Safety and Efficacy of an Oxytocin Gel and an Equivalent Gel but Without Hormonal Ingredients (Vagivital® Gel) in Postmenopausal Women with Symptoms of Vulvovaginal Atrophy: A Randomized, Double-Blind Controlled Study.

PURPOSE: The primary objective was to compare the efficacy of 12 weeks of daily treatment with Aqueous Hypromellose-based vaginal (Vagivital®) gel versus Aqueous Hypromellose-based vaginal gel plus 400 IU oxytocin gel in reducing the severity of the most bothersome vulvovaginal atrophy symptoms (MBS: itching, dysuria, bleeding, and pain/discomfort during vaginal sexual activity) observed at baseline. The secondary objectives were to evaluate the other vulvovaginal atrophy symptoms, vaginal pH, superficial squamous cells, and the safety and tolerability of both gels. PATIENTS AND METHODS: This double-blind, randomized study evaluated the safety and efficacy of subjects randomly assigned to 12 weeks of daily intravaginal oxytocin gel (n=79) or Aqueous Hypromellose-based vaginal gel (n=78). The efficacy evaluation was performed using data from all included subjects who fulfilled entry criteria. RESULTS: Both treatments induced statistically significant reductions in the severity of the MBS from baseline until 4 weeks (Vagivital mean reduction 0.90, p=0.0000; Oxytocin mean reduction 0.82, p=0.0000) and 12 weeks post baseline (Vagivital mean reduction 1.28, p=0.0000; Oxytocin mean reduction 1.16, p=0.0000), but the reduction of MBS severity was not significantly different between the treatment groups at either time point. No serious adverse events were reported in the Aqueous Hypromellose-based vaginal gel group during the treatment period, but one (breast cancer) was reported in the oxytocin gel group (assessed as unlikely related to the study compound). CONCLUSION: Significant reductions in the severity of the MBS were seen in both the Aqueous Hypromellose-based vaginal gel and the oxytocin gel groups, but with no significant differences in severity reduction seen between the groups. Both gels were safe and well tolerated. Given the benefits of avoiding the use of hormones, Aqueous Hypromellose-based vaginal gel is an attractive first choice in the treatment of postmenopausal women with vulvovaginal atrophy symptoms.

Clinical validation of a novel automated cell-free DNA screening assay for trisomies 21, 13, and 18 in maternal plasma.

OBJECTIVE: To evaluate clinical performance of a new automated cell-free (cf)DNA assay in maternal plasma screening for trisomies 21, 18, and 13, and to determine fetal sex. METHOD: Maternal plasma samples from 1200 singleton pregnancies were analyzed with a new non-sequencing cfDNA method, which is based on imaging and counting specific chromosome targets. Reference outcomes were determined by either cytogenetic testing, of amniotic fluid or chorionic villi, or clinical examination of neonates. RESULTS: The samples examined included 158 fetal aneuploidies. Sensitivity was 100% (112/112) for trisomy 21, 89% (32/36) for trisomy 18, and 100% (10/10) for trisomy 13. The respective specificities were 100%, 99.5%, and 99.9%. There were five first pass failures (0.4%), all in unaffected pregnancies. Sex classification was performed on 979 of the samples and 99.6% (975/979) provided a concordant result. CONCLUSION: The new automated cfDNA assay has high sensitivity and specificity for trisomies 21, 18, and 13 and accurate classification of fetal sex, while maintaining a low failure rate. The study demonstrated that cfDNA testing can be simplified and automated to reduce cost and thereby enabling wider population-based screening.

Imaging single DNA molecules for high precision NIPT.

Cell-free DNA analysis is becoming adopted for first line aneuploidy screening, however for most healthcare programs, cost and workflow complexity is limiting adoption of the test. We report a novel cost effective method, the Vanadis NIPT assay, designed for high precision digitally-enabled measurement of chromosomal aneuploidies in maternal plasma. Reducing NIPT assay complexity is achieved by using novel molecular probe technology that specifically label target chromosomes combined with a new readout format using a nanofilter to enrich single molecules for imaging and counting without DNA amplification, microarrays or sequencing. The primary objective of this study was to assess the Vanadis NIPT assay with respect to analytical precision and clinical feasibility. Analysis of reference DNA samples indicate that samples which are challenging to analyze with low fetal-fraction can be readily detected with a limit of detection determined at <2% fetal-fraction. In total of 286 clinical samples were analysed and 30 out of 30 pregnancies affected by trisomy 21 were classified correctly. This method has the potential to make cost effective NIPT more widely available with more women benefiting from superior detection and false positive rates.

