Publications by authors named "Jonathan Shepherd"

182 Publications

Baseline Characteristics, Evaluation, and Management of Women With Complaints of Recurrent Urinary Tract Infections.

Female Pelvic Med Reconstr Surg 2021 May;27(5):275-280

Trinity Health of New England, Hartford, CT.

Objective: The aims of this study were to determine the proportion of women presenting for recurrent urinary tract infections (UTIs) who met the diagnostic criteria (culture-proven UTI ≥3 in 1 year or ≥2 in 6 months) and to assess advanced testing utilization, preventive therapy use, and risk factors.

Methods: This is a retrospective chart review of women seen as new urogynecology consults for recurrent UTI (rUTI) between April 1, 2017, and April 1, 2018, followed through April 1, 2019. Exclusion criteria included catheter use, cancer treatment within 2 years, and prior organ transplant, urinary diversion, conduit, or bladder augmentation.

Results: Of 600 women, 71% had follow-up with a median of 179 days. Urinary tract infection symptoms included frequency (50%), dysuria (46%), urgency (43%), and malodorous urine (7%). One third met the rUTI diagnostic criteria. Two hundred thirty-four (39%) underwent advanced testing, and 9% (21/234) of women who underwent advanced testing had a change in clinical care. Preventive therapy use increased after consultation (P < 0.001), with vaginal estrogen (47%) being most common. Compared with women not meeting the rUTI criteria, women meeting the rUTI criteria were more likely to be older (adjusted odds ratio [aOR], 1.03/year; 95% confidence interval [CI], 1.02-1.04), have a prior history of gynecologic cancer (aOR, 4.07; 95% CI, 1.02-16.25), or report UTI symptoms of dysuria (aOR, 2.27; 95% CI, 1.57-3.27), or malodorous urine (aOR, 2.96; 95% CI, 1.47-5.94) and, while equally likely to be receiving preventive treatment prior to consultation, were more likely after consultation (OR, 3.06; 95% CI, 2.05-4.55).

Discussion: Thirty-seven percent of women seen for rUTI met the diagnostic criteria. Advanced imaging rarely changed care. Education about diagnostic criteria and preventive therapy is warranted.
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http://dx.doi.org/10.1097/SPV.0000000000001065DOI Listing
May 2021

Alcohol affordability: implications for alcohol price policies. A cross-sectional analysis in middle and older adults from UK Biobank.

J Public Health (Oxf) 2021 Apr 9. Epub 2021 Apr 9.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.

Background: Increasing the price of alcohol reduces alcohol consumption and harm. The role of food complementarity, transaction costs and inflation on alcohol demand are determined and discussed in relation to alcohol price policies.

Methods: UK Biobank (N = 502,628) was linked by region to retail price quotes for the years 2007 to 2010. The log residual food and alcohol prices, and alcohol availability were regressed onto log daily alcohol consumption. Model standard errors were adjusted for clustering by region.

Results: Associations with alcohol consumption were found for alcohol price (β = -0.56, 95% CI, -0.92 to -0.20) and availability (β = 0.06, 95% CI, 0.04 to 0.07). Introducing, food price reduced the alcohol price consumption association (β = -0.26, 95% CI, -0.50 to -0.03). Alcohol (B = 0.001, 95% CI, 0.0004 to 0.001) and food (B = 0.001, 95% CI, 0.0005 to 0.0006) price increased with time and were associated (ρ = 0.57, P < 0.001).

Conclusion: Alcohol and food are complements, and the price elasticity of alcohol reduces when the effect of food price is accounted for. Transaction costs did not affect the alcohol price consumption relationship. Fixed alcohol price policies are susceptible to inflation.
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http://dx.doi.org/10.1093/pubmed/fdab095DOI Listing
April 2021

Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer.

Breast Cancer Res Treat 2021 Mar 26. Epub 2021 Mar 26.

Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.

Purpose: The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). We strove to understand the biological, genomic, and clinical characteristics associated with SP142 PD-L1 positivity in TNBC patients.

Methods: Using 149 TNBC formalin-fixed paraffin-embedded tumor samples, tissue microarray (TMA) and gene expression microarrays were performed in parallel. The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides. We next generated a gene signature reflective of SP142 status and evaluated signature distribution according to TNBCtype and PAM50 subtypes. A SP142 gene expression signature was identified and was biologically and clinically evaluated on the TNBCs of TCGA, other cohorts, and on other malignancies treated with immune checkpoint inhibitors (ICI).

Results: Using SP142, 28.9% of samples were PD-L1 protein positive. The SP142 PD-L1-positive TNBC had higher CD8+ T cell percentage, stromal tumor-infiltrating lymphocyte levels, and higher rate of the immunomodulatory TNBCtype compared to PD-L1-negative samples. The recurrence-free survival was prolonged in PD-L1-positive TNBC. The SP142-guided gene expression signature consisted of 94 immune-related genes. The SP142 signature was associated with a higher pathologic complete response rate and better survival in multiple TNBC cohorts. In the TNBC of TCGA, this signature was correlated with lymphocyte-infiltrating signature scores, but not with tumor mutational burden or total neoantigen count. In other malignancies treated with ICIs, the SP142 genomic signature was associated with improved response and survival.

Conclusions: We provide multi-faceted evidence that SP142 PDL1-positive TNBC have immuno-genomic features characterized as highly lymphocyte-infiltrated and a relatively favorable survival.
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http://dx.doi.org/10.1007/s10549-021-06193-9DOI Listing
March 2021

Assessing pelvic organ prolapse recurrence after minimally invasive sacrocolpopexy: does mesh weight matter?

Int Urogynecol J 2021 Feb 26. Epub 2021 Feb 26.

Urogynecology and Pelvic Floor Reconstructive Surgery, Magee-Womens Hospital of UPMC, University of Pittsburgh School of Medicine, 300 Halket Street, PA, 15213, Pittsburgh, USA.

Introduction And Hypothesis: There has been a trend toward the use of ultra-lightweight mesh types for minimally invasive sacrocolpopexy. We hypothesized that ultra-lightweight mesh would have a greater proportion of composite anatomical pelvic organ prolapse recurrence than lightweight mesh.

