Transcriptomic and developmental effects of persistent organic pollutants in sentinel fishes collected near an arctic formerly used defense site.

Alaska contains over 600 formerly used defense (FUD) sites, many of which serve as point sources of pollution. These sites are often co-located with rural communities that depend upon traditional subsistence foods, especially lipid-rich animals that bioaccumulate and biomagnify persistent organic pollutants (POPs). Many POPs are carcinogenic and endocrine-disrupting compounds that are associated with adverse health outcomes. Therefore, elevated exposure to POPs from point sources of pollution may contribute to disproportionate incidence of disease in arctic communities. We investigated PCB concentrations and the health implications of POP exposure in sentinel fishes collected near the Northeast Cape FUD site on Sivuqaq (St. Lawrence Island), Alaska. Sivuqaq residents are almost exclusively Yupik and rely on subsistence foods. At the request of the Sivuqaq community, we examined differential gene expression and developmental pathologies associated with exposure to POPs originating at the Northeast Cape FUD site. We found significantly higher levels of PCBs in Alaska blackfish (Dallia pectoralis) collected from contaminated sites downstream of the FUD site compared to fish collected from upstream reference sites. We compared transcriptomic profiles and histopathologies of these same blackfish. Blackfish from contaminated sites overexpressed genes involved in ribosomal and FoxO signaling pathways compared to blackfish from reference sites. Contaminated blackfish also had significantly fewer thyroid follicles and smaller pigmented macrophage aggregates. Conversely, we found that ninespine stickleback (Pungitius pungitius) from contaminated sites exhibited thyroid follicle hyperplasia. Despite our previous research reporting transcriptomic and endocrine differences in stickleback from contaminated vs. reference sites, we did not find significant differences in kidney or gonadal histomorphologies. Our results demonstrate that contaminants from the Northeast Cape FUD site are associated with altered gene expression and thyroid development in native fishes. These results are consistent with our prior work demonstrating disruption of the thyroid hormone axis in Sivuqaq residents.

Elevated mercury and PCB concentrations in Dolly Varden (Salvelinus malma) collected near a formerly used defense site on Sivuqaq, Alaska.

Environmental pollution causes adverse health effects in many organisms and contributes to health disparities for Arctic communities that depend on subsistence foods, including the Yupik residents of Sivuqaq (St. Lawrence Island), Alaska. Sivuqaq's proximity to Russia made it a strategic location for U.S. military defense sites during the Cold War. Two radar surveillance stations were installed on Sivuqaq, including at the Northeast Cape. High levels of persistent organic pollutants and toxic metals continue to leach from the Northeast Cape formerly used defense (FUD) site despite remediation efforts. We quantified total mercury (Hg) and polychlorinated biphenyl (PCB) concentrations, and carbon and nitrogen stable isotope signatures, in skin and muscle samples from Dolly Varden (Salvelinus malma), an important subsistence species. We found that Hg and PCB concentrations significantly differed across locations, with the highest concentrations found in fish collected near the FUD site. We found that 89% of fish collected from near the FUD site had Hg concentrations that exceeded the U.S. Environmental Protection Agency's (EPA) unlimited Hg-contaminated fish consumption screening level for subsistence fishers (0.049 µg/g). All fish sampled near the FUD site exceeded the EPA's PCB guidelines for cancer risk for unrestricted human consumption (0.0015 µg/g ww). Both Hg and PCB concentrations had a significant negative correlation with δ13C when sites receiving input from the FUD site were included in the analysis, but these relationships were insignificant when input sites were excluded. δ15N had a significant negative correlation with Hg concentration, but not with PCB concentration. These results suggest that the Northeast Cape FUD site remains a point source of Hg and PCB pollution and contributes to higher concentrations in resident fish, including subsistence species. Moreover, elevated Hg and PCB levels in fish near the FUD site may pose a health risk for Sivuqaq residents.

Microscopic Hematuria as a Screening Tool for Urologic Malignancies in Women.

