Breast Arterial Calcifications on Mammography: Awareness and Reporting Preferences Amongst Referring Physicians in Canada.

Purpose: Breast arterial calcifications (BAC) on mammography have been correlated with increased cardiovascular risk. The Canadian Society of Breast Imaging released a position statement on BAC reporting in January 2023. This study evaluates the awareness of the clinical significance of BAC and reporting preferences of referring physicians in Canada. Methods: A 15-question survey was distributed to Canadian physicians who may review mammography results via regional and subspecialty associations and on social media following local institutional ethical approval. Responses were collected over 10 weeks from February to April 2023. Results: Seventy-two complete responses were obtained. We are unable to determine the response rate, given the means of distribution. Only 17% (12/72) of responding physicians were previously aware of the association between BAC and increased cardiovascular risk, and 51% (37/72) preferred the inclusion of BAC in the mammography report. Fifty-six percent (40/72) indicated that BAC reporting would prompt further investigation, and 63% (45/72) would inform patients that their mammogram showed evidence of BAC. Sixty-nine percent (50/72) would find grading of BAC beneficial and 71% (51/72) agreed that there is a need for national guidelines. Conclusion: Less than a quarter of responding Canadian referring physicians were previously aware of the association between BAC and cardiovascular risk, although half of respondents indicated a preference for BAC reporting on mammography. Most participating physicians would inform their patients of the presence of BAC and consider further cardiovascular risk management. There was consensus that a national BAC grading system and clinical management guidelines would be beneficial.

Planetary Health and Radiology: Why We Should Care and What We Can Do.

Climate change adversely affects the well-being of humans and the entire planet. A planetary health framework recognizes that sustaining a healthy planet is essential to achieving individual, community, and global health. Radiology contributes to the climate crisis by generating greenhouse gas (GHG) emissions during the production and use of medical imaging equipment and supplies. To promote planetary health, strategies that mitigate and adapt to climate change in radiology are needed. Mitigation strategies to reduce GHG emissions include switching to renewable energy sources, refurbishing rather than replacing imaging scanners, and powering down unused scanners. Radiology departments must also build resiliency to the now unavoidable impacts of the climate crisis. Adaptation strategies include education, upgrading building infrastructure, and developing departmental sustainability dashboards to track progress in achieving sustainability goals. Shifting practices to catalyze these necessary changes in radiology requires a coordinated approach. This includes partnering with key stakeholders, providing effective communication, and prioritizing high-impact interventions. This article reviews the intersection of planetary health and radiology. Its goals are to emphasize why we should care about sustainability, showcase actions we can take to mitigate our impact, and prepare us to adapt to the effects of climate change. © RSNA, 2024 Supplemental material is available for this article. See also the article by Ibrahim et al in this issue. See also the article by Lenkinski and Rofsky in this issue.

Environmental Sustainability and MRI: Challenges, Opportunities, and a Call for Action.

The environmental impact of magnetic resonance imaging (MRI) has recently come into focus. This includes its enormous demand for electricity compared to other imaging modalities and contamination of water bodies with anthropogenic gadolinium related to contrast administration. Given the pressing threat of climate change, addressing these challenges to improve the environmental sustainability of MRI is imperative. The purpose of this review is to discuss the challenges, opportunities, and the need for action to reduce the environmental impact of MRI and prepare for the effects of climate change. The approaches outlined are categorized as strategies to reduce greenhouse gas (GHG) emissions from MRI during production and use phases, approaches to reduce the environmental impact of MRI including the preservation of finite resources, and development of adaption plans to prepare for the impact of climate change. Co-benefits of these strategies are emphasized including lower GHG emission and reduced cost along with improved heath and patient satisfaction. Although MRI is energy-intensive, there are many steps that can be taken now to improve the environmental sustainability of MRI and prepare for the effects of climate change. On-going research, technical development, and collaboration with industry partners are needed to achieve further reductions in MRI-related GHG emissions and to decrease the reliance on finite resources. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 6.

Disparities in Radiologist Fee-For-Service Payments by Gender in Canada.

