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.

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.

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.

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.

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.

Serum proteomic pattern in female stress urinary incontinence.

The pathophysiology of Stress Urinary Incontinence (SUI) is poorly understood. The aim of this study was to identify the serum proteomic profile in patients with SUI and to replicate findings from a preceding study in which a significant difference in the urinary proteome was identified. Serum samples were collected from 38 patients (19 SUI; 19 matched, continent controls). Sample preparation included serum albumin depletion, in-solution enzymatic digestion of proteins applying a combination of Gluc-C and trypsin and peptide separation using nano High Performance Liquid Chromatography. Label-free quantitation of peptides and proteins was performed after triplicate measurements using quadrupole time-of-flight mass spectrometry. Peptide identification was achieved by searching the Human SwissProt Database using Mascot and X!Tandem. Main outcome measure was the relative abundance of each detected protein in serum. Of 7012 identified proteins, 33 proteins were induced (detected in SUI, not in controls) and five proteins were depleted (detected in controls, not in SUI). All depleted proteins play a role in immune/DNA damage response. Induced proteins are involved in inflammatory response, response to cellular stress, coagulation and cytoskeleton stability/ motility. Plasma serine protease inhibitor (SERPINA5) was found induced and previously also showed a higher abundance in urine samples of SUI patients. Data are available via ProteomeXchange with identifier PXD008553.

Management of uterine ectopic pregnancy - local vs. systemic methotrexate.

INTRODUCTION: The aim of this study was to compare ultrasound-guided local methotrexate (MTX) vs. systemic methotrexate in uterine ectopic pregnancy regarding the beta human chorionic gonadotropin (hCG) clearance duration. MATERIAL AND METHODS: Patients with interstitial pregnancy, cervical pregnancy or cesarean scar pregnancy were included. Methotrexate was administered locally ultrasound-guided (25 mg methotrexate fixed dose) or systemically (intramuscular; 50 mg/m2 body weight). Beta hCG clearance duration in days formed the main outcome measure. RESULTS: Forty-six patients with uterine ectopic pregnancy were included. The mean estimated beta hCG clearance duration was 29.2 days longer in patients with local methotrexate compared with systemic methotrexate (64.7 vs. 31.5 days, respectively; p = 0.026). There was no significant difference between local vs. systemic methotrexate regarding adverse events such as bleeding (p = 0.376), pain (p = 0.146) or secondary surgery (p = 0.631). There was no association of initial beta hCG levels (p = 0.746), initial progesterone levels (p = 0.870) or patients' age (p = 0.604) and the beta hCG clearance duration. No significant difference in beta hCG clearance duration comparing local methotrexate injection with aspiration vs. local methotrexate injection without aspiration could be found (mean 49.4 and 71.6 days, respectively, p = 0.225). CONCLUSIONS: In patients with uterine ectopic pregnancies, the mean estimated beta hCG clearance duration was 29.2 days longer when applying local methotrexate compared with systemic methotrexate.

The explicit mentioning of reporting guidelines in urogynecology journals in 2013: A bibliometric study.

AIMS: Poor reporting of research may limit critical appraisal and reproducibility, whereas adherence to reporting guidelines (RG) can guarantee completeness and transparency. We aimed to determine the explicit citing of RGs (CONSORT, PRISMA, STROBE) in urogynecology articles in 2013, the requirements of relevant journals and a potential difference between urogynecology and general gynecology journals. METHODS: All urogynecologic articles published between January and December 2013 in the journals NAU, IUJ, FPMRS, GREEN, AJOG, and BJOG were included. Issues were searched for systematic reviews, RCTs, cohort studies, case-control studies and cross-sectional studies. Each electronic article was searched for the term PRISMA, CONSORT, or STROBE according to the study design. Instructions to Authors of the six journals were screened for requirement of using RGs. RESULTS: We included 296 articles (243 observational studies, 40 RCTs, and 13 systematic reviews). The use of PRISMA guidelines was explicitly declared in 54% of systematic reviews, CONSORT guidelines were referenced in 25% of RCTs and STROBE in 1.2% of observational studies. The use of CONSORT is required by all journals except FPMRS. PRISMA and STROBE are only compulsory in the journals GREEN, AJOG, and BJOG. The overall rate of explicit mentioning of RGs comparing urogynecology and general gynecology journals was 6.7% versus 7.1%, respectively. CONCLUSIONS: The explicit mentioning of RGs was on a relatively low level. A slightly higher adherence was recognized among general gynecology journals compared to urogynecology journals. Stronger efforts should be taken to further promote the use of RGs in urogynecology.

