Uncovering burden disparity: A comparative analysis of the impact of moderate-to-severe psoriasis and hidradenitis suppurativa.

BACKGROUND: Psoriasis and hidradenitis suppurativa (HS) exhibit distinct clinical features, but no studies have directly compared the health-related quality of life (HRQoL) in patients with moderate-to-severe manifestations of these conditions. OBJECTIVE: To determine which disease is associated with more severe HRQoL impairment. METHODS: Weighted averages of each of the following baseline HRQoL measures were determined and compared between HS and psoriasis populations from 5 clinical trials: Visual Analog Scale (VAS) for pain, Total Work Productivity Impairment, Dermatology Life Quality Index; EuroQOL 5D VAS, and Short Form-36 Health Survey. RESULTS: Compared with patients with psoriasis, patients with HS reported higher scores for VAS-pain (54.3 vs 36.1 [P < .0001]), Dermatology Life Quality Index (15.3 vs 11.3 [P < .0001]), EuroQOL 5D VAS (58.8 vs 50.8 [P < .0002]), and Total Work Productivity Impairment (35.4 vs 18.2). Patients with HS had lower Short Form-36 Health Survey scores than did patients with psoriasis (physical, 39.6 vs 49.0; mental, 41.5 vs 47.5 [both P < .0001]). LIMITATIONS: This analysis was performed using published summary data rather than patient-level data, and weighted pooled averages were compared. CONCLUSIONS: Patients with HS have a higher HRQoL burden than patients with psoriasis. This study clearly documents the needs of patients with HS and the potential impact of medical, scientific, and societal consensus for the development of more effective HS treatments.

Lis1 mediates planar polarity of auditory hair cells through regulation of microtubule organization.

The V-shaped hair bundles atop auditory hair cells and their uniform orientation are manifestations of epithelial planar cell polarity (PCP) required for proper perception of sound. PCP is regulated at the tissue level by a conserved core Wnt/PCP pathway. However, the hair cell-intrinsic polarity machinery is poorly understood. Recent findings implicate hair cell microtubules in planar polarization of hair cells. To elucidate the microtubule-mediated polarity pathway, we analyzed Lis1 function in the auditory sensory epithelium in the mouse. We show that conditional deletion of Lis1 in developing hair cells causes defects in cytoplasmic dynein and microtubule organization, resulting in planar polarity defects without overt effects on the core PCP pathway. Lis1 ablation during embryonic development results in defects in hair bundle morphology and orientation, cellular organization and junctional nectin localization. We present evidence that Lis1 regulates localized Rac-PAK signaling in embryonic hair cells, probably through microtubule-associated Tiam1, a guanine nucleotide exchange factor for Rac. Lis1 ablation in postnatal hair cells significantly disrupts centrosome anchoring and the normal V-shape of hair bundles, accompanied by defects in the pericentriolar matrix and microtubule organization. Lis1 is also required for proper positioning of the Golgi complex and mitochondria as well as for hair cell survival. Together, our results demonstrate that Lis1 mediates the planar polarity of hair cells through regulation of microtubule organization downstream of the tissue polarity pathway.

Absence of the G protein-coupled receptor G2A in mice promotes monocyte/endothelial interactions in aorta.

The G protein-coupled receptor G2A is highly expressed on macrophages and lymphocytes and has been localized to atherosclerotic plaques. We examined the role of G2A in modulating monocyte/endothelial interactions in the vessel wall. We measured adhesion of WEHI 78/24 monocytes to aortas of C57BL/6 (B6) and G2A-deficient (G2A(-/-)) mice using an ex vivo adhesion assay. G2A(-/-) mice had 10-fold elevations in adhesion of monocytes to aortas. Injection of GFP-expressing wild-type macrophages into B6 and G2A(-/-) mice in vivo showed increased macrophage accumulation in the aortic wall of G2A(-/-) mice. We isolated aortic endothelial cells (ECs) from B6 and G2A(-/-) mice and found a 2-fold increase in intercellular adhesion molecule-1 and E-selectin surface expression on G2A(-/-) ECs using flow cytometry. Using ELISA, we found a 3-fold increase in interleukin-6 and monocyte chemoattractant protein-1 production by G2A(-/-) ECs compared with B6 ECs. We found a dramatic increase in nuclear localization of the p65 subunit of nuclear factor kappaB in G2A(-/-) ECs. Transfection of G2A into G2A(-/-) ECs to restore normal expression levels reduced p65 nuclear localization to 35%. Restoration of G2A expression in G2A(-/-) ECs significantly reduced intercellular adhesion molecule-1 and endothelial selectin surface expression and reduced monocyte chemoattractant protein-1 and interleukin-6 production. Restoring G2A to G2A(-/-) ECs reduced monocyte adhesion by 80% compared with G2A(-/-) ECs in a flow chamber assay. Absence of G2A in endothelium results in proinflammatory signaling and increased monocyte/endothelial interactions in the aortic wall. Thus, endothelial G2A expression may aid in prevention of vascular inflammation and atherosclerosis.

