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Abstract Background Patients with neurogenic lower urinary tract dysfunction (NLUTD) often rely on some type of catheterization for bladder emptying. Intermittent catheterization (IC) is considered the gold standard and is preferred over continuous catheterization, since it is considered to cause fewer urinary tract infections (UTIs) than indwelling catheterization. The main objective of our study was to describe UTI prevalence (at visit) and incidence (within the last 12 months) and urine culture characteristics between patients using an indwelling catheter versus (vs) those performing IC. Methods In this cross-sectional study, we prospectively evaluated from 02/2020 to 01/2021 patients with NLUTD undergoing urine cultures for prophylactic reasons or due to UTI symptoms. At visit, all patients underwent a standardized interview on current UTI symptoms as well as UTI history and antibiotic consumption within the past year. Patients using an indwelling catheter (n = 206) or IC (n = 299) were included in the analysis. The main outcome was between-group differences regarding UTI characteristics. Results Patients using an indwelling catheter were older (indwelling catheter vs IC: median 66 (Q1-Q3: 55—77) vs 55 (42—67) years of age) and showed a higher Charlson comorbidity index (indwelling catheter vs IC: median 4 (Q1-Q3: 2–6) vs 2 (1–4) (both p

Abstract Bacteriophages operate via pathogen-specific mechanisms of action distinct from conventional, broad-spectrum antibiotics and are emerging as promising alternative antimicrobials. However, phage-mediated killing is often limited by bacterial resistance development. Here, we engineer phages for target-specific effector gene delivery and host-dependent production of colicin-like bacteriocins and cell wall hydrolases. Using urinary tract infection (UTI) as a model, we show how heterologous effector phage therapeutics (HEPTs) suppress resistance and improve uropathogen killing by dual phage- and effector-mediated targeting. Moreover, we designed HEPTs to control polymicrobial uropathogen communities through production of effectors with cross-genus activity. Using phage-based companion diagnostics, we identified potential HEPT responder patients and treated their urine ex vivo. Compared to wildtype phage, a colicin E7-producing HEPT demonstrated superior control of patient E. coli bacteriuria. Arming phages with heterologous effectors paves the way for successful UTI treatment and represents a versatile tool to enhance and adapt phage-based precision antimicrobials.

Abstract The rapid detection and species-level differentiation of bacterial pathogens facilitates antibiotic stewardship and improves disease management. Here, we develop a rapid bacteriophage-based diagnostic assay to detect the most prevalent pathogens causing urinary tract infections: Escherichia coli, Enterococcus spp., and Klebsiella spp. For each uropathogen, two virulent phages were genetically engineered to express a nanoluciferase reporter gene upon host infection. Using 206 patient urine samples, reporter phage-induced bioluminescence was quantified to identify bacteriuria and the assay was benchmarked against conventional urinalysis. Overall, E. coli, Enterococcus spp., and Klebsiella spp. were each detected with high sensitivity (68%, 78%, 87%), specificity (99%, 99%, 99%), and accuracy (90%, 94%, 98%) at a resolution of ≥103 CFU/ml within 5 h. We further demonstrate how bioluminescence in urine can be used to predict phage antibacterial activity, demonstrating the future potential of reporter phages as companion diagnostics that guide patient-phage matching prior to therapeutic phage application.

Context: The role of urodynamic studies (UDSs) in the diagnosis of lower urinary tract symptoms (LUTS) is crucial. Although expert statements and guidelines underline their value for clinical decision-making in various clinical settings, the academic debate as to their impact on patient outcomes continues. Objective: To summarise the evidence from all randomised controlled trials assessing the clinical usefulness of UDS in the management of LUTS. Evidence acquisition: For this systematic review, searches were performed without language restrictions in three electronic databases until November 18, 2020. The inclusion criteria were randomised controlled study design and allocation to receive UDS or not prior to any clinical management. Quality assessment was performed by two reviewers independently, using the Cochrane Collaboration’s tool for assessing the risk of bias. A random-effect meta-analysis was performed on the uniformly reported outcome parameters. Evidence synthesis: Eight trials were included, and all but two focused on women with pure or predominant stress urinary incontinence (SUI). A meta-analysis of six studies including 942 female patients was possible for treatment success, as defined by the authors (relative risk 1.00, 95% confidence interval: 0.93–1.07), indicating no difference in efficacy when managing women with UDS. Conclusions: Although UDSs are not replaceable in diagnostics, since there is no other equivalent method to find out exactly what the lower urinary tract problem is, there are little data supporting its impact on outcomes. Randomised controlled trials have focussed on a small group of women with uncomplicated SUI and showed no added value, but these findings cannot be extrapolated to the overall patient population with LUTS, warranting further well-designed trials. Patient summary: Despite urodynamics being the gold standard to assess lower urinary tract symptoms (LUTS), as it is the only method that can specify lower urinary tract dysfunction, more studies assessing the clinical usefulness of urodynamic studies (UDSs) in the management of LUTS are needed. UDS investigation is not increasing the probability of success in the treatment of stress urinary incontinence.

