GenomeMUSter mouse genetic variation service enables multitrait, multipopulation data integration and analysis.

Hundreds of inbred mouse strains and intercross populations have been used to characterize the function of genetic variants that contribute to disease. Thousands of disease-relevant traits have been characterized in mice and made publicly available. New strains and populations including consomics, the collaborative cross, expanded BXD, and inbred wild-derived strains add to existing complex disease mouse models, mapping populations, and sensitized backgrounds for engineered mutations. The genome sequences of inbred strains, along with dense genotypes from others, enable integrated analysis of trait-variant associations across populations, but these analyses are hampered by the sparsity of genotypes available. Moreover, the data are not readily interoperable with other resources. To address these limitations, we created a uniformly dense variant resource by harmonizing multiple data sets. Missing genotypes were imputed using the Viterbi algorithm with a data-driven technique that incorporates local phylogenetic information, an approach that is extendable to other model organisms. The result is a web- and programmatically accessible data service called GenomeMUSter, comprising single-nucleotide variants covering 657 strains at 106.8 million segregating sites. Interoperation with phenotype databases, analytic tools, and other resources enable a wealth of applications, including multitrait, multipopulation meta-analysis. We show this in cross-species comparisons of type 2 diabetes and substance use disorder meta-analyses, leveraging mouse data to characterize the likely role of human variant effects in disease. Other applications include refinement of mapped loci and prioritization of strain backgrounds for disease modeling to further unlock extant mouse diversity for genetic and genomic studies in health and disease.

Academic training increases grounding of scientific concepts in experiential brain systems.

Scientific concepts typically transcendent our sensory experiences. Traditional approaches to science education therefore assume a shift towards amodal or verbal knowledge representations during academic training. Grounded cognition approaches, in contrast, predict a maintenance of grounding of the concepts in experiential brain networks or even an increase. To test these competing approaches, the present study investigated the semantic content of scientific psychological concepts and identified the corresponding neural circuits using functional magnetic resonance imaging (fMRI) in undergraduate psychology students (beginners) and in graduated psychologists (advanced learners). During fMRI scanning, participants were presented with words denoting scientific psychological concepts within a lexical decision task (e.g. "conditioning", "habituation"). The individual semantic property content of each concept was related to brain activity during abstract concept processing. In both beginners and advanced learners, visual and motor properties activated brain regions also involved in perception and action, while mental state properties increased activity in brain regions also recruited by emotional-social scene observation. Only in advanced learners, social constellation properties elicited brain activity overlapping with emotional-social scene observation. In line with grounded cognition approaches, the present results highlight the importance of experiential information for constituting the meaning of abstract scientific concepts during the course of academic training.

Mouse phenome database: curated data repository with interactive multi-population and multi-trait analyses.

The Mouse Phenome Database continues to serve as a curated repository and analysis suite for measured attributes of members of diverse mouse populations. The repository includes annotation to community standard ontologies and guidelines, a database of allelic states for 657 mouse strains, a collection of protocols, and analysis tools for flexible, interactive, user directed analyses that increasingly integrates data across traits and populations. The database has grown from its initial focus on a standard set of inbred strains to include heterogeneous mouse populations such as the Diversity Outbred and mapping crosses and well as Collaborative Cross, Hybrid Mouse Diversity Panel, and recombinant inbred strains. Most recently the system has expanded to include data from the International Mouse Phenotyping Consortium. Collectively these data are accessible by API and provided with an interactive tool suite that enables users' persistent selection, storage, and operation on collections of measures. The tool suite allows basic analyses, advanced functions with dynamic visualization including multi-population meta-analysis, multivariate outlier detection, trait pattern matching, correlation analyses and other functions. The data resources and analysis suite provide users a flexible environment in which to explore the basis of phenotypic variation in health and disease across the lifespan.

Long-term reoperation risk after apical prolapse repair in female pelvic reconstructive surgery.

