1. University of Texas Health Science Center San Antonio, Texas, 2. University of Texas Southwest... more 1. University of Texas Health Science Center San Antonio, Texas, 2. University of Texas Southwestern, Dallas TX, 3. University of Maryland, Baltimore MD, 4. William Beaumont Hospital, Royal Oak, MI, 5. University of Alabama, Birmingham AL, 6. University of Utah School of Medicine, Salt Lake City, UT, 7. Loyola Medical Center, Maywood IL, 8. University of California San Diego Medical Center/Kaiser Permanente, San Diego CA, 9. University of Pittsburgh, Pittsburgh PA, 10. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 11. New England Research Institutes, Watertown MA
Hypothesis / aims of study It has been established by us and others that genetic factors contribu... more Hypothesis / aims of study It has been established by us and others that genetic factors contribute to the risk of pelvic organ prolapse (POP). Our original POP Genetic Resource focused on identifying siblings, who in most cases were treated surgically. Our Genetic Resource has been expanded to include larger extended pedigrees with elevated risk of POP; some of the cases in these pedigrees may not have received treatment for POP. The objective of this study is to present genome-wide linkage results for pedigrees with women who report at least bothersome symptoms of POP. Compared to our original linkage report of strictly defined POP cases based on surgical treatment, we hypothesized that this more moderate definition of POP might increase power to detect additional linkage regions of interest.
Hypothesis / aims of study Pelvic floor disorders (PFDs) include a variety of continence and orga... more Hypothesis / aims of study Pelvic floor disorders (PFDs) include a variety of continence and organ laxity defects; many women with PFDs have more than one defect. Understanding the clustering of PFDs within families is important because it may suggest underlying risk factors that may be environmental, genetic or both. The aim of this study was to describe clusters of familial cases with PFDs as well as clinical characteristics of familial cases.
Uterosacral ligament suspension (ULS) and sacrospinous ligament fixation (SSLF) are commonly perf... more Uterosacral ligament suspension (ULS) and sacrospinous ligament fixation (SSLF) are commonly performed pelvic organ prolapse procedures despite a lack of long-term efficacy data. To compare outcomes in women randomized to (1) ULS or SSLF and (2) usual care or perioperative behavioral therapy and pelvic floor muscle training (BPMT) for vaginal apical prolapse. This 2 × 2 factorial randomized clinical trial was conducted at 9 US medical centers. Eligible participants who completed the Operations and Pelvic Muscle Training in the Management of Apical Support Loss Trial enrolled between January 2008 and March 2011 and were followed up 5 years after their index surgery from April 2011 through June 2016. Two randomizations: (1) BPMT (n = 186) or usual care (n = 188) and (2) surgical intervention (ULS: n = 188 or SSLF: n = 186). The primary surgical outcome was time to surgical failure. Surgical failure was defined as (1) apical descent greater than one-third of total vaginal length or ant...
Female pelvic medicine & reconstructive surgery, Jan 11, 2017
The aim of the study was to compare anterior and overall prolapse prevalence at 1 year in surgica... more The aim of the study was to compare anterior and overall prolapse prevalence at 1 year in surgical participants with or without concomitant anterior repair (AR) at the time of sacrospinous ligament fixation (SSLF) or uterosacral ligament suspension (ULS). This is a secondary analysis of two surgical trials; concomitant AR was performed at surgeon's discretion. Anterior anatomic success was defined as pelvic organ prolapse quantification of prolapse point Ba ≤0 and overall success was defined as pelvic organ prolapse quantification points Ba, Bp, and C ≤0 at 12 months. Sixty-three percent (441/701) of the participants underwent concomitant AR and were older, more often postmenopausal, had previous hysterectomy, and had higher-stage anterior, but not apical prolapse. Anterior anatomic success was marginally but statistically better in the combined group (SSLF and ULS) with concomitant AR (82% vs 80%, P = 0.03). In subanalyses, the improvement in anatomic support with AR was observ...
Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etio... more Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etiology. We hypothesized that related interstitial cystitis/painful bladder syndrome cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis. We identified interstitial cystitis/painful bladder syndrome cases using diagnostic codes linked to the Utah Population Database genealogy resource and to electronic medical records. For this analysis we used 13 high risk pedigrees, defined as having a statistical excess number of interstitial cystitis/painful bladder syndrome cases among descendants compared to matched hospital population rates. Case status was confirmed in medical records using natural language processing. DNA was obtained from stored, nonneoplastic, formalin fixed, paraffin embedded tissue blocks. Each pedigree had at least 2 cases with DNA available. Parametric linkage analysis was performed. Pedigrees ranged in size from 2 to 12 genotyped cases for a total of 48 cases. Significant genome wide linkage evidence was found under a dominant model on chromosome 3p13-p12.3 (maximum heterogeneity θ logarithm of odds 3.56). Two pedigrees showed at least nominal linkage evidence in this region (logarithm of odds greater than 0.59). The most informative pedigree included 12 interstitial cystitis/painful bladder syndrome cases (pedigree θ logarithm of odds 2.1). Other regions with suggestive linkage evidence included 1p21-q25, 3p21.1-p14.3, 4q12-q13, 9p24-p22 and 14q24-q31, all under a dominant model. While the etiology of interstitial cystitis/painful bladder syndrome is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 and possibly on chromosomes 1, 4, 9 and 14 contribute to an interstitial cystitis/painful bladder syndrome predisposition. Sequence analysis of affected cases in identified pedigrees may provide insight into genes contributing to interstitial cystitis/painful bladder syndrome.
autonomic (sympathetic) dysregulation as well as a role for central augmentation. In this regard,... more autonomic (sympathetic) dysregulation as well as a role for central augmentation. In this regard, activation of spinal cord (SC) glial cells can increase excitability of neurons leading to the initiation and maintenance of bladder hyperalgesia and impaired bladder storage function (urgency, frequency). Our goal was to examine whether chronic stress (using the water avoidance stress or WAS model) can alter neural-glial distribution and chemistry, which may play a role in micturition and pain behavior. METHODS: Adult female Wistar-Kyoto rats were exposed to WAS by placement on a pedestal in a water-filled container (1hr/day x10 consecutive days) versus handled controls. Previous published findings have revealed WAS rats exhibit long-lasting urinary frequency and hyperalgesia. SC (L6) were harvested from anesthetized animals, and either cryosectioned (for immunocytochemistry) or homogenized (for RT-PCR). The following were investigated: calcitonin gene-related peptide (CGRP; sensory fibers), microglia (IBA-1), Toll-like receptor (TLR-4), purinergic receptor subtypes (P2X4, P2X7). Separate groups of both WAS and control animals were treated 2 days prior then every other day with the adrenergic antagonist phenoxybenzamine (PB; 2 mg/ kg i.p.) or saline, respectively. RESULTS: WAS increased neural CGRP (40%) and IBA-1 (2 fold) expression in the L6 SC dorsal horn and central canal (regions receiving input from nociceptive fibers). We find PB reduced CGRP expression (92% decrease) as well as IBA-1 in WAS SC. Further, both TLR-4 as well as P2X4 and P2X7 purinergic receptor are increased (50%) in WAS, suggesting microglia activation with chronic stress. CONCLUSIONS: Taken together, our findings suggest increased communication between the sympathetic nervous system and bladder sensory neurons that may play an important role in chronic pain conditions. This includes abnormal neural sprouting and altered morphology and chemistry of SC glial cells, which are likely to play an important role in modifying neural activity resulting in changes in bladder function and sensory mechanisms.
Pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress and urgency urinary ... more Pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress and urgency urinary incontinence, and faecal incontinence, are common and arise from loss of pelvic support. Although severe disease often does not occur until women become older, pregnancy and childbirth are major risk factors for PFDs, especially POP. We understand little about modifiable factors that impact pelvic floor function recovery after vaginal birth. This National Institutes of Health (NIH)-funded Program Project, 'Bridging physical and cultural determinants of postpartum pelvic floor support and symptoms following vaginal delivery', uses mixed-methods research to study the influences of intra-abdominal pressure, physical activity, body habitus and muscle fitness on pelvic floor support and symptoms as well as the cultural context in which women experience those changes. Using quantitative methods, we will evaluate whether pelvic floor support and symptoms 1 year after the first vaginal d...
