Background & Aims Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in children and adolescents in industrialized countries. It is important to accurately determine ...the stage of fibrosis in these patients. The enhanced liver fibrosis (ELF) test has been validated for staging liver fibrosis in adult patients with chronic liver diseases, including NAFLD. We investigated the performance of this test in assessing liver fibrosis in children and adolescents with NAFLD, identified by biopsy. Methods The ELF test was performed on a panel of serum samples collected from 112 consecutive subjects that were likely to have NAFLD (64 male, mean age of 13.8 ± 3.3). A previously described and validated algorithm was used to analyze the data on hyaluronic acid (HA), amino-terminal propeptide of type III collagen (PIIINP), and tissue inhibitor of metalloproteinase 1 (TIMP-1) levels. Results In pediatric patients with NAFLD, the ELF test predicted liver fibrosis stage with a high degree of sensitivity and specificity; results were superior to those reported for adults. The area under receiver operating characteristic curves/best possible ELF test cut-off values for the prediction of “any” (≥stage 1), moderate-perisinusoidal (≥stage 1b), moderate-portal/periportal (≥stage 1c), significant (≥stage 2), or advanced (≥stage 3) fibrosis were 0.92/9.28, 0.92/9.33, 0.90/9.54, 0.98/10.18 and 0.99/10.51, respectively. Conclusions The ELF test can be used to accurately assess the level of liver fibrosis in pediatric patients with NAFLD. This information is important for identifying patients with progressive fibrosis that require further histopathological analysis or therapeutic follow-up.
Background & Aims:
Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is ...subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis.
Methods:
In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples.
Results:
The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02;
P < .0001; 95% confidence interval, .758–.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists’ agreement over histologic scores ranged from very good to moderate (κ = .97–.46).
Conclusions:
Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.
The biomechanical behavior of a single lumbar vertebral body after various surgical treatments with acrylic vertebroplasty was parametrically studied using finite-element analysis.
To provide a ...theoretical framework for understanding and optimizing the biomechanics of vertebroplasty. Specifically, to investigate the effects of volume and distribution of bone cement on stiffness recovery of the vertebral body.
Vertebroplasty is a treatment that stabilizes a fractured vertebra by addition of bone cement. However, there is currently no information available on the optimal volume and distribution of the filler material in terms of stiffness recovery of the damaged vertebral body.
An experimentally calibrated, anatomically accurate finite-element model of an elderly L1 vertebral body was developed. Damage was simulated in each element based on empirical measurements in response to a uniform compressive load. After virtual vertebroplasty (bone cement filling range of 1-7 cm3) on the damaged model, the resulting compressive stiffness of the vertebral body was computed for various spatial distributions of the filling material and different loading conditions.
Vertebral stiffness recovery after vertebroplasty was strongly influenced by the volume fraction of the implanted cement. Only a small amount of bone cement (14% fill or 3.5 cm3) was necessary to restore stiffness of the damaged vertebral body to the predamaged value. Use of a 30% fill increased stiffness by more than 50% compared with the predamaged value. Whereas the unipedicular distributions exhibited a comparative stiffness to the bipedicular or posterolateral cases, it showed a medial-lateral bending motion ("toggle") toward the untreated side when a uniform compressive pressure load was applied.
Only a small amount of bone cement ( approximately 15% volume fraction) is needed to restore stiffness to predamage levels, and greater filling can result in substantial increase in stiffness well beyond the intact level. Such overfilling also renders the system more sensitive to the placement of the cement because asymmetric distributions with large fills can promote single-sided load transfer and thus toggle. These results suggest that large fill volumes may not be the most biomechanically optimal configuration, and an improvement might be achieved by use of lower cement volume with symmetric placement.
