Validation study of age-independent fibrosis score (Fibrosis-3 index) in patients with metabolic dysfunction-associated steatotic liver disease.

BACKGROUND AND AIMS: Because the accuracy of the Fibrosis-4 (FIB-4) index for predicting liver fibrosis changes with age, the need for different cut-offs in various age groups has frequently been discussed. We developed the age-independent score, the Fibrosis-3 (FIB-3) index, and have shown its usefulness in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to validate the diagnostic ability of the FIB-3 index to predict fibrosis progression using a large new patient cohort. METHODS: The ability of the FIB-3 index to predict liver fibrosis was analyzed by comparing it with that of the FIB-4 index using data from 1398 patients with MASLD enrolled in the Asia-based clinical outcome NAFLD study. RESULTS: The areas under the receiver operating characteristic curves for predicting fibrosis stage F3 or higher were not different between the FIB-3 and FIB-4 indices in the entire cohort. Using the single ideal cut-offs of the indices (3.41 for FIB-3 index and 2.01 for FIB-4 index), the predictive accuracy of the FIB-3 index was not significantly different from that of the FIB-4 index among patients aged <60 years; however, the accuracy of the FIB-3 index was significantly higher than that of the FIB-4 index in those aged ≥60 years (0.645 and 0.529, respectively; p < 0.0001). CONCLUSION: The high ability of the FIB-3 index with a single cut-off to predict liver fibrosis in patients with MASLD was confirmed. The FIB-3 index could serve as a useful tool for assessing liver fibrosis regardless of age.

Growth differentiation factor-1 5 and metabolic features in chronic heart failure: Insights from the SUPPORT Trial -GDF15 across the BMI spectrum.

BACKGROUND: GDF15 plays pivotal metabolic roles in nutritional stress and serves as a physiological regulator of energy balance. However, the patterns of GDF15 levels in underweight or obese patients with chronic heart failure (CHF) are not well-understood. METHODS: We assessed serum GDF15 levels at baseline and 3 years and the temporal changes in 940 Japanese patients (642 paired samples), as a sub-analysis of the SUPPORT trial (age 6 5.9 ±â€¯10.1 years). The GDF15 levels were analyzed across BMI groups (underweight [<18.5 kg/m2; n = 50], healthy weight [18.5-22.9; n = 27 5], overweight [23-24.9; n = 234], and obese [≥2 5; n = 381]), following WHO recommendations for the Asian-Pacific population. Landmark analysis at 3 years assessed the association between GDF15 levels and HF hospitalization or all-cause death. RESULTS: Compared to the healthy weight group, the underweight group included more females (54.0%) with advanced HF (NYHA class III; 20.0%) and exhibited increased GDF15 level (1764 pg/mL [IQR 1067-2633]). Obese patients, younger (64.2 years) and diabetic (53%), had a similar GDF15 level to the healthy weight group. A higher baseline GDF15 level was associated with worse outcomes across the BMI spectrum. GDF15 increased by 208 [21-596] pg/mL over 3 years, with the most substantial increase observed in the underweight group (by +28.9% [6.2-81.0]). Persistently high GDF15 levels (≥1800 pg/mL) was independently associated with worse outcomes after 3 years (adjusted HR 1.8 [9 5%CI 1.1-2.9]). CONCLUSIONS: In underweight patients with CHF, GDF1 5 level was elevated at baseline and experienced the most significant increase over 3 years. Its consistent elevation suggested a worse outcome.

