Racial and ethnic disparity in national practice patterns for stress urinary incontinence surgery.

INTRODUCTION AND HYPOTHESIS: There is a paucity of information assessing whether race/ethnicity is associated with differences in surgical treatment of stress urinary incontinence (SUI). The primary objective was to assess for racial/ethnic disparities in SUI surgeries. Secondary objectives were to assess for surgical complication differences and trends over time. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, we conducted a retrospective cohort analysis of patients undergoing SUI surgery from 2010 to 2019. Chi-squared or Fisher's exact test and ANOVA were used for categorical and continuous variables respectively. Breslow day score and multinomial and multiple logistic regression models were used. RESULTS: A total of 53,333 patients were analyzed. Using White race/ethnicity and sling surgery as references, Hispanic patients underwent more laparoscopic surgeries (OR1.17 [CI 1.03, 1.33]) and anterior vesico-urethropexy/urethropexies (OR 1.97 [CI 1.66, 2.34]); Black patients underwent more anterior vesico-urethropexy/urethropexies (OR 1.49 [CI 1.07, 2.07]), abdomino-vaginal vesical neck suspensions (OR 2.19 [CI 1.05-4.55]), and inflatable urethral slings (OR 4.28 [CI 1.23-14.90]). White patients had lower rates of inpatient stay (p < 0.0001) and blood transfusion (p < 0.0001) compared with patients who were Black, indigenous, people of color (BIPOC). Over time, Hispanic and Black patients were more likely to undergo anterior vesico-urethropexy/urethropexies than White patients (RR 2.03:1 [CI 1.72-2.40]) and (RR 1.59 CI [1.15-2.20]) respectively. Adjusting for possible confounders, Hispanic and Black patients had a greater chance of having a nonsling surgery, 37% (p < 0.0001) and 44% (p = 0.0001) greater chances respectively. CONCLUSION: We observed racial/ethnic differences in SUI surgeries. Although causality cannot be proven here, our results confirm previous findings suggesting inequities in care.

Preoperative Activity Level and Postoperative Pain After Pelvic Reconstructive Surgery.

IMPORTANCE: Higher preoperative activity level is associated with improved postoperative outcomes, but its impact on postoperative pain after urogynecologic surgery is unknown. OBJECTIVE: The aim of the study was to assess the relationship between preoperative activity level and postoperative pain. STUDY DESIGN: In this prospective cohort study, we evaluated women undergoing pelvic reconstructive surgery from April 2019 through September 2021. We used the Activity Assessment Survey (AAS) to create cohorts of high (AAS = 100) and low (AAS < 100) baseline activity (BA). Our primary outcome was postoperative pain scores. Our secondary outcome was postoperative opioid use. RESULTS: Of 132 patients, 90 (68%) were in the low BA group and 42 (32%) were in the high BA group. The groups were similar in age (mean 59 ± 12 years for high BA vs 60 ± 12 for low BA, P = 0.70), body mass index, and surgical procedures performed; however, the high BA group had lower preoperative pain scores (2 ± 6 vs 11 ± 9, P ≤ 0.01). For the primary outcome, the high BA group reported lower postoperative pain scores (16 ± 8 vs 20 ± 9, P = 0.02) and less opioid use (19 ± 32 vs 52 ± 70 morphine milliequivalents, P = 0.01) than the low BA group. However, when adjusting for age, baseline pain, hysterectomy, baseline opioid use, and Charlson Comorbidity Index, high BA did not remain associated with lower postoperative pain scores and less opioid use. CONCLUSION: A higher preoperative activity level among patients undergoing urogynecologic surgery was not associated with lower pain scores nor decreased opioid use.

Are Formal Voiding Trials Necessary After Posterior Compartment Reconstructive Surgery?

