Characteristics associated with blood transfusion among women undergoing laparoscopic myomectomy: a National Surgical Quality Improvement Program study.

BACKGROUND: Uterine fibroids are the most common benign tumors that affect females. A laparoscopic myomectomy is the standard surgical treatment for most women who wish to retain their uterus. The most common complication of a myomectomy is excessive bleeding. However, risk factors for hemorrhage during a laparoscopic myomectomy are not well studied and no risk stratification tool specific for identifying the need for a blood transfusion during a laparoscopic myomectomy currently exists in the literature. OBJECTIVE: This study aimed to identify risk factors for intraoperative and postoperative blood transfusion during laparoscopic myomectomies and to develop a risk stratification tool to determine the risk for requiring a blood transfusion. STUDY DESIGN: This was a retrospective cohort study of the American College of Surgeons National Surgical Quality Improvement Program database from 2012 to 2020. Women who underwent a laparoscopic (conventional or robotic) myomectomy were included. Women who received 1 or more blood transfusions within 72 hours after the start time of a laparoscopic myomectomy were compared with those who did not require a blood transfusion. A multivariable analysis was performed to identify risk factors independently associated with the risk for transfusion. Two risk stratification tools to determine the need for a blood transfusion were developed based on the multivariable results, namely (1) based on preoperative factors and (2) based on preoperative and intraoperative factors. RESULTS: During the study period, 11,498 women underwent a laparoscopic myomectomy. Of these, 331(2.9%) required a transfusion. In a multivariable regression analysis of the preoperative factors, Black or African American and Asian races, Hispanic ethnicity, bleeding disorders, American Society of Anesthesiologists class III or IV classification, and a preoperative hematocrit value ≤35.0% were independently associated with the risk for transfusion. Identified intraoperative factors included specimen weight >250 g or ≥5 intramural myomas and an operation time of ≥197 minutes. A risk stratification tool was developed in which points are assigned based on the identified risk factors. The mean probability of transfusion can be calculated based on the sum of the points. CONCLUSION: We identified preoperative and intraoperative independent risk factors for a blood transfusion among women who underwent a laparoscopic myomectomy. A risk stratification tool to determine the risk for requiring a blood transfusion was developed based on the identified risk factors. Further studies are needed to validate this tool.

Bladder instillation patterns in a cohort of women with interstitial cystitis/bladder pain syndrome.

Purpose: To determine intravesical instillation patterns among women receiving treatment for interstitial cystitis/bladder pain syndrome (IC/BPS). Methods: Using the Veterans Affairs Informatics and Computing Infrastructure, active female users of the Veterans Affairs system with an ICD-9 diagnosis of IC/BPS (595.1) were randomly sampled. Patients were considered to have IC/BPS (by chart review) if they had two visits complaining of bladder-centric pain in the absence of positive urine culture ≥6 weeks apart or history of bladder pain with one additional visit for bladder-centric pain. We abstracted the dates of intravesical instillations for each patient. A "course" of instillations was defined as ≥1 instillations made with <21 days between visits. Results: We identified 641 women with confirmed diagnosis of IC/BPS, 78 of whom underwent a total of 344 intravesical instillations. On average each subject had 1.5 +/- 0.8 courses between October 2004-July 2016. Each course was an average of 3.1 +/- 2.6 instillations. 55% of courses consisted of one instillation. Only 22% of courses had 6 or more instillations, the number typically recommended to achieve clinical response. Each instillation within a course was an average of 9.4 +/- 4.0 days apart. Most instillations (77%) were a cocktail of two or more drugs. Conclusions: In our cohort, few women with IC/BPS received a recommended treatment course of six weekly instillations, with most receiving only one per course. Future studies are needed to determine if instillation courses were altered from the guideline due to provider practice patterns, early improvement, or poor tolerance of instillations.

Simultaneous Bladder Drainage via Suprapubic and Urethral Catheters: Which Drains More Completely and Why?

