Vision 2020: A View of Our Energy Future

The Morning Address was given by The Honorable George Allen. “The Regulatory Framework: Where Are We Headed?” session by Eric Finkbeiner, Senior Adviser for Policy, Office of Governor Robert McDonnell; David Christian, Chief Executive Officer, Dominion Generation; and Professor Joel Eisen, University of Richmond School of Law. Professor Noah Sachs, University of Richmond School of Law, served as moderator. “The Future of Coal” session by John Lain, Partner at McGuireWoods LLP; Cale Jaffe, Senior Attorney with the Southern Environmental Law Center; and W. Thomas Hudson, President of W. Thomas Hudson and Associates, Inc. and of the Virginia Coal Association. Stephen E. Taylor, Allen Chair Editor for the University of Richmond Law Review, served as moderator. “Nuclear Power: Is There a ‘Renaissance’?” session by Donald Irwin, Hunton & Williams; Christopher Paine, Director of Nuclear Program, Natural Resources Defense Council (invited); and Michael H. Montgomery, Vice President of Fuel Development, Lightbridge Corporation. Tricia Dunlap, Robert R. Merhige, Jr. Fellow at the University of Richmond School of Law, served as moderator. “Emerging Issues in Energy Policy” session by Mark Rosen, Deputy General Counsel, CNA Corporation; Jefferson Reynolds, Water Policy Director with the Virginia Department of Environmental Quality; Kruskaia Sierra-Escalante, Senior Counsel for the International Finance Corporation; and Edward Lowe, General Manager for Renewable Energy Market Development, GE Energy. Andrea W. Wortzel, Counsel with Hunton & Williams and Vice Chair of the Environmental Law Section of the Virginia State Bar, served as moderator. The Closing Address was given by The Honorable Carol M. Browner, Assistant to the President for Energy and Climate Change and Former Administrator of the Environmental Protection Agency (invited)

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Enhancing Topical Pharmacotherapy for Acne and Rosacea: Vehicle Choices and Outcomes

The choice of vehicle is an important consideration in the treatment of acne and rosacea. Agents used to treat these common conditions may be limited by multiple factors, including poor stability during storage, limited residence time in the skin and follicular unit, and high potential for skin irritation. Novel drug delivery systems have been developed to address these problems, including microencapsulation, liposomal encapsulation, and the use of a variety of nanocarriers. New vehicle technologies for acne and rosacea treatments have appeared over the past 20 years and have somewhat improved stability, tolerability, and possibly efficacy. One of the latest vehicle technologies in acne and rosacea to enhance efficacy, stability, and tolerability is microencapsulation of benzoyl peroxide and tretinoin, which resulted in significant efficacy and good tolerability in patients with each of these two diseases. Other new vehicle technologies include a polymeric form of tretinoin and a microsphere product that combines tretinoin plus clindamycin. It is likely that there will be more reports of clinical success as experience with the rapidly evolving delivery technologies increases. This review summarizes drug delivery systems that have been developed with the aim of improving outcomes for patients being treated for either acne or rosacea. It also focuses, where possible, on formulations that have been evaluated in clinical studies

The antiinflammatory properties of ivermectin and brimonidine in the treatment of papulopustular rosacea

