Bi-Gaussian analysis reveals distinct education-related alterations in spherical equivalent and axial length-results from the Gutenberg Health Study.

PURPOSE: The aim of this study is to investigate the distribution of spherical equivalent and axial length in the general population and to analyze the influence of education on spherical equivalent with a focus on ocular biometric parameters. METHODS: The Gutenberg Health Study is a population-based cohort study in Mainz, Germany. Participants underwent comprehensive ophthalmologic examinations as part of the 5-year follow-up examination in 2012-2017 including genotyping. The spherical equivalent and axial length distributions were modeled with gaussian mixture models. Regression analysis (on person-individual level) was performed to analyze associations between biometric parameters and educational factors. Mendelian randomization analysis explored the causal effect between spherical equivalent, axial length, and education. Additionally, effect mediation analysis examined the link between spherical equivalent and education. RESULTS: A total of 8532 study participants were included (median age: 57 years, 49% female). The distribution of spherical equivalent and axial length follows a bi-Gaussian function, partially explained by the length of education (i.e., < 11 years education vs. 11-20 years). Mendelian randomization indicated an effect of education on refractive error using a genetic risk score of education as an instrument variable (- 0.35 diopters per SD increase in the instrument, 95% CI, - 0.64-0.05, p = 0.02) and an effect of education on axial length (0.63 mm per SD increase in the instrument, 95% CI, 0.22-1.04, p = 0.003). Spherical equivalent, axial length and anterior chamber depth were associated with length of education in regression analyses. Mediation analysis revealed that the association between spherical equivalent and education is mainly driven (70%) by alteration in axial length. CONCLUSIONS: The distribution of axial length and spherical equivalent is represented by subgroups of the population (bi-Gaussian). This distribution can be partially explained by length of education. The impact of education on spherical equivalent is mainly driven by alteration in axial length.

Web-Based Exercise as an Effective Complementary Treatment for Patients With Nonalcoholic Fatty Liver Disease: Intervention Study.

BACKGROUND: Physical inactivity is a major risk factor for nonalcoholic fatty liver disease (NAFLD). Exercise-based prevention interventions for improving cardiorespiratory fitness are a recommended complementary treatment for NAFLD. Achievement of minimally effective physical activity to improve cardiorespiratory fitness among patients typically involves high personal and financial expenses in face-to-face settings. We designed an eHealth approach for patients with NAFLD to improve the cardiorespiratory fitness and report the first results of the HELP (Hepatic Inflammation and Physical Performance in Patients With NASH [nonalcoholic steatohepatitis]) study. OBJECTIVE: We aimed to assess the effectiveness of an 8-week, tailored, Web-based exercise intervention for cardiorespiratory fitness improvement, expressed as peak oxygen uptake (peak volume of oxygen [VO2peak]), in patients with histologically confirmed NAFLD. METHODS: In a 24-month period, 44 patients were enrolled into an 8-week, prospective, single-arm study with 12 weeks of follow-up. After a medical examination and performance diagnostics, a sports therapist introduced the patients to a Web-based platform for individualized training support. Regular individual patient feedback was provided to systematically adapt the weekly exercise schedule, which allowed us to monitor and ensure patient adherence to strength and endurance training and optimize the step-wise progressive exercise load. Exercise progression was based on an a priori algorithm that considered the subjective rate for both perceived exhaustion and general physical discomfort. The VO2peak was assessed at baseline and at the end of the study by spiroergometry. RESULTS: A total of 43 patients completed the intervention with no adverse events. The VO2peak increased significantly by 2.4 mL/kg/min (8.8%; 95% confidence interval [CI]: 1.48-3.27; P<.001) accompanied by a reduction of 1.0 kg in a body weight (95% CI: 0.33-1.58; P=.004) and 1.3 kg in body fat mass (95% CI: 0.27-2.27; P=.01). In an exploratory analysis, step-wise logistic regression analysis revealed low body fat and VO2peak at baseline and the total minutes of endurance training during the intervention as main contributors to a positive change in VO2peak. Our predictive model indicated that the average patient with NAFLD needed 223 min for stabilization of VO2peak and 628 min for average improvement in VO2peak. However, in patients with a VO2peak approximately 20% higher than the average VO2peak, 628 min were only sufficient to stabilize the VO2peak and >40% reduction in the average fat mass would be required to achieve an average outcome. CONCLUSIONS: This is the first study to show that patients with NAFLD can be effectively supported by a Web-based approach, which can increase the VO2peak to a similar extent as face-to-face interventions. Patients with low body fat and low VO2peak benefited the most from our intervention. In terms of future treatment strategies, NAFLD patients with high body fat may particularly benefit from body-fat reduction through a strict nutritional intervention, subsequently enabling a more effective exercise intervention. TRIAL REGISTRATION: ClinicalTrials.gov NCT02526732; https://clinicaltrials.gov/ct2/show/NCT02526732 (Archived by WebCite at http://www.webcitation.org/74pXhXXfq). INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.8607.