Objective: To examine differences in fee-for-service (FFS) payments to men and women radiologists in Canada and evaluate potential contributors. Methods: Publicly available FFS radiology billing data was analyzed from British Columbia (BC), Ontario (ON), Prince-Edward Island (PEI) and Nova Scotia (NS) between 2017 and 2021. Data was analyzed by gender on a per-province and national level. Variables evaluated included year, province, procedure billings, and days worked (BC and ON only). The gender pay gap was expressed as the difference in mean billing payments between men and women divided by mean payments to men. Results: Data points from 8478 radiologist years were included (2474 [29%] women and 6004 [71%] men). The unadjusted difference in annual FFS billings between men and women was $126,657. Overall, payments to women were 81% of payments to men with a 19% gender pay gap. The difference in billings between men and women did not change significantly between 2017 and 2021 (range in gender pay gap, 17-21%) but did vary by province (highest gap NS). Compared to men, women worked fewer days per year (weighted mean 218 ± 29 vs 236 ± 25 days/year, P < .001, 8% difference). Conclusion: In an analysis of fee-for-service payments to radiologists in 4 Canadian provinces between 2017 and 2021, payments to women were 81% of payments to men with a 19% gender pay gap. Payments were lower to women across all years evaluated. Women worked 8% fewer days per year on average than men, which did not fully account for the difference in FFS billing payments between men and women. Summary Statement: In an analysis of fee-for-service payments to Canadian radiologists between 2017 and 2021, payments to women were 81% of payments to men with a 19% gender pay gap which is not fully accounted for by time spent working.

Retrospective Evaluation of Splenic Artery Embolization Outcomes in the Management of Blunt Splenic Trauma: A Single Centre Experience at a Large Level 1 Trauma Centre.

PURPOSE: Retrospective review of splenic artery embolization (SAE) outcomes performed for blunt abdominal trauma. MATERIALS AND METHODS: 11-year retrospective review at a large level-1 Canadian trauma centre. All patients who underwent SAE after blunt trauma were included. Technical success was defined as angiographic occlusion of the target vessel and clinical success was defined as successful non-operative management and splenic salvage on follow-up. RESULTS: 138 patients were included of which 68.1% were male. The median age was 47 years (interquartile range (IQR) = 32.5 years). The most common mechanisms of injury were motor vehicle accidents (37.0%), mechanical falls (25.4%), and pedestrians hit by motor vehicles (10.9%). 70.3% of patients had American Association for the Surgery of Trauma (AAST) grade 4 injuries. Patients were treated with proximal SAE (n = 97), distal SAE (n = 23) or combined SAE (n = 18), and 68% were embolized with an Amplatzer plug. No significant differences were observed across all measures of hospitalization (Length of hospital stay: x2(2) = .358, P = .836; intensive care unit (ICU) stay: x2(2) = .390, P = .823; ICU stay post-procedure: x2(2) = 1.048, P = .592). Technical success and splenic salvage were achieved in 100% and 97.8% of patients, respectively. 7 patients (5%) had post-embolization complications and 7 patients (5%) died during hospital admission, but death was secondary to other injuries sustained in the trauma rather than complications related to splenic injury or its management. CONCLUSION: We report that SAE as an adjunct to non-operative management of blunt splenic trauma can be performed safely and effectively with a high rate of clinical success.

Latent burnout profiles of veterinarians in Canada: Findings from a cross-sectional study.

BACKGROUND: Although burnout is often discussed as 'present' or 'not-present', the conceptual framework of an engagement-burnout continuum is more accurate and useful. Recognition of individuals' transitional states of burnout also allows for earlier detection of issues and tailored interventions to address the full burnout spectrum. METHODS: Previously reported Maslach Burnout Inventory-Human Services Scale (MBI-HSS) data from a 2017 national survey of 1272 veterinarians across Canada were re-analysed using a latent profile analysis to classify individuals along the engagement-burnout continuum. RESULTS: Four clusters were identified: engaged (10.8%), ineffective (18.9%), overextended (29.6%) and burnout (40.7%). These results indicate that most participants (89.2%) had one, or a combination, of high exhaustion, high depersonalisation and low professional efficacy. LIMITATIONS: This cross-sectional study represents data from one point in time and may be subject to response bias. CONCLUSION: We discuss strategies-particularly long-term, organisational-level interventions-to promote engagement and help address workplace issues contributing to inefficacy, overextension and burnout in the veterinary profession. We also recommend MBI data be analysed via latent profiles to provide a more nuanced view of burnout, allow for earlier recognition of workplace issues and facilitate more meaningful interventions and comparisons across populations.

