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Objectives: Recently it was shown that the magnetic resonance imaging (MRI) T1ρ value increased with the severity of liver fibrosis in rats with bile duct ligation. Using a rat carbon tetrachloride (CCl(4)) liver injury model, this study further investigated the merit of T1ρ relaxation for liver fibrosis evaluation.Methods: Male Sprague-Dawley rats received intraperitoneal injection of 2 ml/kg CCl(4) twice weekly for up to 6 weeks. Then CCl(4) was withdrawn and the animals were allowed to recover. Liver T1ρ MRI and conventional T2-weighted images were acquired. Animals underwent MRI at baseline and at 2 days, 2 weeks, 4 weeks and 6 weeks post CCl(4) injection, and they were also examined at 1 week and 4 weeks post CCl(4) withdrawal. Liver histology was also sampled at these time points.Results: Liver T1ρ values increased slightly, though significantly, on day 2, and then increased further and were highest at week 6 post CCl(4) insults. The relative liver signal intensity change on T2-weighted images followed a different time course compared with that of T1ρ. Liver T1ρ values decreased upon the withdrawal of the CCl(4) insult. Histology confirmed the animals had typical CCl(4) liver injury and fibrosis progression and regression processes.Conclusions: MR T1ρ imaging can monitor CCl(4)-induced liver injury and fibrosis.Key Points: • MR T1ρ is a valuable imaging biomarker for liver injury/fibrosis. • Liver T1ρ was only mildly affected by oedema and acute inflammation. • Liver MR T1ρ decreased when liver fibrosis and injury regressed. [ABSTRACT FROM AUTHOR]

Background: We have previously demonstrated that peroxisome proliferator-activated receptor (PPARγ) activation inhibits hepatocarcinogenesis. We aim to investigate the effect of PPARγ on hepatocellular carcinoma (HCC) metastatic potential and explore its underlying mechanisms.Methods: Human HCC cells (MHCC97L, BEL-7404) were infected with adenovirus-expressing PPARγ (Ad-PPARγ) or Ad-lacZ and treated with or without PPARγ agonist (rosiglitazone). The effects of PPARγ on cell migration and invasive activity were determined by wound healing assay and Matrigel invasive model in vitro, and in an orthotopic liver tumour metastatic model in mice.Results: Pronounced expression of PPARγ was demonstrated in HCC cells (MHCC97L, BEL-7404) treated with Ad-PPARγ, rosiglitazone or Ad-PPARγ plus rosiglitazone, compared with control (Ad-LacZ). Such induction markedly suppressed HCC cell migration. Moreover, the invasiveness of MHCC97L and BEL-7404 cells infected with Ad-PPARγ, or treated with rosiglitazone was significantly diminished up to 60%. Combination of Ad-PPARγ and rosiglitazone showed an additive effect. Activation of PPARγ by rosiglitazone significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. Key mechanisms underlying the effect of PPARγ in HCC include upregulation of cell adhesion genes, E-cadherin and SYK (spleen tyrosine kinase), extracellular matrix regulator tissue inhibitors of metalloproteinase (TIMP) 3, tumour suppressor gene retinoblastoma 1, and downregulation of pro-metastatic genes MMP9 (matrix metallopeptidase 9), MMP13, HPSE (heparanase), and Hepatocyte growth factor (HGF). Direct transcriptional regulation of TIMP3, MMP9, MMP13, and HPSE by PPARγ was shown by ChIP-PCR.Conclusion: Peroxisome proliferator-activated receptor-gamma exerts an inhibitory effect on the invasive and metastatic potential of HCC in vitro and in vivo, and is thus, a target for the prevention and treatment of HCC metastases. [ABSTRACT FROM AUTHOR]

The current diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe form, metabolic dysfunction-associated steatohepatitis (MASH), is suboptimal. Here, we recruited 700 individuals, including 184 from Hong Kong as a discovery cohort and 516 from San Diego, Wenzhou, and Hong Kong as three validation cohorts. A panel of 3 parameters (C-X-C motif chemokine ligand 10 [CXCL10], cytokeratin 18 fragments M30 [CK-18], and adjusted body mass index [BMI]) was formulated (termed N3-MASH), which discriminated patients with MASLD from healthy controls with an area under the receiver operating characteristic (AUROC) of 0.954. Among patients with MASLD, N3-MASH could identify patients with MASH with an AUROC of 0.823, achieving 90.0% specificity, 62.9% sensitivity, and 88.6% positive predictive value. The diagnostic performance of N3-MASH was confirmed in three validation cohorts with AUROC of 0.802, 0.805, and 0.823, respectively. Additionally, N3-MASH identifies patients with MASH improvement with an AUROC of 0.857. In summary, we developed a robust blood-based panel for the non-invasive diagnosis of MASH, which might help clinicians reduce unnecessary liver biopsies., Competing Interests: Declaration of interests R.L. serves as a consultant to Aardvark Therapeutics, Altimmune, Arrowhead Pharmaceuticals, AstraZeneca, Cascade Pharmaceuticals, Eli Lilly, Gilead, Glympse bio, Inipharma, Intercept, Inventiva, Ionis, Janssen Inc., Lipidio, Madrigal, Neurobo, Novo Nordisk, Merck, Pfizer, Sagimet, 89 bio, Takeda, Terns Pharmaceuticals, and Viking Therapeutics. In addition, his institution received research grants from Arrowhead Pharmaceuticals, Astrazeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, Galectin Therapeutics, Gilead, Intercept, Hanmi, Intercept, Inventiva, Ionis, Janssen, Madrigal Pharmaceuticals, Merck, Novo Nordisk, Pfizer, Sonic Incytes, and Terns Pharmaceuticals. He is a co-founder of LipoNexus Inc. V.W.-S.W. has served as an advisory board member or consultant for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna and as a speaker for Abbott, AbbVie, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences and is a co-founder of Illuminatio Medical Technology Limited. V.W.-S.W. serves as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, and TARGET PharmaSolutions and as a speaker for Abbott, AbbVie, Gilead Sciences, and Novo Nordisk. He has received a grant from Gilead Sciences for fatty liver research and is a co-founder of Illuminatio Medical Technology Limited., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Gut probiotic depletion is associated with non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC). Here, we investigated the prophylactic potential of Lactobacillus acidophilus against NAFLD-HCC., Methods: NAFLD-HCC conventional and germ-free mice were established by diethylnitrosamine (DEN) injection with feeding of high-fat high-cholesterol (HFHC) or choline-deficient high-fat (CDHF) diet. Orthotopic NAFLD-HCC allografts were established by intrahepatic injection of murine HCC cells with HFHC feeding. Metabolomic profiling was performed using liquid chromatography-mass spectrometry. Biological functions of L. acidophilus conditional medium (L.a CM) and metabolites were determined in NAFLD-HCC human cells and mouse organoids., Findings: L. acidophilus supplementation suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice. This was confirmed in orthotopic allografts and germ-free tumourigenesis mice. L.a CM inhibited the growth of NAFLD-HCC human cells and mouse organoids. The protective function of L. acidophilus was attributed to its non-protein small molecules. By metabolomic profiling, valeric acid was the top enriched metabolite in L.a CM and its upregulation was verified in liver and portal vein of L. acidophilus-treated mice. The protective function of valeric acid was demonstrated in NAFLD-HCC human cells and mouse organoids. Valeric acid significantly suppressed NAFLD-HCC formation in HFHC-fed DEN-treated mice, accompanied by improved intestinal barrier integrity. This was confirmed in another NAFLD-HCC mouse model induced by CDHF diet and DEN. Mechanistically, valeric acid bound to hepatocytic surface receptor GPR41/43 to inhibit Rho-GTPase pathway, thereby ablating NAFLD-HCC., Interpretation: L. acidophilus exhibits anti-tumourigenic effect in mice by secreting valeric acid. Probiotic supplementation is a potential prophylactic of NAFLD-HCC., Funding: Shown in Acknowledgments., Competing Interests: Declaration of interests The authors disclose no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Photodynamic Therapy (PDT) is a clinically approved cancer treatment. Sex hormones, the key drivers for the development of female hormonal dependent cancers, might affect cancer treatment. There are seldom studies to evaluate the effect of sex hormones mimicked the menstrual cycle on the PDT mediated by prodrug 5-aminolevulinic acid (ALA) and its ester derivatives to the hormonal dependent cancers., Aims: To evaluate the efficacy of sex hormones on Hexyl-ALA-PDT in hormonal dependent cancers and the effect of the sex hormones on heme biosynthetic pathway., Methods: Cell culture system that mimicked the fluctuation of sex hormones 17β-estradiol (E2) and progesterone (PG) in the menstrual cycle was developed. Two pairs of hormonal-independent and hormonal dependent uterine sarcoma and breast cancer cell lines were used as cell models. Hexyl-ALA induced PpIX production and intracellular localization were examined. Key enzymes for PpIX synthesis were analysed. Hexyl-ALA-PDT mediated phototoxicity was evaluated., Results: The PpIX generation was increased in the hormonal-dependent cells (28-50 %) when cultured in the hormonal microenvironment with long incubation of Hexyl-ALA for 15 and 24 h compared to that cultured without hormones; whereas only slight difference in PpIX generation in their hormonal-independent counterpart. The PpIX generation was in a time-dependent manner. The CPOX, PPOX and FECH expressions were significantly enhanced by Hexyl-ALA-PDT in uterine sarcoma cells in hormonal microenvironment. Hexyl-ALA-PDT triggered significant increase of PPOX expression in breast cancer cells in hormonal microenvironment. The Hexyl-ALA-PDT phototoxicity was enhanced by 18-40 % in cells cultured in the hormonal system in a dose-dependent manner., Conclusion: The PpIX generation and the efficacy of Hexyl-ALA-PDT in both uterine sarcoma and breast cancer cells was significantly enhanced by the sex hormones via cultured in the hormonal microenvironment., (Copyright © 2024. Published by Elsevier B.V.)