Abstract Objective: To investigate clinically relevant microbiological characteristics of uropathogens and to compare patients with catheter-associated urinary tract infections (CAUTIs) to those with non-CAUTIs. Methods: All urine cultures from the calendar year 2019 of the Swiss Centre for Antibiotic Resistance database were analyzed. Group differences in the proportions of bacterial species and antibiotic-resistant isolates from CAUTI and non-CAUTI samples were investigated. Results: Data from 27,158 urine cultures met the inclusion criteria. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis together represented 70% and 85% of pathogens identified in CAUTI and non-CAUTI samples, respectively. Pseudomonas aeruginosa was significantly more often detected in CAUTI samples. The overall resistance rate for the empirically often-prescribed antibiotics ciprofloxacin (CIP), norfloxacin (NOR), and trimethoprim-sulfamethoxazole (TMP-SMX) was between 13% and 31%. Except for nitrofurantoin, E. coli from CAUTI samples were more often resistant (P ≤ .048) to all classes of antibiotics analyzed, including third-generation cephalosporines used as surrogate for extended-spectrum β-lactamase (ESBL). Significanty higher resistance proportions in CAUTI samples versus non-CAUTI samples were observed for CIP (P = .001) and NOR (P = .033) in K. pneumoniae, for NOR (P = .011) in P. mirabilis, and for cefepime (P = .015), and piperacillin-tazobactam (P = .043) in P. aeruginosa. Conclusion: CAUTI pathogens were more often resistant to recommended empirical antibiotics than non-CAUTI pathogens. This finding emphasizes the need for urine sampling for culturing before initiating therapy for CAUTI and the importance of considering therapeutic alternatives.

Transcutaneous tibial nerve stimulation (TTNS) is a promising treatment for neurogenic lower urinary tract symptoms. However, the evidence is limited due to a general lack of randomised controlled trials (RCTs) and, also, inconsistency in the sham and blinding conditions. In the context of much-needed RCTs, we aimed to develop a suitable sham-control protocol for a clinical setting to maintain blinding but avoid meaningful stimulation of the tibial nerve. Three potential electrode positions (lateral malleolus/5th metatarsal/plantar calcaneus) and two electrode sizes (diameter: 2.5 cm/3.2 cm) were tested to determine which combination provided the optimal sham configuration for a TTNS approach, based on a visible motor response. Sixteen healthy volunteers underwent sensory and motor assessments for each sham configuration. Eight out of them came back for an extra TTNS visit. Sensory thresholds were present for all sham configurations, with linear regression models revealing a significant effect regarding electrode position (highest at plantar calcaneus) but not size. In addition, motor thresholds varied with the position—lowest for the 5th metatarsal. Only using this position and 3.2 cm electrodes attained a 100% response rate. Compared to TTNS, sensory and motor thresholds were generally higher for the sham configurations; meanwhile, perceived pain was only higher at the lateral malleolus. In conclusion, using the 5th metatarsal position and 3.2 cm electrodes proved to be the most suitable sham configuration. Implemented as a four-electrode setup with standardized procedures, this appears to be a suitable RCT protocol for maintaining blinding and controlling for nonspecific TTNS effects in a clinical setting.

Overactive bladder (OAB) is a global problem reducing the quality of life of patients and increasing the costs of any healthcare system. The etiology of OAB is understudied but likely involves supraspinal network alterations. Here, we characterized supraspinal resting-state functional connectivity in 12 OAB patients and 12 healthy controls (HC) who were younger than 60 years. Independent component analysis showed that OAB patients had a weaker presence of the salience (Cohen’s d = 0.9) and default mode network (Cohen’s d = 1.1) and weaker directed connectivity between the fronto-parietal network and salience network with a longer lag time compared to HC. A region of interest analysis demonstrated weaker connectivity in OAB compared to HC (Cohen’s d > 1.6 or < −1.6), particularly within the frontal and prefrontal cortices. In addition, weaker seed (insula, ventrolateral prefrontal cortex) to voxel (anterior cingulate cortex, frontal gyrus, superior parietal lobe, cerebellum) connectivity was found in OAB compared to HC (Cohen’s d > 1.9). The degree of deviation in supraspinal connectivity in OAB patients (relative to HC) appears to be an indicator of the severity of the lower urinary tract symptoms and an indication that such symptoms are directly related to functional supraspinal alterations. Thus, future OAB therapy options should also consider supraspinal targets, while neuroimaging techniques should be given more consideration in the quest for better phenotyping of OAB.

