Histologic studies have become increasingly important in recognizing morphologic differences in photoaged versus intrinsically aged skin. Earlier histologic studies have attempted to evaluate these changes by examining anatomical sites which are not comparable, such as face and buttocks. As part of a multicenter study, we have quantitatively examined a panel of 16 histologic features in baseline facial skin biopsies from 158 women with moderate to severe photodamage. When compared to the postauricular area (photo protected), biopsies of the crow's feet area (photo exposed) had a twofold increase in melanocytes and a statistically significant increase in melanocytic atypia (p < .0001) and epidermal melanin (p < .0001). Other epidermal changes included reduced epidermal thickness (p < .01), more compact stratum corneum (p < .0001) and increased granular layer thickness (p < .0001) in the crow's feet skin. There was increased solar elastosis (p < .0001), dermal elastic tissue (p < .0001), melanophages (p < .0001), perivascular inflammation (p < .05) and perifollicular fibrosis (p < .01) but no change in the number of mast cells or dermal mucin in the photo exposed skin. Our data document quantitative differences in photoaged versus intrinsically aged facial skin and provides the groundwork for future studies to evaluate the efficacy of new treatments for photoaged skin.

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, 5,6,9 EWS (Ewing's Sarcoma) gene encodes an RNA/DNA-binding protein that is ubiquitously expressed and involved in various cellular processes. EWS deficiency leads to impaired development and early senescence through unknown mechanisms. We found that EWS regulates the expression of Drosha and microRNAs (miRNAs). EWS deficiency resulted in increased expression of Drosha, a well-known microprocessor, and increased levels of miR-29b and miR-18b. Importantly, miR-29b and miR-18b were directly involved in the post-transcriptional regulation of collagen IV alpha 1 (Col4a1) and connective tissue growth factor (CTGF) in EWS knock-out (KO) mouse embryonic fibroblast cells. The upregulation of Drosha, miR-29b and miR-18b and the sequential downregulation of Col4a1 and CTGF contributed to the deregulation of dermal development in EWS KO mice. Otherwise, knockdown of Drosha rescued miRNA-dependent downregulation of Col4a1 and CTGF proteins. Taken together, our data indicate that EWS is involved in post-transcriptional regulation of Col4a1 and CTGF via a Drosha-miRNA-dependent pathway. This finding suggests that EWS has a novel role in dermal morphogenesis through the modulation of miRNA biogenesis. 1 EWS also interacts with subunits of transcription factor II D, CREB-binding protein (CBP) and RNA polymerase II complexes, suggesting a role in basic transcription.2 Subsequent studies have shown that EWS acts as a transcriptional activator for BRN3A, HNF3, and OCT4 in a cell-type-and promoter-specific manner.3-5 Interestingly, EWS gene is frequently rearranged by chromosomal translocations in several cancers, leading to its fusion with many transcription factors including FLI1, ATF1, and WT1. The resulting chimeric fusion proteins, such as EWS-FLI1, EWS-ATF1, and EWS-WT1, function as aberrant transcription factors that drive proliferation, survival, and transformation.

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KeywordsClinical decision support, interfaces and usability, human-computer interaction, computerized order entry, alert fatigue SummaryObjective: The Instrument for Evaluating Human-Factor Principles in Medication-Related Decision Support Alerts (I-MeDeSA) was developed recently in the US with a view towards improving considerations of human-factor principles when designing alerts for clinical decision support (CDS) systems. This study evaluated the generalizability of this tool, in cooperation with its authors, across cultures by applying it to a Korean system. We also examined opportunities to promote user acceptance of the system. Methods: We developed a Korean version of the I-MeDeSA (K-I-MeDeSA) and used it to evaluate drug-drug interaction alerts in a large academic tertiary hospital in Seoul. We involved four reviewers (A, B, C, and D). Two (A and B) conducted the initial independent scoring, while the other two (C and D) performed a final review and assessed feedback from the initial reviewers. The obtained scores were compared with those from 13 previously reported CDS systems. The feedback was summarized qualitatively. Results: The translation of the I-MeDeSA had excellent interrater agreement in terms of face validity (scale-level content validity index = 0.95). The system's K-I-MeDeSA score was 10 out of 26, with a good agreement between reviewers (κ = 0.77), which showed a lack of human-factor considerations. The reviewers readily identified two of the nine principles that needed primary improvement: prioritization and text-based information. The reviewers also expressed difficulty judging the following four principles: alarm philosophy, visibility, color, and learnability and confusability. Conclusion: The K-I-MeDeSA was semantically and operationally equivalent to the original tool. Only minor cultural problems were identified, leading the reviewers to suggest the need for clarification of certain words plus a more detailed description of the tool's rationale and exemplars. Further evaluation is needed to empirically assess whether the implementation of changes in an electronic health record system could improve the adoption of CDS alerts. Citation: Cho I, Lee J, Han H, Phansalkar S, Bates DW. Evaluation of a Korean version of a tool for assessing the incorporation of human factors into a medicationrelated decision support system: the I-MeDeSA. Appl Clin Inf 2014; 5: 571-588 http://dx Research Article

To evaluate diagnostic accuracy of perfusion weighted imaging (PWI) and positron emission tomography (PET) using an integrated PET/MR system in tumor grading as well as in differentiating recurrent tumor from treatment-induced effects (TIE) in brain tumor patients. Twenty patients (Group A: treatment naïve, 9 patients with 16 lesions; Group B: post-therapy, 11 patients with 18 lesions) underwent fluorine 18 ((18)F) fluorodeoxyglucose (FDG) brain PET/MR with PWI. Two blinded readers predicted low versus high-grade tumor (for Group A) and tumor recurrence versus TIE (for Group B) based solely on tumor rCBV (regional cerebral blood volume) and SUV (standardized uptake values). Tumor histopathology at resection was the reference standard. Using rCBV(mean) ≤ 1.74 as a cut-off, 100% sensitivity and 74% specificity were observed, whereas 75% sensitivity and 89.7% specificity were observed with SUV(mean) ≤ 4.0 as a cut-off to classify patients as test positive for low-grade tumors (Group A) and TIE (Group B). Diagnostic accuracy for detection of low-grade tumors was 90% using PWI and 40% using PET in Group A (p = 0.056); for detection of TIE in Group B, diagnostic accuracy was 94.1% using PWI and 55.6% using PET (p = 0.033). No significant correlation was demonstrated between rCBV parameters and SUV in Group A (mean values: p > 0.403), Group B (p > 0.06) and in the entire population (p > 0.07). Best overall sensitivity and specificity were obtained using rCBV(mean) ≤ 1.74 and SUV(mean) ≤ 4.0 cut-off values. PWI demonstrated better diagnostic accuracy in both groups. Poor correlation was observed between FDG and rCBV parameters.

An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p< 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.

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