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| 6. |
- Govaere, O., et al.
(författare)
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Macrophage scavenger receptor 1 mediates lipid-induced inflammation in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 76:5, s. 1001-1012
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Obesity-associated inflammation is a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the role of macrophage scavenger receptor 1 (MSR1, CD204) remains incompletely understood. Methods: A total of 170 NAFLD liver biopsies were processed for transcriptomic analysis and correlated with clinicopathological features. Msr1-/- and wild-type mice were subjected to a 16-week high-fat and high-cholesterol diet. Mice and ex vivo human liver slices were treated with a monoclonal antibody against MSR1. Genetic susceptibility was assessed using genome-wide association study data from 1,483 patients with NAFLD and 430,101 participants of the UK Biobank. Results: MSR1 expression was associated with the occurrence of hepatic lipid-laden foamy macrophages and correlated with the degree of steatosis and steatohepatitis in patients with NAFLD. Mice lacking Msr1 were protected against diet-induced metabolic disorder, showing fewer hepatic foamy macrophages, less hepatic inflammation, improved dyslipidaemia and glucose tolerance, and altered hepatic lipid metabolism. Upon induction by saturated fatty acids, MSR1 induced a pro-inflammatory response via the JNK signalling pathway. In vitro blockade of the receptor prevented the accumulation of lipids in primary macrophages which inhibited the switch towards a pro-inflammatory phenotype and the release of cytokines such as TNF-ɑ. Targeting MSR1 using monoclonal antibody therapy in an obesity-associated NAFLD mouse model and human liver slices resulted in the prevention of foamy macrophage formation and inflammation. Moreover, we identified that rs41505344, a polymorphism in the upstream transcriptional region of MSR1, was associated with altered serum triglycerides and aspartate aminotransferase levels in a cohort of over 400,000 patients. Conclusions: Taken together, our data suggest that MSR1 plays a critical role in lipid-induced inflammation and could thus be a potential therapeutic target for the treatment of NAFLD. Lay summary: Non-alcoholic fatty liver disease (NAFLD) is a chronic disease primarily caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary lifestyle. Herein, we show that the macrophage scavenger receptor MSR1, an innate immune receptor, mediates lipid uptake and accumulation in Kupffer cells, resulting in liver inflammation and thereby promoting the progression of NAFLD in humans and mice. © 2021 The Authors
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| 7. |
- Musso, G., et al.
(författare)
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Association of non-alcoholic fatty liver disease with chronic kidney disease : a systematic review and meta-analysis
- 2014
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Ingår i: PLoS Medicine. - : Public Library of Science. - 1549-1277 .- 1549-1676. ; 11:7, s. e1001680-
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Tidskriftsartikel (refereegranskat)abstract
- Background:Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.Methods and Findings:English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) andlt;60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.Conclusion:The presence and severity of NAFLD are associated with an increased risk and severity of CKD.Please see later in the article for the Editors Summary. © 2014 Musso et al.
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| 8. |
- Pavlides, Michael, et al.
(författare)
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Liver investigation: Testing marker utility in steatohepatitis (LITMUS): Assessment & validation of imaging modality performance across the NAFLD spectrum in a prospectively recruited cohort study (the LITMUS imaging study): Study protocol
- 2023
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Ingår i: Contemporary Clinical Trials. - : ELSEVIER SCIENCE INC. - 1551-7144 .- 1559-2030. ; 134
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is the liver manifestation of the metabolic syndrome with global prevalence reaching epidemic levels. Despite the high disease burden in the population only a small proportion of those with NAFLD will develop progressive liver disease, for which there is currently no approved pharmacotherapy. Identifying those who are at risk of progressive NAFLD currently requires a liver biopsy which is problematic. Firstly, liver biopsy is invasive and therefore not appropriate for use in a condition like NAFLD that affects a large proportion of the population. Secondly, biopsy is limited by sampling and observer dependent variability which can lead to misclassification of disease severity. Non-invasive biomarkers are therefore needed to replace liver biopsy in the assessment of NAFLD. Our study addresses this unmet need. The LITMUS Imaging Study is a prospectively recruited multi-centre cohort study evaluating magnetic resonance imaging and elastography, and ultrasound elastography against liver histology as the reference standard. Imaging biomarkers and biopsy are acquired within a 100-day window. The study employs standardised processes for imaging data collection and analysis as well as a real time central monitoring and quality control process for all the data submitted for analysis. It is anticipated that the high-quality data generated from this study will underpin changes in clinical practice for the benefit of people with NAFLD. Study Registration: clinicaltrials.gov: NCT05479721
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| 10. |
- Govaere, Olivier, et al.