Background: Reconstructive urologists often place both a urethral and suprapubic catheter intraoperatively to prevent extravasation of undrained urine across anastomosis sutures. As no consensus exists on which catheter drains the bladder more completely, many surgeons leave one catheter to gravity drainage and cap the other postoperatively. We sought to identify differences in catheter urine outflow during dual bladder drainage with suprapubic and urethral catheters in postoperative urology patients. Methods: Urine output (UOP) from transgender men who underwent Stage II Phalloplasty with urethral lengthening was retrospectively reviewed. Both 16 French urethral and suprapubic catheters were placed to gravity drainage postoperatively. Urine output from each catheter was recorded separately, twice daily. Mixed model regression modeling tested for differences in urine output by time of day (day/night) and activity status (Bedrest: Postop Day 0-2, Ambulatory: Postop Day 3+). Results: The aggregate number of 12-hour shift urine output observations was 250 (125 for urethral and 125 for suprapubic catheters) across 14 inpatients. Suprapubic catheters had a mean 410 ml higher output than urethral catheters per 12-hour shift (p=0.002; 95% CI: 185, 636 ml). During daytime, Suprapubic catheters demonstrated higher UOP than urethral catheters per 12-hour shift (Estimated Difference: 464 ml; p=0.002; 95% CI: 211, 718 ml). During nighttime, a similar phenomenon was observed (Estimated Difference: 356 ml; p=0.009; 95% CI: 104, 606 ml). When comparing mean UOP from each catheter during the Bedrest Phase, suprapubic catheters averaged an estimated 295 ml higher UOP compared to urethral catheters per 12-hour shift with a trend toward statistical significance (p=0.052; 95% CI -3, 594 ml). During the Ambulatory Phase, mean suprapubic catheter UOP was an estimated 472 ml higher than urethral catheters per 12-hour shift (p=0.009; 95% CI 142, 802 ml). Conclusions: Simultaneous bladder drainage with urethral and suprapubic catheters shows greater drainage from the suprapubic catheter (35% vs 65%). When using two catheters, both can be placed to gravity to maximize bladder drainage as the suprapubic catheter can drain residual urine not adequately drained by the urethral catheter.

The Streaming Web-Based Exercise at Home Study for Breast and Prostate Cancer Survivors: A Feasibility Study Protocol.

BACKGROUND: Despite the known benefits of physical activity in cancer survivors, adherence to exercise guidelines remains low. Known barriers to adhering to guidelines include a lack of time and an unwillingness to return to treatment facilities. Virtual exercise programming could assist in mitigating these barriers. This protocol presents a single arm pilot study exploring the feasibility of personalized Zoom-delivered exercise training for breast and prostate cancer survivors. A secondary objective is to determine the preliminary efficacy of participation on body composition, estimated VO2max, hand grip, one repetition maximum leg press, resting heart rate, resting blood pressure, exercise self-efficacy, and intentions to remain active. METHODS: Breast (n = 10) and prostate (n = 10) cancer survivors will participate in a 24-week feasibility study, including (1) 12 weeks of one-on-one virtual personal training with an exercise physiologist (EP) via Zoom, and (2) individual exercise for a 12-week follow-up period using recordings of Zoom sessions for guidance. Physical assessments and surveys will be implemented at baseline, 12 weeks, and at the end of the study (24 weeks from baseline). CONCLUSIONS: While virtual exercise programming became popularized during the pandemic, evidence is still required to understand whether it can successfully address barriers and promote participation.

A compensatory RNase E variation increases Iron Piracy and Virulence in multidrug-resistant Pseudomonas aeruginosa during Macrophage infection.

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial.

Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3-5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation.

Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty.