IMPORTANCE: Posterior compartment surgery is considered a risk factor for postoperative urinary retention because of the impact of postoperative pain on the pelvic floor; however, few studies have examined the association between posterior compartment reconstructive surgery and urinary retention. OBJECTIVE: The aim of the study was to compare rates of urinary retention in patients undergoing vaginal reconstructive surgery, without hysterectomy, in the posterior compartment only versus any apical and/or anterior compartment (with or without posterior compartment). STUDY DESIGN: In this retrospective cohort study, we evaluated patients who underwent surgery, without hysterectomy, in the posterior compartment only versus any apical and/or anterior compartment (with or without posterior compartment) from January 2015 to November 2020. Our primary outcome was rate of postoperative urinary retention, defined as a failed voiding trial before discharge. Secondary outcome was days of catheterization. Multivariable logistic regression was performed to assess variables associated with a failed voiding trial. RESULTS: Of 362 patients, 141 (39.0%) underwent surgery in the posterior compartment only and 221 (61.0%) underwent vaginal apical and/or anterior compartment surgical procedures. Rate of retention was significantly lower in the posterior compartment only group (9.9% vs 41.6%, P < 0.001). The median numbers of days of catheterization were significantly fewer in the posterior compartment only group (0 [0,0] vs 0 [0,3], P < 0.001). In multivariable logistic regression, posterior compartment only surgery was associated with passing the voiding trial (odds ratio, 6.0; 95% confidence interval, 2.97-12.03). CONCLUSIONS: Rates of postoperative urinary retention after surgery in the posterior compartment are low, and these patients may not require formal voiding trials after surgery.

Genetic variants and copy number changes in soft tissue leiomyosarcoma detected by targeted amplicon sequencing.

AIMS: Leiomyosarcomas (LMSs) occur in various tissues and harbour potential for metastases. The genomic landscape of LMS is poorly understood. In an effort to improve understanding of the LMS genome, we analysed 11 LMSs of somatic soft tissue including matching tissue of normal phenotype. METHODS: DNA derived from microdissected tumour domains and matching normal tissue underwent amplicon sequencing of 409 tumour suppressors and oncogenes using the Ion Torrent Comprehensive Cancer Panel. RESULTS: Genomic changes were heterogeneous with few recurrent abnormalities detected. Coding variants were identified in genes involved in signal transduction, transcriptional regulation and DNA repair. There were variants in several genes related to angiogenesis and GPR124 variants (TEM5) were confirmed by immunohistochemical analysis of a LMS tissue microarray. Surprisingly, there were shared coding variants in tumour and corresponding normal tissue. CONCLUSIONS: LMSs are a very heterogeneous population lacking recurrent somatic abnormalities. The presence of damaging mutations in normal tissue may reflect either a germline predisposition or field effect rather than tissue contamination. Hopeful therapeutic targets appear to be those related to AKT/MTOR pathway.

Fate of abstracts presented at the 2004-2008 International Liver Transplantation Society meetings.

Only 20.5% to 61.6% of abstracts presented at biomedical meetings are subsequently published as full-length articles. The aim of this study was to analyze the abstract-to-publication rate of International Liver Transplantation Society (ILTS) meeting abstracts. Abstracts presented at 5 consecutive annual ILTS meetings (2004-2008) were included to ensure a minimum follow-up period of 4 years. For each abstract, a PubMed Central search was conducted with the first author's name and affiliation along with keywords from the title. The following abstract characteristics were examined and used to obtain the abstract-to-publication rate: (1) the year of presentation, (2) the presentation category (plenary session, concurrent oral presentation, or poster presentation), (3) the type of study (randomized clinical study, case report, other clinical study, or basic science study), (4) the first author's discipline (surgery, medicine, anesthesiology/critical care medicine, pathology, radiology, or pharmacology), and (5) the location of the authors (ie, an English-speaking or non-English-speaking country). A total of 2345 abstracts (469 ± 144 abstracts per meeting) were presented, and 913 of those abstracts (38.9%) were expanded into full-length publications. It took 46 months for 90% of the abstracts to be published as full-length journal articles. The abstract-to-publication rates differed with the year of abstract presentation (50.2% in 2004, 45.9% in 2005, 47.6% in 2006, 30.6% in 2007, and 30.3% in 2008; P < 0.001), with the presentation category (49.6% for plenary sessions, 48.5% for concurrent oral presentations, and 34.8% for poster presentations; P < 0.001), and with the type of study (66.7% for randomized clinical studies, 63.1% for basic science studies, 36.7% for other clinical studies, and 35.0% for case reports; P < 0.001). Abstracts from authors from non-English-speaking countries had a higher publication rate (41.1% versus 33.6%, P < 0.001). No differences were found between first authors' disciplines.

Axon sorting within the spinal cord marginal zone via Robo-mediated inhibition of N-cadherin controls spinocerebellar tract formation.

