A prospective observational study of urinary cytokines and inflammatory response in patients with Overactive Bladder Syndrome.

BACKGROUND: Contemporary studies have discredited the methods used to exclude urinary tract infection (UTI) when treating overactive bladder (OAB). Thus we must revisit the OAB phenotype to check that UTI has not been overlooked. AIMS: To examine the differences in urinary cytokines IL6 and lactoferrin in OAB patients compared to controls, with references to microscopy of urine and enhanced quantitative urine culture. METHODS: A blinded, prospective cohort study with normal controls using six repeated measures, achieved two-monthly, over 12 months. RESULTS: The differences between patients and controls in urine IL6 (F = 49.0, p < .001) and lactoferrin (F = 228.5, p < .001) were significant and of a magnitude to have clinical implications. These differences were for lactoferrin correlated to symptoms (9.3, p = .003); for both to pyuria (IL6 F = 66.2, p < .001, Lactoferrin F = 73.9, p < .001); and for IL6 microbial abundance (F = 5.1, p = .024). The pathological markers had been missed by urinary dipsticks and routine MSU culture. CONCLUSION: The OAB phenotype may encompass patients with UTI that is being overlooked because of the failure of standard screening methods.

A revalidation and critique of assumptions about urinary sample collection methods, specimen quality and contamination.

INTRODUCTION AND HYPOTHESIS: Midstream urine (MSU) is key in assessing lower urinary tract syndrome (LUTS), but contingent on some assumptions. The aim of this study was to compare the occurrence of contamination and the quality of substrates obtained from four different collections: MSU, catheter specimen urine (CSU), a commercial MSU collecting device (Peezy) and a natural void. Contamination was quantified by differential, uroplakin-positive, urothelial cell counts. METHODS: This was a single blind, crossover study conducted in two phases. First, we compared the MSU with CSU using urine culture, pyuria counts and differential counting of epithelial cells after immunofluorescence staining for uroplakin III (UP3). Second, we compared the three non-invasive (MSU, Peezy MSU™, natural void) methods using UP3 antibody staining only. RESULTS: The natural void was best at collecting bladder urinary sediment, with the majority of epithelial cells present derived from the urinary tract. CSU sampling missed much of the urinary sediment and showed sparse culture results. Finally, the MSU collection methods did not capture much of the bladder sediment. CONCLUSION: We found little evidence for contamination with the four methods. Natural void was the best method for harvesting shed urothelial cells and white blood cells. It provides a richer sample of the inflammatory exudate, including parasitised urothelial cells and the microbial substrate. However, if the midstream sample is believed to be important, the MSU collection device is advantageous.

Reassessment of Routine Midstream Culture in Diagnosis of Urinary Tract Infection.

Midstream urine (MSU) culture remains the gold standard diagnostic test for confirming urinary tract infection (UTI). We previously showed that patients with chronic lower urinary tract symptoms (LUTS) below the diagnostic cutoff on MSU culture may still harbor bacterial infection and that their antibiotic treatment was associated with symptom resolution. Here, we evaluated the results of the United Kingdom's MSU culture in symptomatic patients and controls. Next, we compared the bacterial enrichment capabilities of the MSU culture with those of a 50-µl uncentrifuged culture, a 30-ml centrifuged sediment culture, and 16S rRNA gene sequencing. This study was conducted on urine specimens from 33 LUTS patients attending their first clinical appointment (mean age, 48.7 years; standard deviation [SD], 16.5 years), 30 LUTS patients on treatment (mean age, 47.8 years; SD, 16.5 years) whose symptoms had relapsed, and 29 asymptomatic controls (mean age, 40.7 years, SD, 15.7 years). We showed that the routine MSU culture, adopting the UK interpretation criteria tailored to acute UTI, failed to detect a variety of bacterial species, including recognized uropathogens. Moreover, the diagnostic MSU culture was unable to discriminate between patients and controls. In contrast, genomic analysis of urine enriched by centrifugation discriminated between the groups, generating a more accurate understanding of species richness. In conclusion, the United Kingdom's MSU protocol misses a significant proportion of bacteria, which include recognized uropathogens, and may be unsuitable for excluding UTI in patients with LUTS.

Cross-over data supporting long-term antibiotic treatment in patients with painful lower urinary tract symptoms, pyuria and negative urinalysis.

PURPOSE: To measure the effects of an unplanned, sudden cessation of treatment in an unselected group of patients with chronic painful LUTS managed with protracted antimicrobial treatment and to report these observational data collected from a cross-over process. MATERIALS AND METHODS: The imposition of a guideline resulted in the immediate cessation of antibiotic treatment in a cohort of patients with chronic painful LUTS and microscopic pyuria. Patients were assessed before treatment withdrawal, whilst off treatment, and following reinstatement. Outcome measures included a validated symptom score, microscopic enumeration of urinary white cells and uroepithelial cells, and routine urine culture. RESULTS: These patients had reported treatment-resistant, painful LUTS for a mean of 6.5 years before treatment at this centre. Treatment was stopped in 221 patients (female = 210; male = 11; mean age = 56 years; SD = 17.81). Sixty-six per cent of women were post-menopausal. After unplanned treatment cessation, 199 patients (90%; female = 188; male = 9) reported deterioration. Eleven patients required hospital care in association with disease recurrence, including acute urinary tract infection (UTI) and urosepsis. Symptom scores increased after cessation and recovered on reinitiating treatment (F = 33; df = 2; p < 0.001). Urinary leucocyte (F = 3.7; df = 2; p = 0.026) and urothelial cells counts mirrored symptomatic changes (F = 6.0; df = 2; p = 0.003). Routine urine culture results did not reflect changes in disease status. CONCLUSION: These data support the hypothesis that treating painful LUTS associated with pyuria with long-term antimicrobial courses, despite negative urine culture, is effective. The microscopy of fresh unspun, unstained urine to count white cells and epithelial cells offers a valid method of monitoring disease. An unplanned cessation of antibiotic therapy produced a resurgence of symptoms and lower urinary tract inflammation in patients with chronic LUTS, supporting an infective aetiology below the level of routine detection.

A blinded observational cohort study of the microbiological ecology associated with pyuria and overactive bladder symptoms.

INTRODUCTION AND HYPOTHESIS: This study sought to characterise the microbial ecology of the lower urinary tract in patients with symptoms of overactive bladder (OAB) using culture of the urinary urothelial cell sediment. The pathological significance of the microbiome was assessed through its relationship with known urothelial inflammatory markers and patient reported symptoms. METHODS: Adult female patients with OAB symptoms and asymptomatic controls were assessed at 12 study visits scheduled every 4 weeks. At each visit, all participants provided a clean-catch midstream urine (MSU) that was analysed to count white and uroepithelial cells, submitted to standard culture and spun urothelial-cell-sediment culture. Symptoms were assessed using validated questionnaires. RESULTS: This analysis shows that OAB patients differ consistently from controls, demonstrating differences in bacterial ecology (t -4.57, p 0.0001), in the microscopic pyuria count (t -6.37, p 0.0001) and presence of infected urothelial cells (t -4.21, p 0.0001). The primary outcome measure of bacterial growth [colony-forming units (CFU) ml-1] was higher in OAB patients than in controls throughout the 12 months. Data showed a correlation between symptoms and pyuria, with notable urgency correlating with pyuria and epithelial cell shedding. The routine urine cultures (with a threshold of reporting a positive result as 105 CFU/ml) were unable to distinguish OAB patients from controls. However, sediment cultures differed significantly, and there was a correlated increased immune response amongst OAB patients. CONCLUSIONS: This study supports the need to re-examine the OAB phenotype given this association with microbial colonisation.

Recalcitrant chronic bladder pain and recurrent cystitis but negative urinalysis: What should we do?

