Can we use machine learning to improve the interpretation and application of urodynamic data?: ICI-RS 2023.

INTRODUCTION: A "Think Tank" at the International Consultation on Incontinence-Research Society meeting held in Bristol, United Kingdom in June 2023 considered the progress and promise of machine learning (ML) applied to urodynamic data. METHODS: Examples of the use of ML applied to data from uroflowmetry, pressure flow studies and imaging were presented. The advantages and limitations of ML were considered. Recommendations made during the subsequent debate for research studies were recorded. RESULTS: ML analysis holds great promise for the kind of data generated in urodynamic studies. To date, ML techniques have not yet achieved sufficient accuracy for routine diagnostic application. Potential approaches that can improve the use of ML were agreed and research questions were proposed. CONCLUSIONS: ML is well suited to the analysis of urodynamic data, but results to date have not achieved clinical utility. It is considered likely that further research can improve the analysis of the large, multifactorial data sets generated by urodynamic clinics, and improve to some extent data pattern recognition that is currently subject to observer error and artefactual noise.

Elastin homeostasis is altered with pelvic organ prolapse in cultures of vaginal cells from a lysyl oxidase-like 1 knockout mouse model.

Pelvic organ prolapse (POP) decreases quality of life for many women, but its pathophysiology is poorly understood. We have previously shown that Lysyl oxidase-like 1 knockout (Loxl1 KO) mice reliably prolapse with age and increased parity, similar to women. Both this model and clinical studies also indicate that altered elastin metabolism in pelvic floor tissues plays a role in POP manifestation, although it is unknown if this is a cause or effect. Using Loxl1 KO mice, we investigated the effects of genetic absence of Loxl1, vaginal parity, and presence of POP on the expression of genes and proteins key to the production and regulation of elastic matrix. Cultured cells isolated from vaginal explants of mice were assayed with Fastin for elastic matrix, as well as RT-PCR and Western blot for expression of genes and proteins important for elastin homeostasis. Elastin synthesis significantly decreased with absence of LOXL1 and increased with parity (p < .001), but not with POP. Cells from prolapsed mice expressed significantly decreased MMP-2 (p < .05) and increased TIMP-4 (p < .05). The results suggest changes to elastin structure rather than amounts in prolapsed mice as well as poor postpartum elastin turnover, resulting in accumulation of damaged elastic fibers leading to abnormal tropoelastin deposition. POP may thus, be the result of an inability to initiate the molecular mechanisms necessary to clear and replace damaged elastic matrix in pelvic floor tissues after vaginal birth.

Combination phosphodiesterase type 4 inhibitor and phosphodiesterase type 5 inhibitor treatment reduces non-voiding contraction in a rat model of overactive bladder.

INTRODUCTION: Current treatments for overactive bladder (OAB) are often discontinued due to side effects or lack of efficacy. The goal of this study was to determine if combining a phosphodiesterase type 4 inhibitor (PDE4i); with a type 5 inhibitor (PDE5i); would have a beneficial effect on OAB symptoms and if a reduced dose of PDE4i in combination with PDE5i could also provide a beneficial effect in OAB. We hypothesized that PDE5i and PDE4i combination treatment could be utilized to reduce non-voiding contractions and smooth muscle disruption in a rat model of OAB. METHODS: Fifty-eight age-matched Sprague-Dawley rats underwent PBOO and daily gavage with PDE4i alone (roflumilast; 1mg/kg), PDE5i alone (tadalafil;10mg/kg), high dose combination (PDE4i 1mg/kg, PDE5i 10mg/kg), low dose combination (PDE4i 0.2mg/kg, PDE5i 10mg/kg), or vehicle for 28 days. Fourteen animals underwent sham PBOO with vehicle. Rats underwent conscious and anesthetized cystometry 28 days after PBOO and were euthanized for qualitative bladder histology. One-way ANOVA on ranks with a Dunn's post hoc test was used to indicate statistically significant differences between groups (p<0.05). RESULTS: Bladder & urethral weight was significantly increased after PBOO with vehicle, PDE4i alone, and PDE5i alone, but not with either combination treatment. Frequency of non-voiding contractions during both conscious and anesthetized cystometry increased significantly after PBOO with vehicle, but not after PDE4i or high dose combination treatments compared to sham PBOO. Threshold pressure for voiding was significantly decreased with high dose combination compared to vehicle. PBOO treated with PDE4i alone or high dose combination showed less bladder smooth muscle fibrosis than vehicle, PDE5i alone, or low dose combination treatments. CONCLUSION: A PDE4i and PDE5i combination treatment has potential benefit in reducing OAB symptoms, but future research is needed.