INTRODUCTION: No nomogram exists to predict maximum achievable neovaginal depth before penile inversion vaginoplasty (PIV) based on available penile & scrotal skin (SS). Maximal depth is important to patients and is determined by available skin and available anatomic space within the pelvis and varies with surgical technique. AIM: We endeavored to create a nomogram to predict expected postoperative vaginal depth. METHODS: Retrospective review of all patients undergoing primary PIV at a single institution from June 2017 to February 2020 (n = 60). Pre-op: Dorsal penile and midline scrotal skin length were measured. Intra-op: Tubularized scrotal skin length measured on a dilator. Immediate post-op: Final vaginal depth measured with a dilator. OUTCOMES: The amount of available penile and scrotal skin was not associated with vaginal depth. The only variable that did significantly increase depth was the use of penile + scrotal skin, as compared to penile skin alone. (P < .001) RESULTS: In patients who underwent PIV-SS, the final vaginal depth (13.3 ± 1.9 cm) was 87% of pre-op measured penile skin length (15.3 ±- 3.0 cm). In patients who underwent PIV+SS, pre-op penile skin length was 11.1 ± 4.7±cm and pre-op midline scrotal length was 22.8 ± 2.6 cm. with a final post-op vaginal canal depth of 15.2 ± 1.3 cm. In 45/46 (98%) surgeries utilizing SS grafts, SS tube length exceeded the length necessary to achieve maximal vaginal depth, and required trimming and discard. Given that in most cases there was an excess of SS, final post-op depth equaled the maximal vaginal depth that could be surgically dissected, and was not limited by the amount of available skin. CLINICAL IMPLICATIONS: Our findings suggest that for most patients it should not be necessary to include additional tissue sources (eg, peritoneum) to create a vaginal canal during primary vaginoplasty. STRENGTHS AND LIMITATIONS: Any penile skin that was discarded due to poor quality (eg, tight phimosis, poor viability) was not measured and accounted for. This likely resulted in a slight overestimation of the contribution of the penile skin to the final vaginal depth, but did not change the overall finding that final depth was not limited by available skin. CONCLUSION: SS grafts, when harvested and tubularized using optimized technique, supplied an excess of skin necessary to line a vaginal canal space of maximal achievable depth. We found that additional tissue sources can, instead, be reserved for future salvage surgery if it becomes necessary to augment depth. Smith SM, Yuan N, Stelmar J, et al. Penile and Scrotal Skin Measurements to Predict Final Vaginal Depth With Penile Inversion Vaginoplasty. Sex Med 2022;10:100569.

National prevalence of IC/BPS in women and men utilizing veterans health administration data.

Importance: Interstitial cystitis/bladder pain syndrome (IC/BPS) is an immense burden to both patients and the American healthcare system; it is notoriously difficult to diagnose. Prevalence estimates vary widely (150-fold range in women and >500-fold range in men). Objectives: We aimed to create accurate national IC/BPS prevalence estimates by employing a novel methodology combining a national population-based dataset with individual chart abstraction. Study design: In this epidemiological survey, all living patients, with ≥2 clinic visits from 2016 to 2018 in the Veterans Health Administration, with an ICD-9/10 code for IC/BPS (n = 9,503) or similar conditions that may represent undiagnosed IC/BPS (n = 124,331), were identified (other were controls n = 5,069,695). A detailed chart review of random gender-balanced samples confirmed the true presence of IC/PBS, which were then age- and gender-matched to the general US population. Results: Of the 5,203,529 patients identified, IC/BPS was confirmed in 541 of 1,647 sampled charts with an IC/BPS ICD code, 10 of 382 charts with an ICD-like code, and 3 of 916 controls. After age- and gender-matching to the general US population, this translated to national prevalence estimates of 0.87% (95% CI: 0.32, 1.42), with female and male prevalence of 1.08% (95% CI: 0.03, 2.13) and 0.66% (95% CI: 0.44, 0.87), respectively. Conclusions: We estimate the prevalence of IC/BPS to be 0.87%, which is lower than prior estimates based on survey data, but higher than prior estimates based on administrative data. These potentially represent the most accurate estimates to date, given the broader and more heterogeneous population studied and our novel methodology of combining in-depth chart abstraction with administrative data.

Measures of glucose homeostasis during and after duodenal exclusion using a duodenal-jejunal bypass liner in a normoglycemic, nonobese canine model.

BACKGROUND: Discovering the role duodenal exclusion plays in weight loss and resolution of type 2 diabetes (T2D) may help refine the surgical and nonsurgical treatment of obesity and T2D. OBJECTIVES: To assess changes in glucose homeostasis due to duodenal exclusion using a duodenal-jejunal bypass liner (DJBL) in a nonobese canine model. SETTING: Academic laboratory setting. METHODS: An intravenous glucose tolerance test (IVGTT), and a mixed-meal tolerance test (MMTT) at baseline, 1, and 6 weeks post DJBL implantation (I1 and I6, respectively), and 1 and 6 weeks post DJBL removal (R1 and R6, respectively) were done in canines (n = 7) fed a normal chow diet. RESULTS: Placement of the DJBL induced weight loss that was maintained until 4 weeks post removal (R4), despite normal food intake. Total bile acids (TBA) and glucagon-like peptide-1 (GLP-1) during the MMTT were significantly increased at I1 and were associated with increased lactate and free fatty acids. Hypoglycemia counter-regulation was blunted during the IVGTT at I1 and I6, returning to baseline at R1. While there were no changes to insulin sensitivity during the experiment, glucose tolerance was significantly increased following the removal of the DJBL at R1. CONCLUSION: These data show that in a normoglycemic, nonobese canine model, duodenal exclusion induces energy intake-independent weight loss and negative metabolic effects that are reversed following re-exposure of the small intestine to nutrients.