PURPOSE: Lower urinary tract symptoms (LUTS) may be associated with chronic urinary tract infection (UTI) undetected by routine diagnostic tests. Antimicrobial therapy might confer benefit for these patients. MATERIALS AND METHODS: Over 10 years, we treated patients with chronic LUTS. Pyuria was adopted as the principal biomarker of infection. Urinary leucocyte counts were recorded from microscopy of fresh midstream urine (MSU) samples. Antibiotics were prescribed and the prescription adjusted to achieve a measurable clinical response and a reduction in pyuria. RESULTS: We treated 624 women [mean age = 53.4 years; standard deviation (SD) = 18] with chronic LUTS and pyuria. Mean duration of symptoms prior to presentation was 6.5 years. Only 16% of MSU cultures submitted were positive (≥105 cfu ml-1). Mean treatment length was 383 days [SD = 347; 95% confidence interval (CI) = 337-428]. Treatment was associated with a reduction in total LUTS (F = 98; p = 0.0001), 24-h frequency (F = 75; p = 0.0001), urinary urgency (F = 90; p = 0.0001), lower urinary tract pain (F = 108; p = 0.0001), voiding symptoms (F = 10; p = 0.002), and pyuria (F = 15.4; p = 0.0001). Full-dose first-generation antibiotics for UTI, such as cefalexin, nitrofurantoin, or trimethoprim, were combined with methenamine hippurate. We recorded 475 adverse events (AEs) during 273,762 treatment days. There was only one serious adverse event (SAE). We observed no increase in the proportion of resistant bacterial isolates. CONCLUSION: This large case series demonstrates that patients with chronic LUTS and pyuria experience symptom regression and a reduction in urinary tract inflammation associated with antimicrobial therapy. Disease regression was achieved with a low frequency of AEs. These results provide preliminary data to inform a future randomized controlled trial (RCT).

Lower urinary tract symptoms that predict microscopic pyuria.

INTRODUCTION AND HYPOTHESIS: Urinary dipsticks and culture analyses of a mid-stream urine specimen (MSU) at 105 cfu ml-1 of a known urinary pathogen are considered the gold standard investigations for diagnosing urinary tract infection (UTI). However, the reliability of these tests has been much criticised and they may mislead. It is now widely accepted that pyuria (≥1 WBC µl-1) detected by microscopy of a fresh unspun, unstained specimen of urine is the best biological indicator of UTI available. We aimed to scrutinise the greater potential of symptoms analysis in detecting pyuria and UTI. METHODS: Lower urinary tract symptom (LUTS) descriptions were collected from patients with chronic lower urinary tract symptoms referred to a tertiary referral unit. The symptoms informed a 39-question inventory, grouped into storage, voiding, stress incontinence and pain symptoms. All questions sought a binary yes or no response. A bespoke software package was developed to collect the data. The study was powered to a sample of at least 1,990 patients, with sufficient power to analyse 39 symptoms in a linear model with an effect size of Cohen's f2 = 0.02, type 1 error probability = 0.05; and power (1-ß); 95% where ß is the probability of type 2 error). The inventory was administered to 2,050 female patients between August 2004 and November 2011. The data were collated and the following properties assessed: internal consistency, test-retest reliability, inter-observer reliability, internal responsiveness, external responsiveness, construct validity analysis and a comparison with the International Consultation on Incontinence Modular Questionnaire for female lower urinary tract symptoms (ICIQ-FLUTS). The dependent variable used as a surrogate marker of UTI was microscopic pyuria. An MSU sample was sent for routine culture. RESULTS: The symptoms proved reliable predictors of microscopic pyuria. In particular, voiding symptoms correlated well with microscopic pyuria (χ2 = 88, df = 1, p < 0.001). The symptom inventory has significant psychometric characteristics as below: test-retest reliability: Cronbach's alpha was 0.981; inter-observer reliability, Cronbach's alpha was 0.995, internal responsiveness F = 221, p < 0.001, external responsiveness F = 359, df = 5, p < 0.001. The correlation coefficients for the domains of the ICIQ-FLUTS were around R = 0.5, p < 0.001. CONCLUSION: This symptoms score performed well on the standard, psychometric validation. The score changed in response to treatment and in a direction appropriate to the changes in microscopic pyuria. It correlated with measures of quality of life. It would seem to make a good candidate for monitoring treatment progress in ordinary clinical practice.

Intermittent catheterisation after botulinum toxin injections: the time to reassess our practice.

