Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice. Conclusion : The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA. (Hepatology 2014;60:211–223)

Background: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. Methods: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. Results: Fourteen of 47 livers displayed predominant histological features of inflammation (N = 9) or fibrosis (N = 5), with the remainder showing similar levels of both simultaneously. By differential profiling of gene expression, the 14 livers had a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. Conclusions: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.

Background: The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database. Results: Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value = 2.55 × 10⁻⁷) and was replicated in African (2.57 × 10⁻⁴) and Hispanic (1.18 × 10⁻³) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases. Conclusion: Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top-ranked asthma genes across populations suggests that such loci are less likely to be false positives and could indicate true associations. Variants that are associated with asthma across populations could be used to identify individuals who are at high risk for asthma regardless of genetic ancestry.

Home healthcare workers (HHCWs) are subjected to variable working environments which increase their risk of being exposed to numerous occupational hazards. One of the potential occupational hazards within the industry includes exposure to bioaerosols. This study aimed to characterize concentrations of three types of bioaerosols utilizing a novel fluorescence-based direct-reading instrument during seven activities that HHCWs typically encounter in patients’ homes. Bioaerosols were measured in an indoor residence throughout all seasons in Cincinnati, OH, USA. A fluorescence-based direct-reading instrument (InstaScope, DetectionTek, Boulder, CO, USA) was utilized for all data collection. Total particle counts and concentrations for each particle type, including fluorescent and non-fluorescent particles, were utilized to form the response variable, a normalized concentration calculated as a ratio of concentration during activity to the background concentration. Walking experiments produced a median concentration ratio of 52.45 and 2.77 for pollen and fungi, respectively. Fungi and bacteria produced the highest and lowest median concentration ratios of 17.81 and 1.90 for showering, respectively. Lastly, our current study showed that sleeping activity did not increase bioaerosol concentrations. We further conclude that utilizing direct-reading methods may save time and effort in bioaerosol-exposure assessment.

Objectives: Multidisciplinary cancer clinic (MDC) is an evaluation option for the management of prostate cancer (PCa). The purpose of MDC is to provide the patient with a comprehensive assessment and risk/benefit discussion of all pertinent treatment options. Our objective was to obtain a contemporary measure and analysis of urologists’ opinion regarding PCa MDC. Material and Methods: We created a 14-item questionnaire for respondent baseline characteristics, subjective and objective inquiries regarding MDC for PCa management. The survey was distributed through email to members of the Society of Urologic Oncology and the Endourological Society. Data were analyzed using R (R Core team, 2017). Results: One hundred and seven (51%) respondents reported participation in MDC; the majority of which were male (97.6%), academic (61.4%) urologists with urologic oncology fellowship training (50%), and >20 years in practice (40.3%). MDC patients were most commonly referrals (78.5%) and with high-risk disease (Gleason sum 8–10) (83.2%). A majority of the respondents felt that MDC was very or extremely beneficial for PCa research (45% and 19%, respectively) and treatment (35% and 20%, respectively). Responses dissuading the use of MDC included lack of infrastructure (41%) and time commitment (21%). On multivariate analysis, urologists with >10 years in practice were less likely to find MDC beneficial in the management of PCa (11–20 years, P = 0.028 and >20 years P = 0.009). Conclusion: A contemporary sampling of urologists’ opinion and practice patterns alludes to the benefits that advocate for and the resource demand that hinders routine use of MDC for PCa evaluation. Urologist training and practice environment can affect participation in PCa MDC.