Cytokeratin-18 fragments predict treatment response and overall survival in gastric cancer in a randomized controlled trial.

BACKGROUND: Gastric cancer is common malignancy and exhibits a poor prognosis. At the time of diagnosis, the majority of patients present with metastatic disease which precludes curative treatment. Non-invasive biomarkers which discriminate early from advanced stages or predict the response to treatment are urgently required. This study explored the cytokeratin-18 fragment M30 and full-length cytokeratin-18 M65 in predicting treatment response and survival in a randomized, placebo-controlled trial of advanced gastric cancer. METHODS: Patients enrolled in the SUN-CASE study received sunitinib or placebo as an adjunct to standard therapy with leucovorin (Ca-folinate), 5-fluorouracil, and irinotecan in second or third line. Treatment response rates, progression-free survival and overall survival were assessed during a follow-up period of 12 months. Cytokeratin-18 fragments were analyzed in 52 patients at baseline and day 14 of therapy. RESULTS: Levels of M30 correlated with the presence of metastasis and lymph node involvement and decreased significantly during chemotherapy. Importantly, baseline levels of M30 were significantly higher in patients who failed therapy. In addition, patients who did not respond to treatment were also identifiable at day 14 based on elevated M30 levels. By stepwise regression analysis, M30 at day 14 was identified as independent predictor of treatment response. Likewise, serum levels of full-length cytokeratin-18 M65 at baseline also correlated with treatment failure and progression-free survival. The addition of sunitinib did not exert any effects on serum levels of M30 or M65. CONCLUSION: The cytokeratin-18 fragment M30 at day 14 identifies patients that fail to second- or third-line therapy for advanced gastric cancer. Validation of this non-invasive biomarker in gastric cancer is warranted.

Insulin resistance alters hepatic ethanol metabolism: studies in mice and children with non-alcoholic fatty liver disease.

OBJECTIVE: Increased fasting blood ethanol levels, suggested to stem from an increased endogenous ethanol synthesis in the GI tract, are discussed to be critical in the development of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to further delineate the mechanisms involved in the elevated blood ethanol levels found in patients with NAFLD. DESIGN: In 20 nutritionally and metabolically screened children displaying early signs of NAFLD and 29 controls (aged 5-8 years), ethanol plasma levels were assessed. Ethanol levels along the GI tract, in vena cava and portal vein, intestinal and faecal microbiota, and activity of alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) were measured in wild-type, ob/ob and anti-TNFα antibody (aT) treated ob/ob mice. RESULTS: Despite not differing in dietary pattern or prevalence of intestinal overgrowth, fasting ethanol levels being positively associated with measures of insulin resistance were significantly higher in children with NAFLD than in controls. Ethanol levels were similar in portal vein and chyme obtained from different parts of the GI tract between groups while ethanol levels in vena cava plasma were significantly higher in ob/ob mice. ADH activity was significantly lower in liver tissue obtained from ob/ob mice in comparison to wild-type controls and ob/ob mice treated with aT. CONCLUSIONS: Taken together, our data of animal experiments suggest that increased blood ethanol levels in patients with NAFLD may result from insulin-dependent impairments of ADH activity in liver tissue rather than from an increased endogenous ethanol synthesis. TRIAL REGISTRATION NUMBER: NCT01306396.

