The association between nocturia, hormonal symptoms and bladder parameters in women: an observational study.

OBJECTIVE: Postmenopausal nocturia is poorly understood. This study aimed to identify hormonal and lifestyle factors associated with nocturia and to understand the relative contribution of altered urine production and bladder storage dysfunction in women. DESIGN, SETTING, POPULATION AND METHODS: Women ≥40 years presenting to public continence services were enrolled in a cross-sectional study. A total of 153 participants completed a hormone status questionnaire, a validated nocturia causality screening tool and a 3-day bladder diary. Descriptive statistics and logistic regression models for nocturia severity and bladder diary parameters were computed. RESULTS: Overall, 91.5% reported nocturia, 55% ≥2 /night. There was a difference of 167.5 ml (P < 0.001) in nocturnal urine volume between women with nocturia ≥2 (median 736 ml) versus less often (517 ml). Significant predictors of self-reported disruptive nocturia were age (odds ratio [OR] 1.04, 95% CI 1.002-1.073) and vitamin D supplementation (OR 2.33, 95% CI 1.11-4.91). Nocturnal polyuria was significantly more common with nocturia ≥2 compared with less frequent nocturia (P < 0.002). Exercise for 150 minutes a week was protective for nocturnal polyuria (OR 0.22, P = 0.001). Nocturia index >1.3 was significantly predicted by age (OR 1.07, P < 0.001), regular exercise (OR 0.41, P = 0.036), day flushes (OR 4.00, P = 0.013) and use of vitamin D (OR 2.34, P = 0.043). Maximum voided volumes were significantly lower with nocturia ≥2 versus less often (night: 268 ml versus 350 ml; day: 200 ml versus 290 ml). CONCLUSIONS: Bothersome nocturia in postmenopausal women is associated with changes to both nocturnal diuresis and bladder storage. Regular physical activity, prolapse reduction and oestrogen replacement may be adjunctive in managing bothersome nocturia in women.

Bacterial colonization of bladder urothelial cells in women with refractory Detrusor Overactivity: the effects of antibiotic therapy.

Bacterial infection may have a pathophysiological role in refractory Detrusor Overactivity (DO). The aim of this study was to observe any impact of antibiotic therapy upon bacterial colonization of urothelial cells, and to determine whether a relationship existed between colonization and symptom severity. Mid-stream urine samples were collected as part of a clinical trial of antibiotics in women with refractory DO. Wright stained urothelial cells were categorized according to the degree of bacterial colonization as; 'clear' (free of bacteria), or as associated with bacteria that were 'adjacent' to the cell or 'intracellular' at low or high density. The average percentages were compared with routine microbiology cultures, over the 26 week trial, and with patient clinical outcome measures of DO severity. In patients receiving placebo, 'high-density intracellular bacteria' significantly increased during urinary tract infection (P = 0.0008). In antibiotic patients, 'clear' cells were more prevalent. Amoxicillin & Clavulanic Acid significantly decreased bacterial colonization within urothelial cells, suggesting that these antibiotics possess the greatest intracellular efficacy. 'High-density intracellular bacteria' positively correlated with symptom severity, measured by leakage on pad test (P = 0.014), leaks per day (P = 0.004), and voids per day (P = 0.005). Thus, by decreasing high density intracellular bacteria, antibiotic treatment may improve the refractory DO condition.

Laparoscopic sacrocolpopexy: how low does the mesh go?