BACKGROUND: Although several different apical suspension procedures are available to women with pelvic organ prolapse, data on long-term efficacy and safety profiles are limited. OBJECTIVE: The primary aim of this study was to analyze longitudinal reoperation risk for recurrent prolapse among the 4 apical suspension procedures over 2 to 15 years. Secondary aims included evaluation of all-cause reoperation, defined as a repeated surgery for the indications of recurrent prolapse and adverse events, and total retreatment rate, which included a repeated treatment with another surgery or a pessary. STUDY DESIGN: This was a multicenter, retrospective cohort study within Kaiser Permanente Southern California that included women who underwent sacrocolpopexy, uterosacral ligament suspension, sacrospinous ligament fixation, or colpocleisis from January 2006 through December 2018. Women who underwent concomitant rectal prolapse repair or vaginal prolapse repair with mesh augmentation were excluded. Data were abstracted using procedural and diagnostic codes through July 2021, with manual review of 10% of each variable. Patient demographics and pessary use were compared using analysis of variance or chi square tests for continuous and categorical variables, respectively. Time-to-event analysis was used to contrast reoperation rates. A Cox regression model was used to perform an adjusted multivariate analysis of the following predictors of reoperation for recurrence: index surgery, concomitant procedures, patient demographics, baseline comorbidities, and year of index surgery. Censoring events included exit from the health maintenance organization and death. RESULTS: The cohort included 9681 women with maximum follow-up of 14.8 years. The overall incidence of reoperation for recurrent prolapse was 7.4 reoperations per 1000 patient-years, which differed significantly by type of apical suspension (P<.0001). The incidence of reoperation was lower after colpocleisis (1.4 events per 1000 patient-years) and sacrocolpopexy (4.8 events per 1000 patient-years) when compared with uterosacral ligament suspension (9 events per 1000 patient-years) and sacrospinous ligament fixation (13.9 events per 1000 patient-years). All pairwise comparisons between procedures were significant (P=.0003-.0018) after correction for multiplicity, except for uterosacral ligament suspension or uterosacral ligament hysteropexy vs sacrospinous ligament fixation or sacrospinous ligament hysteropexy (P=.05). The index procedure was the only significant predictor of reoperation for recurrence (P=.0003-.0024) on multivariate regression analysis. Reoperations for complications or sequelae (overall 2.9 events per 1000 patient-years) also differed by index procedure (P<.0001) and were highest after sacrocolpopexy (4.4 events per 1000 patient-years). The incidence of all-cause reoperation for recurrence and adverse events after sacrocolpopexy, however, was comparable to that of the other reconstructive procedures (P=.1-.4) in pairwise comparisons with Bonferroni correction. Similarly, frequency of pessary use differed by index procedure (P<.0001) and was highest after sacrospinous ligament fixation at 9.3% (43/464). CONCLUSION: Among nearly 10,000 patients undergoing prolapse surgery within a large managed care organization, colpocleisis and sacrocolpopexy offered the most durable obliterative and reconstructive prolapse repairs, respectively. All-cause reoperation rates were lowest after colpocleisis by a large margin, but similar among reconstructive apical suspension procedures.

The impact of midurethral sling surgery on the development of urinary tract infections.

PURPOSE/OBJECTIVE: To measure the impact of the placement of a midurethral sling (MUS) on development of urinary tract infections (UTI) in women with stress urinary incontinence. METHODS: This is an analysis of a large managed care organization MUS database from 2005 to 2016. The database was queried to identify UTI and diagnosis of recurrent UTI. The primary outcome was the UTI rate after MUS. Secondary outcomes included the recurrent UTI rate and rates of UTI over time. RESULTS: Over the study period, 13,404 MUS were performed. In the 12 postoperative months, 23% of patients developed a UTI, while 4% developed a de novo recurrent UTI diagnosis. UTIs were most frequently diagnosed in the 1st month, with the 7th postoperative day the most common. Predictors of UTI development included increased age (OR 3.69 [95% CI 2.58-5.26]), being diabetic (OR 1.43 [95% CI 1.28-1.60]), and having urinary retention requiring prolonged catheterization (OR 2.45 [95% CI 2.11-2.85]). UTIs were less likely to be diagnosed in those with transobturator MUS (OR 0.85 [95% CI 0.78-0.94]). Patients who developed a UTI were more likely to have a reoperation (p = 0.0147), including a reoperation for mesh revision/removal (p = 0.0287), and recurrent SUI (p = 0.0394). Patients who developed a UTI were more likely to develop postoperative de novo urgency urinary incontinence (UUI) (p < 0.0001). CONCLUSION: Patients are at risk of UTI and rUTI after MUS. Risk of developing UTIs decreases with time. Predictors of developing UTI can help surgeons in the care of patients after MUS.

Ground Contact Time Estimating Wearable Sensor to Measure Spatio-Temporal Aspects of Gait.

