Miracle-dz/UniFAR-FTUs huggingface dataset:
Recently Arrested Adolescents are at High Risk for Sexually Transmitted Diseases

Background: Adolescent offenders may be at high risk for sexually transmitted diseases (STDs). With previous research and interventions focused on incarcerated adolescents, data are needed on STD prevalence and risk factors among newly arrested youth released to the community, a far larger subgroup. Methods: Participants were recruited from all arrested youth processed at the Hillsborough County, Florida Juvenile Assessment Center during the last half of 2006 (506 males, 442 females). Participants voluntarily providing urine samples for drug testing as part of standard protocol were also consented to having their specimens split and tested for chlamydia and gonorrhea, using an FDA-approved nucleic acid amplification test. Results: STD prevalence was similar to those previously reported among incarcerated adolescents: 11.5% tested positive for chlamydia, 4.2% for gonorrhea, and 13.2% for either or both infections. Prevalence was significantly higher among females: 19.2% of females had either or both infections compared with 10.5% of males. Prevalence was higher for 17 to 18 year olds (15.2% of males, 25.5% of females), blacks, detained youths, drug users, and those engaged in sexual risk behaviors. Previous STD testing experience was limited. Conclusions: The study indicated that a voluntary STD screening protocol is feasible for arrested youth entering the juvenile justice system, and these offenders are at high risk for STDs. Because most arrested youths are released back to the community, routine testing and treatment of recently arrested youths, and expanded access to risk reduction and prevention programs, can yield substantial public health benefits.
Human liver sinusoidal endothelial cells promote intracellular crawling of lymphocytes during recruitment: A new step in migration

The recruitment of lymphocytes via the hepatic sinusoidal channels and positioning within liver tissue is a critical event in the development and persistence of chronic inflammatory liver diseases. The hepatic sinusoid is a unique vascular bed lined by hepatic sinusoidal endothelial cells (HSECs), a functionally and phenotypically distinct subpopulation of endothelial cells. Using flow‐based adhesion assays to study the migration of lymphocytes across primary human HSECs, we found that lymphocytes enter into HSECs, confirmed by electron microscopy demonstrating clear intracellular localization of lymphocytes in vitro and by studies in human liver tissues. Stimulation by interferon‐γ increased intracellular localization of lymphocytes within HSECs. Furthermore, using confocal imaging and time‐lapse recordings, we demonstrated “intracellular crawling” of lymphocytes entering into one endothelial cell from another. This required the expression of intracellular adhesion molecule‐1 and stabilin‐1 and was facilitated by the junctional complexes between HSECs. Conclusion: Lymphocyte migration is facilitated by the unique structure of HSECs. Intracellular crawling may contribute to optimal lymphocyte positioning in liver tissue during chronic hepatitis. (Hepatology 2017;65:294‐309).
Uptake of hepatitis C screening, characteristics of patients tested, and intervention costs in the BEST‐C study

From December 2012 to March 2014, three randomized trials, each implementing a unique intervention in primary care settings (repeated mailing, an electronic health record best practice alert [BPA], and patient solicitation), evaluated hepatitis C virus (HCV) antibody testing, diagnosis, and costs for each of the interventions compared with standard‐of‐care testing. Multilevel multivariable models were used to estimate the adjusted risk ratio (aRR) for receiving an HCV antibody test, and costs were estimated using activity‐based costing. The goal of this study was to estimate the effects of interventions conducted as part of the Birth‐Cohort Evaluation to Advance Screening and Testing for Hepatitis C study on HCV testing and costs among persons of the 1945‐1965 birth cohort (BC). Intervention resulted in substantially higher HCV testing rates compared with standard‐of‐care testing (26.9% versus 1.4% for repeated mailing, 30.9% versus 3.6% for BPA, and 63.5% versus 2.0% for patient solicitation) and significantly higher aRR for testing after controlling for sex, birth year, race, insurance type, and median household income (19.2 [95% confidence interval (CI), 9.7–38.2] for repeated mailing, 13.2 [95% CI, 3.6–48.6] for BPA, and 32.9 [95% CI, 19.3–56.1] for patient solicitation). The BPA intervention had the lowest incremental cost per completed test ($24 with fixed startup costs, $3 without) and also the lowest incremental cost per new case identified after omitting fixed startup costs ($1691). Conclusion: HCV testing interventions resulted in an increase in BC testing compared with standard‐of‐care testing but also increased costs. The effect size and incremental costs of BPA intervention (excluding startup costs) support more widespread adoption compared with the other interventions. (Hepatology 2017;65:44‐53).
Managing multiple generations: scenarios from the workplace.

