High efficacy treatment of murine Pseudomonas aeruginosa catheter-associated urinary tract infections using the c-di-GMP modulating anti-biofilm compound Disperazol in combination with ciprofloxacin.

Persistent urinary tract infections (UTIs) in hospitalized patients constitute an important medical problem. It is estimated that 75% of nosocomial UTIs are associated with urinary tract catheters with P. aeruginosa being a species that forms biofilms on these catheters. These infections are highly resistant to standard-of-care antibiotics, and the effects of the host immune defenses, which allows for development of persistent infections. With antibiotics losing their efficacy, new treatment options against resilient infections, such as catheter-associated urinary tract infections (CAUTIs), are critically needed. Central to our anti-biofilm approach is the manipulation of the c-di-GMP signaling pathway in P. aeruginosa to switch bacteria from the protective biofilm to the unprotected planktonic mode of life. We recently identified a compound (H6-335-P1), that stimulates the c-di-GMP degrading activity of the P. aeruginosa BifA protein which plummets the intracellular c-di-GMP content and induces dispersal of P. aeruginosa biofilm bacteria into the planktonic state. In the present study, we formulated H6-335-P1 as a hydrochloride salt (Disperazol), which is water-soluble and facilitates delivery via injection or oral administration. Disperazol can work as a monotherapy, but we observed a 100-fold improvement in efficacy when treating murine P. aeruginosa CAUTIs with a Disperazol/ciprofloxacin combination. Biologically active Disperazol reached the bladder 30 min after oral administration. Our study provides proof of concept that Disperazol can be used in combination with a relevant antibiotic for effective treatment of CAUTIs.

Airway pressure release ventilation (APRV) versus pressure support ventilation (PSV)-A prospective intervention trial comparing haemodynamic parameters in intensive care patients.

BACKGROUND AND AIM: Assisted mechanical ventilation may alter the pressure profile in the thorax compared to normal breathing, which can affect the blood flow to and from the heart. Studies suggest that in patients with severe lung disease, airway pressure release ventilation (APRV) may be haemodynamically beneficial compared to other ventilator settings. The primary aim of this study was to investigate if APRV affects cardiac index in intubated intensive care patients without severe lung disease when compared to pressure support ventilation (PSV). The secondary aim comprised potential changes in other haemodynamic and ventilatory parameters. METHODS: Twenty patients were enrolled in the intensive care unit (ICU) at Sahlgrenska University Hospital. Eligible patients met the inclusion criteria; 18 years of age or above, intubated and mechanically ventilated, triggering and stable on PSV mode, with indwelling haemodynamic monitoring via a pulse-induced continuous cardiac output (PiCCO) catheter. The study protocol started with a 30-min interval on PSV mode, followed by a 30-min interval on APRV mode, and finally a 30-min interval back on PSV mode. At the end of each interval, PiCCO outputs, ventilator outputs, arterial and venous blood gas analyses, heart rate and central venous pressure were recorded and compared between modes. RESULTS: There was no significant difference in cardiac index (3.42 vs. 3.39 L/min/m2) between PSV and APRV, but a significant increase in central venous pressure (+1.0 mmHg, p = .027). Furthermore, we found a significant reduction in peak airway pressure (-3.16 cmH2O, p < .01) and an increase in mean airway pressure (+2.1 cmH2O, p < .01). No statistically significant change was found in oxygenation index (partial pressure of O2 [pO2]/fraction of inspired oxygen) nor in other secondary outcomes when comparing PSV and APRV. There was no significant association between global end-diastolic volume index and cardiac index (R2 = 0.0089) or central venous pressure (R2 = 0.278). All parameters returned to baseline after switching the ventilator mode back to PSV. CONCLUSION: We could not detect any changes in cardiac index in ICU patients without severe lung disease during APRV compared to PSV mode, despite lower peak airway pressure and increased mean airway pressure.

Five-year results of a randomized trial comparing retropubic and transobturator midurethral slings for stress incontinence.