INTRODUCTION AND HYPOTHESIS: Botulinum toxin has become a widely adopted treatment for patients with recalcitrant overactive bladder (OAB) symptoms. Some recommend clean intermittent self-catheterisation (CISC) if a postvoid residual (PVR) >200 ml posttreatment, but there is no evidence for this recommendation. The aim of this study was to identify whether abstinence from CISC as a routine strategy for patients with a PVR following intradetrusor botulinum toxin injections is associated with any measurable adversity. METHODS: This was a cohort observation study. Patients with lower urinary tract symptoms (LUTS) attending a medical urology centre were observed before and after botulinum toxin treatment. Intradetrusal botulinum toxin injections were administered in the day-treatment centre at a medical urology centre in London, UK. Patients were reviewed at follow-up consultations to measure PVR. RESULTS: Of the 240 patients studied, 215 were women and 25 were men, of whom, 196 (82%) received botulinum toxin injections and were not managed with CISC; 18% were using CISC prior to injections and continued. None of the 196 patients developed acute retention or significant voiding symptoms. CONCLUSIONS: Our study indicates that routine administration of CISC based on an arbitrary PVR volume is unlikely to confer benefit. In order to avoid patients being deterred from botulinum treatment, we recommend that CISC be reserved for those who have troublesome voiding symptoms as well as a raised PVR. It is unlikely that CISC, initiated on the basis of an arbitrary PVR volume, would benefit the patient.

Altered urothelial ATP signaling in a major subset of human overactive bladder patients with pyuria.

Overactive Bladder (OAB) is an idiopathic condition, characterized by urgency, urinary frequency, and urgency incontinence, in the absence of routinely traceable urinary infection. We have described microscopic pyuria (≥10 wbc/µl) in patients suffering from the worst symptoms. It is established that inflammation is associated with increased ATP release from epithelial cells, and extracellular ATP originating from the urothelium following increased hydrostatic pressure is a mediator of bladder sensation. Here, using bladder biopsy samples, we have investigated urothelial ATP signaling in OAB patients with microscopic pyuria. Basal, but not stretch-evoked, release of ATP was significantly greater from the urothelium of OAB patients with pyuria than from non-OAB patients or OAB patients without pyuria (<10 wbc/µl). Basal ATP release from the urothelium of OAB patients with pyuria was inhibited by the P2 receptor antagonist suramin and abolished by the hemichannel blocker carbenoxolone, which differed from stretch-activated ATP release. Altered P2 receptor expression was evident in the urothelium from pyuric OAB patients. Furthermore, intracellular bacteria were visualized in shed urothelial cells from ∼80% of OAB patients with pyuria. These data suggest that increased ATP release from the urothelium, involving bacterial colonization, may play a role in the heightened symptoms associated with pyuric OAB patients.

Variable selection in covariate dependent random partition models: an application to urinary tract infection.

Lower urinary tract symptoms can indicate the presence of urinary tract infection (UTI), a condition that if it becomes chronic requires expensive and time consuming care as well as leading to reduced quality of life. Detecting the presence and gravity of an infection from the earliest symptoms is then highly valuable. Typically, white blood cell (WBC) count measured in a sample of urine is used to assess UTI. We consider clinical data from 1341 patients in their first visit in which UTI (i.e. WBC ≥ 1) is diagnosed. In addition, for each patient, a clinical profile of 34 symptoms was recorded. In this paper, we propose a Bayesian nonparametric regression model based on the Dirichlet process prior aimed at providing the clinicians with a meaningful clustering of the patients based on both the WBC (response variable) and possible patterns within the symptoms profiles (covariates). This is achieved by assuming a probability model for the symptoms as well as for the response variable. To identify the symptoms most associated to UTI, we specify a spike and slab base measure for the regression coefficients: this induces dependence of symptoms selection on cluster assignment. Posterior inference is performed through Markov Chain Monte Carlo methods.

Urinary ATP as an indicator of infection and inflammation of the urinary tract in patients with lower urinary tract symptoms.

BACKGROUND: Adenosine-5'-triphosphate (ATP) is a neurotransmitter and inflammatory cytokine implicated in the pathophysiology of lower urinary tract disease. ATP additionally reflects microbial biomass thus has potential as a surrogate marker of urinary tract infection (UTI). The optimum clinical sampling method for ATP urinalysis has not been established. We tested the potential of urinary ATP in the assessment of lower urinary tract symptoms, infection and inflammation, and validated sampling methods for clinical practice. METHODS: A prospective, blinded, cross-sectional observational study of adult patients presenting with lower urinary tract symptoms (LUTS) and asymptomatic controls, was conducted between October 2009 and October 2012. Urinary ATP was assayed by a luciferin-luciferase method, pyuria counted by microscopy of fresh unspun urine and symptoms assessed using validated questionnaires. The sample collection, storage and processing methods were also validated. RESULTS: 75 controls and 340 patients with LUTS were grouped as without pyuria (n = 100), pyuria 1-9 wbc µl(-1) (n = 120) and pyuria ≥10 wbc µl(-1) (n = 120). Urinary ATP was higher in association with female gender, voiding symptoms, pyuria greater than 10 wbc µl(-1) and negative MSU culture. ROC curve analysis showed no evidence of diagnostic test potential. The urinary ATP signal decayed with storage at 23°C but was prevented by immediate freezing at ≤ -20°C, without boric acid preservative and without the need to centrifuge urine prior to freezing. CONCLUSIONS: Urinary ATP may have a role as a research tool but is unconvincing as a surrogate, clinical diagnostic marker.