American journal of obstetrics and gynecology, Jan 3, 2016
Female urinary microbiota are associated with urgency urinary incontinence and response to medica... more Female urinary microbiota are associated with urgency urinary incontinence and response to medication. The urinary microbiota of women with stress urinary incontinence has not been described. Study the cross-sectional relationships between urinary microbiota features and demographic and clinical characteristics of women undergoing stress urinary incontinence surgery. Pre-operative urine specimens were collected from women without urinary tract infection and were available from 197 women (174 voided, 23 catheterized) enrolled in a multi-center prospective randomized trial, the Value of Urodynamic Evaluation study. Demographic and clinical variables were obtained including stress urinary incontinence and urgency urinary incontinence symptoms, menopausal status, and hormone use. The bacterial composition of the urine was qualitatively assessed by sequencing the bacterial 16S ribosomal RNA gene. Phylogenetic relatedness and microbial alpha diversity were compared to demographics and sym...
1. We excluded 2199 women from the cost analysis as not meeting inclusion criteria, but an additi... more 1. We excluded 2199 women from the cost analysis as not meeting inclusion criteria, but an additional 509 subjects were excluded for study reasons (e.g., could not or did not want to participate). We argue that in a cost study, such subjects should not be considered as complicated patients who would have benefited from UDS. 2. The investigators are all at tertiary care centers in the U.S. who see a disproportionate share of complicated patients. Our estimate that 50% of women would qualify for the ‘‘uncomplicated’’ descriptor is probably an underestimate (i.e., the majority of women are likely to be uncomplicated). 3. In an effort to make the study generalizable to different patient populations, table 2 is a sensitivity analysis that assumes a range from 10% complicated patients to 90% complicated patients, so this addresses the concerns no matter what percentage is assumed.
Vaginal Surgery for Incontinence and Prolapse, 2006
After pelvic organ prolapse repair, nearly 30% of women undergo additional surgical intervention ... more After pelvic organ prolapse repair, nearly 30% of women undergo additional surgical intervention for prolapse recurrence (1). Despite this fact, there are few published reports specifically examining prolapse recurrence and its optimal surgical management. Furthermore, the definition of a surgical failure is not always clear, as there are cases in which organ dysfunction may persist, despite a technically sound outcome,
1. University of Texas Health Science Center San Antonio, Texas, 2. University of Texas Southwest... more 1. University of Texas Health Science Center San Antonio, Texas, 2. University of Texas Southwestern, Dallas TX, 3. University of Maryland, Baltimore MD, 4. William Beaumont Hospital, Royal Oak, MI, 5. University of Alabama, Birmingham AL, 6. University of Utah School of Medicine, Salt Lake City, UT, 7. Loyola Medical Center, Maywood IL, 8. University of California San Diego Medical Center/Kaiser Permanente, San Diego CA, 9. University of Pittsburgh, Pittsburgh PA, 10. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 11. New England Research Institutes, Watertown MA
Hypothesis / aims of study It has been established by us and others that genetic factors contribu... more Hypothesis / aims of study It has been established by us and others that genetic factors contribute to the risk of pelvic organ prolapse (POP). Our original POP Genetic Resource focused on identifying siblings, who in most cases were treated surgically. Our Genetic Resource has been expanded to include larger extended pedigrees with elevated risk of POP; some of the cases in these pedigrees may not have received treatment for POP. The objective of this study is to present genome-wide linkage results for pedigrees with women who report at least bothersome symptoms of POP. Compared to our original linkage report of strictly defined POP cases based on surgical treatment, we hypothesized that this more moderate definition of POP might increase power to detect additional linkage regions of interest.
Hypothesis / aims of study Pelvic floor disorders (PFDs) include a variety of continence and orga... more Hypothesis / aims of study Pelvic floor disorders (PFDs) include a variety of continence and organ laxity defects; many women with PFDs have more than one defect. Understanding the clustering of PFDs within families is important because it may suggest underlying risk factors that may be environmental, genetic or both. The aim of this study was to describe clusters of familial cases with PFDs as well as clinical characteristics of familial cases.