Mirabegron as Add-On Treatment to Solifenacin in Patients with Incontinent Overactive Bladder and an Inadequate Response to Solifenacin Monotherapy: Responder Analyses and Patient-Reported Outcomes from the BESIDE Study [corrected].

PURPOSE: We investigated improvements in overactive bladder and patient reported outcomes in patients with overactive bladder and refractory incontinence treated with mirabegron 50 mg plus solifenacin 5 mg vs solifenacin 5 or 10 mg. MATERIALS AND METHODS: Patients with overactive bladder who were incontinent despite 4 weeks of single-blind daily solifenacin 5 mg were randomized 1:1:1 to a double-blind daily combination of mirabegron 50 mg/solifenacin 5 mg, or solifenacin 5 or 10 mg for 12 weeks. The mirabegron dose was increased from 25 to 50 mg after week 4. Symptom bother, health related quality of life and patient perception of bladder condition were assessed by OAB-q (Overactive Bladder Questionnaire) and the PPBC (Patient Perception of Bladder Condition) questionnaire, respectively. Responder rates were based on a 50% reduction in daily incontinence, zero incontinence episodes and fewer than 8 micturitions per 24 hours with minimal important differences in OAB-q and PPBC. RESULTS: Overall 2,174 patients with a median age of 59 years were randomized, including 727 to the combination, 728 to solifenacin 5 mg and 719 to solifenacin 10 mg. Symptom bother, total health related quality of life and its subscales (coping, concern and social), and PPBC were significantly improved with combination vs solifenacin monotherapy (p <0.05). The odds of achieving clinically meaningful improvements in incontinence, micturition frequency, symptom bother, health related quality of life and PPBC were significantly higher for combination than solifenacin monotherapy. The odds of becoming continent was 47% and 28% higher for combination vs solifenacin 5 and 10 mg (OR 1.47, 95% CI 1.17-1.84, p = 0.001 and OR 1.28; 95% CI 1.02-1.61, p = 0.033, respectively). CONCLUSIONS: Significantly more patients on the combination achieved clinically meaningful improvements in incontinence and micturition frequency. Improvements were accompanied by similar improvements in PPBC, symptom bother and health related quality of life.

Clinical value of a patient-reported goal-attainment measure: the global development of self-assessment goal achievement (SAGA) questionnaire for patients with lower urinary tract symptoms.

AIMS: To discuss the importance of patients' treatment goals and perceived goal attainment to better address expectations in the treatment of lower urinary tract symptoms (LUTS), including overactive bladder (OAB). METHODS: The development of the Self-Assessment Goal Achievement (SAGA) questionnaire was driven by measurement principles from the field of qualitative and psychometric research adapted to elicit patients' treatment goals. At baseline, SAGA solicits individualized responses of patient's treatment expectations and goals, and at follow-up SAGA uses a goal-attainment scale (GAS) to document goal achievement. RESULTS: The SAGA questionnaire provides a basis for the patient and physician to discuss realistic treatment expectations and to measure the alignment between patients' expectations and treatment outcomes in terms of improvement in symptoms and impact on function. Therefore, incorporating the SAGA questionnaire into clinical trials may provide an additional dimension of treatment efficacy by incorporating data on treatment satisfaction from the patient's perspective. CONCLUSIONS: The SAGA questionnaire is a useful tool for patient-centered discussions about the treatment and management of LUTS, including OAB, and assisting physicians in tracking progress and managing patient expectations during therapy.

European content validation of the Self-Assessment Goal Achievement (SAGA) questionnaire in patients with overactive bladder.

