The biological basis of disease recurrence in psoriasis: a historical perspective and current models.

A key challenge in psoriasis therapy is the tendency for lesions to recur in previously affected anatomical locations after treatment discontinuation following lesion resolution. Available evidence supports the concept of a localized immunological 'memory' that persists in resolved skin after complete disappearance of visible inflammation, as well as the role of a specific subpopulation of T cells characterized by the dermotropic CCR4 <sup>+</sup> phenotype and forming a local memory. Increasing knowledge of the interleukin (IL)-23/T helper 17 (Th17) cell pathway in psoriasis immunopathology is pointing away from the historical classification of psoriasis as primarily a Th1-type disease. Research undertaken from the 1990s to the mid-2000s provided evidence for the existence of a large population of CD8 <sup>+</sup> and CD4 <sup>+</sup> tissue-resident memory T cells in resolved skin, which can initiate and perpetuate immune responses of psoriasis in the absence of T-cell recruitment from the blood. Dendritic cells (DCs) are antigen-presenting cells that contribute to psoriasis pathology via the secretion of IL-23, the upstream regulator of Th17 cells, while plasmacytoid DCs are involved via IL-36 signalling and type I interferon activation. Overall, the evidence discussed in this review indicates that IL-23-driven/IL-17-producing T cells play a critical role in psoriasis pathology and recurrence, making these cytokines logical therapeutic targets. The review also explains the clinical efficacy of IL-17 and IL-23 receptor blockers in the treatment of psoriasis

Experimental design of a cavity flameholder in a Mach 8 Shape-Transitioning Scramjet

The significant volume constraints placed on the design of airframe-integrated scramjet engines calls for fuels with high energy per unit volume. Therefore, low-order hydrocarbons, such as ethylene and methane are candidates for use in engines such as the Mach 8 Rectangular-to-Elliptical Shape Transition (REST) engine, a flow-path which has been extensively tested for hydrogen. Cavity ame- holders are being investigated as a means of ensuring the robust combustion of these fuels. A modular cavity has been designed for a Mach 8 REST engine model suitable for shock tunnel testing. The depth, L/D ratio, and aft wall angle of the cavity ameholder have been determined using previous experimental studies, coupled with axisymmetric simulations. The L/D ratio and aft wall angle have been chosen to minimise stagnation pressure losses and promote a stable flowfield for ameholding. Unsteady axisymmetric simulations reveal that for all cavity depths investigated, the recirculating cavity flow is established within a small fraction of the test time available in the University of Queens- land's T4 Hypersonic Shock Tunnel. The flow temperatures achieved within the simulated cavities are used in conjunction with correlations for cavity residence time and fuel ignition delay to estimate the cavity depths required to auto-ignite low-order hydrocarbon fuels. Consideration is also given to the level of disturbance to the flow through the core of the combustor caused by cavities of various depths. The initial cavity dimensions selected to be experimentally tested are L/D ratio, depth and aft wall angle of 4:0, 4:4 mm, and 22:5°, respectively. Analysis indicates conditions in this cavity should cause the auto-ignition of ethylene. An external ignition source, using conventional spark plugs, will be installed in the cavity to promote ignition of the low-order hydrocarbon fuels, should auto-ignition not occur

Guselkumab-Treated Patients with Plaque Psoriasis Who Achieved Complete Skin Clearance for ≥ 156 Consecutive Weeks: A Post-Hoc Analysis From the VOYAGE 1 Clinical Trial.

Treatment of moderate-to-severe plaque psoriasis with biologics, such as guselkumab, has demonstrated greater efficacy over traditional non-biologic treatments. However, given patient diversity, greater understanding of the relationship between patient characteristics, positive clinical outcomes, and long-term response to biologics is crucial for optimizing treatment choices. This post-hoc analysis of the 5-year VOYAGE 1 clinical trial compares baseline characteristics of patients maintaining a Psoriasis Area and Severity Index (PASI) score of 0 at all visits for ≥ 156 consecutive weeks (PASI = 0 group) with those that never achieve PASI = 0 (comparator group), using descriptive statistics and a multiple logistic regression model. Guselkumab plasma trough concentrations in both response groups were assessed from Weeks 4-156. Of patients who started guselkumab treatment at Week 0 or at Week 16 after switching from placebo, 22.7% (112/494) maintained PASI = 0 for ≥ 156 consecutive weeks. Numerical differences in baseline characteristics, including age, obesity, diabetes, PASI score, disease duration, smoking status, and psoriatic arthritis comorbidity, were identified between the PASI = 0 group and comparator group. Plasma guselkumab levels were consistently higher in the PASI = 0 group. Multiple logistic regression analysis revealed absence of diabetes, lower Dermatology Life Quality Index score at baseline, and higher Week 4 guselkumab plasma concentration as significantly (p < 0.05) associated with the PASI = 0 group. A substantial (22.7%) number of guselkumab-treated patients in the VOYAGE 1 clinical trial maintained complete skin clearance for a consecutive period of ≥ 156 weeks. Factors associated with this outcome may suggest clinical benefits of holistic treatment approaches. NCT02207231

Development of a rapid inviscid-boundary layer aerodynamics tool

Hypersonic vehicles, combined with scramjet propulsion, offer significant and unique flexibility, performance and reusability benefits over rockets. These characteristics will likely reduce the cost of access-to-space. However, the realisation of such vehicles is significantly complicated by engine performance requirements which dictate relatively low altitude, high dynamic pressure trajectories. The thick atmosphere and high velocities result in high aerodynamic drag and heating. This paper introduces a simple, aerothermodynamic model for the analysis of hypersonic vehicles using Cart3D to calculate the inviscid flow-field and provide edge conditions to boundary layer calculations. Comparisons are made between two viscous methods of varying fidelity; flat plate correlations for skin friction with a simplified running length calculation and integral methods applied along inviscid, surface streamlines. Three validation cases are presented; (1) a hypersonic, blunt body; (2) a delta-wing, lifting body at subsonic to hypersonic Mach numbers and (3) a hypersonic, realistic vehicle configuration with internal flow-paths. In general, Cart3D predicts the lift and pitching moment coefficients well but consistently under-predicts drag given the absence of shear stress. The viscous contribution to aerodynamic forces was found to be adequately modelled using flat plate correlations and a simple Euclidean distance in place of the true running length. Preliminary results, however, suggest predictions of surface heat transfer rates benefit from a streamline running length and higher fidelity boundary layer methods

Physicians' guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry

Background: Physicians' adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. Methods and results: Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). Conclusion: These results suggest that physicians' adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiolog