Genetic polymorphisms associated with urinary tract infection in children and adults: a systematic review and meta-analysis.

INTRODUCTION: The lifetime risk of urinary tract infection is known from first-degree relative studies to be highly heritable. Associations have also been observed across the life course from pediatric urinary tract infection to recurrent urinary tract infection in adulthood, suggesting lifelong susceptibility factors. Candidate gene studies and genome-wide association studies have tested for genetic associations of urinary tract infection; however, no contemporary systematic synthesis of studies is available. OBJECTIVE: We conducted a systematic review to identify all genetic polymorphisms tested for an association with urinary tract infection in children and adults; and to assess their strength, consistency, and risk of bias among reported associations. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: PubMed, HuGE Navigator and Embase were searched from January 1, 2005 to November 16, 2023, using a combination of genetic and phenotype key words. STUDY APPRAISAL AND SYNTHESIS METHODS: Fixed and random effects meta-analyses were conducted using codominant models of inheritance in metan. The interim Venice criteria were used to assess their credibility of pooled associations. RESULTS: After removing 451 duplicates, 1821 studies reports were screened, with 106 selected for full-text review, 22 were included in the meta-analysis (7 adult studies and 15 pediatric studies). Our meta-analyses demonstrated significant pooled associations for pediatric urinary tract infection with variation in CXCR1, IL8, TGF, TLR4 and VDR; all of which have plausible roles in the pathogenesis of urinary tract infection. Our meta-analyses also demonstrated a significant pooled association for adult urinary tract infection with variation in CXCR1. All significant pooled associations were graded according to their epidemiological credibility, sample sizes, heterogeneity between studies, and risk of bias. CONCLUSION: This systematic review provides a current synthesis of the known genetic architecture of urinary tract infection in childhood and adulthood; and should provide important information for researchers analysing future genetic association studies. Although, overall, the credibility of pooled associations was weak, the consistency of findings for rs2234671 single nucleotide polymorphisms of CXCR1 in both populations suggest a key role in the urinary tract infection pathogenesis.

Long-term adherence to pessary use in women with pelvic organ prolapse: A retrospective cohort study.

PURPOSE OF THE RESEARCH: Vaginal pessary use is an established, non-surgical treatment option for pelvic organ prolapse. While satisfaction rates are initially high, they seem to decline over time. We aimed to determine the median duration of pessary use among our patients and to evaluate reasons for discontinuation. METHODS: All patients who were treated with a vaginal pessary for pelvic organ prolapse between 2007 and 2022 at our institution (a maximum observation period of 15 years) were included in this retrospective cohort study. Data were collected from the in-house electronic databases and the date of pelvic floor surgery was defined as the primary endpoint. In case of no documented surgery, the date of the last follow-up visit (for patients lost to follow-up or who discontinued pessary use without subsequent surgery) or the date of final data collection (for those with presumed continued pessary use) was used as the primary endpoint. Duration of pessary use is represented by Kaplan-Meier curves. Effects of possible confounders were investigated by Cox regression models. A Cox regression model was evaluated for patients with the three most common types of pessary: ring, cube and shell. A chi-square test was performed to compare therapy adherence according to pessary type. PRINCIPAL RESULTS: Data of 779 patients could be included in the statistical analysis. The estimated median duration of pessary use was 173 weeks (95 % CI 104-473) - approximately 3.3 years. Overall, 30 % of patients opted for surgical therapy and the majority of them did so within 4 months of initiation of pessary use (median time: 19 weeks, 95 % CI 16-26). In 5 % of cases a discontinuation of pessary use without subsequent surgery was documented and 18 % were lost to follow-up before a planned visit, thus leaving 47 % of our patients with presumed continued pessary use. Possible confounding factors for discontinuation of pessary use were tested but were found to be non-significant (body mass index, Pelvic Organ Prolapse - Quantification score, pelvic floor training, age, parity, menopausal status, nicotine consumption, incontinence or size of pessary). Reasons for discontinuation of pessary use were documented in 51 % of patients: unspecified patient wish (23 %), pessary use tiredness (10 %), general dissatisfaction with pessary therapy (7 %), unspecified reasons (5 %), pessary self-change not possible (1 %), erosion, bleeding, pain (2 %); none of the pessary types fitted (2 %). CONCLUSIONS: According to our data, almost half of our patients with pelvic organ prolapse and pessary therapy continued pessary use until a maximum follow-up time of 15 years, whereas about one-third of patients finally opted for surgical repair (a majority of these within 4 months after pessary therapy initiation). The remaining patients were either lost to follow-up or discontinued pessary use without subsequent surgery. The stated reasons for discontinuation of pessary use were mostly non-specific, but only 1 % reported that pessary self-change was not possible. Erosion bleeding or pain was documented in only 2 % of cases as reason for discontinuation. This information helps clinicians to inform their patients with pelvic organ prolapse about expected pessary therapy success and strengthens individual counselling. Furthermore, our data indicates vaginal pessary use for pelvic organ prolapse is feasible and safe for all women and that therapy adherence can extend beyond 5 years.