Spectrum of bacterial colonization associated with urothelial cells from patients with chronic lower urinary tract symptoms.

Chronic lower urinary tract symptoms (LUTS), such as urgency and incontinence, are common, especially among the elderly, but their etiology is often obscure. Recent studies of acute urinary tract infections implicated invasion by Escherichia coli into the cytoplasm of urothelial cells, with persistence of long-term bacterial reservoirs, but the role of infection in chronic LUTS is unknown. We conducted a large prospective study with eligible patients with LUTS and controls over a 3-year period, comparing routine urine cultures of planktonic bacteria with cultures of shed urothelial cells concentrated in centrifuged urinary sediments. This comparison revealed large numbers of bacteria undetected by routine cultures. Next, we typed the bacterial species cultured from patient and control sediments under both aerobic and anaerobic conditions, and we found that the two groups had complex but significantly distinct profiles of bacteria associated with their shed bladder epithelial cells. Strikingly, E. coli, the organism most responsible for acute urinary tract infections, was not the only or even the main offending pathogen in this more-chronic condition. Antibiotic protection assays with shed patient cells and in vitro infection studies using patient-derived strains in cell culture suggested that LUTS-associated bacteria are within or extremely closely associated with shed epithelial cells, which explains how routine cultures might fail to detect them. These data have strong implications for the need to rethink our common diagnoses and treatments of chronic urinary tract symptoms.

Discrediting microscopic pyuria and leucocyte esterase as diagnostic surrogates for infection in patients with lower urinary tract symptoms: results from a clinical and laboratory evaluation.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Microscopic pyuria is widely used as a surrogate marker of infection, although there is little data supporting its use in patients who present with non-acute LUTS. The effects of urinary storage, preservation, and the use of laboratory methods to enhance leucocyte detection, are also unclear. This large, prospective study highlights the poor performance of dipstick urine analysis, and direct microscopy, as surrogate markers of UTI in patients with LUTS. A series of laboratory analyses also examine the effects of urine handling and processing on test integrity, which have important implications for clinical practice. OBJECTIVE: To evaluate the diagnostic performance of pyuria as a surrogate marker of urinary tract infection (UTI) in patients with chronic lower urinary tract symptoms (LUTS), and determine the impact of sample storage, cytocentrifugation, and staining techniques, on test performance. PATIENTS AND METHODS: Between 2008 and 2011, we recruited 1223 patients (120 men; 1103 women; mean age 54 years) with one or more LUTS from a specialist urological outpatient service. We conducted a prospective observational study to determine the performance of microscopic pyuria ≥10 wbc/µL as a surrogate marker of UTI in patients with LUTS. All patients provided clean-catch midstream urine (MSU) samples for analysis, and routine microbiological cultures were used as our reference standard. We also scrutinised the performance of dipstick leucocyte esterase ≥ 'trace' in the detection of microscopic pyuria. The influence of sample handling and processing on test performance was examined in a series of laboratory studies. The effects of storage on leucocyte decay were determined using repeated microscopic assessments of individual urine samples, to plot temporal changes in leucocyte numbers. This study used varied storage conditions (≈20 °C and 4 °C), and boric acid preservation. Paired microscopic assessments were used to determine the effects of centrifugation on leucocyte salvage in spun/unspun samples (relative centrifugal force range 39-157 g). Similar methods were used to assess microscopic leucocyte quantification in stained/unstained urine (Sternheimer-Malbin protocol). RESULTS: The positive predictive value (PPV) and negative predictive value (NPV) of pyuria as a surrogate marker of UTI were 0.40 (95% confidence interval [CI] 0.37-0.43) and 0.75 (95% CI 0.73-0.76), respectively. The dipstick was unable to identify significant microscopic pyuria (≥10 wbc/µL) in 60% of the samples: PPV 0.51 (95% CI 0.48-0.55); NPV 0.75 (95% CI 0.73-0.76). Microscopic pyuria performed poorly as a surrogate of UTI defined by bacterial culture. Whilst refrigeration and preservation did retard leucocyte loss (F = 11; DF = 2; P < 0.001), 40% of cells were still lost by 4 h. Centrifugation had an unpredictable influence on cell salvage (coefficient of variation 5750%) and the use of staining to improve leucocyte detection proved ineffective (Z = -0.356; P = 0.72). CONCLUSIONS: Pyuria performs badly as a surrogate of UTI in patients with LUTS. This is exacerbated by cell loss during storage, and neither centrifugation, nor staining, appears to confer any diagnostic advantage. Clinicians should be alerted to the significant limitations of these tests.

