REViewer: haplotype-resolved visualization of read alignments in and around tandem repeats.

BACKGROUND: Expansions of short tandem repeats are the cause of many neurogenetic disorders including familial amyotrophic lateral sclerosis, Huntington disease, and many others. Multiple methods have been recently developed that can identify repeat expansions in whole genome or exome sequencing data. Despite the widely recognized need for visual assessment of variant calls in clinical settings, current computational tools lack the ability to produce such visualizations for repeat expansions. Expanded repeats are difficult to visualize because they correspond to large insertions relative to the reference genome and involve many misaligning and ambiguously aligning reads. RESULTS: We implemented REViewer, a computational method for visualization of sequencing data in genomic regions containing long repeat expansions and FlipBook, a companion image viewer designed for manual curation of large collections of REViewer images. To generate a read pileup, REViewer reconstructs local haplotype sequences and distributes reads to these haplotypes in a way that is most consistent with the fragment lengths and evenness of read coverage. To create appropriate training materials for onboarding new users, we performed a concordance study involving 12 scientists involved in short tandem repeat research. We used the results of this study to create a user guide that describes the basic principles of using REViewer as well as a guide to the typical features of read pileups that correspond to low confidence repeat genotype calls. Additionally, we demonstrated that REViewer can be used to annotate clinically relevant repeat interruptions by comparing visual assessment results of 44 FMR1 repeat alleles with the results of triplet repeat primed PCR. For 38 of these alleles, the results of visual assessment were consistent with triplet repeat primed PCR. CONCLUSIONS: Read pileup plots generated by REViewer offer an intuitive way to visualize sequencing data in regions containing long repeat expansions. Laboratories can use REViewer and FlipBook to assess the quality of repeat genotype calls as well as to visually detect interruptions or other imperfections in the repeat sequence and the surrounding flanking regions. REViewer and FlipBook are available under open-source licenses at https://github.com/illumina/REViewer and https://github.com/broadinstitute/flipbook respectively.

Complications After Reperitonealization of Mesh at Time of Sacrocolpopexy: A Retrospective Cohort Study.

OBJECTIVES: To determine if there is a difference in rates of surgical complications among patients who have reperitonealization of mesh versus no reperitonealization at time of sacrocolpopexy. METHODS: This was a retrospective cohort study of all patients who underwent sacrocolpopexy at an academic medical center between 2008 and 2017. The medical record was reviewed for the operative method of sacrocolpopexy, concomitant surgeries, intraoperative or postoperative complications, and readmissions. Groups were compared on whether mesh was reperitonealized under pelvic peritoneum or not. RESULTS: A total of 209 patients underwent sacrocolpopexy, with mesh reperitonealization performed in 115 (55%). Demographics were similar in both groups, except race/ethnicity and stage of prolapse. The majority (190 [91%]) of surgeries included concomitant procedures. A total of 18 intraoperative or postoperative complications (8.6%) were recorded. Relative risk of complication with mesh reperitonealization is 0.81 (95% confidence interval, 0.1-1.70). Complications for subjects without mesh reperitonealization included 4 cystostomies, 1 urethrotomy, 3 postoperative ileuses, and 1 small bowel obstruction. Among subjects with mesh reperitonealization, complications included 5 cystotomies, 2 proctotomies, 1 ureteral obstruction, and 1 small bowel obstruction. Rates of hospital readmission among both groups were not significantly different, with 3.2% of subjects without mesh reperitonealization versus 3.5% of mesh reperitonealization patients (P = 0.91) (relative risk, 1.09; 95% confidence interval, 0.38-2.56). CONCLUSIONS: There is no significant difference in rates of complications or readmissions among patients with and without mesh reperitonealization at time of sacrocolpopexy. The only intraoperative complication solely attributed to mesh closure was a case with ureteral obstruction at time of reperitonealization.

Use of Ultrasound Urodynamics to Identify Differences in Bladder Shape Between Individuals With and Without Overactive Bladder.