While the detrimental consequences of racial/ethnic discrimination for adolescent adaptation are well established, little is known about the long-term impact of hukou-based discrimination from the hukou (household registration) system and the potential protective benefits of adolescents' internal capabilities; furthermore, there have been even fewer studies examining potential migrant pattern differences in the association. The current study addressed these gaps by investigating the longitudinal associations between hukou-based discrimination and migrant adolescents' adaptation outcomes (cognitive ability, depressive symptoms, and behavioral problems), as well as whether school engagement moderated these pathways, and whether this function varied by adolescents' migrant patterns. The data were obtained from 1226 migrant adolescents (51.31% male; 51.47% urban migrants, 48.53% rural migrants) aged 12 to 16 years (M age  = 13.56, SD = 0.69 at Wave 1) from the China Education Panel Survey in two waves separated by twelve months. Multilevel modeling revealed that hukou-based discrimination from peers and teachers was negatively related to cognitive abilities, but positively related to depressive symptoms and behavioral problems. School engagement served not only as a facilitator of adaptation but also as a protective factor against hukou-based discrimination. The moderating effect of school engagement was more pronounced in urban migrants than in rural migrants. The current study's findings highlight the role of hukou-based discrimination in adaptation disparities and shed light on the importance of internal capabilities in protecting migrant adolescents with different migration patterns from the detrimental impacts of discrimination on the adaptation process., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Delays in treatment of in-hospital cardiac arrests (IHCAs) are associated with worsened survival. We sought to assess the impact of a bundled intervention on IHCA survival in patients on centralised telemetry. A retrospective quality improvement study was performed of a bundled intervention which incorporated (1) a telemetry hotline for telemetry technicians to reach nursing staff; (2) empowerment of telemetry technicians to directly activate the IHCA response team and (3) a standardised escalation system for automated critical alerts within the nursing mobile phone system. In the 4-year study period, there were 75 IHCAs, including 20 preintervention and 55 postintervention. Cox proportional hazard regression predicts postintervention individuals have a 74% reduced the risk of death (HR 0.26, 95% CI 0.08 to 0.84) during a code and a 55% reduced risk of death (HR 0.45, 95% CI 0.23 to 0.89) prior to hospital discharge. Overall code survival improved from 60.0% to 83.6% (p=0.031) with an improvement in ventricular tachycardia/ventricular fibrillation (VT/VF) code survival from 50.0% to 100.0% (p=0.035). There was no difference in non-telemetry code survival preintervention and postintervention (71.4% vs 71.3%, p=0.999). The bundled intervention, including improved communication between telemetry technicians and nurses as well as empowerment of telemetry technicians to directly activate the IHCA response team, may improve IHCA survival, specifically for VT/VF arrests., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The second Multicenter Medication Reconciliation Quality Improvement Study demonstrated a marked reduction in medication discrepancies per patient. The aim of the current analysis was to determine the association of patient exposure to each system-level intervention and receipt of each patient-level intervention on these results., Methods: This study was conducted at 17 North American Hospitals, the study period was 18 months per site, and sites typically adopted interventions after 2-5 months of preintervention data collection. We conducted an on-treatment analysis (ie, an evaluation of outcomes based on patient exposure) of system-level interventions, both at the category level and at the individual component level, based on monthly surveys of implementation site leads at each site (response rate 65%). We then conducted a similar analysis of patient-level interventions, as determined by study pharmacist review of documented activities in the medical record. We analysed the association of each intervention on the adjusted number of medication discrepancies per patient in admission and discharge orders, based on a random sample of up to 22 patients per month per site, using mixed-effects Poisson regression with hospital site as a random effect. We then used a generalised linear mixed-effects model (GLMM) decision tree to determine which patient-level interventions explained the most variance in discrepancy rates., Results: Among 4947 patients, patient exposure to seven of the eight system-level component categories was associated with modest but significant reductions in discrepancy rates (adjusted rate ratios (ARR) 0.75-0.97), as were 15 of the 17 individual system-level intervention components, including hiring, reallocating and training personnel to take a best possible medication history (BPMH) and training personnel to perform discharge medication reconciliation and patient counselling. Receipt of five of seven patient-level interventions was independently associated with large reductions in discrepancy rates, including receipt of a BPMH in the emergency department (ED) by a trained clinician (ARR 0.40, 95% CI 0.37 to 0.43), admission medication reconciliation by a trained clinician (ARR 0.57, 95% CI 0.50 to 0.64) and discharge medication reconciliation by a trained clinician (ARR 0.64, 95% CI 0.57 to 0.73). In GLMM decision tree analyses, patients who received both a BPMH in the ED and discharge medication reconciliation by a trained clinician experienced the lowest discrepancy rates (0.08 per medication per patient)., Conclusion and Relevance: Patient-level interventions most associated with reductions in discrepancies were receipt of a BPMH of admitted patients in the ED and admission and discharge medication reconciliation by a trained clinician. System-level interventions were associated with modest reduction in discrepancies for the average patient but are likely important to support patient-level interventions and may reach more patients. These findings can be used to help hospitals and health systems prioritise interventions to improve medication safety during care transitions., Competing Interests: Competing interests: JLS and ASM received remuneration from American Society of Health-System Pharmacists (ASHP) to develop their best possible medication history training curriculum. JLS received funding from Synapse Medicine for an investigator-initiated study to evaluate the effects of their medication decision support software on hospital pharmacists’ medication recommendations., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Acute heart failure (AHF) exacerbations are a leading cause of hospitalization in the United States. Despite the frequency of AHF hospitalizations, there are inadequate data or practice guidelines on how quickly diuresis should be achieved., Objective: To study the association of 48-h net fluid change and (A) 72-h change in creatinine and (B) 72-h change in dyspnea among patients with acute heart failure., Designs, Settings, and Participants: This is a retrospective, pooled cohort analysis of patients from the DOSE, ROSE, and ATHENA-HF trials., Interventions: The primary exposure was 48-h net fluid status., Main Outcomes and Measures: The co-primary outcomes were 72-h change in creatinine and 72-h change in dyspnea. The secondary outcome was risk of 60-day mortality or rehospitalization., Results: Eight hundred and seven patients were included. The mean 48-h net fluid status was -2.9 L. A nonlinear association was observed with net fluid status and creatinine change, such that creatinine improved with each liter net negative up to 3.5 L (-0.03 mg/dL per liter negative [95% confidence interval [CI]: -0.06 to -0.01) and remained stable beyond 3.5 L (-0.01 [95% CI: -0.02 to 0.001], p = .17). Net fluid loss was associated with a monotonic improvement of dyspnea (1.4-point improvement per liter negative [95% CI: 0.7-2.2], p = .0002). Each liter net negative by 48 h was also associated with 12% decreased odds of 60-day rehospitalization or death (odds ratio: 0.88; 95% CI: 0.82-0.95; p = .002)., Conclusion: Aggressive net fluid targets within the first 48 h are associated with effective relief of patient self-reported dyspnea and improved long-term outcomes without adversely affecting renal function., (© 2023 Society of Hospital Medicine.)

Background: Adolescents, especially the socioeconomically disadvantaged, are facing devastating psychosocial impact of the COVID-19 pandemic during their critical developmental period. This study aims to (i) examine the socioeconomic patterning of the worsening of psychosocial wellbeing, (ii) delineate the underlying mediating factors (i.e., overall worry about COVID-19, family's financial difficulty, learning problems, and loneliness), and (iii) explore the moderating effect of resilience in the inter-relationship among adolescents under COVID-19., Methods: Based on maximum variation sampling of 12 secondary schools of diverse socioeconomic background in Hong Kong, 1018 students aged 14-16 years were recruited and completed the online survey between September and October 2021. Multi-group structural equation modeling (SEM) by resilience levels was employed to delineate the pathways between socioeconomic position and the worsening of psychosocial wellbeing., Results: SEM analysis showed a significant total effect of socioeconomic ladder with the worsening of psychosocial wellbeing during the pandemic in the overall sample (β = -0.149 [95% CI = -0.217 - -0.081], p < 0.001), which operated indirectly through learning problems and loneliness (both p < 0.001 for their indirect effects). Consistent pattern with stronger effect size was observed in the lower resilience group; nonetheless, the associations were substantially mitigated in the higher resilience group., Conclusion: In addition to facilitating self-directed learning and easing loneliness during the pandemic, evidence-based strategies to build up resilience among adolescents are critical to buffer against the adverse socioeconomic and psychosocial impacts of the pandemic or other potential catastrophic events in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chung, Chan, Lee, Chan, Chen, Wong, Chung and Ho.)

Background: Hospitalists who seek academic careers are interested in developing skills in research, education, and quality improvement (QI). Since these are not major foci of residency programs, hospitalists may pursue a hospital medicine fellowship to acquire these skill sets., Objective: We sought to characterize the current state of hospital medicine fellowships in the United States, including demographics, clinical requirements, curricular focus, financial structure, and scholarly outputs. DESIGNS, SETTINGS, AND PARTICIPANTS: This was a cross-sectional study of 32 hospital medicine fellowship programs across the United States in 2020-2021. An electronic survey was emailed to program leaders., Results: Out of 32 eligible programs contacted, 19 (59.4%) programs responded, representing 22 fellowship tracks. Most (63.2%) programs have been in existence for 5 years or less. Fourteen (63.6%) of the tracks had multiple focus areas, while 8 (36.4%) had a single focus. Of the 14 fellowship tracks with multiple focus areas, 6 (42.8%) reported research, QI and medical education as curricular elements. All 14 reported research as one of the curricular elements. The majority (68.4%) of programs offered opportunities to obtain a master's degree, though the field of degree varied widely. A median of 50% (IQR 0) of fellows' time was spent in clinical activities. Considerable heterogeneity exists among adult hospital medicine fellowship programs. The majority focus on research, QI, and/or medical education. Hospital medicine fellowships offer opportunities for intesive faculty development and unique career pathways., (© 2023 Society of Hospital Medicine.)

Background: Hospitalized medical patients with concurrently decompensated psychiatric and medical conditions experience worse clinical outcomes. Health care providers caring for this patient population are at increased risk of workplace violence. The authors sought to understand the effects of a clinical microsystem specifically designed to care for patients too psychiatrically ill for medical units and too medically ill for psychiatry units., Methods: The research team performed a quality improvement study in which a medicine-psychiatry co-managed clinical microsystem incorporating high performance teamwork principles was engineered in an urban academic medical center to improve patient and staff safety, as well as operational outcomes. Poisson regression was performed to determine differences between workplace violence events, falls, 30-day emergency department (ED) revisits, and hospital readmissions, comparing the baseline period to the intervention period., Results: There were 321 patients discharged in the baseline period and 310 during the intervention period. Workplace violence events decreased by 65.6% (incidence rate ratio [IRR] 0.34, 95% confidence interval [CI] 0.20-0.57, p < 0.001) after implementation of the clinical microsystem when compared to the baseline period. The rate of ED utilization at 30 days postdischarge also decreased from 30.6% at baseline to 21.0% postintervention (adjusted odds ratio [aOR] 0.60, 95% CI 0.42-0.87, p = 0.006). No differences were detected in falls and 30-day readmissions., Conclusion: For patients with concurrently decompensated medical and psychiatric conditions, the incidence of workplace violence and postdischarge ED utilization can be improved by creating a clinical microsystem that integrates changes to both the physical environment and teamwork processes., (Copyright © 2022 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Objectives: Emerging adults transitioning from pediatric to adult care experience worse outcomes including increased mortality. Improved patient experience (PEX) correlates with decreased inpatient mortality and better adherence to quality guidelines. We aimed to evaluate trends in the PEX of inpatients aged 14-29 years in the United States (US)., Methods: We performed a retrospective cohort study using a national, de-identified PEX survey obtained from hospitalized patients aged 14-29 years between 2017 and 2019. We described and compared survey responses across 10 domains. Composite mean scores for each health facility were converted to percentile rankings, which were then compared by age group to determine differences in percentile ranking (ΔPR)., Results: We evaluated the results of 174,174 PEX surveys across a national sample of 1519 US hospitals. The PEX percentile rankings for ages 18-21 were lower than ages 14-17 in almost every domain including experience with nurses (ΔPR = 43.4, p < 0.001), physicians (ΔPR = 31.1, p < 0.001), treatment (ΔPR = 12.3, p < 0.001), and overall experience (ΔPR = 26.5, p < 0.001). Similarly, 22-25-year-olds reported a worse PEX across nearly all domains when compared to 26-29-year-olds., Conclusion: In a national sample of PEX surveys, hospitalized emerging adults aged 18-25 reported worse PEX when compared to both older children and established adults. These lower ratings were most strongly attributed to people, processes, and relationships as opposed to differences in the hospital environment. By ages 26-29, PEX returned to levels similar to those reported by ages 14-17. These results suggest that further investigation to elucidate the unique needs of hospitalized emerging adults may be warranted.

The pediatric-to-adult care transition has been correlated with worse outcomes, including increased mortality. Emerging adults transitioning from child-specific healthcare facilities to adult hospitals encounter marked differences in environment, culture, and processes of care. Accordingly, emerging adults may experience care differently than other hospitalized adults. We performed a retrospective cohort study of patients admitted to a large urban safety net hospital and compared all domains of patient experience between patients in 3 cohorts: ages 18 to 21, 22 to 25, and 26 years and older. We found that patient experience for emerging adults aged 18 to 21, and, to a lesser extent, aged 22 to 25, was significantly and substantially worse as compared to adults aged 26 and older. The domains of worsened experience were widespread and profound, with a 38-percentile difference in overall experience between emerging adults and established adults. While emerging adults experienced care worse in nearly all domains measured, the greatest differences were found in those pertinent to relationships between patients and care providers, suggesting a substantial deficit in our understanding of the preferences and values of emerging adults., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Background: Scholarship remains the principal currency for faculty promotion in academic medicine. Reference points for scholarly growth and productivity at academic medical centers (AMCs) are lacking., Methods: We identified hospital medicine full professors (HMFPs) at AMCs ranked in research by US News & World Report. Scopus was used to identify each HMFP's publications, citations, and Hirsch-index (H-index). Publications; citations; and first, middle, and senior author papers were measured in 3-year intervals postresidency. Scholarly productivity was analyzed by quintile based on publications, AMC research ranking, years postresidency, and grant funding., Results: Data were extracted for 128 HMFPs from 54 AMCs. HMFPs were a mean of 20.5 (SD: 5.4) years postresidency. The median H-index was 7.0 (interquartile range [IQR]: 2.0-16.0); the median number of publications was 15.0 (IQR: 4.0-51.0). Top quintile HMFPs had a median of 175.5 (IQR: 101.5-248.0) publications, whereas fifth quintile HMFPs had a median of 0.0 (IQR: 0.0-1.0) (p < .001). HMFPs on faculty at the top 20 AMCs had a median of 35.5 (IQR: 11.0-108.0) publications, whereas HMFPs in AMCs ranked 81-122 had a median of 3.0 (IQR: 1.0-9.0) (p < .001). Grant-funded HMFPs had a median of 177.0 (IQR: 71.0-278.0) publications, while nongrant-funded HMFPs had a median of 11.0 (IQR: 3.0-25.0) (p < .001). At 3, 6, and 9 years postresidency, HMFPs had a median of 0.0 (IQR: 0.0-1.0), 1.5 (IQR: 0.0-5.0), and 3.5 (IQR: 0.0-11.0) publications. Fellowship training, additional degrees, and top 25 residency programs correlated with the top half of scholarly productivity., Conclusions: Scholarly productivity among HMFPs varies considerably. At 3, 6, and 9 years postresidency, it is minimal to modest. Grant funding and AMC research rank may establish separate frames of reference for scholarly growth., (© 2022 Society of Hospital Medicine.)

The impact of supply chain and supply chain logistics, including personnel directly and indirectly related to the movement of supplies, has come to light in a variety of industries since the global COVID-19 pandemic. Acutely, the experience with baby formula and iodinated contrast material exposes key vulnerabilities to supply chains. The rather sudden diminished availability of iodinated contrast material has forced health care systems to engage in more judicious use of product through catalyzing the adoption of behaviors that had been recommended and deemed reasonable prior to the shortage. The authors describe efforts at a large, academic safety net county health system to conserve iodinated contrast media by optimizing contrast media use in the CT department and changing ordering patterns of referring providers. Special attention is given to opportunities to conserve contrast material in cardiothoracic imaging, including low kV and dual-energy CT techniques. A values-based leadership philosophy and collaboration with key stakeholders facilitate effective response to the critical shortage and rapid deployment of iodinated contrast media conservation strategies. Last, while the single-supplier model is efficient and cost-effective, its application to critically necessary services such as health care must be questioned considering disruptions related to the COVID-19 pandemic. Keywords: CT, Intravenous Contrast Agents, CT-Spectral Imaging (Dual Energy) ©RSNA, 2022., Competing Interests: Disclosures of conflicts of interest: L.A. No relevant relationships. F.U.K. Associate editor for Radiology: Cardiothoracic Imaging; RSNA Seed Grant (RSD2119) Lunit Edwards; support for attending meetings from UT Southwestern Medical Center. E.A.Z. No relevant relationships. E.S.C. No relevant relationships. J.C. No relevant relationships. J.D.B. No relevant relationships. N.M.R. Advisory board for Bracco Diagnostics, GE Healthcare, Medscape Education, Philips Healthcare, and Insightec; UT Southwestern Hospital and Practice Plan Board Member (both, nonprofit); Southwestern Healthcare Resources: Accountable Care Network Board Member and Extended Physician Network Board Member (both, nonprofit). S.A. Royalties from Elsevier for textbooks; editor of Radiology: Cardiothoracic Imaging; board of directors on SCCT., (© 2022 by the Radiological Society of North America, Inc.)

Competing Interests: The authors declare no conflicts of interest.

Despite the rapid growth of academic hospital medicine, scholarly productivity remains poorly characterized. In this cross-sectional study, distribution of academic rank and scholarly output of academic hospital medicine faculty are described. We extracted data for 1,554 hospitalists on faculty at the top 25 internal medicine residency programs. Only 11.7% of faculty had reached associate (9.0%) or full professor (2.7%). The median number of publications was 0.0 (interquartile range [IQR], 0.0-4.0), with 51.4% without a single publication. Faculty 6 to 10 years post residency had a median of 1.0 (IQR, 0.0-4.0) publication, with 46.8% of these faculty without a publication. Among men, 54.3% had published at least one manuscript, compared to 42.7% of women (P < .0001). Predictors of promotion included H-index, number of years post residency graduation, completion of chief residency, and graduation from a top 25 medical school. Promotion remains uncommon in academic hospital medicine, which may be partially due to low rates of scholarly productivity.

Background and Aim: We have previously shown that fecal microbial markers might be useful for non-invasive diagnosis of colorectal cancer (CRC) and adenoma. Here, we assessed the application of microbial DNA markers, as compared with and in combination with fecal immunochemical test (FIT), in detecting CRC and adenoma in symptomatic patients and asymptomatic subjects., Methods: We recruited 676 subjects [210 CRC, 115 advanced adenoma (AA), 86 non-advanced adenoma, and 265 non-neoplastic controls], including 241 symptomatic and 435 asymptomatic subjects. Fecal abundances of Fusobacterium nucleatum, a Lachnoclostridium sp. m3, Bacteroides clarus, and Clostridium hathewayi were quantified by quantitative PCR. Combining score of the four microbial markers (4Bac) and diagnostic prediction were determined using our previously established scoring model and cutoff values and FIT with a cutoff of 100 ng Hb/mL., Results: 4Bac detected similar percentages of CRC [85.3% (95%CI: 79.2-90.2%) vs 84.9% (68.1-94.9%)] and AA [35.7% (12.8-64.9%) vs 38.6% (29.1-48.8%)], while FIT detected more CRC [72.1% (63.7-79.4%) vs 66.7% (48.2-82.0%)] and AA [28.6% (8.4-58.1%) vs 16.8% (10.1-25.6%)], in symptomatic vs asymptomatic subjects, respectively. Focusing on the asymptomatic cohort, 4Bac was more sensitive for diagnosing CRC and AA than FIT (P < 0.001), with lower specificity [83.3% (77.6-88.0%) vs 98.6% (96.0-99.7%)]. FIT failed to detect any non-advanced adenoma [0% (0.0-4.2%)] compared with 4Bac [41.9% (31.3-53.0%), P < 0.0001]. Combining 4Bac with FIT improved sensitivities for CRC [90.9% (75.7-98.1%)] and AA [48.5% (38.4-58.7%)] detection., Conclusion: Quantitation of fecal microbial DNA markers may serve as a new test, stand alone, or in combination with FIT for screening colorectal neoplasm in asymptomatic subjects., (© 2020 The Authors. Journal of Gastroenterology and Hepatology published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objective: Non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is an increasing healthcare burden worldwide. We examined the role of dietary cholesterol in driving NAFLD-HCC through modulating gut microbiota and its metabolites., Design: High-fat/high-cholesterol (HFHC), high-fat/low-cholesterol or normal chow diet was fed to C57BL/6 male littermates for 14 months. Cholesterol-lowering drug atorvastatin was administered to HFHC-fed mice. Germ-free mice were transplanted with stools from mice fed different diets to determine the direct role of cholesterol modulated-microbiota in NAFLD-HCC. Gut microbiota was analysed by 16S rRNA sequencing and serum metabolites by liquid chromatography-mass spectrometry (LC-MS) metabolomic analysis. Faecal microbial compositions were examined in 59 hypercholesterolemia patients and 39 healthy controls., Results: High dietary cholesterol led to the sequential progression of steatosis, steatohepatitis, fibrosis and eventually HCC in mice, concomitant with insulin resistance. Cholesterol-induced NAFLD-HCC formation was associated with gut microbiota dysbiosis. The microbiota composition clustered distinctly along stages of steatosis, steatohepatitis and HCC. Mucispirillum, Desulfovibrio, Anaerotruncus and Desulfovibrionaceae increased sequentially; while Bifidobacterium and Bacteroides were depleted in HFHC-fed mice, which was corroborated in human hypercholesteremia patients. Dietary cholesterol induced gut bacterial metabolites alteration including increased taurocholic acid and decreased 3-indolepropionic acid. Germ-free mice gavaged with stools from mice fed HFHC manifested hepatic lipid accumulation, inflammation and cell proliferation. Moreover, atorvastatin restored cholesterol-induced gut microbiota dysbiosis and completely prevented NAFLD-HCC development., Conclusions: Dietary cholesterol drives NAFLD-HCC formation by inducing alteration of gut microbiota and metabolites in mice. Cholesterol inhibitory therapy and gut microbiota manipulation may be effective strategies for NAFLD-HCC prevention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The role of macrophages in fibrosing steatohepatitis is largely unclear. We characterized the origin and molecular mechanisms of macrophages and its targeted therapy of fibrosing steatohepatitis. Fibrosing steatohepatitis was established in Alms1 mutant (foz/foz) and C57BL/6J wildtype mice fed high-fat/high-cholesterol or methionine- and choline-deficient diet. Bone marrow transplantation was performed to track the macrophage origin in fibrosing steatohepatitis. Macrophages were depleted using liposomal clodronate. Primary macrophages were isolated from bone marrow for adoptive transfer into mice. We found that macrophage infiltration is induced in two mouse models of fibrosing steatohepatitis and human nonalcoholic steatohepatitis-fibrosis patients. Bone marrow-derived macrophages (BMMs) contribute to the hepatic macrophage accumulation in experimental fibrosing steatohepatitis. Depletion of hepatic BMMs by liposomal clodronate during liver injury attenuated fibrosing steatohepatitis, whilst BMMs depletion after liver injury delayed the regression of fibrosing steatohepatitis. The pro-fibrotic effect of macrophages was associated with reduced activation of hepatic stellate cells (HSCs), collagen deposition and hepatic expression of key pro-fibrotic factors (TIMP1, TIMP2, and TGFβ1) and endoplasmic reticulum stress markers (GRP78, IRE1α, and PDI). Conversely, adoptive transfer of BMMs significantly aggravated fibrosing steatohepatitis. Moreover, macrophage-conditioned medium directly promoted the phenotypic transition of primary quiescent HSCs to activated HSCs; it enhanced activation and proliferation but decreased apoptosis of HSC cell lines (LX-2 and HSC-T6). The effect of BMMs in promoting fibrosing steatohepatitis was mediated by inducing key pro-fibrosis factors and signaling pathways including cytokine/chemokine, TGFβ and complement cascade as assessed by cDNA expression array. Complement 3a receptor (C3ar1) was a predominant effector of macrophage mediated fibrosing steatohepatitis. Knockout of C3ar1 in mice blunted development of fibrosing steatohepatitis. In conclusion, BMMs promoted the progression of fibrosing steatohepatitis during injury, whereas macrophages reduced fibrosing steatohepatitis in the recovery phase of liver injury. Increasing anti-fibrotic macrophages and decreasing pro-fibrotic macrophages are promising approaches for fibrosing steatohepatitis. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Mitochondrial dysfunction plays a crucial role in the development of non-alcoholic steatohepatitis (NASH). However, the regulator of mitochondrial dysfunction in the pathogenesis of NASH is still largely unclear. CXCR3 is an essential pro-inflammatory factor in chronic liver diseases. We explored the significance of CXCR3 in regulating mitochondrial function during NASH development in animal models and cultured hepatocytes., Methods: The effects of CXCR3 on mitochondrial function were evaluated by genetic knockout or pharmacological inhibition in mouse models and in vitro . The ultrastructural changes of mitochondria were assessed by transmission electron microscopy (TEM). Hepatic levels of mitochondrial reactive oxygen species (ROS), DNA damage, membrane potential and ATP were examined., Results: CXCR3 ablation by genetic knockout or pharmacological inhibition in mice protected against NASH development by influencing mitochondrial function. Similarly, depletion of CXCR3 reduced steatohepatitis injury in cultured hepatocytes. TEM analysis revealed that liver mitochondrial integrity was much improved in CXCR3 knockout (CXCR3 -/- ) compared to wildtype (WT) mice. In agreement with this, impaired mitochondrial function was pronounced in WT mice compared to CXCR3 -/- mice, evidenced by increased protein expression of dynamic-related protein-1 (DRP1) and fission-1 (FIS1) and decreased protein expression of mitofusin-1 (MFN1). Mitochondrial dysfunction was induced in AML-12 hepatocytes by methionine and choline deficient medium and in HepG2 cells by palmitic acid. The impaired mitochondrial function in both cell lines was evidenced by reduced membrane potential and ATP content, and by increased mitochondrial ROS accumulation and DNA damage. However, CXCR3 knockdown by siCXCR3 significantly diminished the mitochondrial dysfunction in both AML-12 and HepG2 hepatocytes. In addition, inhibition of CXCR3 by CXCR3 specific antagonists SCH546738 and AMG487 restored mitochondrial function and inhibited mitochondrial-dependent apoptosis in the liver of WT mice fed with methionine and choline deficient diet., Conclusion: CXCR3 induces mitochondrial dysfunction, which contributes to the pathogenesis of steatohepatitis. Pharmacologic blockade of CXCR3 prevents mitochondrial dysfunction and restores the severity of steatohepatitis, indicating a potential clinical impact for controlling the disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Epidemiological studies showed that obesity and its related non-alcoholic fatty liver disease (NAFLD) promote hepatocellular carcinoma (HCC) development. We aimed to uncover the genetic alterations of NAFLD-HCC using whole-exome sequencing. We compared HCC development in genetically obese mice and dietary obese mice with wild-type lean mice fed a normal chow after treatment with diethylnitrosamine. HCC tumor and adjacent normal samples from obese and lean mice were then subjected to whole-exome sequencing. Functional and mechanistic importance of the identified mutations in Carboxyl ester lipase (Cel) gene and Harvey rat sarcoma virus oncogene 1 (Hras) was further elucidated. We demonstrated significantly higher incidences of HCC in both genetic and dietary obese mice with NAFLD development as compared with lean mice without NAFLD. The mutational signatures of NAFLD-HCC and lean HCC were distinct, with <3% overlapped. Eight metabolic or oncogenic pathways were found to be significantly enriched by mutated genes in NAFLD-HCC, but only two of these pathways were dysregulated by mutations in lean HCC. In particular, Cel was mutated significantly more frequently in NAFLD-HCC than in lean HCC. The multiple-site mutations in Cel are loss-of-function mutations, with effects similar to Cel knock-down. Mutant Cel caused accumulation of cholesteryl ester in liver cells, which led to induction of endoplasmic reticulum stress and consequently activated the IRE1α/c-Jun N-terminal kinase (JNK)/c-Jun/activating protein-1 (AP-1) signaling cascade to promote liver cell growth. In addition, single-site mutations in Hras at codon 61 were found in NAFLD-HCC but none in lean HCC. The gain-of-function mutations in Hras (Q61R and Q61K) significantly promoted liver cell growth through activating the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt pathways. In conclusion, we have identified mutation signature and pathways in NAFLD-associated HCC. Mutations in Cel and Hras have important roles in NAFLD-associated hepatocellular carcinogenesis.

Background: To explore black blood T1rho (T1ρ) liver imaging and investigate the earliest stage when biliary duct ligation (BDL) induced liver fibrosis can be diagnosed., Methods: MR was performed at 3 Tesla. A T1ρ prepared 2D fast spin echo (FSE) sequence with acquisition of four spin lock times (TSLs: 1, 10, 30, and 50 msec) and spin-lock frequency of 500 Hz was applied. Inherent black blood effect of FSE and double inversion recovery (DIR) achieved blood signal suppression, and 3 axial sections per liver were obtained. Male Sprague-Dawley rats were scanned at baseline (n=32), and on day-3 (n=13), day-5 (n=11), day-7 (n=10), day-10 (n=4) respectively after BDL. Hematoxylin-eosin (HE) and picrosirius red staining liver histology was obtained at these time points., Results: The physiological liver parenchyma T1ρ was 38.38±1.53 msec (range, 36.05-41.53 msec). Liver T1ρ value elevated progressively after BDL. On day-10 after BDL all experimental animals can be separated from normal liver based on T1ρ measurement with lowest value being 42.82 msec. Day-7 and day-10 liver resembled METAVIR stage-F1/F2 fibrosis, and fibrous area counted for 0.22%±0.13% and 0.38%±0.44% of liver parenchyma area, respectively., Conclusions: This study provides the first proof-of-principle that T1ρ might diagnose early stage liver fibrosis., Competing Interests: The authors have no conflicts of interest to declare.