INTRODUCTION: Most causes of microscopic hematuria (MH) are benign but may indicate an underlying malignancy. Current MH evaluation guidelines are reflective of male urologic malignancy risks. The objective of this systematic review was to evaluate whether the finding of MH predicts subsequent urologic malignancy in women. METHODS: MEDLINE was searched between January 1990 and June 8, 2018. The positive predictive value (PPV) of MH as a screening tool for urologic malignancy was calculated for each study individually and collectively. The pooled relative risk of urologic malignancy associated with MH was calculated. RESULTS: Seventeen studies were included. Eight studies included only women. In total, 300 urinary tract cancers were identified in 110,179 women with MH. The PPV of MH as a screening tool for cancer ranged from approximately 0.6% to 2.8%; confidence intervals (CIs) suggested this is a relatively unstable performance indicator because of small sample sizes. Average PPV across all studies was 2.13%, but the weighted average PPV was 0.24%. The risk of urologic malignancies among women with relative those without MH was 2.01 (95% CI, 1.61-2.51). Based on these limited data, we estimate that 859 (95% CI, 654-1250) women with MH would require complete evaluation to identify 1 urinary tract malignancy. CONCLUSIONS: A very small proportion of women with MH are likely to have a urologic malignancy. Approximately 859 women require full screening to identify 1 malignancy. Current evidence is limited, and further studies, specifically in women, are needed.

American Urogynecologic Society Systematic Review: The Impact of Weight Loss Intervention on Lower Urinary Tract Symptoms and Urinary Incontinence in Overweight and Obese Women.

OBJECTIVE: Obesity can contribute to urinary symptoms such as urgency, frequency, and incontinence. In addition to classic treatments, weight loss interventions offer a unique clinical opportunity to improve these symptoms. STUDY DESIGN: The American Urogynecologic Society Systematic Review Group conducted a review of articles on the impact of surgical and behavioral weight loss (BWL) interventions on urinary symptoms in overweight and obese women. The certainty of the evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: The review group identified 43 publications from 39 studies, including 10 reports that used data from 5 randomized trials. Overall, there is high-certainty evidence that BWL, such as diet and exercise, decreases the prevalence of stress urinary incontinence 15% to 18% and overall urinary incontinence (UI) by 12% to 17% at 1 to 2.9 years. The certainty of evidence on the long-term impact of these interventions was lower. The certainty of the evidence was moderate to low regarding the benefit of BWL on urgency UI and overactive bladder symptoms. No randomized trials evaluated the impact of surgical weight loss on urinary symptoms, and the certainty of evidence of other study types was very low. CONCLUSIONS: There is high-certainty evidence that BWL results in modest improvements in stress and overall UI in overweight and obese women at 1 to 2.9 years after the intervention. Robust studies with low risk of bias are needed to assess whether these benefits are maintained over the long term and are associated with adverse events and to assess the impact of surgical weight loss interventions on urinary outcomes in overweight and obese women.

Volume at First Leak Is Associated With Sling Failure Among Women With Stress Urinary Incontinence.

INTRODUCTION: Stress urinary incontinence at a low bladder volume is a clinically observed phenomenon that is not well studied with regard to treatment outcomes. The primary aim of our study was to determine if the volume at first leak is associated with sling outcome. METHODS: This is a retrospective cohort study evaluating whether urodynamic stress urinary incontinence observed at low volumes is associated with sling failure using the Synthetic Derivative database. Sling failure was defined as (1) undergoing a subsequent surgery for stress incontinence (eg, urethral bulking agent, repeat sling) or (2) leakage that was subjectively worse or unchanged from baseline. Sling success was defined as subjective improvement in incontinence or being dry. Intrinsic sphincter deficiency was defined as maximum urethral closure pressure 20 cm H20 or less or abdominal leak point pressure less than 60 cm H20. RESULTS: Outcome data were available for 168 of 206 women who underwent a sling after urodynamic testing from 2006 to 2014. Of the 168 women, 80 were transobturator, 79 were retropubic, 8 lacked data regarding the approach to the midurethral sling, and 1 was an autologous pubovaginal sling. Similar failure rates were seen for transobturator (10%) and retropubic slings (7.6%). Preoperative urodynamic parameters, such as cystometric capacity and intrinsic sphincter deficiency, were similar among failed and successful slings. For every additional 50 mL in bladder volume at first leak (SUIvol), there was a 1.6 increased odds of having a successful sling (odds ratio, 1.576; 95% confidence interval, 1.014-2.450; P = 0.04). There was no statistically significant association between maximum urethral closure pressure, abdominal leak point pressure, body mass index, age, sling type, or whether a prior anti-incontinence procedure had been performed and sling success. CONCLUSIONS: Bladder volume at first leak is a strong predictor of sling failure.

Vosaroxin in combination with decitabine in newly diagnosed older patients with acute myeloid leukemia or high-risk myelodysplastic syndrome.