Multicompartment Polyion Complex Micelles Based on Triblock Polypept(o)ides Mediate Efficient siRNA Delivery to Cancer-Associated Fibroblasts for Antistromal Therapy of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and the third leading cause for cancer-related death worldwide. The tumor is difficult-to-treat due to its inherent resistance to chemotherapy. Antistromal therapy is a novel therapeutic approach, targeting cancer-associated fibroblasts (CAF) in the tumor microenvironment. CAF-derived microfibrillar-associated protein 5 (MFAP-5) is identified as a novel target for antistromal therapy of HCC with high translational relevance. Biocompatible polypept(o)ide-based polyion complex micelles (PICMs) constructed with a triblock copolymer composed of a cationic poly(l-lysine) complexing anti-MFAP-5 siRNA (siMFAP-5) via electrostatic interaction, a poly(γ-benzyl-l-glutamate) block loading cationic amphiphilic drug desloratatine (DES) via π-π interaction as endosomal escape enhancer and polysarcosine poly(N-methylglycine) for introducing stealth properties, are generated for siRNA delivery. Intravenous injection of siMFAP-5/DES PICMs significantly reduces the hepatic tumor burden in a syngeneic implantation model of HCC, with a superior MFAP-5 knockdown effect over siMFAP-5 PICMs or lipid nanoparticles. Transcriptome and histological analysis reveal that MFAP-5 knockdown inhibited CAF-related tumor vascularization, suggesting the anti-angiogenic effect of RNA interference therapy. In conclusion, multicompartment PICMs combining siMFAP-5 and DES in a single polypept(o)ide micelle induce a specific knockdown of MFAP-5 and demonstrate a potent antitumor efficacy (80% reduced tumor burden vs untreated control) in a clinically relevant HCC model.

Elevated serum levels of glial fibrillary acidic protein are associated with covert hepatic encephalopathy in patients with cirrhosis.

Background & Aims: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. Astrocyte swelling is a major component of hepatic encephalopathy. Thus, we hypothesised that glial fibrillary acidic protein (GFAP), the major intermediate filament of astrocytes, might facilitate early diagnosis and management. This study aimed to investigate the utility of serum GFAP (sGFAP) levels as a biomarker of CHE. Methods: In this bicentric study, 135 patients with cirrhosis, 21 patients with ongoing harmful alcohol use and cirrhosis, and 15 healthy controls were recruited. CHE was diagnosed using psychometric hepatic encephalopathy score. sGFAP levels were measured using a highly sensitive single-molecule array (SiMoA) immunoassay. Results: In total, 50 (37%) people presented with CHE at study inclusion. Participants with CHE displayed significantly higher sGFAP levels than those without CHE (median sGFAP, 163 pg/ml [IQR 136; 268] vs. 106 pg/ml [IQR 75; 153]; p <0.001) or healthy controls (p <0.001). sGFAP correlated with results in psychometric hepatic encephalopathy score (Spearman's ρ = -0.326, p <0.001), model for end-stage liver disease score (Spearman's ρ = 0.253, p = 0.003), ammonia (Spearman's ρ = 0.453, p = 0.002), and IL-6 serum levels (Spearman's ρ = 0.323, p = 0.006). Additionally, sGFAP levels were independently associated with the presence of CHE in multivariable logistic regression analysis (odds ratio 1.009; 95% CI 1.004-1.015; p <0.001). sGFAP levels did not differ between patients with alcohol-related cirrhosis vs. patients with non-alcohol-related cirrhosis or between patients with ongoing alcohol use vs. patients with discontinued alcohol use.Conclusions: sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker. Impact and implications: Blood biomarkers facilitating the diagnosis of covert hepatic encephalopathy (CHE) in patients with cirrhosis are lacking. In this study, we were able to demonstrate that sGFAP levels are associated with CHE in patients with cirrhosis. These results suggest that astrocyte injury may already occur in patients with cirrhosis and subclinical cognitive deficits and that sGFAP could be explored as a novel biomarker.