Predictability of noninvasive liver fibrosis score for cardiac events in patients with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Patients with nonalcoholic fatty liver disease (NAFLD) have a higher risk of cardiac events. However, although the severity of liver fibrosis is related to worsening prognosis in patients with NAFLD, it is unclear whether the noninvasive liver fibrosis score has a predictive value for cardiac events. METHODS AND RESULTS: We evaluated 4071 patients with NAFLD diagnosed using ultrasonography. Liver fibrosis was assessed and divided into three groups based on the Fibrosis-4 (FIB4) index and NAFLD fibrosis score (NFS). The primary outcome of this study was major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. The median age of the evaluated patients was 61 (52-69) years, and 2201 (54.1%) were male. During the median follow-up period of 6.6 years, 179 (4.4%) patients experienced MACE. Kaplan-Meier survival analysis demonstrated that MACE increased progressively with the FIB4 index (log-rank, p < 0.001) and NFS (log-rank, p < 0.001). Multivariable analysis showed that the higher the FIB4 index, the higher the risk for MACE (low group as reference vs. intermediate group, hazard ratio [HR]: 1.860 [95% confidence interval (CI), 1.326-2.610; p < 0.001]; vs. high group, HR:3.325 [95% CI, 2.017-5.479; p < 0.001]), as well as NFS (low NFS group as reference vs. intermediate group, HR: 1.938 [95% CI, 1.391-2.699; p < 0.001]; vs. high group, HR: 3.492 [95% CI, 1.997-6.105; p < 0.001]). CONCLUSIONS: The FIB4 index and NFS are associated with the probability of MACE in patients with NAFLD. CLINICAL TRIALS: The study design was approved by the ethics review board of Ogaki Municipal Hospital (approval number: 20221124-12, registration date: November 28th, 2022). https://www.ogaki-mh.jp/chiken/kenkyu.html.

Relationship between 2nd-generation angiotensin receptor blockers and the risk of hypotension in COVID-19 patients admitted to hospital.

It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities.

Effect of Luseogliflozin on Myocardial Flow Reserve in Patients with Type 2 Diabetes Mellitus (LUCENT-J Study).

INTRODUCTION: In patients with type 2 diabetes (T2D), treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors has been shown to reduce hospital admission rates for heart failure (HF). However, the multiple mechanisms hypothesized and investigated to explain the cardioprotection of SGLT2 inhibitors are not fully understood. OBJECTIVES: The effect of luseogliflozin on myocardial flow reserve (MFR) in patients with T2D (LUCENT-J) study aims to examine the effects of SGLT2 inhibitors on myocardial perfusion. METHODS: The LUCENT-J study is a prospective, single-center, randomized, two-arm, parallel-group, open-label (i.e., the radiology readers are blinded), active-controlled study. A cohort of 40 patients with T2D with no or stable (with no history of myocardial infarction and with or without previous percutaneous coronary intervention) coronary artery disease will be included. Patients will be randomized in a 1:1 ratio to luseogliflozin or control and treated for 24 weeks. The primary outcome is the change in MFR, as measured by 13N-ammonia positron emission tomography/computed tomography, from baseline to 24 weeks after treatment initiation. PLANNED OUTCOMES: The LUCENT-J study will elucidate the mechanisms of cardioprotection by SGLT2 inhibitors in patients with T2D. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs051220016).

Age-stratified profiles and outcomes of patients with heart failure with preserved ejection fraction.

AIMS: This study aimed to elucidate age-stratified clinical profiles and outcomes in patients with heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF). METHODS AND RESULTS: The Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) Study included 2824 consecutive HFpEF patients with LVEF ≥ 50% (mean age 69.0 ± 12.3 years; 67.7% male) with a median follow-up of 9.8 years. We stratified them into five age groups: ≤54 (N = 349, 12.4%), 55-64 (N = 529, 18.7%), 65-74 (N = 891, 31.6%), 75-84 (N = 853, 30.2%), and ≥85 years (N = 202, 7.2%), and we categorized these age groups into younger (≤64 years) and older (≥65 years) groups. We compared the clinical profiles and outcomes of HFpEF patients across age groups. Younger HFpEF groups exhibited a male predominance, elevated body mass index (BMI), and poorly controlled diabetes (haemoglobin A1c > 7.0%). Older HFpEF groups were more likely to be female with multiple comorbidities, including coronary artery disease, hypertension, renal impairment, and atrial fibrillation. The positive association between elevated BMI and HFpEF was more pronounced with lower classes of age from ≥85 to ≤54 years, especially in males. With higher classes of age from ≤54 to ≥85 years, mortality rates increased, and HF death became proportionally more prevalent (Ptrend < 0.001), whereas sudden cardiac death (SCD) exhibited the opposite trend (Ptrend = 0.002). Poorly controlled diabetes emerged as the only predictor of SCD in the younger groups (adjusted hazard ratio 4.26; 95% confidence interval 1.45-12.5; P = 0.008). Multiple comorbidities were significantly associated with an increased risk of HF-related mortality in the older groups. CONCLUSIONS: Younger HFpEF patients (≤64 years) exhibit a male predominance, elevated BMI, and poorly controlled diabetes, highlighting the importance of glycaemic control in reducing SCD risk. Older HFpEF patients (≥65 years) are more likely to be female, with multiple comorbidities linked to an increased risk of HF-related mortality. These findings underscore the need for physicians to recognize age-related, distinct HFpEF phenotypes for personalized patient management.

