Limited impact on decadal-scale climate change from increased use of natural gas.

The most important energy development of the past decade has been the wide deployment of hydraulic fracturing technologies that enable the production of previously uneconomic shale gas resources in North America. If these advanced gas production technologies were to be deployed globally, the energy market could see a large influx of economically competitive unconventional gas resources. The climate implications of such abundant natural gas have been hotly debated. Some researchers have observed that abundant natural gas substituting for coal could reduce carbon dioxide (CO2) emissions. Others have reported that the non-CO2 greenhouse gas emissions associated with shale gas production make its lifecycle emissions higher than those of coal. Assessment of the full impact of abundant gas on climate change requires an integrated approach to the global energy-economy-climate systems, but the literature has been limited in either its geographic scope or its coverage of greenhouse gases. Here we show that market-driven increases in global supplies of unconventional natural gas do not discernibly reduce the trajectory of greenhouse gas emissions or climate forcing. Our results, based on simulations from five state-of-the-art integrated assessment models of energy-economy-climate systems independently forced by an abundant gas scenario, project large additional natural gas consumption of up to +170 per cent by 2050. The impact on CO2 emissions, however, is found to be much smaller (from -2 per cent to +11 per cent), and a majority of the models reported a small increase in climate forcing (from -0.3 per cent to +7 per cent) associated with the increased use of abundant gas. Our results show that although market penetration of globally abundant gas may substantially change the future energy system, it is not necessarily an effective substitute for climate change mitigation policy.

IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis.

BACKGROUND: Hyperactivity of the IL-23/IL-17 axis is central to plaque psoriasis pathogenesis. Secukinumab, a fully human mAb that selectively inhibits IL-17A, is approved for treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab improves the complete spectrum of psoriasis manifestations, with durable clinical responses beyond 5 years of treatment. In the feed-forward model of plaque chronicity, IL-17A has been hypothesized as the key driver of pathogenic gene expression by lesional keratinocytes, but in vivo evidence in human subjects is lacking. METHODS: We performed a randomized, double-blind, placebo-controlled study (NCT01537432) of patients receiving secukinumab at the clinically approved dose up to 12 weeks. We then correlated plaque and nonlesional skin transcriptomic profiles with histopathologic and clinical measures of efficacy. RESULTS: After 12 weeks of treatment, secukinumab reversed plaque histopathology in the majority of patients and modulated thousands of transcripts. Suppression of the IL-23/IL-17 axis by secukinumab was evident at week 1 and continued through week 12, including reductions in levels of the upstream cytokine IL-23, the drug target IL-17A, and downstream targets, including ß-defensin 2. Suppression of the IL-23/IL-17 axis by secukinumab at week 4 was associated with clinical and histologic responses at week 12. Secukinumab did not affect ex vivo T-cell activation, which is consistent with its favorable long-term safety profile. CONCLUSION: Our data suggest that IL-17A is the critical node within the multidimensional pathogenic immune circuits that maintain psoriasis plaques and that early reduction of IL-17A-dependent feed-forward transcripts synthesized by hyperplastic keratinocytes favors plaque resolution.

QUiC Clinics in the Central Texas Market: Value-Based Primary Care in Military Medicine.

INTRODUCTION: For the past 16 years, Military Health System primary care providers have been incentivized to pursue work in a fee-for-service (FFS) model. The system values documentation of productivity to earn as many relative value units as possible. The result is densely packed clinic schedules that often lack the space or flexibility to accommodate patients when sick. Leakage ensues. Furthermore, prevention and patient experience are not directly incentivized. METHODS: The Central Texas Market's Accountable Care Organization reformed incentives in its #5 FFS-designed community-based medical homes to value outcomes over productivity. The resulting quality, urgent, internet, and phone care (QUiC) clinics are value-based and, therefore, better structured to achieve the Quad aim (better care, better health/readiness, and low cost). Forsaking deeply ingrained FFS practices, QUiC clinics funnel all routine (information-sharing) appointments into efficient internet or phone appointments. With the time freed by managing common needs in short bursts, QUiC clinics see sick patients with no notice (urgent care). They also focus on prevention and patient experience. We measured the effectiveness of the QUiC clinics in the value-based metrics of (1) patient experience, (2) Healthcare Effectiveness Data and Information Set measures of quality and prevention. (3) access-to-care, (4) leakage, and (5) enrollment. RESULTS: Over a 19 month period, the five community-based medical homes improved significantly in all areas. Specifically, measures of patient satisfaction improved from the mid-80s percent satisfied to the mid-90s percent satisfied. Healthcare Effectiveness Data and Information Set measures increased from average compared to national benchmarks (<50th percentile to 75th percentile) to the 90th percentile in four of five measures of quality and the 75th percentile in the remaining measure. Access to care for routine appointments decreased from 15.4 days to the third next available appointment to 2.8 days. Leakage decreased from 12.2% to 9.6%. These successes were attained without cost or significant reductions in patient enrollments. In changing workflows, the market became the #1 user of virtual video visits in the DOD. CONCLUSIONS: This performance improvement project proved the concept that a military market can vastly improve value-based primary care outcomes at no cost and within multiple community-based clinics.

