following SLK was 51.1% corresponding to native kidney eGFR of 44.5 mL/min/1.73 m 2 and native kidney function eGFR improvement of 30.3 mL/min/1.73 m 2 ( P < 0.001). Twenty-six of 31 patients had native kidney contribution of eGFR ≥30 mL/min/1.73 m 2 . Hepatorenal syndrome as the sole primary etiology of kidney dysfunction was 100% specific for native kidney eGFR >30 mL/min/1.73 m 2 and predicted native eGFR improvement ( P = 0.03). CONCLUSIONS: Substantial improvement in native kidney function follows SLK, and hepatorenal syndrome as the sole primary etiology of kidney dysfunction is predictive of improvement. Whether such patients are suitable for liver transplant followed by surveillance with option for subsequent kidney transplants requires investigation.

Neural networks outperform expert humans in predicting patient impressions of symptomatic improvement following overactive bladder treatment.

INTRODUCTION AND HYPOTHESIS: The objective was to accurately predict patient-centered subjective outcomes following the overactive bladder (OAB) treatments OnabotulinumtoxinA (OBTX-A) injection and sacral neuromodulation (SNM) using a neural network-based machine-learning approach. In the context of treatments designed to improve quality of life, a patient's perception of improvement should be the gold standard outcome measure. METHODS: Cutting-edge neural network-based algorithms using reproducing kernel techniques were trained to predict patient-reported improvements in urinary leakage and bladder function as assessed by Patient Global Impression of Improvement score using the ROSETTA trial datasets. Blinded expert urologists provided with the same variables also predicted outcomes. Receiver operating characteristic curves and areas under the curve were generated for algorithm and human expert predictions in an out-of-sample holdout dataset. RESULTS: Algorithms demonstrated excellent accuracy in predicting patient subjective improvement in urinary leakage (OBTX-A: AUC 0.75; SNM: 0.80). Similarly, algorithms accurately predicted patient subjective improvement in bladder function (OBTX-A: AUC 0.86; SNM: 0.96). The top-performing algorithms outcompeted human experts across outcome measures. CONCLUSIONS: Novel neural network-based machine-learning algorithms accurately predicted OBTX-A and SNM patient subjective outcomes, and generally outcompeted expert humans. Subtle aspects of the physician-patient interaction remain uncomputable, and thus the machine-learning approach may serve as an aid, rather than as an alternative, to human interaction and clinical judgment.

Diagnostic stewardship for urinary tract infection: A snapshot of the expert guidance.

The urine culture, the cornerstone for laboratory diagnosis of urinary tract infection (UTI), is associated with a high frequency of false-positive and false-negative results, and its diagnostic threshold is debated. Urine culture takes days to result, and antibiotics are often initiated while awaiting final culture readings. Further, asymptomatic bacteriuria-the presence of bacteria in urine in the absence of UTI symptoms-generally does not warrant treatment. The authors review current expert guidance on the use of urine culture, including approaches to ordering, processing, and reporting of urine cultures, with the goal of reducing unnecessary antibiotic use and misdiagnosis of UTI.