Vosaroxin is an anti-cancer quinolone-derived DNA topoisomerase II inhibitor. We investigated vosaroxin with decitabine in patients ≥60 years of age with newly diagnosed acute myeloid leukemia (n=58) or myelodysplastic syndrome (≥10% blasts) (n=7) in a phase II non-randomized trial. The initial 22 patients received vosaroxin 90 mg/m2 on days 1 and 4 with decitabine 20 mg/m2 on days 1-5 every 4-6 weeks for up to seven cycles. Due to a high incidence of mucositis the subsequent 43 patients were given vosaroxin 70 mg/m2 on days 1 and 4. These 65 patients, with a median age of 69 years (range, 60-78), some of whom with secondary leukemia (22%), adverse karyotype (35%), or TP53 mutation (20%), are evaluable. The overall response rate was 74% including complete remission in 31 (48%), complete remission with incomplete platelet recovery in 11 (17%), and complete remission with incomplete count recovery in six (9%). The median number of cycles to response was one (range, 1-4). Grade 3/4 mucositis was noted in 17% of all patients. The 70 mg/m2 induction dose of vosaroxin was associated with similar rates of overall response (74% versus 73%) and complete remission (51% versus 41%, P=0.44), reduced incidence of mucositis (30% versus 59%, P=0.02), reduced 8-week mortality (9% versus 23%; P=0.14), and improved median overall survival (14.6 months versus 5.5 months, P=0.007). Minimal residual disease-negative status by multiparametric flow-cytometry at response (± 3 months) was achieved in 21 of 39 (54%) evaluable responders and was associated with better median overall survival (34.0 months versus 8.3 months, P=0.023). In conclusion, the combination of vosaroxin with decitabine is effective and well tolerated at a dose of 70 mg/m2 and warrants randomized prospective evaluation. ClinicalTrials.gov: NCT01893320.

Admixture mapping of pelvic organ prolapse in African Americans from the Women's Health Initiative Hormone Therapy trial.

Evidence suggests European American (EA) women have two- to five-fold increased odds of having pelvic organ prolapse (POP) when compared with African American (AA) women. However, the role of genetic ancestry in relation to POP risk is not clear. Here we evaluate the association between genetic ancestry and POP in AA women from the Women's Health Initiative Hormone Therapy trial. Women with grade 1 or higher classification, and grade 2 or higher classification for uterine prolapse, cystocele or rectocele at baseline or during follow-up were considered to have any POP (N = 805) and moderate/severe POP (N = 156), respectively. Women with at least two pelvic exams with no indication for POP served as controls (N = 344). We performed case-only, and case-control admixture-mapping analyses using multiple logistic regression while adjusting for age, BMI, parity and global ancestry. We evaluated the association between global ancestry and POP using multiple logistic regression. European ancestry at the individual level was not associated with POP risk. Case-only and case-control local ancestry analyses identified two ancestry-specific loci that may be associated with POP. One locus (Chromosome 15q26.2) achieved empirically-estimated statistical significance and was associated with decreased POP odds (considering grade ≥2 POP) with each unit increase in European ancestry (OR: 0.35; 95% CI: 0.30, 0.57; p-value = 1.48x10-5). This region includes RGMA, a potent regulator of the BMP family of genes. The second locus (Chromosome 1q42.1-q42.3) was associated with increased POP odds with each unit increase in European ancestry (Odds ratio [OR]: 1.69; 95% confidence interval [CI]: 1.28, 2.22; p-value = 1.93x10-4). Although this region did not reach statistical significance after considering multiple comparisons, it includes potentially relevant genes including TBCE, and ACTA1. Unique non-overlapping European and African ancestry-specific susceptibility loci may be associated with increased POP risk.

Variables affecting maximum urethral closure pressure (MUCP) and abdominal leak point pressure (ALPP) measurements.