Correlation Between Breast Arterial Calcifications and Higher Cardiovascular Risk: Awareness and Attitudes Amongst Canadian Radiologists Who Report Mammography.

Background: Breast arterial calcification (BAC) on mammography correlates with increased cardiovascular risk. Reporting BAC is not standard practice. Our study evaluates the awareness of Canadian radiologists who report mammography of the clinical significance of BAC and their attitudes towards reporting BAC compared to their European and American counterparts. Methods: Following local institutional ethics approval, a 25 question survey (SurveyMonkey) was disseminated to Canadian radiologists via provincial and national society email lists. Responses were collected over 5 weeks (April-June 2022). Results: One hundred and eighty-six complete responses were collected. Sixty percent (112/186) were aware of the association between BAC and cardiovascular risk and 16% (29/186) document its presence in mammogram reports. Thirty five percent (65/186) occasionally document BAC if severe or in a young patient. Four percent (7/186) had local departmental guidelines on BAC reporting and 82% (153/186) agreed there is a need for national BAC reporting guidelines. Fewer Canadian radiologists were aware of the association between BAC and cardiovascular risk compared to European radiologists (60% vs 81%), report the presence of BAC compared to both European (15% vs 62%) and American (15% vs 35%) radiologists, and inform the patient of the presence of BAC compared to European radiologists (1% vs 46%). Conclusion: Canadian radiologists who report mammography were less aware of the association between BAC and cardiovascular risk than their European and American counterparts and were less likely to document the presence of BAC. Given the correlation of BAC with increased cardiovascular event risk, there is increased need for awareness as well as national BAC reporting guidelines.

PHASE 2 RANDOMIZED STUDY (ORION-1) OF A NOVEL, BIODEGRADABLE DEXAMETHASONE IMPLANT (AR-1105) FOR THE TREATMENT OF MACULAR EDEMA DUE TO CENTRAL OR BRANCH RETINAL VEIN OCCLUSION.

PURPOSE: AR-1105 is a novel biodegradable sustained-release dexamethasone implant designed to deliver 6-month durability. This Phase 2 study evaluated two AR-1105 formulations with different release profiles in patients with macular edema due to retinal vein occlusion. METHODS: Patients received a single intravitreal injection with 340 µg dexamethasone. In the initial phase, five patients received clinical formulation (CF) 1. In the randomized phase, 44 patients were randomized 1:1 to CF1 or CF2. The follow-up was 6 months. Patients had vision loss due to macular edema diagnosed ≥9 (central retinal vein occlusion) or ≥12 months (branch retinal vein occlusion) before screening, and could be treatment-naive or -experienced (if received prior steroids, must have demonstrated response). RESULTS: Both formulations improved vision and reduced retinal thickening from baseline across all visits. At Month 6, mean changes in best-corrected visual acuity were +4.3 and +8.0 letters, and mean changes in central subfield thickness were -93 µm and -211 µm in CF1 and CF2 randomized patients, respectively. Most common adverse events were reduced visual acuity, worsening macular edema, conjunctival hemorrhage, and increased intraocular pressure. No patients required surgery or laser for intraocular pressure control. CONCLUSION: Both formulations were well tolerated and demonstrated clinically meaningful and sustained improvements in vision and retinal thickening in patients with retinal vein occlusion with longstanding edema.

High Psychosocial Work Demands, Decreased Well-Being, and Perceived Well-Being Needs Within Veterinary Academia During the COVID-19 Pandemic.