PROBLEM The current nursing workforce is composed of multigenerational staff members creating challenges and at times conflict for managers. METHODS Generational cohorts are defined and two multigenerational scenarios are presented and discussed using the ACORN imperatives and Hahn's Five Managerial Strategies for effectively managing a multigenerational staff. FINDINGS Communication and respect are the underlying key strategies to understanding and bridging the generational gap in the workplace. CONCLUSION Embracing and respecting generational differences can bring strength and cohesiveness to nursing teams on the managerial or unit level.
Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups

Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large‐scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk‐stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high‐risk tumors were characterized by up‐regulated nuclear factor, erythroid 2–like 2 activity; high lin‐28 homolog B, high mobility group AT‐hook 2, spalt‐like transcription factor 4, and alpha‐fetoprotein expression; and high coordinated expression of oncofetal proteins and stem‐cell markers, while low‐risk tumors had low lin‐28 homolog B and lethal‐7 expression and high hepatic nuclear factor 1 alpha activity. Conclusion: Analysis of immunohistochemical assays using antibodies targeting these genes in a prospective study of 35 HBs suggested that these candidate biomarkers have the potential to improve risk stratification and guide treatment decisions for HB patients at diagnosis; our results pave the way for clinical collaborative studies to validate candidate biomarkers and test their potential to improve outcome for HB patients. (Hepatology 2017;65:104‐121).
Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate

Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between “true” and calculated glomerular filtration rate (GFR). We compared the performance of the four‐variable and six‐variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with “true,” or measured, GFR (mGFR) and the impact of this difference on Model for End‐Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≥3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine–0·836) × (urea–0·229) × (international normalized ratio–0·113) × (age−0.129 [Corrected November 29, 2016: originally written as “age‐129.”]) × (sodium0·972) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl. ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. Conclusion: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582‐591).
The hepatic “matrisome” responds dynamically to injury: Characterization of transitional changes to the extracellular matrix in mice

The extracellular matrix (ECM) consists of diverse components that work bidirectionally with surrounding cells to create a responsive microenvironment. In some contexts (e.g., hepatic fibrosis), changes to the ECM are well recognized and understood. However, it is becoming increasingly accepted that the hepatic ECM proteome (i.e., matrisome) responds dynamically to stress well before fibrosis. The term “transitional tissue remodeling” describes qualitative and quantitative ECM changes in response to injury that do not alter the overall architecture of the organ; these changes in ECM may contribute to early disease initiation and/or progression. The nature and magnitude of these changes to the ECM in liver injury are poorly understood. The goals of this work were to validate analysis of the ECM proteome and compare the impact of 6 weeks of ethanol diet and/or acute lipopolysaccharide (LPS). Liver sections were processed in a series of increasingly rigorous extraction buffers to separate proteins by solubility. Extracted proteins were identified using liquid chromatography/tandem mass spectrometry (LC‐MS/MS). Both ethanol and LPS dramatically increased the number of matrisome proteins ∼25%. The enhancement of LPS‐induced liver damage by ethanol preexposure was associated with unique protein changes. Conclusion: An extraction method to enrich the hepatic ECM was characterized. The results demonstrate that the hepatic matrisome responds dynamically to both acute (LPS) and chronic (ethanol) stresses, long before more‐dramatic fibrotic changes to the liver occur. The changes to the mastrisome may contribute, at least in part, to the pathological responses to these stresses. It is also interesting that several ECM proteins responded similarly to both stresses, suggesting a common mechanism in both models. Nevertheless, there were responses that were unique to the individual and combined exposures. (Hepatology 2017;65:969‐982).
Differential DNA methylation in umbilical cord blood of infants exposed to mercury and arsenic in utero