Hepatic inflammation and fibrosis are profiles related to mid-term mortality in biopsy-proven MASLD: A multicenter study in Japan.

AIMS: A multi-stakeholder consensus has proposed MASLD (metabolic dysfunction-associated steatotic liver disease). We aimed to investigate the pathological findings related to the mid-term mortality of patients with biopsy-proven MASLD in Japan. METHODS: We enrolled 1349 patients with biopsy-proven MASLD. The observational period was 8010 person years. We evaluated independent factors associated with mortality in patients with MASLD by Cox regression analysis. We also investigated pathological profiles related to mortality in patients with MASLD using data-mining analysis. RESULTS: The prevalence of MASH and stage 3/4 fibrosis was observed in 65.6% and 17.4%, respectively. Forty-five patients with MASLD died. Of these, liver-related events were the most common cause at 40% (n = 18), followed by extrahepatic malignancies at 26.7% (n = 12). Grade 2/3 lobular inflammation and stage 3/4 fibrosis had a 1.9-fold and 1.8-fold risk of mortality, respectively. In the decision-tree analysis, the profiles with the worst prognosis were characterised by Grade 2/3 hepatic inflammation, along with advanced ballooning (grade 1/2) and fibrosis (stage 3/4). This profile showed a mortality at 8.3%. Furthermore, the random forest analysis identified that hepatic fibrosis and inflammation were the first and second responsible factors for the mid-term prognosis of patients with MASLD. CONCLUSIONS: In patients with biopsy-proven MASLD, the prevalence of MASH and advanced fibrosis was approximately 65% and 20%, respectively. The leading cause of mortality was liver-related events. Hepatic inflammation and fibrosis were significant factors influencing mid-term mortality. These findings highlight the importance of targeting inflammation and fibrosis in the management of patients with MASLD.

Glucagon-like Peptide-1 analogues and delipidation of coronary atheroma in statin-treated type 2 diabetic patients with coronary artery disease: The prespecified sub-analysis of the OPTIMAL randomized clinical trial.

Background and aims: Randomized clinical trials have demonstrated the ability of glucagon-like peptide-1 analogues (GLP-1RAs) to reduce atherosclerotic cardiovascular disease events in patients with type 2 diabetes (T2D). How GLP-1RAs modulate diabetic atherosclerosis remains to be determined yet. Methods: The OPTIMAL study was a prospective randomized controlled study to compare the efficacy of 48-week continuous glucose monitoring- and HbA1c-guided glycemic control on near infrared spectroscopty (NIRS)/intravascular ultrasound (IVUS)-derived plaque measures in 94 statin-treated patients with T2D (jRCT1052180152, UMIN000036721). Of these, 78 patients with evaluable serial NIRS/IVUS images were analyzed to compare plaque measures between those treated with (n = 16) and without GLP-1RAs (n = 72). Results: All patients received a statin, and on-treatment LDL-C levels were similar between the groups (66.9 ± 11.6 vs. 68.1 ± 23.2 mg/dL, p = 0.84). Patients receiving GLP-1RAs demonstrated a greater reduction of HbA1c [-1.0 (-1.4 to -0.5) vs. -0.4 (-0.6 to -0.2)%, p = 0.02] and were less likely to demonstrate a glucose level >180 mg/dL [-7.5 (-14.9 to -0.1) vs. 1.1 (-2.0 - 4.2)%, p = 0.04], accompanied by a significant decrease in remnant cholesterol levels [-3.8 (-6.3 to -1.3) vs. -0.1 (-0.8 - 1.1)mg/dL, p = 0.008]. On NIRS/IVUS imaging analysis, the change in percent atheroma volume did not differ between the groups (-0.9 ± 0.25 vs. -0.2 ± 0.2%, p = 0.23). However, GLP-1RA treated patients demonstrated a greater frequency of maxLCBI4mm regression (85.6 ± 0.1 vs. 42.0 ± 0.6%, p = 0.01). Multivariate analysis demonstrated that the GLP-1RA use was independently associated with maxLCBI4mm regression (odds ratio = 4.41, 95%CI = 1.19-16.30, p = 0.02). Conclusions: In statin-treated patients with T2D and CAD, GLP-1RAs produced favourable changes in lipidic plaque materials, consistent with its stabilization.

