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There is an urgent need for new high‐quality markers for the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2‐bound α1‐acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2‐bound AGP in the early detection of HCC. In a retrospective case–control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct‐acting antiviral agents (n = 93), we measured S2‐bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow‐up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty‐one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction‐associated steatotic liver disease and HCC of different etiologies were analysed. S2‐bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2‐bound AGP for the early detection of HCC during treatment and follow‐up. Interestingly, S2‐bound AGP levels correlated with aspartate aminotransferase (ρ =.56, p = 9.5×10−15) and liver elastography (ρ =.67, p = 2.2×10−16). Of note, S2‐bound AGP decreased in patients chronically infected with HCV after treatment‐induced HCV clearance. Fucosylated S2‐bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2‐bound AGP as a novel tumour marker requires further investigation. [ABSTRACT FROM AUTHOR]

Background: Desmin is a major cytoskeletal protein considered ubiquitous in mature muscle fibers. However, we earlier reported that a subgroup of muscle fibers in the soft palate of healthy subjects and obstructive sleep apnea patients (OSA) lacked immunoexpression for desmin. This raised the question of whether these fibers also lack messenger ribonucleic acid (mRNA) for desmin and can be considered a novel fiber phenotype. Moreover, some fibers in the OSA patients had an abnormal distribution and aggregates of desmin. Thus, the aim of the study was to investigate if these desmin protein abnormalities are also reflected in the expression of desmin mRNA in an upper airway muscle of healthy subjects and OSA patients. Methods: Muscle biopsies from the musculus uvulae in the soft palate were obtained from ten healthy male subjects and six male patients with OSA. Overnight sleep apnea registrations were done for all participants. Immunohistochemistry, in-situ hybridization, and reverse transcription–quantitative polymerase chain reaction (RT–qPCR) techniques were used to evaluate the presence of desmin protein and its mRNA. Results: Our findings demonstrated that a group of muscle fibers lacked expression for desmin mRNA and desmin protein in healthy individuals and OSA patients (12.0 ± 5.6% vs. 23.1 ± 10.8%, p = 0.03). A subpopulation of these fibers displayed a weak subsarcolemmal rim of desmin accompanied by a few scattered mRNA dots in the cytoplasm. The muscles of OSA patients also differed from healthy subjects by exhibiting muscle fibers with reorganized or accumulated aggregates of desmin protein (14.5 ± 6.5%). In these abnormal fibers, the density of mRNA was generally low or concentrated in specific regions. The overall quantification of desmin mRNA by RT–qPCR was significantly upregulated in OSA patients compared to healthy subjects (p = 0.01). Conclusions: Our study shows evidence that muscle fibers in the human soft palate lack both mRNA and protein for desmin. This indicates a novel cytoskeletal structure and challenges the ubiquity of desmin in muscle fibers. Moreover, the observation of reorganized or accumulated aggregates of desmin mRNA and desmin protein in OSA patients suggests a disturbance in the transcription and translation process in the fibers of the patients. [ABSTRACT FROM AUTHOR]

Ultrasound screening for hepatocellular carcinoma (HCC) in patients with liver cirrhosis has a poor sensitivity for small tumors. Circulating microRNAs (miRNAs) have been explored as HCC biomarkers, but results are diverging. Here, we evaluate if miRNAs up-regulated in HCC tissue can be detected in plasma and used as screening biomarkers for HCC. In this cross-sectional study, plasma, HCC tissue and surrounding non-tumorous liver tissue were collected from liver resections. Tissue miRNAs were identified and quantitated by RNA-sequencing analysis, and the fold-changes between HCC and surrounding liver tissue were calculated. The miRNAs up-regulated in HCCs were then re-analyzed in plasma from the same patients, and the miRNAs with the highest plasma levels were subsequently measured in plasma from an independent cohort of patients with cirrhosis or HCC. In tissues from 84 resected patients, RNA-sequencing detected 197 differentially expressed miRNAs, 40 of which had a raw count above 200 and were analyzed in plasma from the same cohort. Thirty-one miRNAs were selected for further analysis in 200 patients with HCC or cirrhosis. Of these, eleven miRNAs were significantly increased in HCC as compared to cirrhosis patients. Only miR-93-5p and miR-151a-3p were significantly associated with HCC, with an AUC of 0.662. In comparison, alpha-fetoprotein and des-gamma-carboxy prothrombin yielded an AUC of 0.816, which increased to 0.832 if miR-93-5p and miR-151a-3p were added. When including sex and age, the addition of miR-93-5p and miR-151a-3p did not further improve the AUC (from 0.910 to 0.911). In conclusion, micro-RNAs up-regulated in HCCs are detectable in plasma but have a poor performance as screening biomarkers of HCC. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti‐HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti‐HDV testing was analysed in relation to liver‐related outcomes with logistic regression. Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti‐HDV screening; within a median of 1.8 months (range 0.0–57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti‐HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty‐five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow‐up. The predictive factors for anti‐HDV screening were Asian origin, diagnosis after the year 2012, HIV co‐infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co‐infection was the only remaining factor in multivariable analysis. Delayed anti‐HDV test >5 years was independently associated with worsened liver‐related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8–31.6). Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low‐endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis. [ABSTRACT FROM AUTHOR]

Vocal signals, including human speech and birdsong, are produced by complicated, precisely coordinated body movements, whose execution is fitness-determining in resource competition and mate choice. While the acquisition and maintenance of motor skills generally requires practice to develop and maintain both motor circuitry and muscle performance, it is unknown whether vocal muscles, like limb muscles, exhibit exercise-induced plasticity. Here, we show that juvenile and adult zebra finches (Taeniopygia castanotis) require daily vocal exercise to first gain and subsequently maintain peak vocal muscle performance. Experimentally preventing male birds from singing alters both vocal muscle physiology and vocal performance within days. Furthermore, we find females prefer song of vocally exercised males in choice experiments. Vocal output thus contains information on recent exercise status, and acts as an honest indicator of past exercise investment in songbirds, and possibly in all vocalising vertebrates. Control of sound production by fast vocal muscle is critical to vocal communication. Here the authors show that zebra finches need daily singing exercise to build and maintain peak vocal muscle performance. Lack of exercise alters vocal muscle physiology and reduces attractiveness to females. [ABSTRACT FROM AUTHOR]

The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is estimated as 2–46% among patients without known pancreatic diseases. An association between NAFPD and non-alcoholic fatty liver disease (NAFLD) has been proposed, as well as an association between NAFPD and pancreatic exocrine insufficiency (PEI). Patients with histologically confirmed NAFLD were included in the study. The control group consisted of individuals included in a surveillance screening program. Magnetic resonance imaging (MRI) of the pancreas was performed in all patients and fat measurement was made using 2-point Dixon imaging. Fecal elastase-1 (FE-1) was performed to evaluate pancreatic exocrine function. Additionally, a 13C-mixed triglyceride breath test (13 C-MTG-BT) was performed in patients with FE-1 < 200 μg/g. Imaging signs of NAFPD were present in 17 (71%) patients; 11 (85%) from the NAFLD group and 6 (55%) from the control group. FE-1 < 200 μg/g was found in six (25%) patients (four in the NAFLD group and two in the control group); however, none of them had clinical symptoms of PEI. Therefore, in five out of six patients with low FE-1, a 13C-MTG-BT was performed, showing normal results (>20.9%) in all tested patients. Furthermore, the serum nutritional panel was normal in all patients with low FE-1. A systematic review identified five studies relevant to the topic. NAFPD was found in 85% of patients with NAFLD and in 55% of control patients. We did not diagnose PEI in either group. A literature review showed PEI in 9–56% of patients with NAFPD. [ABSTRACT FROM AUTHOR]

