Preclinical and clinical characterization of the RORγt inhibitor JNJ-61803534.

The nuclear receptor retinoid-related orphan receptor gamma t (RORγt) plays a critical role in driving Th17 cell differentiation and expansion, as well as IL-17 production in innate and adaptive immune cells. The IL-23/IL-17 axis is implicated in several autoimmune and inflammatory diseases, and biologics targeting IL-23 and IL-17 have shown significant clinical efficacy in treating psoriasis and psoriatic arthritis. JNJ-61803534 is a potent RORγt inverse agonist, selectively inhibiting RORγt-driven transcription versus closely-related family members, RORα and RORß. JNJ-61803534 inhibited IL-17A production in human CD4+ T cells under Th17 differentiation conditions, but did not inhibit IFNγ production under Th1 differentiation conditions, and had no impact on in vitro differentiation of regulatory T cells (Treg), nor on the suppressive activity of natural Tregs. In the mouse collagen-induced arthritis model, JNJ-61803534 dose-dependently attenuated inflammation, achieving ~ 90% maximum inhibition of clinical score. JNJ-61803534 significantly inhibited disease score in the imiquimod-induced mouse skin inflammation model, and dose-dependently inhibited the expression of RORγt-regulated genes, including IL-17A, IL-17F, IL-22 and IL-23R. Preclinical 1-month toxicity studies in rats and dogs identified doses that were well tolerated supporting progression into first-in-human studies. An oral formulation of JNJ-61803534 was studied in a phase 1 randomized double-blind study in healthy human volunteers to assess safety, pharmacokinetics, and pharmacodynamics. The compound was well tolerated in single ascending doses (SAD) up to 200 mg, and exhibited dose-dependent increases in exposure upon oral dosing, with a plasma half-life of 164 to 170 h. In addition, dose-dependent inhibition of ex vivo stimulated IL-17A production in whole blood was observed, demonstrating in vivo target engagement. In conclusion, JNJ-61803534 is a potent and selective RORγt inhibitor that exhibited acceptable preclinical safety and efficacy, as well as an acceptable safety profile in a healthy volunteer SAD study, with clear evidence of a pharmacodynamic effect in humans.

Cost-utility analysis of percutaneous mitral valve repair in inoperable patients with functional mitral regurgitation in German settings.

BACKGROUND: To determine the cost-effectiveness of the percutaneous mitral valve repair (PMVR) using Carillon® Mitral Contour System® (Cardiac Dimensions Inc., Kirkland, WA, USA) in patients with congestive heart failure accompanied by moderate to severe functional mitral regurgitation (FMR) compared to the prolongation of optimal medical treatment (OMT). METHODS: Cost-utility analysis using a combination of a decision tree and Markov process was performed. The clinical effectiveness was determined based on the results of the Transcatheter Implantation of Carillon Mitral Annuloplasty Device (TITAN) trial. The mean age of the target population was 62 years, 77% of the patients were males, 64% of the patients had severe FMR and all patients had New York Heart Association functional class III. The epidemiological, cost and utility data were derived from the literature. The analysis was performed from the German statutory health insurance perspective over 10-year time horizon. RESULTS: Over 10 years, the total cost was €36,785 in the PMVR arm and €18,944 in the OMT arm. However, PMVR provided additional benefits to patients with an 1.15 incremental quality-adjusted life years (QALY) and an 1.41 incremental life years. The percutaneous procedure was cost-effective in comparison to OMT with an incremental cost-effectiveness ratio of €15,533/QALY. Results were robust in the deterministic sensitivity analysis. In the probabilistic sensitivity analysis with a willingness-to-pay threshold of €35,000/QALY, PMVR had a 84 % probability of being cost-effective. CONCLUSIONS: Percutaneous mitral valve repair may be cost-effective in inoperable patients with FMR due to heart failure.

Percutaneous mitral annuloplasty for functional mitral regurgitation: results of the CARILLON Mitral Annuloplasty Device European Union Study.

BACKGROUND: Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care. METHODS AND RESULTS: Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction <40%, and a 6-minute walk distance between 150 and 450 m were enrolled in the CARILLON Mitral Annuloplasty Device European Union Study (AMADEUS). Percutaneous mitral annuloplasty was achieved through the coronary sinus with the CARILLON Mitral Contour System. Echocardiographic FMR grade, exercise tolerance, New York Heart Association class, and quality of life were assessed at baseline and 1 and 6 months. Of the 48 patients enrolled in the trial, 30 received the CARILLON device. Eighteen patients did not receive a device because of access issues, insufficient acute FMR reduction, or coronary artery compromise. The major adverse event rate was 13% at 30 days. At 6 months, the degree of FMR reduction among 5 different quantitative echocardiographic measures ranged from 22% to 32%. Six-minute walk distance improved from 307+/-87 m at baseline to 403+/-137 m at 6 months (P<0.001). Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, improved from 47+/-16 points at baseline to 69+/-15 points at 6 months (P<0.001). CONCLUSIONS: Percutaneous reduction in FMR with a novel coronary sinus-based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.

Ultra-low level plutonium isotopes in the NIST SRM 4355A (Peruvian Soil-1).

For more than 20 years, countries and their agencies which monitor radionuclide discharge sites and storage facilities have relied on the National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) 4355 Peruvian Soil. Its low fallout contamination makes it an ideal soil blank for measurements associated with terrestrial-pathway-to-man studies. Presently, SRM 4355 is out of stock, and a new batch of the Peruvian soil is currently under development as future NIST SRM 4355A. Both environmental radioanalytical laboratories and mass spectrometry communities will benefit from the use of this SRM. The former must assess their laboratory procedural contamination and measurement detection limits by measurement of blank sample material. The Peruvian Soil is so low in anthropogenic radionuclide content that it is a suitable virtual blank. On the other hand, mass spectrometric laboratories have high sensitivity instruments that are capable of quantitative isotopic measurements at low plutonium levels in the SRM 4355 (first Peruvian Soil SRM) that provided the mass spectrometric community with the calibration, quality control, and testing material needed for methods development and legal defensibility. The quantification of the ultra-low plutonium content in the SRM 4355A was a considerable challenge for the mass spectrometric laboratories. Careful blank control and correction, isobaric interferences, instrument stability, peak assessment, and detection assessment were necessary. Furthermore, a systematic statistical evaluation of the measurement results and considerable discussions with the mass spectroscopy metrologists were needed to derive the certified values and uncertainties. The one sided upper limit of the 95% tolerance with 95% confidence for the massic (239)Pu content in SRM 4355A is estimated to be 54,000 atoms/g.

Which Arteries Are Expendable? The Practice and Pitfalls of Embolization throughout the Body.

This article outlines general concepts of, and strategies for, therapeutic embolization throughout the body, touching on all major arterial distributions. Clinical scenarios that allow or prevent safe embolization of vessels are presented. Specific agents are recommended where appropriate, as are alternate approaches when embolization is not an option. Pre-embolization precautions and adjunctive measures are described in high-risk areas.

Facilitating superior chronic disease management through a knowledge-based systems development model.

To date, the adoption and diffusion of technology-enabled solutions to deliver better healthcare has been slow. There are many reasons for this. One of the most significant is that the existing methodologies that are normally used in general for Information and Communications Technology (ICT) implementations tend to be less successful in a healthcare context. This paper describes a knowledge-based adaptive mapping to realisation methodology to traverse successfully from idea to realisation rapidly and without compromising rigour so that success ensues. It is discussed in connection with trying to implement superior ICT-enabled approaches to facilitate superior Chronic Disease Management (CDM).