(författare)
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A proteo-transcriptomic map of non-alcoholic fatty liver disease signatures
- 2023
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Ingår i: Nature Metabolism. - : NATURE PORTFOLIO. - 2522-5812. ; 5:4, s. 572-578
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Tidskriftsartikel (refereegranskat)abstract
- Govaere et al. integrate circulating protein data from more than 300 patients with non-alcoholic fatty liver disease (NAFLD) with transcriptomics and develop a non-invasive diagnostics tool to identify patients with at-risk NAFLD based on body mass index, type 2 diabetes status and four circulating proteins. Non-alcoholic fatty liver disease (NAFLD) is a common, progressive liver disease strongly associated with the metabolic syndrome. It is unclear how progression of NAFLD towards cirrhosis translates into systematic changes in circulating proteins. Here, we provide a detailed proteo-transcriptomic map of steatohepatitis and fibrosis during progressive NAFLD. In this multicentre proteomic study, we characterize 4,730 circulating proteins in 306 patients with histologically characterized NAFLD and integrate this with transcriptomic analysis in paired liver tissue. We identify circulating proteomic signatures for active steatohepatitis and advanced fibrosis, and correlate these with hepatic transcriptomics to develop a proteo-transcriptomic signature of 31 markers. Deconvolution of this signature by single-cell RNA sequencing reveals the hepatic cell types likely to contribute to proteomic changes with disease progression. As an exemplar of use as a non-invasive diagnostic, logistic regression establishes a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and TREM2), body mass index and type 2 diabetes mellitus status, to identify at-risk steatohepatitis.
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| 11. |
- Hardy, Timothy, et al.
(författare)
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The European NAFLD Registry : A real-world longitudinal cohort study of nonalcoholic fatty liver disease
- 2020
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Ingår i: Contemporary Clinical Trials. - : Elsevier. - 1551-7144 .- 1559-2030. ; 98
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Tidskriftsartikel (refereegranskat)abstract
- Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS Liver Investigation: Testing Marker Utility in Steatohepatitis consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace.
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| 13. |
- Johnson, Katherine, et al.
(författare)
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Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression : Diagnostic and mechanistic relevance
- 2022
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Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Serum microRNA (miRNA) levels are known to change in non-alcoholic fatty liver disease (NAFLD) and may serve as useful biomarkers. This study aimed to profile miRNAs comprehensively at all NAFLD stages.Methods: We profiled 2,083 serum miRNAs in a discovery cohort (183 cases with NAFLD representing the complete NAFLD spectrum and 10 population controls). miRNA libraries generated by HTG EdgeSeq were sequenced by Illumina NextSeq. Selected serum miRNAs were profiled in 372 additional cases with NAFLD and 15 population controls by quantitative reverse transcriptase PCR.Results: Levels of 275 miRNAs differed between cases and population controls. Fewer differences were seen within individual NAFLD stages, but miR-193a-5p consistently showed increased levels in all comparisons. Relative to NAFL/non-alcoholic steatohepatitis (NASH) with mild fibrosis (stage 0/1), 3 miRNAs (miR-193a-5p, miR-378d, and miR378d) were increased in cases with NASH and clinically significant fibrosis (stages 2-4), 7 (miR193a-5p, miR-378d, miR-378e, miR-320b, miR-320c, miR-320d, and miR-320e) increased in cases with NAFLD activity score (NAS) 5-8 compared with lower NAS, and 3 (miR-193a-5p, miR-378d, and miR-378e) increased but 1 (miR-19b-3p) decreased in steatosis, activity, and fibrosis (SAF) activity score 2-4 compared with lower SAF activity. The significant findings for miR-193a-5p were replicated in the additional cohort with NAFLD. Studies in Hep G2 cells showed that following palmitic acid treatment, miR-193a-5p expression decreased significantly. Gene targets for miR-193a-5p were investigated in liver RNAseq data for a case subgroup (n = 80); liver GPX8 levels correlated positively with serum miR-193a-5p.Conclusions: Serum miR-193a-5p levels correlate strongly with NAFLD activity grade and fibrosis stage. MiR-193a-5p may have a role in the hepatic response to oxidative stress and is a potential clinically tractable circulating biomarker for progressive NAFLD.Lay summary: MicroRNAs (miRNAs) are small pieces of nucleic acid that may turn expression of genes on or off. These molecules can be detected in the blood circulation, and their levels in blood may change in liver disease including non-alcoholic fatty liver disease (NAFLD). To see if we could detect specific miRNA associated with advanced stages of NAFLD, we carried out miRNA sequencing in a group of 183 patients with NAFLD of varying severity together with 10 population controls. We found that a number of miRNAs showed changes, mainly increases, in serum levels but that 1 particular miRNA miR-193a-5p consistently increased. We confirmed this increase in a second group of cases with NAFLD. Measuring this miRNA in a blood sample may be a useful way to determine whether a patient has advanced NAFLD without an invasive liver biopsy.