Methods: Retrospective cohort study of minimally invasive sacrocolpopexies at two academic institutions from 2009 to 2016. Our primary outcome was composite anatomical prolapse recurrence, defined as prolapse beyond the hymen or retreatment with pessary or surgery, compared between ultra-lightweight (≤21 g/m [range 19-21]) and lightweight (>21 g/m [range 35-50]) mesh types. We assessed time to prolapse recurrence using Kaplan-Meier and Cox regression.

Results: The cohort consisted of 1,272 laparoscopic (n = 530, 41.7%) and robotic-assisted sacrocolpopexies (n = 742, 58.4%). Lightweight mesh was used in 745 procedures (58.6%) and ultra-lightweight mesh in 527 (41.4%). The lightweight mesh had longer median follow-up than the ultra-lightweight group (344 [IQR 50-670] vs 143 days [IQR 44-379], p < 0.01). There was no difference in composite anatomical prolapse recurrence between lightweight and ultra-lightweight mesh (54 [7.2%] vs 35 [6.6%], p = 0.68). Ultra-lightweight mesh demonstrated a shorter time to prolapse recurrence (p < 0.01), which remained significant on multivariate Cox regression (HR 2.38 [95% CI 1.47-3.87]). The lightweight mesh had significantly more mesh complications (43 [5.8%] vs 7 [1.3%], p < 0.01).

Conclusions: Ultra-lightweight mesh for minimally invasive sacrocolpopexy was not associated with a higher proportion of composite anatomical prolapse recurrence; however, it was associated with a shorter time to recurrence. Longer follow-up is needed to assess the clinical importance of this finding, particularly given the trade-off of more complications with lightweight mesh.
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http://dx.doi.org/10.1007/s00192-021-04681-6DOI Listing
February 2021

The Risk of Primary Uterine and Cervical Cancer After Hysteropexy.

Female Pelvic Med Reconstr Surg 2021 Mar;27(3):e493-e496

From the University of Missouri Kansas City School of Medicine, Kansas City, MO.

Objective: The aim of the study was to determine the rate of subsequent uterine/cervical cancer after hysteropexy compared with hysterectomy with apical prolapse repair.

Methods: The study used a retrospective cohort of women with uterovaginal prolapse using the Cerner Health Facts database between 2010 and 2018. We identified sacrospinous or uterosacral ligament suspensions or sacral colpopexy/hysteropexy and excluded those with previous hysterectomy. We used the International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes for endometrial cancer/hyperplasia and cervical cancer and then reviewed each case, excluding those whose cancer existed at time of prolapse repair. Given that 0 cancer cases were identified, we used Wilson, Jeffreys, Agresti-Coull, Clopper-Pearson, and Rule of 3 to define 95% confidence intervals to estimate the highest possible rate of cancer in each cohort.

Results: A total of 8,927 patients underwent apical prolapse surgery. Of 4,510 with uterovaginal prolapse, 755 (16.7%) underwent hysteropexy. Seventy one with hysterectomy and 5 with hysteropexy had codes for subsequent gynecologic cancer but were excluded on further review. This left 0 gynecologic cancer cases with the largest 95% confidence interval of 0%-0.61% for hysteropexy versus 0%-0.13% for hysterectomy (P > 0.05). The hysteropexy cohort was older (62.6 years vs 57.3 years, P < 0.0001), more likely to have public insurance (51.0% vs 37.9%, P < 0.0001), and less likely to smoke (4.5% vs 7.6%, P = 0.0026). Median follow-up was longer after hysteropexy (1,480 days vs 1,164 days, P < 0.0009).

Conclusions: We can say with 95% certainty that uterine or cervical cancer will develop after hysteropexy in fewer than 0.61% of women, which was not different if hysterectomy was performed. This should be included in preoperative counseling for hysteropexy. Studying longer follow-up after hysteropexy may capture more cases of subsequent cancer development.
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http://dx.doi.org/10.1097/SPV.0000000000001030DOI Listing
March 2021

Optimizing public services after COVID.

Nature 2021 01;589(7840):19

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http://dx.doi.org/10.1038/d41586-020-03644-zDOI Listing
January 2021

Developing an Advanced Alternative Payment Model for Stress Urinary Incontinence.

Female Pelvic Med Reconstr Surg 2021 Apr;27(4):217-222

Obstetrics and Gynecology, Vanderbilt University, Nashville, TN.

Abstract: Historically, our health care system has been based on a fee-for-service model, which has resulted in high-cost and fragmented care. The Center for Medicare & Medicaid Services is moving toward a paradigm in which health care providers are incentivized to provide cost-effective, coordinated, value-based care in an effort to control costs and ensure high-quality care for all patients. In 2015, the Medicare Access and Children's Health Insurance Program Reauthorization Act repealed the Sustainable Growth Rate and the fee-for-service model, replacing them with a 2-track system: Merit-based Incentive Payment System and the advanced Alternative Payment Model (aAPM) system. In 2016, the American Urogynecologic Society Payment Reform Committee was created and tasked with developing aAPMs for pelvic floor disorders. The purpose of this article is to describe the stress urinary incontinence aAPM framework, the data selected and associated data plan, and some of the challenges considered and encountered during the aAPM development.
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http://dx.doi.org/10.1097/SPV.0000000000000997DOI Listing
April 2021

A Blueprint for Creating Mentored, Collaborative Networks for Early-Career Physician-Scientists.

Female Pelvic Med Reconstr Surg 2021 Jan;27(1):5-8

Duke University, Durham, NC.

Objectives: The objective is to improve the high-quality collaborative research of early-career investigators, the American Urogynecologic Society/Pelvic Floor Disorders Foundation funded and developed the Junior Faculty Research Network (JFRN). The purpose of this report is to describe the process of development of the network, discuss barriers, acknowledge accomplishments, and provide a framework for future collaborations.

Methods: The development of the JFRN provided sponsorship and mentorship, supported collaboration, and created a network structure for early-career investigators. A request for applications was circulated, requiring a competitive submission process, and 6 physician-scientists were selected to participate in a multicenter trial whose initial focus was on the urinary microbiome and its interaction with sacral neuromodulation.

Results: The JFRN infrastructure consisted of early-career investigators, senior advisors, and research support staff. Study development and roll-out progressed over monthly conference calls. Initial barriers included the development of institutional participation agreements, logistics of funding disbursement, and coordination of support staff. In addition to the inaugural research project, the network continued to collaborate, and the initial grant provided pilot data for a National Institutes of Health-funded project.

