Double-Masked, Vehicle-Controlled, Randomized, Phase II Study of the Ocular Hypotensive Activity and Safety of VVN539 Ophthalmic Solution.

Purpose: To assess safety and ocular hypotensive efficacy of VVN539 ophthalmic solution in a first-in-human study. Design: Multicenter, double-masked, randomized, vehicle-controlled, dose-response, parallel-comparison study. Participants: Sixty-eight subjects with ocular hypertension (OHT) or open-angle glaucoma enrolled at 5 private practices. Methods: After washout of ocular hypotensive medications as required, the subjects were randomized to receive either VVN539 ophthalmic solution 0.02%, 0.04%, or vehicle once-daily (QD) in the morning (5 days), once-daily in the evening (6 days) and then twice-daily (6 days). Main Outcome Measures: Comparison of VVNM539 to its vehicle in mean intraocular pressure (IOP) at each diurnal time point (8:00am, 10:00am, and 4:00pm) at visit 4 (day 7), visit 5 (day 14), and visit 6 (day 21). Results: Mean IOP decreased throughout dosing in the active groups to between 18 and 20 mmHg in both active groups, to between 22 to 23 mmHg in the vehicle group. VVN539 0.04% was statistically superior to vehicle at all 9 diurnal time points (QD AM, QD PM, and twice daily, P ≤ 0.0109). VVN539 0.02% was statistically superior to vehicle at only 6 of 9 diurnal time points (selected QD times and twice daily). The most common ocular treatment-emergent adverse event was conjunctival hyperemia (11 [47.8%], 10 [4.5%], and 1 [4.3%]), followed by ocular hyperemia (3 [13.0%], 5 [22.7%] and 0), respectively. There were no clinically significant changes of note in visual acuity, biomicroscopy, dilated ophthalmoscopy, blood chemistry, hematology, or cardiovascular measures. Conclusions: In conclusion, the results of this initial phase II study indicate that VVN539 ophthalmic solution showed clinically and statistically significant ocular hypertensive activity and was relatively well tolerated for the treatment of subjects with primary open-angle glaucoma or OHT. Additional studies will be required for a more complete evaluation of the utility of VVN539 ophthalmic solution. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A phase 2a, double-masked, randomized, vehicle-controlled trial of VVN001 in subjects with dry eye disease.

PURPOSE: Evaluate the initial ocular safety and tolerability and efficacy of VVN001 Ophthalmic Solution (VVN001), a small-molecule antagonist of lymphocyte function-associated antigen-1 (LFA-1), in subjects with dry eye disease (DED). METHODS: This was a multi-center, double-masked, randomized, dose-response, vehicle-controlled, parallel-group study conducted in 170 subjects with DED. Subjects were randomized to receive VVN001 (1% or 5%) or its vehicle, twice-daily in both eyes for 84 days. The primary outcome measure was inferior region corneal fluorescein staining (iCFS, 0-4 scale) at Day 84. Visual Analogue Scale eye dryness (VAS, 0-100 scale) was a secondary outcome. RESULTS: The primary and first secondary outcomes were not met. At Day 84 treatment effects in favor of VVN001 5% relative to its vehicle for iCFS were 0.29 units (p = 0.054), and for VAS were 3.18 units (p = 0.533). In other secondary outcomes, treatment effects in favor of VVN001 5% relative to its vehicle were seen in total CFS (1.61 units, 0-20 scale, p = 0.004) and Schirmer score (1.77 and 2.32 mm, p = 0.049 and p = 0.17 at Days 14 and 28 respectively). Adverse events of incidence 5% or greater in either active treatment group were instillation site pain (3/57, 5.3%), dysgeusia (3/56, 5.4%) and urinary tract infection (3/57, 5.3%). CONCLUSIONS: There were no major safety issues of note. Appropriately powered studies will be required with a priori selection of the efficacy endpoints to evaluate VVN001's therapeutic potential.

Racial and Socioeconomic Disparities in MRI-Fusion Biopsy Utilization to Assess for Prostate Cancer.

