Same-Day Discharge is Safe, Feasible Following Vaginal Hysterectomy with Apical Suspension.

Purpose: Studies involving minimally invasive hysterectomy and robotic sacrocolpopexy have demonstrated safety and feasibility of same-day discharge. There are limited data, however, on same-day discharge outcomes for vaginal hysterectomy and pelvic reconstruction. This study aimed to compare 30 and 90-day surgical outcomes between same-day discharge versus overnight stay following vaginal hysterectomy and apical suspension. Patients and Methods: This retrospective study evaluated surgeries performed over two time periods. Overnight stay was standard between December 2018 and February 2020. Same-day discharge was standard from December 2020 to February 2022. All patients who underwent vaginal hysterectomy with apical suspension were included. The primary outcome was to determine if there was an increase in 30-day readmission rates. Secondary outcomes included emergency department visits and reoperations within 30 days, the previous variables at 90 days, and the rate for successful same-day discharge. Results: A total of 324 patients were analyzed over the 30 months: 149 (46%) in the overnight stay group and 175 (54%) in the same-day discharge group. At 30 days, no difference was found between groups for readmissions (2.7% vs 4.0%, p = 0.56), emergency department visits (14.8% vs 14.9%, p = 1.0), or reoperations (2.0% vs.1.7%, p = 1.0). At 90 days, outcomes were also similar. Same-day discharge as standard practice was successful in 80% of patients. Conclusion: In this retrospective two cohort study, the safety of same-day discharge following vaginal hysterectomy with apical suspension was demonstrated with no increased risk of 30 or 90-day readmissions, emergency visits, or reoperation rates. The majority (80%) of patients were discharged on the day of surgery, suggesting feasibility of this model.

Breast Cancer and Obesity: a Qualitative Analysis of a Diverse Population of Breast Cancer Patients' Perspectives on Weight Management.

PURPOSE: Obesity and weight gain in breast cancer survivors leads to a greater risk of recurrence and a decreased chance of survival. A paucity of data exists regarding strengths, weaknesses, and barriers for implementing culturally sensitive, patient-centered interventions for weight management among minority communities. The objective of this study was to evaluate breast cancer patients' experience and perspectives regarding weight management in a racially diverse population. METHODS: Semi-structured qualitative interviews were conducted with breast cancer patients with a body mass index ≥ 25 kg/m2 regarding their experience with weight management. Interviews were transcribed verbatim, and a thematic analysis was conducted. RESULTS: Participants (n = 17) most commonly self-identified as non-Hispanic Black (70.6%). Nearly all participants felt comfortable being approached about weight management, yet less than half (41.2%) reported that they knew about the link between breast cancer and body weight prior to the interview. Four themes emerged: (1) lack of knowledge regarding the link between body weight and breast cancer risk, (2) barriers to weight management including family stressors, high cost, mental health issues, and chronic medical conditions, (3) previous attempts at weight loss including bariatric surgery, and (4) best practices for approaching weight management including discussion of weight management prior to survivorship. CONCLUSION: There is a need for a multidisciplinary, patient-centered weight management program for minority breast cancer patients that improves awareness of the link between weight and breast cancer risk. Weight management should be introduced early on as an element of the treatment plan for breast cancer.

Patient experiences following prolapse surgery implementing a same-day discharge model: a prospective study.

INTRODUCTION AND HYPOTHESIS: Previous research has not evaluated patient experiences following vaginal reconstructive surgery using a same-day discharge model. The objective of this study was to describe patient experiences following major vaginal reconstructive surgery and same-day discharge. METHODS: In this descriptive study, patients undergoing vaginal hysterectomy with pelvic reconstruction were preoperatively enrolled. Questionnaires detailing experience with same-day discharge, surgical recovery, and advice for prospective patients were completed. Our primary outcome was question 7 of the Surgical Satisfaction Questionnaire: Looking back, if you "had to do it all over again" would you have the surgery again? Descriptive statistics were performed, and correlations were performed with Spearman's rank test. RESULTS: Sixty patients were enrolled; 54 underwent surgery. Eighty-seven percent of patients completed the 12-week questionnaire. At 12 weeks, 96% of patients (n = 45) would have the surgery again, and 91% (n = 42) were satisfied with the results of surgery. Twelve weeks postoperatively, the most common patient-reported complications were urinary tract infection (n = 8, 17%), catheter concerns (n = 5, 11%), and constipation (n = 5, 11%). When asked to list the best parts of their surgical experience, half of patients felt that this was the office staff or physician themselves (n = 24, 51%). When asked what advice they would provide to future patients, the most common responses included having a support person at home and taking time for recovery. CONCLUSIONS: In this sample of women receiving same-day discharge following vaginal hysterectomy with pelvic reconstruction, we present a unique insight into the most common patient concerns postoperatively. Rates of satisfaction and comfort were high.