Introduction: The pathophysiology of papulopustular rosacea (PPR) is not fully understood; however, there is increasing evidence that immune and inflammatory responses play an important role in the persistent and perilesional erythema of PPR. Multiple trials have demonstrated the efficacy of ivermectin 1% cream (IVM) and brimonidine 0.33% gel (BR) for treatment of the inflammatory lesions and erythema of PPR, respectively. Two recent studies suggest a promising synergy between IVM and BR in PPR. Methods: In mice, ear edema was induced via topical TPA 0.01%, followed by topical vehicle, IVM (0.1% to 1%), or BR 0.2%. Ear thickness (μm) was measured using a micrometer. In human subjects, in a multicenter, randomized, double-blind, vehicle-controlled study of moderate/severe rosacea (Investigator Global Assessment [IGA] ≥3) patients were treated with once-daily: 1. BR (morning) and IVM (evening), 12 weeks (IVM+BR/12W; n = 49); 2. BR vehicle and IVM, 4 weeks, followed by BR and IVM, 8 weeks (IVM+BR/8W; n = 46); 3. BR vehicle and IVM vehicle, 12 weeks (n = 95). Assessments included IGA (0-4), Clinician’s Erythema Assessment (CEA; 0-4), and inflammatory lesion count. Adverse events (AEs) were monitored throughout the study. Results: In the mouse, IVM treatment inhibited TPA induced skin inflammation in a dose dependent manner, and combination treatment using topical IVM and BR further reduced ear edema. Clinically, IVM+BR showed superior efficacy in all subgroups, with the greatest efficacy seen in the IVM+BR/12W group vs. vehicle (IGA success [clear/almost clear], 61.2% vs. 36.8%; P = .003). Eight treatment-related AEs in 6 subjects (3.2%) were reported (including treatment-related worsening of rosacea: 1 with IVM+BR [subject 8090-116], 3 with vehicle). Summary: Adding BR to IVM treatment reduced inflammation in vivo, and demonstrated good efficacy and safety clinically. This treatment combination may improve treatment success without impairing tolerability

27611 Fixed-combination halobetasol propionate 0.01%/tazarotene 0.045% (HP/TAZ) lotion for the treatment of plaque psoriasis in patients with 3-5% body surface area (BSA) and poor quality of life (QoL)

Use of TAZ with topical steroids, such as superpotent HP, is recommended for mild-to-moderate psoriasis as the combination may provide synergistic efficacy while increasing duration of treatment effect and remission. The objective of this analysis was to investigate HP 0.01%/TAZ 0.045% lotion in patients with relatively low affected BSA and poor QoL, as objective measures such as BSA may underestimate disease severity. Two phase 3, multicenter, double-blind studies enrolled 418 adults with 3-12% BSA and Investigator’s Global Assessment (IGA) score of 3 or 4 (‘moderate’ or ‘severe’) at baseline. Participants were randomized (2:1) to receive HP/TAZ or vehicle lotion once-daily for 8 weeks, with a 4-week posttreatment follow-up. Pooled, post hoc analyses were conducted in a subset of 65 participants with baseline BSA of 3-5% and Dermatology Life Quality Index (DLQI) score ≥11. At week 8, 50.3% of HP/TAZ-treated participants achieved treatment success (≥2-grade reduction from baseline in IGA and score of 0 or 1 [‘clear’ or ‘almost clear’]), vs 14.6% of vehicle-treated participants (P ˂.05). BSA was significantly reduced with HP/TAZ ( 39.2%) vs vehicle lotion (+15.9%; P ˂.05). The percentage of participants experiencing a clinically meaningful ≥4-point reduction in DLQI score was greater for HP/TAZ (85.3%) vs vehicle (55.6%). Numerical improvements with HP/TAZ lotion were maintained 4-weeks posttreatment for efficacy measures and DLQI, consistent with the overall population. Though analyses were limited by the small population, HP/TAZ lotion provided significantly greater efficacy vs vehicle in participants with low BSA and poor QoL, with clinically relevant improvements in QoL

Treatment of Rosacea With Concomitant Use of Topical Ivermectin 1% Cream and Brimonidine 0.33% Gel: A Randomized, Vehicle-controlled Study