Do medication prescription patterns follow guidelines in a cohort of women with interstitial cystitis/bladder pain syndrome?

OBJECTIVE: To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines. METHODS: We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression. RESULTS: There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression. CONCLUSIONS: Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.

AAV9-MCT8 Delivery at Juvenile Stage Ameliorates Neurological and Behavioral Deficits in a Mouse Model of MCT8-Deficiency.

Background: Allan-Herndon-Dudley syndrome (AHDS) is a severe psychomotor disability disorder that also manifests characteristic abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in monocarboxylate transporter 8 (MCT8), a specific TH plasma membrane transporter widely expressed in the central nervous system (CNS). MCT8 mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. Earlier work has shown that intravenous (IV), but not intracerebroventricular adeno-associated virus serotype 9 (AAV9) -based gene therapy given to newborn Mct8 knockout (Mct8-/y) male mice increased triiodothyronine (T3) brain content and partially rescued TH-dependent gene expression, suggesting a promising approach to treat this neurological disorder. Methods: The potential of IV delivery of AAV9 carrying human MCT8 was tested in the well-established Mct8-/y/Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/ - double knockout (dKO) mouse model of AHDS, which, unlike Mct8-/y mice, displays both neurological and TH phenotype. Further, as the condition is usually diagnosed during childhood, treatment was given intravenously to P30 mice and psychomotor tests were carried out blindly at P120-P140 after which tissues were collected and analyzed. Results: Systemic IV delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive functions at P120-P140, which was accompanied by a near normalization of T3 content and an increased response of positively regulated TH-dependent gene expression in different brain regions examined (thalamus, hippocampus, and parietal cortex). The effects on serum TH concentrations and peripheral tissues were less pronounced, showing only improvement in the serum T3/reverse T3 (rT3) ratio and in liver deiodinase 1 expression. Conclusion: IV administration of AAV9, carrying the human MCT8, to juvenile dKO mice manifesting AHDS has long-term beneficial effects, predominantly on the CNS. This preclinical study indicates that this gene therapy has the potential to ameliorate the devastating neurological symptoms in patients with AHDS.

Seeking the Truth About Primary Elective Cesarean Delivery and Pelvic Floor Disorders: A Systematic Review and Meta-Analysis.

IMPORTANCE: A better understanding of the effect of elective cesarean delivery (CD) on the development of pelvic floor disorders can help obstetricians counsel pregnant women. OBJECTIVE: This study aimed to perform a systematic review and meta-analysis evaluating whether primary elective CD is protective against pelvic floor disorders. STUDY DESIGN: Using the MOOSE criteria, electronic databases were searched for studies that compared the prevalence of pelvic floor disorders among primiparous women. Outcomes of interest were urinary incontinence (UI), fecal incontinence (FI), anal incontinence (AI), and pelvic organ prolapse (POP). Comparisons were made between CD before the onset of labor ("Elective CD"), CD after trial of labor ("Labor CD"), and vaginal delivery (VD). Risk ratios (RRs) were computed using STATA. Between-study heterogeneity was assessed via Cochrane's homogeneity test and review of the I2 statistic. RESULTS: Nineteen studies were included. The overall prevalence of UI for Elective CD was estimated at 7% (95% confidence interval [CI], 3%-13%), Labor CD at 14% (95% CI, 8%-21%), and VD at 26% (95% CI, 20%-32%). Meta-analysis demonstrated a decreased risk of UI after Elective CD compared with Labor CD (RR, 0.75; P = 0.011) or VD (RR, 0.43; P < 0.001). There was a decreased risk of FI or AI after Elective CD compared with VD, but not when compared with Labor CD. Only 2 studies examined POP, precluding meta-analysis. CONCLUSIONS: Among primiparous women, Elective CD may be protective against UI when compared with Labor CD. There was not a protective effect of Elective CD against FI and AI when compared with Labor CD. More data on the effect of elective CD on POP are needed.