Paralog-specific signaling by IRAK1/4 maintains MyD88-independent functions in MDS/AML.

Dysregulation of innate immune signaling is a hallmark of hematologic malignancies. Recent therapeutic efforts to subvert aberrant innate immune signaling in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) have focused on the kinase IRAK4. IRAK4 inhibitors have achieved promising, though moderate, responses in preclinical studies and clinical trials for MDS and AML. The reasons underlying the limited responses to IRAK4 inhibitors remain unknown. In this study, we reveal that inhibiting IRAK4 in leukemic cells elicits functional complementation and compensation by its paralog, IRAK1. Using genetic approaches, we demonstrate that cotargeting IRAK1 and IRAK4 is required to suppress leukemic stem/progenitor cell (LSPC) function and induce differentiation in cell lines and patient-derived cells. Although IRAK1 and IRAK4 are presumed to function primarily downstream of the proximal adapter MyD88, we found that complementary and compensatory IRAK1 and IRAK4 dependencies in MDS/AML occur via noncanonical MyD88-independent pathways. Genomic and proteomic analyses revealed that IRAK1 and IRAK4 preserve the undifferentiated state of MDS/AML LSPCs by coordinating a network of pathways, including ones that converge on the polycomb repressive complex 2 complex and JAK-STAT signaling. To translate these findings, we implemented a structure-based design of a potent and selective dual IRAK1 and IRAK4 inhibitor KME-2780. MDS/AML cell lines and patient-derived samples showed significant suppression of LSPCs in xenograft and in vitro studies when treated with KME-2780 as compared with selective IRAK4 inhibitors. Our results provide a mechanistic basis and rationale for cotargeting IRAK1 and IRAK4 for the treatment of cancers, including MDS/AML.

Fatty acids negatively regulate platelet function through formation of noncanonical 15-lipoxygenase-derived eicosanoids.

The antiplatelet effect of polyunsaturated fatty acids is primarily attributed to its metabolism to bioactive metabolites by oxygenases, such as lipoxygenases (LOX). Platelets have demonstrated the ability to generate 15-LOX-derived metabolites (15-oxylipins); however, whether 15-LOX is in the platelet or is required for the formation of 15-oxylipins remains unclear. This study seeks to elucidate whether 15-LOX is required for the formation of 15-oxylipins in the platelet and determine their mechanistic effects on platelet reactivity. In this study, 15-HETrE, 15-HETE, and 15-HEPE attenuated collagen-induced platelet aggregation, and 15-HETrE inhibited platelet aggregation induced by different agonists. The observed anti-aggregatory effect was due to the inhibition of intracellular signaling including αIIbß3 and protein kinase C activities, calcium mobilization, and granule secretion. While 15-HETrE inhibited platelets partially through activation of peroxisome proliferator-activated receptor ß (PPARß), 15-HETE also inhibited platelets partially through activation of PPARα. 15-HETrE, 15-HETE, or 15-HEPE inhibited 12-LOX in vitro, with arachidonic acid as the substrate. Additionally, a 15-oxylipin-dependent attenuation of 12-HETE level was observed in platelets following ex vivo treatment with 15-HETrE, 15-HETE, or 15-HEPE. Platelets treated with DGLA formed 15-HETrE and collagen-induced platelet aggregation was attenuated only in the presence of ML355 or aspirin, but not in the presence of 15-LOX-1 or 15-LOX-2 inhibitors. Expression of 15-LOX-1, but not 15-LOX-2, was decreased in leukocyte-depleted platelets compared to non-depleted platelets. Taken together, these findings suggest that 15-oxylipins regulate platelet reactivity; however, platelet expression of 15-LOX-1 is low, suggesting that 15-oxylipins may be formed in the platelet through a 15-LOX-independent pathway.

Intrarectal diazepam following pelvic reconstructive surgery: a double-blind, randomized placebo-controlled trial.