OBJECTIVES: The objective of this study was to identify differences in bladder shape changes between individuals with overactive bladder (OAB) and unaffected individuals during ultrasound urodynamics. METHODS: A prospective urodynamic study was performed with concurrent transabdominal ultrasound (ultrasound urodynamics) on individuals with and without OAB based on validated International Consultation on Incontinence Questionnaire - OAB survey scores. Three-dimensional ultrasound images were acquired at 1-minute increments during filling and used to measure bladder diameters in the height, width, and depth orientations. The engineering strain for each diameter was compared between participants with OAB and controls during urodynamic filling. The height-to-width ratio at capacity was used to determine if individuals were shape outliers. RESULTS: A total of 22 subjects were enrolled, including 11 with OAB and 11 without OAB. During urodynamic filling in both groups, the greatest degree of geometric strain was found in the height orientation, indicating that bladders generally fill in a craniocaudal shape. The mean ± SD height-to-width ratio of the control group was 1.06 ± 0.12 yielding a 95% confidence interval of 0.82 to 1.30. Five (45.5%) of 11 OAB subjects had height-to-width ratios outside this interval as compared with none of the control subjects, identifying a potential shape-mediated subgroup of OAB. CONCLUSIONS: Three-dimensional ultrasound urodynamics can be used to identify differences in bladder shape comparing individuals with and without OAB. This method may be used to identify a subset of OAB patients with abnormal bladder shapes which may play a role in the pathophysiology of their OAB symptoms.

Comparative-fill urodynamics in individuals with and without detrusor overactivity supports a conceptual model for dynamic elasticity regulation.

AIMS: Dynamic elasticity was previously identified in individuals with overactive bladder (OAB) using comparative-fill urodynamics (UD) and is a biomechanical mechanism for acutely regulating detrusor wall tension. On the basis of this data, a conceptual model of dynamic elasticity regulation mediated through a balance of passive mechanisms and active contractions was constructed. The present study tested this model by determining whether individuals with detrusor overactivity (DO) exhibit less dynamic elasticity than individuals without DO. METHODS: Individuals with and without urgency based on International Consultation on Incontinence Questionnaire-OAB surveys were prospectively enrolled in a comparative-fill UD study. An initial fill defined the presence or absence of DO and determined cystometric capacity. Three additional fills were employed with either passive emptying via a catheter or active voiding. To identify dynamic elasticity, average filling pressures (Pves ) were compared for fill 1 (before strain softening), fill 2 (after strain softening), and fill 3 (after active void). A dynamic elasticity index was defined. RESULTS: From 28 participants, those without DO showed decreased Pves during filling after strain softening and restored Pves during filling following active voiding, revealing dynamic elasticity. Participants with DO did not show dynamic elasticity. A dynamic elasticity index less than 1.0 cmH2 O/40% capacity was identified in 2 out of 13 participants without DO and 9 out of 15 with DO, revealing a significant association between DO and reduced/absent dynamic elasticity (P = .024). CONCLUSIONS: This study supports a conceptual model for dynamic elasticity, a mechanism to acutely regulate detrusor wall tension through a balance of competing active contractile and passive strain mechanisms. Improved understanding of this mechanistic model may help us to identify novel treatment strategies for OAB.

A longitudinal examination of event-related potentials sensitive to monetary reward and loss feedback from late childhood to middle adolescence.

Brain regions involved in reward processing undergo developmental changes from childhood to adolescence, and alterations in reward-related brain function are thought to contribute to the development of psychopathology. Event-related potentials (ERPs), such as the reward positivity (RewP) component, are valid measures of reward responsiveness that are easily assessed across development and provide insight into temporal dynamics of reward processing. Little work has systematically examined developmental changes in ERPs sensitive to reward. In this longitudinal study of 75 youth assessed 3 times across 6years, we used principal components analyses (PCA) to differentiate ERPs sensitive to monetary reward and loss feedback in late childhood, early adolescence, and middle adolescence. We then tested reliability of, and developmental changes in, ERPs. A greater number of ERP components differentiated reward and loss feedback in late childhood compared to adolescence, but components in childhood accounted for only a small proportion of variance. A component consistent with RewP was the only one to consistently emerge at each of the 3 assessments. RewP demonstrated acceptable reliability, particularly from early to middle adolescence, though reliability estimates varied depending on scoring approach and developmental period. The magnitude of the RewP component did not significantly change across time. Results provide insight into developmental changes in the structure of ERPs sensitive to reward, and indicate that RewP is a consistently observed and relatively stable measure of reward responsiveness, particularly across adolescence.

Social processing in early adolescence: Associations between neurophysiological, self-report, and behavioral measures.