Patients with liver cirrhosis are recommended ultrasonography screening for early detection of hepatocellular carcinoma to increase the chances of curative treatment. However, ultrasonography alone lacks in sensitivity. Adding plasma biomarkers may increase the detection rate. We performed a broad exploratory analysis to find new plasma proteins with potential applicability for HCC screening in patients with cirrhosis. In a protein discovery cohort of 172 patients with cirrhosis or HCC, we screened for 481 proteins with suspension bead array or proximity extension assay. From these, 24 proteins were selected for further analysis in a protein verification cohort (n = 160), using ELISA, Luminex or an electrochemiluminescence platform. A cut-off model and a stepwise logistic regression model were used to find combinations of proteins with the best discriminatory performance between HCC and cirrhosis. Stepwise logistic regression revealed alpha-fetoprotein (AFP), decarboxy-prothrombin (DCP), thioredoxin reductase 1 (TXNRD1), and fibroblast growth factor 21 (FGF21) as the proteins with the best discriminatory performance between HCC and cirrhosis. Adding TXNRD1 to DCP and AFP increased the AUC from 0.844 to 0.878, and combining AFP, DCP and TXNRD1 with age and sex resulted in an AUC of 0.920. FGF21, however, did not further increase the performance when including age and sex. In the present study, TXNRD1 improves the sensitivity and specificity of AFP and DCP as HCC screening tools in patients with cirrhosis. We suggest that TXNRD1 should be validated in prospective settings as a new complementary HCC biomarker together with AFP and DCP. [ABSTRACT FROM AUTHOR]

The middle ear muscles have vital roles, yet their precise function in hearing and protection remains unclear. To better understand the function of these muscles in humans, the morphology, fiber composition, and metabolic properties of nine tensor tympani and eight stapedius muscles were analyzed with immunohistochemical, enzyme‐histochemical, biochemical, and morphometric techniques. Human orofacial, jaw, extraocular, and limb muscles were used as references. The immunohistochemical analysis showed that the stapedius and tensor tympani muscles were markedly dominated by fibers expressing fast contracting myosin heavy chain MyHC‐2A and MyHC‐2X (79 ± 6% vs. 86 ± 9%, respectively, p = 0.04). In fact, the middle ear muscles had one of the highest proportions of MyHC‐2 fibers ever reported for human muscles. Interestingly, the biochemical analysis revealed a MyHC isoform of unknown identity in both the stapedius and tensor tympani muscles. Muscle fibers containing two or more MyHC isoforms were relatively frequently observed in both muscles. A proportion of these hybrid fibers expressed a developmental MyHC isoform that is normally absent in adult human limb muscles. The middle ear muscles differed from orofacial, jaw, and limb muscles by having significantly smaller fibers (220 vs. 360 μm2, respectively) and significantly higher variability in fiber size, capillarization per fiber area, mitochondrial oxidative activity, and density of nerve fascicles. Muscle spindles were observed in the tensor tympani muscle but not in the stapedius muscle. We conclude that the middle ear muscles have a highly specialized muscle morphology, fiber composition, and metabolic properties that generally showed more similarities to orofacial than jaw and limb muscles. Although the muscle fiber characteristics in the tensor tympani and stapedius muscles suggest a capacity for fast, fine‐tuned, and sustainable contractions, their difference in proprioceptive control reflects different functions in hearing and protection of the inner ear. [ABSTRACT FROM AUTHOR]

common chronic liver disease. The prognosis may vary from simple steatosis to more severe outcomes such as nonalcoholic steatohepatitis (NASH), liver cirrhosis, and hepatocellular carcinoma. The understanding of the biological processes leading to NASH is limited and non-invasive diagnostic tools are lacking. Methods: The peripheral immunoproteome in biopsy-proven NAFL (n=35) and NASH patients (n=35) compared to matched, normal-weight healthy controls (n=15) was studied using a proximity extension assay, combined with spatial and single cell hepatic transcriptome analysis. Results: We identified 13 inflammatory serum proteins that, independent of comorbidities and fibrosis stage, distinguished NASH from NAFL. Analysis of coexpression patterns and biological networks further revealed NASH-specific biological perturbations indicative of temporal dysregulation of IL-4/-13, -10, -18, and non-canonical NF-ĸb signaling. Of the identified inflammatory serum proteins, IL-18 and EN-RAGE as well as ST1A1 mapped to hepatic macrophages and periportal hepatocytes, respectively, at the single cell level. The signature of inflammatory serum proteins further permitted identification of biologically distinct subgroups of NASH patients. Conclusion: NASH patients have a distinct inflammatory serum protein signature, which can be mapped to the liver parenchyma, disease pathogenesis, and identifies subgroups of NASH patients with altered liver biology. [ABSTRACT FROM AUTHOR]

Liver transplantation (LT) is the only available cure for end-stage liver disease and one of the best treatment options for hepatocellular carcinomas (HCC). Patients with known alcohol-associated cirrhosis (AC) are routinely assessed for alcohol dependence or abuse before LT. Patients with other liver diseases than AC may consume alcohol both before and after LT. The aim of this study was to assess the effects of alcohol drinking before and after LT on patient and graft survival regardless of the etiology of liver disease. Between April 2012 and December 2015, 200 LT-recipients were interviewed using the Lifetime Drinking History and the Addiction Severity Index questionnaire. Patients were categorized as having AC, n = 24, HCC and/or hepatitis C cirrhosis (HCV), n = 69 or other liver diseases, n = 107. Patients were monitored and interviewed by transplantation-independent staff for two years after LT with questions regarding their alcohol consumption. Patient and graft survival data were retrieved in October 2019. Patients with AC had an increased hazard ratio (HR) for death after LT (crude HR: 4.05, 95% CI: 1.07–15.33, p = 0.04) and for graft loss adjusted for age and gender (adjusted HR: 3.24, 95% CI 1.08–9.77, p = 0.04) compared to the other patients in the cohort. There was no significant effect of the volume of alcohol consumed before or after LT on graft loss or overall survival. Patients transplanted for AC have a worse prognosis, but we found no correlation between alcohol consumed before or after LT and graft or patient survival. [ABSTRACT FROM AUTHOR]

In the current study, we compared muscle morphology in three advanced aging cohorts that differed in physical function, including a unique cohort of lifelong endurance athletes. Biopsies from the vastus lateralis muscle of seven lifelong endurance athletes (EAs) aged 82–92 yr, and 19 subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87–91 yr were analyzed. ULSAM subjects were divided into high- (n = 9, HF) and low- (n = 10, LF) function groups based on strength and physical function tests. The analysis included general morphology, fiber type and cross-sectional area, capillarization, deficient cytochrome c oxidase (COX) activity, number of myonuclei and satellite cells, and markers of regeneration and denervation. Fibers with central nuclei and/or nuclear clumps were observed in all groups. EA differed from LF and HF by having a higher proportion of type I fibers, 52% more capillaries in relation to fiber area, fewer COX-negative fibers, and less variation in fiber sizes (all P < 0.05). There were no differences between the groups in the number of myonuclei and satellite cells per fiber, and no significant differences between LF and HF (P > 0.05). In conclusion, signs of aging were evident in the muscle morphology of all groups, but neither endurance training status nor physical function influenced signs of regeneration and denervation processes. Lifelong endurance training, but not higher physical function, was associated with higher muscle oxidative capacity, even beyond the age of 80. [ABSTRACT FROM AUTHOR]