Effects of aliskiren, a direct Renin inhibitor, on cardiac repolarization and conduction in healthy subjects.

This multicenter, double-blind study evaluated the effects of aliskiren, a direct renin inhibitor approved for hypertension, on cardiac repolarization and conduction. Healthy volunteers (n = 298) were randomized to aliskiren 300 mg, aliskiren 1200 mg, moxifloxacin 400 mg (positive control), or placebo once daily for 7 days. Digitized electrocardiograms were obtained at baseline and day 7 of treatment over 23 hours postdose. Placebo-adjusted mean changes from baseline in QTcF (Fridericia corrected), QTcI (individualized correction), PR, and QRS intervals were compared at each time point (time-matched analysis) and for values averaged across the dosing period (baseline-averaged analysis). In time-matched analysis, mean changes in QTcF with aliskiren were below predefined limits for QTc prolongation (mean increase <5 milliseconds; upper 90% confidence interval [CI] <10 milliseconds) except aliskiren 1200 mg at 23 hours (5.2 milliseconds; 90% CI 2.2, 8.1). With moxifloxacin, significant QTcF prolongation occurred at most time points, confirming the sensitivity of the assay. Baseline-averaged analysis was consistent with time-matched analysis. Instances of QTcF interval >450 milliseconds or a >30-millisecond increase from baseline with aliskiren (< or = 1%) were similar or lower than placebo (< or = 4%). Results were similar for QTcI. Aliskiren had no effect on PR or QRS duration. In conclusion, aliskiren at the highest approved dose (300 mg) and a 4-fold higher dose had no effect on cardiac repolarization or conduction in healthy volunteers.

Pharmacokinetics/pharmacodynamics of desloratadine and fluoxetine in healthy volunteers.

The authors assessed the potential for a pharmacokinetic/pharmacodynamic interaction between desloratadine and fluoxetine. This randomized, placebo-controlled, open-label study was conducted in 54 healthy volunteers. Subjects received 1 of 3 treatments: desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo. Serial electrocardiograms (ECGs) were performed at baseline and day 35. Treatment effects on C(max) and AUC were assessed. During coadministration of desloratadine with fluoxetine, the ratio of the mean log-transformed C(max) and AUC values for desloratadine following concomitant fluoxetine therapy revealed a small increase in C(max) values of 15% (90% confidence interval [CI], 95%-139%) but no increase for AUC values (90% CI, 82%-123%). Corresponding values for 3-OH desloratadine demonstrated small increases in mean log-transformed C(max) and AUC ratios: 17% (90% CI, 100%-136%) and 13% (90% CI, 96%-132%), respectively. Statistical evaluation of the ratio of the mean C(max) and AUC values for fluoxetine following concomitant desloratadine therapy revealed small decreases of 9% (90% CI, 72%-115%) and 11% (90% CI, 69%-113%), respectively. Corresponding values for norfluoxetine demonstrated modest increases in mean log-transformed C(max) and AUC ratios: 22% (90% CI, 100%-139%) and 18% (90% CI, 101%-136%), respectively. Coadministration of desloratadine with a potent inhibitor of CYP2D6 did not result in clinically relevant changes in its pharmacokinetic parameters. Desloratadine administration was not associated with clinically important changes in the pharmacokinetics of fluoxetine, a drug metabolized by CYP2D6. The most common adverse event in all groups was headache (65%). Desloratadine plus fluoxetine caused no significant changes in ECGs or ventricular rate.

Effect of food on the pharmacokinetics of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet in healthy volunteers.

OBJECTIVE: Vildagliptin is an orally active, potent and selective DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes by increasing alpha- and beta-cell responsiveness to glucose. RESEARCH DESIGN AND METHODS: This open-label, single-center, randomized, two-period crossover study in healthy subjects (n=23) ages 18-45 years investigated the effect of food on the pharmacokinetics of vildagliptin and metformin following administration of a vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet. RESULTS: Administration of the fixed-dose combination tablet following a high-fat meal had no effect on vildagliptin AUC(0-infinity) (ratio of geometric mean for fed:fasted state, 1.10 [90% CI 1.03, 1.18]), C(max) (ratio of means 0.98 [90% CI 0.85, 1.13]) or median t(max) (2.5 h in fed and fasted states). The rate of absorption of metformin was decreased when given with food, as reflected by the prolonged t(max) (2-4 h) and reduction in C(max) (by 26%), but the extent of absorption was not changed. The food effect on the metformin component of the fixed-dose combination tablets was consistent with, but of a lesser magnitude compared with data stated. CONCLUSIONS: The vildagliptin/metformin (50/1000 mg) fixed-dose combination tablet can be administered in the same manner as metformin, and can be recommended to be taken with meals to reduce the gastrointestinal symptoms associated with metformin.

Disposition of posaconazole following single-dose oral administration in healthy subjects.

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 microCi) oral dose of [(14)C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.