Conclusions: The JFRN is a successful mentored collaborative of early-career investigators. The creation of this self-sustaining, independent research network may serve as a blueprint for other early-career physician-scientists to participate in productive multicenter research.
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http://dx.doi.org/10.1097/SPV.0000000000000994DOI Listing
January 2021

A Survey of Operative Techniques Used by Female Pelvic Medicine and Reconstructive Surgeons Performing Minimally Invasive Sacral Colpopexy.

Cureus 2020 Oct 13;12(10):e10931. Epub 2020 Oct 13.

Female Pelvic Medicine and Reconstructive Surgery, University of Connecticut School of Medicine, Hartford, USA.

Objective Assess variability of surgical technique for minimally invasive sacral colpopexy (MISC) among Female Pelvic Medicine and Reconstructive Surgery (FPMRS). Methods A voluntary anonymous questionnaire was given to the 2018 American Urogynecologic Society (AUGS) annual meeting attendees. Comparisons were made by age, gender, experience (years), practice setting, and U.S. region. Results There were 59 responses from 671 physician conference attendees. Most were male (64.4%), U.S. physicians (94.6%), completed Obstetrics and Gynecology residencies (91.5%), practicing in University settings (66.1%). The mean age was 47.4±8.6 years, practicing>15 years (47.5%). Predominant routes were 53.8% robotic, 42.2% laparoscopic, and 4.0% open. Surgeons used 3-4 ports (both 50.0%), with 0-degree (46.0%) or 0 and 30 degree laparoscopes (36%). For sacral mesh attachment, 83.1% used suture as opposed to tacking devices, most often Gortex (56.3%). Anterior (48.1%) and posterior (50.0%) vaginal attachment used 5-6 sutures. Concomitant procedures included anterior repair (83.4% "not usually"/"not at all"), posterior repair/perineorrhaphy (77.8% "yes, often"/"yes, sometimes"), midurethral sling (42.6% "yes, often"/51.9% "yes, sometimes"), and hysteropexy (86.5% "not usually"/"not at all"). Post void residual (PVR) was assessed after surgery by 89.8%, 75.5% via retrograde fill voiding trial. Most patients were discharged post-operative day 1 (POD1) (47.6% AM, 29.1% PM) or day of surgery (15.2%).  Females more commonly performed hysteropexy (p=0.028) with no other significant differences by age, gender, experience, practice setting or region.  Conclusion Most FPMRS surgeons perform MISC, equally robotic and laparoscopic. Concomitant posterior wall procedures and midurethral slings are common. Other than more hysteropexies performed by females, no other variables predicted technique variations, suggesting technique homogeneity.
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http://dx.doi.org/10.7759/cureus.10931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660122PMC
October 2020

Survival, Pathologic Response, and Genomics in CALGB 40601 (Alliance), a Neoadjuvant Phase III Trial of Paclitaxel-Trastuzumab With or Without Lapatinib in HER2-Positive Breast Cancer.

J Clin Oncol 2020 12 23;38(35):4184-4193. Epub 2020 Oct 23.

Lineberger Comprehensive Center, University of North Carolina, Chapel Hill, NC.

Purpose: CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) -targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival.

Patients And Methods: Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples.

Results: One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS.

Conclusion: In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.
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http://dx.doi.org/10.1200/JCO.20.01276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723687PMC
December 2020

Predicting postoperative day 1 hematocrit levels after hysterectomy for malignant indication: Validating a previously published model.

Int J Gynaecol Obstet 2021 Mar 17;152(3):416-420. Epub 2020 Nov 17.

Department of Obstetrics & Gynecology, Trinity Health of New England, Hartford, CT, USA.

Objective: To determine whether the Swenson model of postoperative day 1 (POD1) hematocrit after benign hysterectomy is applicable to gynecologic oncology hysterectomies.

Methods: Data were retrospectively collected from cases of hysterectomy with malignant pathology in Hartford, USA, from 2014 to 2016. Predicted POD1 hematocrit was compared with actual hematocrit. ROC curve analysis was used to determine the optimal cut-off point for predicting hematocrit levels of 30% or less.

Results: Among 107 women, mean age was 62.9 years and body mass index was 34.0. Most underwent robotic (44.9%) or abdominal (43.9%) hysterectomy. The published equation correctly predicted hematocrit to within ±5% for 83.2% of women, which was less accurate than observed in the original validation set. The equation was more likely to underestimate lower hematocrit levels, adding safety to its use. By ROC curve analysis, the best cut-off point for predicting actual hematocrit above 30% was predicted hematocrit 32.3% (100% specificity).

Conclusion: The Swenson equation predicted POD1 hematocrit less accurately in the current dataset. As a screening tool for hematocrit below 30%, however, ordering postoperative hematocrit is probably unnecessary if the predicted value is 32.3% or higher. This equation should be used as a screening tool to reduce unnecessary laboratory tests.
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http://dx.doi.org/10.1002/ijgo.13422DOI Listing
March 2021

Age and Perioperative Outcomes After Implementation of an Enhanced Recovery After Surgery Pathway in Women Undergoing Major Prolapse Repair Surgery.

Female Pelvic Med Reconstr Surg 2021 Feb;27(2):e392-e398

From the Department of Obstetrics, Gynecology and Reproductive Sciences of the University of Pittsburgh, Pittsburgh, PA.

Objective: As perioperative care pathways are developed to improve recovery, there is a need to explore the impact of age. The aim of this study was to compare the impact of a urogynecology-specific enhanced recovery after surgery (ERAS) pathway on perioperative outcomes across 3 age categories: young, middle age, and elderly.

Methods: A retrospective cohort study was conducted assessing same-day discharge, opioid administration, pain scores, and complications differences across and within 3 age categories, young (<61 years), middle age (61-75 years), elderly (>75 years), before and after ERAS implementation.

Results: Among 98 (25.7%) young, 202 (52.9%) middle-aged, and 82 (21.5%) elderly women, distribution before and after ERAS implementation was similar. In each age category, we found a commensurate increase in same-day discharge and decrease in length of stay independent of age. Age was associated with a variable response to opioid administration after ERAS. In women who received opioids, we found there was a greater reduction in opioids in elderly. Young women received 22.5 mg more than middle-aged women, whereas elderly women received 24.3 mg less than middle-aged women (P < 0.0001, P < 0.0001) for a mean difference of 46.8 mg between the youngest and oldest group. We found no significant differences in postanesthesia care unit pain scores with ERAS implementation. Complications did not increase after ERAS implementation in any age group, although younger and elderly women were more likely to experience complications independent of ERAS.

Conclusions: Elderly women had similar outcomes compared with their younger counterparts after implementation of an ERAS pathway. Further research is needed to assess whether our age-related observations are generalizable.
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http://dx.doi.org/10.1097/SPV.0000000000000944DOI Listing
February 2021

Stimulation of Oncogene-Specific Tumor-Infiltrating T Cells through Combined Vaccine and αPD-1 Enable Sustained Antitumor Responses against Established HER2 Breast Cancer.

Clin Cancer Res 2020 Sep 30;26(17):4670-4681. Epub 2020 Jul 30.

Department of Surgery, Division of Surgical Sciences, Duke University, Durham North Carolina.

Purpose: Despite promising advances in breast cancer immunotherapy, augmenting T-cell infiltration has remained a significant challenge. Although neither individual vaccines nor immune checkpoint blockade (ICB) have had broad success as monotherapies, we hypothesized that targeted vaccination against an oncogenic driver in combination with ICB could direct and enable antitumor immunity in advanced cancers.

Experimental Design: Our models of HER2 breast cancer exhibit molecular signatures that are reflective of advanced human HER2 breast cancer, with a small numbers of neoepitopes and elevated immunosuppressive markers. Using these, we vaccinated against the oncogenic HER2Δ16 isoform, a nondriver tumor-associated gene (GFP), and specific neoepitopes. We further tested the effect of vaccination or anti-PD-1, alone and in combination.

Results: We found that only vaccination targeting HER2Δ16, a driver of oncogenicity and HER2-therapeutic resistance, could elicit significant antitumor responses, while vaccines targeting a nondriver tumor-specific antigen or tumor neoepitopes did not. Vaccine-induced HER2-specific CD8 T cells were essential for responses, which were more effective early in tumor development. Long-term tumor control of advanced cancers occurred only when HER2Δ16 vaccination was combined with αPD-1. Single-cell RNA sequencing of tumor-infiltrating T cells revealed that while vaccination expanded CD8 T cells, only the combination of vaccine with αPD-1 induced functional gene expression signatures in those CD8 T cells. Furthermore, we show that expanded clones are HER2-reactive, conclusively demonstrating the efficacy of this vaccination strategy in targeting HER2.

Conclusions: Combining oncogenic driver targeted vaccines with selective ICB offers a rational paradigm for precision immunotherapy, which we are clinically evaluating in a phase II trial (NCT03632941).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483405PMC
September 2020

SOX9 Is Essential for Triple-Negative Breast Cancer Cell Survival and Metastasis.

Mol Cancer Res 2020 12 13;18(12):1825-1838. Epub 2020 Jul 13.

Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Triple-negative breast cancer (TNBC) has the worst prognosis of all breast cancers, and lacks effective targeted treatment strategies. Previously, we identified 33 transcription factors highly expressed in TNBC. Here, we focused on six sex determining region Y-related HMG-box (SOX) transcription factors (SOX4, 6, 8, 9, 10, and 11) highly expressed in TNBCs. Our siRNA screening assay demonstrated that SOX9 knockdown suppressed TNBC cell growth and invasion . Thus, we hypothesized that SOX9 is an important regulator of breast cancer survival and metastasis, and demonstrated that knockout of SOX9 reduced breast tumor growth and lung metastasis . In addition, we found that loss of SOX9 induced profound apoptosis, with only a slight impairment of G to S progression within the cell cycle, and that SOX9 directly regulates genes controlling apoptosis. On the basis of published CHIP-seq data, we demonstrated that SOX9 binds to the promoter of apoptosis-regulating genes (, and ), and represses their expression. SOX9 knockdown upregulates these genes, consistent with the induction of apoptosis. Analysis of available CHIP-seq data showed that SOX9 binds to the promoters of several epithelial-mesenchymal transition (EMT)- and metastasis-regulating genes. Using CHIP assays, we demonstrated that SOX9 directly binds the promoters of genes involved in EMT (, and ) and that SOX9 knockdown suppresses the expression of these genes. IMPLICATIONS: Our studies identified the SOX9 protein as a "master regulator" of breast cancer cell survival and metastasis, and provide preclinical rationale to develop SOX9 inhibitors for the treatment of women with metastatic triple-negative breast cancer.
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http://dx.doi.org/10.1158/1541-7786.MCR-19-0311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718423PMC
December 2020

Sacral Neuromodulation: Determining Predictors of Success.

Urology 2020 Jun 30. Epub 2020 Jun 30.

UPMC Magee Women's Hospital, Pittsburgh, PA. Electronic address:

Objective: To determine predictors of success for sacral neuromodulation in women with overactive bladder, urinary retention, and fecal incontinence.

Methods: A retrospective chart review was performed on women who underwent a staged sacral neuromodulation implantation between 2007 and 2018. Clinical and procedural characteristics were recorded. Presence of intraoperative motor responses in either all 4 or <4 electrodes were used to group women. Endpoints included completion of stage II implant, tined lead revision, and patient-reported success.

Results: In 198 women with a mean age of 62.9 years (SD+/- 14.7), completion of stage II implant occurred in 92.4% of women, and 83.3% of these women reported success at the first postoperative visit. Continued success at 6 months was reported in 70.3%. Lead revision was noted in 23.0%. Age >65 years (odds ratio [OR] = 0.2, 95% confidence interval [CI] = 0.06-0.8) and prior onabotulinumtoxinA (onaBoNT-A) (OR = 0.2, 95% CI = 0.06-0.9) were negative predictors for completion of stage II implant on multivariable analysis. Also, prior pelvic floor physical therapy was a significant negative predictor of postoperative patient-reported success on multivariable analysis (OR = 0.25, 95% CI = 0.1-0.6). There were no differences seen in women who had motor responses with either all 4 electrodes or <4 electrodes in any endpoint (P > .05).

Conclusion: Patient age >65 and history of prior onaBoNT-A were associated with failure to complete stage II implant. Women with prior pelvic floor physical therapy were less likely to report success after sacral neuromodulation. Motor responses in <4 electrodes during lead testing did not impact patient-reported success.
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http://dx.doi.org/10.1016/j.urology.2020.06.023DOI Listing
June 2020

Hysterectomy Versus Hysteropexy at the Time of Native Tissue Pelvic Organ Prolapse Repair: A Cost-Effectiveness Analysis.