INTRODUCTION AND HYPOTHESIS: The relationship between pelvic floor muscles and measurements of urethral function is not well studied. It is not known whether adjusting for clinical, demographic and urodynamic parameters would improve the association between MUCP and ALPP. Our hypothesis was that pelvic floor muscle strength (PFMS) influences the relationship between MUCP and ALPP. METHODS: This was a retrospective study of women who underwent a complex urodynamic study with evaluation of MUCP and ALPP using ICD-9 codes with documentation of PFMS. RESULTS: Urodynamic stress incontinence was confirmed in 478 patients, of whom 323 had MUCP recorded and 263 had both MUCP and ALPP recorded. Women with higher PFMS had a higher MUCP. In regression analysis ALPP at 150 mL and MUCP were weakly associated (coefficient 0.43, 95% CI 0.08-0.78; p = 0.02), whereas ALPP at capacity and MUCP were moderately associated (coefficient 0.60, 95% CI 0.25-0.95; p < 0.001). CONCLUSIONS: This study showed that MUCP and ALPP at 150 mL were weakly associated and that this improved to a moderate association for ALPP at capacity. MUCP increased with increasing PFMS among women with stress urinary incontinence and decreased with increasing age. There was no evidence that ALPP was associated with PFMS or age. The relationship between MUCP and ALPP was unchanged when accounting for covariates of PFMS (age, parity, BMI, prior procedure, urethral mobility, bladder capacity, stage of cystocele, or stage of uterine or apical prolapse).

Graft and Mesh Use in Transvaginal Prolapse Repair: A Systematic Review.

OBJECTIVE: To update clinical practice guidelines on graft and mesh use in transvaginal pelvic organ prolapse repair based on systematic review. DATA SOURCES: Eligible studies, published through April 2015, were retrieved through ClinicalTrials.gov, MEDLINE, and Cochrane databases and bibliography searches. METHODS OF STUDY SELECTION: We included studies of transvaginal prolapse repair that compared graft or mesh use with either native tissue repair or use of a different graft or mesh with anatomic and symptomatic outcomes with a minimum of 12 months of follow-up. TABULATION, INTEGRATION, AND RESULTS: Study data were extracted by one reviewer and confirmed by a second reviewer. Studies were classified by vaginal compartment (anterior, posterior, apical, or multiple), graft type (biologic, synthetic absorbable, synthetic nonabsorbable), and outcome (anatomic, symptomatic, sexual function, mesh complications, and return to the operating room). We found 66 comparative studies reported in 70 articles, including 38 randomized trials; quality of the literature has improved over time, but some outcomes still show heterogeneity and limited power. In the anterior vaginal compartment, synthetic nonabsorbable mesh consistently showed improved anatomic and bulge symptom outcomes compared with native tissue repairs based on meta-analyses. Other subjective outcomes, including urinary incontinence or dyspareunia, generally did not differ. Biologic graft or synthetic absorbable mesh use did not provide an advantage in any compartment. Synthetic mesh use in the posterior or apical compartments did not improve success. Mesh erosion rates ranged from 1.4-19% at the anterior vaginal wall, but 3-36% when mesh was placed in multiple compartments. Operative mesh revision rates ranged from 3-8%. CONCLUSION: Synthetic mesh augmentation of anterior wall prolapse repair improves anatomic outcomes and bulge symptoms compared with native tissue repair. Biologic grafts do not improve prolapse repair outcomes in any compartment. Mesh erosion occurred in up to 36% of patients, but reoperation rates were low.

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

BACKGROUND: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). INTERPRETATION: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. FUNDING: Sunesis Pharmaceuticals.

Vaginal estrogen use in postmenopausal women with pelvic floor disorders: systematic review and practice guidelines.

INTRODUCTION AND HYPOTHESIS: Risk of pelvic floor disorders increases after menopause and may be linked to estrogen deficiency. We aimed to systematically and critically assess the literature on vaginal estrogen in the management of pelvic floor disorders in postmenopausal women and provide evidence-based clinical practice guidelines. METHODS: MEDLINE and Cochrane databases were searched from inception to July 2014 for randomized controlled trials of commercially available vaginal estrogen products compared with placebo, no treatment, or any medication for overactive bladder or urinary incontinence. We double-screened 1,805 abstracts and identified 12 eligible papers. Studies were extracted for participant information, intervention, comparator, efficacy outcomes, and adverse events, and they were individually and collectively assessed for methodological quality and strength of evidence. RESULTS: Evidence was generally of poor to moderate quality. Vaginal estrogen application before pelvic organ prolapse surgery improved the vaginal maturation index and increased vaginal epithelial thickness. Postoperative vaginal estrogen use after a midurethral sling resulted in decreased urinary frequency and urgency. Vaginal estrogen and immediate-release oxybutynin were similar in improvement of urinary urgency, frequency, and urgency urinary incontinence in women with overactive bladder, but oxybutynin had higher rates of side effects and discontinuation. Conversely, the addition of vaginal estrogen to immediate or extended-release tolterodine did not improve urinary symptoms more than tolterodine alone. One study reported an improvement in stress urinary incontinence with use of vaginal estrogen. CONCLUSION: Vaginal estrogen application may play a useful role as an adjunct in the management of common pelvic floor disorders in postmenopausal women.