CONSORT and the internal validity of randomized controlled trials in Female Pelvic Medicine.

AIMS: To investigate authors' adherence to the CONSORT reporting guideline for randomized controlled trials (RCTs) in the sub-specialty Female Pelvic Medicine and to detect any changes in adherence between the years 2008 and 2013. METHODS: Bibliometric study. We included Female Pelvic Medicine RCTs published in 2008 and 2012-2013 in 10 journals. Full-text versions of RCTs for the inclusion of the CONSORT checklist items Randomization, Allocation, Blinding, and Participants' flowchart were screened. Each CONSORT checklist item was categorized for each included RCT as either "complete reporting", "insufficient reporting", "no reporting," or "not applicable". We screened the "Instructions to authors" for the requirement to adhere to CONSORT. RESULTS: We included 94 Female Pelvic Medicine RCTs for analysis. Most RCTs in 2008, 2012, and 2013 were published by IUJ (n =n39), followed by NAU (n = 13), GREEN (n = 12), European Urology (n = 8), FMPRS (n = 6), AJOG (n = 4), Urology (n = 3), NEJM (n = 3), Lancet (n = 1), and BJOG (n = 1). Proportion of RCTs in the category "complete reporting" comparing 2008 and 2013 was (47 and 70%) for Randomization, (18 and 45%) for Allocation, and (29 and 52%) for Blinding; a flowchart was presented in (71 and 91%). The increase was not statistically significant in any of the investigated CONSORT items. CONCLUSIONS: Complete reporting of Female Pelvic Medicine RCTs has increased between 2008 and 2013. However, there are still a relevant number of published RCTs, which do not fulfill these criteria. Reporting according to the CONSORT guidelines should be further encouraged to improve internal validity of Female Pelvic Medicine RCTs. Neurourol. Urodynam. 35:826-830, 2016. © 2015 Wiley Periodicals, Inc.

Risk Factors for De Novo Malignancies in Women After Kidney Transplantation: A Multicenter Transversal Study.

OBJECTIVE: Transplantation results in a 5-time elevated risk for a variety of malignancies (Kaposi sarcoma, skin, liver, lung, gastrointestinal cancer). A patient's risk for malignancies could be of particular interest for the follow-up programs of patients and risk adaption after kidney transplantation. The aim of this study was to identify independent risk factors for de novo malignancies in women after renal transplantation. METHODS AND MATERIALS: This is a multicenter transversal study, conducted at the Medical University of Vienna and Hospital Rudolfstiftung, Vienna, Austria. We included female kidney graft recipients who were transplanted between 1980 and 2012 and followed-up at our institutions (N = 280). Clinical data of patients were extracted from hospital charts and electronic patient files. Patients were interviewed using a standardized questionnaire regarding their medical history, history of transplantation, and malignant diseases. Detailed information about present and past immunosuppressive regimens, rejection episodes and therapies, renal graft function, and information about primary disease was obtained. Diagnostic work-up and/or surgical exploration was performed if any presence of malignancy was suspected during routine follow-up. Histological specimens were obtained from all patients. MAIN OUTCOME MEASURES: the presence of de novo malignancy after kidney transplantation. RESULTS: Two hundred sixty-two women were included for statistical analysis. Median (interquartile range) follow-up period after transplantation was 101.1 (27.3-190.7) months. Thirty-two patients (12.2%) developed a malignancy: dermatologic malignancies (5.7%), breast cancer (3.4%), cervical cancer (0.8%), lung cancer (0.4%), gastrointestinal malignancies (1.5%), vulvar cancer (0.4%), and unclassified malignancies (1.9%). Median (interquartile range) time to malignancy after transplantation was 185.9 (92.0-257.6) months. Cumulative cancer rates were 4.9% (1 year), 14.4% (3 years), 16.4% (5 years), and 21.8% (10 years). Second transplantations were identified as independent risk factor for development of malignancy after transplantation. CONCLUSIONS: Long-term risk of developing a malignancy after kidney transplantation is high, which might justify a follow-up of more than 10 years.

The human urinary microbiome and how it relates to urogynecology.