The S-type lectin galectin-9 binds to the negative regulatory molecule Tim-3 on T cells and induces their apoptotic deletion or functional inactivation. We investigated whether galectin-9/Tim-3 ...interactions contribute to the deletion and exhaustion of the antiviral T cell response in chronic hepatitis B virus infection (CHB). We found Tim-3 to be expressed on a higher percentage of CD4 and CD8 T cells from patients with CHB than healthy controls (p<0.0001) and to be enriched on activated T cells and those infiltrating the HBV-infected liver. Direct ex vivo examination of virus-specific CD8 T cells binding HLA-A2/peptide multimers revealed that Tim-3 was more highly upregulated on HBV-specific CD8 T cells than CMV-specific CD8 T cells or the global CD8 T cell population in patients with CHB (p<0.001) or than on HBV-specific CD8 after resolution of infection. T cells expressing Tim-3 had an impaired ability to produce IFN-γ and TNF-α upon recognition of HBV-peptides and were susceptible to galectin-9-triggered cell death in vitro. Galectin-9 was detectable at increased concentrations in the sera of patients with active CHB-related liver inflammation (p = 0.02) and was strongly expressed by Kupffer cells within the liver sinusoidal network. Tim-3 blockade resulted in enhanced expansion of HBV-specific CD8 T cells able to produce cytokines and mediate cytotoxicity in vitro. Blocking PD-1 in combination with Tim-3 enhanced the number of patients from whom functional antiviral responses could be recovered and/or the strength of responses, indicating that these co-inhibitory molecules play a non-redundant role in driving T cell exhaustion in CHB. Patients taking antivirals able to potently suppress HBV viraemia continued to express Tim-3 on their T cells and respond to Tim-3 blockade. In summary, both Tim-3 and galectin-9 are increased in CHB and may contribute to the inhibition and deletion of T cells as they infiltrate the HBV-infected liver.
Tissue-resident memory T cells have critical roles in long-term pathogen and tumor immune surveillance in the liver. We investigate the role of autophagy in equipping human memory T cells to acquire ...tissue residence and maintain functionality in the immunosuppressive liver environment. By performing ex vivo staining of freshly isolated cells from human liver tissue, we find that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells. CD8+ T cells with increased autophagy are those best able to proliferate and mediate cytotoxicity and cytokine production. Conversely, blocking autophagy induction results in the accumulation of depolarized mitochondria, a feature of exhausted T cells. Primary hepatic stellate cells or the prototypic hepatic cytokine interleukin (IL)-15 induce autophagy in parallel with tissue-homing/retention markers. Inhibition of T cell autophagy abrogates tissue-residence programming. Thus, upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence.
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•An increased rate of basal autophagy is a hallmark of liver-resident CD8+ T cells•Enhanced T cell autophagy can be imprinted by IL-15 or hepatic stellate cells•Autophagy induction is required for tissue-residence programming in vitro•Enhanced autophagy maintains TRM mitochondrial fitness in the liver
Swadling et al. show that an increased rate of basal autophagy is a hallmark of intrahepatic lymphocytes, particularly liver-resident CD8+ T cells and that in vitro TRM programming requires autophagy induction. Upregulation of autophagy adapts CD8+ T cells to combat mitochondrial depolarization, optimize functionality, and acquire tissue residence.
With the advent of direct acting antivirals, the World Health Organisation proposed eliminating Hepatitis C as a public health threat by 2030. To achieve this, countries need to diagnose, engage in ...care and treat their undiagnosed populations. This will require sensitisation campaigns. However previous media campaigns have had mixed impact. We conducted a scoping review to identify and understand the impact of previous Hepatitis C media campaigns. These findings could inform the delivery of future campaigns. We searched five electronic databases for published literature on media campaigns conducted for Hepatitis C awareness, testing, and treatment in Organisation for Economic Co-operation and Development (OECD) countries since 2010. Two independent reviewers screened citations for inclusion. Additionally, we spoke to stakeholders in the Hepatitis C field in the UK and conducted a Google search to identify any unpublished literature. A quantitative synthesis was conducted to identify targeted populations, strategies and media used, aims and impact of the campaigns. A title and year of publication screening of 3815 citations resulted in 113 papers that had a full abstract screen. This left 50 full-text papers, 18 were included of which 9 (50%) were from Europe. 5 (27.8%) of campaigns targeted minority ethnicities, and 9 (50%) aimed to increase testing. A Google search identified 6 grey literature sources. Most campaigns were not evaluated for impact. Discussions with stakeholders identified several barriers to successful campaigns including lack of targeted messaging, stigmatising or accusatory messaging, and short-lived or intermittent campaign strategies. Future campaigns will likely need to be multifaceted and have multiple tailored interventions. Campaigns will need to be sizeable and robust, integrated into health systems and viewed as an ongoing service rather than one-offs.