Evaluation of fractional flow reserve and atherosclerotic plaque characteristics on coronary non-contrast T1-weighted magnetic resonance imaging.

BACKGROUND AND AIMS: The relationship between high-risk coronary plaque characteristics regardless of the severity of lesion stenosis and myocardial ischemia remains unsettled. High-intensity plaques (HIPs) on non-contrast T1-weighted magnetic resonance imaging (T1WI) have been characterized as high-risk coronary plaques. We sought to elucidate whether the presence of coronary HIPs on T1WI influences fractional flow reserve (FFR) in the distal segment of the vessel. METHODS: We retrospectively analyzed 281 vessels in 231 patients with chronic coronary syndrome who underwent invasive FFR measurement and coronary T1WI using a multicenter registry. The plaque-to-myocardial signal intensity ratio (PMR) of the most stenotic lesion was evaluated; a coronary plaque with PMR ≥1.4 was defined as a HIP. RESULTS: The median PMR of coronary plaques on T1WI in vessels with FFR ≤0.80 was significantly higher than that of plaques with FFR >0.80 (1.17 [interquartile range (IQR): 0.99-1.44] vs. 0.97 [IQR: 0.85-1.09]; p < 0.001). Multivariable analysis showed that an increase in PMR of the most stenotic segment was associated with lower FFR (beta-coefficient, -0.050; p < 0.001). The presence of coronary HIPs was an independent predictor of FFR ≤0.80 (odds ratio (OR), 6.18; 95% confidence interval (CI), 1.93-19.77; p = 0.002). Even after adjusting for plaque composition characteristics based on computed tomography angiography, the presence of coronary HIPs was an independent predictor of FFR ≤0.80 (OR, 4.48; 95% CI, 1.19-16.80; p = 0.026). CONCLUSIONS: Coronary plaques with high PMR are associated with low FFR in the corresponding vessel, indicating that plaque morphology might influence myocardial ischemia severity.

Cryo-EM structure of P-glycoprotein bound to triple elacridar inhibitor molecules.

P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp.

Outcomes of patients with cerebral microbleeds undergoing percutaneous coronary intervention and dual antiplatelet therapy.

INTRODUCTION: Cerebral microbleeds (CMBs) on brain magnetic resonance imaging (MRI) are predictive of intracerebral hemorrhage (ICH). However, the risk of ICH in patients with CMBs who undergo percutaneous coronary intervention (PCI) while receiving dual antiplatelet therapy (DAPT) is unclear. MATERIALS AND METHODS: We conducted a study on 329 consecutive patients with coronary artery disease who underwent PCI and were evaluated using a 3T MRI scanner. Based on T2*-weighted imaging, patients were classified into three groups: no CMBs, < 5 CMBs, or ≥ 5 CMBs. We determined the occurrence of ICH during follow-up. RESULTS: At least 1 CMB was found in 109 (33%) patients. The mean number of CMBs per patient was 2.9 ± 3.6. Among the 109 patients with CMBs, 16 (15%) had ≥ 5 CMBs. Coronary stent implantation was performed in 321 patients (98%). DAPT was prescribed for 325 patients (99%). During a mean follow-up period of 2.3 years (interquartile range, 1.9-2.5 years), ICH occurred in one patient (1.1%) with four CMBs. There were no significant differences in the incidence of ICH (0% vs. 1.1% vs. 0%; p = 0.28). However, the rate of DAPT at 6 months of follow-up was significantly lower in patients with ≥ 5 CMBs than in patients with no CMBs or < 5 CMBs (89% vs. 91% vs. 66%, p = 0.026). Furthermore, there were no significant differences in systemic blood pressure during follow-up (123 ± 16 vs. 125 ± 16 vs. 118 ± 11 mmHg; p = 0.40). CONCLUSION: Although a substantial number of patients who underwent PCI had cerebral microbleeds, at approximately two years of follow-up, intracerebral hemorrhage was very rare in our study population.