Simultaneous quantification of 12 different nucleotides and nucleosides released from renal epithelium and in human urine samples using ion-pair reversed-phase HPLC.

Nucleotides and nucleosides are not only involved in cellular metabolism but also act extracellularly via P1 and P2 receptors, to elicit a wide variety of physiological and pathophysiological responses through paracrine and autocrine signalling pathways. For the first time, we have used an ion-pair reversed-phase high-performance liquid chromatography ultraviolet (UV)-coupled method to rapidly and simultaneously quantify 12 different nucleotides and nucleosides (adenosine triphosphate, adenosine diphosphate, adenosine monophosphate, adenosine, uridine triphosphate, uridine diphosphate, uridine monophosphate, uridine, guanosine triphosphate, guanosine diphosphate, guanosine monophosphate, guanosine): (1) released from a mouse renal cell line (M1 cortical collecting duct) and (2) in human biological samples (i.e., urine). To facilitate analysis of urine samples, a solid-phase extraction step was incorporated (overall recovery rate ≥ 98 %). All samples were analyzed following injection (100 µl) into a Synergi Polar-RP 80 Å (250 × 4.6 mm) reversed-phase column with a particle size of 10 µm, protected with a guard column. A gradient elution profile was run with a mobile phase (phosphate buffer plus ion-pairing agent tetrabutylammonium hydrogen sulfate; pH 6) in 2-30 % acetonitrile (v/v) for 35 min (including equilibration time) at 1 ml min(-1) flow rate. Eluted compounds were detected by UV absorbance at 254 nm and quantified using standard curves for nucleotide and nucleoside mixtures of known concentration. Following validation (specificity, linearity, limits of detection and quantitation, system precision, accuracy, and intermediate precision parameters), this protocol was successfully and reproducibly used to quantify picomolar to nanomolar concentrations of nucleosides and nucleotides in isotonic and hypotonic cell buffers that transiently bathed M1 cells, and urine samples from normal subjects and overactive bladder patients.

An evidence-based perspective on Lower Urinary Tract Symptoms and telemedicine during the COVID-19 pandemic.

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causing the COVID-19 pandemic, has had an enormous effect on conventional clinical practice. Telemedicine has emerged as critical to the provision of healthcare services when reducing the transmission of COVID-19 among patients, families, and clinicians. It has been an essential tool for continuing care for patients with lower urinary tract symptoms (LUTS) during the COVID-19 pandemic and has been the link between socially distant patient contact. The aim of this perspective paper was to identify the strengths and limitations of technology-based care focusing on literature linked to patients with lower urinary tract symptoms (LUTS). We search PubMed and CINHAL Plus for grey literature and secondary research on LUTS and telemedicine during the COVID-19 pandemic. Publications dated between the year March 2020 and March 2021were searched. We gathered key specialist opinions in the field of LUTS from several countries around the world, including the countries that had been hit significantly with COVID-19. This perspective paper proposes that there is evidence to support the use of modern technology to facilitate continued healthcare services for patients with LUTS during the COVID-19 pandemic. Telemedicine has been recognised a crucial digital tool for diagnosis, treatment and follow-up appointments during a time of social distancing. Although there are many advantages of telemedicine, the older adult population and those economically disadvantaged with technology may not benefit from technology-based healthcare. The available literature on telemedicine during the COVID-19 pandemic has proven to be successful in the management of some patients with LUTS. It is certain that the COVID-19 pandemic has given telemedicine a significant drive for implementation now and in the immediate future. Robust data on long-term efficacy and safety of telemedicine is required to ensure there are governance protocols embedded when looking after patients with LUTS.