Background and Aims: Several genotypes associate with a worse histopathological profile in patients with non‐alcoholic fatty liver disease (NAFLD). Whether genotypes impact long‐term outcomes is unclear. We investigated the importance of PNPLA3, TM6SF2, MBOAT7 and GCKR genotype for the development of severe outcomes in NAFLD. Method: DNA samples were collected from 546 patients with NAFLD. Advanced fibrosis was diagnosed by liver biopsy or elastography. Non‐alcoholic steatohepatitis (NASH) was histologically defined. Additionally, 5396 controls matched for age, sex and municipality were identified from population‐based registers. Events of severe liver disease and all‐cause mortality were collected from national registries. Hazard ratios (HRs) adjusted for age, sex, body mass index and type 2 diabetes were estimated with Cox regression. Results: In NAFLD, the G/G genotype of PNPLA3 was associated with a higher prevalence of NASH at baseline (odds ratio [OR] 3.67, 95% CI = 1.66–8.08), but not with advanced fibrosis (OR 1.81, 95% CI = 0.79–4.14). After up to 40 years of follow‐up, the PNPLA3 G/G genotype was associated with a higher rate of severe liver disease (adjusted hazard ratio [aHR] 2.27, 95% CI = 1.15–4.47) compared with the C/C variant. NAFLD patients developed cirrhosis at a higher rate than controls (aHR 9.00, 95% CI = 6.85–11.83). The PNPLA3 G/G genotype accentuated this rate (aHR 23.32, 95% = CI 9.14–59.47). Overall mortality was not affected by any genetic variant. Conclusion: The PNPLA3 G/G genotype is associated with an increased rate of cirrhosis in NAFLD. Our results suggest that assessment of the PNPLA3 genotype is of clinical relevance in patients with NAFLD to individualize monitoring and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Adipocyte hypertrophy and expression of adipokines in subcutaneous adipose tissue (SAT) have been linked to steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis in morbidly obese (BMI ≥ 40 kg/m2) subjects. It is unknown if this is also true for subjects with NAFLD with lesser degrees of obesity (BMI < 35 kg/m2). Thirty-two subjects with biopsy-proven NAFLD and 15 non-diabetic controls matched for BMI underwent fine-needle biopsies of SAT. Adipocyte volume was calculated. RNA-sequencing of SAT was performed in a subset of 20 NAFLD patients. Adipocyte volume and gene expression levels were correlated to the presence of NASH or significant fibrosis. Subjects with NAFLD had larger adipocyte volume compared with controls, (1939 pL, 95% CI 1130–1662 vs. 854 pL, 95% CI 781–926, p < 0.001). There was no association between adipocyte volume and the presence of NASH. Gene expression of adipokines previously described to correlate with NASH in morbid obesity, was not associated with NASH or fibrosis. Our results suggest that persons with NAFLD have larger SAT adipocytes compared with controls and that adipocytes are involved in the pathophysiology of hepatic steatosis in NAFLD. However, adipocyte volume was not associated with NASH or fibrosis in NAFLD subjects with varying degrees of obesity. [ABSTRACT FROM AUTHOR]

Background: Post-hepatectomy liver failure (PHLF) is one of the most serious postoperative complications after hepatectomy. The aim of this study was to assess the impact of the International Study Group of Liver Surgery (ISGLS) definition of PHLF on morbidity and short- and long-term survival after major hepatectomy. Methods: This was a retrospective review of all patients who underwent major hepatectomy (three or more liver segments) for various liver tumours between 2010 and 2018 at two Swedish tertiary centres for hepatopancreatobiliary surgery. Descriptive statistics, regression models, and survival analyses were used. Results: A total of 799 patients underwent major hepatectomy, of which 218 patients (27 per cent) developed ISGLS-defined PHLF, including 115 patients (14 per cent) with ISGLS grade A, 76 patients (10 per cent) with grade B, and 27 patients (3 per cent) with grade C. The presence of cirrhosis, perihilar cholangiocarcinoma, and gallbladder cancer, right-sided hemihepatectomy and trisectionectomy all significantly increased the risk of clinically relevant PHLF (grades B and C). Clinically relevant PHLF increased the risk of 90-day mortality and was associated with impaired long-term survival. ISGLS grade A had more major postoperative complications compared with no PHLF but failed to be an independent predictor of both 90-day mortality and long-term survival. The impact of PHLF grade B/C on long-term survival was no longer present in patients surviving the first 90 days after surgery. Conclusions: The presently used ISGLS definition for PHLF should be reconsidered regarding mortality as only PHLF grade B/C was associated with a negative impact on short-term survival; however, even ISGLS grade A had clinical implications. [ABSTRACT FROM AUTHOR]

Objective: Previous reports of muscle changes in the upper airways of obstructive sleep apnea (OSA) patients have primarily been attributed to acquired nerve lesions due to snoring vibrations. The aim of this study was to investigate whether alterations reflecting muscle fiber injuries also occur in the upper respiratory tract of snoring and OSA patients and if these changes relate to upper airway dysfunction. Methods: Muscle changes in biopsies from the soft palate of 20 patients suffering from snoring and OSA were investigated with enzyme, immunohistochemical, and morphometric techniques. Biopsies from eight healthy non‐snoring subjects were used as controls. Swallowing dysfunction was assessed with videoradiography. Results: Fourteen patients had various degrees of swallowing dysfunction. The muscle samples from all the patients showed changes typical for both motor‐nerve lesions and muscle fiber injuries. The most common alterations reflecting myopathy were fibers having aggregates and disorganization of cytoskeletal proteins (15.5 ± 10.7%). Other changes were fibers with vacuole‐like structures (5.0 ± 4.4%), centrally positioned myonuclei (7.9 ± 4.8%), subsarcolemmal accumulations of nuclei, and various forms and sizes of ring fibers, that is, fibers where the myofilaments were disorganized peripherally (2.8 ± 2.8%). Conclusion: The results show that muscle changes mirroring both myopathy and neuropathy co‐exist in the upper airway of snoring OSA patients. These findings suggest muscle weakness as a contributing factor to the upper airway dysfunction in OSA patients. [ABSTRACT FROM AUTHOR]

Background and Study Aims In patients with obesity and type-2 diabetes, short-time very low-calorie diet may ameliorate hyperglycemia and hepatic steatosis. Whether this also implies the glucose-regulating hormone glucagon remains to be elucidated. This study investigated the effects of a very low-calorie diet on plasma levels of glucagon and liver fat in obese patients with type-2 diabetes. Patients and Methods Ten obese patients with type-2 diabetes, 6 men and 4 women, were included. At baseline, fasting plasma glucagon, insulin and glucose were determined, and liver fat and stiffness evaluated by transient elastography. The subjects were then prescribed a very low-calorie diet of maximum 800 kcal/day for 7 weeks and reexamined after 7 weeks and 12 months. Results At baseline, BMI was 42±4 kg/m2 and fasting glucose 10.6±3.4 mmol/l. All patients had hepatic steatosis. Plasma glucagon was strongly related to liver fat (r2 =0.52, p=0.018). After 7 weeks of very low-calorie diet, plasma glucagon was significantly decreased by nearly 30% (p=0.004) along with reductions of BMI (p<0.0001), glucose (p=0.02), insulin (p=0.03), liver fat (p=0.007) and liver stiffness (p=0.05). At 12 months follow-up, both glucagon and liver fat increased and were not different to basal levels, despite persistent reductions of BMI (p<0.002) and glucose (p=0.008). Conclusion In obese type-2 diabetic subjects, plasma glucagon and liver fat are correlated and similarly affected by a very low-calorie diet, supporting a role of hepatic steatosis in glucagon metabolism. [ABSTRACT FROM AUTHOR]