Peer relationships play a major role in adolescent development, but few methods exist for measuring social processing at the neurophysiological level. This study extends our pilot study of Island Getaway, a task for eliciting event-related potentials (ERPs) to peer feedback. We differentiated ERPs using principal components analysis (PCA) and examined associations with behavioral and self-report measures in young adolescents (N=412). PCA revealed an early negativity in the ERP enhanced for rejection feedback, followed by a series of positivities (consistent with reward positivity [RewP], P300, and late positive potential) that were enhanced for acceptance feedback. Greater self-reported task engagement correlated with a larger RewP to acceptance and lower rates of rejecting peers. Youth higher in depressive symptoms exhibited a blunted RewP to social acceptance and reported lower engagement. Results highlight ERP components sensitive to peer feedback that may inform understanding of social processes relevant to typical and atypical development.

A pilot study to measure dynamic elasticity of the bladder during urodynamics.

AIMS: Previous studies using isolated strips of human detrusor muscle identified adjustable preload tension, a novel mechanism that acutely regulates detrusor wall tension. The purpose of this investigation was to develop a method to identify a correlate measure of adjustable preload tension during urodynamics. METHODS: Patients reporting urgency most or all of the time based on ICIq-OAB survey scores were prospectively enrolled in an extended repeat fill-and-empty urodynamics study designed to identify a correlate of adjustable preload tension which we now call "dynamic elasticity." Cystometric capacity was determined during initial fill. Repeat fills to defined percentages of capacity with passive emptying (via syringe aspiration) were performed to strain soften the bladder. A complete fill with active voiding was included to determine whether human bladder exhibits reversible strain softening. RESULTS: Five patients completed the extended urodynamics study. Intravesical pressure (pves ) decreased with subsequent fills and was significantly lower during Fill 3 compared to Fill 1 (P = 0.008), demonstrating strain softening. Active voiding after Fill 3 caused strain softening reversal, with pves in Fill 4 returning to the baseline measured during Fill 1 (P = 0.29). Dynamic elasticity, the urodynamic correlate of adjustable preload tension, was calculated as the amount of strain softening (or its reversal) per %capacity (Δaverage pves between fills/Δ%capacity). Dynamic elasticity was lost via repeat passive filling and emptying (strain softening) and regained after active voiding regulated the process (strain softening reversal). CONCLUSIONS: Improved understanding of dynamic elasticity in the human bladder could lead to both improved sub-typing and novel treatments of overactive bladder. Neurourol. Urodynam. 36:1086-1090, 2017. © 2016 Wiley Periodicals, Inc.

Sequential compression device compliance in postoperative obstetrics and gynecology patients.

OBJECTIVE: To assess the association of patient and nursing education on sequential compression device compliance in patients who have undergone major obstetric or benign gynecologic procedures. METHODS: We performed a prospective observational study on all English-speaking patients who underwent cesarean delivery or benign gynecologic surgery and were prescribed to wear sequential compression devices postoperatively at a university medical center. The 4-month study was divided into 1-month segments. The first month consisted of baseline observations of compliance. The second month was comprised of structured patient education, the third month involved nursing education, and the final month included both interventions. Observations were made twice daily. All educational interventions and observations were performed by two coauthors. A patient was noted to be compliant if she was ambulating, sitting, or lying in bed with sequential compression devices applied, tubing attached, and the machine powered on. RESULTS: A total of 859 observations was recorded for 228 patients. The number of hospitalization days ranged from 1 to 13 (mean 2.40 days, median 2 days). There was no difference in compliance among the months with 141 of 230 (61.3%), 106 of 194 (54.6%), 155 of 277 (56.0%), and 95 of 158 (60.1%) compliance for each consecutive month (P=.44). Noncompliance increased with each successive postoperative day (odds ratio 1.18 per day, 95% confidence interval 1.07-1.30). The most common patient-stated reason for noncompliance was "the nurse said I don't need them anymore" (82/362 observations [22.6%]). Overall, cesarean delivery was associated with the lowest rate of compliance when compared with gynecologic surgeries (272/519 [52.4%] compared with 225/340 [66.2%], P<.001). CONCLUSION: Compliance with postoperative use of sequential compression devices is approximately 58% and did not improve with patient or nursing educational interventions. LEVEL OF EVIDENCE: III.

Unanticipated uterine pathologic finding after morcellation during robotic-assisted supracervical hysterectomy and cervicosacropexy for uterine prolapse.