BACKGROUND: Midurethral slings have become the most preferred surgical treatment for female urinary incontinence. OBJECTIVE: To compare the efficacy and safety of two midurethral sling procedures with a different technique of sling insertion 5 yr after intervention. DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial conducted in seven public hospitals in Finland including primary cases of stress urinary incontinence. INTERVENTION: Surgical treatment with the retropubic tension-free vaginal tape (TVT) procedure or the transobturator tension-free vaginal tape (TVT-O) procedure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Objective treatment success criteria were a negative stress test, a negative 24-h pad test, and no retreatment for stress incontinence. Patient satisfaction was assessed by condition-specific quality-of-life questionnaires. RESULTS AND LIMITATIONS: A total of 95% of the included women could be assessed according to the protocol 5 yr after surgery. The objective cure rate was 84.7% in the TVT group and 86.2% in the TVT-O group, with no statistical difference between the groups. Subjective treatment satisfaction was 94.2% in the TVT group and 91.7% in the TVT-O group, with no difference between groups. Complication rates were low, with no difference between groups. CONCLUSIONS: Both objective and subjective cure rates were >80% in both groups even when women lost to follow-up were included as failures. The complication rates were low, with no difference between the groups. No late-onset adverse effects of the tape material were seen. PATIENT SUMMARY: Female urinary stress incontinence can be treated surgically with minimally invasive midurethral sling procedures. Two main approaches of sling placement have been developed: the retropubic and the transobturatory. We compared both approaches and followed the patients for 5 yr. We found no difference in cure rate between the procedures, and patient satisfaction was high. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00379314.

Prevalence of urinary urgency symptoms decreases by mid-urethral sling procedures for treatment of stress incontinence.

INTRODUCTION AND HYPOTHESIS: Conflicting opinions on the effect of incontinence surgery on the prevalence of postoperative urgency symptoms exists. Our aim was to evaluate the prevalence of urgency symptoms preoperatively and during 3-year of follow-up in women undergoing mid-urethral sling procedures for stress incontinence. METHODS: Two hundred and sixty-seven women were randomly assigned to a retropubic or a transobturator operation. Detrusor instability score (DIS) and Urogenital Distress Inventory-6 (UDI-6) questionnaires were used to assess prevalence of urgency symptoms. The Incontinence Impact Questionnaire-7, visual analog scale, urinary incontinence severity score, and the EuroQol-5D assessed overall quality of life changes. RESULTS: A significant decrease in the DIS and UDI-6 score was seen postoperatively. Signs of de novo urgency symptoms were low. CONCLUSIONS: Mid-urethral sling procedures can be recommended in cases of mixed incontinence, and the procedures seems to decrease prevalence of urgency symptoms.

Dynamic MRI confirms support of the mid-urethra by TVT and TVT-O surgery for stress incontinence.

OBJECTIVE: To study changes in mid-urethral function with dynamic MRI in stress urinary incontinent women undergoing either tension-free vaginal tape (TVT) or TVT-obturator sling operations. DESIGN: Prospective clinical study. SETTING: University hospital. SAMPLE: Forty-two parous women with stress urinary incontinence recruited to dynamic magnetic resonance imaging before and after mid-urethral sling surgery. Control group of 16 healthy women. METHODS: Dynamic magnetic resonance imaging at rest, during pelvic floor muscle contraction, coughing and voiding with a bladder volume of 200-300 ml. X- and Y- coordinates were used to determine the location of the mid-urethra during these activities. MAIN OUTCOME MEASURES: Changes in mid-urethral position after TVT and TVT-obturator operations during the different activities. RESULTS: Postoperatively the women could elevate their mid-urethra by pelvic floor muscle contraction significantly higher than before the operation (p<0.05). Despite a different support angle between the TVT and the TVT-O mid-urethral slings, we could not see any differences in the movement patterns. CONCLUSION: Mid-urethral slings support the mid-urethra and restrict downward movement during different activities. Movement patterns are similar after TVT and TVT-O operations.

A randomized trial comparing tension-free vaginal tape with tension-free vaginal tape-obturator: 36-month results.

INTRODUCTION AND HYPOTHESIS: This is a randomized multicenter study comparing two mid-urethra tape procedures, the tension-free vaginal tape (TVT) with the tension-free vaginal tape-obturator (TVT-O) in terms of cure rate and complication rate. METHODS: Seven Finnish hospitals participated. Power calculations required 130 women in each group to detect a 10% difference in cure rate. A total of 267 underwent the allocated operation. Follow-up was scheduled at 2, 12, 36 and 60 months. A cough stress test was used as an objective outcome measure. Subjective outcome was assessed by five different condition-specific quality of life questionnaires. RESULTS: At 36 months of follow-up, 96% of the patients were evaluated. Objective cure rate was 94.6% in the TVT group and 89.5% in the TVT-O group (p = 0.131). Subjective cure rates were significant with no difference between the groups. CONCLUSION: The TVT and the TVT-O are equally effective in the treatment of stress urinary incontinence after 36-month follow-up with no difference in complication rates.

Updated systematic review and meta-analysis of the comparative data on colposuspensions, pubovaginal slings, and midurethral tapes in the surgical treatment of female stress urinary incontinence.

CONTEXT: Burch colposuspension, pubovaginal sling, and midurethral retropubic tape (RT) and transobturator tape (TOT) have been the most popular surgical treatments for female stress urinary incontinence (SUI). Several randomized controlled trials (RCTs) have been published comparing the different techniques, with conflicting results. OBJECTIVE: Our aim was to evaluate the efficacy, complication, and reoperation rates of midurethral tapes compared with other surgical treatments for female SUI. EVIDENCE ACQUISITION: A systematic review of the literature was performed using the Medline, Embase, Scopus, Web of Science databases, and Cochrane Database of Systematic Reviews. EVIDENCE SYNTHESIS: Thirty-nine RCTs were identified. Patients receiving midurethral tapes had significantly higher overall (odds ratio [OR]: 0.61; confidence interval [CI]: 0.46-0.82; p=0.00009) and objective (OR: 0.38; CI: 0.25-0.57; p<0.0001) cure rates than those receiving Burch colposuspension, although they had a higher risk of bladder perforations (OR: 4.94; CI: 2.09-11.68; p=0.00003). Patients undergoing midurethral tapes and pubovaginal slings had similar cure rates, although the latter were slightly more likely to experience storage lower urinary tract symptoms (LUTS) (OR: 0.31; CI: 0.10-0.94; p=0.04) and had a higher reoperation rate (OR: 0.31; CI: 0.12-0.82; p=0.02). Patients treated with RT had slightly higher objective cure rates (OR: 0.8;CI: 0.65-0.99; p=0.04) than those treated with TOT; however, subjective cure rates were similar, and patients treated with TOT had a much lower risk of bladder and vaginal perforations (OR: 2.5; CI: 1.75-3.57; p<0.00001), hematoma (OR: 2.62; CI: 1.35-5.08; p=0.005), and storage LUTS (OR: 1.35; CI: 1.05-1.72; p=0.02). Meta-analysis demonstrated similar outcomes for TVT-O (University of Liège, Liège, Wallonia, Belgium) and Monarc (AMS, Minnetonka, MN, USA). CONCLUSIONS: Patients treated with RT experienced slightly higher continence rates than those treated with Burch colposuspension, but they faced a much higher risk of intraoperative complications. RT and pubovaginal slings were similarly effective, although patients with pubovaginal slings were more likely to experience storage LUTS. The use of RT was followed by objective cure rates slightly higher than TOT, but subjective cure rates were similar. TOT had a lower risk of bladder and vaginal perforations and storage LUTS than RT. The strength of these findings is limited by the heterogeneity of the outcome measures and the short length of follow-up.

Dynamic magnetic resonance imaging of the behavior of the mid-urethra in healthy and stress incontinent women.

OBJECTIVES: Support of the mid-urethra is thought to be an essential element of urinary continence in the female. Our aim was to image the behavior of the mid-urethra in healthy volunteers and in stress urinary incontinence (SUI) patients by dynamic magnetic resonance imaging (MRI). DESIGN: Prospective study. SETTING: Gynecology outpatient clinic association with Department of Radiology in University Hospital of Kuopio, Finland. SAMPLE AND METHODS: Fifteen healthy volunteers and 40 SUI women underwent dynamic MRI at rest, during pelvic floor muscle contraction, coughing and voiding with a bladder volume of 200 ml. Our aim was to determine the precise location and movement of the mid-urethra during these activities. MAIN OUTCOME MEASURE: The co-ordinate location and movement of the mid-urethra. RESULTS: Continent volunteers can elevate their mid-urethra significantly higher than incontinent women. Moreover, the mid-urethra of incontinent women rotated significantly more dorsocaudally during straining and coughing than in continent women. CONCLUSIONS: Elevation of the mid-urethra was more marked in continent compared to urinary incontinent women on pelvic floor muscle contraction suggesting sufficient support of the urethra. Downward movement of the mid-urethra was more significant in stress incontinent women than in continent volunteers.