Hepatitis D virus (HDV) infection causes a severe chronic viral hepatitis with accelerated development of liver cirrhosis and decompensation, but whether it further increases the risk of hepatocellular carcinoma (HCC) is unclear. We performed a comprehensive systematic review of the published literature and meta‐analysis to assess the risk of HCC in HDV and hepatitis B virus (HBV) co‐infected, compared to HBV mono‐infected patients. The study was conducted per a priori defined protocol, including only longitudinal studies, thus excluding cross‐sectional studies. Random‐effects models were used to determine aggregate effect sizes (ES) with 95% confidence intervals (CI). Meta‐regression was used to examine the associations among study level characteristics. Twelve cohort studies comprising a total of 6099 HBV/HDV co‐infected and 57,620 chronic HBV mono‐infected patients were analysed. The overall pooled ES showed that HBV/HDV co‐infected patients were at 2‐fold increased risk of HCC compared to HBV mono‐infected patients (ES = 2.12, 95% CI 1.14–3.95, I2 = 72%, N = 12). A six‐fold significant increased risk of HCC was noted among HIV/HBV/HDV triple‐infected, compared to HIV/HBV co‐infected patients. The magnitude of ES did not differ significantly after adjustment for study design and quality, publication year and follow‐up duration in univariable meta‐regression analysis. This systematic review and meta‐analysis shows that infection with HDV is associated with a 2‐fold higher risk of HCC development compared to HBV mono‐infection. HCC surveillance strategies taking this increased risk into account, and new treatment options against HDV, are warranted. [ABSTRACT FROM AUTHOR]

Background: Textural parameters extracted using quantitative imaging techniques have been shown to have prognostic value for hepatocellular carcinoma (HCC).Purpose: To evaluate whether the contrast medium timing of the image acquisition affects the reproducibility of textural parameters in HCC and hepatic tissue.Material and Methods: This retrospective study included 17 patients with 37 HCC lesions. Perfusion computed tomography (CT) was obtained after 50 mL contrast medium injection. HCC lesions were segmented for analysis. The gray-level co-occurrence (GLCM) textural analysis parameters, homogeneity, energy, entropy, inertia, and correlation were calculated. Variation was quantified by calculating the SD of each parameter during respective perfusion series and the inter lesion variation as the SD among the lesions.Results: The average change in texture parameters in both HCC and hepatic tissue per second after injection was 0.01% to 0.3% of the respective texture parameter. In HCC, the average variation in homogeneity, energy, and entropy within each lesion after contrast medium injection was significantly less than the variation observed among the lesions (23% to 74%, P < 0.001). Significant differences in energy, entropy, inertia, and correlation between hepatic tissue and HCC were observed. However, when considering the intra-individual variation of hepatic tissue over time, only the HCC parameter energy was significantly outside that 95% confidence interval (P < 0.02).Conclusion: The contrast medium timing does not affect the reproducibility of textural parameters in HCC and hepatic tissue. Thus, contrast medium timing should not be an issue at CT texture analysis of HCC. [ABSTRACT FROM AUTHOR]

Skeletal muscle in individuals with CP also contains lower amounts of mtDNA, potentially indicating fewer mitochondria in CP skeletal muscle compared with typically developing muscle. We compared skeletal muscle samples from children with cerebral palsy (CP) and typically developing children and observed evidence of reduced mtDNA and OXPHOS protein content in CP skeletal muscle, indicating reduced mitochondrial abundance. Cerebral palsy (CP) muscle contains fewer energy-generating organelles than typically developing muscle. [Extracted from the article]

Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin–antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child–Pugh and MELD score. TAT was increased in all Child–Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only. [ABSTRACT FROM AUTHOR]

The aspartate‐to‐alanine aminotransferase ratio (AAR) is associated with liver fibrosis, but its predictive performance is suboptimal. We hypothesized that the association between AAR and liver disease depends on absolute transaminase levels and developed and validated a model to predict liver‐related outcomes in the general population. A Cox regression model based on age, AAR, and alanine aminotransferase (ALT) level (dynamic AAR [dAAR]) using restricted cubic splines was developed in Finnish population‐based health‐examination surveys (FINRISK, 2002‐2012; n = 18,067) with linked registry data for incident liver‐related hospitalizations, hepatocellular carcinoma, or liver death. The model was externally validated for liver‐related outcomes in a Swedish population cohort (Swedish Apolipoprotein Mortality Risk [AMORIS] subcohort; n = 126,941) and for predicting outcomes and/or prevalent fibrosis/cirrhosis in biopsied patients with nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C, or alcohol‐related liver disease (ALD). The dynamic AAR model predicted liver‐related outcomes both overall (optimism‐corrected C‐statistic, 0.81) and in subgroup analyses of the FINRISK cohort and identified persons with >10% risk for liver‐related outcomes within 10 years. In independent cohorts, the C‐statistic for predicting liver‐related outcomes up to a 10‐year follow‐up was 0.72 in the AMORIS cohort, 0.81 in NAFLD, and 0.75 in ALD. Area‐under‐the‐curve (AUC) for detecting prevalent cirrhosis was 0.80‐0.83 in NAFLD, 0.80 in hepatitis C, but only 0.71 in ALD. In ALD, model performance improved when using aspartate aminotransferase instead of ALT in the model (C‐statistic, 0.84 for outcome; AUC, 0.82 for prevalent cirrhosis). Conclusion: A dAAR score provides prospective predictions for the risk of incident severe liver outcomes in the general population and helps detect advanced liver fibrosis/cirrhosis. The dAAR score could potentially be used for screening the unselected general population and as a trigger for further liver evaluations. [ABSTRACT FROM AUTHOR]