Here, Rosenberg examines the difficulties tsarist military censors had in accessing the moods of Russian soldiers during World War I through their correspondence, a task deemed essential to prevent ...dissidence and deploy army units effectively. His article is based on a rich trove of archival materials revealing the ways in which censors configured soldiers' emotions within circulating fields of assumption and expectation, filtering their expression into "useful" categories at some distance from their actual emotional fields. While these documents may have served the needs of military commanders, they also reflected processes of mediation that were not ultimately in the army's interests. In analyzing these processes, he uses historical specificities to raise a more general question on the ways in which emotions are read make it more difficult for historians to access them. In other words, when expressions of emotions in their sources are filtered through their own social and cultural norms, it is hard to see for sure that the feelings being described reflect what was actually felt.
The Glasgow Coma Scale (GCS) score is the most frequently used neurologic assessment in traumatic brain injury (TBI). The risk for neurosurgical intervention based on GCS is heavily modified by age. ...The objective is to create a recalibrated Glasgow Coma Scale (GCS) score that accounts for an interaction by age and determine the predictive performance of the recalibrated GCS (rGCS) compared to the standard GCS for predicting neurosurgical intervention.
This retrospective cohort study utilized the National Trauma Data Bank and included all patients admitted from 2010-2015 with TBI (ICD9 diagnosis code 850–854.19). The study population was divided into 2 subsets: a model development dataset (75% of patients) and a model validation dataset (remaining 25%). In the development dataset, logistic regression models were used to calculate conditional probabilities of having a neurosurgical intervention for each combination of age and GCS score, to develop a point-based risk score termed the rGCS. Model performance was examined in the validation dataset using area under the receiver operating characteristic (AUROC) curves and calibration plots.
There were 472,824 patients with TBI. The rGCS ranged from 1–15, where rGCS 15 denotes the baseline risk for neurosurgical intervention (4.4%) and rGCS 1 represents the greatest risk (62.6%). In the validation dataset there was a statistically significant improvement in predictive performance for neurosurgical intervention for the rGCS compared to the standard GCS (AUROC: 0.71 versus 0.67, difference, -0.04, P<0.001), overall and by trauma level designation. The rGCS was better calibrated than the standard GCS score.
The relationship between GCS score and neurosurgical intervention is significantly modified by age. A revision to the GCS that incorporates age, the rGCS, provides risk of neurosurgical intervention that has better predictive performance than the standard ED GCS score.
The absence of a serological surrogate outcome measure of fibrosis in systemic sclerosis (SSc) is a major deficiency for intervention studies and clinical management. An algorithm including the serum ...concentration of procollagen-III aminoterminal-propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid, has recently been validated as predictive of severity and clinical outcome in chronic liver diseases (enhanced liver fibrosis (ELF) test) and implemented as a clinical grade test available for physicians. We evaluated the ELF test as a surrogate outcome measure in SSc.
The ELF score was determined blindly in 210 patients with SSc. Results were correlated with clinical, functional and instrumental variables including disease severity, activity and disability.
The ELF test was above normal range in 83% of SSc patients (175/210). The ELF score showed a significant correlation (p<0.0001) with extent of skin involvement (r=0.28), diffusing lung capacity of carbon monoxide (DLCO) (r=-0.32), health assessment questionnaire-disability index (HAQ-DI) (r=0.32), disease severity score (r=0.3) and age (r=0.41). In addition, ELF correlated with disease activity (r=0.23; p=0.02). Using regression analysis, the extent of skin involvement, age, DLCO and gender were independently associated with the ELF score. The ELF score did not correlate with the presence of pulmonary artery hypertension, digital ulcers or any other measure of vasculopathy.
The ELF test is a clinical-grade serum test that significantly correlates with several measures of fibrosis in SSc and with overall disease activity, severity and HAQ-DI. The specific correlation with fibrosis and its face validity, together with the feasibility of the test, warrant its further development as a surrogate outcome measure of fibrosis in SSc.
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