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| 14. |
- Lazarus, J.V., et al.
(författare)
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A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 72:1, s. 14-24
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimsNon-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH).MethodsIn 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively.ResultsNone of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD.ConclusionsWe found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries.Lay summaryWe conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries.
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| 15. |
- Lee, Jenny, et al.
(författare)
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Machine learning algorithm improves the detection of NASH (NAS-based) and at-risk NASH: A development and validation study
- 2023
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Ingår i: Hepatology. - : LIPPINCOTT WILLIAMS & WILKINS. - 0270-9139 .- 1527-3350. ; 78:1, s. 258-271
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Tidskriftsartikel (refereegranskat)abstract
- Background and Aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F >= 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD. Approach and Results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS >= 4;53%), at-risk NASH (NASH with F >= 2;35%), significant (F >= 2;47%), and advanced fibrosis (F >= 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82). Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis.
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| 16. |
- Vali, Yasaman, et al.
(författare)
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Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project) : a comparative diagnostic accuracy study
- 2023
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Ingår i: The Lancet Gastroenterology & Hepatology. - : Elsevier Ltd. - 2468-1253. ; 8:8, s. 714-725
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Tidskriftsartikel (refereegranskat)abstract
- Background: The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis—liver biopsy—is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment. Methods: This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials. Findings: Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54–0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75–0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86–0·94]), ADAPT (0·85 [0·81–0·89]), and FibroScan liver stiffness measurement (0·83 [0·80–0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4–5]), then ADAPT (six [5–7]), MACK-3 (seven [6–8]), and PRO-C3 (nine [7–11]). Interpretation: None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort. Funding: The Innovative Medicines Initiative 2 Joint Undertaking. © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
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| 17. |
- Zikra, M., et al.
(författare)
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Global wave climate based on the JMA/MRI-AGCM3.2 climate change projection
- 2020
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Ingår i: Proceedings of the 7th International Conference on Asian and Pacific Coasts, APAC 2013. - 9789795301257 ; , s. 926-931
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Konferensbidrag (refereegranskat)abstract
- In this study, global wave climates for present and future climates are simulated by the WAM model, based on wind climate data from the JMA/MRI-AGCM3.2 climate change projection. This study is based on two 6-hourly wind data sets, covering two periods of 1979-2003 (present climate) and 2075-2099 (future climate). These wind data are used to run the WAM model for generating output of wave characteristics. The outputs from each period then were used to study global wave climate in the future. It is found that the wave climate is strongly dependent on latitude, with the largest waves, as well as most significant seasonal variations, located at the mid to high latitude regions. These areas are also where the climate induced changes from present to future climate are most noteworthy. The largest increases of significant wave height of approximately +5%, is experienced in the southern parts of the Indian, Pacific and Atlantic Oceans as well as in the Antarctic Ocean. The largest decreases are of the same order, and limited to the northern Atlantic Ocean.
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| 20. |
- Akerstedt, TG, et al.
(författare)
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Sleep and burnout
- 2002
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Ingår i: SLEEP. - 0161-8105. ; 25, s. A403-A403
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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| 23. |
- Anstee, Quentin M., et al.
(författare)
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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:3, s. 505-515
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.METHODS: The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.RESULTS: Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.
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| 26. |
- Børøsund, Elin, et al.