Higher psychosocial work demands in veterinary and academic professions are associated with decreased occupational, physical, and mental well-being. COVID-19 introduced far-reaching challenges that may have increased the psychosocial work demands for these populations, thereby impacting individual- and institutional-level well-being. Our objective was to investigate the psychosocial work demands, health and well-being, and perceived needs of faculty, staff, residents and interns at the Ontario Veterinary College, in Ontario, Canada, during COVID-19. A total of 157 respondents completed a questionnaire between November 2020 and January 2021, that included the Third Version of the Copenhagen Psychosocial Questionnaire (COPSOQ-III) and open-text questions on perceived needs for well-being. Results showed that COPSOQ-III dimensions of quantitative demands, recognition, sense of community, burnout, stress, and depressive symptoms, were significantly worse in our study population than the Canadian norm. Quantitative and emotional demands, health and well-being (including depressive symptoms, stress, cognitive stress, somatic stress, and burnout), and work-life conflict were also reported to have worsened since the COVID-19 restrictions for most respondents. Females and caregivers had higher odds of experiencing increased work demands, and decreased health and well-being, compared to males and non-caregivers. However, male caregivers experienced worsened supervisor relations, compared to female caregivers. Social capital also worsened for clinical and part-time employees, compared to full-time and non-clinical employees. Respondents identified increased workload support, community-building, recognition of employees' capacities and personal needs, flexible work schedules, and consistent communication, as strategies to increase well-being during COVID-19 and generally. Overall, our findings suggest that COVID-19 has increased occupational demands, work-life conflicts, and decreased well-being in veterinary academia. Institutional-level interventions are discussed and recommended to aid individual and institutional well-being.

Netarsudil Improves Trabecular Outflow Facility in Patients with Primary Open Angle Glaucoma or Ocular Hypertension: A Phase 2 Study.

PURPOSE: Intraocular pressure (IOP) reduction is key to controlling primary open angle glaucoma (POAG). Pharmacotherapies for POAG or ocular hypertension (OHT) commonly lower IOP by increasing uveoscleral outflow or decreasing aqueous humor production. Netarsudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by improving trabecular outflow facility, which is reduced in POAG. We investigated the effects of netarsudil on aqueous humor dynamics in patients with POAG or OHT. DESIGN: Double-masked, randomized, vehicle-controlled, Phase 2 trial. METHODS: Netarsudil 0.02% was instilled in 1 eye and vehicle into the contralateral eye of 20 patients once daily in the morning for 7 days. The primary endpoint was change in mean diurnal outflow facility on day 8 versus that on day 1 (baseline). Outflow facility was measured by using Schiøtz tonography, IOP by pneumotonometry, and episcleral venous pressure (EVP) by automated venomanometry. RESULTS: Eighteen patients (90%) completed the study. Mean diurnal outflow facility increased 0.039 versus 0.007 µL/min/mm Hg from baseline in the netarsudil- and the vehicle-treated groups, respectively (P < .001 vs. baseline for netarsudil), a treatment difference of 0.03 µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change from baseline at day 8 was -4.52 mm Hg for netarsudil versus -0.98 mm Hg for vehicle, a treatment difference of -3.54 mm Hg (P < .0001). Mean diurnal EVP change from baseline was -0.79 mm Hg in the netarsudil-treated group versus 0.10 mm Hg for vehicle, a treatment difference of -0.89 mm Hg (P < .001). All patients reporting an adverse event reported conjunctival hyperemia of mild or moderate severity. CONCLUSIONS: Netarsudil acts on the conventional outflow pathway, both proximal and distal, to significantly reduce IOP in POAG and OHT by improving trabecular outflow facility and decreasing EVP.

A Randomized, Phase 2 Study of 24-h Efficacy and Tolerability of Netarsudil in Ocular Hypertension and Open-Angle Glaucoma.

