BackgroundPatients often express strong preferences for the forms of treatment available for their disease. Incorporating these preferences into the process of treatment decision-making might improve patients' adherence to treatment, contributing to better outcomes. We describe the methodology used in a study aiming to assess treatment outcomes when patients' preferences for treatment are closely matched to recommended treatments.MethodParticipants included patients with moderate and severe psoriasis attending outpatient dermatology clinics at the University Medical Centre Mannheim, University of Heidelberg, Germany. A self-administered online survey used conjoint analysis to measure participants' preferences for psoriasis treatment options at the initial study visit. Physicians' treatment recommendations were abstracted from each participant's medical records. The Preference Matching Index (PMI), a measure of concordance between the participant's preferences for treatment and the physician's recommended treatment, was determined for each participant at t1 (initial study visit). A clinical outcome measure, the Psoriasis Area and Severity Index, and two participant-derived outcomes assessing treatment satisfaction and health related quality of life were employed at t1, t2 (twelve weeks post-t1) and t3 (twelve weeks post-t2). Change in outcomes was assessed using repeated measures analysis of variance. The association between participants' PMI scores at t1 and outcomes at t2 and t3 was evaluated using multivariate regressions analysis.DiscussionWe describe methods for capturing concordance between patients' treatment preferences and recommended treatment and for assessing its association with specific treatment outcomes. The methods are intended to promote the incorporation of patients' preferences in treatment decision-making, enhance treatment satisfaction, and improve treatment effectiveness through greater adherence.

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Liver sinusoidal endothelium (LSEC) is a prime example of organ-specific microvascular differentiation and functions. Disease-associated capillarization of LSEC in vivo and dedifferentiation of LSEC in vitro indicate the importance of the hepatic microenvironment. To identify the LSEC-specific molecular differentiation program in the rat we used a twosided gene expression profiling approach comparing LSEC freshly isolated ex vivo with both lung microvascular endothelial cells (LMEC) and with LSEC cultured for 42 hours. The LSEC signature consisted of 48 genes both down-regulated in LMEC and in LSEC upon culture (fold change >7 in at least one comparison); quantitative reverse-transcription polymerase chain reaction confirmation of these genes included numerous family members and signaling pathway-associated molecules. The LSEC differentiation program comprised distinct sets of growth (Wnt2, Fzd4, 5, 9, Wls, vascular endothelial growth factors [VEGFR] 1, 2, 3, Nrp2) and transcription factors (Gata4, Lmo3, Tcfec, Maf ) as well as endocytosis-related (Stabilin-1/2, Lyve1, and Ehd3) and cytoskeleton-associated molecules (Rnd3/RhoE). Specific gene induction in cultured LSEC versus freshly isolated LSEC as well as LMEC (Esm-1, Aatf ) and up-regulation of gene expression to LMEC levels (CXCR4, Apelin) confirmed true transdifferentiation of LSEC in vitro. In addition, our analysis identified a novel 26-kDa single-pass transmembrane protein, liver endothelial differentiation-associated protein (Leda)-1, that was selectively expressed in all liver endothelial cells and preferentially localized to the abluminal cell surface. Upon forced overexpression in MDCK cells, Leda-1 was sorted basolaterally to E-cadherin-positive adherens junctions, suggesting functional involvement in cell adhesion and polarity. Conclusion: Comparative microvascular analysis in rat identified a hepatic microenvironment-dependent LSEC-specific differentiation program including the novel junctional molecule Leda-1. (HEPATOLOGY 2010;52:313-326)

Treatment dissatisfaction and non-adherence are common among patients with psoriasis, partly due to discordance between individual preferences and recommended treatments. However, patients are more satisfied with biologicals than with other treatments. The aim of our study was to assess patient preferences for treatment of psoriasis with biologicals by using computer-based conjoint analysis. Biologicals approved for psoriasis in Germany were decomposed into outcome (probability of 50% and 90% improvement, time until response, sustainability of success, probability of mild and severe adverse events (AE), probability of American College of Rheumatology (ACR) 20 response) and process attributes (treatment location, frequency, duration and delivery method). Impact of sociodemographic and socioeconomic characteristics and disease severity on Relative Importance Scores (RIS) of each attribute was assessed with analyses of variance, post hoc tests, and multivariate regression. Averaged across the cohort of 200 participants with moderate-to-severe psoriasis, preferences were highest for avoiding severe AE (RIS = 17.3), followed by 90% improvement (RIS = 14.0) and avoiding mild AE (RIS = 10.5). Process attributes reached intermediate RIS (8.2–8.8). Men were more concerned about efficacy than women (50% improvement: RIS = 6.9 vs. 9.5, p = 0.008; β = -0.191, p = 0.011 in multivariate models; 90% improvement: RIS = 12.1 vs. 15.4, p = 0.002; β = -0.197, p = 0.009). Older participants judged the probability of 50% and 90% improvement less relevant than younger ones (50% improvement: Pearson’s Correlation (PC) = -0.161, p = 0.022; β = -0.219, p = 0.017; 90% improvement: PC = -0.155, p = 0.028; β = -0.264, p = 0.004) but worried more about severe AE (PC = 0.175, p = 0.013; β = 0.166, p = 0.082). In summary, participants with moderate-to-severe psoriasis were most interested in safety of biologicals, followed by efficacy, but preferences varied with sociodemographic characteristics and working status. Based on this knowledge, physicians should identify preferences of each individual patient during shared decision-making in order to optimize treatment satisfaction, adherence and outcome.

FADD, caspase-8, and cFLIP regulate the outcome of cell death signaling. Mice that constitutively lack these molecules die at an early embryonic age, whereas tissue-specific constitutive deletion of FADD or caspase-8 results in inflammatory skin disease caused by increased necroptosis. The function of cFLIP in the skin in vivo is unknown. In contrast to tissue-specific caspase-8 knockout, we show that mice constitutively lacking cFLIP in the epidermis die around embryonic days 10 and 11. When cFLIP expression was abrogated in adult skin of cFLIPfl/fl-K14CreERtam mice, severe inflammation of the skin with concomitant caspase activation and apoptotic, but not necroptotic, cell death developed. Apoptosis was dependent of autocrine tumor necrosis factor production triggered by loss of cFLIP. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. Our data demonstrate the importance of cFLIP for the integrity of the epidermis and for silencing of spontaneous skin inflammation.

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Treatment preferences may change over time course and with treatment experience. Participants on injectables attach great importance to efficiency and convenience of therapies, and are highly satisfied with their treatment.

In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.