Mercury and arsenic are known developmental toxicants. Prenatal exposures are associated with adverse childhood health outcomes that could be in part mediated by epigenetic alterations that may also contribute to altered immune profiles. In this study, we examined the association between prenatal mercury exposure on both DNA methylation and white blood cell composition of cord blood, and evaluated the interaction with prenatal arsenic exposure. A total of 138 mother-infant pairs with postpartum maternal toenail mercury, prenatal urinary arsenic concentrations, and newborn cord blood were assessed using the Illumina Infinium Methylation450 array. White blood cell composition was inferred from DNA methylation measurements. A doubling in toenail mercury concentration was associated with a 2.5% decrease (95% CI: 5.0%, 1.0%) in the estimated monocyte proportion. An increase of 3.5% (95% CI: 1.0, 7.0) in B-cell proportion was observed for females only. Among the top 100 CpGs associated with toenail mercury levels (ranked on P-value), there was a significant enrichment of loci located in North shore regions of CpG islands (P = 0.049), and the majority of these loci were hypermethylated (85%). Among the top 100 CpGs for the interaction between arsenic and mercury, there was a greater than expected proportion of loci located in CpG islands (P = 0.045) and in South shore regions (P = 0.009) and all of these loci were hypermethylated. This work supports the hypothesis that mercury may be contributing to epigenetic variability and immune cell proportion changes, and suggests that in utero exposure to mercury and arsenic, even at low levels, may interact to impact the epigenome.
Initiation of aberrant DNA methylation patterns and heterogeneity in precancerous lesions of human hepatocellular cancer

ABSTRACT While intratumor heterogeneity contributes to disease progression, metastasis, and resistance to chemotherapy, it also provides a route to understanding the evolution and drivers of disease. Defects in epigenetic landscapes are intimately linked to pathogenesis of a variety of human diseases, with epigenetic deregulation promoting tumorigenesis. Understanding epigenetic heterogeneity is crucial in hepatocellular carcinoma (HCC), where epigenetic alterations are frequent, early, and pathogenic events. We determined genome-wide DNA methylation and copy number variation leveraging the Infinium 450K in a series of regenerative nodules from within single patient livers. Bioinformatics strategies were used to ascertain within-patient heterogeneity, link epigenetic changes to clinical features, and determine their relevance to disease pathogenesis. Our data demonstrate that DNA methylation and copy number alterations evolve during the pre-neoplastic phase of HCC and independently segregate regenerative nodules into distinct clusters. Regenerative nodules with a high frequency of epigenetic changes have significantly lower copy number variation, suggesting that individual nodules have differential enrichment of epigenetic and genetic components, with both contributing to disease progression. Regenerative nodules were scored based on ‘epigenetic progression’ with higher scores associated with increased proliferation measured by Ki67 staining. Early events observed in epigenetically ‘aggressive’ nodules are enriched for genes involved in liver cancer. Our study demonstrates that marked epigenetic and genetic heterogeneity exists in early pre-neoplastic liver tissue within individual patients, emphasizing the potential contributions of each mechanism to driving liver disease progression, and it unveils strategies for identifying epigenetic drivers of hepatocellular carcinoma.
Estimation of the Rate of Pelvic Inflammatory Disease Diagnoses: Trends in England, 2000–2008

Background: Pelvic inflammatory disease (PID) is difficult to define and diagnose; therefore, a standardized methodology for identifying and monitoring PID diagnoses is required. We estimated the rate of PID in general practice in England, and investigated variations by definition of PID, time, age, and geographical area. Methods: We analyzed the United Kingdom General Practice Research Database between 2000 and 2008. Definitions of “definite,” “probable,” and “possible” PID among female patients (aged 16 to 44 years) were determined according to medical codes that denoted diagnoses or symptoms indicative of PID. Diagnoses rates were calculated per 100,000 person-years (py). Trends were assessed using Poisson regression. Results: The rate of clinical PID diagnoses was 281/100,000 py (95% confidence interval [95% CI]: 277–286) for definite cases; 326/100,000 py (95% CI: 321–331) for definite and probable cases; and 1117/100,000 py (95% CI: 1107–1126) for definite, probable, and possible cases. During 2000 to 2008, the rate of definite/probable PID decreased by 10.4% per year (95% CI: 9.7–11.1; P < 0.001). Rates declined in all areas and among all age groups with greatest decline in women aged 16 to 19 years. Meanwhile, the rate of possible PID increased. Conclusions: The definition of PID used has a major effect on the rate and trends over time. There was heterogeneity in rates of definite/probable PID by age and region, but homogeneity with regard to a trend of declining rates. Ongoing monitoring of PID diagnoses, with standard case definitions, will contribute to the evaluation of chlamydia screening in England.
RIG‐I is a key antiviral interferon‐stimulated gene against hepatitis E virus regardless of interferon production