Uterosacral ligament suspension (ULS) and sacrospinous ligament fixation (SSLF) are commonly perf... more Uterosacral ligament suspension (ULS) and sacrospinous ligament fixation (SSLF) are commonly performed pelvic organ prolapse procedures despite a lack of long-term efficacy data. To compare outcomes in women randomized to (1) ULS or SSLF and (2) usual care or perioperative behavioral therapy and pelvic floor muscle training (BPMT) for vaginal apical prolapse. This 2 × 2 factorial randomized clinical trial was conducted at 9 US medical centers. Eligible participants who completed the Operations and Pelvic Muscle Training in the Management of Apical Support Loss Trial enrolled between January 2008 and March 2011 and were followed up 5 years after their index surgery from April 2011 through June 2016. Two randomizations: (1) BPMT (n = 186) or usual care (n = 188) and (2) surgical intervention (ULS: n = 188 or SSLF: n = 186). The primary surgical outcome was time to surgical failure. Surgical failure was defined as (1) apical descent greater than one-third of total vaginal length or ant...
Female pelvic medicine & reconstructive surgery, Jan 11, 2017
The aim of the study was to compare anterior and overall prolapse prevalence at 1 year in surgica... more The aim of the study was to compare anterior and overall prolapse prevalence at 1 year in surgical participants with or without concomitant anterior repair (AR) at the time of sacrospinous ligament fixation (SSLF) or uterosacral ligament suspension (ULS). This is a secondary analysis of two surgical trials; concomitant AR was performed at surgeon's discretion. Anterior anatomic success was defined as pelvic organ prolapse quantification of prolapse point Ba ≤0 and overall success was defined as pelvic organ prolapse quantification points Ba, Bp, and C ≤0 at 12 months. Sixty-three percent (441/701) of the participants underwent concomitant AR and were older, more often postmenopausal, had previous hysterectomy, and had higher-stage anterior, but not apical prolapse. Anterior anatomic success was marginally but statistically better in the combined group (SSLF and ULS) with concomitant AR (82% vs 80%, P = 0.03). In subanalyses, the improvement in anatomic support with AR was observ...
Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etio... more Interstitial cystitis/painful bladder syndrome is a chronic pelvic pain condition of unknown etiology. We hypothesized that related interstitial cystitis/painful bladder syndrome cases were more likely to have a genetic etiology. The purpose of this study was to perform a genetic linkage analysis. We identified interstitial cystitis/painful bladder syndrome cases using diagnostic codes linked to the Utah Population Database genealogy resource and to electronic medical records. For this analysis we used 13 high risk pedigrees, defined as having a statistical excess number of interstitial cystitis/painful bladder syndrome cases among descendants compared to matched hospital population rates. Case status was confirmed in medical records using natural language processing. DNA was obtained from stored, nonneoplastic, formalin fixed, paraffin embedded tissue blocks. Each pedigree had at least 2 cases with DNA available. Parametric linkage analysis was performed. Pedigrees ranged in size from 2 to 12 genotyped cases for a total of 48 cases. Significant genome wide linkage evidence was found under a dominant model on chromosome 3p13-p12.3 (maximum heterogeneity θ logarithm of odds 3.56). Two pedigrees showed at least nominal linkage evidence in this region (logarithm of odds greater than 0.59). The most informative pedigree included 12 interstitial cystitis/painful bladder syndrome cases (pedigree θ logarithm of odds 2.1). Other regions with suggestive linkage evidence included 1p21-q25, 3p21.1-p14.3, 4q12-q13, 9p24-p22 and 14q24-q31, all under a dominant model. While the etiology of interstitial cystitis/painful bladder syndrome is unknown, this study provides evidence that a genetic variant(s) on chromosome 3 and possibly on chromosomes 1, 4, 9 and 14 contribute to an interstitial cystitis/painful bladder syndrome predisposition. Sequence analysis of affected cases in identified pedigrees may provide insight into genes contributing to interstitial cystitis/painful bladder syndrome.