OBJECTIVE: Laparoscopic sacrocolpopexy is becoming an increasingly popular surgical approach for repair of apical vaginal prolapse. The aim of this study was to document the postoperative anterior mesh position after laparoscopic sacrocolpopexy and to investigate the relationship between mesh location and anterior compartment support. METHODS: This was an external audit of patients who underwent laparoscopic sacrocolpopexy for apical prolapse ≥ Stage 2 or advanced prolapse ≥ Stage 3, between January 2005 and June 2012. All patients were assessed with a standardized interview, clinical assessment using the International Continence Society Pelvic Organ Prolapse quantification and four-dimensional transperineal ultrasound to evaluate pelvic organ support and mesh location. Mesh position was assessed with respect to the symphysis pubis whilst distal mesh mobility was assessed using the formula √[(XValsalva - Xrest )2 + (YValsalva - Yrest )2 ], where X is the horizontal distance and Y is the vertical distance between the mesh and the inferior symphyseal margin, measured at rest and on Valsalva. RESULTS: Ninety-seven women were assessed at a mean follow-up of 3.01 (range, 0.13-6.87) years after laparoscopic sacrocolpopexy, 88% (85/97) of whom considered themselves to be cured or improved, and none had required reoperation. On clinical examination, prolapse recurrence in the apical compartment was not diagnosed in any patient; however, 60 (62%) had recurrence in the anterior compartment and 43 (44%) in the posterior compartment. On ultrasound examination, mesh was visualized in the anterior compartment in 60 patients. Both mesh position and mobility on Valsalva were significantly associated with recurrent cystocele on clinical and on ultrasound assessment (all P < 0.01). For every mm that the mesh was located further from the bladder neck on Valsalva, the likelihood of cystocele recurrence increased by 6-7%. CONCLUSION: At an average follow-up of 3 years, laparoscopic sacrocolpopexy was highly effective for apical support; however, cystocele recurrence was common despite an emphasis on anterior mesh extension. Prolapse recurrence seemed to be related to mesh position and mobility, suggesting that the lower the mesh is from the bladder neck, the lower the likelihood of anterior compartment prolapse recurrence. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

ATP during early bladder stretch is important for urgency in detrusor overactivity patients.

ATP is an important mediator of urgency in women with detrusor overactivity (DO). In order to understand how different degrees of bladder stretch elicited ATP release in DO patients compared with controls, sequential aliquots were collected during cystometry and ATP release was measured at each degree of bladder filling, in female patients with DO and controls. In both DO and control groups, ATP release was induced during bladder filling, suggesting that stretch stimulated further ATP release. However, the luminal ATP concentrations were already high at early filling stage (200 mL), which was even greater than those at the later filling stages (400 mL and maximum cystometric capacity, MCC), indicating that a substantial ATP release has been induced during early filling (200 mL) in both DO and controls. In DO, ATP release at 200 mL was significantly higher in those with low first desire to void (FDV) (≤ 200 mL) than in those with higher FDV (> 200 mL); this may suggest that ATP release at early stretch may play an important role in urgency (early sensation) in DO. ATP concentrations remained unchanged after voiding, suggesting that voiding did not further induce ATP release into intraluminal fluid.

Long-term vaginal ring pessary use: discontinuation rates and adverse events.

OBJECTIVE: To evaluate, at a minimum of 6 years, the long-term discontinuation rates and incidence of adverse events associated with vaginal ring pessary use. DESIGN: Retrospective case identification. SETTING: Tertiary urogynaecology unit. SAMPLE: All women fitted with either a Portex ring pessary or Introl bladder neck support device during the index period (1992-2002). METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Length of use and complications of pessary use, including bleeding, extrusion, malodorous vaginal discharge, constipation and incontinence. RESULTS: Of the 273 women fitted with a ring pessary, 167 were successfully using it at 4 weeks; subsequently, 93 (56%) experienced complications comprising bleeding, extrusion, severe vaginal discharge, pain and constipation, in that order, although 38 women (23%) had more than one type of complication and most had more than one episode. Only 23 of 167 (14%) continued with pessary use at the study endpoint (November 2008). The median duration of use was 7 years (interquartile range, 6-9 years; range, 2.25-13.9 years). Of those who discontinued, the median duration was 1.4 years (range, 0.1-11 years; interquartile range, 0.5-3.6 years). After cessation, 73 (44%) chose conservative treatment and 50 (30%) chose surgery. Twelve women died during the time frame; nine returned to their GP. CONCLUSIONS: We were surprised to find a 56% complication rate in pessary users. Our study shows that, over time, the majority of women chose to discontinue using pessaries. Women should be informed of these data when deciding on the management of their pelvic organ prolapse.