The use of hair as an indicator of occupational 14C contamination.

This paper presents a study in which the specific activity of (14)C in hair has been investigated as an easily determined bio-indicator of the integrated (14)C exposure (over several months). The study includes 28 Swedish workers handling (14)C-labelled compounds, or working in a (14)C-enriched environment. Hair samples from personnel at a Swedish nuclear power plant showed very low levels of (14)C contamination, if any. In contrast, personnel at the investigated research departments showed (14)C levels in hair of up to 60% above the natural specific activity of (14)C. Much higher levels, up to 80 times the natural specific activity of (14)C, were found in hair from individuals working at a pharmaceutical research laboratory. This contamination was, however, not solely an internal contamination. There were indications that most of the (14)C in the hair originated from airborne (14)C-compounds, which were adsorbed onto the hair. The difficulties in removing this external (14)C contamination prior to analysis are discussed, as are the possibilities of using accelerator mass spectrometry to analyse various types of samples for retrospective dose assessment.

Cost-effectiveness analysis of solifenacin flexible dosing in patients with overactive bladder symptoms in four Nordic countries.

OBJECTIVE: The purpose of the present analysis was to analyze and compare the cost-effectiveness of solifenacin flexible dosing (5-10 mg) with tolterodine 4 mg sustained release (SR) or placebo (assumed to be comparable to no treatment) for patients with overactive bladder (OAB) symptoms. DESIGN: A decision-analytic model was constructed. METHODS: Costs and effects were evaluated for the three treatment options in a one-year timeframe. Costs included were treatment costs, cost of pad use, and patients productivity loss based on data from the Nordic countries. SAMPLE: Results from two randomized controlled trials were used as input data in the cost-effectiveness analysis. MAIN OUTCOME MEASURES: Quality adjusted life years and incremental cost-effectiveness ratio. RESULTS: Solifenacin flexible dosing was more effective with respect to reducing OAB symptoms compared to both placebo and tolterodine 4 mg. Treatment with both solifenacin and tolterodine was more costly compared to placebo, but treatment with solifenacin was a less costly alternative compared to tolterodine 4 mg SR. Sensitivity analyses revealed that the conclusions were robust. CONCLUSION: Solifenacin flexible dosing was a cost-effective treatment alternative compared to tolterodine 4 mg SR.

A randomized trial comparing TVT with TVT-O: 12-month results.

The aim of this randomized clinical trial was to compare the cure rate and the rate of complications of the tension-free vaginal tape (TVT) with those of the tension free vaginal tape obturator (TVT-O) procedure after one year of follow-up. The study was powered to show a ten per cent difference in cure rate and/or rate of complications. Of the initially treated 267 women 134 in the TVT group and 131 in the TVT-O group were evaluated. A cough stress test and a 24 h pad test were used as objective outcome measures. Subjective outcome was assessed by different condition-specific quality of life questionnaires and general health by the EQ-5D questionnaire. Objective cure rate was 95.5% in the TVT patients and 93.1% in TVT-O patients. Subjective cure rates showed significant improvement at one the year follow up in both groups. No significant differences in cure rates between groups were seen. The complication rate was equal in both groups.

Retropubic compared with transobturator tape placement in treatment of urinary incontinence: a randomized controlled trial.

OBJECTIVE: To compare the intraoperative and immediate postoperative performance of the retropubic tension-free vaginal tape (TVT) procedure with that of the transobturator tension-free vaginal tape (TVT-O) procedure as primary treatment for female urinary stress incontinence. METHODS: Randomized multicenter comparative trial including four university hospitals and three central hospitals in Finland. Assessment preoperatively and 2 months postoperatively included a cough stress test and the following condition-specific quality of life questionnaires: the Urinary Incontinence Severity Score (UISS), the Detrusor Instability Score, the Incontinence Impact Questionnaire-Short Form, the Urogenital Distress Inventory-Short Form, and a visual analog scale (VAS). Operation time, theater time, hospital stay, intraoperative and immediate postoperative complications were recorded. RESULTS: Of the 273 originally randomized patients, 267 underwent the allocated operation, 136 in the TVT group and 131 in the TVT-O group. No significant differences in objective or subjective cure rates were detected. Patients in the TVT-O group had a significantly longer hospital stay, needed significantly more postoperative opiate analgesia and had significantly more complications than the patients in the TVT group. Patients in both groups had a significant postoperative improvement in quality of life, as indicated by the results of all the questionnaires used, with no difference between the groups. CONCLUSION: The TVT and the TVT-O procedures perform equally in terms of objective and subjective cure. The statistically significant higher complication rate in the TVT-O group is not regarded as clinically significant. CLINICAL TRIAL REGISTRATION: (www.ClinicalTrials.gov), NCT00379314 LEVEL OF EVIDENCE: I.