INTRODUCTION AND HYPOTHESIS: The Self-Assessment Goal Achievement (SAGA) questionnaire is a patient-completed instrument designed to assess goal attainment in the behavioral or pharmacologic treatment of lower urinary tract symptoms (LUTS), including overactive bladder (OAB). The SAGA questionnaire allows patients to identify and rank the importance of treatment goals before treatment is initiated; the follow-up SAGA questionnaire quantifies the achievement of these patient-identified goals. The objective of this qualitative research was to confirm the content validity of the German, Spanish, Swedish, and English (UK) language versions of the SAGA questionnaire in patients with OAB with or without other LUTS. METHODS: The SAGA questionnaire was translated to each language in accordance with a well-established forward and backward harmonization method. Patient interviews were then conducted according to a cognitive debriefing methodology. Qualitative analysis of patients' input allowed assessment of content validity of each linguistically adapted SAGA questionnaire. RESULTS: All patients (n = 29; six to eight per targeted country) found the SAGA questionnaire easy to understand and to complete. Most patients completed the nine prespecified (fixed) treatment goals and were able to add up to five personal goals in the open-ended portion and rate each goal by importance. Differences were identified in how the various languages communicated some of the concepts assessed with the SAGA questionnaire. Rewording of the translated versions of the questionnaire was necessary in some cases. CONCLUSIONS: This linguistic content validation study in four European languages indicates that SAGA is a comprehensive, easy-to-understand, and relevant questionnaire for patient-completed evaluation of LUTS/OAB symptoms and treatment goal attainment.

Treatment of stress urinary incontinence with non-animal stabilised hyaluronic acid/dextranomer (NASHA/Dx) gel : An analysis of utility and cost.

BACKGROUND: The Zuidex system is a treatment for stress urinary incontinence comprising four prefilled syringes of non-animal stabilised hyaluronic acid/dextranomer (NASHA/Dx) gel and the Implacer device. This study aimed to investigate utility (patients' preferences for given health states) with NASHA/Dx gel therapy and to compare resource utilisation of NASHA/Dx gel treatment with tension-free vaginal tape (TVT). METHODS: Utility was measured using EuroQol (EQ-5D), a generic utility instrument. For the cost of NASHA/Dx gel treatment, data were collected prospectively from participants in a 12-month efficacy study (n = 82). Retrospective analysis of a comparable group of patients (n = 77; 3-6 months' follow-up) was used to obtain equivalent costs for TVT. Costs were analysed for both Sweden and France. RESULTS: NASHA/Dx gel produced a utility gain of 0.048 at 3 months and 0.014 at 12 months. The estimated mean total 3-month cost per patient with NASHA/Dx gel was euro 2412 in Sweden and euro 2005 in France. The corresponding values for 12 months, including 14% of patients undergoing TVT, were euro 3370-euro 3417 and euro 2935-euro 2976 for Sweden and France, respectively. In comparison, the total costs of treatment with TVT over 3-6 months were euro 3169-euro 3504 and euro 5181-euro 5471 for Sweden and France, respectively. CONCLUSIONS: NASHA/Dx gel provides utility benefits that are similar to those previously reported for TVT and, depending on the country in which the treatment is performed, are associated with similar or lower overall costs in the short to medium term. From an economic perspective, NASHA/Dx gel could be considered at least as favourable as TVT, pending the availability of long-term effectiveness data.

The clinical diagnosis of pelvic inflammatory disease--reuse of electronic medical record data from 189 patients visiting a Swedish university hospital emergency department.

BACKGROUND: The pelvic inflammatory disease (PID) diagnosis is mostly based on clinical findings. However, few studies have examined the clinical basis for the diagnostics of PID, which was the aim of this study. METHODS: A retrospective study was performed of 189 out-patients diagnosed as having PID at the obstetric and gynecological emergency department of a Swedish university hospital. Data on symptoms, signs, pelvic examination and laboratory tests were extracted from the electronic medical records in comparison with the diagnostic criteria of the PID Guideline of the US Center of Disease Control from 2002 (CDC 2002 Guidelines). RESULTS: Eight symptoms in varying combinations were associated with the PID diagnosis. Most of them are mentioned in the CDC 2002 Guidelines. Detected rates of C. Trachomatis (CT) and N. Gonorrhoeae (NG) were 5% and 0%, respectively, among the tested patients (CT = 52% and NG = 12%). The C-reactive protein was normal in the majority of tested patients. CONCLUSION: The clinical basis for the diagnostics of PID was largely in accordance with the criteria in the CDC 2002 Guidelines. The limited number of CT tests performed is somewhat disappointing, considering the fact that effective disease prevention includes widespread CT screening. Further studies in different settings are needed in order to analyze how the testing rate for CT can be improved in clinical praxis.

Microvascular density, vascular endothelial growth factor A, and its receptors in endometrial blood vessels in patients with menorrhagia.