BACKGROUND: Patients undergoing vaginal hysterectomy with native tissue pelvic reconstruction typically have low pain levels overall in the postoperative period. Notwithstanding, pain control immediately after surgery may be more challenging and a barrier to same-day discharge. Intrarectal diazepam has been used for acute and chronic pelvic pain and has a pharmacokinetic profile ideal for intermittent use. However, its use has not been investigated after the surgical intervention. OBJECTIVE: This study aimed to evaluate the effect of diazepam rectal suppositories on early postoperative pain after hysterectomy and vaginal reconstruction for pelvic organ prolapse. STUDY DESIGN: This was a double-blind, randomized, placebo-controlled trial comparing postoperative pain scores after vaginal hysterectomy with native tissue prolapse repairs. Patients were randomized to receive either an intrarectal 10-mg diazepam suppository or an identical placebo. Moreover, the participants completed the questionnaires at baseline, the morning of postoperative day 1, and 2 weeks after the operation. Surveys included visual analog scales for pain, a validated Surgical Satisfaction Questionnaire, and queries regarding medication side effects and postoperative recovery. The primary outcome was pain scores based on a visual analog scale approximately 3 hours after surgery. The secondary outcomes included total morphine equivalents after surgery, patient satisfaction with pain control, same-day discharge outcome, and overall satisfaction. The chi-square, Fisher exact, and Mann-Whitney tests were used. Based on a 10-mm difference in postoperative vaginal pain using the visual analog scale, sample size was calculated to be 55 patients in each arm to achieve 80% power with an alpha of.05. RESULTS: From February 2020 to August 2021, 130 participants were randomized. Of those participants, 7 withdrew, and 123 were analyzed: 60 in the diazepam group and 63 in the placebo group. The median age was 65 years (interquartile range, 27-80), the median body mass index was 27.9 kg/m2 (interquartile range, 18.70-45.90), and 119 of 123 participants (96.7%) were White. There was no difference in the baseline characteristics, prolapse stage, or types of procedures performed between groups. Most participants had concurrent uterosacral ligament suspension with anterior and posterior repairs. Of note, 50 of 123 participants (41%) had midurethral slings. Moreover, 61 of 123 participants (50%) were discharged on the day of surgery. There was no difference in the primary outcome of vaginal pain 3.5 to 6.0 hours postoperatively (25 vs 21 mm; P=.285). In addition, the amount of rescue narcotics used in the immediate postoperative period (19.0 vs 17.0 MME; P=.202) did not differ between groups. At 2-weeks postoperatively, patients in the placebo group reported higher satisfaction with pain control in the hospital (31 vs 43 mm; P=.006) and pain control at home (31 vs 42 mm; P=.022). No difference was noted between same-day discharges and those who were admitted overnight. CONCLUSION: The placement of a 10-mg diazepam rectal suppository immediately after pelvic reconstructive surgery did not improve pain or narcotic usage in the early postoperative period. Although the placebo group reported slightly higher satisfaction with pain control 2 weeks after surgery, overall pain levels were low. Therefore, we do not believe that the addition of diazepam to the postoperative regimen is warranted.

Methenamine Hippurate With Cranberry Capsules Versus Cranberry Alone for Urinary Tract Infection Prevention in a Short-Term Indwelling Foley Catheter Population After Urogynecologic Surgery: A Double-Blinded Randomized Controlled Trial.

IMPORTANCE: There is little consensus on an effective nonantibiotic agent for the prevention of urinary tract infection (UTI) after pelvic reconstructive surgery. OBJECTIVE: The aim of the study was to investigate the impact of methenamine hippurate with cranberry capsules on rates of UTI after pelvic reconstructive surgery, among patients requiring short-term catheterization. STUDY DESIGN: In this randomized, double-blinded placebo-controlled trial, patients discharged with a catheter after pelvic reconstructive surgery were approached to participate. Participants were randomized to receive cranberry with methenamine or cranberry with placebo. Primary outcome was number of UTIs treated within 1 week after surgery. Secondary outcomes included incidence of UTIs treated within 6 weeks postoperatively, bacterial species on culture, urinary pH, catheter duration, patient adherence, and satisfaction. A sample size of 88 participants per arm was planned. RESULTS: From June 2019 to July 2021, 185 patients were randomized and 182 analyzed; 89 received placebo and 93 received methenamine. Both groups were similar. Incidence of UTI at 1 week was significantly higher in the placebo group (79.8%) compared with the methenamine group (66.7%; odds ratio, 1.97; 95% confidence interval, 1.01-3.87; P = 0.048). This difference increased by 6 weeks postoperatively (89.9% vs 72.0%; odds ratio, 3.45; 95% confidence interval, 1.51-7.87; P = 0.003). There were fewer pseudomonal UTIs in the methenamine group (P = 0.041). Duration of catheterization and urinary pH were similar. Overall adherence and level of satisfaction was high. CONCLUSIONS: In this high-risk population, methenamine was well tolerated and significantly reduced UTI rates. Methenamine with cranberry should be considered as an effective prophylactic therapy to reduce this common complication after pelvic surgery.

TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity.

Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with CH are healthy, they are at an increased risk of developing myeloid malignancies, suggesting that additional alterations are needed for the transition from a pre-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemia and is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in a subset of patients with myeloid malignancies, suggesting that subversion of TRAF6 signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, an event that does not affect its protein stability but rather represses its functional activity by antagonizing an acetylation modification.

The effect of mindfulness-based stress reduction on the urinary microbiome in interstitial cystitis.

INTRODUCTION AND HYPOTHESIS: The objective was to investigate the impact of mindfulness-based stress reduction therapy on the urinary microbiome of patients with interstitial cystitis/bladder pain syndrome. METHODS: In this Institutional Review Board-approved prospective cohort study, patients with interstitial cystitis/bladder pain syndrome were recruited to attend an 8-week mindfulness-based stress reduction course involving yoga and meditation. Eligible participants were English-speaking women aged 18 or older with interstitial cystitis/bladder pain syndrome. All participants had a negative urinalysis within 2 months of enrollment and were currently undergoing first- or second-line treatment at the time of recruitment. The mindfulness-based stress reduction course met weekly for 1 h. A straight-catheter urine sample was obtained prior to and following the mindfulness-based stress reduction series. DNA from urine samples underwent bacterial 16S ribosomal gene sequencing at Johns Hopkins University Laboratories followed by taxonomic abundance and diversity analysis by Resphera Biosciences Laboratory. Participants completed validated symptom questionnaires pre- and post-intervention. RESULTS: A total of 12 participants completed the 8-week course and were included in the analysis. The average age was 59 and the majority identified as white. Patient symptoms, measured by the Urogenital Distress Inventory Short Form and Interstitial Cystitis Symptom and Pain Indices, improved significantly (all p < 0.05). Overall composition of the urinary microbiome changed significantly (p < 0.01) and demonstrated an increase in diversity following the intervention. CONCLUSIONS: Mindfulness-based stress reduction therapy improves patient symptoms and was associated with significant changes in the urinary microbiome in patients with interstitial cystitis/bladder pain syndrome.

Chlorhexidine Versus Iodine for Vaginal Preparation Before Hysterectomy: A Randomized Clinical Trial.

OBJECTIVE: The American College of Obstetricians and Gynecologists does not provide a recommendation regarding the preferred vaginal preparation solution. We intended to compare the effectiveness of chlorhexidine versus iodine in decreasing vaginal bacterial counts. METHODS: In this institutional review board-approved study, participants undergoing total hysterectomy via vaginal or laparoscopic approach were randomized to 4% chlorhexidine or 10% iodine for presurgical vaginal preparation. Swabs were collected from the vaginal mucosa before, then 30, 60, and 90 minutes after preparation. Our primary outcome was the number of positive cultures (≥5,000 bacteria) at 90 minutes. The secondary outcomes included the presence of selected pathogens, postoperative complications, and infections. The sample size of 71 per arm was calculated using ɑP = 0.05, 80% power, and anticipating a 22% difference in positive cultures. RESULTS: Between May 2018 and August 2019, 85 participants were randomized. The average age was 59.8 years (SD, 11.4), and the median Charlson Comorbidity Index score was 2 (minimum, 0; maximum, 6). Baseline bacterial counts were similar in both groups. Chlorhexidine demonstrated a lower percentage of positive cultures at 90 minutes (47.6% vs 85.4%; odds ratio, 10.6; P = 0.001). In addition, the median bacterial count in the chlorhexidine group was significantly lower than the iodine group (3,000 vs 24,000 colony-forming units, P < 0.001) at 90 minutes. No surgical site infections were identified in either group during the 30-day postoperative period, and there were no reported adverse reactions to either solution. CONCLUSIONS: Chlorhexidine resulted in substantially lower bacterial counts after preparation compared with iodine. Gynecologic surgeons may consider switching to 4% chlorhexidine for vaginal preparation before hysterectomy.