Vaginal estrogen for genitourinary syndrome of menopause: a systematic review.

OBJECTIVE: To comprehensively review and critically assess the literature on vaginal estrogen and its alternatives for women with genitourinary syndrome of menopause and to provide clinical practice guidelines. DATA SOURCES: MEDLINE and Cochrane databases were searched from inception to April 2013. We included randomized controlled trials and prospective comparative studies. Interventions and comparators included all commercially available vaginal estrogen products. Placebo, no treatment, systemic estrogen (all routes), and nonhormonal moisturizers and lubricants were included as comparators. METHODS OF STUDY SELECTION: We double-screened 1,805 abstracts, identifying 44 eligible studies. Discrepancies were adjudicated by a third reviewer. Studies were individually and collectively assessed for methodologic quality and strength of evidence. TABULATION, INTEGRATION, AND RESULTS: Studies were extracted for participant, intervention, comparator, and outcomes data, including patient-reported atrophy symptoms (eg, vaginal dryness, dyspareunia, dysuria, urgency, frequency, recurrent urinary tract infection (UTI), and urinary incontinence), objective signs of atrophy, urodynamic measures, endometrial effects, serum estradiol changes, and adverse events. Compared with placebo, vaginal estrogens improved dryness, dyspareunia, urinary urgency, frequency, and stress urinary incontinence (SUI) and urgency urinary incontinence (UUI). Urinary tract infection rates decreased. The various estrogen preparations had similar efficacy and safety; serum estradiol levels remained within postmenopausal norms for all except high-dose conjugated equine estrogen cream. Endometrial hyperplasia and adenocarcinoma were extremely rare among those receiving vaginal estrogen. Comparing vaginal estrogen with nonhormonal moisturizers, patients with two or more symptoms of vulvovaginal atrophy were substantially more improved using vaginal estrogens, but those with one or minor complaints had similar symptom resolution with either estrogen or nonhormonal moisturizer. CONCLUSION: All commercially available vaginal estrogens effectively relieve common vulvovaginal atrophy-related complaints and have additional utility in patients with urinary urgency, frequency or nocturia, SUI and UUI, and recurrent UTIs. Nonhormonal moisturizers are a beneficial alternative for those with few or minor atrophy-related symptoms and in patients at risk for estrogen-related neoplasia. CLINICAL TRIAL REGISTRATION: PROSPERO International prospective register of systematic reviews, http://www.crd.york.ac.uk/PROSPERO/, CRD42013006656.

The fellowship effect: how the establishment of a fellowship in female pelvic medicine and reconstructive surgery affected resident vaginal hysterectomy training.

OBJECTIVE: We report on trends in resident-performed vaginal hysterectomies before and after the establishment of a female pelvic medicine and reconstructive surgery fellowship at Vanderbilt University Medical Center. STUDY DESIGN: We examined medical records and resident self-reports concerning all hysterectomies at our institution in an 8-year period: 4 years before fellowship and 4 years after. Route of hysterectomy, resident and fellow involvement, and division of attending surgeon were recorded from the electronic medical record. Resident Accreditation Council for Graduate Medical Education (ACGME) case log data were used to estimate the number of hysterectomies where residents reported themselves as the primary surgeon. RESULTS: During the 8-year period of this study, 3317 hysterectomies were performed at our institution, 41% (1371) before and 59% (1946) after fellowship. Prior to fellowship, 29% (393) were vaginal, 56% (766) were abdominal, and 15% (212) were laparoscopic/robotic. After addition of fellowship, 23% (449) were vaginal, 31% (597) were abdominal, and 46% (900) were laparoscopic/robotic. Of the total vaginal hysterectomies (TVH), there was resident involvement in 98.0% (385) cases before fellowship and 98.2% (441) cases after fellowship. From the ACGME case log data, the resident identified himself/herself as the primary surgeon in 388 cases before and 393 cases after fellowship. During this time period, medical records indicate a fellow was involved in 42% (189) of TVH, with resident involvement in all but 5 of these procedures. CONCLUSION: Frequency of resident involvement in TVH cases, either as primary surgeon or team member, remained constant after the addition of the female pelvic medicine and reconstructive surgery fellowship.