Background: Training volume is paramount in the magnitude of physiological adaptations following resistance training. However, patients with severe COPD are limited by dyspnea during traditional two-limb low-load/high-repetition resistance training (LLHR-RT), resulting in suboptimal training volumes. During a single exercise session, single-limb LLHR-RT decreases the ventilatory load and enables higher localized training volumes compared with two-limb LLHR-RT.Research Question: Does single-limb LLHR-RT lead to more profound effects compared with two-limb LLHR-RT on exercise capacity (6-min walk distance [6MWD]), health status, muscle function, and limb adaptations in patients with severe COPD?Study Design and Methods: Thirty-three patients (mean age 66 ± 7 years; FEV1 39 ± 10% predicted) were randomized to 8 weeks of single- or two-limb LLHR-RT. Exercise capacity (6MWD), health status, and muscle function were compared between groups. Quadriceps muscle biopsy specimens were collected to examine physiological responses.Results: Single-limb LLHR-RT did not further enhance 6MWD compared with two-limb LLHR-RT (difference, 14 [-12 to 39 m]. However, 73% in the single-limb group exceeded the known minimal clinically important difference of 30 m compared with 25% in the two-limb group (P = .02). Health status and muscle function improved to a similar extent in both groups. During training, single-limb LLHR-RT resulted in a clinically relevant reduction in dyspnea during training compared with two-limb LLHR-RT (-1.75; P = .01), but training volume was not significantly increased (23%; P = .179). Quadriceps muscle citrate synthase activity (19%; P = .03), hydroxyacyl-coenzyme A dehydrogenase protein levels (32%; P < .01), and capillary-to-fiber ratio (41%; P < .01) were increased compared with baseline after pooling muscle biopsy data from all participants.Interpretation: Single-limb LLHR-RT did not further increase mean 6MWD compared with two-limb LLHR-RT, but it reduced exertional dyspnea and enabled more people to reach clinically relevant improvements in 6MWD. Independent of execution strategy, LLHR-RT improved exercise capacity, health status, muscle endurance, and enabled several physiological muscle adaptations, reducing the negative consequences of limb muscle dysfunction in COPD.Clinical Trial Registration: ClinicalTrials.gov; No.: NCT02283580; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

There are no currently available biomarkers that can accurately indicate the presence of non-alcoholic steatohepatitis (NASH). We investigated the association between endotrophin, a cleavage product of collagen type 6α3, and disease severity in patients with non-alcoholic fatty liver disease (NAFLD). We measured serum endotrophin levels in 211 patients with NAFLD and nine healthy controls. Liver biopsy data was available for 141 (67%) of the patients. Associations between endotrophin and the presence of NASH and advanced fibrosis were investigated alone and in combination with standard clinical parameters using logistic regression. A total of 211 patients were enrolled in this study, consisting of 108 (51%) men and 103 (49%) women with a mean age of 55.6 years. 58 (27%) of the patients had advanced fibrosis. Of those with biopsy data, 87 (62%) had NASH. Serum levels of endotrophin were significantly higher in patients with NAFLD than those in healthy controls (37[±12] vs. 17[±7] ng/mL, p<.001). Serum levels of endotrophin were also significantly higher in patients with NASH than in those without NASH (40[±12] vs. 32[±13] ng/mL, p<.001). A model using age, sex, body mass index and levels of alanine aminotransferase (ALT), glucose and endotrophin effectively predicted the presence of NASH in a derivation (AUROC 0.83, 95%CI = 0.74–0.92) and validation cohort (AUROC 0.71, 95%CI = 0.54–0.88). There was no significant association between serum levels of endotrophin and advanced fibrosis. These data suggest that serum endotrophin could be a valuable biomarker for diagnosing NASH, but not for detecting advanced fibrosis in NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims: Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra‐hepatic diseases, especially breast and colorectal cancer. Here we investigated long‐term outcomes of Swedish patients with HFE mutations. Methods: We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson's disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes. Results: Median age at diagnosis was 52 years, 44% were females. During a mean follow‐up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver‐related outcomes were rare, with a cumulative incidence of <1%. Conclusions: Individuals found to be HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed. [ABSTRACT FROM AUTHOR]

Objective: Liver transplantation (LT) is a life-saving procedure for patients with end-stage liver disease, acute liver failure or hepatocellular carcinoma (HCC). Patients with known alcoholic liver cirrhosis (ALC) are usually assessed by an addiction specialist, but patients with other liver diseases may also exhibit harmful drinking. This study aims to assess the drinking habits in LT-recipients with or without a diagnosis of ALC. Patients and methods: Between April 2012 and December 2015, 190 LT-recipients were interviewed using the Lifetime Drinking History (LDH) and the Addiction Severity Index (ASI). Patients were categorized according to their diagnoses: ALC (group A, n = 39), HCC or hepatitis C (group B, n = 56) or other liver diseases (group C, n = 95). Data were analysed using descriptive statistic methods. Results: Fifteen of 95 patients (15.8%) in group C – a cohort without suspected addiction problems – had either alcohol consumption or binge drinking within the upper quartile of the overall cohort. The aetiology of liver disease in this subgroup included mainly cholestatic and cryptogenic liver disease. Illicit drugs had been used by 35% of all patients. Cannabis and amphetamine were the most common drugs and had the longest duration of regular use. Conclusions: LT candidates without known alcohol or drug use may have a clinically significant consumption of alcohol and previous illicit drug use. Efforts should be put on identification of these patients during LT evaluation. The use of structured questionnaires such as the ASI and the LDH could facilitate detection of alcohol and drug problems. [ABSTRACT FROM AUTHOR]

Aim: Doxorubicin-eluting beads transarterial chemoembolization (DEB-TACE) is reported to improve survival and tolerability when compared with conventional lipiodol-TACE (cTACE) for the treatment of hepatocellular carcinoma (HCC). The aim of this study was to evaluate tolerability and long-term survival in patients treated with cTACE or DEB-TACE in a real-life setting. Methods: Incidence of adverse events and overall survival in HCC patients treated with either cTACE or DEB-TACE at Karolinska University Hospital 2004–2012 were analyzed retrospectively. Median follow-up was 7.1 years. Patients were censored when transplanted or at the end of follow-up. Patients receiving both cTACE and DEB-TACE, or treated with resection or ablation post-TACE were excluded from the survival analysis. Results: A total of 202 patients (76 cTACE and 126 DEB-TACE) were eligible for analysis of adverse events, and 179 patients (69 cTACE and 110 DEB-TACE) were included in the survival analysis. cTACE patients were younger and had fewer tumors but higher BCLC stage than DEB-TACE. Child-Pugh and ECOG performance status were similar between groups. Adverse events (abdominal pain, nausea and vomiting, fever, fatigue) were significantly less common in the DEB-TACE group. Median survival was 17.1 months in the cTACE group and 19.1 months in the DEB-TACE (NS). In multivariate Cox regression analysis, portal vein thrombosis and tumor size were associated with increased, and sorafenib treatment post-TACE with decreased mortality. Conclusion: In this retrospective real-life analysis, DEB-TACE had better tolerability compared to cTACE, but overall survival did not differ between the two treatments. Portal vein thrombosis, tumor size and sorafenib treatment after TACE influence survival. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD), and the progressive stage non-alcoholic steatohepatitis (NASH), is the predominant cause of chronic liver disease globally. As part of the complex pathogenesis, natural killer (NK) cells have been implicated in the development of liver inflammation in experimental murine models of NASH. However, there is a lack of knowledge on how NK cells are affected in humans with this disease. Here, we explored the presence of disease-specific changes within circulating and tissue-resident NK cell populations, as well as within other major immune cell subsets, in patients with liver biopsy-confirmed NAFLD. Using 18-color-flow cytometry, substantial changes were observed in certain myeloid populations in patients as compared to controls. NK cell numbers, on the other hand, were not altered. Furthermore, only minor differences in expression of activating and inhibitory NK cell receptors were noted, with the exception of an increased expression of NKG2D on NK cells from patients with NASH. NK cell differentiation remained constant, and NK cells from these patients retain their ability to respond adequately upon stimulation. Instead, considerable alterations were observed between liver, adipose tissue, and peripheral blood NK cells, independently of disease status. Taken together, these results increase our understanding of the importance of the local microenvironment in shaping the NK cell compartment and stress the need for further studies exploring how NASH affects intrahepatic NK cells in humans. [ABSTRACT FROM AUTHOR]