Inpatient gait analysis is an essential part of rehabilitation for foot amputees and includes the ground contact time (GCT) difference of both legs as an essential component. Doctors communicate improvement advice to patients regarding their gait pattern based on a few steps taken at the doctor's visit. A wearable sensor system, called Suralis, consisting of an inertial measurement unit (IMU) and a pressure measuring sock, including algorithms calculating GCT, is presented. Two data acquisitions were conducted to implement and validate initial contact (IC) and toe-off (TO) event detection algorithms as the basis for the GCT difference determination for able-bodied and prosthesis wearers. The results of the algorithms show a median GCT error of -51.7 ms (IMU) and 14.7 ms (sensor sock) compared to the ground truth and thus represent a suitable possibility for wearable gait analysis. The wearable system presented, therefore, enables a continuous feedback system for patients and, above all, a remote diagnosis of spatio-temporal aspects of gait behaviour based on reliable data collected in everyday life.

The Impact of Surgical Center Volume on Reoperation Risk after Mid Urethral Sling.

PURPOSE: We sought to determine whether a center's surgical volume affects patient reoperation rates after mid urethral sling (MUS) surgery. MATERIALS AND METHODS: We performed a retrospective cohort study evaluating a large managed care organization from 2005 to 2016. The primary outcome was the MUS reoperation rate. Perioperative factors and reoperation of patients were compared using Wilcoxon rank-sum for continuous variables and chi-square for categorical variables. We estimated the adjusted hazard ratio and the 95% confidence interval of reoperation using Cox proportional hazards model. RESULTS: Within the managed care system, 13,404 primary MUSs were performed at 11 centers over the study period (19/105 center years were considered low volume). Higher-volume centers (>58 procedures/year based on concentration curve) performed 93% of surgeries in this cohort. Overall reoperation risk for patients of higher-volume centers was smaller than those of lower-volume centers, 4.9% vs 9.8% at 9 years (hazard ratio 0.45 [p <0.01]). Risk of reoperation for recurrent stress urinary incontinence (SUI) for patients was lower in the higher-volume centers, 4% vs 9.1% at 9 years (p <0.01). Patient of higher-volume centers were less likely to have a reoperation for mesh exposure 0.2% vs 0.7% (p <0.01) or infection 0% vs 0.2% (p <0.01). CONCLUSIONS: Patients who had their MUS surgery at a higher-volume medical center were less likely to have any reoperation including for recurrent SUI, mesh exposure or infection. These findings persisted even when controlling for potential covariates including patient demographics and surgeon volume and specialty.

Readmission and emergency department visits after minimally invasive sacrocolpopexy and vaginal apical pelvic organ prolapse surgery.

BACKGROUND: Minimally invasive pelvic reconstructive surgery is becoming increasingly common; however, data on readmission and emergency department visits within 30 days of surgery are limited. OBJECTIVE: Our objective was to report the risk factors for 30-day readmission and emergency department visits after minimally invasive pelvic organ prolapse surgery. STUDY DESIGN: This retrospective cohort study included all minimally invasive urogynecologic prolapse procedures with and without concomitant hysterectomy performed within a large managed healthcare organization of 4.5 million members from 2008 to 2018. We queried the system-wide medical record for current procedural terminology and International Classification of Diseases, Ninth or Tenth Revision codes for all included procedures and patient demographic and perioperative data. Our primary outcome was 30-day hospital readmission, and our secondary outcome was 30-day emergency department visits. Risk factors including demographics, surgical approach, and characteristics for 30-day outcomes were examined using odds ratios and chi-square tests for categorical variables and Wilcoxon rank sum tests for continuous variables. RESULTS: Of the 13,445 patients undergoing prolapse surgery, 6171 patients underwent concomitant hysterectomy whereas 7274 did not. Readmission within 30 days was 2.1% for those with and 1.5% for those without a concomitant hysterectomy. Emergency department visit within 30 days was 9.5% in those with and 9.2% in those without a concomitant hysterectomy. Concomitant hysterectomy (adjusted odds ratio, 1.41; 95% confidence interval, 1.07-1.81) was associated with an increased risk of 30-day readmission. There was no difference in risk of 30-day readmission when comparing the various approaches to hysterectomy. When compared with patients who underwent sacrocolpopexy, undergoing a sacrospinous ligament suspension increased the risk (adjusted odds ratio, 2.43; 95% confidence interval, 1.22-4.70) of 30-day readmission, while undergoing uterosacral ligament suspension (adjusted odds ratio, 0.99; 95% confidence interval, 0.57-1.63) or colpocleisis (adjusted odds ratio, 1.79; 95% confidence interval, 0.50-5.24) did not in the concomitant hysterectomy subgroup, when compared with patients who underwent sacrocolpopexy, there was no difference in the risk of 30-day readmission for sacrospinous ligament suspension (adjusted odds ratio, 1.09; 95% confidence interval, 0.61-3.34), uterosacral ligament suspension (adjusted odds ratio, 1.39; 95% confidence interval, 0.61-3.34) or colpocleisis (adjusted odds ratio, 1.88; 95% confidence interval, 0.71-4.02). Similarly, sacrocolpopexy was not associated with an increased risk of emergency department visits in either subgroup. For those who had a concomitant hysterectomy, the patient factors that were associated with an increased 30-day readmission risk were hypertension (odds ratio, 1.54; 95% confidence interval, 1.03-2.31; P=.03) and chronic obstructive pulmonary disease (odds ratio, 2.52; 95% confidence interval, 1.32-4.81; P<.01). For those whose prolapse procedure did not include concomitant hysterectomy, the patient factors that were associated with an increased 30-day readmission risk were age (odds ratio, 1.05; 95% confidence interval, 1.02-1.07; P<.01) and heart failure (odds ratio, 3.26; 95% confidence interval, 1.68-6.33; P<.01). CONCLUSION: In women undergoing minimally invasive pelvic organ prolapse surgery, sacrocolpopexy was not associated with an increased risk of 30-day readmission and emergency department visits. Clinicians may consider surgical approach and other factors when counseling patients about their risks after minimally invasive pelvic organ prolapse surgery.