autonomic (sympathetic) dysregulation as well as a role for central augmentation. In this regard,... more autonomic (sympathetic) dysregulation as well as a role for central augmentation. In this regard, activation of spinal cord (SC) glial cells can increase excitability of neurons leading to the initiation and maintenance of bladder hyperalgesia and impaired bladder storage function (urgency, frequency). Our goal was to examine whether chronic stress (using the water avoidance stress or WAS model) can alter neural-glial distribution and chemistry, which may play a role in micturition and pain behavior. METHODS: Adult female Wistar-Kyoto rats were exposed to WAS by placement on a pedestal in a water-filled container (1hr/day x10 consecutive days) versus handled controls. Previous published findings have revealed WAS rats exhibit long-lasting urinary frequency and hyperalgesia. SC (L6) were harvested from anesthetized animals, and either cryosectioned (for immunocytochemistry) or homogenized (for RT-PCR). The following were investigated: calcitonin gene-related peptide (CGRP; sensory fibers), microglia (IBA-1), Toll-like receptor (TLR-4), purinergic receptor subtypes (P2X4, P2X7). Separate groups of both WAS and control animals were treated 2 days prior then every other day with the adrenergic antagonist phenoxybenzamine (PB; 2 mg/ kg i.p.) or saline, respectively. RESULTS: WAS increased neural CGRP (40%) and IBA-1 (2 fold) expression in the L6 SC dorsal horn and central canal (regions receiving input from nociceptive fibers). We find PB reduced CGRP expression (92% decrease) as well as IBA-1 in WAS SC. Further, both TLR-4 as well as P2X4 and P2X7 purinergic receptor are increased (50%) in WAS, suggesting microglia activation with chronic stress. CONCLUSIONS: Taken together, our findings suggest increased communication between the sympathetic nervous system and bladder sensory neurons that may play an important role in chronic pain conditions. This includes abnormal neural sprouting and altered morphology and chemistry of SC glial cells, which are likely to play an important role in modifying neural activity resulting in changes in bladder function and sensory mechanisms.
Pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress and urgency urinary ... more Pelvic floor disorders (PFDs), including pelvic organ prolapse (POP), stress and urgency urinary incontinence, and faecal incontinence, are common and arise from loss of pelvic support. Although severe disease often does not occur until women become older, pregnancy and childbirth are major risk factors for PFDs, especially POP. We understand little about modifiable factors that impact pelvic floor function recovery after vaginal birth. This National Institutes of Health (NIH)-funded Program Project, 'Bridging physical and cultural determinants of postpartum pelvic floor support and symptoms following vaginal delivery', uses mixed-methods research to study the influences of intra-abdominal pressure, physical activity, body habitus and muscle fitness on pelvic floor support and symptoms as well as the cultural context in which women experience those changes. Using quantitative methods, we will evaluate whether pelvic floor support and symptoms 1 year after the first vaginal d...
American journal of obstetrics and gynecology, Jan 3, 2016
Female urinary microbiota are associated with urgency urinary incontinence and response to medica... more Female urinary microbiota are associated with urgency urinary incontinence and response to medication. The urinary microbiota of women with stress urinary incontinence has not been described. Study the cross-sectional relationships between urinary microbiota features and demographic and clinical characteristics of women undergoing stress urinary incontinence surgery. Pre-operative urine specimens were collected from women without urinary tract infection and were available from 197 women (174 voided, 23 catheterized) enrolled in a multi-center prospective randomized trial, the Value of Urodynamic Evaluation study. Demographic and clinical variables were obtained including stress urinary incontinence and urgency urinary incontinence symptoms, menopausal status, and hormone use. The bacterial composition of the urine was qualitatively assessed by sequencing the bacterial 16S ribosomal RNA gene. Phylogenetic relatedness and microbial alpha diversity were compared to demographics and sym...
1. We excluded 2199 women from the cost analysis as not meeting inclusion criteria, but an additi... more 1. We excluded 2199 women from the cost analysis as not meeting inclusion criteria, but an additional 509 subjects were excluded for study reasons (e.g., could not or did not want to participate). We argue that in a cost study, such subjects should not be considered as complicated patients who would have benefited from UDS. 2. The investigators are all at tertiary care centers in the U.S. who see a disproportionate share of complicated patients. Our estimate that 50% of women would qualify for the ‘‘uncomplicated’’ descriptor is probably an underestimate (i.e., the majority of women are likely to be uncomplicated). 3. In an effort to make the study generalizable to different patient populations, table 2 is a sensitivity analysis that assumes a range from 10% complicated patients to 90% complicated patients, so this addresses the concerns no matter what percentage is assumed.
Vaginal Surgery for Incontinence and Prolapse, 2006
After pelvic organ prolapse repair, nearly 30% of women undergo additional surgical intervention ... more After pelvic organ prolapse repair, nearly 30% of women undergo additional surgical intervention for prolapse recurrence (1). Despite this fact, there are few published reports specifically examining prolapse recurrence and its optimal surgical management. Furthermore, the definition of a surgical failure is not always clear, as there are cases in which organ dysfunction may persist, despite a technically sound outcome,
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