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Background & aimsDe novo lipogenesis is increased in livers of patients with nonalcoholic steatohepatitis (NASH). Acetyl-coenzyme carboxylase catalyzes the rate-limiting step in this process. We evaluated the safety and efficacy of GS-0976, an inhibitor of acetyl-coenzyme A carboxylase in liver, in a phase 2 randomized placebo-controlled trial of patients with NASH.MethodsWe analyzed data from 126 patients with hepatic steatosis of at least 8%, based on the magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF), and liver stiffness of at least 2.5 kPa, based on magnetic resonance elastography measurement or historical biopsy result consistent with NASH and F1-F3 fibrosis. Patients were randomly assigned (2:2:1) to groups given GS-0976 20 mg, GS-0976 5 mg, or placebo daily for 12 weeks, from August 8, 2016 through July 18, 2017. Measures of hepatic steatosis, stiffness, serum markers of fibrosis, and plasma metabolomics were evaluated. The primary aims were to confirm previous findings and evaluate the relation between dose and efficacy.ResultsA relative decrease of at least 30% from baseline in MRI-PDFF (PDFF response) occurred in 48% of patients given GS-0976 20 mg (P = .004 vs placebo), 23% given GS-0976 5 mg (P = .43 vs placebo), and 15% given placebo. Median relative decreases in MRI-PDFF were greater in patients given GS-0976 20 mg (decrease of 29%) than those given placebo (decrease of 8%; P = .002). Changes in magnetic resonance elastography-measured stiffness did not differ among groups, but a dose-dependent decrease in the fibrosis marker tissue inhibitor of metalloproteinase 1 was observed in patients given GS-0976 20 mg. Plasma levels of acylcarnitine species also decreased in patients with a PDFF response given GS-0976 20 mg. GS-0976 was safe, but median relative increases of 11% and 13% in serum levels of triglycerides were observed in patients given GS-0976.ConclusionsIn a randomized placebo-controlled trial of patients with NASH, we found 12-week administration of GS-0976 20 mg decreased hepatic steatosis, selected markers of fibrosis, and liver biochemistry. ClinicalTrials.gov ID NCT02856555.

Objective Proteomics may discover pathophysiological changes related to hepatocellular carcinoma, an aggressive and lethal type of cancer with low sensitivity for early stage diagnosis. Design We measured 1305 prediagnostic (median = 12.7 years) SomaScan proteins from 54 pairs of healthy individuals who subsequently developed hepatocellular carcinoma and matched non–hepatocellular carcinoma control individuals from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). Results In NHS and HPFS, we identified 56 elevated proteins in hepatocellular carcinoma with an absolute fold change of more than 1.2 and a Wald test P value less than  .05 in conditional logistic regression analysis. Ingenuity pathway analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins—chitinase-3-like protein 1, growth differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin—showed strong positive associations with hepatocellular carcinoma and were thus validated by enzyme-linked immunosorbent assay (odds ratio = 2.48-14.7, all P  <  .05) in the NHS and HPFS and by Olink platform (hazard ratio = 1.90-3.93, all P  <  .05) in the UKB-PPP. Adding these 4 proteins to a logistic regression model of traditional hepatocellular carcinoma risk factors increased the area under the curve from 0.67 to 0.87 in the NHS and HPFS. Consistently, model area under the curve was 0.88 for hepatocellular carcinoma risk prediction in the UKB-PPP. Conclusion However, the limited number of hepatocellular carcinoma patients in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations. [ABSTRACT FROM AUTHOR]

Socioscientific Issues (SSI) provide a strong framework for engaging students and teachers in meaningful and relevant scientific discourse in the development of functional scientific literacy. However, while most teachers recognize the value of introducing students to SSI, they themselves have limited knowledge of SSI and often lack the confidence and support to teach these issues. For this study, the SSI framework provided a lens for exploring and understanding how 24 pre-service and in-service teachers navigated science, technology, engineering, and mathematics (STEM) curriculum to incorporate SSI into their classroom practice. The following questions guided our inquiry: (a) In what ways, if any, do practicing elementary classroom teachers' notions of SSI, with particular attention to reducing carbon dioxide, change before and after completion of a STEM and Society course? (b) To what extent do practicing elementary teachers change their implementation of SSI in their lessons and classroom instruction? The findings of this study showed positive views of teaching controversial and complex case-based issues. The reasons our teachers provided included raising environmental awareness, teaching social responsibility, and teachers' interest on SSI topics. Our findings also supported development of the cultural issues component of SSI that we can attribute to teachers' field experiences in Pennsylvania, USA and in Sicily, Italy, which included shifts on teachers' perceived cultural practices, reducing carbon dioxide, and teaching of SSI in their classrooms. Our study can potentially provide useful resources for developing STEM education programs and courses with research-based content and methods for introducing new contexts to elementary science teachers.