Background & Aims: CXC chemokine receptor 3 (CXCR3) is involved in virus-related chronic liver inflammation. However, the role of CXCR3 in non-alcoholic steatohepatitis (NASH) remains unclear. We aimed to investigate the role of CXCR3 in NASH., Methods: Human liver tissues were obtained from 24 non-alcoholic fatty liver disease (NAFLD) patients and 20 control subjects. CXCR3 knockout (CXCR3(-/-)), obese db/db mice and their wild-type (WT) littermates were used in both methionine-and-choline-deficient (MCD) diet and high-fat high-carbohydrate high-cholesterol (HFHC) diet-induced NASH models. In addition, MCD-fed WT mice were administrated with CXCR3 specific antagonists., Results: CXCR3 was significantly upregulated in liver tissues of patients with NAFLD and in dietary-induced NASH animal models. Compared with WT littermates, CXCR3(-/-) mice were more resistant to both MCD and HFHC diet-induced steatohepatitis. Induction of CXCR3 in dietary-induced steatohepatitis was associated with the increased expression of hepatic pro-inflammatory cytokines, activation of NF-κB, macrophage infiltration and T lymphocytes accumulation (Th1 and Th17 immune response). CXCR3 was also linked to steatosis through inducing hepatic lipogenic genes. Moreover, CXCR3 is associated with autophagosome-lysosome impairment and endoplasmic reticulum (ER) stress in steatohepatitis as evidenced by LC3-II and p62/SQSTM1 accumulation and the induction of GRP78, phospho-PERK and phospho-eIF2α. Inhibition of CXCR3 using CXCR3 antagonist significantly suppressed MCD-induced steatosis and hepatocytes injury in AML-12 hepatocytes. Blockade of CXCR3 using CXCR3 antagonists in mice reversed the established steatohepatitis., Conclusions: CXCR3 plays a pivotal role in NASH development by inducing production of cytokines, macrophage infiltration, fatty acid synthesis and causing autophagy deficiency and ER stress., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

microRNA-29b (miR-29b) is known to be associated with TGF-β-mediated fibrosis, but the mechanistic action of miR-29b in liver fibrosis remains unclear and is warranted for investigation. We found that miR-29b was significantly downregulated in human and mice fibrotic liver tissues and in primary activated HSCs. miR-29b downregulation was directly mediated by Smad3 through binding to the promoter of miR-29b in hepatic stellate cell (HSC) line LX1, whilst miR-29b could in turn suppress Smad3 expression. miR-29b transduction in the liver of mice prevented CCl4 induced-fibrogenesis, concomitant with decreased expression of α-SMA, collagen I and TIMP-1. Ectopic expression of miR-29b in activated HSCs (LX-1, HSC-T6) inhibited cell viability and colony formation, and caused cell cycle arrest in G1 phase by downregulating cyclin D1 and p21cip1. Further, miR-29b induced apoptosis in HSCs mediated by caspase-9 and PARP. miR-29b inhibited its downstream effectors of PIK3R1 and AKT3 through direct targeting their 3'UTR regions. Moreover, knockdown of PIK3R1 or AKT3 suppressed α-SMA and collagen I and induced apoptosis in both HSCs and in mice. In conclusion, miR-29b prevents liver fibrogenesis by inhibiting HSC activation and inducing HSC apoptosis through inhibiting PI3K/AKT pathway. These results provide novel mechanistic insights for the anti-fibrotic effect of miR-29b.

B cell CLL/lymphoma 6 member B (BCL6B) is a novel tumor suppressor silenced in human cancer. In this study, we investigated the functional role and underlying mechanisms of BCL6B in hepatocellular carcinoma (HCC). BCL6B was expressed in normal HCC tissues, but its expression was suppressed in 6 out of 9 HCC cell lines. Loss of BCL6B expression was associated with promoter hypermethylation. Ectopic expression of BCL6B in HepG2 and Huh7 cell lines inhibited colony formation (P <0.05), cell viability (P <0.01), and tumorigenicity in nude mice (P <0.05). BCL6B expression also induced apoptosis (P <0.05), an effect associated with activation of the caspase cascade and cleavage of PARP. Stable expression of BCL6B in MHCC97L cells suppressed cell migration (P <0.05) and invasion (P <0.05), and significantly reduced the incidence and severity of lung metastasis in an orthotopic HCC mouse model. The anti-metastatic effect of BCL6B was mediated by up-regulation of cell adhesion gene E-cadherin, OB-cadherin, HIV-1 Tat interactive protein 2, and transient receptor potential cation channel, subfamily M, member 1; and down-regulation of angiogenesis gene VEGFA. BCL6B functions as a tumor suppressor that inhibits HCC metastases in vitro and in vivo., (Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Background & Aims: Perpetuate liver inflammation is crucial in the pathogenesis of non-alcoholic steatohepatitis (NASH). Expression of CXCL10, a pro-inflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 plays a role in NASH was unknown. We aimed to investigate the functional and clinical impact of CXCL10 in NASH., Methods: Cxcl10 gene-deleted (Cxcl10(-/-)) and C57BL/6 wild type (WT) mice were fed a methionine- and choline-deficient (MCD) diet for 4 or 8 weeks. In other experiments, we injected neutralizing anti-CXCL10 mAb into MCD-fed WT mice. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 control subjects., Results: WT mice, fed the MCD diet, developed steatohepatitis with higher hepatic CXCL10 expression. Cxcl10(-/-) mice were refractory to MCD-induced steatohepatitis. We further revealed that CXCL10 was associated with the induction of important pro-inflammatory cytokines (TNF-α, IL-1β, and MCP-1) and activation of the NF-κB pathway. CXCL10 was linked to steatosis through upregulation of the lipogenic factors SREBP-1c and LXR, and also to oxidative stress (upregulation of CYP2E1 and C/EBPβ). Blockade of CXCL10 protected against hepatocyte injury in vitro and against steatohepatitis development in mice. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, the circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients., Conclusions: We demonstrate for the first time that CXCL10 plays a pivotal role in the pathogenesis of experimental steatohepatitis. CXCL10 maybe a potential non-invasive biomarker for NASH patients., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Peroxisome proliferator-activated receptor alpha (PPARα) ligands have been reported to suppress cancer growth. However, the role of PPARα in hepatocarcinogenesis remains unclear. We investigated the functional significance of PPARα in HCC. PPARα-knockout (PPARα-/-) mice were more susceptible to diethylnitrosamine (DEN)-induced HCC at 6 months compared with wild-type (WT) littermates (80% versus 43%, P < 0.05). In resected HCCs, TUNEL-positive apoptotic cells were significantly less in PPARα-/- mice than in WT mice (P < 0.01), commensurate with a reduction in cleaved caspase-3 and caspase-7 protein expression. Ki-67 staining showed increased cell proliferation in PPARα-/- mice (P < 0.01), with concomitant up-regulation of cyclin-D1 and down-regulation of p15. Moreover, ectopic expression of PPARα in HCC cells significantly suppressed cell proliferation and induced apoptosis. The anti-tumorigenic function of PPARα was mediated via NF-κB as evidenced by inhibition of NF-κB promoter activity, diminution of phosphor-p65, phosphor-p50 and BCL2 levels, and enhancing IkBα protein. Chromatin immunoprecipitation analysis confirmed PPARαdirectly binds to the IkBα promoter. In conclusion, PPARα deficiency enhances susceptibility to DEN-initiated HCC. PPARα suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting IκBα and NF-κB signaling pathway.