Perioperative Techniques for the Use of Botulinum Toxin in Overactive Bladder: Results of a Multinational Online Survey of Urogynecologists in Germany, Austria, and Switzerland.

INTRODUCTION AND HYPOTHESIS: Botulinum toxin (BoNT) is a widely used treatment for overactive bladder (OAB). Despite its common use, no standardized treatment regimen exists so far. The aim of this survey was to evaluate the variation in perioperative treatment strategies among members of the German-speaking urogynecologic societies. MATERIALS AND METHODS: A clinical practice online survey was carried out between May 2021 and May 2022, and all members of the German, Swiss, and Austrian urogynecologic societies were invited to participate. Participants were grouped in two ways. First, they were grouped into (1) urogynecologists with board certification and (2) non-board-certified general obstetricians and gynecologists (OBGYNs). Second, we set a cut-off at 20 transurethral BoNT procedures per year to differentiate between (1) high- and (2) low-volume surgeons. RESULTS: One hundred and six completed questionnaires were received. Our results demonstrated that BoNT is mostly used as a third-line treatment (93%, n = 98/106), while high-volume surgeons used it significantly more often as a first/second-line treatment (21% vs. 6%, p = 0.029). Large variations existed in the use of perioperative antibiotics, preferred sites of injection, the number of injections, and the timing of the measurement of the postvoid residual volume (PVRV). Forty percent of participants did not offer outpatient treatment to patients. Local anesthesia (LA) was mostly used by board-certified urogynecologists (49% vs. 10%, p < 0.001) and high-volume surgeons (58% vs. 27%, p = 0.002). Injections into the trigone were also more often performed by board-certified urogynecologists and high-volume surgeons (22% vs. 3% (p = 0.023) and 35% vs. 6% (p < 0.001), respectively). PVRV was controlled between weeks 1 and 4 by only 54% of participants (n = 57/106). Clean intermittent self-catheterization (CISC) was infrequently taught (26%). CONCLUSIONS: Our survey confirmed that BoNT is widely used by urogynecologists in the three German-speaking countries, but practice patterns vary widely, and no standardized method could be detected, despite interviewing urogynecologic experts. These results clearly demonstrate that there is a need for studies to define standardized treatment strategies for the best perioperative and surgical approach regarding the use of BoNT in patients with OAB.

Use of polysaccharide hemostatic agent (HaemoCer™) in breast cancer surgery to reduce postoperative complications: A randomised controlled trial.