(författare)
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Comparing effects in regular practice of e-communication and web-based self-management support among breast cancer patients : Preliminary results from a randomized controlled trial
- 2014
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Ingår i: Journal of Medical Internet Research. - : JMIR Publications Inc.. - 1438-8871. ; 16:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: While Web-based interventions have been shown to assist a wide range of patients successfully in managing their illness, few studies have examined the relative contribution of different Web-based components to improve outcomes. Further efficacy trials are needed to test the effects of Web support when offered as a part of routine care. Objective: Our aim was to compare in regular care the effects of (1) an Internet-based patient provider communication service (IPPC), (2) WebChoice, a Web-based illness management system for breast cancer patients (IPPC included), and (3) usual care on symptom distress, anxiety, depression, (primary outcomes), and self-efficacy (secondary outcome). This study reports preliminary findings from 6 months' follow-up data in a 12-month trial. Methods: We recruited 167 patients recently diagnosed with breast cancer and undergoing treatment from three Norwegian hospitals. The nurse-administered IPPC allowed patients to send secure e-messages to and receive e-messages from health care personnel at the hospital where they were treated. In addition to the IPPC, WebChoice contains components for symptom monitoring, tailored information and self-management support, a diary, and communication with other patients. A total of 20 care providers (11 nurses, 6 physicians, and 3 social workers) were trained to answer questions from patients. Outcomes were measured with questionnaires at study entry and at study months 2, 4, and 6. Linear mixed models for repeated measures were fitted to compare effects on outcomes over time. Results: Patients were randomly assigned to the WebChoice group (n=64), the IPPC group (n=45), or the usual care group (n=58). Response rates to questionnaires were 73.7% (123/167) at 2 months, 65.9 (110/167) at 4 months, and 62.3% (104/167) at 6 months. Attrition was similar in all study groups. Among those with access to WebChoice, 64% (41/64) logged on more than once and 39% (25/64) sent e-messages to care providers. In the IPPC group, 40% (18/45) sent e-messages. Linear mixed models analyses revealed that the WebChoice group reported significantly lower symptom distress (mean difference 0.16, 95% CI 0.06-0.25, P=.001), anxiety (mean difference 0.79, 95% CI 0.09-1.49, P=.03), and depression (mean difference 0.79, 95% CI 0.09-1.49, P=.03) compared with the usual care group. The IPPC group reported significant lower depression scores compared with the usual care group (mean difference 0.69, 95% CI 0.05-1.32, P=.03), but no differences were observed for symptom distress or anxiety. No significant differences in self-efficacy were found among the study groups. Conclusions: In spite of practice variations and moderate use of the interventions, our results suggest that offering Web support as part of regular care can be a powerful tool to help patients manage their illness. Our finding that a nurse-administered IPPC alone can significantly reduce depression is particularly promising. However, the multicomponent intervention WebChoice had additional positive effects.
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| 27. |
- Cheng, Q., et al.
(författare)
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Clinical epidemiology of Guillain-Barré syndrome in adults in Sweden 1996-97 : A prospective study
- 2000
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 7:6, s. 685-692
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Tidskriftsartikel (refereegranskat)abstract
- We described clinical manifestations, outcomes, prognostic indicators and clinico-epidemiological subgroups for 53 adult patients with Guillain-Barré syndrome (GBS) in Sweden during the period 1996-97. These patients were identified from a population of 2.8 million inhabitants and prospectively followed up for one year by a network of neurologists. An additional 10 cases, of whom five were adults who had not been prospectively followed up, were not included in the analyses. At 6 months after onset 80% of the patients could walk without aid, while at 1 year 46% were fully recovered, 42% had mild residual signs or symptoms, 4% had moderate and 6% severe disabilities, and 2% had died. Intravenous human immunoglobulin or plasmapheresis were used in 72% of the patients. The sum of the Medical Research Council (MRC) score at nadir was found as the only significant predictor for residual signs at 1 year in a multivariate model. Three subgroups, with different clinico-epidemiological characteristics, were identified by using cluster analysis. In conclusion, GBS in Sweden is frequently preceded by a respiratory infection, is often treated with immunomodulatory therapies, and exhibits a high recovery rate and a low fatality rate.
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| 31. |
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| 32. |
- Ekstedt, M, et al.
(författare)
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Reply
- 2016
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Ingår i: Hepatology (Baltimore, Md.). - : Ovid Technologies (Wolters Kluwer Health). - 1527-3350 .- 0270-9139. ; 64:1, s. 310-311
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 33. |
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| 34. |
- Ericson, E., et al.
(författare)
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Hepatic patatin-like phospholipase domain-containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans
- 2022
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Ingår i: Hepatology communications.. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 6:10, s. 2689-2701
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Tidskriftsartikel (refereegranskat)abstract
- In nonalcoholic fatty liver disease (NAFLD) the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well-characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2-4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported.
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- Govaere, Olivier, et al.