Genetic epidemiology of pelvic organ prolapse: a systematic review.

Given current evidence supporting a genetic predisposition for pelvic organ prolapse, we conducted a systematic review of published literature on the genetic epidemiology of pelvic organ prolapse. Inclusion criteria were linkage studies, candidate gene association and genome-wide association studies in adult women published in English and indexed in PubMed through Dec. 2012, with no limit on date of publication. Methodology adhered to the PRISMA guidelines. Data were systematically extracted by 2 reviewers and graded by the Venice criteria for studies of genetic associations. A metaanalysis was performed on all single nucleotide polymorphisms evaluated by 2 or more studies with similar methodology. The metaanalysis suggests that collagen type 3 alpha 1 (COL3A1) rs1800255 genotype AA is associated with pelvic organ prolapse (odds ratio, 4.79; 95% confidence interval, 1.91-11.98; P = .001) compared with the reference genotype GG in populations of Asian and Dutch women. There was little evidence of heterogeneity for rs1800255 (P value for heterogeneity = .94; proportion of variance because of heterogeneity, I(2) = 0.00%). There was insufficient evidence to determine whether other single nucleotide polymorphisms evaluated by 2 or more papers were associated with pelvic organ prolapse. An association with pelvic organ prolapse was seen in individual studies for estrogen receptor alpha (ER-α) rs2228480 GA, COL3A1 exon 31, chromosome 9q21 (heterogeneity logarithm of the odds score 3.41) as well as 6 single nucleotide polymorphisms identified by a genome-wide association study. Overall, individual studies were of small sample size and often of poor quality. Future studies would benefit from more rigorous study design as outlined in the Venice recommendations.

Sling surgery for stress urinary incontinence in women: a systematic review and metaanalysis.

OBJECTIVE: Understanding the long-term comparative effectiveness of competing surgical repairs is essential as failures after primary interventions for stress urinary incontinence (SUI) may result in a third of women requiring repeat surgery. STUDY DESIGN: We conducted a systematic review including English-language randomized controlled trials from 1990 through April 2013 with a minimum 12 months of follow-up comparing a sling procedure for SUI to another sling or Burch urethropexy. When at least 3 randomized controlled trials compared the same surgeries for the same outcome, we performed random effects model metaanalyses to estimate pooled odds ratios (ORs). RESULTS: For midurethral slings (MUS) vs Burch, metaanalysis of objective cure showed no significant difference (OR, 1.18; 95% confidence interval [CI], 0.73-1.89). Therefore, we suggest either intervention; the decision should balance potential adverse events (AEs) and concomitant surgeries. For women considering pubovaginal sling vs Burch, the evidence favored slings for both subjective and objective cure. We recommend pubovaginal sling to maximize cure outcomes. For pubovaginal slings vs MUS, metaanalysis of subjective cure favored MUS (OR, 0.40; 95% CI, 0.18-0.85). Therefore, we recommend MUS. For obturator slings vs retropubic MUS, metaanalyses for both objective (OR, 1.16; 95% CI, 0.93-1.45) and subjective cure (OR, 1.17; 95% CI, 0.91-1.51) favored retropubic slings but were not significant. Metaanalysis of satisfaction outcomes favored obturator slings but was not significant (OR, 0.77; 95% CI, 0.52-1.13). AEs were variable between slings; metaanalysis showed overactive bladder symptoms were more common following retropubic slings (OR, 1.413; 95% CI, 1.01-1.98, P = .046). We recommend either retropubic or obturator slings for cure outcomes; the decision should balance AEs. For minislings vs full-length MUS, metaanalyses of objective (OR, 4.16; 95% CI, 2.15-8.05) and subjective (OR, 2.65; 95% CI, 1.36-5.17) cure both significantly favored full-length slings. Therefore, we recommend a full-length MUS. CONCLUSION: Surgical procedures for SUI differ for success rates and complications, and both should be incorporated into surgical decision-making. Low- to high-quality evidence permitted mostly level-1 recommendations when guidelines were possible.

Pelvic mesh complications in women before and after the 2011 FDA public health notification.