Role of lysyl oxidase like 1 in regulation of postpartum connective tissue metabolism in the mouse vagina†.

Pelvic organ prolapse (POP) in lysyl oxidase like-1 knockout (Loxl1 KO) mice occurs primarily in parous mice and is rare in nulliparous mice. We determined the effect of Loxl1 deficiency on postpartum regulation of connective tissue metabolism genes and degradative enzyme activity in the vagina at 20 days gestation or 4 h, 48 h, 7 days, 15 days, 25 days, 7 weeks, or 12 weeks postpartum. Nulliparous Loxl1 KO and wildtype (WT) mice aged 11, 18, or 23 weeks were controls. Gene expression and enzyme activity were assessed using real-time quantitative reverse transcription PCR and fluorescein conjugated gelatin zymography, respectively. Parity, but not aging, had a significant influence on gene expression both with time postpartum and between KO and WT mice. Mmp2, Timp1, Timp2, Timp3, Timp4, Col1a1, Col3a1, Acta2, and Bmp1 were differentially expressed between KO and WT mice. Correlational analysis of gene-gene pairs revealed 10 significant differences between parous KO and WT groups, 5 of which were due to lack of co-expression of Bmp1 in KO mice. The overall enzyme activity that could be attributed to MMPs was significantly higher in WT compared to KO mice both 25 days and 12 weeks postpartum, and MMP activity was significantly lower 15 days and 25 days postpartum compared to KO nulliparous controls, but not WT. These findings suggest that Loxl1 deficiency combined with parity has a significant impact on postpartum regulation of connective tissue metabolism, particularly as it relates to co-expression of Bmp1 and altered proteolytic activity.

Performance analysis of the T-DOC® air-charged catheters: An alternate technology for urodynamics.

AIMS: Urodynamics (UDS) is widely used for the diagnosis of lower urinary tract dysfunction. Air-Charged catheters (ACC), one of the newer technologies for UDS pressure recording, has been adopted in growing numbers around the world for the past 15 years. Currently, there is a lack of published studies characterizing specific performance of the ACC. Since linearity, hysteresis, pressure drift, and frequency response are important components in characterizing accuracy for catheter-manometer systems; this study aimed to assess these four aspects in ACC. METHODS: A total of 180 T-DOC® ACC were used in three different laboratory settings to assess pressure linearity and hysteresis (15 dual-sensor vesical and urethral and 30 single-sensor abdominal), pressure drift over 2 h (115 single-sensor), and frequency response (20 single-sensor). Data are presented as mean ± standard deviation. RESULTS: ACC showed linearity of 0.99 ± 0.01, 0.99 ± 0.01, and 1.01 ± 0.01; and hysteresis of 0.57 ± 0.3%, 0.76 ± 0.48%, and 1 ± 0.89% for the abdominal, vesical, and urethral sensors, respectively. A pressure drift of 2.2 ± 1.4% at 1 h and 4.4 ± 2.5% at 2 h were observed when compared to baseline pressures. The catheters did not show any amplification factor during the sweep from 1 to 30 Hz, and recorded signals up to 5 Hz attenuating higher frequency signals. CONCLUSIONS: In this study the T-DOC® ACC showed a linear performance with minimal hysteresis associated with acceptable pressure drift, and adequate frequency response to capture clinically relevant pressures. The accurate results observed in this study suggest that these catheters are technically suitable to be used as a measuring instrument for UDS.

Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse.

OBJECTIVES: The aim of this study was to determine the effect of pregnancy and delivery mode on cytokine expression in the pelvic organs and serum of lysyl oxidase like-1 knockout (LOXL1 KO) mice, which develop pelvic organ prolapse after delivery. METHODS: Bladder, urethra, vagina, rectum, and blood were harvested from female LOXL1 KO mice during pregnancy, after vaginal or cesarean delivery, and from sham cesarean and unmanipulated controls. Pelvic organs and blood were also harvested from pregnant and vaginally delivered wild-type (WT) mice and from unmanipulated female virgin WT controls. Specimens were assessed using quantitative real-time reverse transcription polymerase chain reaction and/or enzyme-linked immunosorbent assay. RESULTS: Both CXCL12 and CCL7 mRNA were significantly up-regulated in the vagina, urethra, bladder, and rectum of pregnant LOXL1 KO mice compared with pregnant WT mice, suggesting systemic dysregulation of both of these cytokines in LOXL1 KO mice as a response to pregnancy.The differences in cytokine expression between LOXL1 KO and WT mice in pregnancy persisted after vaginal delivery. CCL7 gene expression increases faster and to a greater extent in LOXL1 KO mice, translating to longer lasting increases in CCL7 in serum of LOXL1 KO mice after vaginal delivery, compared with pregnant mice. CONCLUSIONS: Lysyl oxidase like-1 KO mice have an increased cytokine response to pregnancy perhaps because they are less able to reform and re-cross-link stretched elastin to accommodate pups, and this resultant tissue stretches during pregnancy. The up-regulation of CCL7 after delivery could provide an indicator of level of childbirth injury, to which the urethra and vagina seem to be particularly vulnerable.

Functional status in older women diagnosed with pelvic organ prolapse.

BACKGROUND: Functional status plays an important role in the comprehensive characterization of older adults. Functional limitations are associated with an increased risk of adverse treatment outcomes, but there are limited data on the prevalence of functional limitations in older women with pelvic floor disorders. OBJECTIVE: The aim of the study was to describe the prevalence of functional limitations based on health status in older women with pelvic organ prolapse (POP). STUDY DESIGN: This pooled, cross-sectional study utilized data from the linked Health and Retirement Study and Medicare files from 1992 through 2008. The analysis included 890 women age ≥65 years with POP. We assessed self-reported functional status, categorized in strength, upper and lower body mobility, activities of daily living (ADL), and instrumental ADL (IADL) domains. Functional limitations were evaluated and stratified by respondents self-reported general health status. Descriptive statistics were used to compare categorical and continuous variables, and logistic regression was used to measure differences in the odds of functional limitation by increasing age. RESULTS: The prevalence of functional limitations was 76.2% in strength, 44.9% in upper and 65.8% in lower body mobility, 4.5% in ADL, and 13.6% in IADL. Limitations were more prevalent in women with poor or fair health status than in women with good health status, including 91.5% vs 69.9% in strength, 72.9% vs 33.5% in upper and 88.0% vs 56.8% in lower body mobility, 11.6% vs 0.9% in ADL, and 30.6% vs 6.7% in IADL; all P < .01. The odds of all functional limitations also increased significantly with advancing age. CONCLUSION: Functional limitations, especially in strength and body mobility domains, are highly prevalent in older women with POP, particularly in those with poor or fair self-reported health status. Future research is necessary to evaluate if functional status affects clinical outcomes in pelvic reconstructive and gynecologic surgery and whether it should be routinely assessed in clinical decision-making when treating older women with POP.

Validation of genetically matched wild-type strain and lysyl oxidase-like 1 knockout mouse model of pelvic organ prolapse.