Nasopharyngeal carcinoma (NPC) is one of the top ten cancers highly prevalent in Hong Kong and South China. Epstein-Barr virus (EBV) infection contributes to the tumorigenesis of NPC through the expression of different viral proteins. Among these, Latent Membrane Protein 1(LMP1) is the major oncoprotein expressed by EBV. Foscan® (Biolitec AG), m-tetrahydroxyphenylchlorin (mTHPC)-based photosensitizing drug, has been used in the photodynamic therapy (PDT) for head and neck cancers. FosPeg® (Biolitec AG) is a new formulation of mTHPC contained in PEGylated liposomes with optimized distribution properties. In this in vitro study, the potential of FosPeg®-PDT on human EBV positive NPC cell (c666-1) and EBV negative cells (HK1 and CNE2) were investigated. Effects of FosPeg®-PDT on the expression of EBV BART miRNAs (EBV miRNA BART 1-5p, BART 16, and BART 17-5p), LMP1 mRNA and proteins on c666-1 cells were also elucidated. The killing efficacy of FosPeg®-PDT on NPC cells were determined by MTT assay after LED activation. Effects of FosPeg®-PDT on the expression of LMP1 mRNA and protein were examined by real time PCR and western blot analysis. FosPeg®-PDT demonstrated its antitumor effect on c666-1 cells in a drug and light dose dependent manner. LD30, LD50 and LD70 were achieved by applying LED activation (3J/cm(2)) at 4h post incubated cells with 0.05μg/ml, 0.07μg/ml and 0.3μg/ml FosPeg®, respectively. Up-regulation of both LMP1 mRNA and protein were observed after FosPeg®-PDT in a dose dependent manner. FosPeg®-PDT exerted antitumor effect on c666-1 cells through up-regulation of LMP1 protein. Understanding the mechanism of FosPeg®-PDT may help to develop better strategies for the treatment of NPC., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Smad7 is a principal inhibitor of the TGFβ-Smad signalling pathway. We have investigated the functional significance of Smad7 in hepatocellular carcinoma (HCC). Smad7 knockout (KO) and wild-type (WT) mice were injected with diethylnitrosamine (DEN) to induce HCC. The effects of Smad7 on cellular features were examined in HCC cells, using a Smad7 over-expression or deletion approach. Signalling pathway components modulated by Smad7 in HCC were evaluated using luciferase reporter assay and co-immunoprecipitation. Smad7 was down-regulated in human HCCs compared with the adjacent normal tissues (p < 0.001). Smad7 KO mice were more susceptible to DEN-induced HCC than WT mice (78% versus 22%, p < 0.05). HCCs from KO mice displayed a greater proliferation activity (p < 0.05) and a reduced apoptotic index compared with WT littermates (p < 0.05). Deletion of Smad7 promoted cell proliferation in primary cultured HCC cells. In addition, over-expression of Smad7 in HCC cell lines markedly suppressed cell growth (p < 0.0001) and colony formation (p < 0.01). Cell cycle analysis revealed an increase in the G1 phase and a reduction in the S-phase populations, accompanied by up-regulation of p27(Kip1) and down-regulation of cyclin D1. Smad7 increased cell apoptosis (p < 0.01) by mediating an intrinsic [caspase-9, caspase-3 and poly(ADP-ribose) polymerase] apoptotic pathway. Moreover, Smad7 inhibited NF-κB signalling by interacting with TAB2, an upstream activator of NF-κB, and inhibited TGFβ signalling by suppressing phosphorylation of Smad3. In conclusion, loss of Smad7 enhances susceptibility to HCC. Smad7 suppresses HCC cell growth by inhibiting proliferation and G1 -S phase transition and inducing apoptosis through attenuation of NF-κB and TGFβ signalling. Smad7 acts as a potential tumour suppressor in liver., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Objectives: Erxian Decoction (EXD) is a well-documented Chinese medicinal formulation, which has been clinically applied for years for relieving menopausal syndromes by modulating hormonal levels indicating that EXD might also be effective in treating hormone-related tumors. This study aimed to differentially investigate the efficacy of EXD and its antimetastatic property on human ovarian cancer cells, OVCA429., Methods: The efficacy and cell cycle progression of EXD on OVCA429 cells was determined by MTT assay and flow cytometry, respectively. The modulated expression of metastatic markers by EXD in OVCA429 cells and xenografts was evaluated at transcriptional and translational levels by Western blotting and real-time polymerase chain reaction, respectively. The migrating and invasive ability of the cancer cells were determined by wound healing and invasive assays., Results: The IC50 value of EXD on OVCA429 cells was determined after 24 hours incubation with EXD at 1 mg/mL. EXD (1.5 mg/mL) mediated S-phase cell cycle arrest and apoptotic cell death at 24 hours posttreatment. EXD repressed the expression of several metastatic mediators, including EGFR, ErbB2, MMP2, MMP7, MMP9, and VEGF in OVCA429 cells and xenografts at transcriptional and/or translational levels. Furthermore, EXD functionally demonstrated significant inhibition of migrating and invasive ability of OVCA429 cells. EXD suppressed tumor size in xenografts without any adverse effects on body weight., Conclusions: This is the first study that illustrates the antimetastatic property of EXD on human ovarian cancer models. This decoction merits serious consideration for further delineation of its multiple pharmacological effects, especially on hormone-related cancers, and these would be valuable for future clinical applications of EXD as an alternative regime for cancers.

Aim: To improve the outcome of orthotopic transplantation in a mouse model, we used an absorbable gelatin sponge (AGS) in nude mice to establish an orthotopic implantation tumor model., Methods: MHCC-97L hepatocellular carcinoma (HCC) cells stably expressing the luciferase gene were injected into the subcutaneous region of nude mice. One week later, the ectopic tumors were harvested and transplanted into the left liver lobe of nude mice. The AGS was used to establish the nude mouse orthotopic implantation tumor model. The tumor suppressor gene, paired box gene 5 (PAX5), which is a tumor suppressor in HCC, was transfected into HCC cells to validate the model. Tumor growth was measured by bioluminescence imaging technology. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and histopathology were used to confirm the tumorigenicity of the implanted tumor from the MHCC-97L cell line., Results: We successfully developed an orthotopic transplantation tumor model in nude mice with the use of an AGS. The success rate of tumor transplantation was improved from 60% in the control group to 100% in the experimental group using AGS. The detection of fluorescent signals showed that tumors grew in all live nude mice. The mice were divided into 3 groups: AGS-, AGS+/PAX5- and AGS+/PAX5+. Tumor size was significantly smaller in PAX5 transfected nude mice compared to control mice (P < 0.0001). These fluorescent signal results were consistent with observations made during surgery. Pathologic examination further confirmed that the tissues from the ectopic tumor were HCC. Results from RT-PCR proved that the HCC originated from MHCC-97L cells., Conclusion: Using an AGS is a convenient and efficient way of establishing an indirect orthotopic liver transplantation tumor model with a high success rate.

Introduction and Hypothesis: Dimethyl sulfoxide (DMSO) bladder instillation is a standard therapy for interstitial cystitis (IC); however, there are varying degrees of success. We hypothesize that first-line intravesical therapy with a DMSO cocktail will optimize treatment outcome., Methods: Ninety women with newly diagnosed IC were enrolled consecutively for the treatment. The IC symptom and problem index was used as an outcome measure., Results: Six (6.7%) patients dropped out of the treatment due to intolerable bladder irritation. Fifty-five (65.5%) of the remaining 84 patients, who completed the treatment, experienced ≧50% symptomatic improvement. After a regression analysis, three clinical variables were found to affect treatment adversely, i.e., the presence of advanced cystoscopic glomerulations, microscopic hematuria, and urodynamic detrusor underactivity, respectively., Conclusions: Our results suggest bladder instillation with a DMSO cocktail may well be considered as first-line therapy for IC patients. However, there exists a subgroup of nonresponders who may have severe disease.

Hospitalists are uniquely positioned to implement strategies to improve patient flow and efficiency. Hospital leaders have stated they expect hospitalists to comanage surgical patients, participate in observation units, and screen medical admissions, in addition to providing inpatient care for medical patients. We review how the hospitalists' role in acute inpatient care, surgical comanagement, short stay units, chest pain units, and active bed management has improved throughput and patient flow., (Copyright © 2012 Society of Hospital Medicine.)