Interferons (IFNs) are broad antiviral cytokines that exert their function by inducing the transcription of hundreds of IFN‐stimulated genes (ISGs). However, little is known about the antiviral potential of these cellular effectors on hepatitis E virus (HEV) infection, the leading cause of acute hepatitis globally. In this study, we profiled the antiviral potential of a panel of important human ISGs on HEV replication in cell culture models by overexpression of an individual ISG. The mechanism of action of the key anti‐HEV ISG was further studied. We identified retinoic acid–inducible gene I (RIG‐I), melanoma differentiation–associated protein 5, and IFN regulatory factor 1 (IRF1) as the key anti‐HEV ISGs. We found that basal expression of RIG‐I restricts HEV infection. Pharmacological activation of the RIG‐I pathway by its natural ligand 5′‐triphosphate RNA potently inhibits HEV replication. Overexpression of RIG‐I activates the transcription of a wide range of ISGs. RIG‐I also mediates but does not overlap with IFN‐α‐initiated ISG transcription. Although it is classically recognized that RIG‐I exerts antiviral activity through the induction of IFN production by IRF3 and IRF7, we reveal an IFN‐independent antiviral mechanism of RIG‐I in combating HEV infection. We found that activation of RIG‐I stimulates an antiviral response independent of IRF3 and IRF7 and regardless of IFN production. However, it is partially through activation of the Janus kinase (JAK)–signal transducer and activator of transcription (STAT) cascade of IFN signaling. RIG‐I activated two distinct categories of ISGs, one JAK‐STAT‐dependent and the other JAK‐STAT‐independent, which coordinately contribute to the anti‐HEV activity. Conclusion: We identified RIG‐I as an important anti‐HEV ISG that can be pharmacologically activated; activation of RIG‐I stimulates the cellular innate immunity against HEV regardless of IFN production but partially through the JAK‐STAT cascade of IFN signaling. (Hepatology 2017;65:1823‐1839).
One additional histone deacetylase and 2 histone acetyltransferases are involved in cellular patterning of Arabidopsis root epidermis

ABSTRACT The cellular patterning of Arabidopsis root epidermis is a well-characterized system for study of how single-layered cells are arranged in a particular spatial order. Previously, we found that histone acetylation plays an important role in regulating epidermal differentiation by relaying positional information. To investigate the underlying mechanisms, we screened all available mutants of both HDAC and HAT families. Analyses of mutants of HDAC family members revealed that among single mutants, only HDA6, HDA18 and HDA19 exhibited ectopic H cells at the N position. Similarly, among HAT family members, only single mutants for GCN5 and HAF2 exhibited altered epidermal phenotypes, which were unexpectedly similar to the phenotypes observed in HDAC mutants. Based on these results, together with the previous findings regarding the regulatory mechanisms of HDA18 and HDA6, we proposed that homeostasis of histone acetylation is important for robustness of the regulatory network responsible for the cellular patterning of the Arabidopsis root epidermis.
Toll‐like receptor 5 signaling restrains T‐cell/natural killer T‐cell activation and protects against concanavalin A–induced hepatic injury

Toll‐like receptor‐5 (TLR5) signaling regulates the immune privileged status of the liver and is involved in hepatic immune disorders. However, the role of TLR5 has not yet been investigated in experimental models of concanavalin A (Con A)–mediated liver injury. Here, we show that TLR5 is highly up‐regulated in the hepatic mononuclear cells of mice during Con A–induced hepatitis. Increased mortality and liver histopathology of TLR5‐deficient mice correlated with excessive production of proinflammatory cytokines, suggesting that TLR5 knockout mice were more susceptible to Con A–induced hepatitis. We also report that administration of CBLB502, an exogenous TLR5 agonist, substantially alleviated Con A–mediated hepatitis in wild‐type mice as shown by increased survival rates, reduced aminotransferase and proinflammatory cytokine production, impaired lymphocyte infiltration, and ameliorated hepatocyte necrosis and/or apoptosis. Mechanistic studies revealed that CBLB502 acts as a negative regulator in limiting T‐cell/natural killer T‐cell activity and cytokine production in the Con A–hepatitis model. Bone marrow transplantation experiments showed that TLR5 in bone marrow–derived cells contributed to the hepatoprotective efficacy of CBLB502 against Con A–induced liver injury. Moreover, interleukin‐6 elevation induced by CBLB502 is an important protective factor against Con A–induced liver injury. In addition, we demonstrate that CBLB502 suppresses α‐galactosylceramide‐induced natural killer T cell–dependent inflammatory liver injury. Conclusion: The TLR5 signaling pathway plays an important role in T cell–mediated hepatic injury and may be exploited for therapeutic treatment of inflammatory liver diseases. (Hepatology 2017;65:2059‐2073).