INTRODUCTION: Pharmacotherapy to lower intraocular pressure (IOP) is a mainstay of treatment aimed at delaying progression of visual field loss in ocular hypertension (OHT) and open-angle glaucoma (OAG), but some topical treatments are less effective in controlling IOP at night. Peak IOP may be related to glaucoma progression and can occur outside office hours. A phase 2 study was conducted to evaluate the IOP-lowering efficacy of netarsudil across the diurnal and nocturnal periods. METHODS: This was a randomized, double-masked, single-center, vehicle-controlled, 9-day study. After washout of any prior ocular hypotensive agents, 12 patients with OHT or OAG underwent baseline IOP assessment at 15:00, 18:00, 21:00, 00:00, 03:00, 06:00, 09:00, and 12:00 h on day 1/day 2. Participants were then randomized in a 2:1 ratio to netarsudil ophthalmic solution 0.02% (n = 8) or vehicle (n = 4) for 7 days of self-administered dosing each evening. IOP was assessed at the same time points on day 8/day 9. All measurements were conducted with a Perkins tonometer in habitual positions by day (seated) and at night (supine). RESULTS: Baseline mean 24-h IOP was 22.4 mmHg in the netarsudil group and 22.9 mmHg in the vehicle group. Netarsudil was associated with a reduction in mean nocturnal IOP (measurements at 21:00, 00:00, 03:00, 06:00 h) of 3.5 mmHg, which was significant relative to baseline nocturnal IOP (P < 0.001) and the reduction in the vehicle group (0.4 mmHg; P < 0.001 vs. netarsudil). Reduction in mean diurnal IOP with netarsudil (3.5 mmHg) was the same as the nocturnal reduction and statistically significant versus baseline (P < 0.001) and the vehicle group (0.9 mmHg; P < 0.01). The magnitude of IOP reductions with netarsudil was consistent at each time point assessed over the 24-h period. No adverse events were reported. CONCLUSION: Netarsudil exhibited consistent IOP-lowering efficacy over a 24-h period in this short-term study. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02874846.

When pressure inside the eye (called intraocular pressure [IOP]) builds up, a patient may develop a condition known as glaucoma, in which damage to the optic nerve and possibly irreversible vision loss occur. Glaucoma can be preceded in some patients by a condition called ocular hypertension (OHT). Patients with OHT and the most common type of glaucoma (open-angle glaucoma [OAG]) should be treated to lower their IOP and decrease the risk for progressive visual loss. Several studies that have evaluated 24-h IOP control have indicated that some eye drops lower IOP less effectively at night than during the day. A pilot study was conducted in 12 patients with OHT or OAG to evaluate netarsudil's IOP lowering effect during the day and at night. After a week of treatment with netarsudil or a similar eye drop that did not contain the active drug, patients who took netarsudil experienced the same decrease in IOP at night as during the day. IOP was statistically lower with netarsudil than with the drug-free comparator both during the day and at night. Although this was a small study in 12 patients, the results are of interest because they suggest that netarsudil might consistently reduce IOP over a 24-h period.

One Year of Netarsudil and Latanoprost Fixed-Dose Combination for Elevated Intraocular Pressure: Phase 3, Randomized MERCURY-1 Study.

PURPOSE: A phase 3 trial (MERCURY-1) investigated efficacy and safety of a once-daily, fixed-dose combination (FDC) of netarsudil and latanoprost, compared with each active component, in reducing elevated intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). A planned 3-month analysis demonstrated the superiority of netarsudil/latanoprost FDC over its individual active components at every assessment. Herein, the 12-month efficacy and safety of netarsudil/latanoprost FDC are reported. DESIGN: Double-masked, randomized, active-controlled, parallel-group trial. PARTICIPANTS: Patients had unmedicated IOP >20 to <36 mmHg in both eyes at 8:00 am and met other standard criteria for OAG or OHT. METHODS: Randomization to once-daily netarsudil 0.02%/latanoprost 0.005% FDC (n = 238), netarsudil 0.02% only (n = 243), or latanoprost 0.005% only (n = 237). Patients instilled study drug into each eye between 8:00 pm and 10:00 pm. MAIN OUTCOME MEASURES: IOP was obtained at 8:00 am, 10:00 am, and 4:00 pm on day 1 (baseline); at weeks 2 and 6; and at months 3, 6, 9, and 12. Ocular and systemic safety were evaluated up to month 12. RESULTS: Netarsudil/latanoprost FDC maintained statistically superior IOP lowering compared to its components at every assessment for 12 months. Least squares mean diurnal IOP (± standard error) at month 12 was 16.2 ± 0.23 mmHg for netarsudil/latanoprost FDC, 17.9 ± 0.20 mmHg for netarsudil, and 17.6 ± 0.18 mmHg for latanoprost (P < 0.05 for netarsudil/latanoprost FDC versus each comparator). The safety profile of netarsudil/latanoprost FDC was consistent with its individual components. The proportion of patients who experienced at least 1 adverse event (AE) was 82.8% (197/238) in the netarsudil/latanoprost FDC group, 78.2% (190/243) in the netarsudil group, and 54.0% (128/237) in the latanoprost group. The most common AE was conjunctival hyperemia, mostly of mild severity, with an incidence of 63.0% in the netarsudil/latanoprost FDC treatment group compared with 51.4% in the netarsudil group and 21.9% in the latanoprost group. CONCLUSIONS: Results at 12 months revealed superior efficacy for netarsudil/latanoprost FDC compared with the individual components, netarsudil and latanoprost, at every time point assessed and an ocular tolerability profile similar to that of netarsudil alone.