BACKGROUND: There is currently a lack of data on the simultaneous treatment of different features of rosacea. Individually, ivermectin 1% (IVM) cream and brimonidine 0.33% (BR) gel have demonstrated efficacy on inflammatory lesions and persistent erythema, respectively. OBJECTIVE: To evaluate the efficacy, safety, patient satisfaction, and optimal timing of administration of IVM associated with BR (IVM+BR) versus their vehicles in rosacea (investigator global assessment [IGA] ≥3). METHODS: Multicenter, randomized, double-blind study including subjects with rosacea characterized by moderate to severe persistent erythema and inflammatory lesions. The active treatment group included the IVM+BR/12 weeks subgroup (once-daily BR and once-daily IVM for 12 weeks), and the IVM+BR/8 weeks subgroup (once-daily BR vehicle for 4 weeks followed by once-daily BR for the remaining 8 weeks and once-daily IVM for 12 weeks). The vehicle group received once-daily BR vehicle and once-daily IVM vehicle for 12 weeks. RESULTS: The association showed superior efficacy (IGA success [clear/almost clear]) for erythema and inflammatory lesions in the total active group (combined active subgroups) compared to vehicle (55.8% vs. 36.8%, P=0.007) at week 12. The success rate increased from 32.7% to 61.2% at hour 0 and hour 3, respectively, in the IVM+BR/12 weeks subgroup, and from 28.3% to 50% in the IVM+BR/8 weeks subgroup. Reductions in erythema and inflammatory lesion counts confirmed the additive effect of BR to IVM treatment. Subjects reported greater improvement in the active subgroups than in the vehicle group, and similar rates for facial appearance satisfaction after the first 4 weeks of treatment in both active subgroups. All groups showed similar tolerability profiles. CONCLUSION: Concomitant administration of IVM cream with BR gel demonstrated good efficacy and safety, endorsing the comprehensive approach to this complex disease. Early introduction of BR, along with a complete daily skin care regimen may accelerate treatment success without impairing tolerability. J Drugs Dermatol. 2017;16(9):909-916

Efficacy and safety of topical oxymetazoline cream 1.0% for the treatment of facial erythema associated with rosacea: Findings from the second of 2 pivotal trials

Introduction: A phase 3 pivotal trial examined the efficacy and safety of oxymetazoline, a specific α1A-adrenoceptor agonist, for treatment of moderate to severe persistent facial erythema associated with rosacea. Methods: In this multicenter double-blind trial, eligible patients were randomized 1:1 to receive vehicle or oxymetazoline hydrochloride cream 1.0% (oxymetazoline) applied topically to the face once daily for 29 days. The primary efficacy outcome was the proportion of patients with ≥2-grade decrease from baseline on Clinician Erythema Assessment (CEA) and Subject Self-Assessment (SSA) at 3, 6, 9, and 12 hours postdose on day 29. Safety assessments included treatment-emergent adverse events (TEAEs), inflammatory lesions, dermal tolerability, and posttreatment rebound erythema (defined as composite CEA/SSA increase of 1-grade severity from baseline). Results: A total of 445 eligible patients (mean age: 50.3 years; 78.7% females) were randomized (oxymetazoline, n = 224; vehicle, n = 221). Most patients had moderate erythema (CEA: 84.0%; SSA: 91.5%). On day 29, the proportions of patients achieving ≥2-grade composite improvement in both CEA/SSA at 3, 6, 9, and 12 hours postdose were significantly greater with oxymetazoline vs vehicle at each time point ( P ≤ .03) and overall ( P = .001). Improvements in individual CEA and SEA components were also significantly greater with oxymetazoline vs vehicle on day 29 (overall P = .011). Incidences of TEAEs were low (oxymetazoline: 25.1%; placebo: 21.3%); most were mild or moderate in severity. The most common TEAEs with oxymetazoline and vehicle, respectively, were rosacea (3.1% [related to papules and/or pustules in all 7 patients] and 0.5% [inflammatory flare of rosacea in 1 patient]), application-site pruritus (1.8%, 1.8%), application-site dermatitis (1.8%, 0.0%), and headache (1.8%, 4.1%). Discontinuations due to TEAEs were low (oxymetazoline: 2.7%; vehicle: 0.5%). No clinically meaningful between-group differences were observed for worsening of inflammatory lesions or dermal tolerability. Following treatment cessation, low proportions of patients experienced rebound erythema (oxymetazoline: 1.2%; vehicle: 0.0%). Conclusion: Topical oxymetazoline was safe and effective in the treatment of moderate to severe persistent facial erythema associated with rosacea. There was no apparent rebound effect following cessation of oxymetazoline treatment compared with that experienced following cessation of vehicle treatment

Supplement Article: Skin Barrier Deficiency in Rosacea: An Algorithm Integrating OTC Skincare Products Into Treatment Regimens