Demographic Differences and Disparities in the Misdiagnosis of Interstitial Cystitis/Bladder Pain Syndrome in a National Cohort of VA Patients.

OBJECTIVE: To explore association between misdiagnosis of IC/BPS and demographics. Interstitial cystitis/bladder pain syndrome (IC/BPS) is associated with significant diagnostic uncertainty, resulting in frequent misdiagnosis as there is little known about the potential impact of key demographic factors. METHODS: All patients in the VA system between 1999-2016 were identified by ICD-9/10 codes for IC/BPS (595.1/N30.10) (n = 9,503). ICD code accuracy for true IC/BPS (by strict criteria) was assessed by in-depth chart abstraction (n = 2,400). Associations were explored between rates of misdiagnosis and demographics. RESULTS: IC/BPS criteria were met in only 651 (48.8%) of the 1,334 charts with an ICD code for IC/BPS reviewed in depth. There were no differences in the misdiagnosis rate by race (P=.27) or by ethnicity (P=.97), after adjusting for differences in age and gender. In IC/BPS-confirmed cases, female patients were diagnosed at a younger age than males (41.9 vs. 58.2 years, P<.001). Black and Hispanic patients were diagnosed at a younger age compared to White (41.9 vs. 50.2 years, P<.001) and non-Hispanic patients, respectively (41.1 vs. 49.1 years, P=.002). CONCLUSION: There was a high rate of misdiagnosis of IC/BPS overall, with only 48.8% of patients with an ICD code for IC/BPS meeting diagnostic criteria. There were no significant associations between diagnostic accuracy and race/ethnicity. Black and Hispanic patients were more likely to receive a diagnosis of IC/BPS at a younger age, suggesting there may be differing natural histories or presentation patterns of IC/BPS between racial/ethnic groups.

The Impact of Provider Sex and Experience on the Quality of Care Provided for Women with Urinary Incontinence.

BACKGROUND: Although specialists are skilled in the management of urinary incontinence, primary care clinicians are integral in early diagnosis and initiation of management in order to decrease overuse of specialty care and improve the quality of specialist visits. We measured the quality of incontinence care provided by primary care clinicians prior to referral to a specialist and evaluated the impact of provider variables on quality of care. METHODS: We performed a retrospective review of 200 women referred for urinary incontinence to a Female Pelvic Medicine and Reconstructive Surgery specialist between March 2017 and July 2018. We measured primary care adherence to 12 quality indicators in the 12 months prior to specialist consultation. We stratified adherence to quality indicators by clinician sex and years of experience. RESULTS: Half of women with incontinence underwent a pelvic examination or had a urinalysis ordered. Few patients with urge urinary incontinence were recommended behavioral therapy (14%) or prescribed medication (8%). When total aggregate scores were compared, female clinicians performed the recommended care 47% ± 25% of the time, compared with 35% ± 23% for male clinicians (P = .003). Increasing years of experience was associated with worse overall urinary incontinence care (r -0.157, P = .02). CONCLUSIONS: We found low rates of adherence to a set of quality indicators for women with urinary incontinence, with male clinicians performing significantly worse than female clinicians. Improvement of incontinence care in primary care could significantly reduce costs of care and preserve outcomes.

How Early in Life do Transgender Adults Begin to Experience Gender Dysphoria? Why This Matters for Patients, Providers, and for Our Healthcare System.