Pooled Efficacy and Safety Profile of Netarsudil Ophthalmic Solution 0.02% in Patients With Open-angle Glaucoma or Ocular Hypertension.

PRECIS: In pooled phase III analyses, once-daily netarsudil 0.02% resulted in intraocular pressure (IOP) reduction that was noninferior to twice-daily timolol 0.5%, with minimal treatment-related serious or systemic adverse events (AEs). Ocular AEs were generally tolerable. PURPOSE: The purpose of this study was to assess the efficacy and safety of the Rho kinase inhibitor netarsudil in patients with open-angle glaucoma or ocular hypertension. PATIENTS AND METHODS: Pooled analysis of data from the ROCKET-1 to 4 phase III studies of once-daily (PM) netarsudil or twice-daily timolol in patients with open-angle glaucoma or ocular hypertension. The primary efficacy measure was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3 in patients with baseline IOP <25 mm Hg. RESULTS: In the pooled primary efficacy population (netarsudil, n=494; timolol, n=510), once-daily netarsudil was noninferior to twice-daily timolol at all 9 timepoints through month 3. Mean treated IOP ranged from 16.4 to 18.1 mm Hg among netarsudil-treated patients and 16.8 to 17.6 mm Hg among timolol-treated patients. In the pooled safety population (n=839 in each treatment group), treatment-related serious AEs occurred at similar frequencies in each treatment group (netarsudil, 0.1%; timolol, 0%). The most common ocular AE, conjunctival hyperemia (netarsudil, 54.4%; timolol, 10.4%), was graded as mild in 77.6% (354/456) of affected netarsudil-treated patients. CONCLUSIONS: Once-daily netarsudil resulted in IOP lowering that was noninferior to twice-daily timolol, with tolerable ocular AEs that were generally mild and self-resolving. As a first-in-class agent in the United States, with a novel mechanism of action, netarsudil may provide a useful therapeutic option for patients who would benefit from IOP lowering.

Fixed-Dose Combination of Netarsudil and Latanoprost in Ocular Hypertension and Open-Angle Glaucoma: Pooled Efficacy/Safety Analysis of Phase 3 MERCURY-1 and -2.

INTRODUCTION: New open-angle glaucoma (OAG) and ocular hypertension (OHT) therapies that reduce treatment burden and improve outcomes relative to currently available agents are needed. Netarsudil, a novel Rho kinase inhibitor approved by the US Food and Drug Administration, reduces intraocular pressure (IOP) by increasing trabecular outflow. Two phase 3 superiority studies compared a fixed-dose combination (FDC) of netarsudil and the prostaglandin latanoprost with each active component for IOP-lowering efficacy. METHODS: Pooled efficacy and safety data were analyzed from MERCURY-1 and -2 studies in patients with OAG or OHT. Patients instilled one drop of netarsudil (0.02%)/latanoprost (0.005%) FDC (n = 483), netarsudil (0.02%, n = 499), or latanoprost (0.005%, n = 486) into each eye once-daily between 20:00 and 22:00. IOP was measured at 08:00, 10:00, and 16:00 at weeks 2, 6, and the primary endpoint at month 3. RESULTS: Baseline mean diurnal IOP was 23.6, 23.6, and 23.5 mmHg in netarsudil/latanoprost FDC, netarsudil, and latanoprost groups, respectively. Mean diurnal IOP in each group was 15.3, 18.1, and 17.5 mmHg at week 2, 15.7, 18.4, and 17.4 mmHg at week 6, and 15.8, 18.4, and 17.3 mmHg at week 12. The netarsudil/latanoprost FDC met criteria for superiority compared with each active component (p < 0.0001 for all nine time points). At month 3, among patients randomized to netarsudil/latanoprost FDC or latanoprost, 58.4% vs 37.3% (p < 0.0001) achieved IOP ≤ 16 mmHg. Among patients randomized to netarsudil/latanoprost FDC or netarsudil or latanoprost, 30.9% vs 5.9% (p < 0.0001) vs 8.5% (p < 0.0001) achieved at least a 40% reduction from baseline in mean diurnal IOP. Pooled safety results were consistent with individual MERCURY studies. CONCLUSION: Once-daily netarsudil/latanoprost FDC produced statistically significant and clinically relevant reductions in mean IOP that were statistically superior to IOP reductions achieved by netarsudil and latanoprost monotherapy. Results of the pooled efficacy and safety analyses were consistent with the individual studies. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT02558400 and NCT02674854.