OBJECTIVE: To analyze the expression of vascular endothelial growth factor A (VEGF-A) and receptors (VEGFR-1 and VEGFR-2) in endometrial blood vessels, as well as microvascular density (MVD), in endometrial biopsy samples from idiopathic menorrhagia patients. DESIGN: Prospective clinical study. SETTING: University hospital, unit of gynecology. PATIENT(S): Twenty-four patients with idiopathic menorrhagia and 18 healthy fertile women. INTERVENTION(S): Blood sampling for hormone measurement, hysteroscopy, and endometrial biopsy sampling. Endometrial biopsy samples were used for immunohistochemistry assessments and image analysis of stained endothelial structures for VEGF-A, VEGFR-1, VEGFR-2, and CD34. MAIN OUTCOME MEASURE(S): Appearance of the endometrial vascular immunoreactivity for VEGF-A, VEGFR-1, and VEGFR-2, MVD and computer-assisted stereological analysis of immunoassayed blood vessels. RESULT(S): Although the MVD did not differ between patients and controls, we observed that vascular expression of VEGF-A, VEGFR-1, and VEGFR-2 in capillaries was 1.8-fold, 1.8-fold, and 2.0-fold higher, respectively, in the menorrhagia group when assessed as the number of stained capillaries per unit area. There were also a twofold higher number of arterioles, which were VEGFR-2 positive in the menorrhagia group. CONCLUSION(S): Up-regulation of VEGF-A and receptors VEGFR-1 and VEGFR-2 in capillaries in menorrhagia could be involved in abnormal endometrial vascular structure and permeability.

An open, multicentre study of NASHA/Dx Gel (Zuidex) for the treatment of stress urinary incontinence.

OBJECTIVE: The Zuidex system facilitates non-endoscopic urethral injection for stress urinary incontinence (SUI). It comprises four pre-filled syringes of non-animal stabilised hyaluronic acid/dextranomer (NASHA/Dx) gel and an Implacer device. This open, 12-month study was performed to evaluate the safety and efficacy of this system in women with SUI. METHODS: Patients were aged > or =18 years with a history of SUI for > or =12 months (hypermobility and/or intrinsic sphincter deficiency), had failed prior non-invasive therapy and were invasive-therapy naïve. Up to two treatments with NASHA/Dx gel were permissible (re-treatment was offered at week 8). Positive response to treatment was defined as a reduction in provocation test leakage of > or =50% compared with baseline. Efficacy was also measured by 24-hour pad weight test leakage, and number of incontinence episodes/24 hours. RESULTS: A total of 142 patients were enrolled, with a mean age of 55.7 years. The response rate was 78% at week 12, and 77% at month 12. Significant reductions in median provocation test leakage, 24-hour pad-weight test leakage and number of incontinence episodes/24 hours were observed at all time-points. At month 12, the median decreases from baseline in these three variables were 93%, 89% and 67%, respectively. Treatment-related adverse events were of a nature expected with urethral injection - most were transient, and of mild or moderate intensity. CONCLUSIONS: Treatment with NASHA/Dx gel produced large, statistically significant reductions in urinary leakage sustained over 12 months and was well tolerated. These findings suggest that NASHA/Dx gel could be considered as an early intervention in treatment-naïve cases of SUI.

Ecological effects of perorally administered pivmecillinam on the normal vaginal microflora.

The knowledge of the effects of antimicrobial agents on the normal vaginal microflora is limited. The objective of the present study was to study the ecological impact of pivmecillinam on the normal vaginal microflora. In 20 healthy women, the estimated day of ovulation was determined during three subsequent menstrual cycles. Microbiological and clinical examinations were performed on the estimated day of ovulation and on day 3 in all cycles and also on day 7 after ovulation in cycles 1 and 2. Anaerobic and facultative anaerobic gram-positive rods, mainly species of lactobacilli and actinomycetes, dominated the microflora. One woman was colonized on the third day of administration with a resistant Escherichia coli strain, and Candida albicans was detected in one woman on days 3 and 7 in cycle 2. No other major changes in the normal microflora occurred during the study. Administration of pivmecillinam had a minor ecological impact on the normal vaginal microflora.

Treatment of stress urinary incontinence using a copolymer system: impact on quality of life.