INTRODUCTION AND HYPOTHESIS: Recent studies applying molecular techniques have demonstrated the presence of a urinary microbiota not detected by standard microbiological techniques. These have been found in the urine of healthy individuals and in those suffering from clinical symptoms. The present article reviews the findings of these studies to date, describing the molecular techniques, and specifically outlining any differences in microbiomes in relation to urogynecological disease. Further, the role of commensal bacteria in the lower urinary tract is considered. METHODS: An extensive literature search was conducted to identify articles on the microbiome of the female urinary tract in health and disease. We searched the electronic meta-databases Ovid MEDLINE® 1946-2015 and Embase 1974-2015. The keywords "microbiome, microbiota, bacterial colonization, microbiology, commensal bacteria, and bacteriuria" were searched in combination with "lower urinary tract symptoms, urogenital symptoms, urinary tract infection, overactive bladder and urinary incontinence." A total of 426 papers were retrieved; 33 were included in this paper. RESULTS: The microbiome of the female lower urinary tract shows variance between individuals and between age groups. There are significant differences between the microbiota in the lower urinary tract of individuals with urological symptoms and those without, relating to type and proportion of commensal Lactobacillus spp. There is only weak evidence to suggest that Lactobacillus might be applied as a therapeutic measure. CONCLUSIONS: It is still unclear what role microbiota plays in female urinary tract health. The discovery of bacteria in the urine of healthy individuals may have implications for future therapies for lower urinary tract symptoms.

Urinary proteomic pattern in female stress urinary incontinence: a pilot study.

INTRODUCTION AND HYPOTHESIS: Previous studies aiming to identify specific pre-defined urine protein biomarkers for stress urinary incontinence (SUI) have not identified clinically important differences. The hypothesis of our study was that the global distribution of urinary proteins, the proteome, differs between women with and those without SUI. METHODS: In this age-matched case-control study, we compared the urinary proteome of 20 women with SUI and 20 controls. Proteins were identified by applying high-performance liquid chromatography separation and tandem mass spectrometry detection. Data analysis was performed using Mascot 2.4.1 embedded in ProteinScape 3.1. RESULTS: We identified 828 different proteins. The concentration of six of those showed a significant difference between urine samples of SUI patients and those of controls (q value < 0.25). Four proteins showed a higher abundance in SUI samples compared with controls: plasma serine protease inhibitor (logFC 1.11), leucine-rich alpha-2-glycoprotein (logFC 3.91), lysosomal alpha-glucosidase (logFC 1.24), and peptidyl-prolyl cis- trans isomerase A (logFC 1.96). We identified two proteins in lower abundance in SUI samples compared with controls: uromodulin (logFC -4.87) and TALPID3 (logFC -1.99). CONCLUSIONS: Overexpression of plasma serine protease inhibitor, leucine-rich alpha-2-glycoprotein, lysosomal alpha-glucosidase, and peptidyl-prolyl cis- trans isomerase A, and lower expression of uromodulin and TALPID3, in urine may be associated with female SUI.

Disclosures, conflict of interest, and funding issues in urogynecology articles: a bibliometric study.

INTRODUCTION AND HYPOTHESIS: The ethical behavior of authors, editors, and journals is increasingly placed in the spotlight, by both the public and the research community. Disclosures and conflict of interest (COI) statements of publishing authors represent one important aspect. We aimed to unravel the current management of disclosures, COI, and funding statements in the subspecialty urogynecology. METHODS: A bibliometric study was carried out. We included six journals that published urogynecology articles between January and December 2013. All original articles, reviews, and opinion articles were assessed for the presence of disclosure/COI and funding statements. Information given on the official disclosure form was compared with information given in the final article (International Urogynecology Journal). RESULTS: All journals investigated require disclosure and funding statements in their instructions to authors. Of the 434 articles included, almost all contained a disclosure statement (98-100 %). Funding statements were present in 41-100 % of articles, indicating a difference in journal type (50 % on average among urogynecology journals; 75 % on average among general gynecology journals). The main source of funding was "grants" (58 %), followed by "none" (16 %), "industry" (16 %), and lastly "hospital/university" (10 %). Disclosure statements in the article were identical to the official disclosure form in 80 % (IUJ). CONCLUSIONS: Disclosure/COI statements were included in almost all urogynecology articles investigated. Their content, however, is sometimes incomplete and should possibly be monitored more closely by journals and authors. Despite universal requirements of journals, the reporting of funding seems inconsistent. This issue in addition to the completeness of disclosures should be given more attention.