(författare)
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Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis
- 2020
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Ingår i: Science Translational Medicine. - Washington, DC, United States : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 12:572
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms that drive nonalcoholic fatty liver disease (NAFLD) remain incompletely understood. This large multicenter study characterized the transcriptional changes that occur in liver tissue across the NAFLD spectrum as disease progresses to cirrhosis to identify potential circulating markers. We performed high-throughput RNA sequencing on a discovery cohort comprising histologically characterized NAFLD samples from 206 patients. Unsupervised clustering stratified NAFLD on the basis of disease activity and fibrosis stage with differences in age, aspartate aminotransferase (AST), type 2 diabetes mellitus, and carriage of PNPLA3 rs738409, a genetic variant associated with NAFLD. Relative to early disease, we consistently identified 25 differentially expressed genes as fibrosing steatohepatitis progressed through stages F2 to F4. This 25-gene signature was independently validated by logistic modeling in a separate replication cohort (n = 175), and an integrative analysis with publicly available single-cell RNA sequencing data elucidated the likely relative contribution of specific intrahepatic cell populations. Translating these findings to the protein level, SomaScan analysis in more than 300 NAFLD serum samples confirmed that circulating concentrations of proteins AKR1B10 and GDF15 were strongly associated with disease activity and fibrosis stage. Supporting the biological plausibility of these data, in vitro functional studies determined that endoplasmic reticulum stress up-regulated expression of AKR1B10, GDF15, and PDGFA, whereas GDF15 supplementation tempered the inflammatory response in macrophages upon lipid loading and lipopolysaccharide stimulation. This study provides insights into the pathophysiology of progressive fibrosing steatohepatitis, and proof of principle that transcriptomic changes represent potentially tractable and clinically relevant markers of disease progression.
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- Mcteer, Matthew, et al.
(författare)
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Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information
- 2024
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 19:2
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Tidskriftsartikel (refereegranskat)abstract
- Aims Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints.Methods Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable.Results Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance.Conclusions This study developed a series of ML models of accuracy ranging from 71.9-99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means.
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- Mozes, Ferenc E., et al.
(författare)
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Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis
- 2023
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Ingår i: The Lancet Gastroenterology & Hepatology. - : ELSEVIER INC. - 2468-1253. ; 8:8, s. 704-713
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Tidskriftsartikel (refereegranskat)abstract
- Background Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. Methods This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score >= 15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs >= 20 kPa; FIB-4: <1<middle dot>3 vs 1<middle dot>3 to <= 2<middle dot>67 vs >2<middle dot>67; NFS: <-1<middle dot>455 vs -1<middle dot>455 to <= 0<middle dot>676 vs >0<middle dot>676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.Findings Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44<middle dot>7%] were female, median age was 54 years [IQR 44-63), and 1161 [46<middle dot>1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5<middle dot>8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0<middle dot>0001 for all comparisons). The tAUC at 5 years were 0<middle dot>72 (95% CI 0<middle dot>62-0<middle dot>81) for histology, 0<middle dot>76 (0<middle dot>70-0<middle dot>83) for LSM-VCTE, 0<middle dot>74 (0<middle dot>64-0<middle dot>82) for FIB-4, and 0<middle dot>70 (0<middle dot>63-0<middle dot>80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.Interpretation Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases.
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- Xin, Zhao, et al.
(författare)
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A framework for optimization of hybrid aircraft
- 2019
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Ingår i: Proceedings of the ASME Turbo Expo. - : American Society of Mechanical Engineers (ASME). - 9780791858608 ; 3
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Konferensbidrag (refereegranskat)abstract
- To achieve the goals of substantial improvements in efficiency and emissions set by Flightpath 2050, fundamentally different concepts are required. As one of the most promising solutions, electrification of the aircraft primary propulsion is currently a prime focus of research and development. Unconventional propulsion sub-systems, mainly the electrical power system, associated thermal management system and transmission system, provide a variety of options for integration in the existing propulsion systems. Different combinations of the gas turbine and the unconventional propulsion sub-systems introduce different configurations and operation control strategies. The trade-off between the use of the two energy sources, jet fuel and electrical energy, is primarily a result of the trade-offs between efficiencies and sizing characteristics of these sub-systems. The aircraft structure and performance are the final carrier of these trade-offs. Hence, full design space exploration of various hybrid derivatives requires global investigation of the entire aircraft considering these key propulsion sub-systems and the aircraft structure and performance, as well as their interactions. This paper presents a recent contribution of the development for a physics-based simulation and optimization platform for hybrid electric aircraft conceptual design. Modeling of each subsystem and the aircraft structure are described as well as the aircraft performance modeling and integration technique. With a focus on the key propulsion sub-systems, aircraft structure and performance that interfaces with existing conceptual design frameworks, this platform aims at full design space exploration of various hybrid concepts at a low TRL level.
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