Postoperative wound-site bleeding, tissue inflammation and seroma formation are well-known complications in the field of breast surgery. Hemostatic agents consisting of polysaccharides may be used intra-operatively to minimise postoperative complications. We conducted a prospective randomised-controlled, single-centre study including 136 patients undergoing breast-conserving surgery for invasive or intraductal breast cancer. Of these, 68 patients were randomised to receive an absorbable polysaccharide hemostatic agent into the wound site during surgery, while 68 patients were randomised to the control group and did not receive any hemostatic agent. Primary outcome was the total volume of postoperative drained fluid from the surgical site. Secondary outcomes were the number of days until drain removal and rate of immediate postoperative surgical site infection Patients in the intervention group had significantly higher drainage output volumes compared with the control group 85 mL (IQR 46.25-110) versus 50 mL (IQR 30-75), respectively; (P = .003). Univariable linear regression analyses showed a significant association between the surgical specimen and the primary outcome (P < .001). After multivariable analysis, the use of absorbable polysaccharide hemostatic product was no longer significantly associated with a higher drainage output and only the size of the surgical specimen remained a significant predictor. The number of days until drainage removal and the postoperative seroma formation were higher in the intervention group (P = .004) and (P = .003), respectively. In our study, intraoperative application of polysaccharide hemostatic agent during breast-conserving surgery did not decrease postoperative fluid production. Only the size of the surgical specimen was significantly associated with postoperative drainage volume.

International Urogynecological Consultation (IUC): pathophysiology of pelvic organ prolapse (POP).

INTRODUCTION AND HYPOTHESIS: This manuscript is the International Urogynecology Consultation (IUC) on pelvic organ prolapse (POP) chapter one, committee three, on the Pathophysiology of Pelvic Organ Prolapse assessing genetics, pregnancy, labor and delivery, age and menopause and animal models. MATERIALS AND METHODS: An international group of urogynecologists and basic scientists performed comprehensive literature searches using pre-specified terms in selected biomedical databases to summarize the current knowledge on the pathophysiology of the development of POP, exploring specifically factors including (1) genetics, (2) pregnancy, labor and delivery, (3) age and menopause and (4) non-genetic animal models. This manuscript represents the summary of three systematic reviews with meta-analyses and one narrative review, to which a basic scientific comment on the current understanding of pathophysiologic mechanisms was added. RESULTS: The original searches revealed over 15,000 manuscripts and abstracts which were screened, resulting in 202 manuscripts that were ultimately used. In the area of genetics the DNA polymorphisms rs2228480 at the ESR1 gene, rs12589592 at the FBLN5 gene, rs1036819 at the PGR gene and rs1800215 at the COL1A1 gene are significantly associated to POP. In the area of pregnancy, labor and delivery, the analysis confirmed a strong etiologic link between vaginal birth and symptoms of POP, with the first vaginal delivery (OR: 2.65; 95% CI: 1.81-3.88) and forceps delivery (OR: 2.51; 95% CI: 1.24-3.83) being the main determinants. Regarding age and menopause, only age was identified as a risk factor (OR : 1.102; 95% CI: 1.02-1.19) but current data do not identify postmenopausal status as being statistically associated with POP. In several animal models, there are measurable effects of pregnancy, delivery and iatrogenic menopause on the structure/function of vaginal support components, though not on the development of POP. CONCLUSIONS: Genetics, vaginal birth and age all have a strong etiologic link to the development of POP, to which other factors may add or protect against the risk.

Systematic review and meta-analysis of genetic association studies of pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: Family and twin studies demonstrate that pelvic organ prolapse (POP) is heritable, but the genetic etiology is poorly understood. This review aimed to identify genetic loci and specific polymorphisms associated with POP, while assessing the strength, consistency, and risk of bias among reported associations. METHODS: Updating an earlier systematic review, PubMed and HuGE Navigator as well as relevant conference abstracts were searched using genetic and phenotype keywords from 2015 to 2020. Screening and data extraction were performed in duplicate. Fixed and random effects meta-analyses were conducted using co-dominant models of inheritance. We assessed credibility of pooled associations using interim Venice criteria. RESULTS: We screened 504 new abstracts and included 46 published and 7 unpublished studies. In pooled analyses we found significant associations for four polymorphisms: rs2228480 at the ESR1 gene (OR 0.67 95% CI 0.46-0.98, I2 = 0.0%, Venice rating BAB), rs12589592 at the FBLN5 gene (OR 1.46 95% CI 1.11-1.82, I2 = 36.3%, Venice rating BBB), rs484389 in the PGR gene (OR 0.61 95% CI 0.39-0.96, I2 = 32.4%, Venice rating CBB), and rs1800012 at the COL1A1 gene (OR 0.80 95% CI 0.66-0.96, I2 = 0.0%, Venice rating BAB). Further credible novel variants have also been recently identified in genome-wide association studies. CONCLUSION: The genetic contributions to POP remain poorly understood. Several biologically plausible variants have been identified, but much work is required to establish the role of these genes in the pathogenesis of POP or to establish a role for genetic testing in clinical practice.