Female Pelvic Med Reconstr Surg 2021 Feb;27(2):e277-e281

Providence Saint John's Health Center, Santa Monica, CA.

Objective: The aim of the study was to determine whether a hysterectomy at the time of native tissue pelvic organ prolapse repair is cost-effective for the prevention of endometrial cancer.

Methods: We created a decision analysis model using TreeAge Pro. We modeled prolapse recurrence after total vaginal hysterectomy with uterosacral ligament suspension (TVH-USLS) versus sacrospinous ligament fixation hysteropexy (SSLF-HPXY). We modeled incidence and diagnostic evaluation of postmenopausal bleeding, including risk of endometrial pathology and diagnosis or death from endometrial cancer. Modeled costs included those associated with the index procedure, subsequent prolapse repair, endometrial biopsy, pelvic ultrasound, hysteroscopy, dilation and curettage, and treatment of endometrial cancer.

Results: TVH-USLS costs US $587.61 more than SSLF-HPXY per case of prolapse. TVH-USLS prevents 1.1% of women from experiencing postmenopausal bleeding and its diagnostic workup. It prevents 0.95% of women from undergoing subsequent major surgery for the treatment of either prolapse recurrence or suspected endometrial cancer. Using our model, it costs US $2,698,677 to prevent one cancer death by performing TVH-USLS. As this is lower than the value of a statistical life, it is cost-effective to perform TVH-USLS for cancer prevention. Multiple 1-way sensitivity analyses showed that changes to input variables would not significantly change outcomes.

Conclusions: TVH-USLS increased costs but reduced postmenopausal bleeding and subsequent major surgery compared with SSLF-HPXY. Accounting for these differences, TVH-USLS was a cost-effective approach for the prevention of endometrial cancer. Uterine preservation/removal at the time of prolapse repair should be based on the woman's history and treatment priorities, but cancer prevention should be one aspect of this decision.
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http://dx.doi.org/10.1097/SPV.0000000000000902DOI Listing
February 2021

Systematic review: measurement properties of patient-reported outcome measures evaluated with childhood brain tumor survivors or other acquired brain injury.

Neurooncol Pract 2020 Jun 8;7(3):277-287. Epub 2019 Dec 8.

The Peninsula Childhood Disability Research Unit, University of Exeter, UK.

Background: Survivors of childhood brain tumors or other acquired brain injury (ABI) are at risk of poor health-related quality of life (HRQoL); its valid and reliable assessment is essential to evaluate the effect of their illness on their lives. The aim of this review was to critically appraise psychometric properties of patient-reported outcome measures (PROMs) of HRQoL for these children, to be able to make informed decisions about the most suitable PROM for use in clinical practice.

Methods: We searched MEDLINE, EMBASE, and PsycINFO for studies evaluating measurement properties of HRQoL PROMs in children treated for brain tumors or other ABI. Methodological quality of relevant studies was evaluated using the consensus-based standards for the selection of health status measurement instruments checklist.

Results: Eight papers reported measurement properties of 4 questionnaires: Health Utilities Index (HUI), PedsQL Core and Brain Tumor Modules, and Child and Family Follow-up Survey (CFFS). Only the CFFS had evidence of content and structural validity. It also demonstrated good internal consistency, whereas both PedsQL modules had conflicting evidence regarding this. Conflicting evidence regarding test-retest reliability was reported for the HUI and PedsQL Core Module only. Evidence of measurement error/precision was favorable for HUI and CFFS and absent for both PedsQL modules. All 4 PROMs had some evidence of construct validity/hypothesis testing but no evidence of responsiveness to change.

Conclusions: Valid and reliable assessment is essential to evaluate impact of ABI on young lives. However, measurement properties of PROMs evaluating HRQoL appropriate for this population require further evaluation, specifically construct validity, internal consistency, and responsiveness to change.
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http://dx.doi.org/10.1093/nop/npz064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274179PMC
June 2020

Digital tools for the recruitment and retention of participants in randomised controlled trials: a systematic map.

Trials 2020 Jun 5;21(1):478. Epub 2020 Jun 5.

Wessex Institute, Faculty of Medicine, University of Southampton, Alpha House, Southampton Science Park, Southampton, SO16 7NS, UK.

Background: Recruiting and retaining participants in randomised controlled trials (RCTs) is challenging. Digital tools, such as social media, data mining, email or text-messaging, could improve recruitment or retention, but an overview of this research area is lacking. We aimed to systematically map the characteristics of digital recruitment and retention tools for RCTs, and the features of the comparative studies that have evaluated the effectiveness of these tools during the past 10 years.

Methods: We searched Medline, Embase, other databases, the Internet, and relevant web sites in July 2018 to identify comparative studies of digital tools for recruiting and/or retaining participants in health RCTs. Two reviewers independently screened references against protocol-specified eligibility criteria. Included studies were coded by one reviewer with 20% checked by a second reviewer, using pre-defined keywords to describe characteristics of the studies, populations and digital tools evaluated.

Results: We identified 9163 potentially relevant references, of which 104 articles reporting 105 comparative studies were included in the systematic map. The number of published studies on digital tools has doubled in the past decade, but most studies evaluated digital tools for recruitment rather than retention. The key health areas investigated were health promotion, cancers, circulatory system diseases and mental health. Few studies focussed on minority or under-served populations, and most studies were observational. The most frequently-studied digital tools were social media, Internet sites, email and tv/radio for recruitment; and email and text-messaging for retention. One quarter of the studies measured efficiency (cost per recruited or retained participant) but few studies have evaluated people's attitudes towards the use of digital tools.

Conclusions: This systematic map highlights a number of evidence gaps and may help stakeholders to identify and prioritise further research needs. In particular, there is a need for rigorous research on the efficiency of the digital tools and their impact on RCT participants and investigators, perhaps as studies-within-a-trial (SWAT) research. There is also a need for research into how digital tools may improve participant retention in RCTs which is currently underrepresented relative to recruitment research.

Registration: Not registered; based on a pre-specified protocol, peer-reviewed by the project's Advisory Board.
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http://dx.doi.org/10.1186/s13063-020-04358-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273688PMC
June 2020

Risk Factors for Returning to the Operating Room for a Second Surgery After Midurethral Sling for Stress Urinary Incontinence.

Female Pelvic Med Reconstr Surg 2020 07;26(7):443-446

From the Department of Obstetrics and Gynecology, School of Medicine, University of Missouri Kansas City, Kansas City, MO.

Objectives: The objective of this study was to identify risk factors for having to return to the operating room for a second surgery after midurethral sling (MUS).

Methods: We used a case-control design. Cases return to operating room were a composite of 6 surgical complications or recurrent stress urinary incontinence because we believed that women would consider return to the operating room (OR) a similar MUS-related complication regardless of indication. Cases were obtained from Cerner Health Facts database, including 213 hospitals, using current procedural technology codes 57288 (repeat sling), 57287 (sling revision), and 53500 (urethrolysis) for procedures after index MUS. Controls no return to OR were randomly selected in 4:1 ratio from the remaining slings without these procedures. Multivariable regression analysis included all variables with P < 0.10 on univariable analysis.

Results: Between January 1, 2010, and December 31, 2016, 1247 patients returned to the OR of 17,953 patients who underwent initial MUS (6.9%). After adjusting for confounders, white race (OR, 1.47 [1.20-1.81]), lack of concomitant prolapse surgery (OR, 1.37 [1.18-1.59]), immunosuppressant drugs (OR, 1.27 [1.12-1.45]), and blood thinner use (OR, 1.38 [1.18-1.62]) significantly impacted the odds for returning to the OR. Anticholinergic use and smoking tobacco or marijuana, although significant on univariable analysis, were no longer significant after adjusting for confounders.

Conclusions: The rate of a second surgery after MUS using a composite outcome, over a 7-year period including multiple diagnoses, is 6.9%. White race, using immunosuppressant drugs, using blood thinners, and not having concomitant prolapse surgery are all risk factors for having second surgery after MUS.
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http://dx.doi.org/10.1097/SPV.0000000000000804DOI Listing
July 2020

Offender trajectories, health and hospital admissions: relationships and risk factors in the longitudinal Cambridge Study in Delinquent Development.

J R Soc Med 2020 03;113(3):110-118

Crime and Security Research Institute, Cardiff University, Cardiff CF10 3AT, UK.

Objectives: Research suggests that antisocial lifestyles constitute significant health risks. However, there are marked individual differences in the stability of antisocial behaviour. These different offending pathways may bear differential risks for adult health.

Design: Injury and illness data were collected prospectively in the longitudinal Cambridge Study in Delinquent Development.

Setting: Working-class inner-city area of South London.

Participants: Participants included the 411 men from the Cambridge Study in Delinquent Development, with interview data collected at ages 18, 32 and 48 years for each individual.

Main Outcome Measures: Organic illness, hospitalisation and injuries.

Results: By age 48, adjusted odds ratios showed that the incidence of organic illness was higher among Life-Course-Persistent, Late-Onset offenders and offenders in general. Based on adjusted odds ratios at age 32, the incidence of hospitalisations was higher for Late-Onset offenders. Adjusted odds ratios at age 48 also showed that the incidence of hospitalisations was higher for all three offender types and offenders in general. Our results also provide evidence that offenders were more likely to suffer injuries than non-offenders.

Conclusions: The findings of this study imply that preventing individuals from offending is likely to have substantial benefits for health.
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http://dx.doi.org/10.1177/0141076820905319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068765PMC
March 2020

The impact of prior prolapse repairs on surgical outcomes with minimally invasive sacral colpopexy.

Int Urogynecol J 2020 10 4;31(10):2061-2067. Epub 2020 Mar 4.

Trinity Health of New England, Hartford, CT, USA.

Introduction And Hypothesis: To determine whether prior prolapse repair has an impact on operative time, surgical complications, and prolapse recurrence with minimally invasive sacral colpopexy (MISC).

Methods: This was a retrospective study of all laparoscopic and robotic MISC procedures performed from January 2009 to July 2014 at the University of Pittsburgh Medical Center. Patient demographics, clinical and surgical data were compared in women who underwent MISC for initial repair versus those undergoing MISC for recurrence after prior prolapse surgery. Our primary outcome was operating room (OR) time (skin incision to closure) using linear regression. Logistic regression compared complications (a composite variable considered present if any major complication occurred) and prolapse recurrence (any POP-Q point ≥0 or retreatment).

Results: Of 816 subjects, the mean age was 59.6 ± 8.7, with mean BMI 27.0 ± 3.0 in a primarily Caucasian population (97.8%). Subjects had predominantly POP-Q stage III prolapse (69.9%), and 21.3% reported prior prolapse repair. OR time was 205.0 ± 69.0 min. Prior prolapse repair did not impact OR time (p = 0.25) after adjusting for age, concomitant procedures, POP-Q measurements, changes in OR personnel, case order in the day, and preoperative stress incontinence. Complications occurred in 15.8% but were not impacted by prior prolapse repair (OR = 0.94, 95% CI = 0.53-1.67) after adjusting for potential confounders. During a median follow-up of 31 weeks, 7.8% had recurrence with no impact from prior prolapse surgery (OR = 1.557, 95% CI = 0.67-3.64) after adjusting for potential confounders.

Conclusions: We were unable to demonstrate increased OR time, complications, or prolapse recurrence for MISC based on history of prior prolapse repair. Longer follow-up is needed to confirm the lack of difference in prolapse recurrence rates.
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http://dx.doi.org/10.1007/s00192-020-04256-xDOI Listing
October 2020

Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1.

NPJ Breast Cancer 2020 3;6. Epub 2020 Jan 3.

1Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas USA.

Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer, and is associated with a poor prognosis due to frequent distant metastasis and lack of effective targeted therapies. Previously, we identified maternal embryonic leucine zipper kinase (MELK) to be highly expressed in TNBCs as compared with ER-positive breast cancers. Here we determined the molecular mechanism by which MELK is overexpressed in TNBCs. Analysis of publicly available data sets revealed that MELK mRNA is elevated in p53-mutant breast cancers. Consistent with this observation, MELK protein levels are higher in p53-mutant vs. p53 wild-type breast cancer cells. Furthermore, inactivation of wild-type p53, by loss or mutation of the p53 gene, increases MELK expression, whereas overexpression of wild-type p53 in p53-null cells reduces MELK promoter activity and MELK expression. We further analyzed MELK expression in breast cancer data sets and compared that with known wild-type p53 target genes. This analysis revealed that MELK expression strongly correlates with genes known to be suppressed by wild-type p53. Promoter deletion studies identified a p53-responsive region within the MELK promoter that did not map to the p53 consensus response elements, but to a region containing a FOXM1-binding site. Consistent with this result, knockdown of FOXM1 reduced MELK expression in p53-mutant TNBC cells and expression of wild-type p53 reduced FOXM1 expression. ChIP assays demonstrated that expression of wild-type p53 reduces binding of E2F1 (a critical transcription factor controlling FOXM1 expression) to the FOXM1 promoter, thereby, reducing FOXM1 expression. These results show that wild-type p53 suppresses FOXM1 expression, and thus MELK expression, through indirect mechanisms. Overall, these studies demonstrate that wild-type p53 represses MELK expression by inhibiting E2F1A-dependent transcription of FOXM1 and that mutation-driven loss of wild-type p53, which frequently occurs in TNBCs, induces MELK expression by suppressing FOXM1 expression and activity in p53-mutant breast cancers.
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http://dx.doi.org/10.1038/s41523-019-0143-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941974PMC
January 2020

Evidence for behavioural interventions addressing condom use fit and feel issues to improve condom use: a systematic review.

Sex Health 2019 11;16(6):539-547

Centre for Sexual Health Research, Department of Psychology, Faculty of Environmental and Life Sciences, Shackleton Building (B44) Room 3073, University of Southampton, Southampton, Hampshire SO17 1BJ, UK.

Continuing high rates of sexually transmissible infections (STIs) in many countries highlight the need to identify effective behavioural interventions. Consistent and correct use of male condoms is a key strategy for the prevention of STIs. However, some men report problems with condom fit (e.g. the size and shape of the condom) and feel (e.g. tightness, irritation, sensitivity), which inhibits their use. We conducted a systematic review to identify existing interventions addressing condom use fit and feel problems. We searched electronic databases for peer-reviewed articles and searched reference lists of retrieved studies. Five studies met the inclusion criteria. These were generally small-scale pilot studies evaluating behavioural interventions to promote safer sex with men aged under 30 years, addressing, among other things, barriers to condom use relating to fit and feel. There were significant increases in the reported use of condoms, including condom use with no errors and problems. Improvements in some condom use mediators were reported, such as condom use self-efficacy, knowledge, intentions and condom use experience. There were mixed findings in terms of the ability of interventions to reduce STI acquisition. Behavioural interventions addressing condom fit and feel are promising in terms of effectiveness but require further evaluation.
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http://dx.doi.org/10.1071/SH19001DOI Listing
November 2019

Violence in England and Wales: does media reporting match the data?

BMJ 2019 Oct 29;367:l6040. Epub 2019 Oct 29.

Crime and Security Research Institute, Cardiff University, Cardiff, UK.

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http://dx.doi.org/10.1136/bmj.l6040DOI Listing
October 2019

Improving fetal congenital heart disease screening using a checklist-based approach.

Prenat Diagn 2020 01 9;40(2):223-231. Epub 2019 Dec 9.

Department of Obstetrics and Gynecology, Saint Francis Hospital and Medical Center/Trinity Health of New England, Hartford, Connecticut.

To determine if using a checklist of specific ultrasound image criteria to screen the fetal heart improves the cardiac exam completion rate, defined as the ability to classify the heart as normal or abnormal. This is a retrospective cohort study of patients with singleton pregnancies who underwent a fetal anatomy survey between 18 and 28 weeks' gestation. A checklist was used from 1 September 2015 to 31 March 2016 to categorize exams as complete-normal, complete-abnormal, or incomplete. Performance was compared with a 7-month period prior to checklist introduction (1 December 2014 to 30 June 2015). Checklist utilization improved the cardiac exam completion rate by 8.9%. With the checklist, 1083 of 1202 exams (90.1%) were completed compared to 987 of 1193 (82.7%) pre-checklist, P < .001. We did not detect a change in cases classified as abnormal and referred for echocardiography: 25 (2.1%) with the checklist and 16 (1.3%) pre-checklist, P = .16. We did not detect more congenital heart disease (CHD), 12 (1.0%) with checklist screening, 5 (0.4%) pre-checklist, P = .14. Critical CHD was not missed in either group. Using the checklist improved the cardiac exam completion rate. There was no change in congenital heart disease detection.
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http://dx.doi.org/10.1002/pd.5581DOI Listing
January 2020

Outcomes of a Staged Midurethral Sling Strategy for Stress Incontinence and Pelvic Organ Prolapse.

Obstet Gynecol 2019 10;134(4):736-744

UPMC Magee-Womens Hospital, and the Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Urogynecology and Pelvic Reconstructive Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and the Department of Obstetrics and Gynecology, Trinity Health Of New England, Hartford, Connecticut.

Objective: To evaluate the proportion of women who experienced resolution of stress urinary incontinence (SUI) symptoms after surgery for pelvic organ prolapse (POP) without a concomitant incontinence procedure.

Methods: We conducted a retrospective observational study of women with preoperative subjective and objective SUI who underwent minimally invasive sacrocolpopexy or uterosacral ligament suspension from 2009 to 2015. We excluded cases with incontinence procedures. The primary outcome was the proportion of women with subjective resolution of SUI postoperatively, defined as the absence of patient reported SUI symptoms during follow-up. Secondary outcomes included the proportion of women who underwent a subsequent staged midurethral sling (MUS) procedure and factors associated with resolution of SUI and staged MUS placement.

Results: Of 93 women, most were white (n=90, 98%) with stage III POP (n=55, 59%). Mean age was 59.5±8.9 years and body mass index 28.7±4.7. Seventy-three patients (78%) underwent minimally invasive sacrocolpopexy, and 20 (22%) underwent uterosacral ligament suspension. Median follow-up was 8.3 months (interquartile range 3.4-26.7). Postoperatively, 28 (30%) patients reported resolution of SUI, and 65 (70%) reported persistent SUI. Of the 93 patients, 47 (51%) were treated for persistent SUI and 34 (37%) underwent a staged MUS procedure. Among the staged MUS procedures, 27 (79%) were placed within 12 months. Median time to staged MUS procedure was 5.5 months (interquartile range 4.2-9.9). After controlling for degree of preoperative SUI bother, obese women were less likely to experience resolution of SUI after prolapse repair (odds ratio 0.28, 95% CI 0.08-0.95). We did not identify any factors that were significantly associated with undergoing a staged MUS procedure on univariate analyses (P>.05).