In patients with open-angle glaucoma (OAG) or ocular hypertension (OHT), treatment to lower intraocular pressure (IOP) is needed to prevent optic nerve damage and vision loss. Many patients do not achieve sufficient IOP lowering with a single drug. The use of multiple IOP-lowering agents, which may have different dose regimens, can be complex and reduce patient adherence. Combination treatments that incorporate multiple agents are available, but until recently none included a prostaglandin analogue, the most widely prescribed first-line therapy. A once-daily, fixed-dose combination (FDC) therapy (ROCKLATAN^®) has been approved in the USA that contains the prostaglandin analogue latanoprost and netarsudil, a novel Rho kinase inhibitor. The netarsudil/latanoprost FDC demonstrated efficacy and safety in lowering IOP among patients with OAG and OHT in the 12-month MERCURY-1 and the 3-month MERCURY-2 clinical trials. To better characterize efficacy and safety, we pooled and analyzed the data from each trial. The pooled data support the findings of the individual studies:Efficacy: 1. Netarsudil/latanoprost FDC demonstrated statistical superiority to the individual components netarsudil and latanoprost in decreasing IOP at all time points assessed over 3 months. 2. Nearly twice as many patients receiving FDC achieved at least a 30% reduction from baseline in IOP, as recommended by the American Academy of Ophthalmology for a first-line treatment, compared to the IOP reduction achieved by netarsudil and latanoprost monotherapy.Safety: No new safety signals were identified. Netarsudil/latanoprost FDC was associated with no treatment-related serious adverse events, minimal systemic adverse events, and manageable ocular adverse events.

Long-term gene expression in dividing and nondividing cells using SV40-derived vectors.

Among the goals of gene therapy is long-term expression of delivered transgenes. Recombinant Tagdeleted SV40 vectors (rSV40s) are especially well suited for this purpose. rSV40s deliver transgene expression that endures for extended periods of time in tissue culture and in vivo, in both dividing and nondividing cells. These vectors are particularly effective in transducing some cell types that have been almost unapproachable using other gene delivery systems, such as quiescent hematopoietic progenitor cells and their differentiated derivatives. Other cellular targets include neurons, brain microglia, hepatocytes, dendritic cells, vascular endothelium, and others. Because rSV40s do not elicit neutralizing antibodies they are useful for in vivo gene delivery in settings where more than one administration may be desirable. The key characteristics of these vectors include their high production titers and therefore suitability for large cell pools, effectiveness in delivering intracellular proteins, and untranslated RNAs, maintenance of transgene expression at constant levels for extended times, suitability for constitutive or conditional promoters and for combinatorial gene delivery and ability to integrate into genomes of both dividing and nondividing cells.

What they are, how they work and why they do what they do? The story of SV40-derived gene therapy vectors and what they have to offer.