We used clinical parameters to develop a prediction model for the occurrence of urodynamic risk factors for upper urinary tract (UUT) damage during the first year after acute spinal cord injury (SCI). A total of 97 patients underwent urodynamic investigation at 1, 3, 6, and 12 months after acute SCI, within the framework of a population-based longitudinal study at a single university SCI center. Candidate predictors included demographic characteristics and neurological and functional statuses 1 month after SCI. Outcomes included urodynamic risk factors for UUT damage: detrusor overactivity combined with detrusor sphincter dyssynergia, maximum storage detrusor pressure (pDetmax) ≥ 40 cmH2O, bladder compliance < 20 mL/cmH2O, and vesicoureteral reflux. Multivariable logistic regression was used for the prediction model development and internal validation, using the area under the receiver operating curve (aROC) to assess model discrimination. Two models showed fair discrimination for pDetmax ≥ 40 cmH2O: (i) upper extremity motor score and sex, aROC 0.79 (95% CI: 0.69–0.89), C-statistic 0.78 (95% CI: 0.69–0.87), and (ii) neurological level, American Spinal Injury Association Impairment Scale grade, and sex, aROC 0.78 (95% CI: 0.68–0.89), C-statistic 0.76 (95% CI: 0.68–0.85). We identified two models that provided fair predictive values for urodynamic risk factors of UUT damage during the first year after SCI. Pending external validation, these models may be useful for clinical trial planning, although less so for individual-level patient management. Therefore, urodynamics remains essential for reliably identifying patients at risk of UUT damage.

Abstract Background Emergency carotid artery stenting (CAS) is a frequent endovascular procedure, especially in combination with intracranial thrombectomy. Balloon guide catheters are frequently used in these procedures. Our aim was to determine if mechanical aspiration through the working lumen of a balloon occlusion catheter during the steps of a carotid stenting procedure achieve flow rates that may lead to internal carotid artery (ICA) flow reversal which consecutively may prevent distal embolism. Methods Aspiration experiments were conducted using a commercially available aspiration pump. Aspiration flow rates/min with 6 different types of carotid stents inserted into a balloon guide catheter were measured. Measurements were repeated three times with increasing pressure in the phantom. To determine if the achieved aspiration flow rates were similar to physiologic values, flow rates in the ICA and external carotid artery (ECA) in 10 healthy volunteers were measured using 4D-flow MRI. Results Aspiration flow rates ranged from 25 to 82 mL/min depending on the stent model. The pressure in the phantom had a significant influence on the aspiration volume. Mean blood flow volumes in volunteers were 210 mL/min in the ICA and 101 mL/min in the ECA. Conclusions Based on the results of this study, flow reversal in the ICA during common carotid artery occlusion is most likely achieved with the smallest diameter stent sheath and the stent model with the shortest outer stent sheath maximum diameter. This implies that embolic protection during emergency CAS through aspiration is most effective with these models.

Background: Lower urinary tract dysfunction is common in the early postoperative phase after spine surgery. Although it is essential for an optimal patient management to balance benefits and harms, it is not known which patient benefit from a perioperative indwelling catheter. We therefore evaluated urological parameters prior and after spine surgery performing a quality assessment of our current clinical practice in bladder management. Methods: Preoperatively, all patients completed the International Prostate Symptom Score and were interviewed for urological history. Decision for preoperative urethral catheter placement was individually made by the responsible anesthesiologist according to an in-house protocol. Within and between group analyses using univariate and probability matching statistics were performed for patients with intraoperative urethral catheter-free management (n = 54) and those with a preoperatively placed catheter (n = 46). Post void residual (PVR) was measured prior and after surgery or after removal of the urethral catheter, respectively. The outcome measures consisted of postoperative urinary retention (POUR) and postoperative urological complications (PUC), defined as POUR and any catheter-related adverse events. Results: Hundred patients undergoing spine surgery were prospectively evaluated. Sixteen of the 54 (30%) patients with urethral catheter-free management developed POUR. Length of surgery and volume of intravenous infusion were associated with POUR (p

Background: Urinary tract infections are commonly encountered and often treated with antibiotics. However, the inappropriate use of the latter has led to the appearance of resistant strains. In this context we investigate the use of calorimetry to rapidly determine if a phage cocktail can be used as alternative to antibiotics. Methods: We used a commercially available phage cocktail from an online pharmacy and tested it against a strain of Escherichia coli and a strain of Proteus mirabilis. We used isothermal microcalorimetry to follow the metabolic activity of the bacterial culture treated with the phage cocktail. Results: Isothermal microcalorimetry was able to follow the dynamic of the bacterial metabolic activity reduction by the phage cocktail. Both pathogens were strongly inhibited; however, some regrowth was observed for E. coli in urine. Conclusions: Isothermal microcalorimetry proved to be a valuable technique when investigating the efficacy of phage cocktails against uropathogens. We foresee that isothermal microcalorimetry could be used to obtain rapid phagograms.