INTRODUCTION: Rosacea is a chronic condition involving inflammation leading to a diminished skin barrier function in sebaceous gland-rich facial skin. The current algorithm represents part II of a series investigating similar topics associated with preventing, treating, and maintaining rosacea, including ceramides-containing skincare. METHODS: The consensus process consisted of a modified Delphi technique. A previously published review by the US Cutaneous Rosacea Outcomes (USCRO) group on skin barrier deficiency in rosacea and the integration of over-the-counter (OTC) products and skincare recommended for rosacea treatment and maintenance informed the development of the current algorithm. The selected information from the literature searches, coupled with the USCRO group\u27s opinion and experience, was used to develop, discuss, and reach a consensus on an evidence-based clinical treatment and maintenance algorithm focusing on rosacea phenotypes. RESULTS: The algorithm includes foundational measures to be taken by all patients with rosacea and rosacea-prone skin. These measures include education, behavioral modifications, avoidance of triggers and skin irritants, preventative skincare, and sun avoidance and sunscreen use. The algorithm further describes how assessment of skin condition and grading of cutaneous rosacea should take place during treatment and maintenance while the preventative measures continue. CONCLUSIONS: Prescription medications combined with gentle cleansers, moisturizers, and sunscreen support a successful rosacea therapy. J Drugs Dermatol. 2022;21:9(Suppl 1):s3-10

Concurrent administration of ivermectin 1% cream with brimonidine 0.33% gel improves efficacy and tolerability in treatment of moderate-to-severe rosacea

Background/Objective: Multiple studies have demonstrated the efficacy of ivermectin 1% (IVM) cream (inflammatory lesions) and brimonidine 0.33% (BR) gel (persistent erythema). This prospective study evaluated the efficacy and safety of IVM and BR versus their vehicles in moderate-to-severe rosacea. Methods: This was a multicenter, randomized, double-blind, vehicle-controlled study in moderate-to-severe rosacea (Investigator Global Assessment [IGA] ?3). The study comprised three arms. The two active treatment arms were: 1) once-daily BR (morning) and IVM (evening) for 12 weeks (IVM+BR/12W; n=49); or 2) Once-daily BR vehicle for four weeks, followed by once-daily BR for eight weeks (morning), and once-daily IVM for 12 weeks (evening; IVM+BR/8W; n=46). The the vehicle arm stipulated once-daily BR vehicle (morning) and IVM vehicle (evening), 12 weeks (n=95). A general skin care regimen (cleanser/moisturizer/sunscreen) was provided/recommended. IGA (0–4), Clinician’s Erythema Assessment (CEA; 0–4), percent change from baseline inflammatory lesion count (ILC), percentage of subjects with 10- percent IL reduction, subject global rosacea improvement, and facial appearance questionnaire. Adverse events (AEs) were monitored throughout the study. Results: The total IVM and BR population showed superior efficacy (Week 12, Hour 3; IGA success [clear/almost clear]) versus vehicle (55.8% vs. 36.8%, p=0.007); IVM and BR/12W showed better efficacy versus vehicle (61.2% vs. 36.8%, p=0.003) than IVM and BR/8W (50% vs. 36.8%, p=0.135). At Week 12, success increased for IVM and BR/12W (32.7%, Hour 0 [pre-BR application]; 61.2%, Hour 3 [post-BR application) and IVM and BR/8W (28.3%, Hour 0; 50%, Hour 3). CEA and median percent change in ILC improved with IVM and BR/12W and IVM and BR/8W vs vehicle (p\u3c0.01). IVM and BR/12W trended toward higher efficacy. Eight treatment-related AEs in six subjects (3.2%) were reported (including treatment-related worsening of rosacea: 1 with IVM and BR, 3 with vehicle). Conclusion: Administration of IVM cream with BR gel demonstrated good efficacy and safety. Early introduction of BR (Day 1; with a complete daily skin care regimen) might benefit efficacy and accelerate treatment success without impairing tolerability. Funding: This analysis was funded by Galderma R&D. G. Schäfer and N. Kerrouche are employees of Galderma