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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 (EA) aged 82-92 years, and nineteen subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87-91 years 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 P0.05). 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 (P0.05). 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 the preservation of muscle oxidative capacity, even beyond the age of 80.

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. Funding Agencies|Stockholm county; Swedish Cancer Foundation

Current risk estimates for hepatocellular carcinoma (HCC) in individuals with cirrhosis vary between studies. The risk has mostly been evaluated for single etiologies separately.We examined the risk of HCC in Swedish outpatients with a new diagnosis of cirrhosis, aiming to identify subgroups with a particularly high risk for incident HCC.All patients with a first diagnosis of cirrhosis in the National Outpatient Register for whom the etiology of cirrhosis could be estimated were identified. Incident cases of HCC were ascertained until the end of 2016 using record linkage to national registers. The cumulative incidence of HCC across etiologies of cirrhosis, sex and age was calculated considering non-HCC death as a competing risk.We identified 15,215 individuals with cirrhosis. The incidence rate for HCC in cirrhosis was 23/1000 person-years (95%CI = 22-24). Stratified on gender, it was 29/1000 person-years (95%CI = 27-31) in men versus 14/1000 person-years (95%CI = 13-16) in women. The cumulative incidence of HCC in cirrhosis was 8.3% (95%CI = 7.8-8.8) at 5 years and 12.2% (95%CI = 11.6-13.0) at 10 years. At 10 years, the lowest cumulative incidence was seen in women with alcohol-related liver disease (4.3%) and the highest in men with viral hepatitis (26.6%). These figures also varied by age.The risk of HCC differs extensively across subgroups of etiologies of cirrhosis, age and sex, suggesting that initiation of HCC surveillance could be individually tailored.

Vocal signals mediate much of human and non-human communication. Key performance traits - such as repertoire size, speed and accuracy of delivery - affect communication efficacy in fitness-decisive contexts such as mate choice and resource competition1. Specialized fast vocal muscles2,3are central to accurate sound production4, but it is unknown whether vocal, like limb muscles5,6, need exercise to gain and maintain peak performance7,8. Here, we show that for song development in juvenile songbirds, the closest analogue to human speech acquisition9, regular vocal muscle exercise is crucial to achieve adult peak muscle performance. Furthermore, adult vocal muscle performance reduces within two days of abolishing exercise, leading to downregulation of critical proteins transforming fast to slower muscle fibre types. Daily vocal exercise is thus required to both gain and maintain peak vocal muscle performance, and if absent changes vocal output. We show that conspecifics can detect these acoustic changes and females prefer the song of exercised males. Song thus contains information on recent exercise status of the sender. Daily investment in vocal exercise to maintain peak performance is an unrecognized cost of singing and could explain why many birds sing daily even under adverse conditions10. Because neural regulation of syringeal and laryngeal muscle plasticity is equivalent, vocal output may reflect recent exercise status in all vocalizing vertebrates.

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.

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 2). 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

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,Patients with AC had an increased hazard ratio (HR) for death after LT (crude HR: 4.05, 95% CI: 1.07-15.33,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.

Background and Hypothesis: Isolated malleus shaft fractures are rare cases. A commonly reported cause is a finger pulled out from a wet outer ear canal after a shower or bath. The objective was to investigate experimentally the mechanism and forces needed to establish an isolated malleus shaft fracture. Methods: Ten fresh-frozen human temporal bones were adapted to allow visual inspection of the structures involved while negative pressure trauma was applied. Thirty malleus bones were broken and the required forces were measured. Measurements from 60 adult test subjects were used to create mathematical and physical models to calculate and measure the forces necessary for generating trauma. To calculate the maximum muscle force developed by the tensor tympani muscle, the muscle area and fiber type composition were determined. Results: The temporal bone experiments showed that applied negative pressure in a wet ear canal could not fracture the malleus shaft with only passive counterforce from supporting structures, although the forces exceeded what was required for a malleus shaft fracture. When adding calculated counteracting forces from the tensor tympani muscles, which consisted of 87% type II fibers, we estimate that a sufficient force is generated to cause a malleus fracture. Conclusion: The combination of a negative pressure created by a finger pulling outward in a wet ear canal and a simultaneous counteracting reflexive force by the tensor tympani muscle were found to be sufficient to cause an isolated malleus fracture with an intact tympanic membrane.