The impact of the 2011 US Food and Drug Administration transvaginal mesh communication on utilization of synthetic mid-urethral sling procedures.

INTRODUCTION AND HYPOTHESIS: We sought to examine the change in utilization of the midurethral sling (MUS) for the treatment of stress urinary incontinence (SUI) after the 2011 US FDA communication regarding transvaginal mesh. METHODS: This is a retrospective cohort study evaluating surgical utilization of MUS at a managed care organization of 4.5 million patients from 2008 to 2016. The primary outcome was the change in utilization of synthetic mesh MUS before and after the July 2011 FDA communication. Secondary outcomes were the changes in surgeon level MUS utilization. RESULTS: MUS procedures decreased from 131 to 116 per 100,000 adult women with a decrease of 11.5% from 2010 to 2012. Year over year utilization of MUS was rapidly increasing (p < 0.01) prior the FDA communication from 116 (in 2008) to 131 (in 2010) per 100,000 women and then significantly declined (p < 0.01) after its release from 135 (in 2011) to 75 (in 2016) per 100,000 women (13% increase vs 44% decrease). The number of surgeons performing MUS increased (p < 0.01) from 172/year to 186/year from 2008 to 2010 (Table 1). This decreased (p < 0.01) from 183/year to 121/year from 2011 to 2016. CONCLUSIONS: MUS for SUI drastically declined after the FDA communication. Despite the 2011 FDA communication concerning only transvaginal mesh for pelvic organ prolapse, there was a significant decrease in MUS with synthetic mesh utilization. Our findings support the importance of continued long-term outcome data regarding the safety and efficacy of MUS and highlight the impact of the FDA warning on MUS utilization.

Anchor vs suture for the attachment of vaginal mesh in a robotic-assisted sacrocolpopexy: a randomized clinical trial.