The natural function of viruses is to deliver their genetic material to cells. Among the most effective of viruses in doing that is Simian Virus-40 (SV40). The properties that make SV40 a successful virus make it an attractive candidate for use as a gene delivery vehicle: high titer replication, infectivity for almost all nucleated cell types whether the cells are dividing or resting, potential for integration into cellular DNA, a peculiar pathway for entering cells that bypasses the cells' antigen processing apparatus, very high stability, and the apparent ability to activate expression of its own capsid genes in trans. Exploiting these and other characteristics of wild type (wt) SV40, increasing numbers of laboratories are studying recombinant (r) SV40-derived vectors. Among the uses to which these vectors have been applied are: delivering therapy to inhibit HIV, hepatitis C virus (HCV) and other viruses; correction of inherited hepatic and other protein deficiencies; immunizing against lentiviral and other antigens; treatment of inherited and acquired diseases of the central nervous system; protecting the lung and other organs from free radical-induced injury; and many others. The effectiveness of these vectors is a reflection of the adaptive evolution that produced their parent virus, wt SV40. This article explores how and why these vectors work, their strengths and their limitations, and provides a functional model for their exploitation for experimental and clinical applications.

Durable cytotoxic immune responses against gp120 elicited by recombinant SV40 vectors encoding HIV-1 gp120 +/- IL-15.

BACKGROUND: A vaccine that elicits durable, powerful anti-HIV immunity remains an elusive goal. In these studies we tested whether multiple treatments with viral vector-delivered HIV envelope antigen (gp120), with and without IL-15, could help to approach that goal. For this purpose, we used recombinant Tag-deleted SV40-derived vectors (rSV40s), since they do not elicit neutralizing antibody responses, and so can be given multiply without loss of transduction efficiency. METHODS: SV(gp120) carried the coding sequences for HIV-1NL4-3 Env, and SV(mIL-15) carried the cDNA for mouse IL-15. Singly, and in combination, these two vectors were given monthly to BALB/cJ mice. Cytotoxic immunity and cytotoxic memory were tested in direct cytotoxicity assays using unselected effector cells. Antibody vs. gp120 was measured in a binding assay. In both cases, targets were P815 cells that were stably transfected with gp120. RESULTS: Multiple injections of SV(gp120) elicited powerful anti-gp120 cytolytic activity (>70% specific lysis) by unselected spleen cells. Cells from multiply-immunized mice that were rested 1 year after their last injections still showed >60% gp120-specific lysis. Anti-gp120 antibody was first detected after 2 monthly injections of SV(gp120) and remained elevated thereafter. Adding SV(mIL-15) to the immunization regimen dramatically accelerated the development of memory cytolytic responses, with >/= 50% specific lysis seen 1 month after two treatments. IL-15 did not alter the development of antibody responses. CONCLUSIONS: Thus, rSV40s encoding antigens and immunostimulatory cytokines may be useful tools for priming and/or boosting immune responses against HIV.

Immune responses against SIV envelope glycoprotein, using recombinant SV40 as a vaccine delivery vector.

Vaccination protocols using viral gene delivery vectors have often generated relatively weak responses, largely owing to difficulties in boosting immune responses effectively following the primary injection. Because recombinant gene delivery vectors derived from SV40 permit multiple inoculations, to yield incremental immune responses, we tested the use of rSV40s to deliver lentiviral envelope antigens for immunization. An rSV40 carrying SIVmac239 envelope glycoprotein gp130 cDNA (SV(gp130)) was given multiple times to BALB/c mice, with or without a prior priming inoculation using vaccinia virus carrying the same SIV envelope cDNA (VVenvSIV). Sera from these mice were tested for antibodies binding gp130, applying a novel cell-based ELISA protocol that used as targets cloned P815 cells stably transfected with plasmid-derived gp130 cDNA. The same gp130-expressing clone of P815 cells, labeled with 51Cr was used as targets for direct lymphocyte-mediated cytolytic assays using spleen and popliteal lymph node cells as effectors. After six inoculations with SV(gp130), mice made detectable anti-gp130 antibody responses, but high levels of splenic and popliteal lymph node cytotoxic activity were apparent after as few as three injections of SV(gp130) (>40% specific lysis). A single primary inoculation with VVenvSIV preceding SV(gp130) boosts significantly enhanced antibody responses against SIV gp130, but had little effect on cytotoxic lymphocyte responses. Thus, rSV40 vectors may be useful vehicles for delivering lentiviral envelope antigens to elicit protective humoral and cell-mediated immune responses.