The inadequacy of urinary dipstick and microscopy as surrogate markers of urinary tract infection in urological outpatients with lower urinary tract symptoms without acute frequency and dysuria.

PURPOSE: Diagnosing urinary infection in patients with chronic lower urinary tract symptoms without dysuria is a critical step. In this study we scrutinize the sensitivity and specificity of dipstick urinalysis and microscopic pyuria (10 or more white blood cells per microl) to identify infection in such patients. MATERIALS AND METHODS: This was a prospective, blinded, observational cohort study of urological outpatients with painless lower urinary tract symptoms. Midstream and catheter urine samples were analyzed. A total of 508 midstream urine samples were used to compare leukocyte esterase, nitrite dipstick and urine microscopy with cultures seeking 10(5) cfu/ml. Similarly 470 catheter urine samples were used to compare the same surrogates with 10(5) cfu/ml and with an enhanced culture method seeking 10(2) cfu/ml. A comparison of leukocyte esterase against microscopic pyuria was made using the 508 midstream and 470 catheter specimens of urine. Midstream urine specimens were provided by 42 normal volunteers for comparison. RESULTS: For a midstream urine culture at 10(5) cfu/ml leukocyte esterase was 56% sensitive, nitrite was 10% sensitive and microscopic pyuria was 56% sensitive. Specificities were 66%, 99% and 72%, respectively. For a catheter specimen of urine culture at 10(5) cfu/ml leukocyte esterase was 59% sensitive, nitrite was 20% sensitive and microscopic pyuria was 66% sensitive. Specificities were 84%, 97% and 73%, respectively. The enhanced culture of catheter specimen of urine at 10(2) cfu/ml was positive in 29% of patients vs 15% at 10(5) cfu/ml. CONCLUSIONS: Despite official guidelines and widespread use these tests cannot be considered appropriate for diagnosing urinary tract infection in patients with lower urinary tract symptoms, and should be abandoned in this context.

Novel antibiotic-loaded particles conferring eradication of deep tissue bacterial reservoirs for the treatment of chronic urinary tract infection.

A significant proportion of urinary tract infection (UTI) patients experience recurrent episodes, due to deep tissue infection and treatment-resistant bacterial reservoirs. Direct bladder instillation of antibiotics has proved disappointing in treating UTI, likely due to the failure of infused antibiotics to penetrate the bladder epithelium and accumulate to high enough levels to kill intracellular bacteria. This work investigates the use of nitrofurantoin loaded poly(lactic-co-glycolic acid) (PLGA) particles to improve delivery to intracellular targets for the treatment of chronic UTI. Using electrohydrodynamic atomisation, we produced particles with an average diameter of 2.8 µm. In broth culture experiments, the biodegradable particles were effective against a number of UTI-relevant bacterial strains. Dye-loaded particles demonstrated that intracellular delivery was achieved in all cells in 2D cultures of a human bladder epithelial progenitor cell line in a dose-dependent manner, achieving far higher efficiency and concentration than equivalent quantities of free drug. Time-lapse video microscopy confirmed that delivery occurred within 30 min of administration, to 100% of cells. Moreover, the particles were able to deliver the drug to cells through multiple layers of a 3D human bladder organoid model causing minimal cell toxicity, displaying superior killing of bacterial reservoirs harboured within bladder cells compared with unencapsulated drug. The particles were also able to kill bacterial biofilms more effectively than the free drug. These results illustrate the potential for using antibiotic-loaded microparticles to effectively treat chronic UTIs. Such a delivery method could be extrapolated to other clinical indications where robust intracellular delivery is required, such as oncology and gene therapy.

Does urodynamic verification of overactive bladder determine treatment success? Results from a randomized placebo-controlled study.