Determinants of a transcriptionally competent environment at the GM-CSF promoter.

Granulocyte macrophage-colony stimulating factor (GM-CSF) is produced by T cells, but not B cells, in response to immune signals. GM-CSF gene activation in response to T-cell stimulation requires remodelling of chromatin associated with the gene promoter, and these changes do not occur in B cells. While the CpG methylation status of the murine GM-CSF promoter shows no correlation with the ability of the gene to respond to activation, we find that the basal chromatin environment of the gene promoter influences its ability to respond to immune signals. In unstimulated T cells but not B cells, the GM-CSF promoter is selectively marked by enrichment of histone acetylation, and association of the chromatin-remodelling protein BRG1. BRG1 is removed from the promoter upon activation concomitant with histone depletion and BRG1 is required for efficient chromatin remodelling and transcription. Increasing histone acetylation at the promoter in T cells is paralleled by increased BRG1 recruitment, resulting in more rapid chromatin remodelling, and an associated increase in GM-CSF mRNA levels. Furthermore, increasing histone acetylation in B cells removes the block in chromatin remodelling and transcriptional activation of the GM-CSF gene. These data are consistent with a model in which histone hyperacetylation and BRG1 enrichment at the GM-CSF promoter, generate a chromatin environment competent to respond to immune signals resulting in gene activation.

Update: the "Contiform" intravaginal device in four sizes for the treatment of stress incontinence.

The aim of this study was to evaluate the efficacy of the Contiform intravaginal device for stress incontinence after the addition of a fourth size. We offered the device to a cohort of 73 women with a main complaint of stress incontinence but no prolapse. Of the 73 women invited to participate, 65 enrolled, of whom 52 were fitted. Of these 52 women, 37 (71%) completed the study protocol. Outcome measures were the 24-h pad test, St George score, and quality of life tests. Urine loss on pad test was significantly reduced from a median 6.6 g (interquartile range [IQR] = 4.3-22.6) to 2.2 g (IQR = 0.5-8.2; P = 0.0016) after 4 weeks with significant benefit seen on the Incontinence Impact Questionnaire and Urinary Distress Inventory. The insertion technique was quickly learnt, and the device was well tolerated. The recently developed medium/large size of Contiform was used by 6/37 (16%) women.

A longitudinal study over 5 to 10 years of clinical outcomes in women with idiopathic detrusor overactivity.

OBJECTIVE: To evaluate the long-term clinical outcome in women with idiopathic detrusor overactivity (IDO) and to identify significant prognostic factors. DESIGN: Longitudinal study incorporating retrospective case note review and a postal questionnaire. SETTING: Tertiary referral urogynaecology clinic in Australia. POPULATION: Women with a sole urodynamic diagnosis of IDO. METHODS: Audit of urodynamic records and case notes. Postal questionnaire incorporating validated disease-specific quality-of-life (QoL) instruments. MAIN OUTCOME MEASURE: Subjective assessment of overall improvement on a 4-point scale followed by scoring of short forms of the urogenital distress inventory and incontinence impact questionnaire. RESULTS: One hundred and thirty two women were identified following examination of 1975 consecutive records with 76 (67%) returning questionnaires. Median follow up was 8 years (6-9), and the duration of symptoms was 13 years (9-18). Improvement was achieved in 25 (35%) women. Disease symptoms fluctuated in severity and QoL were worse in nonresponders to therapy (P < 0.0001). Urge incontinence at presentation was associated with treatment failure (P = 0.001) as was nocturia (P = 0.04), but urodynamic variables were not associated with outcome. Only 3 of 46 (6.5%) women not responding to therapy thought that their symptoms would improve with time. CONCLUSIONS: IDO seldom resolves and fluctuates in severity. Individual response is unpredictable, although the presence of urge incontinence is associated with a significantly worse prognosis.