OBJECTIVE: To evaluate whether racial disparities in MRI-Bx usage persisted after correction for socioeconomic, demographic, and clinical factors. METHODS: This is a retrospective cohort study of patients who received either MRI-Bx or systematic biopsy (SB) within a single academic medical center between January 2018 - June 2020. For each patient, socioeconomic variables including household income, education, percent below poverty, and unemployment were estimated using 2015 American Community Survey census-tract level data. Chi-square analysis was used to examine differences in clinical and demographic characteristics between the two groups. The Benjamini-Hochberg procedure was used to control false discovery rate (FDR) for multiple testing. RESULTS: Eighteen percent of Black men (53/295) received MRI-Bx while 41% (228/561) of white men received MRI-Bx. Patients coming from highly impoverished areas were less likely to receive MRI-Bx, 25% vs 75%, respectively. In multivariate analysis, race remained significantly different across MRI-Bx and SB groups. Clinical factors including family history, DRE, BMI, and prostate volume were not significantly different between patients receiving MRI-Bx and SB. CONCLUSION: Black men are less likely to receive MRI-Bx than white men, even after adjusting for clinical and socioeconomic characteristics. Further work is necessary to identify and study methods to increase equity in PCa diagnostic testing.

Racial Disparities in Prostate Specific Antigen Screening and Referral to Urology in a Large, Integrated Health Care System: A Retrospective Cohort Study.

PURPOSE: Contemporary trends and racial disparities in prostate cancer screening and referral to urology for prostate cancer risk are not well characterized, despite consensus that Black men are at higher risk for poor prostate cancer outcomes. The objective of this study was to characterize current racial disparities in prostate cancer screening and referral from primary care to urology for prostate cancer concern within our large, integrated health care system. MATERIALS AND METHODS: This retrospective cohort study used data from Atrium Health's enterprise data warehouse, which includes patient information from more than 900 care locations across North Carolina, South Carolina and Georgia. We included all men seen in the ambulatory or outpatient setting between 2014 and 2019 who were ≥40 years old. Clinical and demographic data were collected for all men, including age and race. Racial outcomes were reported for all groups with >2% representation in the population. Between-group comparisons were determined using chi-squared analysis, Wilcoxon rank sum testing and multivariable logistic regression, with significance defined as p <0.05. RESULTS: We observed a significant decrease in prostate specific antigen testing across all age and racial groups in a cohort of 606,985 men at Atrium Health, including 87,189 Black men, with an overall relative decline of 56%. As compared to White men, Black men were more likely to undergo prostate specific antigen testing (adjusted OR 1.24, 95% CI 1.22-1.26) and be referred to urology for prostate cancer (adjusted OR 1.94, 95% CI 1.75-2.16). CONCLUSIONS: There was a continued significant decline in prostate cancer screening between 2014 and 2019. Despite having modestly elevated odds of being screened for prostate cancer compared to White men, Black men are relatively underscreened when considering that those who undergo prostate specific antigen screening are more likely to be referred by primary care to urology for additional prostate cancer diagnostic evaluation.

Advancing the Use of Laparoscopy in Trauma: Repair of Intraperitoneal Bladder Injuries.

Traumatic intraperitoneal bladder rupture (IBR) requires surgical repair. Traditionally performed via laparotomy, experience with laparoscopic bladder repair (LBR) after blunt trauma is limited. Benefits of laparoscopy include decreased length of stay (LOS), less pain, early return to work, fewer adhesions, and lower risk of incisional hernia. The aim of this series is to demonstrate the potential superiority of LBR in select trauma patients. This is a retrospective review performed of all IBR patients from 2008 to 2016. Demographics, clinical management, outcomes, and follow-up were compared between LBR and open bladder repair (OBR) patients. Twenty patients underwent OBR, and seven underwent LBR. There was no significant difference in gender, age, or Injury Severity Score. There were no deaths or reoperations in either group. Average hospital length of stay and ICU days were similar between groups. There was one patient with UTI and one with readmission in each group. There were two incisional hernias and two bowel obstructions in the OBR group, with one patient requiring operative intervention. No such complications occurred in the LBR group. LBR for traumatic IBR can be safely performed in select patients, even in those with multiple extra-abdominal injuries.

Retzius-Sparing Robotic-Assisted Laparoscopic Radical Prostatectomy: A Safe Surgical Technique with Superior Continence Outcomes.