OBJECTIVE: To determine whether subjects with or with no detrusor overactivity (DO) determined by urodynamic assessment respond differently to treatment with the antimuscarinic agent tolterodine (extended release formulation, ER). SUBJECTS AND METHODS: Adult subjects with urinary frequency (average >or=8 voids/24 h) and urgency with or without urgency urinary incontinence (UUI) underwent urodynamic assessment and were stratified according to whether they had DO (positive urodynamics) or not (negative urodynamics). Subjects in each urodynamic stratum were randomized to receive tolterodine-ER (4 mg once daily) or placebo for 12 weeks. Diary cards were completed for 7 days before each study visit (at baseline, week 4, and week 12). The volume per void was recorded for 3 of the 7 days. RESULTS: The difference between the positive and negative urodynamic groups in mean change in volume voided between baseline and 12 weeks was 5.38 mL (95% CI, -93 mL to +15.71 mL). This difference is within the pre-stipulated range defined for equivalence (+/-20 mL, P = 0.31). There was also no significant difference in the change from baseline to 12 weeks between the urodynamics groups in mean number of voids per day or UUI episodes. However, there was significant improvement in the treatment group compared with the placebo group, in the number of voids per 24 h (P = 0.003) and in the mean change in volume voided (P = 0.03), from baseline to 12 weeks, but not in UUI episodes (P = 0.35). CONCLUSIONS: Urodynamics status could not predict treatment outcomes between patients treated with tolterodine-ER or placebo. The results add support to evidence suggesting that urodynamic assessment is not a prerequisite for the treatment of overactive bladder (OAB). Therefore, we recommend that anticholinergic treatment may be initiated to patients with OAB symptoms without the need for urodynamics studies.

The comparative pressure-flow plot properties of radiological bladder neck and prostatic obstruction.

OBJECTIVES: To test the hypotheses that: (i) significant differences should exist in pressure/flow data between radiologically determined bladder neck and prostatic obstruction; (ii) these differences should inform understanding of the pathophysiology of male outflow obstruction. The biomechanics of the voiding/pressure/flow plot imply that a urodynamic assessment trace should identify outflow obstruction and characterise the urethral viscoelastic properties. Micturating cystourethrograms (MCUG) images might provide a useful diagnostic dichotomy for testing these assumptions. MATERIALS AND METHODS: The pressure/flow data from 71 men who also provided video-urodynamic imaging data that a radiologist could classify unequivocally as showing bladder neck obstruction (42) or prostatic obstruction (29) were analysed. The following variables were recorded: the detrusor pressure at initiation of voiding (P(det.open)); the detrusor pressure at the end of voiding (P(det.close)); the detrusor pressure at maximum flow rate (Q(max)), (P(det.)Q(max)), and Q(max). The urethral resistance relation (URR) was drawn onto the pressure-flow plot and the gradient of the URR, DeltaP(det)/DeltaQ, was calculated. RESULTS: There were significant between group differences in P(det.open) (95% confidence interval of the difference 5.2-28.6, U = 352, P = 0.003); P(det.close) (0.2-15.0, U = 428, P = 0.034); P(det).Q(max) (0.0-18.9, U = 439, P = 0.05); Q(max) and DeltaP(det)/DeltaQ did not distinguish between the MCUG groups (95% confidence interval of the difference 2.3-18, U = 111; P = 0.004). The best-fit model from linear combinations of the data achieved an area under the receiver operator curve of 0.72 for discriminating between the MCUG groups. CONCLUSIONS: The urodynamic assessment identified interesting and coherent biomechanical differences, and could distinguish between the obstructions with a moderate degree of accuracy.

Bayesian Autoregressive Frailty Models for Inference in Recurrent Events.

We propose autoregressive Bayesian semi-parametric models for gap times between recurrent events. The aim is two-fold: inference on the effect of possibly time-varying covariates on the gap times and clustering of individuals based on the time trajectory of the recurrent event. Time-dependency between gap times is taken into account through the specification of an autoregressive component for the frailty parameters influencing the response at different times. The order of the autoregression may be assumed unknown and is an object of inference. We consider two alternative approaches to perform model selection under this scenario. Covariates may be easily included in the regression framework and censoring and missing data are easily accounted for. As the proposed methodologies lie within the class of Dirichlet process mixtures, posterior inference can be performed through efficient MCMC algorithms. We illustrate the approach through simulations and medical applications involving recurrent hospitalizations of cancer patients and successive urinary tract infections.