The axons of spinal projection neurons transmit sensory information to the brain by ascending within highly organized longitudinal tracts. However, the molecular mechanisms that control the sorting of these axons within the spinal cord and their directed growth to poorly defined targets are not understood. Here, we show that an interplay between Robo and the cell adhesion molecule, N-cadherin, sorts spinal commissural axons into appropriate longitudinal tracts within the spinal cord, and thereby facilitates their brain targeting. Specifically, we show that d1 and d2 spinal commissural axons join the lateral funiculus within the spinal cord and target the cerebellum in chick embryos, and that these axons contribute to the spinocerebellar projection in transgenic reporter mice. Disabling Robo signaling or overexpressing N-cadherin on these axons prevents the formation of the lateral funiculus and the spinocerebellar tract, and simultaneously perturbing Robo and N-cadherin function rescues both phenotypes in chick embryos. Consistent with these observations, disabling Robo function in conditional N-cadherin knock-out mice results in a wild-type-like lateral funiculus. Together, these findings suggest that spinal projection axons must be sorted into distinct longitudinal tracts within the spinal cord proper to project to their brain targets.

Guidance of longitudinally projecting axons in the developing central nervous system.

The directed and stereotypical growth of axons to their synaptic targets is a crucial phase of neural circuit formation. Many axons in the developing vertebrate and invertebrate central nervous systems (CNSs), including those that remain on their own (ipsilateral), and those that cross over to the opposite (commissural), side of the midline project over long distances along the anterior-posterior (A-P) body axis within precisely positioned longitudinally oriented tracts to facilitate the transmission of information between CNS regions. Despite the widespread distribution and functional importance of these longitudinal tracts, the mechanisms that regulate their formation and projection to poorly characterized synaptic targets remain largely unknown. Nevertheless, recent studies carried out in a variety of invertebrate and vertebrate model systems have begun to elucidate the molecular logic that controls longitudinal axon guidance.

Manipulating Robo expression in vivo perturbs commissural axon pathfinding in the chick spinal cord.

In vertebrate embryos, most spinal commissural axons cross the ventral midline (VM) and project either alongside or significant distances away from the floor plate (FP). The upregulation of repulsive Robo1/2 receptors on postcrossing commissural axons, in mammals, presumably allows these axons to respond to the midline-associated repellents, Slit1-3, facilitating their expulsion from, and prohibiting their reentry into, the FP. Compelling data suggest that Robo3 represses Robo1/2 function on precrossing axons and that Robo1/2 inhibit attractive guidance receptors on postcrossing axons, thereby ensuring that decussated axons are selectively responsive to midline Slits. However, whether Robo1/2 expel decussated commissural axons from the VM and/or prevent their reentry into the FP has not been explicitly established in vivo. Furthermore, some commissural axons do not require Robo1/2 to elaborate appropriate contralateral projections in the mouse spinal cord. Here, we use unilateral in ovo electroporation together with Atoh1 and Neurog1 enhancer elements to visualize, and assess the consequences of manipulating Robo expression on, dl1 and dl2 chick commissural axons. In response to misexpressing a cytoplasmic truncation of Robo1 and/or Robo2, which should block all Robo-ligand interactions, postcrossing commissural axons extend alongside, but do not project away from or reenter the FP. In contrast, misexpression of full-length Robo2 prevents many commissural axons from crossing the VM. Together, these findings support key and selective in vivo roles for Robo receptors in presumably altering the responsiveness of decussated commissural axons and facilitating their expulsion from the VM within the chick spinal cord.

Pyrazolo pyrimidine-type inhibitors of SRC family tyrosine kinases promote ovarian steroid-induced differentiation of human endometrial stromal cells in vitro.

Reversible protein tyrosine phosphorylation, coordinately controlled by protein tyrosine kinases and phosphatases, is a critical element in signal transduction pathways regulating a wide variety of biological processes, including cell growth, differentiation, and tumorigenesis. We have previously reported that c-Src belonging to the Src family tyrosine kinase (SFK) becomes dephosphorylated at tyrosine 530 (Y530) and thereby activated during progestin-induced differentiation of human endometrial stromal cells (i.e., decidualization). In this study, to elucidate the role of decidual c-Src activation, we examined whether 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), both potent and selective SFK inhibitors, affected the ovarian steroid-induced decidualization in vitro. Unexpectedly, PP1 paradoxically increased the kinase activity of decidual c-Src together with dephosphorylation of Y530 in the presence of ovarian steroids. Concomitantly, PP1 enhanced morphological and functional decidualization, as determined by induction of decidualization markers, such as insulin-like growth factor binding protein-1 and prolactin. PP2 also advanced decidualization along with up-regulation of the active form of c-Src whose Y-530 was dephosphorylated. In contrast to PP1 and PP2, herbimycin A, a tyrosine kinase inhibitor with less specificity for SFKs, showed little enhancing effect on the expression of both IGFBP-1 and active c-Src. These results suggest that SFKs, including c-Src, may play a significant role in stromal cell differentiation, providing a clue for a possible therapeutic strategy to modulate endometrial function by targeting signaling pathway(s) involving SFKs.

Involvement of histone acetylation in ovarian steroid-induced decidualization of human endometrial stromal cells.

Histone acetyltransferases and histone deacetylases (HDACs) determine the acetylation status of histones, regulating gene transcription. Decidualization is the progestin-induced differentiation of estrogen-primed endometrial stromal cells (ESCs), which is crucial for implantation and maintenance of pregnancy. We here show that trichostatin A (TSA), a specific HDAC inhibitor, enhances the up-regulation of decidualization markers such as insulin-like growth factor binding protein-1 (IGFBP-1) and prolactin in a dose-dependent manner that is directed by 17beta-estradiol (E(2)) plus progesterone (P(4)) in cultured ESCs, but not glandular cells, both isolated from human endometrium. Morphological changes resembling decidual transformation were also augmented by co-addition of TSA. Acid urea triton gel analysis and immunoblot using acetylated histone type-specific antibodies demonstrated that treatment with E(2) plus P(4) significantly increased the levels of acetylated H3 and H4 whose increment was augmented by co-treatment with TSA. Chromatin immunoprecipitation assay revealed that treatment with E(2) plus P(4) increased the amount of proximal progesterone-responsive region of IGFBP-1 promoter associated with acetylated H4, which was dramatically enhanced by co-addition of TSA. Taken together, our results suggest that histone acetylation is deeply involved in differentiation of human ESCs and that TSA has a potential as an enhancer of decidualization through promotion of progesterone action.

Expression and subcellular distribution of the active form of c-Src tyrosine kinase in differentiating human endometrial stromal cells.

Decidual growth factors and locally produced cytokines are thought to activate specific phosphorylation signalling pathway(s), thereby eliciting a variety of decidual functions. We have previously reported the activation of c-Src tyrosine kinase during ovarian steroid-induced decidualization of cultured human endometrial stromal cells. As chicken c-Src is known to be activated upon dephosphorylation of tyrosine 527 (Y527, corresponding to Y530 in human), we here employed a monoclonal antibody, clone 28, directed against the active form of human c-Src whose Y530 is dephosphorylated, and investigated whether c-Src became dephosphorylated at Y530 and thereby activated during decidualization. We found that the active form of c-Src was up-regulated and demonstrated increased kinase activity during in-vitro decidualization. Immunohistochemistry revealed that decidual cells in early pregnancy decidua were intensely stained with clone 28 when compared with the stromal cells in the non-pregnant endometrium. Moreover, the active form of c-Src translocated from a perinuclear region to the cytoplasm upon decidualization. Thus, the Y530 dephosphorylation, kinase activation, and subcellular translocation of c-Src may be intracellular signalling events associated with decidualization in vivo as well as in vitro.

Protein tyrosine phosphorylation signaling in the differentiation of human endometrial stromal cells.

Reversible protein tyrosine phosphorylation, coordinately controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs), is a critical element in signal transduction pathways regulating cell growth, differentiation, apoptosis, and tumorigenesis. The differentiation of human endometrial stromal cells (decidualization) is crucial for successful embryo implantation and maintenance of pregnancy; however, little is known about the molecular events involving tyrosine phosphorylation, PTKs, and PTPs in the process of decidualization. We have previously reported that the tyrosine kinase activity of c-Src belonging to the Src family kinase is increased together with altered tyrosine phosphorylation of several cellular proteins in the in vitro model of decidualization. Focal adhesion kinase (FAK) and paxillin are known to form a complex with c-Src at the focal contacts and to participate in the integrin-mediated signal transduction as c-Src substrates. Those focal adhesion proteins, however, are not hyperphosphorylated on tyrosine during decidualization. Moreover, the loss of focal adhesions and the disorganization of the actin-based cytoskeleton were observed in decidualized stromal cells, suggesting that the escape from regulation by c-Src may be in part due to the decidualization-induced disruption of the interaction between the focal adhesion proteins and c-Src. These findings collectively indicate that decidual c-Src may activate signaling pathway(s) different from the integrin-mediated signaling cascade involving FAK and paxillin. This review summarizes our recent studies on the tyrosine phosphorylation signaling pathway(s) in decidualization.