The cost of urogynaecological treatments: which are more cost-effective?

AIMS: To determine the cost-effectiveness of four urogynaecological treatments. MATERIALS: Two prospective trials were performed in which 205 women with urinary incontinence underwent urogynaecological treatments. The cost incurred and the improvement in quality of life (QOL) as a result of treatment was calculated as cost/quality-adjusted life year (QALY) and then ranked in order of cost-effectiveness. RESULTS: The Nurse Continence Advisor (NCA) group (N = 73) and the Urogynaecologist (UG) group (N = 72) both had significant improvements in leaks per week and incontinence score. QOL improvement was also similar (1.5% vs 1.2%). The economic data found a similar improvement in pad usage costs ($A2.90 vs $A3.52). The clinician costs were significantly lower for the NCA group ($A60.00 vs $A105.00) (P < 0.0001). The cost per QALY was significantly lower for the NCA group ($A28,009 vs $A35,312) (P = 0.03). Both groups had significant improvements in pad testing and leaks per week. The cure/improvement rates were also similar at three months (100% vs 89%). There was no significant difference in the improvement in QOL between the laparoscopic colposuspension (LC) and open colposuspension (OC) groups (2.09% vs 1.54%). The economic data found a similar improvement in pad usage costs ($A11.74 vs $A16.17). The theatre costs were significantly higher for the LC group ($A403.45 vs $A266.94) (P < 0.0001), however the overall costs were significantly lower ($A4,668 vs $A6,124) (P < 0.0001). The cost/QALY was lower for the LC group ($A63,980 vs $A134,069), however this did not reach significance. CONCLUSIONS: Overall, on comparison of the cost/QALY's, conservative treatment of urinary incontinence by a NCA was the most cost-effective.

GAP-43 immunoreactivity of subepithelial and detrusor muscle nerve fibres in patients with refractory idiopathic detrusor overactivity.

AIMS: To determine the relative density of nerve fibres immunoreactive to growth associated protein-43 (GAP-43, an indicator of neuronal sprouting) in the subepithelium and detrusor of patients with idiopathic detrusor overactivity (IDO). To investigate the effect, if any, of age and previous recurrent bacterial cystitis on neuronal sprouting in such patients. MATERIALS AND METHODS: A series of 18 women with urodynamically proven IDO (median age 62 years, range 39-85), who were refractory to treatment, underwent cystoscopy and cold cup biopsy. Controls (n=26, median age 65, range 32-79) were females without urgency/urge incontinence, undergoing cystoscopy for other indications. Recurrent proven bacterial cystitis (rUTI) was documented. Frozen sections were stained with specific antibodies to GAP-43 and protein gene product 9.5 (PGP, a general neuronal marker). The area represented by immunoreactive (ir) subepithelial or muscle nerve fibres was measured. RESULTS: The density of GAP-43ir and PGPir nerves did not differ significantly between IDO patients and controls, in either subepithelium or detrusor. The GAP-43ir nerve density (as percent of PGPir) increased significantly with advancing age amongst patients with IDO in the detrusor muscle but not in the subepithelium; density in controls was unaltered. In IDO patients with rUTI, a significant increase in GAP-43 (as percent of PGPir) was observed in the subepithelium. CONCLUSIONS: Although we found no evidence of increased neuronal proliferation in patients with IDO generally, the increase in GAP-43 with age and with previous cystitis history suggests that neuronal sprouting is important in some subsets of patients with IDO.

The repeatability of the 24-hour pad test.

A prospective observational study was conducted in a tertiary urogynaecology unit in women with the primary symptom of urinary incontinence to assess the repeatability of the 24-hour pad test. One hundred and eight women undertook seven 24-hour pad tests over 7 consecutive days together with 7 simultaneous fluid and activity charts. The results were analysed collectively and according to urodynamic subsets. Repeatability was assessed by repeated measures analysis of variance and univariate analysis of variance for each urodynamic diagnosis group (USI, mixed and no USI). Variation between pad test weights over the 7 days was low, supporting good repeatability. The number of days of pad testing required to approximate the 7-day average was 3 days. However, a single 24-hour pad test correlated highly with the 7-day average (r=0.881) and was considered sufficient to gauge leakage severity.