PURPOSE: To report early operative outcomes and assess continence in 100 consecutive patients who underwent Retzius-sparing robotic-assisted laparoscopic radical prostatectomy (RALP). MATERIALS AND METHODS: This was a prospective, single-center, consecutive case series of 100 and 100 patients undergoing a Retzius-sparing and a conventional RALP, respectively, by a single surgeon between March 2015 and April 2017. RESULTS: Baseline patient characteristics were similar between the two groups. The Retzius-sparing approach required significantly less console time (120.0 minutes vs 144.0 minutes, p < 0.001). There were no differences between intra- and post-operative complication rates, and hospital length of stay was similar in the two groups. Incidence of positive surgical margins was nonsignificantly different between the two groups, with 17% and 13% of pT2 patients and 49% and 48% of pT3 patients in the Retzius-sparing and conventional groups, respectively. Patients in the Retzius-sparing group had significantly superior rates of achieving post-operative urinary continence (log-rank test: p < 0.001), with 20% of patients continent within the first month, compared with 8% of patients in the conventional group. The mean number of pads per day needed at 3, 6, 9, and 12 months post-operatively was also significantly lower in the Retzius-sparing group. CONCLUSIONS: Retzius-sparing RALP requires shorter console time, is oncologically safe, and leads to significantly superior continence outcomes compared with conventional RALP.

Scapula fracture incidence in reverse total shoulder arthroplasty using screws above or below metaglene central cage: clinical and biomechanical outcomes.

BACKGROUND: Reverse total shoulder arthroplasty (RTSA) is a viable treatment option for rotator cuff tear arthropathy but carries a complication risk of scapular fracture. We hypothesized that using screws above the central glenoid axis for metaglene fixation creates a stress riser contributing to increased scapula fracture incidence. Clinical type III scapular fracture incidence was determined with screw placement correlation: superior screw vs. screws placed exclusively below the glenoid midpoint. Cadaveric RTSA biomechanical modeling was employed to analyze scapular fractures. METHODS: We reviewed 318 single-surgeon single-implant RTSAs with screw correlation to identify type III scapular fractures. Seventeen cadaveric scapula specimens were matched for bone mineral density, metaglenes implanted, and fixation with 2 screw configurations: inferior screws alone (group 1INF) vs. inferior screws with one additional superior screw (group 2SUP). Biomechanical load to failure was analyzed. RESULTS: Of 206 patients, 9 (4.4%) from the superior screw group experienced scapula fractures (type III); 0 fractures (0/112; 0%) were identified in the inferior screw group. Biomechanically, superior screw constructs (group 2SUP) demonstrated significantly (P < .05) lower load to failure (1077 N vs. 1970 N) compared with constructs with no superior screws (group 1INF). There was no significant age or bone mineral density discrepancy. CONCLUSION: Clinical scapular fracture incidence significantly decreased (P < .05) for patients with no screws placed above the central cage compared with patients with superior metaglene screws. Biomechanical modeling demonstrates significant construct compromise when screws are used above the central cage, fracturing at nearly half the ultimate load of the inferior screw constructs. We recommend use of inferior screws, all positioned below the central glenoid axis, unless necessary to stabilize the metaglene construct.

Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.

Cross-beta fibrous protein aggregates (amyloids and amyloid-based prions) are found in mammals (including humans) and fungi (including yeast), and are associated with both diseases and heritable traits. The Hsp104/70/40 chaperone machinery controls propagation of yeast prions. The Hsp70 chaperones Ssa and Ssb show opposite effects on [PSI(+)], a prion form of the translation termination factor Sup35 (eRF3). Ssb is bound to translating ribosomes via ribosome-associated complex (RAC), composed of Hsp40-Zuo1 and Hsp70-Ssz1. Here we demonstrate that RAC disruption increases de novo prion formation in a manner similar to Ssb depletion, but interferes with prion propagation in a manner similar to Ssb overproduction. Release of Ssb into the cytosol in RAC-deficient cells antagonizes binding of Ssa to amyloids. Thus, propagation of an amyloid formed because of lack of ribosome-associated Ssb can be counteracted by cytosolic Ssb, generating a feedback regulatory circuit. Release of Ssb from ribosomes is also observed in wild-type cells during growth in poor synthetic medium. Ssb is, in a significant part, responsible for the prion destabilization in these conditions, underlining the physiological relevance of the Ssb-based regulatory circuit.