The study aimed to evaluate the effect of an intervention on the prevalence and severity of incontinence‐associated dermatitis (IAD) in six hospitals in one state in Australia. This quasi‐experimental pre‐and post‐study, conducted in 18 wards, was part of a larger implementation science study on incontinence‐associated dermatitis. Skin and incontinence assessments were conducted on patients during February and March 2020 (pre‐intervention) and July and August 2021 (post‐intervention). The intervention comprised continence assessment and management, an education brochure for patients, family and caregivers on IAD, the Ghent Global IAD Categorisation Tool (GLOBIAD) and a skin care regime with patient skin protection measures (three‐in‐one barrier cream cloths, minimisation of bed protection layers, use of appropriate continence aid). A total of 1897 patients were assessed (pre‐intervention = 964, post‐intervention = 933). A total of 343 (35.6%) pre‐intervention patients and 351 (37.6%) post‐intervention patients had incontinence. The prevalence of hospital‐acquired IAD was 6.71% in the pre‐intervention group and 4.27% in the post‐intervention group; a reduction of 36.3% (p = 0.159) despite higher patient acuity, prevalence of double incontinence and the COVID‐19 pandemic in the post‐intervention group compared with the pre‐intervention group. Our multisite best practice IAD prevention and treatment intervention was able to reduce the prevalence and severity of hospital‐acquired IAD, suggesting enduring effectiveness of the intervention. [ABSTRACT FROM AUTHOR]

Background and Aim: Statin use has shown a reduction in hepatic decompensation and portal hypertension. Its association with portal vein thrombosis (PVT) incidence is unknown. We aim to compare the incidence of PVT in patients with and without statin use. Methods: We excluded patients with a history of hepatocellular cancer, liver transplants, Budd–Chiari syndrome, and intra‐abdominal malignancies. Patients with cirrhosis were followed from their first hepatologist clinical encounter (January 1, 2016, to January 31, 2021) for 180 days to determine PVT incidence. We tested the association of statin use with PVT using 1:1 propensity score (PS) matching and Cox proportional hazard regression. Results: We analyzed 2785 patients with cirrhosis (mean age:61.0 ± 12.3 years, 44.3% female, 63.8% White, mean MELD‐Na score:11.7 ± 6.1, and statin use:23.1%). A total of 89 patients developed PVT during the follow‐up, which was lower in patients with statin use as compared to no statin use (1.3% vs 3.8%, P = 0.001, unadjusted HR:0.28, 95% CI: 0.13–0.62, P = 0.001). After matching for demographics, comorbidities, and hepatic decompensation events, patients with statin use had a lower risk of developing PVT in 180‐day follow‐up as compared to those without statin use (HR:0.24, 95% CI: 0.10–0.55, P = 0.001). Subgroup analysis showed that statin use was associated with lower PVT incidence in non‐NASH (HR: 0.20, 95% CI: 0.07–0.54, P = 0.002) and decompensated cirrhosis (HR: 0.12, 95% CI:0.03–0.53, P = 0.005) than no statin use. Conclusion: PVT incidence was lower in decompensated cirrhosis patients with statin use than in those with no statin use. However, this finding needs to be further tested in randomized control trials. [ABSTRACT FROM AUTHOR]

Key Points: Question: What are the clinical implications of single or serial measurements of vibration–controlled transient elastography (VCTE)–based scores in metabolic dysfunction-associated steatotic liver disease (MASLD)? Findings: In this cohort study of 16 603 patients with MASLD who underwent VCTE examination, the VCTE-based scores outperformed most noninvasive tests and were at least similar if not better than histologic fibrosis staging in predicting liver-related events. On repeated testing, the scores were largely stable, and patients with improvement in the scores had substantial reduction in the risk of liver-related events. Meaning: Findings of this study suggest that the VCTE-based scores are generally accurate for predicting liver-related events, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis. Importance: Metabolic dysfunction–associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis. Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)–based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD. Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE). Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests. Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group. Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis. This cohort study evaluates the prognostic implications of baseline and repeated vibration-controlled transient elastography scores and liver stiffness measurements in a large cohort of patients with metabolic dysfunction–associated steatotic liver disease. [ABSTRACT FROM AUTHOR]