Abstract Background Autonomic dysreflexia is a severe and potentially life-threatening condition in patients with spinal cord injury, as it can lead to myocardial ischemia, brain hemorrhage, or even death. Urodynamic investigation is the gold standard to assess neurogenic lower urinary tract dysfunction due to spinal cord injury and reveal crucial pathological findings, such as neurogenic detrusor overactivity. However, neurogenic detrusor overactivity and urodynamic investigation are known to be leading triggers of autonomic dysreflexia. Therefore, we aimed to determine predictors of autonomic dysreflexia in individuals with spinal cord injury during urodynamic investigation. Methods This prospective cohort study included 300 patients with spinal cord injuries and complete datasets of continuous non-invasive cardiovascular monitoring, recorded during same session repeat urodynamic investigation. We used logistic regression to reveal predictors of autonomic dysreflexia during urodynamic investigation. Results We found that level of injury and presence of neurogenic detrusor overactivity were the only two independent significant predictors for autonomic dysreflexia during urodynamic investigation. A lesion at spinal segment T6 or above (odds ratio (OR) 5.5, 95% CI 3.2–9.4) compared to one at T7 or below, and presence of neurogenic detrusor overactivity (OR 2.7, 95% confidence interval (CI) 1.4–4.9) were associated with a significant increased odds of autonomic dysreflexia during urodynamic investigation. Both odds persisted after adjustment for age, sex, and completeness and stage of injury (adjusted OR (AOR) 6.6, 95% CI 3.8–11.7, and AOR 2.2, 95% CI 1.1–4.5, respectively). Further stratification by lesion level showed level-dependent significantly increased adjusted odds of autonomic dysreflexia, i.e., from C1–C4 (AOR 16.2, 95% CI 5.9–57.9) to T4–T6 (AOR 2.6, 95% CI 1.3–5.2), compared to lesions at T7 or below. Conclusions In patients with neurogenic lower urinary tract dysfunction due to spinal cord injury, autonomic dysreflexia is independently predicted by lesion level and presence of neurogenic detrusor overactivity. Considering the health risks associated with autonomic dysreflexia, such as seizures, stroke, retinal bleeding, or even death, we recommend both continuous cardiovascular monitoring during urodynamic investigation in all spinal cord-injured patients with emphasis on those with cervical lesions, and appropriate neurogenic detrusor overactivity treatment to reduce the probability of potentially life-threatening complications. Trial registration ClinicalTrials.gov, NCT01293110.

Abstract Background Urinary tract infections (UTI) are among the most prevalent microbial diseases and their financial burden on society is substantial. The continuing increase of antibiotic resistance worldwide is alarming. Thus, well-tolerated, highly effective therapeutic alternatives are urgently needed. Although there is evidence indicating that bacteriophage therapy may be effective and safe for treating UTIs, the number of investigated patients is low and there is a lack of randomized controlled trials. Methods and design This study is the first randomized, placebo-controlled, double-blind trial investigating bacteriophages in UTI treatment. Patients planned for transurethral resection of the prostate are screened for UTIs and enrolled if in urine culture eligible microorganisms ≥104 colony forming units/mL are found. Patients are randomized in a double-blind fashion to the 3 study treatment arms in a 1:1:1 ratio to receive either: a) bacteriophage (i.e. commercially available Pyo bacteriophage) solution, b) placebo solution, or c) antibiotic treatment according to the antibiotic sensitivity pattern. All treatments are intended for 7 days. No antibiotic prophylaxes will be given to the double-blinded treatment arms a) and b). As common practice, the Pyo bacteriophage cocktail is subjected to periodic adaptation cycles during the study. Urinalysis, urine culture, bladder and pain diary, and IPSS questionnaire will be completed prior to and at the end of treatment (i.e. after 7 days) or at withdrawal/drop out from the study. Patients with persistent UTIs will undergo antibiotic treatment according to antibiotic sensitivity pattern. Discussion Based on the high lytic activity and the potential of resistance optimization by direct adaptation of bacteriophages, and considering the continuing increase of antibiotic resistance worldwide, bacteriophage therapy is a very promising treatment option for UTIs. Thus, our randomized controlled trial investigating bacteriophages for treating UTIs will provide essential insights into this potentially revolutionizing treatment option. Trial registration This study has been registered at clinicaltrials.gov ( www.clinicaltrials.gov/ct2/show/NCT03140085 ). April 27, 2017.