OBJECTIVES: Lysyl oxidase-like 1 knockout (Loxl1) mice demonstrate deficient elastin homeostasis associated with pelvic organ prolapse (POP). To further investigate the pathophysiology of POP in these animals, a genetically matched homozygous positive (Loxl1) or wild-type strain is needed. This study sought to create and validate genetically matched Loxl1 and Loxl1 strains. METHODS: Female Loxl1 mice were backcrossed with male wild-type mice. The resultant heterozygous mice were bred to produce Loxl1 and Loxl1 mice, whose genotype was confirmed by polymerase chain reaction (PCR). Multiparous female Loxl1 (n = 7) and Loxl1 (n = 9) mice were assessed for POP weekly for 12 weeks after their first vaginal delivery. Pelvic organ prolapse was compared between groups using a Kaplan-Meier survival curve with P of less than 0.05 indicating a significant difference. Vaginal connective tissue histologic finding was assessed qualitatively and quantitatively. RESULTS: There were no significant differences between the groups in age or parity. Of the 7 Loxl1 mice, 4 developed prolapse by 8 weeks and 6 by 12 weeks postpartum. No Loxl1 mouse prolapsed. Loxl1 mice had significantly larger vaginas as determined by area within the lumen and total cross-sectional tissue area. Striated muscle fibers of the urethra in Loxl1 mice were less organized, shorter, and thinner than in Loxl1 mice. CONCLUSIONS: Genetically matched Loxl1 and Loxl1 strains can be reliably created by a backcross method and differentiate in their prolapse phenotype. Loxl1 mice demonstrate pathology primarily characterized by enlargement of the vagina. Further studies are needed to elucidate the cause of this finding.

Animal models of female pelvic organ prolapse: lessons learned.

Pelvic organ prolapse is a vaginal protrusion of female pelvic organs. It has high prevalence worldwide and represents a great burden to the economy. The pathophysiology of pelvic organ prolapse is multifactorial and includes genetic predisposition, aberrant connective tissue, obesity, advancing age, vaginal delivery and other risk factors. Owing to the long course prior to patients becoming symptomatic and ethical questions surrounding human studies, animal models are necessary and useful. These models can mimic different human characteristics - histological, anatomical or hormonal, but none present all of the characteristics at the same time. Major animal models include knockout mice, rats, sheep, rabbits and nonhuman primates. In this article we discuss different animal models and their utility for investigating the natural progression of pelvic organ prolapse pathophysiology and novel treatment approaches.

Effect of petroleum gauze packing on the mechanical properties of suture materials.

OBJECTIVE: To test the tensile properties of knotted suture made of 4 different suture materials and exposed to petroleum gauze. STUDY DESIGN: We tested the tensile strength of United States Pharmacopeia size 0-0 gauge polydioxanone, polyglyconate, glycolide/lactide copolymer, and silk when exposed to petroleum packing or saline. Suture materials were randomized, and knots were tied and then evaluated via tensiometer to the point of knot failure. RESULTS: A total of 285 knots were tied in 8 groups based on material and exposure to saline or petroleum gauze. We found that petroleum exposure knots failed at a mean of 116.7 N (SD = 31.5) and that saline soaked knots failed at 123.8 N (SD = 32.0). We conducted a 4 × 2 factorial analysis of variance, finding knots exposed to petroleum failed at a statistically significantly lower tensile strengths than saline soaked knots (p = 0.002). CONCLUSION: Petroleum-exposed sutures fail at lower tensions than saline-exposed sutures.

Stem cell therapy for incontinence: where are we now? What is the realistic potential?

A significant number of women experience stress urinary incontinence (SUI), which greatly affects their quality of life. Recent research investigating utilization of stem cells and their derivatives for the prevention and treatment of SUI has been performed to test the effect of cell source and method of administration in several animal models of SUI. The type of stem cell, timing of optimal dose or doses after injury, mechanism of action of stem cells, and route of administration must be investigated both preclinically and clinically before stem cell therapy becomes a possible treatment for SUI, although the future of this therapy looks promising. This article reviews the progress in stem cell research for incontinence and describes areas of future work as suggested by research in other fields.