OBJECTIVES: On July 13, 2011, the US Food and Drug Administration (FDA) released a public health notification with concerns regarding vaginal mesh for the treatment of pelvic organ prolapse. Our study compares the frequency and type of mesh complications related to female pelvic floor disorders presenting to our center before and after this notification. METHODS: We performed a retrospective cohort study comparing the percentage of women found to have mesh complications related to pelvic floor disorders for the year preceding and the 6 months following the FDA notification. The 2011 International Urogynecological Association/International Continence Society (IUGA/ICS) guidelines were used to classify mesh complications. RESULTS: We identified 109 women in the 12 months before and 98 women in the 6 months after the FDA notification who presented for new consultation with a history of pelvic mesh placement. Of the women with prior mesh, a higher percentage had a mesh complaint after the FDA notification (31.2% before vs 45.9% after notification; P = 0.029). There was no difference in the frequency of diagnosed mesh complications (38.5% before vs 43.9% after notification; P = 0.435) or the types of complications seen as classified by the IUGA/ICS guidelines. The rate of complications among women with a prior sacral colpopexy (35%) or midurethral sling (30%) was higher than expected for both time periods. CONCLUSIONS: Whereas the number of patient-perceived mesh complications increased after the FDA notification, neither the frequency, type, or location of complications changed. The complications were not limited to transvaginal mesh, and an unexpectedly high proportion of the complications were related to sacral colpopexy and midurethral sling procedures.

Antibiotic prophylaxis for selected gynecologic surgeries.

BACKGROUND: Antibiotic prophylaxis for surgery is commonly used and is recommended by multiple organizations. OBJECTIVE: To critically review gynecology-specific data regarding surgical antibiotic prophylaxis in selected benign gynecologic surgeries. SEARCH STRATEGY: MEDLINE and Cochrane databases were searched from inception to July 2010. SELECTION CRITERIA: Randomized controlled trials of benign vaginal, cervical, transcervical, abdominal, or laparoscopic procedures other than hysterectomy comparing prophylactic antibiotic use with placebo or with another antibiotic. Outcomes of interest were postoperative infections, additional treatments, and adverse events. DATA COLLECTION AND ANALYSIS: In total, 19 trials met the inclusion criteria. Studies were individually assessed for methodologic quality, then grouped by procedure and evaluated for evidence quality. MAIN RESULTS: There was no difference in infectious outcome for loop electrosurgical excision, hysteroscopic ablation, or laparoscopy, although evidence quality was poor. Fair evidence supports antibiotic prophylaxis for suction curettage or laparotomy. There were insufficient data regarding vaginal surgery prophylaxis. CONCLUSION: Antibiotic prophylaxis may be beneficial in first-trimester suction curettage and laparotomy. No advantage was found for loop electrosurgical excision, hysteroscopy, or laparoscopic gynecologic surgery. Newer procedures and vaginal surgery lack research and merit study.

Clinical findings associated with bladder trabeculations in women.

INTRODUCTION AND HYPOTHESIS: This study evaluated whether bladder trabeculations are associated with advanced prolapse, urinary urgency, or detrusor overactivity among women undergoing office cystoscopy. It is well established that bladder trabeculations are associated with bladder outlet obstruction (BOO) in men; however, the clinical significance of trabeculations in women is unclear. Whereas an analogous relationship has been proposed between prostatic obstruction in men and advanced pelvic organ prolapse (POP) in women, little data in the medical literature supports this theory. METHODS: A retrospective cohort study was conducted using Current Procedural Terminology (CPT) codes (52000, 52204) to identify all women who underwent office cystoscopy at our urogynecology center between January 2008 and May 2011. The 551 women identified were grouped by the presence or absence of bladder trabeculations. Multivariable logistic regression was used to estimate the association between trabeculations and the primary aim, increasing stage of prolapse, and the secondary aims: bladder outlet obstruction, detrusor overactivity, or urge urinary incontinence (UUI). RESULTS: Of the 551 women meeting inclusion criteria, 86 had trabeculations. Controlling for age, the odds of bladder trabeculations were eightfold greater for women with stage IV POP when compared with women with stage 0 prolapse [odds ratio (OR) 8.2, 95% confidence interval (CI) 1.6-43.1]. The odds of bladder trabeculations were twofold greater for women with detrusor overactivity (OR 2.3, 95% CI 1.3-4.0) found on urodynamic study and also as reflected subjectively by answers to Pelvic Floor Distress Inventory (PFDI) item number 16 (OR 4.2, 95% CI 1.3-14.5). CONCLUSION: In this study, bladder trabeculations were associated with stage IV prolapse in the anterior compartment as well as with detrusor overactivity and UUI.