BACKGROUND: Vaginal mesh attachment can be one of the most time-consuming components of a minimally invasive sacrocolpopexy. OBJECTIVE: To assess the impact on the duration vaginal mesh attachment of using absorbable anchors compared to interrupted sutures for vaginal mesh attachment in robotic-assisted sacrocolpopexy. STUDY DESIGN: This was a single-masked, randomized clinical trial of women with pelvic organ prolapse that underwent a robotic-assisted sacrocolpopexy at 2 clinical sites. The participants were randomized to receive either interrupted delayed absorbable anchors or sutures during the vaginal mesh attachment portion of the surgery. The participants completed validated questionnaires at baseline and at 6 weeks, 6 months, and 12 months after the surgery. A certified examiner, masked to the attachment technique that was used, performed a clinical examination using the Pelvic Organ Prolapse Quantification system and also assessed for mesh exposure and the overall appearance of the vaginal walls using a 10-cm visual analog scale at each follow-up visit. The primary outcome was the vaginal mesh attachment time. The categorical variables were compared using chi-square or Fischer's Exact test, whereas the continuous variables were compared using Student's t-test or Mann-Whitney U test where appropriate. An intention-to-treat analysis was performed. RESULTS: Fifty-three participants were randomized, 26 to mesh attachment with anchor, 27 to mesh attachment with suture, and 81% (21/26) and 93% (25/27) had 12-month follow up respectively. There were no significant differences between the groups with regard to age (P=.12), body mass index (P=.23), stage of prolapse (P=.97), or other preoperative factors. Mesh attachment interval time was faster in the anchor compared to suturing study arm (12.2±7.8 vs 21.2±5.2 minutes; P<.001), while sacrocolpopexy times (107.6±33.2 vs 109.8±21.2 minutes; P=.774) were not different. The ease of placement for the surgeon based on a visual analog scale (P=.16), the appearance of the mesh attachment (P=.07), and the overall satisfaction with the use of the specific attachment type (P=.65) were similar for the arms. There was no difference in perioperative adverse events rates between arms and by 12 months follow-up there were no sacrocolpopexy mesh, anchor, or suture exposures. There was no difference in outcomes at 12 months including composite failure (10% vs 12%; P=.79), patient global impression of improvement (1.06 vs 1.19; P=.27), or patient pelvic pain (9.81 vs 9.67; P=.56). CONCLUSION: In patients undergoing a robotic-assisted sacrocolpopexy, the anchor vaginal mesh attachment technique required significantly less time than suturing. There was no difference between techniques in complications, failure, surgeon, or patient-reported outcomes through 12 months of follow-up. Mesh attachment during sacrocolpopexy can be performed in less time by using the anchor technique, providing surgeons with an alternative surgical technique for this procedure.

Data-driven, projection-based respiratory motion compensation of PET data for cardiac PET/CT and PET/MR imaging.

BACKGROUND: Respiratory patient motion causes blurring of the PET images that may impact accurate quantification of perfusion and infarction extents in PET myocardial viability studies. In this study, we investigate the feasibility of correcting for respiratory motion directly in the PET-listmode data prior to image reconstruction using a data-driven, projection-based, respiratory motion compensation (DPR-MoCo) technique. METHODS: The DPR-MoCo method was validated using simulations of a XCAT phantom (Biograph mMR PET/MR) as well as experimental phantom acquisitions (Biograph mCT PET/CT). Seven patient studies following a dual-tracer (18F-FDG/13N-NH3) imaging-protocol using a PET/MR-system were also evaluated. The performance of the DPR-MoCo method was compared against reconstructions of the acquired data (No-MoCo), a reference gate method (gated) and an image-based MoCo method using the standard reconstruction-transform-average (RTA-MoCo) approach. The target-to-background ratio (TBRLV) in the myocardium and the noise in the liver (CoVliver) were evaluated for all acquisitions. For all patients, the clinical effect of the DPR-MoCo was assessed based on the end-systolic (ESV), the end-diastolic volumes (EDV) and the left ventricular ejection fraction (EF) which were compared to functional values obtained from the cardiac MR. RESULTS: The DPR-MoCo and the No-MoCo images presented with similar noise-properties (CoV) (P = .12), while the RTA-MoCo and reference-gate images showed increased noise levels (P = .05). TBRLV values increased for the motion limited reconstructions when compared to the No-MoCo reconstructions (P > .05). DPR-MoCo results showed higher correlation with the functional values obtained from the cardiac MR than the No-MoCo results, though non-significant (P > .05). CONCLUSION: The projection-based DPR-MoCo method helps to improve PET image quality of the myocardium without the need for external devices for motion tracking.

Assessing patients' preferences for gender, age, and experience of their urogynecologic provider.

INTRODUCTION AND HYPOTHESIS: Understanding patient preferences regarding provider characteristics is an under-explored area in urogynecology. This study aims to describe patient preferences for urogynecologic care, including provider gender, age, experience, and presence of medical trainees. METHODS: This was a multicenter, cross-sectional, survey-based study assessing patient preferences with a voluntary, self-administered, anonymous questionnaire prior to their first urogynecology consult. A 5-point Likert scale addressing provider gender, age, experience, and presence of trainees was used. Descriptive statistics summarized patient characteristics and provider preferences. Chi-squared (or Fisher's exact) test was used to test for associations. RESULTS: Six hundred fifteen women participated from eight sites including all geographic regions across the US; 70.8% identified as white with mean age of 58.5 ± 14.2 years. Urinary incontinence was the most commonly reported symptom (45.9%); 51.4% saw a female provider. The majority of patients saw a provider 45-60 years old (42.8%) with > 15 years' experience (60.9%). Sixty-five percent of patients preferred a female provider; 10% preferred a male provider. Sixteen percent preferred a provider < 45 years old, 36% preferred 45-60 years old, and 11% of patients preferred a provider > 60 years old. Most patients preferred a provider with 5-15 or > 15 years' experience (49% and 46%, respectively). Eleven percent preferred the presence of trainees while 24% preferred trainee absence. CONCLUSION: Patient preferences regarding urogynecologic providers included female gender and provider age 45-60 years old with > 5 years' experience. Further study is needed to identify qualitative components associated with these preferences.