OBJECTIVE: To investigate the effect on quality of life (QoL) of a novel system for treatment of stress urinary incontinence (SUI). PATIENTS AND METHODS: In an open, prospective, multicentre study, 42 women not previously treated by invasive therapy and with urodynamically verified SUI received 4 x 1.0 mL or 4 x 0.7 mL of non-animal stabilized hyaluronic acid/dextranomer copolymer injected transurethrally into the urethra via the Implacer device (Zuidex system, Q-Med AB, Uppsala, Sweden). QoL was assessed using the King's Health Questionnaire. The patients' perception of treatment benefit and the number of incontinence episodes/24 h were also investigated. RESULTS: There were significant improvements over baseline in seven of 10 domains of the King's Health Questionnaire at 3 months, and these improvements were sustained at 1 year. For the change from baseline to 1 year, eight of 10 domains showed a significant positive correlation with the number of incontinence episodes/24 h. In terms of treatment benefit, most of the women perceived an improvement at 1, 3, 6 and 12 months. Of the 18 women requiring re-treatment, most perceived an improvement at 3, 6 and 12 months. CONCLUSION: Treatment with the Zuidex system produced significant improvements over a year in both subjective QoL and objective incontinence measures, with a significant positive correlation between them.

Efficacy and safety of a novel system (NASHA/Dx copolymer using the Implacer device) for treatment of stress urinary incontinence.

OBJECTIVES: To investigate the efficacy and safety of non-animal-stabilized hyaluronic acid/dextranomer (NASHA/Dx) copolymer for transurethral injection using a new guiding instrument (the Implacer) for stress urinary incontinence. METHODS: In an open, prospective, multicenter study, 42 invasive therapy-naive female patients with stress urinary incontinence were given 4 x 1.0 mL or 4 x 0.7 mL of NASHA/Dx copolymer using the Implacer. The efficacy parameters, measured at baseline and 1, 3, 6, and 12 months after treatment, included cough-induced leak point pressure, urine leakage by provocation test, number of incontinence episodes in 24 hours, and patient perception of bladder condition, rated on a 6-point scale. RESULTS: The collected cough-induced leak point pressure data were not judged to be valid and reliable. Statistically significant reductions in median urine leakage were observed (P <0.0001), from 36 g (range 0.0-300) after 20 "jumping jacks" or vigorous coughs at baseline to 5.5 g (range 0.0-98) at 3 months and sustained at 12 months (7.0 g, range 0.0-98). Of the 42 patients, 32 (76%) demonstrated a degree of improvement in urine leakage at 3 and 12 months. The median number of incontinence episodes in 24 hours decreased significantly from 1.9 (range 0.0-24) at baseline to 0.4 (range 0.0-24) at 12 months (P <0.0001). At both 3 and 12 months, 29 patients (69%) had improved by at least one category on the 6-point patient perception scale. Treatment was well tolerated, and no complications were reported with use of the Implacer. CONCLUSIONS: The results of this study indicate that a novel system (NASHA/Dx copolymer insertion using the Implacer) is an effective and well-tolerated treatment for invasive therapy-naive patients with stress urinary incontinence, with improvement sustained for at least 12 months. These encouraging results warrant additional study.

Treatment of stress urinary incontinence: recent developments in the role of urethral injection.

Stress urinary incontinence is prevalent in adult women and has a considerable impact on quality of life. However, it often remains undiagnosed and therefore untreated. Non-invasive treatment is likely to be offered in mild cases and may entail physiotherapy, minimally invasive devices or pharmacotherapy. Surgical intervention is widely considered as the only effective option for more severe cases. These strategies are not suitable for all patients, and urethral injection represents an alternative, minimally invasive procedure. The choice of the bulking agent is the key to the success of this treatment: the most extensively studied are silicone, polytetrafluoroethylene and bovine collagen. However, doubts regarding the safety and efficacy of these materials has led to the development of carbon-coated zirconium beads, calcium hydroxylapatite and dextranomer/hyaluronic acid (Dx/HA) copolymer. Of these, the most clinical experience has been gained with Dx/HA copolymer. Until 2 years ago, urethral injection could only be administered endoscopically. The recent development of devices for 'blind' injection has increased the speed and convenience of urethral injection, removing the need for surgical facilities. Although few data are yet available, it is conceivable that urethral injection administered 'blind' may in future be considered as an option for all patients failing non-invasive treatment.