INTRODUCTION: The age at which transgender women (TW) and men (TM) first experience gender dysphoria (GD) has not been reported in a U.S. population of adults seeking genital gender-affirming surgery (gGAS). Because gender is an innate part of identity, we hypothesized that untreated GD would be a part of individuals' earliest memories. Understanding GD onset can help guide providers with when and how to focus care to patients not yet identified as "transgender AIM: (i) Determine the age at which transgender adults seeking gGAS first experience GD (ii) Determine the number of life-years that transgender adults spend living with untreated GD METHODS: During initial consultation for gGAS, we asked patients the earliest age at which they experienced GD and the age at which they had their earliest episodic memory. We also queried history of anxiety, depression, and suicide attempt. MAIN OUTCOME MEASURES: Patients self-reported their earliest recollections of experiencing GD, earliest memories in general, and history of anxiety, depression, and suicide attempt. RESULTS: Data from 155 TW (mean age 41.3; SD 16.3) and 55 TM (mean age 35.4; SD 10.8) were collected. Most patients (TM: 78%; TW: 73%) reported experiencing GD for the first time between ages 3 and 7 years.  For TM the mean age of onset was 6.17 years; for TW it was 6.71 years. A total of 81% of TW and 80% of TM described their first recollection of GD as one of their earliest memories. Mean years of persistent GD before the start of gender transition were 22.9 (TM) and 27.1 (TW). Rates of depression, anxiety, and suicide ideation decreased following gender transition. CONCLUSION: Our findings suggest that GD typically manifests in early childhood and persists untreated for many years before individuals commence gender transition. Diagnosis and early management during childhood and adolescence can improve quality of life and survival. Zaliznyak M, Yuan N, Bresee C, et al. How Early in Life do Transgender Adults Begin to Experience Gender Dysphoria? Why This Matters for Patients, Providers, and for Our Healthcare System. Sex Med 2021;9:100448.

Pseudomonas aeruginosa mexR and mexEF Antibiotic Efflux Pump Variants Exhibit Increased Virulence.

Antibiotic-resistant Pseudomonas aeruginosa infections are the primary cause of mortality in people with cystic fibrosis (CF). Yet, it has only recently become appreciated that resistance mutations can also increase P. aeruginosa virulence, even in the absence of antibiotics. Moreover, the mechanisms by which resistance mutations increase virulence are poorly understood. In this study we tested the hypothesis that mutations affecting efflux pumps can directly increase P. aeruginosa virulence. Using genetics, physiological assays, and model infections, we show that efflux pump mutations can increase virulence. Mutations of the mexEF efflux pump system increased swarming, rhamnolipid production, and lethality in a mouse infection model, while mutations in mexR that increased expression of the mexAB-oprM efflux system increased virulence during an acute murine lung infection without affecting swarming or rhamnolipid gene expression. Finally, we show that an efflux pump inhibitor, which represents a proposed novel treatment approach for P. aeruginosa, increased rhamnolipid gene expression in a dose-dependent manner. This finding is important because rhamnolipids are key virulence factors involved in dissemination through epithelial barriers and cause neutrophil necrosis. Together, these data show how current and proposed future anti-Pseudomonal treatments may unintentionally make infections worse by increasing virulence. Therefore, treatments that target efflux should be pursued with caution.

IMACTIV: A Pilot Study of the Impact of Unrestricted Activity Following Urethral Sling Surgery.

OBJECTIVES: To compare continence outcomes and health-related quality of life (HRQOL) among women with limited activity restrictions vs traditional restrictions following mid-urethral sling (MUS) surgery. METHODS: Thirty-six women who underwent MUS surgery were randomized: (1) the Restrictions group was given traditional postoperative restrictions for 6 weeks while (2) the Limited Restrictions group was instructed to resume normal activities other than pelvic rest. Patients undergoing concomitant surgery for Stage III and IV prolapse were excluded. Participants completed questionnaires related to urinary symptoms (UDI-6, IIQ-7) for continence outcomes and HRQOL (SF-12) at baseline, 1 to 6 weeks, 3 months, 6 months, and at least 1 year after surgery. RESULTS: There was no difference in mean scores on the UDI-6 or IIQ-7 between groups at baseline or any time after surgery. The Limited Restrictions group reported better scores than the Restrictions group on the SF-12 mental health component at 1 week (56.7 vs 50.2, P = .01) and 4 weeks (58.4 vs 53.3, P = .04). The Restrictions group reported better SF-12 physical health scores at 5 weeks (55.7 vs 53.0, P = .02) but there was no difference in HRQOL scores between the two groups at any other time. CONCLUSION: In this pilot study, there was no difference in continence outcomes for women with traditional vs limited activity restrictions following MUS surgery. There were differences in HRQOL in the early post-operative period, but these differences were not sustained. Larger prospective studies are needed, but it appears that activity restrictions after MUS surgery may not be necessary.

Comorbidities in a Nationwide, Heterogenous Population of Veterans with Interstitial Cystitis/Bladder Pain Syndrome.