Utilization of a Mirror During Pelvic Examinations: Does it Improve the Patient's Experience?

OBJECTIVE: This study was conducted to assess the utility of a mirror in improving pain and vulnerability during a pelvic examination. METHODS: In this prospective, institutional review board-approved, 2-cohort trial, all "new" patients presenting to a urogynecology office were offered to have a mirror or no-mirror present during their pelvic examination. Patients completed 100-mm visual analog scales regarding pain, anxiety, knowledge, control, embarrassment, and vulnerability before and after examination. The primary outcome was difference in level of pain and vulnerability between groups. Secondary outcomes included comparisons from baseline to postexamination scores within groups, patient satisfaction, and examination duration. A sample size of 68 participants in each arm was planned. RESULTS: From April 2019 to May 2020, 147 participants were enrolled. Two participants were excluded, 145 were included in the final analysis; 74 in the no-mirror group and 71 in the mirror group. The average age was 55.9 (±13) years, and the groups were overall similar. There was no difference in primary outcomes of pain or vulnerability, but the mirror group showed improved levels of control (P = 0.006) and knowledge (P = 0.018) following examination. All participants reported high satisfaction, and those that selected a mirror reported strong preference for future use. CONCLUSIONS: Patients who chose to use the mirror did not demonstrate a difference in pain or vulnerability scores; however, they exhibited benefit to their sense of control and knowledge after the pelvic examination. Although the mirror did not benefit all patients, this is a simple option that could improve the examination experience for some.Clinical Trial Registration:ClinicalTrials.gov, NCT03785548.

GPR56/ADGRG1 is a platelet collagen-responsive GPCR and hemostatic sensor of shear force.

Circulating platelets roll along exposed collagen at vessel injury sites and respond with filipodia protrusion, shape change, and surface area expansion to facilitate platelet adhesion and plug formation. Various glycoproteins were considered to be both collagen responders and mediators of platelet adhesion, yet the signaling kinetics emanating from these receptors do not fully account for the rapid platelet cytoskeletal changes that occur in blood flow. We found the free N-terminal fragment of the adhesion G protein-coupled receptor (GPCR) GPR56 in human plasma and report that GPR56 is the platelet receptor that transduces signals from collagen and blood flow-induced shear force to activate G protein 13 signaling for platelet shape change. Gpr56-/- mice have prolonged bleeding, defective platelet plug formation, and delayed thrombotic occlusion. Human and mouse blood perfusion studies demonstrated GPR56 and shear-force dependence of platelet adhesion to immobilized collagen. Our work places GPR56 as an initial collagen responder and shear-force transducer that is essential for platelet shape change during hemostasis.

Omega-6 DPA and its 12-lipoxygenase-oxidized lipids regulate platelet reactivity in a nongenomic PPARα-dependent manner.

Arterial thrombosis is the underlying cause for a number of cardiovascular-related events. Although dietary supplementation that includes polyunsaturated fatty acids (PUFAs) has been proposed to elicit cardiovascular protection, a mechanism for antithrombotic protection has not been well established. The current study sought to investigate whether an omega-6 essential fatty acid, docosapentaenoic acid (DPAn-6), and its oxidized lipid metabolites (oxylipins) provide direct cardiovascular protection through inhibition of platelet reactivity. Human and mouse blood and isolated platelets were treated with DPAn-6 and its 12-lipoxygenase (12-LOX)-derived oxylipins, 11-hydroxy-docosapentaenoic acid and 14-hydroxy-docosapentaenoic acid, to assess their ability to inhibit platelet activation. Pharmacological and genetic approaches were used to elucidate a role for DPA and its oxylipins in preventing platelet activation. DPAn-6 was found to be significantly increased in platelets following fatty acid supplementation, and it potently inhibited platelet activation through its 12-LOX-derived oxylipins. The inhibitory effects were selectively reversed through inhibition of the nuclear receptor peroxisome proliferator activator receptor-α (PPARα). PPARα binding was confirmed using a PPARα transcription reporter assay, as well as PPARα-/- mice. These approaches confirmed that selectivity of platelet inhibition was due to effects of DPA oxylipins acting through PPARα. Mice administered DPAn-6 or its oxylipins exhibited reduced thrombus formation following vessel injury, which was prevented in PPARα-/- mice. Hence, the current study demonstrates that DPAn-6 and its oxylipins potently and effectively inhibit platelet activation and thrombosis following a vascular injury. Platelet function is regulated, in part, through an oxylipin-induced PPARα-dependent manner, suggesting that targeting PPARα may represent an alternative strategy to treat thrombotic-related diseases.