BACKGROUND: Identification of occult malignancy after intra-abdominal morcellation at the time of robotic-assisted supracervical hysterectomy and cervicosacropexy for uterine prolapse may lead to challenging postoperative management and leads one to question the need for preoperative evaluation. CASES: We present 2 cases of occult endometrial carcinoma after robotic-assisted supracervical hysterectomy and cervicosacropexy with intra-abdominal uterine morcellation from January 2008 to December 2010. A total of 63 patients underwent the stated surgical procedure with 2 patients (3.17%) found to have abnormal uterine pathologic finding with International Federation of Gynecology and Obstetrics grade 1 endometrial adenocarcinoma. Both cases occurred in asymptomatic postmenopausal patients without risk factors for endometrial cancer, including no history of postmenopausal bleeding or hormone replacement therapy. Owing to intraoperative uterine morcellation and cervical retention, appropriate postoperative management was controversial and problematic. Each patient was referred to gynecologic oncology. To date, both patients are without evidence of residual disease. CONCLUSION: Owing to the risk of occult uterine pathologic finding and complicated postoperative management, preoperative endometrial assessment should be considered on all postmenopausal patients undergoing intra-abdominal uterine morcellation, regardless of risk factors.

Routine use of preoperative cystourethroscopy on the surgical management of urinary incontinence and pelvic organ prolapse.

OBJECTIVES: To determine the impact of routine preoperative cystourethroscopy on the surgical management of urinary incontinence and pelvic organ prolapse. METHODS: Retrospective review of consecutive women undergoing surgery for urinary incontinence and/or pelvic organ prolapse at a tertiary referral urogynecology center to determine whether the routine use of preoperative cystourethroscopy changed the surgical management. Patients with other indications for cystourethroscopy were excluded. RESULTS: A total of 283 consecutive charts were reviewed of which 235 met inclusion criteria. Five patients accounted for 6 abnormal findings on preoperative cystourethroscopic examination including 2 bladder calculi, 2 lesions suspicious for neoplasm, and 2 cases of absent unilateral ureteric efflux. In only one case (0.5%) was the surgical plan altered. CONCLUSION: The routine use of preoperative cystourethroscopy in low-risk patients being prepared for surgery for urinary incontinence and pelvic prolapse is not required when no other indications for cystourethroscopy exist.

Prospective evaluation of surgical outcomes of robot-assisted sacrocolpopexy and sacrocervicopexy for the management of apical pelvic support defects.

OBJECTIVE: To evaluate outcomes of robot-assisted sacrocolpopexy (RSCP) and sacrocervicopexy (RCSP). METHODS: We conducted a prospective study of women undergoing RSCP or RCSP between June 2008 and January 2010. RESULTS: A total of 85 cases (48 RSCP and 37 supracervical hysterectomy with concomitant RCSP) were performed: 33% (28/85) for stage II, 54% (46/85) for stage III, and 13% (11/85) for stage IV pelvic organ prolapse (POP). Six weeks postoperatively, 96% (80/83) had stage 0, 2.4% (2/83) had stage I, and 1.2% (1/83) had stage II POP (P < 0.001). Six months postoperatively, 77% (24/31) had stage 0, 6.5% (2/31) had stage I, and 16% (5/31) had stage II POP (P < 0.001). Mean surgical time, estimated blood loss, and length of hospital stay was 194 ± 54 minutes, 49 ± 48 cm, and 1.6 ± 0.72 days, respectively. There were 2 cases of mesh erosion (2.3%), both in the RSCP group. CONCLUSIONS: RSCP and RCSP are effective, efficient, and safe procedures.

Surgical management of apical pelvic support defects: the impact of robotic technology.

INTRODUCTION AND HYPOTHESIS: Our aim was to determine what effect access to robotic technology had on our approach to managing apical pelvic support defects. METHODS: This was a retrospective chart review of 187 pelvic floor reconstructive surgeries performed for the 18 months prior to (time period 1: January 2007 to July 2008) and following (time period 2: July 2009 to December 2009) the introduction of the robot. Chi-square was used to compare percentages, and analysis of variance (ANOVA) was used to compare demographic data among groups. RESULTS: Overall, 187 procedures were performed for apical prolapse during the study period: 61 in time period 1 and 126 in time period 2. Following the introduction of robotic technology, a significant change from vaginal to abdominal reconstruction occurred. Uterosacral ligament suspension declined from 67 % to 22 % (p < 0.0001), whereas sacrocolpopexy increased from 25 % (15/61) to 66 % (83/126) (p < 0.0001). The rate of abdominal sacrocolpopexy, however, declined from 25 % (15/61) to 2 % (2/126) over the two time periods (p < 0.0001). CONCLUSION: The introduction of robotic technology significantly affected the surgical procedure and mode of surgical access for repair of apical pelvic support defects.