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, I-2 = 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.

AIM To provide a detailed gene and protein expression analysis related to mitochondrial biogenesis and assess mitochondrial content in skeletal muscle of children with cerebral palsy (CP). METHOD Biceps brachii muscle samples were collected from 19 children with CP (mean [SD] age 15y 4mo [2y 6mo], range 9-18y, 16 males, three females) and 10 typically developing comparison children (mean [SD] age 15y [4y], range 7-21y, eight males, two females). Gene expression (quantitative reverse transcription polymerase chain reaction [PCR]), mitochondrial DNA (mtDNA) to genomic DNA ratio (quantitative PCR), and protein abundance (western blotting) were analyzed. Microarray data sets (CP/aging/bed rest) were analyzed with a focused query investigating metabolism- and mitochondria-related gene networks. RESULTS The mtDNA to genomic DNA ratio was lower in the children with CP compared to the typically developing group (-23%, p=0.002). Out of five investigated complexes in the mitochondrial respiratory chain, we observed lower protein levels of all complexes (I, III, IV, V, -20% to -37%; p

Post-hepatectomy liver failure (PHLF) is the leading cause of postoperative mortality following major liver resection. Between December 2012 and May 2015, 10 consecutive patients with PHLF (according to the Balzan criteria) following major/extended hepatectomy were included in a prospective treatment study with the molecular adsorbent recirculating system (MARS). Sixty- and 90-day mortality rates were 0% and 10%, respectively. Of the nine survivors, four still had liver dysfunction at 90 days postoperatively. One-year overall survival (OS) of the MARS-PHLF cohort was 50%. The present study aims to assess long-term outcome of this cohort compared to a historical control cohort.To compare long-term outcome of the MARS-PHLF treatment cohort with PHLF patients not treated with MARS, the present study includes all 655 patients who underwent major hepatectomy at Karolinska University Hospital between 2010 and 2018. Patients with PHLF were identified according to the Balzan criteria.The cohort was split into three time periods: pre-MARS period (MARS treatment may contribute to improved outcome of patients with PHLF. Further studies are needed.The initial pilot study was registered at ClinicalTrials.gov (NCT03011424).

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.

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 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

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 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.

BACKGROUND AND AIMS It is unclear if improving glycemic control in persons with type 2 diabetes (T2D) also has liver-related effects. We aimed to evaluate if a personalized treatment program associates with improvement of liver-related parameters in persons with advanced T2D in a real-life setting. METHODS Persons with advanced T2D underwent a 4-day personalized treatment program, with the aim of improving glycemic control by dietary advice, instructions on how to achieve optimal glucose control and individualized dosage of medications. Transient elastography was used to estimate liver steatosis and fibrosis. Persons with liver diseases other than non-alcoholic fatty liver disease (NAFLD) were excluded. After 3 months, study participants were offered re-examination. RESULTS Ninety-one persons were included. Of these, 75 persons (82%) had controlled attenuation parameter (CAP) measurements of acceptable quality at baseline. Of these, 57 (76%) had NAFLD (defined as >268 dB/m). Twenty-two persons (24%) had elevated liver stiffness (>7.9 kPa), and eight (9%) had liver stiffness above 13.9 kPa, indicating advanced fibrosis. Over a median follow-up of 101 days, mean CAP in persons with NAFLD was reduced by 18.33 dB/m (P = 0.035). In persons with elevated liver stiffness, mean stiffness was reduced by 2.6 kPa (P = 0.047). In linear regression, one-unit improvement in fasting glucose (mg/dl) was associated with a decrease in hepatic steatosis with 0.48 dB/m (adjusted R2 = 0.35, P < 0.01). CONCLUSION The prevalence of NAFLD with advanced fibrosis is high in persons with advanced T2D. Improving glycemic control through a personalized treatment program is associated with a reduction in liver steatosis and stiffness in this cohort.