Characteristics of the Urinary Proteome in Women with Overactive Bladder Syndrome: A Case-Control Study.

Despite an estimated prevalence of 13% in women, the exact etiology of non-neurogenic overactive bladder syndrome is unclear. The aim of our study was to gain a better understanding of the pathophysiology of female overactive bladder syndrome by mapping the urinary proteomic profile. We collected urine samples of 20 patients with overactive bladder syndrome and of 20 controls. We used mass spectrometric analysis for label-free quantitation, Swissprot human database for data search, Scaffold for data allocation and the Reactome Knowledgebase for final pathway enrichment analysis. We identified 1897 proteins at a false discovery rate of 1% and significance level p < 0.001. Thirty-seven significant proteins of the case group and 53 of the control group met the criteria for further pathway analysis (p < 0.0003 and Log2 (fold change) >2). Significant proteins of the overactive bladder group were, according to the 25 most relevant pathways, mainly involved in cellular response to stress and apoptosis. In the control group, significant pathways mainly concerned immunological, microbial-protective processes and tissue- elasticity processes. These findings may suggest a loss of protective factors as well as increased cellular response to stress and apoptosis in overactive bladder syndrome.

Genetic association in female stress urinary incontinence based on proteomic findings: a case-control study.

INTRODUCTION AND HYPOTHESIS: Previous studies have indicated a hereditary component of stress urinary incontinence; however, evidence on candidate genes or single-nucleotide polymorphisms (SNPs) is scarce. We hypothesize a genetic association of female stress urinary incontinence based on significant differences of the urinary and serum proteomic pattern in the identical study population. METHODS: Case-control study of 19 patients and 19 controls. We searched for known SNPs of SUI candidate genes (COL1A1, MMP1, SERPINA5, UMOD) in the database of short genetic variations and PubMed. Genomic DNA was isolated using QIAamp DNA Blood Midi Kit (Qiagen). We performed Sanger sequencing of selected exons and introns. RESULTS: The rs885786 SNP of the SERPINA5 gene was identified in 15 cases and 10 controls (p = 0.09). The rs6113 SNP of the SERPINA5 gene was present in 4 controls compared to 0 cases (p = 0.105). The rs4293393, rs13333226 and rs13335818 SNPs of the UMOD gene were identified in five cases and two controls (p = 0.20), the rs1800012 SNP of the COL1A1 gene in five cases versus four controls (p = 0.24) and the homozygous rs1799750 SNP of the MMP1 gene in eight cases versus five controls (p = 0.18). The combination of the rs885786 SNP of the SERPINA5 gene and rs179970 SNP of the MMP1 gene was detected in ten cases versus five controls (p = 0.072). CONCLUSIONS: We found nonsignificant trends toward associations of SNPs on the SERPINA5, UMOD and MMP1 gene and SUI.

Changes in serum markers of patients with PCOS during consecutive clomiphene stimulation cycles: a retrospective study.