12/15-Lipoxygenase activity increases the degradation of macrophage ATP-binding cassette transporter G1.

OBJECTIVE: The purpose of this study was to evaluate the effect of 12/15-lipoxygenase (12/15LO) in macrophage ABCG1 expression and function associated with cholesterol efflux. METHODS AND RESULTS: 12/15LO was stably overexpressed in J774 macrophages. 12/15LO-overexpressing macrophages had a 30% reduction in HDL-mediated cholesterol efflux, corresponding with significantly reduced ABCG1 protein expression. Treatment of 12/15LO-overexpressing macrophages with a 12/15LO ribozyme to reduce 12/15LO restored HDL-mediated efflux and ABCG1 protein expression. Treating macrophages with 12/15LO unsaturated fatty acid substrates or eicosanoid products also reduced HDL-mediated cholesterol efflux. Additionally, both 12/15LO overexpression in macrophages and incubation of macrophages with eicosanoids reduced ABCG1 protein, but not mRNA, expression. However, incubation of macrophages with linoleic or arachidonic acids significantly reduced both ABCG1 mRNA and protein expression, suggesting that 12/15LO substrates and eicosanoid products differentially regulate ABCG1 expression. 12/15LO fatty acids did not decrease ABCG1 translation; however, 12/15LO fatty acids increased ABCG1 degradation when blocked by cyclohexidmide. ABCG1 degradation may be regulated through posttranslational modifications. Treatment with the 12/15LO eicosanoid product 12SHETE increased serine phosphorylation of ABCG1. CONCLUSIONS: We conclude that serine phosphorylation may increase the degradation rate of ABCG1, and as a result cause macrophage cholesterol accumulation. These findings provide evidence that 12/15LO activity in the vessel wall contributes to atherogenesis by impairing the macrophage ABCG1 cholesterol efflux pathway.

A Systematic Review of Coding Systems Used in Pharmacoepidemiology and Database Research.

BACKGROUND: Clinical coding systems have been developed to translate real-world healthcare information such as prescriptions, diagnoses and procedures into standardized codes appropriate for use in large healthcare datasets. Due to the lack of information on coding system characteristics and insufficient uniformity in coding practices, there is a growing need for better understanding of coding systems and their use in pharmacoepidemiology and observational real world data research. OBJECTIVES: To determine: 1) the number of available coding systems and their characteristics, 2) which pharmacoepidemiology databases are they adopted in, 3) what outcomes and exposures can be identified from each coding system, and 4) how robust they are with respect to consistency and validity in pharmacoepidemiology and observational database studies. METHODS: Electronic literature database and unpublished literature searches, as well as hand searching of relevant journals were conducted to identify eligible articles discussing characteristics and applications of coding systems in use and published in the English language between 1986 and 2016. Characteristics considered included type of information captured by codes, clinical setting(s) of use, adoption by a pharmacoepidemiology database, region, and available mappings. Applications articles describing the use and validity of specific codes, code lists, or algorithms were also included. Data extraction was performed independently by two reviewers and a narrative synthesis was performed. RESULTS: A total of 897 unique articles and 57 coding systems were identified, 17% of which included country-specific modifications or multiple versions. Procedures (55%), diagnoses (36%), drugs (38%), and site of disease (39%) were most commonly and directly captured by these coding systems. The systems were used to capture information from the following clinical settings: inpatient (63%), ambulatory (55%), emergency department (ED, 34%), and pharmacy (13%). More than half of all coding systems were used in Europe (59%) and North America (57%). 34% of the reviewed coding systems were utilized in at least 1 of the 16 pharmacoepidemiology databases of interest evaluated. 21% of coding systems had studies evaluating the validity and consistency of their use in research within pharmacoepidemiology databases of interest. The most prevalent validation method was comparison with a review of patient charts, case notes or medical records (64% of reviewed validation studies). The reported performance measures in the reviewed studies varied across a large range of values (PPV 0-100%, NPV 6-100%, sensitivity 0-100%, specificity 23-100% and accuracy 16-100%) and were dependent on many factors including coding system(s), therapeutic area, pharmacoepidemiology database, and outcome. CONCLUSIONS: Coding systems vary by type of information captured, clinical setting, and pharmacoepidemiology database and region of use. Of the 57 reviewed coding systems, few are routinely and widely applied in pharmacoepidemiology database research. Indication and outcome dependent heterogeneity in coding system performance suggest that accurate definitions and algorithms for capturing specific exposures and outcomes within large healthcare datasets should be developed on a case-by-case basis and in consultation with clinical experts.