Surgeon volume and reoperation risk after midurethral sling surgery.

BACKGROUND: Emerging research supports that fewer complications occur in patients who undergo surgery by higher surgical volume surgeons. The midurethral sling surgery has been involved in recent warnings and litigation, which further supports a need to understand features that enhance its safety and efficacy. OBJECTIVE: The purpose of this study was to measure the impact of a surgeon's volume on their patient's rate of reoperation after midurethral sling surgery. STUDY DESIGN: This was a retrospective cohort study that evaluated all surgeons who performed synthetic mesh midurethral sling surgery for stress urinary incontinence at a large managed care organization with >4.5 million members from 2005-2016. Physicians Current Procedural Terminology and International Classification of Diseases, version 9/10, codes were used to identify the procedures and the reoperations that were performed. The system-wide medical record was queried for demographic and perioperative data. The primary outcome was the overall reoperation rate after midurethral sling surgery. Concentration curves were used to identify the impact of a surgeon's surgical volume on their rate of reoperation. Demographics, characteristics, and reoperation of patients were compared with the use of chi-square test for categoric variables and Wilcoxon rank sum test for continuous variables. Poisson regression models with a robust error variance were used to calculate the unadjusted and the adjusted risk ratios of reoperation with the use of age, body mass index, marital status, race, parity, vaginal estrogen use, sling type, smoking, diabetes mellitus, and menopausal status as covariates. RESULTS: Two hundred twenty-seven surgeons performed 13,404 midurethral sling surgeries over the study period; patients had a mean of 4.4 years of follow up. Higher-volume surgeons (>40 procedures/year, ≥95th percentile) performed 47% of the surgeries in this cohort and had an overall lower rate of reoperation (3.6% vs 4.2%; 95% confidence interval, 0.67-0.94; P=.04) compared with lower-volume surgeons. Higher-volume surgeons had a lower rate of reoperation for surgical failure (2.7% vs 3.6%; 95% confidence interval, 0.55-0.92; P<.01). Rates of reoperation for complications were similar between the 2 groups (1.1% vs 0.9%; 95% confidence interval, 0.82-1.13; P=.32). For patients whose condition required a reoperation secondary to complication, the rates of reoperation for urinary retention (0.9% vs 0.6%; P=.06), mesh exposure (0.2% vs 0.3%; P=.31), hemorrhage/bleeding (0.1% vs 0.0%; P=.11), pain (0.1% vs 0.1%; P=.52), and infection (0.0% vs 0.0%; P=.37) did not differ between higher- and lower-volume surgeons. The risk ratio for reoperation that compared higher- and lower-volume surgeons was 0.83 (95% confidence interval, 0.67-0.98; P=.01) in the adjusted model. CONCLUSION: Although the reoperation rates were low for both higher- and lower-volume surgeons, higher-volume surgeons had lower overall rates of reoperation after midurethral sling surgery. This effect is seen most dramatically in reoperation for surgical failure, in which patients who have surgery with a higher-volume surgeon are 25% less likely to have postoperative stress urinary incontinence that leads to reoperation.

3D vascular anatomy of the presacral space: impact of age and adiposity.

INTRODUCTION AND HYPOTHESIS: Defining patient characteristics that alter vascular anatomy at the sacrum is critical for avoiding life-threatening bleeding at the time of sacrocolpopexy. We tested the hypothesis that in thinner/older women, the bifurcations of the aorta and inferior vena cava (IVC) are lower relative to S1 resulting in less space accessible for suture/mesh placement, placing this group at increased risk of major vascular injury. METHODS: In a retrospective cross-sectional study, CT scans were used to make 2D measurements and a 3D model of the aorta/IVC, intervertebral disc space, and bony anatomy using segmentation and modeling software. For analysis, Spearman's and Pearson's correlation, Student's t test and the Mann-Whitney U test were used along with multivariate analysis of variance. RESULTS: Of eligible women who had undergone abdominal/pelvic CT, 107 were included. The median locations of the aortic and IVC bifurcations utilizing 2D analysis were at the inferior L4 and middle L5 vertebral body, respectively. In 10.2% of patients, the IVC was located at the L5-S1 disc space or lower; however, 3D modeling of this space which allowed assessment of the area below the S1 "drop off" showed that the amount of accessible space for suture/mesh placement was not decreased. Utilizing 2D analysis there was no statistically significant independent correlation between age or adiposity and the aortic or IVC bifurcation. Patients who were both elderly and thinner had a lower aortic bifurcation (p = 0.005) and a trend towards a lower IVC bifurcation (p = 0.082). CONCLUSIONS: In 10.2% of women, the IVC bifurcation descended at or below the L5-S1 disc space, suggesting that this group of women is at increased risk of major vascular injury. Patients who were both thin and elderly had lower bifurcations, but there was no difference in accessible surface area for suture placement on 3D analysis. 3D modeling improved visualization of the anatomy beyond the S1 "drop off" and may provide a future tool for surgical planning once predictors of high-risk anatomy are defined.

6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells.

BACKGROUND/AIMS: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). METHODS: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. RESULTS: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. CONCLUSION: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.

Plants Release Precursors of Histone Deacetylase Inhibitors to Suppress Growth of Competitors.

To secure their access to water, light, and nutrients, many plant species have developed allelopathic strategies to suppress competitors. To this end, they release into the rhizosphere phytotoxic substances that inhibit the germination and growth of neighbors. Despite the importance of allelopathy in shaping natural plant communities and for agricultural production, the underlying molecular mechanisms are largely unknown. Here, we report that allelochemicals derived from the common class of cyclic hydroxamic acid root exudates directly affect the chromatin-modifying machinery in Arabidopsis thaliana. These allelochemicals inhibit histone deacetylases both in vitro and in vivo and exert their activity through locus-specific alterations of histone acetylation and associated gene expression. Our multilevel analysis collectively shows how plant-plant interactions interfere with a fundamental cellular process, histone acetylation, by targeting an evolutionarily highly conserved class of enzymes.

Fatty metaplasia quantification and impact on regional myocardial function as assessed by advanced cardiac MR imaging.

OBJECTIVE: This study aimed to investigate the advantages of recently developed cardiac imaging techniques of fat-water separation and feature tracking to characterize better individuals with chronic myocardial infarction (MI). MATERIALS AND METHODS: Twenty patients who had a previous MI underwent CMR imaging. The study protocol included routine cine and late gadolinium enhancement (LGE) technique. In addition, mDixon LGE imaging was performed in every patient. Left ventricular (LV) circumferential (EccLV) and radial (ErrLV) strain were calculated using dedicated software (CMR42, Circle, Calgary, Canada). The extent of global scar was measured in LGE and fat-water separated images to compare conventional and recent CMR imaging techniques. RESULTS: The infarct size derived from conventional LGE and fat-water separated images was similar. However, detection of lipomatous metaplasia was only possible with mDixon imaging. Subjects with fat deposition demonstrated a significantly smaller percentage of fibrosis than those without fat (10.68 ± 5.07% vs. 13.83 ± 6.30%; p = 0.005). There was no significant difference in EccLV or ErrLV between myocardial segments containing fibrosis only and fibrosis with fat. However, EccLV and ErrLV values were significantly higher in myocardial segments adjacent to fibrosis with fat deposition than in those adjacent to LGE only. CONCLUSIONS: Advanced CMR imaging ensures more detailed tissue characterization in patients with chronic MI without a relevant increase in imaging and post-processing time. Fatty metaplasia may influence regional myocardial deformation especially in the myocardial segments adjacent to scar tissue. A simplified and shortened myocardial viability CMR protocol might be useful to better characterize and stratify patients with chronic MI.

High-dose dobutamine stress steady-state free precession (SSFP) cine MRI at 3T with patient adaptive local radiofrequency (RF) shimming using dual-source RF transmission.