Mechanisms of adhesion G protein-coupled receptor activation.

Adhesion G protein-coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the N terminus of the G protein-coupling seven-transmembrane-spanning bundle. GAIN domain-mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently, there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological contexts.

Uterosacral Ligament Suspension: A Radiographic Study of Suture Location in Live Subjects.

OBJECTIVES: This study aimed to describe uterosacral ligament suspension (USLS) suture location relative to the surrounding anatomy in a living model using computed tomographic imaging. METHODS: This was an institutional review board-approved prospective descriptive study. Women aged 18 to 85 years undergoing vaginal hysterectomy with USLS were eligible. A size 'small' titanium vascular clip was applied to the base of each USLS suture. Computed tomography of the pelvis was performed on postoperative day 1. Preoperative and postoperative neurologic questionnaires and physical examinations were performed. A sample size of 15 subjects was deemed appropriate for this pilot study. RESULTS: Seventeen subjects were enrolled: 2 excluded and 15 analyzed. The median (interquartile range) age of the subjects was 57 (22) years. The closest branch of the internal iliac complex was 2.6 (0.9) cm (median [interquartile range]) from the proximal suture on the right and 2.6 (0.5) cm on the left. The right ureter was 2.1 (0.7) cm from the right proximal suture. The left ureter was 2.3 (1.0) cm from the left proximal suture. The rectal lumen were 3.0 (1.6) cm from the right proximal suture and 2.8 (1.4) cm from the left proximal suture. No subjects were found to have neurologic involvement of the sutures based on neurologic questionnaire responses and physical examination. CONCLUSIONS: In live subjects, our study confirms that the vasculature, ureter, and rectum of the pelvic side wall are near suture placement for USLS. This information highlights the importance of careful dissection and awareness of anatomic landmarks.

Self-Removal of a Urinary Catheter After Urogynecologic Surgery: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether self-discontinuation of a transurethral catheter is noninferior to office discontinuation in patients requiring indwelling catheterization for postoperative urinary retention after pelvic reconstructive surgery. METHODS: In this randomized noninferiority trial, patients with postoperative urinary retention after pelvic reconstructive surgery were assigned to self-discontinuation or office discontinuation of their catheter 1 week after surgery. The primary outcome was a noninferiority comparison of postoperative urinary retention at 1 week. Self-discontinuation patients were instructed on home catheter removal on postoperative day 7. Office discontinuation patients underwent a standard voiding trial on postoperative day 6-8. Postoperative urinary retention at 1 week was defined as continued catheterization on postoperative day 6-8. Secondary outcomes included urinary tract infections (UTI), residual volume at 2 weeks, duration of catheter use, recurrent postoperative urinary retention, number of patient encounters, and visual analog scales (VAS) regarding patient experience. Given a known incidence of postoperative urinary retention at 1 week (16%) and 15% noninferiority margin, a sample size of 74 per group (n=148) was planned. RESULTS: From January 2017 through March 2019, 217 women were screened and 157 were analyzed: 78 self-discontinuation and 79 office discontinuation. Demographic characteristics and surgeries performed were similar. Eleven patients in each group experienced postoperative urinary retention at 1 week (14.1% self-discontinuation vs 13.9% office discontinuation, P=.97), establishing noninferiority (difference 0.2%, 95% CI: -1.00, 0.10). There were significantly fewer patient encounters with self-discontinuation (42/78, 53.8% vs 79/79, 100%). Self-discontinuation patients demonstrated better VAS scores regarding pain, ease, disruption, and likelihood to use the same method again (all P<.05). Though the rate of UTI was high, there was no difference between groups (59.0% self-discontinuation vs 66.7% office discontinuation, P=.32). Residual volume at 2 weeks, recurrent postoperative urinary retention, and duration of catheter use were also similar. CONCLUSION: Self-discontinuation of a transurethral catheter was noninferior to office-based discontinuation in the setting of postoperative urinary retention after pelvic reconstructive surgery. Self-discontinuation resulted in fewer patient encounters and improved patient experience. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02996968.

MRI-Based Predictors of Hemorrhagic Transformation in Patients With Stroke Treated by Intravenous Thrombolysis.