Background and Aims: Non‐alcoholic fatty liver disease (NAFLD) is a growing cause of hepatocellular carcinoma (HCC). In NAFLD, HCC occurs more commonly in the absence of cirrhosis compared with other liver diseases; yet, patients with non‐cirrhotic NAFLD‐HCC are poorly characterized. Here, we characterized a large cohort of HCC cases and assessed the outcomes of patients with non‐cirrhotic NAFLD‐HCC. Methods: We identified all cases of HCC treated at the Karolinska University Hospital, Stockholm, Sweden from 2004 to 2017. Patient charts were manually reviewed for variable extraction. Cases were followed passively for all‐cause and HCC‐related mortality until the end of April 2018. Cox regression was performed to estimate mortality rates and identify mortality risk factors in patients with non‐cirrhotic NAFLD‐HCC. Results: Totally, 1562 cases with HCC were identified. Of these, 225 (14.4%) had NAFLD‐HCC, of which 83 (37%) did not have cirrhosis. Compared with patients with cirrhotic NAFLD‐HCC, patients with non‐cirrhotic NAFLD‐HCC were older (74 vs 70 years, P < 0.001), had a lower prevalence of type 2 diabetes (T2DM) (66% vs 80%, P = 0.02), larger tumours, less frequently underwent liver transplantation (0% vs 11%, P = 0.002), but more frequently underwent resection (35% vs 8%, P < 0.001). Mortality was similar (aHR for non‐cirrhotic NAFLD‐HCC vs cirrhotic NAFLD‐HCC 0.93, 95% CI 0.58‐1.51, P = 0.78). Parameters independently associated with increased mortality included the Barcelona Clinic Liver Cancer stage, number of tumours, lower albumin and presence of T2DM. Conclusions: Patients with non‐cirrhotic NAFLD‐HCC differ from those with cirrhosis in age, tumour size and allocated treatments. Despite these differences, survival is similar. [ABSTRACT FROM AUTHOR]

Background and aim: Transient elastography can detect liver fibrosis by estimation of liver stiffness. Results may be falsely high when blood flow to the liver is increased, such as during late stages of pregnancy. The aim of the present study was to longitudinally evaluate transient elastography in healthy pregnant women. Methods: We recruited 24 healthy women with normal singleton pregnancies in a longitudinal cohort study. All women underwent transient elastography at gestational week 18–20, week 26–28 and week 36–38, as well as after a minimum of 8 weeks postpartum. Results: Mean age at baseline was 30.6 years ± 4.1, and mean BMI was 22.3 kg/m2±1.9. 14 women (58%) were nulliparous. The pregnancy outcomes were normal, with no cases of preeclampsia or gestational diabetes. Mean gestational length was 284 days ± 7. Mean liver stiffness increased from 3.8 kPa during the second trimester to 5.9 kPa during the third trimester (p =.002). At the third trimester, 2 women (8%) had an elastography measurement of >7.9 kPa. Postpartum, liver stiffness decreased to early second trimester levels (5.9 to 3.8 kPa, p =.002), and no woman had liver stiffness values above 7.9 kPa. Likewise, the mean Controlled Attenuation Parameter (CAP) increased from 186 dB/m in the second trimester to 215 dB/m in the third trimester (p =.01) and reversed postpartum (215 to 193 dB/m, p =.03). Conclusion: Liver stiffness and CAP increase reversibly during normal pregnancies, and slightly elevated levels in the third trimester can be considered a normal finding. Lay summary An ultrasound-based method called transient elastography can be used to measure fat content and estimate fibrosis in the liver. In this study, we examined healthy women three times during their pregnancy and once after labor to evaluate the effects of a normal pregnancy on a healthy liver. The ultrasound-estimation of fibrosis and fat content increased during pregnancy and reversed afterwards, without any other signs of disease in the liver. [ABSTRACT FROM AUTHOR]

Objectives: Neuromuscular injuries are suggested to contribute to upper airway collapse and swallowing dysfunction in patients with sleep apnea. Neurotrophins, a family of proteins involved in survival, development, and function of neurons, are reported to be upregulated in limb muscle fibers in response to overload and nerve damage. We aimed to investigate the expression of two important neurotrophins, brain‐derived neurotrophic factor (BDNF) and nerve growth factor (NGF), in muscle fibers of uvula from snorers and sleep apnea patients and to compare these findings with pharyngeal function. Methods: Uvula muscle biopsies from 22 patients and 10 controls were analyzed for BDNF, NGF, and cytoskeletal protein desmin using immunohistochemistry. Pharyngeal swallowing function was assessed using videoradiography. Results: BDNF, but not NGF, was significantly upregulated in a subpopulation of muscle fibers in snoring and sleep apnea patients. Two major immunoreaction patterns for BDNF were observed; a fine grainy point like BDNF staining was displayed in muscle fibers of both patients and controls (41 ± 23 vs. 25 ± 17%, respectively, P =.06), while an abnormal upregulated intense‐dotted or disorganized reaction was mainly observed in patients (8 ± 8 vs. 2 ± 2%, P =.02). The latter fibers, which often displayed an abnormal immunoreaction for desmin, were more frequent in patients with than without swallowing dysfunction (10 ± 8 vs. 3 ± 3%, P =.05). Conclusion: BDNF is upregulated in the upper airway muscles of snorers and sleep apnea patients, and especially in patients with swallowing dysfunction. Upregulation of BDNF is suggested to be a response to denervation, reinnervation, and repair of injured muscle fibers. Our findings propose that damaged upper airway muscles might heal following treatment for snoring and sleep apnea. Level of Evidence: NA [ABSTRACT FROM AUTHOR]

Background & Aims: Patients with non‐alcoholic fatty liver disease (NAFLD) are at an increased risk for cardiovascular disease (CVD). It is unclear whether histological variables may help predict CVD risk. We evaluated histology and traditional CV risk factors as predictors of CVD outcomes in a large NAFLD cohort. Methods: We included 603 biopsy‐proven NAFLD patients free of baseline CVD and matched these (1:10, by age, sex and municipality) to 6269 population controls. All individuals were cross‐linked to national registries to ascertain incident CVD events, defined as acute ischaemic heart disease or stroke. The presence of CV risk factors and liver histology were available in NAFLD patients only. Cox regression models were used to estimate hazard ratios (HR) for incident CVD. Results: During a mean follow‐up of 18.6 years, 168 (28%) of NAFLD patients and 1325 (21%) of controls experienced a CVD event (HR 1.54, 95%CI 1.30‐1.83). Within the NAFLD cohort, age, male sex, type 2 diabetes, smoking and triglycerides were associated with risk of CVD. Taking these CV risk factors into account, no histological parameter, including presence of NASH and fibrosis stage, were associated with incident CVD. Conclusions: Patients with NAFLD are at an increased risk for CVD compared to matched controls, but histological parameters do not seem to independently predict this risk. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic fatty liver disease(NAFLD) is the second most common cause of liver transplantation in the US. Data on NAFLD as a liver transplantation indication from countries with lower prevalences of obesity are lacking. We studied the temporal trends of NAFLD as an indication for liver transplantation in the Nordic countries, and compared outcomes for patients with NAFLD to patients with other indications for liver transplantation. Method: Population‐based cohort study using data from the Nordic Liver Transplant Registry on adults listed for liver transplantation between 1994 and 2015. NAFLD as the underlying indication for liver transplantation was defined as a listing diagnosis of NAFLD/nonalcoholic steatohepatitis, or cryptogenic cirrhosis with a body mass index ≥25 kg/m2 and absence of other liver diseases. Waiting time for liver transplantation, mortality and withdrawal from the transplant waiting list were registered. Survival after liver transplantation was calculated using multivariable Cox regression, adjusted for age, sex, body mass index and model for end‐stage liver disease. Results: A total of 4609 patients listed for liver transplantation were included. NAFLD as the underlying indication for liver transplantation increased from 2.0% in 1994‐1995 to 6.2% in 2011‐2015 (P = .01) and was the second most rapidly increasing indication. NAFLD patients had higher age, model for end‐stage liver disease and body mass index when listed for liver transplantation, but overall survival after liver transplantation was comparable to non‐‐NAFLD patients (aHR 1.03, 95% CI 0.70‐1.53 P = .87). Conclusion: NAFLD is an increasing indication for liver transplantation in the Nordic countries. Despite more advanced liver disease, NAFLD patients have a comparable survival to other patients listed for liver transplantation. [ABSTRACT FROM AUTHOR]