Definition of mild, moderate and severe incontinence on the 24-hour pad test.

The values for 'mild', 'moderate' and 'severe' urinary incontinence have not been determined for the 24-hour pad test. To define these values, a prospective observational study was performed on 110 women with the primary symptom of urinary incontinence. Consenting women performed two 1-hour pad tests one week apart, and seven 24-hour pad tests for seven consecutive days. The 1-hour pad test definitions for mild, moderate and severe were translated to centiles, and used to categorise the 24-hour test values. This revealed that the range for 'mild incontinence' was between 1.3 and 20 g, 'moderate incontinence' ranged from 21 to 74 g, and 'severe incontinence' was defined as 75 g or more in 24 hours. Severity of leakage was analysed in relation to urodynamic diagnosis, age, parity and pelvic floor muscle strength. Increasing severity was associated with increasing age and parity. Women with detrusor overactivity were most likely to have severe leakage. In conclusion, this study defines the three grades of severity for the 24-hour pad test, which may help to guide patients' choice between conservative and surgical treatment and is useful for stratified randomisation of controlled trial participants.

Criterion validity, test-retest reliability and sensitivity to change of the St George Urinary Incontinence Score.

OBJECTIVE: To assess the criterion validity, test-retest reliability and the sensitivity to change after treatment of the St George Urinary Incontinence Score (SGUIS). PATIENTS AND METHODS: Women presenting with urinary incontinence completed two SGUIS tests one week apart. A frequency-volume chart (FVC) was completed before the first attendance and the women had a 1-h pad test before treatment. Patients were treated conservatively under the care of a urogynaecologist or nurse continence advisor, or surgically with an open or laparoscopic colposuspension. After treatment, the SGUIS, FVC and 1-h pad test were repeated. RESULTS: The SGUIS correlated moderately well with the number of leaks per week (Spearman's r = 0.610, 95% confidence interval 0.516-0.689, P < 0.001) but less well with the 1-h pad test loss (r = 0.257, 0.124-0.380, P = 0.002). The test-retest reliability was acceptable, as the mean (SD) difference between the first and second SGUIS was 0.337 (2.675), with limits of agreement of -5.012 to -5.686. The change in the SGUIS after treatment correlated well with the improvement in the number of leaks per week (r = 0.742, 0.662-0.805, 156 samples, P < 0.001) but not as well with the change in 1-h pad test loss (r = 0.531, 0.405-0.636, 151, P < 0.001), although the trend was similar. CONCLUSION: The criterion validity of the SGUIS appeared adequate for both the number of leaks per week on the FVC and leakage on the 1-h pad test. The statistical reproducibility of the test was adequate and appeared more responsive to change after treatment than the other measures. The score is suitable for rapid self-administration by patients with a range of incontinence types, unlike most other currently available test instruments.

The Contiform incontinence device - efficacy and patient acceptability.

A consecutive series of 59 women with urodynamic stress incontinence but no prolapse were offered treatment with Contiform (available in small/medium/large sizes). The 24-h pad test was the primary outcome measure. Of the 59 enrolled women, 41 (69%) completed the trial protocol. Median use was 21 days (IQR 10-24.5). Two severity groups were categorized based on pretreatment pad testing (mild <30 g/day n=24 patients, 59%) and moderate/severe >30 g/day, n= 17(41%). Overall, loss was reduced by a median of 72% (5-92), p<0.0001, with the greatest reduction seen in the moderate/severe group of 85% (75-100) p<0.0001. No significant benefit on pad testing was noted in the mild group. Both groups showed significant benefit on the Incontinence Impact Questionnaire. The insertion technique was quickly learnt and the device well tolerated. A medium-sized Contiform was used by 33 (80%) women. No serious adverse events occurred.