Patterns of treatment and costs associated with transfusion burden in patients with myelodysplastic syndromes.

Transfusion dependence (TD) among myelodysplastic syndromes (MDS) patients negatively impacts survival and health-related quality of life. We evaluated cost patterns of MDS care during TD and transfusion independence (TI). MDS patients were identified from a US claims database (2008-2013). TD was defined as ≥2 consecutive 8-week periods with ≥1 claim during each, and no interim 56-day period without transfusion; TI as 8 subsequent transfusion-free weeks; and transfusion frequency as the mean interval between transfusions during the TD period. 13,741 patients were included; 19% were TD and 70% had a mean interval between transfusions of ≤28 days. During a 2-year period, TD patients incurred a mean total cost of $17,815/patient-month; 53% higher for those with ≤28 days ($19,498) vs. >28 days ($12,717) between transfusions. Among patients who achieved TI, mean total cost was $7874/patient-month. For TD-MDS patients, cost increases are proportional to transfusion frequency and achieving TI yields economic benefits.

PTK7-Src signaling at epithelial cell contacts mediates spatial organization of actomyosin and planar cell polarity.

Actomyosin contractility plays a key role in tissue morphogenesis. During mammalian development, PTK7 regulates epithelial morphogenesis and planar cell polarity (PCP) through modulation of actomyosin contractility, but the underlying mechanism is unknown. Here, we show that PTK7 interacts with the tyrosine kinase Src and stimulates Src signaling along cell-cell contacts. We further identify ROCK2 as a target of junctional PTK7-Src signaling. PTK7 knockdown in cultured epithelial cells reduced the level of active Src at cell-cell contacts, resulting in delocalization of ROCK2 from cell-cell contacts and decreased junctional contractility, with a concomitant increase in actomyosin on the basal surface. Moreover, we present in vivo evidence that Src family kinase (SFK) activity is critical for PCP regulation in the auditory sensory epithelium and that PTK7-SFK signaling regulates tyrosine phosphorylation of junctional ROCK2. Together, these results delineate a PTK7-Src signaling module for spatial regulation of ROCK activity, actomyosin contractility, and epithelial PCP.

PTK7 regulates myosin II activity to orient planar polarity in the mammalian auditory epithelium.

BACKGROUND: Planar cell polarity (PCP) signaling is a key regulator of epithelial morphogenesis, including neural tube closure and the orientation of inner ear sensory hair cells, and is mediated by a conserved noncanonical Wnt pathway. Ptk7 is a novel vertebrate-specific regulator of PCP, yet the mechanisms by which Ptk7 regulates mammalian epithelial PCP remain poorly understood. RESULTS: Here we show that, in the mammalian auditory epithelium, Ptk7 is not required for membrane recruitment of Dishevelled 2; Ptk7 and Frizzled3/Frizzled6 receptors act in parallel and have opposing effects on hair cell PCP. Mosaic analysis identified a requirement of Ptk7 in neighboring supporting cells for hair cell PCP. Ptk7 and the noncanonical Wnt pathway differentially regulate a contractile myosin II network near the apical surface of supporting cells. We provide evidence that this apical myosin II network exerts polarized contractile tension on hair cells to align their PCP, as revealed by asymmetric junctional recruitment of vinculin, a tension-sensitive actin binding protein. In Ptk7 mutants, compromised myosin II activity resulted in loss of planar asymmetry and reduced junctional localization of vinculin. By contrast, vinculin planar asymmetry and stereociliary bundle orientation were restored in Fz3(-/-);Ptk7(-/-) double mutants. CONCLUSIONS: These findings suggest that PTK7 acts in conjunction with the noncanonical Wnt pathway to orient epithelial PCP through modulation of myosin II-based contractile tension between supporting cells and hair cells.