Background: The pathophysiologic mechanism of nocturnal obstruction and swallowing dysfunction commonly occurring in patients with sleep apnea is unclear. The goal of this study was to investigate whether nerve injuries in the upper airways of snorers and patients with sleep apnea are associated with pharyngeal dysfunction and severity of sleep apnea.Methods: Twenty-two patients undergoing palatal surgery due to snoring and sleep apnea were investigated for a swallowing dysfunction by using videoradiography. Twelve healthy nonsnoring subjects were included as control subjects. Tissue samples from the soft palate at the base of the uvula were obtained in all patients and control subjects. Nerves and muscle were analyzed with immunohistochemical and morphologic methods, and the findings were correlated with swallowing function and degree of sleep apnea.Results: In the soft palate of patients, nerve fascicles exhibited a significantly lower density of axons (5.4 vs 17.9 × 10-3 axons/μm2; P = .02), a smaller percentage area occupied by Schwann cells (17.5% vs 45.2%; P = .001) and a larger number of circular shaped Schwann cells lacking central axons (43.0% vs 12.7%; P < 0.001) compared with control subjects. The low density of axons was significantly related to degree of swallowing dysfunction (r = 0.5; P = .03) and apnea-hypopnea index > 5 (P = .03). Regenerating axons were frequently observed in patients compared with control subjects (11.3 ± 4.2% vs 4.8 ± 2.4%; P = .02).Conclusions: Axon degeneration in preterminal nerves of the soft palate is associated with pharyngeal dysfunction in snorers and patients with sleep apnea. The most likely cause for the nerve injuries is traumatic snoring vibrations and tissue stretch, leading to swallowing dysfunction and increased risk for upper airway obstruction during sleep. [ABSTRACT FROM AUTHOR]

Introduction: Children with cerebral palsy (CP) and acquired brain injury (ABI) commonly develop muscle contractures with advancing age. An underlying growth defect contributing to skeletal muscle contracture formation in CP/ABI has been suggested.Methods: The biceps muscles of children and adolescents with CP/ABI (n = 20) and typically developing controls (n = 10) were investigated. We used immunohistochemistry, quantitative real-time polymerase chain reaction, and Western blotting to assess gene expression relevant to growth and size homeostasis.Results: Classical pro-inflammatory cytokines and genes involved in extracellular matrix (ECM) production were elevated in skeletal muscle of children with CP/ABI. Intramuscular collagen content was increased and satellite cell number decreased and this was associated with reduced levels of RNA polymerase I transcription factors, 45s pre-rRNA and 28S rRNA.Discussion: The present study provides novel data suggesting a role for pro-inflammatory cytokines and reduced ribosomal production in the development/maintenance of muscle contractures, possibly underlying stunted growth and perimysial ECM expansion. Muscle Nerve 58: 277-285, 2018. [ABSTRACT FROM AUTHOR]

Introduction. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease globally. The majority of NAFLD patients have fatty liver without inflammation (nonalcoholic fatty liver, NAFL), whereas a minority develop steatohepatitis (nonalcoholic steatohepatitis, NASH). Only NASH and not NAFL has been considered to increase the risk for fibrosis progression. The present study investigates risk factors for fibrosis progression in patients with NAFLD, and if fibrosis progression associates with subsequent mortality. Material and Methods. All patients with at least two liver biopsies more than a year apart at our hospital between 1971 and 2016 were identified. Data on plausible risk factors for fibrosis progression were collected. Biopsies were scored for the presence of NASH and fibrosis stage. Regression models were used to investigate the association between baseline NASH and fibrosis progression and fibrosis progression with future mortality. Results. 60 patients had undergone serial biopsies (median interval between biopsies 8.4 years, range 1–33 years), with 26 patients (43%) having fibrosis progression. We found no significant risk factors for progression of fibrosis except time between biopsies. Among patients with fibrosis progression, 54% had NAFL and 46% had NASH at baseline. There was a trend for an association between fibrosis progression per se and increased mortality (hazard ratio 2.83, 95% CI 1.0–8.1, p=0.05). Conclusions. In this study on NAFLD, baseline steatohepatitis was not associated with an increased risk for fibrosis progression. NAFLD patients without steatohepatitis may develop progressive fibrosis, and those with progressive fibrosis appear to have a higher mortality risk irrespective of baseline NASH status. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: Prognostication in hepatocellular carcinoma (HCC) is demanding. Not only tumour extent and performance status are to be considered, but also liver function, which is often limiting for both survival itself and for treatment possibilities. This study was conducted to assess whether patient‐reported questionnaires containing general and liver‐specific questions could improve prognostication of survival. Methods: 185 patients with hepatocellular carcinoma in Norway and Sweden were prospectively included. Patients completed the quality‐of‐life questionnaires EORTC QLQ C30 and HCC18, and clinical, radiological and laboratory parameters were registered. Multivariate Cox regression and Harrell's C‐statistics were used to identify the model that best predicted mortality. Results: Quality‐of‐life data were prognostic for overall survival. Fatigue and nutrition scales were prognostic in the multivariable analyses alone and in combination with clinical parameters. The prognostic value of established scoring systems was increased by the addition of QoL data. The best prognostic power was achieved by combining HCC18 nutrition scale with selected background parameters. Conclusion: Quality‐of‐life questionnaires can prognosticate mortality in HCC patients. When combined with established scoring systems, both the general cancer questionnaire EORTC QLQ C30, and the additional liver cancer‐specific HCC18 increased the prognostic accuracy slightly. [ABSTRACT FROM AUTHOR]