Portal vein thrombosis is associated with an increased risk of bone fractures.

BACKGROUND: Portal vein thrombosis (PVT) is a rare but severe disease that often leads to portal hypertension-related complications. It is well-known that patients with portal hypertension associated with liver cirrhosis are at increased risk for bone fractures, however data on the impact of PVT on fracture risk are lacking. AIMS: This study aimed to explore the impact of PVT on the incidence of bone fractures in a large German primary care cohort. METHODS: Patients with PVT were extensively matched to non-PVT individuals in a 1:5 ratio. The primary outcome of the study was the incidence of any bone fracture. RESULTS: This study included 596 patients with PVT and 2,980 non-PVT individuals. During five years of follow-up, the cumulative incidence of bone fractures was significantly higher in PVT patients (n = 87, 13.6%) than in those without PVT (n = 186, 6.7%) (p<0.001). In Cox-regression analyses, PVT was positively associated with bone fractures (HR: 2.16; 95% CI: 1.59-2.93). This association was stronger in women (HR: 2.55; 95% CI: 1.65-3.95) than in men (HR: 1.87; 95% CI: 1.22-2.87). The strongest association was observed in the age group 51-60 years (HR: 2.50, 95% CI: 1.40-4.47). The association between PVT and bone fractures was maintained in subgroup analyses of patients with (HR: 2.03, 95% CI: 1.13-3.63) and without liver cirrhosis (HR: 1.82, 95% CI: 1.28-2.58). CONCLUSIONS: PVT is independently associated with a higher incidence of bone fractures. Patients with PVT should be critically evaluated for fracture risk and preventive measures should be considered.

Transforming Growth Factor-ß Activated Kinase 1 (Tak1) Is Activated in Hepatocellular Carcinoma, Mediates Tumor Progression, and Predicts Unfavorable Outcome.

Although knowledge on inflammatory signaling pathways driving cancer initiation and progression has been increasing, molecular mechanisms in hepatocarcinogenesis are still far from being completely understood. Hepatocyte-specific deletion of the MAPKKK Tak1 in mice recapitulates important steps of hepatocellular carcinoma (HCC) development, including the occurrence of cell death, steatohepatitis, dysplastic nodules, and HCCs. However, overactivation of Tak1 in mice upon deletion of its deubiquitinase Cyld also results in steatohepatitis and HCC development. To investigate Tak1 and Cyld in human HCCs, we created a tissue microarray to analyze their expression by immunohistochemistry in a large and well-characterized cohort of 871 HCCs of 561 patients. In the human liver and HCC, Tak1 is predominantly present as its isoform Tak1A and predominantly localizes to cell nuclei. Tak1 is upregulated in diethylnitrosamine-induced mouse HCCs as well as in human HCCs independent of etiology and is further induced in distant metastases. A high nuclear Tak1 expression is associated with short survival and vascular invasion. When we overexpressed Tak1A in Huh7 cells, we observed increased tumor cell migration, whereas overexpression of full-length Tak1 had no significant effect. A combined score of low Cyld and high Tak1 expression was an independent prognostic marker in a multivariate Cox regression model.

Cell death and hepatocarcinogenesis: Dysregulation of apoptosis signaling pathways.

Hepatocellular carcinoma (HCC) remains a disease with a poor prognosis despite recent advances in the pathophysiology and treatment. Although the disease is biologically heterogeneous, dysregulation of cellular proliferation and apoptosis both occur frequently and contribute to the malignant phenotype. Chronic liver disease is associated with intrahepatic inflammation which promotes dysregulation of cellular signaling pathways; this triggers proliferation and thus lays the ground for expansion of premalignant cells. Cancer emerges when immunological control fails and transformed cells develop resistance against cell death signaling pathways. The same mechanisms underlie the poor responsiveness of HCC towards chemotherapy. Only recently advances in understanding the signaling pathways involved has led to the development of an effective pharmacological therapy for advanced disease. The current review will discuss apoptosis signaling pathways and focus on apoptosis resistance of HCC involving derangements in cell death receptors (e.g. tumor necrosis factor-alpha [TNF], CD95/Apo-1, TNF-related apoptosis-inducing ligand [TRAIL]) and associated adapter molecules (e.g. FADD and FLIP) of apoptotic signaling pathways. In addition, the role of the transcription factor nuclear factor-kappaB (NFκB) and members of the B cell leukemia-2 (Bcl-2) family that contribute to the regulation of apoptosis in hepatocytes are discussed. Eventually, the delineation of cell death signaling pathways could contribute to the implementation of new therapeutic strategies to treat HCC.

Applicability of a Web-Based, Individualized Exercise Intervention in Patients With Liver Disease, Cystic Fibrosis, Esophageal Cancer, and Psychiatric Disorders: Process Evaluation of 4 Ongoing Clinical Trials.

BACKGROUND: In the primary and secondary prevention of civilization diseases, regular physical activity is recommended in international guidelines to improve disease-related symptoms, delay the progression of the disease, or to enhance postoperative outcomes. In the preoperative context, there has been a paradigm shift in favor of using preconditioning concepts before surgery. Web-based interventions seem an innovative and effective tool for delivering general information, individualized exercise recommendations, and peer support. OBJECTIVE: Our first objective was to assess feasibility of our Web-based interventional concept and analyze similarities and differences in a sustained exercise implementation in different diseases. The second objective was to investigate the overall participants' satisfaction with our Web-based concept. METHODS: A total of 4 clinical trials are still being carried out, including patients with esophageal carcinoma scheduled for oncologic esophagectomy (internet-based perioperative exercise program, iPEP, study), nonalcoholic fatty liver disease (hepatic inflammation and physical performance in patients with nonalcoholic steatohepatitis, HELP, study), depression (exercise for depression, EXDEP, study), and cystic fibrosis (cystic fibrosis online mentoring for microbiome, exercise, and diet, COMMED, study). During the intervention period, the study population had access to the website with disease-specific content and a disease-specific discussion forum. All participants received weekly, individual tailored exercise recommendations from the sports therapist. The main outcome was the using behavior, which was obtained by investigating the log-in rate and duration. RESULTS: A total of 20 participants (5 from each trial) were analyzed. During the intervention period, a regular contact and a consequent implementation of exercise prescription were easily achieved in all substudies. Across the 4 substudies, there was a significant decrease in log-in rates (P<.001) and log-in durations (P<.001) over time. A detailed view of the different studies shows a significant decrease in log-in rates and log-in durations in the HELP study (P=.004; P=.002) and iPEP study (P=.02; P=.001), whereas the EXDEP study (P=.58; P=.38) and COMMED study (P=.87; P=.56) showed no significant change over the 8-week intervention period. There was no significant change in physical activity within all studies (P=.31). Only in the HELP study, the physical activity level increased steadily over the period analyzed (P=.045). Overall, 17 participants (85%, 17/20) felt secure and were not scared of injury, with no major differences in the subtrials. CONCLUSIONS: The universal use of the Web-based intervention appears to be applicable across the heterogonous collectives of our study patients with regard to age and disease. Although the development of physical activity shows only moderate improvements, flexible communication and tailored support could be easily integrated into patients' daily routine. TRIAL REGISTRATION: iPEP study: ClinicalTrials.gov NCT02478996; https://clinicaltrials.gov/ct2/show/NCT02478996 (Archived by WebCite at http://www.webcitation.org/6zL1UmHaW); HELP study: ClinicalTrials.gov NCT02526732; http://www.webcitation.org/6zJjX7d6K (Archived by WebCite at http://www.webcitation.org/6Nch4ldcL); EXDEP study: ClinicalTrials.gov NCT02874833; https://clinicaltrials.gov/ct2/show/NCT02874833 (Archived by WebCite at http://www.webcitation.org/6zJjj7FuA).