Background: Clinical and biological risk factors for hemorrhagic transformation (HT) after intravenous thrombolysis (IT) have been well-established in several registries. The added value of magnetic resonance imaging (MRI) variables has been studied in small samples, and is controversial. We aimed to assess the added value of MRI variables in HT, beyond that of clinical and biological factors. Methods: We enrolled 474 consecutive patients with brain infarction treated by IT alone at our primary stroke center between January 2011 and August 2017. Baseline demographic, clinical, biological, and imaging characteristics were collected. MRI variables were: brain infarction volume in cm3; parenchymal fluid attenuated inversion recovery (FLAIR) hyperintensity; FLAIR hyperintense vessel signs; number of microbleeds; subcortical white matter hyperintensity; and thrombus length. Results: Overall, 301 patients were included out of 474 (64%). The main causes of exclusion were combined thrombectomy (n = 98) and no MRI before IT (n = 44). In the bivariate analysis, HT was significantly associated with the presence of more FLAIR hyperintense vessel signs, thrombus length (>8 mm), and larger brain infarction volume (diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) < 500 × 10-6 mm2/s). In the multivariable analysis, only brain infarction volume was significantly associated with HT. The discrimination value of the multivariable model, including both the DWI volume and the clinical model (area under the receiver operating characteristic curve, 0.80; 95% confidence interval 0.74-0.86), was improved significantly compared with the model based only on clinical variables (P = 0.012). Conclusions: Brain infarction volume on DWI was the only MRI variable that added value to clinico biological variables for predicting HT after IT.

Platelet Signaling and Disease: Targeted Therapy for Thrombosis and Other Related Diseases.

Platelets are essential for clotting in the blood and maintenance of normal hemostasis. Under pathologic conditions such as atherosclerosis, vascular injury often results in hyperactive platelet activation, resulting in occlusive thrombus formation, myocardial infarction, and stroke. Recent work in the field has elucidated a number of platelet functions unique from that of maintaining hemostasis, including regulation of tumor growth and metastasis, inflammation, infection, and immune response. Traditional therapeutic targets for inhibiting platelet activation have primarily been limited to cyclooxygenase-1, integrin αIIbß3, and the P2Y12 receptor. Recently identified signaling pathways regulating platelet function have made it possible to develop novel approaches for pharmacological intervention in the blood to limit platelet reactivity. In this review, we cover the newly discovered roles for platelets as well as their role in hemostasis and thrombosis. These new roles for platelets lend importance to the development of new therapies targeted to the platelet. Additionally, we highlight the promising receptor and enzymatic targets that may further decrease platelet activation and help to address the myriad of pathologic conditions now known to involve platelets without significant effects on hemostasis.

Genetic Variant in Human PAR (Protease-Activated Receptor) 4 Enhances Thrombus Formation Resulting in Resistance to Antiplatelet Therapeutics.

OBJECTIVE: Platelet activation after stimulation of PAR (protease-activated receptor) 4 is heightened in platelets from blacks compared with those from whites. The difference in PAR4 signaling by race is partially explained by a single-nucleotide variant in PAR4 encoding for either an alanine or threonine at amino acid 120 in the second transmembrane domain. The current study sought to determine whether the difference in PAR4 signaling by this PAR4 variant is because of biased Gq signaling and whether the difference in PAR4 activity results in resistance to traditional antiplatelet intervention. APPROACH AND RESULTS: Membranes expressing human PAR4-120 variants were reconstituted with either Gq or G13 to determine the kinetics of G protein activation. The kinetics of Gq and G13 activation were both increased in membranes expressing PAR4-Thr120 compared with those expressing PAR4-Ala120. Further, inhibiting PAR4-mediated platelet activation by targeting COX (cyclooxygenase) and P2Y12 receptor was less effective in platelets from subjects expressing PAR4-Thr120 compared with PAR4-Ala120. Additionally, ex vivo thrombus formation in whole blood was evaluated at high shear to determine the relationship between PAR4 variant expression and response to antiplatelet drugs. Ex vivo thrombus formation was enhanced in blood from subjects expressing PAR4-Thr120 in the presence or absence of antiplatelet therapy. CONCLUSIONS: Together, these data support that the signaling difference by the PAR4-120 variant results in the enhancement of both Gq and G13 activation and an increase in thrombus formation resulting in a potential resistance to traditional antiplatelet therapies targeting COX-1 and the P2Y12 receptor.