Introduction: Muscle changes in patients with diabetes and lower leg pain due to chronic exertional compartment syndrome (CECS) were investigated before and after fasciotomy.Methods: The tibialis anterior muscle was analyzed with histochemical and morphological techniques in 7 patients with diabetes and CECS before fasciotomy and in 5 of them 1 year after fasciotomy. Nondiabetic patients with CECS and healthy participants served as references.Results: Before treatment, walking distance until occurrence of pain was limited (<0.2 km). Intramuscular pressure was significantly higher than in reference participants. Muscle analysis showed changes pathognomonic for neuropathy and myopathy and a restricted capillary network, with significantly more severe changes in the muscles of patients with diabetes than in the muscles of nondiabetic patients. Treatment with fasciotomy improved clinical signs, increased walking ability, and reduced muscle abnormalities, but muscle capillarization remained low.Discussion: Patients with diabetes and CECS have distinct pathological changes in affected muscles. Pressure-relieving fasciotomy triggers a regenerative response in the muscle tissue but not in the capillary bed. Muscle Nerve 57: 229-239, 2018. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a common response to many chronic liver diseases. The aim of our study was to explore whether pharmacotherapy for concurrent diseases affects overall mortality, liver-related mortality and liver-related morbidity in patients with chronic liver disease. We performed a register-based cohort study of all patients with a first-time diagnosis of chronic liver disease between 2005 and 2012 in Sweden (n = 70 546). Data from the Patient Register, the Prescribed Drug Register and the Death Certificate Register were linked. We studied whether the use of statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and antibiotics affected the risk of total mortality, liver-specific mortality and morbidity. We found a reduction in mortality risk for statin users (n = 11,245) with hazard ratios from 0.57 (95% CI: 0.32-0.99) for patients with autoimmune hepatitis to 0.84 (95% CI: 0.75-0.95) for patients with alcoholic liver disease. There was a significantly reduced liver-related mortality for patients with alcoholic liver disease who used angiotensin-converting enzyme inhibitors, 0.85 (95% CI: 0.65-0.96). There were increased overall mortality risks for antibiotic users (n = 44,572), with hazard ratios up to 1.67 (95% CI, 1.55-1.80) for viral hepatitis. Statin use was associated with decreased risks of liver-specific mortality and morbidity, and reduced total mortality foremost among patients with alcoholic liver disease. Angiotensin-converting enzyme inhibitors was associated with reduced liver-related mortality among patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]

Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long‐term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy‐proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0‐29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population‐based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long‐term risk of mortality and liver‐related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow‐up of 19.9 years (range 0.4‐40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P =  0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P =  0.007). Conclusion: Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. (Hepatology Communications 2018;2:48–57) [ABSTRACT FROM AUTHOR]

Background and aims:Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease globally. Advanced fibrosis (stage 3–4) is the most robust marker for future mortality, but diagnosis requires liver biopsy. Current non-invasive scoring systems aimed to identify advanced fibrosis are imperfect. Insulin-like growth factor I (IGF-I) and its binding protein IGFBP-1 are liver derived proteins, that are involved in various liver disorders. The aim of this study was to examine the possible association between advanced fibrosis and IGF-I and IGFBP-1 in NAFLD. Methods:Fasting blood samples were obtained from 52 patients diagnosed with NAFLD by liver biopsy. Total IGF-I and IGFBP-1 concentrations were determined in serum by in-house radio-immuno-assays. IGF-I levels were age-standardized (IGF-SD). A logistic regression model was used to investigate the association of IGF-SD and IGFBP-1 with advanced fibrosis (stage 3–4). Results:Patients with advanced fibrosis (stage 3–4 vs. 0–2) had lower IGF-SD (−1.17 vs. 0.11,p = .01) and higher mean levels of IGFBP-1 (29.9 vs. 18.8 µg/l,p = .02). IGFBP-1 was associated with presence of advanced fibrosis (OR 1.04 per unit increase, 95%CI 1.0–1.07,p = .05), while IGF-1 was negatively associated with advanced fibrosis (OR 0.63 per standard deviation, 95%CI 0.44–0.92,p = .02). Conclusions:This pilot study suggests an association between serum IGFBP-1 and IGF-I levels with advanced fibrosis in NAFLD patients. IGFBP1 and IGF-1 could be of interest as future biomarkers. Similar studies in larger cohorts are needed. [ABSTRACT FROM PUBLISHER]

Background: TNF-alpha is suggested to be involved in muscle damage and muscle inflammation (myositis). In order to evaluate whether TNF-alpha is involved in the myositis that occurs in response to muscle overuse, the aim was to examine the expression patterns of TNF receptors in this condition.Methods: A rabbit muscle overuse model leading to myositis in the soleus muscle was used. The expression patterns of the two TNF receptors Tumor Necrosis Factor Receptor type 1 (TNFR1) and Tumor Necrosis Factor Receptor type 2 (TNFR2) were investigated. In situ hybridization and immunofluorescence were utilized. Immunostainings for desmin, NK-1R and CD31 were made in parallel.Results: Immunoreactions (IR) for TNF receptors were clearly observed in white blood cells, fibroblasts and vessel walls, and most interestingly also in muscle fibers and nerve fascicles in the myositis muscles. There were very restricted reactions for these in the muscles of controls. The upregulation of TNF receptors was for all types of structures seen for both the experimental side and the contralateral nonexperimental side. TNF receptor expressing muscle fibers were present in myositis muscles. They can be related to attempts for reparation/regeneration, as evidenced from results of parallel stainings. Necrotic muscle fibers displayed TNFR1 mRNA and TNFR2 immunoreaction (IR) in the invading white blood cells. In myositis muscles, TNFR1 IR was observed in both axons and Schwann cells while TNFR2 IR was observed in Schwann cells. Such observations were very rarely made for control animals.Conclusions: The findings suggest that there is a pronounced involvement of TNF-alpha in the developing myositis process. Attempts for reparation of the muscle tissue seem to occur via both TNFR1 and TNFR2. As the myositis process also occurs in the nonexperimental side and as TNF receptors are confined to nerve fascicles bilaterally it can be asked whether TNF-alpha is involved in the spreading of the myositis process to the contralateral side via the nervous system. Taken together, the study shows that TNF-alpha is not only associated with the inflammation process but that both the muscular and nervous systems are affected and that this occurs both on experimental and nonexperimental sides. [ABSTRACT FROM AUTHOR]

Altered fucosylation of glycoproteins is associated with development of hepatocellular carcinoma (HCC). Lectins have been commonly used to assay changes in fucosylation of plasma glycoproteins. In the present study a recombinantly engineered form of the fucose binding lectin Aleuria aurantia (AAL) consisting of a single binding site for fucose (S2), was used to construct a reverse lectin ELISA method. Microtiter plates coated with the S2 lectin were used to capture glycoproteins from plasma samples followed by antibody detection of S2-bound fucosylated α1-acid glycoprotein (S2-bound AGP). The method was used to compare the level of S2-bound AGP in serum samples from a small cohort of patients with hepatitis, cirrhosis or HCC. Using the reverse S2 lectin ELISA it was shown that the levels of S2-bound AGP was significantly higher in HCC patients compared to non-cancer patients and that there was also a significant elevation of S2-bound AGP in HCC patients compared to cirrhosis patients. There was no correlation between the level of S2-bound AGP and total AGP concentration. The performance of S2-bound AGP in differentiating HCC from cirrhosis samples or hepatitis samples were compared to other markers. A combination of S2-bound AGP, α-fetoprotein and AGP concentration showed performances giving area under receiver operating curves of 0.87 and 0.95 respectively. [ABSTRACT FROM AUTHOR]

Background and aim:Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD. Methods:We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled. Results:An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76–0.97;p = .017). The lowest risk for fibrosis was found with the lowes`t odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08–0.66;p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth ≥0.3 μmol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01–7.59;p = .047). Conclusion:Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis. [ABSTRACT FROM PUBLISHER]