OBJECTIVE: To examine the prevalence of comorbid conditions in a nationwide population of men and women with IC/BPS utilizing a more heterogeneous sample than most studies to date. METHODS: Using the Veterans Affairs Informatics and Computing Infrastructure, we identified random samples of male and female patients with and without an ICD-9/ICD-10 diagnosis of IC/BPS. Presence of comorbidities (NUAS [chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, migraines], back pain, diabetes, and smoking) and psychosocial factors (alcohol abuse, post-traumatic stress disorder, sexual trauma, and history of depression) were determined using ICD-9 and ICD-10 codes. Associations between these variables and IC/BPS status were evaluated while adjusting for the potential confounding impact of race/ethnicity, age, and gender. RESULTS: Data was analyzed from 872 IC/BPS patients (355 [41%] men, 517 [59%] women) and 558 non-IC/BPS patients (291 [52%] men, 267 [48%] women). IC/BPS patients were more likely than non-IC/BPS patients to have a greater number of comorbidities (2.72+/-1.77 vs 1.73+/-1.30, P < 0.001), experience one or more NUAS (chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and migraines) (45% [388/872] vs. 18% [101/558]; P < 0.001) and had a higher prevalence of at least one psychosocial factor (61% [529/872] v. 46% [256/558]; P < 0.001). Differences in the frequencies of comorbidities between patients with and without IC/BPS were more pronounced in female patients. CONCLUSION: These findings validate the findings of previous comorbidity studies of IC/BPS in a more diverse population.

Progesterone in Addition to Standard of Care vs Standard of Care Alone in the Treatment of Men Hospitalized With Moderate to Severe COVID-19: A Randomized, Controlled Pilot Trial.

BACKGROUND: Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care (SOC) would improve clinical outcomes of hospitalized men with moderate to severe COVID-19. RESEARCH QUESTION: Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19? STUDY DESIGN AND METHODS: We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes. RESULTS: Forty-two patients were enrolled from April 2020 to August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study before receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to day 7 in patients in the progesterone group as compared with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects. INTERPRETATION: Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC, may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov.

Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHD.

PURPOSE: Severe (grade 3-4) acute graft-versus-host disease (AGVHD) is a major cause of death after unrelated-donor (URD) hematopoietic cell transplant (HCT), resulting in particularly high mortality after HLA-mismatched transplantation. There are no approved agents for AGVHD prevention, underscoring the critical unmet need for novel therapeutics. ABA2 was a phase II trial to rigorously assess safety, efficacy, and immunologic effects of adding T-cell costimulation blockade with abatacept to calcineurin inhibitor (CNI)/methotrexate (MTX)-based GVHD prophylaxis, to test whether abatacept could decrease AGVHD. METHODS: ABA2 enrolled adults and children with hematologic malignancies under two strata: a randomized, double-blind, placebo-controlled stratum (8/8-HLA-matched URD), comparing CNI/MTX plus abatacept with CNI/MTX plus placebo, and a single-arm stratum (7/8-HLA-mismatched URD) comparing CNI/MTX plus abatacept versus CNI/MTX CIBMTR controls. The primary end point was day +100 grade 3-4 AGVHD, with day +180 severe-AGVHD-free-survival (SGFS) a key secondary end point. Sample sizes were calculated using a higher type-1 error (0.2) as recommended for phase II trials, and were based on predicting that abatacept would reduce grade 3-4 AGVHD from 20% to 10% (8/8s) and 30% to 10% (7/8s). ABA2 enrolled 142 recipients (8/8s, median follow-up = 716 days) and 43 recipients (7/8s, median follow-up = 708 days). RESULTS: In 8/8s, grade 3-4 AGVHD was 6.8% (abatacept) versus 14.8% (placebo) (P = .13, hazard ratio = 0.45). SGFS was 93.2% (CNI/MTX plus abatacept) versus 82% (CNI/MTX plus placebo, P = .05). In the smaller 7/8 cohort, grade 3-4 AGVHD was 2.3% (CNI/MTX plus abatacept, intention-to-treat population), which compared favorably with a nonrandomized matched cohort of CNI/MTX (30.2%, P < .001), and the SGFS was better (97.7% v 58.7%, P < .001). Immunologic analysis revealed control of T-cell activation in abatacept-treated patients. CONCLUSION: Adding abatacept to URD HCT was safe, reduced AGVHD, and improved SGFS. These results suggest that abatacept may substantially improve AGVHD-related transplant outcomes, with a particularly beneficial impact on HLA-mismatched HCT.