The building blocks of DNA, dNTPs, can be produced de novo or can be salvaged from deoxyribonucleosides. However, to what extent the absence of de novo dNTP production can be compensated for by the salvage pathway is unknown. Here, we eliminated de novo dNTP synthesis in the mouse heart and skeletal muscle by inactivating ribonucleotide reductase (RNR), a key enzyme for the de novo production of dNTPs, at embryonic day 13. All other tissues had normal de novo dNTP synthesis and theoretically could supply heart and skeletal muscle with deoxyribonucleosides needed for dNTP production by salvage. We observed that the dNTP and NTP pools in WT postnatal hearts are unexpectedly asymmetric, with unusually high dGTP and GTP levels compared with those in whole mouse embryos or murine cell cultures. We found that RNR inactivation in heart led to strongly decreased dGTP and increased dCTP, dTTP, and dATP pools; aberrant DNA replication; defective expression of muscle-specific proteins; progressive heart abnormalities; disturbance of the cardiac conduction system; and lethality between the second and fourth weeks after birth. We conclude that dNTP salvage cannot substitute for de novo dNTP synthesis in the heart and that cardiomyocytes and myocytes initiate DNA replication despite an inadequate dNTP supply. We discuss the possible reasons for the observed asymmetry in dNTP and NTP pools in WT hearts.

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 ...

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

4109 Background: Pembrolizumab monotherapy showed durable antitumor activity and a manageable safety profile in patients with sorafenib-treated (cohort 1) and treatment-naive (cohort 2) aHCC in the open-label, phase 2 KEYNOTE-224 (NCT02702414) study. Longer term data from KEYNOTE-224 after ̃3 years of follow-up for patients with treatment-naive aHCC are reported. Methods: Eligible patients in cohort 2 had histologically, cytologically, or radiologically confirmed aHCC, Barcelona Clinic Liver Cancer stage C or B not amenable or refractory to locoregional therapy and not amenable to curative treatment, Child-Pugh A liver function, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for ≤35 cycles (̃2 years). Primary end point was ORR assessed per RECIST v1.1 by BICR. Secondary end points included DOR, DCR, TTP, and PFS, all assessed per RECIST v1.1 by BICR, OS, and safety/tolerability. Results: All 51 patients enrolled in cohort 2 received ≥1 dose of pembrolizumab. Median follow-up, defined as the time from first dose to the data cutoff (October 1, 2021), was 35 months (range, 31-37). ORR was 16% (95% CI, 7-29). Median DOR was not reached (NR; range, 3 to 24+ months); 58% of responders were estimated to have a response duration ≥18 months. Best overall response was 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; no CRs were observed and response was not evaluable for 2 patients (4%) and not assessed for 3 patients (6%). DCR was 57% (95% CI, 42-71). ORR was generally consistent among patients with a viral and nonviral etiology for HCC, although sample sizes were small. The median TTP was 4 months (95% CI, 3-9). Median PFS was 4 months (95% CI, 2-8). Estimated PFS rate at 24 months was 15%. Median OS was 17 months (95% CI, 8-23). Estimated OS rate at 24 months was 34%. No new or unexpected adverse events (AEs) occurred. Treatment-related AEs were reported in 28 patients (55%; grade 3-5, 8 [16%]). Conclusions: Updated results from cohort 2 of the KEYNOTE-224 study continued to demonstrate durable antitumor activity, promising OS, and manageable safety for pembrolizumab monotherapy in patients with aHCC and no prior systemic therapy. These data, together with recent positive results from KEYNOTE-394, underscore the broad applicability of pembrolizumab in patients with aHCC both as monotherapy and in combination with other therapies. Clinical trial information: NCT02702414.

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.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?Thirty-three patients (mean age 66 ± 7 years; FEVSingle-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.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.ClinicalTrials.gov; No.: NCT02283580; URL: www.clinicaltrials.gov.

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, Parkinsons 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 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. Funding Agencies|Stockholm Count Council; Swedish Gastrointestinal Foundation; Tore Nilssons Foundation for medical research; Ruth and Richard Julin Foundation; Stockholm County CouncilStockholm County Council [K2017-4579, ALF LS 2019-0064]; Center for innovative medicine [CIMED 20180889]; Swedish Cancer SocietySwedish Cancer Society [170690]

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 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.

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 surv ...

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. MethodResultsPopulation-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 25kg/m(2) 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. 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). ConclusionNAFLD 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.

Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'"

Simple Summary Hepatocellular carcinoma (HCC) causes many deaths worldwide, and current treatments have limitations. Immunotherapies have shown the most promising clinical outcomes for advanced HCC. However, there are many patients with HCC who still respond poorly to these treatments. Circulating biomarkers that can easily be obtained through blood sampling are promising in predicting treatment responses, since they are minimally invasive and enable us to constantly monitor disease progression. The aim of this review is to discuss the most promising types of blood-based biomarkers for the diagnosis and prognosis of HCC, with the focus on circulating tumor cells and circulating tumor DNA. We also discuss technologies for detecting these biomarkers, as well as their clinical applications for immunotherapies in HCC. We conclude that despite their encouraging results to accurately predict responses to immunotherapies, more and larger clinical studies are still necessary, in order to improve the precision of biomarkers, which are used in the treatment decision for patients with HCC. Abstract Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.

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.

Background & Aims Nonalcoholic fatty liver disease (NAFLD) is a strong risk factor for development of type 2 diabetes, but little is known about how long-term NAFLD or its histologic features affect risk. We aimed to investigate the cumulative incidence of type 2 diabetes in patients with NAFLD and to identify histologic factors that affect risk of diabetes. Methods We performed a retrospective study of 396 patients in Sweden diagnosed with NAFLD by biopsy analysis from 1971 through 2009 who did not have type 2 diabetes at baseline. Data on development of type 2 diabetes were collected from patient charts and national registers. Patients were categorized into groups with fibrosis stages 0–2 (n = 357) or stages 3–4 (n = 39). Hazard ratios of histologic parameters for type 2 diabetes development were calculated separately in a multivariate Cox regression model adjusted for sex, age, body mass index, and serum levels of triglycerides greater than 150 mg/dL. Results During a mean follow-up period of 18.4 years (range, 0–41 years), 132 individuals (33%) developed type 2 diabetes. A significantly higher proportion of patients with fibrosis stages 3–4 (51.2%) developed type 2 diabetes than patients with fibrosis stages 0–2 (31.3%) ( P = .02). For patients with fibrosis stages 0–2, fat score associated independently with development of type 2 diabetes (adjusted hazard ratio, 1.34; 95% confidence interval, 1.03–1.74; P = .03). No histologic factors associated with development of diabetes in patients with fibrosis stages 3–4. Presence of nonalcoholic steatohepatitis was not associated with development of type 2 diabetes. Conclusions In a retrospective study we found a higher proportion of patients with fibrosis stages 3–4 to develop type 2 diabetes than patients with fibrosis stages 0–2. In patients with fibrosis stages 0–2, fat score associates with risk of type 2 diabetes.

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.

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 ...

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all-cause and liver-related mortality in NAFLD. Through a systematic review and meta-analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0-4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all-cause and liver-related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow-up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all-cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19-2.11); stage 2, MRR = 2.52 (95% CI 1.85-3.42); stage 3, MRR = 3.48 (95% CI 2.51-4.83); and stage 4, MRR = 6.40 (95% CI 4.11-9.95). The results were more pronounced as the risk of liver-related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17-11.95); stage 2, MRR = 9.57 (95% CI 1.67-54.93); stage 3, MRR = 16.69 (95% CI 2.92-95.36); and stage 4, MRR = 42.30 (95% CI 3.51-510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver-related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (Hepatology 2017;65:1557-1565).

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 alcoho...

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.

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is common in the general population, but its association with dementia is unclear. We aimed to assess the risk of dementia related to NAFLD, and to determine whether histological parameters could improve the predictive capacity of a conventional risk model for dementia in patients with biopsy-proven NAFLD. Methods A retrospective matched cohort study of 656 NAFLD patients underwent liver biopsy at 2 hospitals between 1971 and 2009. Up to 10 individuals (controls) from the general population (n = 6,436) were matched for age, sex, and municipality to each patient. Dementia was ascertained from National registers until 2014. Using Cox regression, we estimated hazard ratios for dementia with 95% confidence intervals. In the biopsy cohort, the discriminative power of adding histological markers to a conventional risk model was assessed by Harrell’s C-index and compared with a likelihood-ratio test. Results During a mean follow-up of 19.7 ± 8.7 years, 3.3% of the NAFLD patients and 4.9% of the controls developed dementia (p = 0.07). Overall, NAFLD was not significantly associated with incident dementia. In the biopsy cohort, the model of conventional risk factors (age, sex, hypertension, and cardiovascular diseases) had a C-index of 0.912 to predict incident dementia. Adding individual histological parameters significantly increased the prediction of dementia, with the most pronounced improvement for fibrosis stage (C-index = 0.938, p, Graphical abstract, Highlights • The link between NAFLD and dementia is unclear. • We assessed the association between biopsy-proven NAFLD and dementia. • NAFLD is not associated with an increased risk of dementia. • Adding histological markers to a conventional risk model for dementia enhanced its predictive capacity.

297 Background: Results from cohort 1 of KEYNOTE-224, an open-label, single-arm, multi-country phase II trial, demonstrated that pembro monotherapy was efficacious and tolerable in patients (pts) with advanced HCC previously treated with sorafenib. Here, we report results from KEYNOTE-224 cohort 2, which enrolled pts with advanced HCC and no prior systemic therapy. Methods: Eligible pts in cohort 2 had radiologically, histologically, or cytologically confirmed, incurable HCC not amenable or refractory to locoregional therapy, Child Pugh A liver disease, measurable disease based on RECIST 1.1 by blinded independent central review (BICR), ECOG PS 0-1, and BCLC stage C or B. Pts received pembro 200 mg IV Q3W for ~2 years or until disease progression, unacceptable toxicity, consent withdrawal, or investigator decision. Primary endpoint was ORR (RECIST 1.1 by BICR). Secondary endpoints included DOR, DCR, TTP, PFS, OS, and safety/tolerability. Response was assessed every 9 weeks. Efficacy and safety were assessed in pts who received ≥1 dose of study treatment. DOR was assessed in responders. The estimate and 95% CI of the ORR and DCR were based on the Clopper-Pearson method. Kaplan-Meier method was used to estimate OS, PFS, and DOR. A sample size of ~50 pts was chosen to provide acceptable precision for the assessment of ORR. Results: Cohort 2 enrolled 51 pts. The median time from the first dose to data cutoff (July 31, 2020) was 21 (range, 17-23) mo. The median age of pts was 68 (range, 41-91) years, one pt was HBV+, 80% had alcohol use, 8% were HCV+, 18% had vascular invasion, 35% had extrahepatic disease, 33% had BCLC Stage B disease, and 67% had BCLC Stage C HCC. ORR was 16% (95% CI, 7-29) and was similar across most subgroups. Median DOR was not reached (range, 3-20+ mo); 70% were estimated to have response duration ≥12 mo. Best overall responses were 0 CR, 8 (16%) PRs, 21 (41%) SDs, and 17 (33%) PDs; response was not evaluable or not assessed for 5 (10%) pts. DCR was 57%. The median TTP was 4 (95% CI, 3-8) mo. The median PFS was 4 (95% CI, 2-6) mo, and median OS was 17 (95% CI, 8-NA) mo. PFS rate at 18 mo was 16%, and OS rate at 18 mo was 46%. Treatment-related AEs (TRAEs) occurred in 27 (53%) pts; the most common TRAEs were diarrhea, fatigue, hypothyroidism, and myalgia. Grade ≥3 TRAEs occurred in 7 (14%) pts. TRAEs led to treatment discontinuation in 6% of pts. Immune-mediated AEs and infusion reactions occurred in 11 (22%) pts. One treatment-related death occurred due to myocarditis, with associated immune-related hepatitis. Conclusions: In pts with advanced HCC and no prior systemic therapy, pembro monotherapy provided durable anti-tumor activity, promising overall survival, and demonstrated a safety profile consistent with that previously observed for pembro in advanced HCC. These findings support further evaluation of pembro-based regimens for the treatment of HCC in the frontline setting. Clinical trial information: NCT02702414.

BACKGROUND & AIMS High levels of ferritin in patients with non-alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD. METHODS We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into 'high' (n = 89) and 'normal' (n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality were obtained from a national, population-based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy. RESULTS The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin (P < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, P < 0.05). There was no difference in mortality between patients with different iron overload patterns. CONCLUSIONS High levels of ferritin are associated with a long-term increased risk of death.

Data on healthcare resource use and costs associated with nonalcoholic fatty liver disease (NAFLD) in clinical practice are lacking. We compared real-life healthcare costs of patients with NAFLD to matched controls.We performed a retrospective study of 646 patients with biopsy-proven NAFLD in Sweden from 1971 through 2009. Each patient was matched for age, sex, and county of residence with 10 persons from the general population (controls). We retrieved all healthcare contacts through Dec 31, 2014 from national registers. Unit costs were assigned to arrive at a total healthcare cost (in USD [$]) per study subject.During a mean follow-up of 19.9 years, we recorded a mean of 0.27 hospitalizations per year for patients with NAFLD vs 0.16 for controls (P.001). This corresponded to an incremental cost of $635 per year for patients with NAFLD. Patients with NAFLD had a higher mean use of outpatient care visits: 1.46 contacts per year compared with 0.86 per year in controls, corresponding to $255 in additional costs (P.001). Total costs incurred by patients with stage 3-4 fibrosis were higher than by patients with fibrosis stage 0-2 (mean annual costs, $4397 vs $629). Cumulative costs were higher for all stages of fibrosis compared to controls.Healthcare costs are nearly twice as high in patients with NAFLD than in matched controls. This is mostly attributable to higher costs for hospitalizations, but also to more outpatient visits. Patients with advanced fibrosis had the highest costs.

to determine if tooth loss and dental implant placement in rats induce changes in the morphological and histochemical features of the Anterior Digastric muscle.Adult male Sprague-Dawley rats had their right maxillary molar teeth extracted. 'Extraction-1' and 'Extraction-2 groups were sacrificed, respectively, 4 or 8 weeks later, and an Implant group had an implant placement 2 weeks after the molar extraction, and rats were sacrificed 3 weeks later (n = 4/group). Naive rats (n = 3) had no treatment. Morphometric and immunohistochemical techniques quantified Anterior Digastric muscle myofibres' cross-sectional area (CSA) and myosin heavy chain (MyHC) isoform proportions. Significant ANOVAs were followed by post-hoc tests; p 0.05 and 0.1 were considered to reflect levels of statistical significance.In naïve rats, the peripheral regions of the Anterior Digastric muscle was dominated by MyHC-IIx/b isoform and there were no MyHC-I isoforms; the central regions dominated by MyHC-IIx/b and MyHC-IIa isoforms. Compared with naive rats, tooth extraction produced, 8 (but not 4) weeks later, a decreased proportion of fast-contracting fatigue-resistant MyHC-IIa isoform (p = 0.08), and increased proportion of fast and intermediate fatigue-resistance MyHC-IIa/x/b isoform (p = 0.03). Dental implant placement following tooth extraction attenuated the extraction effects but produced a decreased proportion of fast-contracting fatiguable MyHC-llx/b isoform (p = 0.03) in the peripheral region, and increased inter-animal variability in myofibre-CSAs.Given the crucial role that the Anterior Digastric muscle plays in many vital oral functions (e.g., chewing, swallowing), these changes may contribute to the changes in oral sensorimotor functions that occur in humans following such treatments.

Purpose To develop and evaluate a triple arterial phase CT liver protocol with a similar radiation dose to that of standard single arterial phase CT in study subjects suspected of having hepatocellular carcinoma (HCC). Materials and Methods The study consisted of a retrospective part A for protocol development (n = 15) and a prospective part B to evaluate diagnostic accuracy (n = 38). All 53 participants underwent perfusion CT with 50 mL contrast material between August 2013 and September 2014. Group B underwent an additional standard multiphasic liver CT examination with 120 mL of contrast material (range, 70-143 mL). Image sets from triple arterial phase imaging were reconstructed from perfusion CT by fusing images from three dedicated arterial time points. Triple arterial phase CT and standard single arterial phase CT were compared by two readers, who assessed subjective image quality and HCC detection rate. A third reader served as reference reader and assessed objective image quality. The paired Student t test, Wilcoxon signed rank test, jackknife alternative free-response receiver operating characteristic (JAFROC), and JAFROC curve were applied. Results The mean volume CT dose index was 11.6 mGy for triple arterial phase CT and 11.9 mGy for standard single arterial phase CT (P = .73). Triple arterial phase CT showed lower image noise and better contrast-to-noise ratio compared with standard single arterial phase CT (P < .001 and P = .032, respectively); however, there was no significant difference in lesion-to-liver-contrast ratio (P = .31). Subjective image quality was good for both protocols. The detection rate of the 65 HCC lesions was 82% for reader 1 and 83% for reader 2 at triple arterial phase CT and 80% for reader 1 and 77% for reader 2 at standard single arterial phase CT (P = .4). Conclusion Triple arterial phase imaging is feasible at the same radiation dose as that used for standard single arterial phase CT. Triple arterial phase imaging provides equivalent to superior image quality and equal HCC detection rate despite the use of less than half the contrast material dose used at standard single arterial phase CT. © RSNA, 2018.

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.

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

Background One-third of patients with non-alcoholic fatty liver disease (NAFLD) develop dysmetabolic iron overload syndrome (DIOS), the pathogenesis of which is unknown. Altered production of the iron-regulatory peptide hepcidin has been reported in NAFLD, but it is unclear if this is related to iron accumulation, lipid status or steatohepatitis. Methods Eighty-four patients with liver disease, 54 of which had iron overload, underwent liver biopsy (n = 66) and/or magnetic resonance imaging (n = 35) for liver iron content determination. Thirty-eight of the patients had NAFLD, 29 had chronic liver disease other than NAFLD, and 17 had untreated genetic hemochromatosis. Serum hepcidin was measured with ELISA in all patients and in 34 controls. Hepcidin antimicrobial peptide (HAMP) mRNA in liver tissue was determined with real-time-quantitative PCR in 36 patients. Results Serum hepcidin was increased similarly in NAFLD with DIOS as in the other chronic liver diseases with iron overload, except for genetic hemochromatosis. HAMP mRNA in liver tissue, and serum hepcidin, both correlated to liver iron content in NAFLD patients (r 2 = 0.45, p

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.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.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.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.

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 x 10(-3) axons/mu m(2); 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.

The human oropharyngeal muscles have a unique anatomy with diverse and intricate functions. To investigate if this specialization is also reflected in the cytoarchitecture of muscle fibers, intermediate filament proteins and the dystrophin‐associated protein complex have been analyzed in two human palate muscles, musculus uvula (UV) and musculus palatopharyngeus (PP), with immunohistochenmical and morphological techniques. Human limb muscles were used as reference. The findings show that the soft palate muscle fibers have a cytoskeletal architecture that differs from the limb muscles. While all limb muscles showed immunoreaction for a panel of antibodies directed against different domains of cytoskeletal proteins desmin and dystrophin, a subpopulation of palate muscle fibers lacked or had a faint immunoreaction for desmin (UV 11.7% and PP 9.8%) and the C‐terminal of the dystrophin molecule (UV 4.2% and PP 6.4%). The vast majority of these fibers expressed slow contractile protein myosin heavy chain I. Furthermore, an unusual staining pattern was also observed in these fibers for β‐dystroglycan, caveolin‐3 and neuronal nitric oxide synthase nNOS, which are all membrane‐linking proteins associated with the dystrophin C‐terminus. While the immunoreaction for nNOS was generally weak or absent, β‐dystroglycan and caveolin‐3 showed a stronger immunostaining. The absence or a low expression of cytoskeletal proteins otherwise considered ubiquitous and important for integration and contraction of muscle cells indicate a unique cytoarchitecture designed to meet the intricate demands of the upper airway muscles. It can be concluded that a subgroup of muscle fibers in the human soft palate appears to have special biomechanical properties, and their unique cytoarchitecture must be taken into account while assessing function and pathology in oropharyngeal muscles.