Long-term results of the tension-free vaginal tape operation in an unselected group of 129 stress incontinent women.

BACKGROUND: This study was undertaken to examine the long-term effects and effectiveness of the tension-free vaginal tape (TVT) procedure in an unselected group of women. METHOD: One hundred and twenty-nine stress urinary incontinent women (including primary, recurrent, mixed, and low pressure urethra cases) were studied prospectively and examined according to a strict protocol at a mean time of 6 years after their TVT operation. Cough and pad tests were used for objective evaluation, whereas visual analog scale and patients' verbal estimation were applied for subjective evaluation. RESULTS: As assessed by the cough stress test and the pad test, 74 and 81% of the women were totally cured, respectively. Symptoms possibly indicating reduced urine flow were reported from 17% of the women and recurrent urinary tract infections from 9.3% of the women. The de novo urge rate was 4.7%. The tape was visualized in 3.1% of the women and necessitated resection in 1.6% of the cases due to subjective discomfort. No serious or unexpected adverse events were revealed. CONCLUSION: The TVT operation appears to be a safe and effective anti-incontinence procedure in all female stress incontinence subgroups.

A cost-effectiveness analysis of tension-free vaginal tape versus laparoscopic mesh colposuspension for primary female stress incontinence.

BACKGROUND: Evaluation of cost-effectiveness of new surgical techniques is important. As the data on incontinence procedures are scarce, we evaluated the cost-effectiveness of tension-free vaginal tape procedure and laparoscopic mesh colposuspension as a primary surgical treatment for female stress urinary incontinence. METHODS: In four university teaching hospitals and two central hospitals 128 stress incontinent women were randomized to tension-free vaginal tape procedure (n=70) or laparoscopic mesh colposuspension (n=51) in order to investigate the clinical performance of these two procedures. Primary objective clinical outcome measures were: stress test and 48-h pad test. Secondary subjective outcome measures were health-related quality of life measured in terms of visual analogue scale and Urinary Incontinence Severity Score. Alongside the clinical trial, a cost-effectiveness analysis for the main outcome measures was performed. RESULTS: The changes in the 48-h pad test result did not reach statistical significance (p=0.105). When the visual analogue scale or Urinary Incontinence Severity Score are used as the outcome measure, the tension-free vaginal tape is more cost-effective than laparoscopic mesh colposuspension over a follow-up period of one year (p<0.000). CONCLUSION: The clinical and economic data of the present study suggest that over a follow-up period of one year the tension-free vaginal tape procedure is more cost-effective than laparoscopic mesh colposuspension as a primary treatment for female stress urinary incontinence.

Seven-year follow-up of the tension-free vaginal tape procedure for treatment of urinary incontinence.

OBJECTIVE: To evaluate the long-term cure rates and late complication rates after treatment of female urinary stress incontinence with the minimally invasive tension-free vaginal tape operation. METHODS: Prospective observational, 3-center cohort study originally of 90 women requiring surgical treatment for primary urinary stress incontinence. Assessment variables included a 24-hour pad weighing test, a stress test, visual analog scale for assessing the degree of bother, and a questionnaire assessing the subjective perception of the women on their continence status. RESULTS: The follow-up time was a mean of 91 months (range 78-100 months). Both objective and subjective cure rates were 81.3% for the 80 women available for follow-up. Asymptomatic pelvic organ prolapse was found in 7.8%, de novo urge symptoms in 6.3%, and recurrent urinary tract infection in 7.5% of the women. No other long-term adverse effects of the procedure were detected. CONCLUSION: The tension-free vaginal tape procedure for treatment of female urinary stress incontinence is effective over a period of 7 years.