BACKGROUND: A retrospective case-control study was performed to evaluate whether PCOS-specific serum markers would change in women with polycystic ovary syndrome (PCOS) during the course of two consecutive cycles of clomiphene citrate (CC)-stimulation, which did not lead to a pregnancy. METHODS: Anovulatory PCOS patients who underwent two consecutive CC-cycles (n = 41) and anovulatory PCOS controls who chose an observational approach for two months (n = 24) were included in the study. The main outcome measures were levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), anti-Mullerian hormone (AMH), total testosterone, androstenedione, and sexual hormone binding globulin (SHBG). RESULTS: In the control group, PCOS-specific serum parameters did not change during two months (p > 0.05). In the CC-group, there were decreases in LH (11.8 ± 4.9 mU/mL vs. 10.9 ± 4.0 mU/mL; p = 0.029), the LH:FSH ratio (2.1 ± 0.8 mU/mL vs. 1.8 ± 0.5 mU/mL; p = 0.007), and AMH (8.08 ± 4.27 ng/mL vs. 7.17 ± 3.37 ng/mL; p = 0.011), as well as an increase in SHBG (46.0 ± 20.2 nmol/L vs. 51.2 ± 21.0 nmol/L; p < 0.001). A higher age and lower baseline total testosterone and AMH levels were predictive of an AMH decline (p < 0.05). CONCLUSION: Two cycles of CC-stimulation that did not lead to a pregnancy were accompanied by mean LH, AMH, and LH:FSH ratio declines and an SHBG increase. The clinical significance seems of minor relevance.

Vaginismus and pregnancy: epidemiological profile and management difficulties.

BACKGROUND: Vaginismus affects up to 1% of the female population and often represents a physical manifestation of an underlying psychological problem. Our objective was to investigate the psychosomatic impact of vaginismus in pregnant women and evaluate the quality of their therapeutic care in Tunisia. METHODS: We included pregnant patients with vaginismus who presented at our obstetric emergency department between October 2016 and March 2017. All patients were interviewed by one expert psychiatrist and gynecologist using a standardized questionnaire. The State-Trait Anxiety Inventory (STAI) was used to determine anxiety and depression levels. Patients were prospectively followed until their postpartum period and were interviewed by the same experts after delivery. Sixteen weeks after hospital discharge, we contacted all patients via phone. All the information was simultaneously recorded in written form. RESULTS: Twenty pregnant patients with vaginismus were included (85% primary, 15% secondary). Most women described a conservative family background (70%) in which they received little or no sexual education (60%). All women described a feeling of anxiety and anger immediately before sexual intercourse and 40% have never sought medical consultation regarding their vaginismus before. Only 50% reported regular follow-up visits during their pregnancy (without vaginal examination), whereas 25% reported irregular follow-up visits with subjectively bad experiences during attempts of vaginal examinations. CONCLUSION: Pregnant women with vaginismus are at risk of non-follow-up during their pregnancy due to underlying feelings of shame and experienced lack of understanding by medical staff. Obstetricians should carefully and attentively approach pregnant women with vaginismus in order to ensure adequate medical care during pregnancy.

Association of uterine leiomyoma and overactive bladder syndrome.

OBJECTIVE: To assess associations between anterior and/or fundal uterine leiomyoma and overactive bladder syndrome. METHODS: The present cohort study recruited women diagnosed with fundal/anterior uterine leiomyoma by standardized transvaginal ultrasonography at the Medical University of Vienna, Austria, between January 1, 2010, and December 31, 2013, in addition to an age-matched control group of women without uterine leiomyoma. The International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OAB) was mailed to all eligible participants. The main outcome was the ICIQ-OAB sum score. RESULTS: Among 304 questionnaires sent out, 129 were returned. After the exclusion of incomplete datasets, 80 women were included in the analysis (uterine leiomyoma group, 43; control group, 37). The mean ± SD ICIQ-OAB sum score was 9.7 ± 10.2 for women with uterine leiomyoma and 4.2 ± 5.3 for women in the control group; thus, the ICIQ-OAB sum score was on average 5.5 points higher in the uterine leiomyoma group (P=0.003). The Spearman correlation coefficient between the total volume of leiomyoma per woman and the ICIQ-OAB sum score was 0.072 (P=0.645). CONCLUSION: The study found a significant association between anterior and/or fundal leiomyoma and overactive bladder syndrome. The presence of uterine leiomyoma should be ruled out during the evaluation of overactive bladder.