Insulin increases the intracellular concentration of total oxalyl thiolesters in BC3H-1 myocytes: potential anti-insulin mediators.

Oxalyl thiolesters (RS-CO-COOH) may represent negative intracellular messengers for insulin action. Using a reverse-phase, ion-pair high pressure liquid chromatographic technique, total intracellular oxalyl thiolesters were measured in insulin-sensitive BC3H-1 myocytes after the addition of insulin. The total oxalyl thiolester concentration increased to a maximum of 2.9 times the basal concentration by 30 min after the addition of 100 microU/ml insulin and decreased to 1.8 times by 180 min. Insulin's stimulation of pyruvate dehydrogenase as measured by lactate oxidation ([1-14C]-lactate --> 14CO2) in intact BC3H-1 myocytes reached a maximum at 15-30 min and returned to basal activity during the 60-90 min measurement interval. These results suggest that oxalyl thiolesters are increased in concentration following insulin-induced signal transduction to reverse insulin-stimulated metabolic events.

Is objective cure of mild undifferentiated incontinence more readily achieved than that of moderate incontinence? Costs and 2-year outcome.

Because the prognostic value of 1-h pad testing has received scant attention, we tested the hypothesis that mild incontinence of any etiology is more readily cured than moderate incontinence. A consecutive series of 150 patients with mild (2-9.9 g) to moderate (10-49.9 g) incontinence (as judged by weight gain on 1-h pad testing) [1] attending a urogynecology unit were recruited, of whom 145 completed all baseline objective measures: 110 completed 12 weeks of conservative therapy, with follow-up data at 2 years available for 51 subjects. At 12 weeks 81% of 'mild' patients became 'dry' on the 1-h pad test versus 36.8% in the moderate group (chi2<0.0001). Interestingly the post-treatment changes seen in all other outcomes demonstrated equally positive responses for the mild and moderate groups. At 2-year follow-up 29/71 (40.8%) of patients with mild incontinence and 22/74 (29.7%) of patients with moderate incontinence were satisfied and had no requirement for further therapy, the remainder having sought other treatments (chi2=1.963 P=0.161). Of the responders, (11/29) (37.9%) of mildly incontinent patients and (8/22 (36.4%)) of moderately affected subjects remained continent (on 20-point incontinence score < or =2 m, chi2=0.013, P=0.9087). Improvements in quality of life persisted to an equal degree in both groups.

Randomised controlled trial of nurse continence advisor therapy compared with standard urogynaecology regimen for conservative incontinence treatment: efficacy, costs and two year follow up.

OBJECTIVE: To compare the efficacy and labour costs of nurse continence advisors and urogynaecologists in conservative management of urinary incontinence. DESIGN: Single centre randomised controlled trial of patients with mild or moderate leakage. SETTING: Tertiary urogynaecology unit. SAMPLE: One hundred and forty-five consecutive patients with stress and/or urge incontinence. METHODS: Standardised conservative therapy regimens, provided by nurse continence advisors and urogynaecologists. MAIN OUTCOME MEASURE: One-hour pad test, frequency volume charts, a 20-point incontinence score and two quality of life tests, staff treatment times and costs. RESULTS: Of 110 women who completed 12-week treatments, 64% of the women in the nurse continence advisor group (n = 58) and 52% of women treated by urogynaecologists (n = 52) were asymptomatic (dry pad test; OR 1.63, 95% CI 0.71-3.75). There was no significant difference between clinician groups for change in pad test result (P = 0.71), voids/day (0.43), incontinence score (P = 0.57) or quality of life scores (urogenital distress inventory, P = 0.27; Incontinence Impact Questionnaire, P = 0.41). Despite the expected longer consultation times for the advisor group (median 160 min, interquartile range [IQR] 130-210) versus the urogynaecologist group (median 90 min, IQR 60-120), the per capita labour cost for advisor treatment (median AU$59.20, IQR 48.10-77.70) was lower than for treatment given by urogynaecologists (median cost AU$ 189.70, IQR 120.60-250.70, Mann-Whitney U test, P < 0.0001). At 2.5 years, 23/58 patients (40%) treated by advisor and 27/52 patients (52%) treated by urogynaecologist group, who had been cured and discharged, were available for contact. Of these, 29% of women in the nurse continence advisor group and 41% of those treated by urogynaecologists remained continent (on 20-point score). Quality of life improvement persisted equally in both groups. These data should be interpreted cautiously due to a 24% dropout rate. CONCLUSIONS: The reduction in urine leakage and improvement in quality of life observed in patients treated by nurse continence advisors and urogynaecologists were similar at 12 weeks and 2 years, but lower costs arose from treatment provided by nurse advisors. We suggest that conservative treatment by the nurse continence advisor could be used more widely in mild to moderate incontinence.