PURPOSE: To prospectively assess the feasibility, image quality, and diagnostic accuracy of high-dose dobutamine stress magnetic resonance imaging (DSMR) using steady-state free precession (SSFP) cine imaging at 3T applying a dual-source radiofrequency (RF) excitation magnetic resonance imaging (MRI) system with parallel transmission and patient adaptive local RF shimming. MATERIALS AND METHODS: DSMR using SSFP cine imaging was performed in 44 patients at 3T scheduled for a clinically indicated coronary angiography. The effect of conventional versus dual-source RF transmission was assessed regarding homogeneity of the B1 field, contrast-to-noise ratios (CNRs) at rest, image quality, and diagnostic accuracy of DSMR using long and short axis. RESULTS: The mean percentage of the intended flip angle within the heart increased from 88 ± 9.1% with single-source to 103 ± 5.6% (P < 0.001) dual-source RF transmission. CNR increased for dual-source particularly at the apex (63.4 ± 24.2 vs. 36.5 ± 16.5, P < 0.001) but also at the base of the left ventricle (LV) (50.1 ± 14.8 vs. 39.3 ± 15.8, P < 0.001). Image quality of dual-source was higher both at rest (2.8 ± 0.5 vs. 2.6 ± 0.7, P < 0.001) and stress (2.5 ± 0.7 vs. 2.0 ± 1.0, P < 0.001). The number of segments with severe artifacts or nondiagnostic image quality at stress was lower with dual-source RF transmission (8% vs. 27%, P < 0.001). The diagnostic accuracy of DSMR in coronary territories using dual-source RF transmission was significantly higher (77% vs. 65%, P = 0.04). CONCLUSION: Patient adaptive local RF shimming using dual-source RF transmission provided significantly improved image quality and higher diagnostic accuracy of SSFP during DSMR at 3T compared to conventional RF transmission.

The ROS-induced cytotoxicity of ascorbate is attenuated by hypoxia and HIF-1alpha in the NCI60 cancer cell lines.

Intravenous application of high-dose ascorbate is used in complementary palliative medicine to treat cancer patients. Pharmacological doses of ascorbate in the mM range induce cytotoxicity in cancer cells mediated by reactive oxygen species (ROS), namely hydrogen peroxide and ascorbyl radicals. However, little is known about intrinsic or extrinsic factors modulating this ascorbate-mediated cytotoxicity. Under normoxia and hypoxia, ascorbate IC50 values were determined on the NCI60 cancer cells. The cell cycle, the influence of cobalt chloride-induced hypoxia-inducible factor-1α (HIF-1α) and the glucose transporter 1 (GLUT-1) expression (a pro-survival HIF-1α-downstream-target) were analysed after ascorbate exposure under normoxic and hypoxic conditions. The amount of ascorbyl radicals increased with rising serum concentrations. Hypoxia (0.1% O2 ) globally increased the IC50 of ascorbate in the 60 cancer cell lines from 4.5 ± 3.6 mM to 10.1 ± 5.9 mM (2.2-fold increase, P < 0.001, Mann-Whitney t-test), thus inducing cellular resistance towards ascorbate. This ascorbate resistance depended on HIF-1α-signalling, but did not correlate with cell line-specific expression of the ascorbate transporter GLUT-1. However, under normoxic and hypoxic conditions, ascorbate treatment at the individual IC50 reduced the expression of GLUT-1 in the cancer cells. Our data show a ROS-induced, HIF-1α- and O2 -dependent cytotoxicity of ascorbate on 60 different cancer cells. This suggests that for clinical application, cancer patients should additionally be oxygenized to increase the cytotoxic efficacy of ascorbate.

Enhanced killing of therapy-induced senescent tumor cells by oncolytic measles vaccine viruses.

Therapy-induced senescence (TIS) as a permanent growth arrest can be induced by various stimuli, including anticancer compounds. TIS emerged as a promising strategy to overcome resistance phenomena. However, senescent cancer cells might regain proliferation activity in vivo or even secrete tumor-promoting cytokines. Therefore, successful exploitation of TIS in cancer treatment simultaneously requires the development of effective strategies to eliminate senescent cancer cells. Virotherapy aims to selectively hit tumor cells, thus a combination with senescence-inducing drugs was explored. As a model, we chose measles vaccine virus (MeV), which does not interfere with cellular senescence by itself. In different tumor cell types, such as hepatoma, pancreatic and mammary gland carcinoma, we demonstrate efficient viral replication and lysis after TIS by gemcitabine, doxorubicin or taxol. Applying real time imaging, we even found an accelerated lysis of senescent cancer cells, supporting an enhanced viral replication with an increase in cell-associated and released infectious MeV particles. In summary, we show as a proof-of-concept that senescent tumor cells can be efficiently exploited as virus host cells by oncolytic MeV. These observations open up a new field for preclinical and clinical research to further investigate TIS and oncolytic viruses as an attractive combinatorial future treatment approach.