Conclusion: Preoperative SUI resolved in nearly a third of women after prolapse surgery without a concomitant incontinence procedure. In a population typically offered a concomitant MUS procedure at the time of prolapse repair, a staged approach may result in nearly two-thirds fewer patients undergoing MUS procedures. This information may be helpful during preoperative shared decision making.
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http://dx.doi.org/10.1097/AOG.0000000000003448DOI Listing
October 2019

Reply.

Am J Obstet Gynecol 2019 09 7;221(3):289-290. Epub 2019 Jun 7.

Division of Urogynecology, Department of Obstetrics and Gynecology, Trinity Health Of New England, Hartford, CT.

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http://dx.doi.org/10.1016/j.ajog.2019.05.052DOI Listing
September 2019

Comparing laparoscopic and robotic sacrocolpopexy surgical outcomes with prior versus concomitant hysterectomy.

Int Urogynecol J 2020 02 29;31(2):401-407. Epub 2019 Jun 29.

Trinity Health Of New England , Hartford, CT, USA.

Introduction And Hypothesis: The objective was to compare surgical outcomes after prior hysterectomy versus concomitant hysterectomy with laparoscopic/robotic minimally invasive sacral colpopexy (MISC).

Methods: Using all MISC from 2009 to 2014, patient sociodemographic and surgical data were compared between MISC with prior versus concomitant hysterectomy. Operative time (skin incision to closure) was compared with linear regression. Logistic regression compared complications, a composite variable including ≥1 transfusion, infection, readmission, reoperation, bowel obstruction/ileus, conversion to laparotomy, bowel/bladder injury, or mesh complication. Logistic regression compared prolapse recurrence defined as retreatment (pessary/surgery) or postoperative POP-Q points ≥ 0.

Results: Eight hundred and sixteen patients were 59.6 ± 8.7 years old and predominantly Caucasians (97.8%), with BMI 27.4 ± 4.5 and predominantly POP-Q stage III prolapse (69.9%). Operative time was 205.0 ± 69.0 min. Concomitant hysterectomy increased operative time 17.8 min (p = 0.004) adjusting for age, POP-Q stage, total vaginal length, perineal body, lysis of adhesions or perineorrhaphy, changes in operating personnel (scrub tech/circulating nurse), case order during the day, and preoperative stress incontinence. Complications occurred in 15.8% and were more likely with prior hysterectomy (odds ratio [OR] = 2.30, 95% confidence interval [CI] = 1.43-3.70) adjusting for preoperative genital hiatus and perineal body, concomitant midurethral sling, obesity, and immunosuppression. During a follow-up of 31 weeks, 7.8% had prolapse recurrence with no impact from concomitant hysterectomy (OR = 0.96, 95% CI 0.41-2.24). Post-hoc power calculation would have required an unattainable size of >2,800 per group for this outcome.

Conclusions: For MISC, concomitant hysterectomy is associated with longer operative time but lower risk of complications. There was no impact of concomitant hysterectomy on prolapse recurrence, but longer follow-up may be needed for this outcome.
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http://dx.doi.org/10.1007/s00192-019-04017-5DOI Listing
February 2020

A cost-minimization analysis of treatment options for postmenopausal women with dysuria.

Am J Obstet Gynecol 2019 11 2;221(5):505.e1-505.e7. Epub 2019 May 2.

Department of Obstetrics and Gynecology, Trinity Health of New England, Hartford, CT.

Background: Empiric therapy for urinary tract infection is difficult in postmenopausal women because of the higher rates of confounding lower urinary tract symptoms and differential resistance profiles of uropathogens in this population.

Objective: The objective of the study was to determine the least costly strategy for treatment of postmenopausal women with the primary complaint of dysuria.

Study Design: We performed a cost minimization analysis modeling the following clinical options: (1) empiric antibiotic therapy followed by urine culture, (2) urinalysis with empiric antibiotic therapy only if positive nitrites and leukocyte esterase, or (3) waiting for culture prior to initiating antibiotics. For all strategies we included nitrofurantoin, trimethoprim/sulfamethoxazole, fosfomycin, ciprofloxacin, or cephalexin. Pathogens included Escherichia coli, Enterococcus faecalis, Klebsiella pneumonaie, or Proteus mirabalis. Pathogens, resistance, treatment success, and medication side effects were specific to postmenopausal women.

Results: Cost minimization modeling with TreeAge Pro assumed 73.4% of urinary tract infections were caused by Escherichia coli with 24.4% resistance to nitrofurantoin, trimethoprim/sulfamethoxazole. With our assumptions, empiric antibiotics with nitrofurantoin, trimethoprim/sulfamethoxazole was the least costly approach ($89.64/patient), followed by waiting for urine culture ($97.04/patient). Except for empiric antibiotics with fosfomcyin, empiric antibiotics was always less costly than using urinalysis to discriminate antibiotic use. This is due to the cost of urinalysis ($38.23), high rate of both urinary tract infection (91%), and positive urinalysis (69.3%) with dysuria in postmenopausal women and resultant high rate of antibiotic use with or without urinalysis. Options with fosfomycin were the most expensive because of the highest drug costs ($98/dose), and tornado analyses showed fosfomycin cost was the most impactful variable for model outcomes. Sensitivity analyses showed empiric fosfomycin became the least costly option if drug costs were $25.80, a price still more costly than almost all modeled baseline drug costs. This outcome was largely predicated on low resistance to fosfomycin. Conversely, ciprofloxacin was never the least costly option because of higher resistance and side effect cost, even if the drug cost was $0. We modeled 91% positive urine culture rate in postmenopausal women with dysuria; waiting for the urine culture prior to treatment would be the least costly strategy in a population with a predicted positive culture rate of <65%.

Conclusion: The least costly strategy was empiric antibiotics with nitrofurantoin and trimethoprim/sulfamethoxazole, followed by waiting on culture results. Local resistance patterns will have an impact on cost minimization strategies. Empiric fosfomycin would be least costly with reduced drug costs, even at a level at which drug costs were higher than almost all other antibiotics. In a population with high posttest probability of positive urine culture, urinalysis adds unnecessary cost. Antibiotic stewardship programs should continue efforts to decrease fluoroquinolone use because of high resistance, side effects, and increased cost.
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http://dx.doi.org/10.1016/j.ajog.2019.04.031DOI Listing
November 2019