The 24-hour pad test in continent women and men: normal values and cyclical alterations.

OBJECTIVE: To obtain control values for the 24-hour pad test in a wide age range of continent women using accurate weighing scales and to compare the results obtained from pantyliners and pads in women and men. DESIGN: Prospective anonymous study. SETTING: A Sydney Tertiary Urogynaecology Unit. POPULATION: One hundred and forty continent women and 14 continent men. METHODS: A 24-hour pad test was performed in 120 continent women of widely varying ages, in whom hormonal status and exercise habits were documented. These continent women wore a standardised pantyliner for 24 hours and a high precision beam balance (accuracy 0.1 g) was used to measure the loss on the pad. To assess any variation in pad weights with differing pads, 20 female volunteers undertook the 24-hour test firstly with pantyliners then larger pads. To understand evaporative qualities of the two types of pads, one male wore each type of pad, instilled with 5 mL normal saline for eight hours overnight. Furthermore, to understand the contribution of vaginal secretions, a group of male volunteers performed a 24-hour test with pantyliners followed by pads. MAIN OUTCOMES MEASURES: Pad weight, with regard to hormonal status, exercise, pad type and gender. The median age of subjects was 48 (interquartile range [IQR] 32-60), with a median pad weight gain of 0.3 g (IQR 0.2-0.6; 95th centile 1.3 g). Subgroup analysis showed no significant trends for pad loss in relation to menopause status, use of hormone replacement therapy or hormonal contraception and exercise status during the 24-hour period. Control values for pantyliners were not significantly different from those for continence pads. In addition, normal values in 14 males showed similar results, regardless of pad type. CONCLUSIONS: The response rate of 39% might limit the applicability of the results. However, our finding that women lose only 0.3 g of vaginal secretions in 24 hours is much lower than previously reported. This might arise from the use of a highly accurate beam balance and the recruitment of a large sample of women with widely varying ages. This result might lower the threshold for objective diagnosis of urinary incontinence and alters the pad test definition of 'cure'.

Rational dose selection for a nonnucleoside reverse transcriptase inhibitor through use of population pharmacokinetic modeling and Monte Carlo simulation.

In order to choose a rational dose for GW 420867X, we first set a goal of therapy. We hypothesized that, for optimal antiretroviral activity, the trough free drug concentration should remain above the 90% effective concentration (EC90) of human immunodeficiency virus type 1. We performed population pharmacokinetic analysis on three different doses of GW 420867X (50, 100, and 200 mg). Monte Carlo simulation was performed, assuming a log-normal distribution for 1,000 simulated subjects for each dose, and was repeated three times. The trough concentrations were divided by 76 to account for protein binding and for the difference between EC50 and EC90. We then determined the fraction of the simulated population whose free drug trough concentrations would exceed an EC90 over a broad range of values. The target attainment for all three doses exceeded 95% out to a starting EC50 of 10 nM. For 16 viral isolates, the EC50 range encountered for GW 420867X did not exceed 8 nM, implying that the three doses could not be differentiated by effect in a clinical trial in naive patients. This prediction was shown to be correct in a randomized, double-blind trial with 1 week of monotherapy with GW 420867X.