Aims: This study employed a doxorubicin resistant (MES-SA-Dx5) human uterine sarcoma cell line and its counterpart (MES-SA), to elucidate the efficacy of aminolevulinic acid-hexylester (hexyl-ALA) mediated PDT at molecular and transcriptional levels., Methods: Hexyl-ALA generated protoporphyrin IX in both cells were determined by molecular probes using Confocal Laser Scanning Microscopy. The hexyl-ALA-PDT induced signal transduction proteins and mode of cell death were quantitated by CASE ELISA assays and DAPI staining. The modulation of hTERT mRNA expression and telomerase activity were investigated by TaqMan real-time PCR and ELISA respectively. Hexyl-ALA-PDT mediated cell migratory effect was determined by wound-healing assay., Results: The results demonstrated that mitochondria were the major target of hexyl-ALA. At LD(30), hexyl-ALA-PDT significantly provoked an up-regulation of phosphorylated p38MAPK and JNK proteins in both cells. Hexyl-ALA-PDT down-regulated hTERT (a catalytic subunit of telomerase) mRNA expression and showed a strong correlation with diminished telomerase activity in both cells (MES-SA: r(2) = 0.9932; MES-SA-Dx5: r(2) = 0.9775). The suppression of cell migratory effect in both cells was obtained after hexyl-ALA-PDT. Further, 50% and 30% of apoptotic cells were attained at LD(50), for wild-type and drug resistant cells respectively. Unlike the wild-type, a higher PDT dose was crucial to induce apoptosis in the drug resistant cells., Conclusions: Our study provides the first evidence that p38MAPK and JNK kinases played a vital role in triggering hexyl-ALA-PDT-induced apoptosis, down-regulated hTERT mRNA expression and telomerase activity in both proposed cells. In vivo studies are worth examining for the benefit of clinical applications in drug resistant cancers and PDT development., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Admitted patients boarding in the emergency department (ED) leads to hospital diversion. Active bed management and care for boarded patients can improve throughput. We developed a hospital medicine ED (HMED) team to participate in active bed management, and to care for boarded patients, to decrease diversion and improve throughput., Methods: An HMED team was created to participate in active bed management and to care for boarded patients. The HMED team worked with the ED, nursing supervisors, and medical floors to manage inpatient beds. The primary outcome was percentage of hours of diversion attributed to lack of bed capacity. Secondary outcomes included the proportion of patients discharged within 8 hours of transfer to a medical floor, and the proportion of patients discharged from the ED. Promptness of clinical care was measured by rounding times. Satisfaction was obtained via survey., Results: There was a relative reduction of diversion due to medicine bed capacity of 27% (4.5%-3.3%; P < 0.01), a relative reduction in the percentage of patients transferred to a medicine floor and discharged within 8 hours of 67% (1.5%-0.5%; P < 0.01), and a relative increase in the number of discharges from the ED of admitted medicine patients of 61% (4.9%-7.9%; P < 0.001). Boarded admitted patients were rounded upon 2 hours earlier (P < 0.0001) by the HMED team. Satisfaction with the HMED team was high., Conclusion: An HMED team can improve patient flow and decrease ED diversion while providing more timely care to patients boarded in the ED., (Copyright © 2012 Society of Hospital Medicine.)

Objective: Using genome-wide promoter methylation assay, B cell CLL/lymphoma 6 member B (BCL6B) was found to be preferentially methylated in cancer. A study was undertaken to examine the epigenetic regulation, biological function and clinical significance of BCL6B in gastric cancer (GC)., Methods: BCL6B promoter methylation was evaluated by combined bisulfite restriction analysis and sequencing. The biological functions of BCL6B were determined by cell viability, colony formation, flow cytometry and in vivo tumorigenicity assays. The molecular targets of BCL6B were identified by cDNA expression array., Results: BCL6B was silenced or downregulated in all nine GC cell lines and readily expressed in normal gastric tissues. Loss of BCL6B expression was regulated by promoter hypermethylation. Re-expression of BCL6B in GC cell lines inhibited colony formation, suppressed cell viability, induced apoptosis and restrained the tumorigenecity in nude mice. These effects were associated with upregulation of the pro-apoptosis genes tumour necrosis factor receptor superfamily member 1A, caspase-8, caspase-9, caspase-3 and caspase-7 and nuclear enzyme poly (ADP-ribose) polymerase, downregulation of the pro-proliferation genes S100 calcium binding protein A4 and vascular endothelial growth factor A, and induction of the tumour suppressor genes ataxia telangiectasia mutated homologue and p53. BCL6B hypermethylation was detected in 49.0% (102/208) and 66.3% (67/101) of two independent cohorts of patients with GC, respectively. BCL6B methylation was an independent factor for the survival of patients with GC (p=0.001 for cohort I, p=0.02 for cohort II)., Conclusions: BCL6B plays a pivotal role as a potential tumour suppressor in GC. Detection of methylated BCL6B may serve as an independent biomarker for the prognosis of GC.

The aim of this study was to determine the photodynamic antimicrobial effect of hypericin on clinically isolated Staphylococcus aureus and Escherichia coli cells. Bacterial cells (10(8) cells per mL) were incubated with hypericin (0-40 μM) for 30 min and followed by light irradiation of 600-800 nm at 5-30 J cm(-2). Cell survival was determined by colony counting, cellular hypericin uptake examined by flow cytometer, and cell membrane damage examined by scanning electron microscopy and leakage assay. The effectiveness of hypericin-mediated photodynamic killing was strongly affected by cellular structure and photosensitizer uptake. The combination of hypericin and light irradiation could induce significant killing of Gram positive methicillin-sensitive and -resistant S. aureus cells (>6 log reduction), but was not effective on Gram negative E. coli cells (<0.2 log reduction). The difference was caused by different cell wall/membrane structures that directly affected cellular uptake of hypericin., (© 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.)

Background: While patients with anorexia nervosa have a high mortality rate, more are living into adulthood. Patients with severe malnutrition secondary to anorexia nervosa often require hospitalization for medical stabilization prior to treatment in eating disorders programs., Methods: We developed the ACUTE Center at Denver Health Medical Center to medically stabilize adults with the medical complications of severe malnutrition due to an eating disorder. The first 2 years of patient characteristics and outcomes are reported., Results: From October 2008 through December 2010, the ACUTE unit had 76 admissions of which 62 were for medical stabilization, comprising 54 patients. Eighty-nine percent of patients were female. The mean age was 27 years old (range 17-65). The mean body mass index on admission was 12.9 kg/m(2) (standard deviation [SD] 2.0). At admission, patients were hyponatremic, anemic, and leukopenic, with low bone density, but had normal albumin levels. The mean body mass index on discharge was 13.1 ± 1.9 kg/m(2). Median length of stay was 16 days (interquartile range [IQR] 9-29 days). Eighteen percent were discharged to home and eighty-two percent were discharged to inpatient psychiatric eating disorder units. Inpatient mortality was zero., Discussion: Patients with this degree of severe malnutrition due to eating disorders are medically complex and relatively uncommon. Regionalized subspecialty centers of excellence, in which a multidisciplinary team is led by practitioners of hospital medicine who have developed expertise in a rare condition, may improve clinical outcomes, optimize healthcare resources, and provide unique professional and academic opportunities for the clinicians involved., (Copyright © 2012 Society of Hospital Medicine.)

A Web-based training course with embedded video clips for reducing central line-associated bloodstream infections (CLABSIs) was evaluated and shown to improve clinician knowledge and retention of knowledge over time. To our knowledge, this is the first study to evaluate Web-based CLABSI training as a stand-alone intervention.

Background and Objectives: To investigate the association of uPA system genes, including uPA, uPA receptor (uPAR), and plasminogen activator inhibitor (PAI)-1 gene polymorphisms, with risk of endometrial cancer., Methods: In the present case control study, we enrolled a total of 134 patients with endometrial cancer confirmed by histopathology and 302 unrelated healthy individuals. Genetic polymorphisms of uPA system genes, including uPA rs4065 C/T SNP, uPAR rs344781 T/C SNP, and PAI-1 rs1799889 4G/5G SNP were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) genotyping analysis., Results: Frequency of PAI-1 rs1799889 4G/4G genotype and 4G allele differed significantly between patients with endometrial cancer (36.6% and 61.6%, respectively) and healthy individuals (25.5% and 52.2%, respectively). Individuals with PAI-1 rs1799889 4G/4G genotype were at higher risk of endometrial cancer (OR = 2.26; 95% CI: 1.20-4.27). Stratification analysis showed individuals with PAI-1 rs1799889 4G/4G genotype were at elevated risk for endometrioid type (OR = 2.49; 95% CI 1.27-4.88), low stage (stages I-II) endometrial cancer (OR = 2.34; 95% CI 1.21-4.52). However, no significant differences in uPA C/T SNP, uPAR T/C SNP genotypes were observed between endometrial carcinoma cases and controls., Conclusions: Individuals with PAI-1 rs1799889 4G/4G genotype were at significantly higher risk of endometrial cancer in this study., (Copyright © 2011 Wiley Periodicals, Inc.)