Antithrombotic therapy for stable coronary artery disease and atrial fibrillation in patients with and without revascularisation: the AFIRE trial.

BACKGROUND: The Atrial Fibrillation and Ischemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial demonstrated non-inferior efficacy endpoints for rivaroxaban monotherapy versus combination therapy (rivaroxaban plus a single antiplatelet) and superior safety endpoints in patients with atrial fibrillation and stable coronary artery disease. AIMS: This post hoc analysis investigated whether the AFIRE trial results reflected the presence or absence of prior revascularisation. METHODS: Among 2,215 patients, 1,697 (76.6%) had previously undergone revascularisation, and the remaining 518 (23.4%) had not undergone prior revascularisation. The primary efficacy endpoint was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation, or death from any cause, while the primary safety endpoint was major bleeding. RESULTS: In 1,697 patients with prior revascularisation, the efficacy and safety endpoints were superior for monotherapy versus combination therapy (efficacy: hazard ratio [HR] 0.62, 95% confidence interval [CI]: 0.45-0.85; p=0.003; safety: HR 0.62, 95% CI: 0.39-0.98; p=0.042). Among 518 without prior revascularisation, there were no significant differences in endpoints (efficacy: HR 1.19, 95% CI: 0.67-2.12; p=0.554; safety: HR 0.47, 95% CI: 0.18-1.26; p=0.134). There was borderline interaction of the efficacy endpoints (p=0.055) between two treatments. The safety benefit of monotherapy on any bleeding was significant in patients without prior revascularisation (HR 0.59, 95% CI: 0.38-0.93; p=0.022). CONCLUSIONS: In high-risk thrombosis patients with a history of prior revascularisation, rivaroxaban monotherapy versus combination therapy demonstrated favourable safety and efficacy outcomes.

Clinical usefulness of newly developed prognostic predictive score for atezolizumab plus bevacizumab for hepatocellular carcinoma.

AIMS: The aim of the present study was to elucidate detailed parameters for prediction of prognosis for patients with unresectable hepatocellular carcinoma (uHCC) receiving atezolizumab plus bevacizumab (Atez/Bev) treatment. METHODS: A total of 719 patients (males 577, median age 74 years) treated with Atez/Bev between September 2020 and January 2023 were enrolled. Factors related to overall survival (OS) were extracted and a prognostic scoring system based on hazard ratio (HR) was created. OS and progression-free survival (PFS) were retrospectively examined, and the prognostic ability of the newly developed system was compared to CRAFITY score using concordance index (c-index) and Akaike information criterion (AIC) results. RESULTS: Cox-hazards multivariate analysis showed BCLC classification C/D (HR 1.4; 1 point), AFP ≥100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP ≥100 mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points were added and used to develop the IMmunotherapy with AFP, BCLC staging, mALBI, and DCP evaluation (IMABALI-De) scoring system. For IMABALI-De scores of 0, 1, 2, 3, 4, and 5, OS was not applicable (NA), NA, 26.11, 18.79, 14.07, and 8.32 months, respectively (p < .001; AIC 2788.67, c-index 0.699), while for CRAFITY scores of 0, 1, and 2, OS was 26.11, 20.29, and 11.32 months, respectively (p < .001; AIC 2864.54, c-index 0.606). PFS periods for those IMABALI-De scores were 21.75, 12.89, 9.18, 8.0, 5.0, and 3.75 months, respectively (p < .001; AIC 5203.32, c-index 0.623) and for the CRAFITY scores were 10.32, 7.68, and 3.57 months, respectively (p < .001; AIC 5246.61, c-index 0.574). As compared with CRAFITY score, IMABALI-De score had better AIC and c-index results for both OS and PFS. CONCLUSION: The present results indicated that the proposed IMABALI-De score may be favorable for predicting prognosis of uHCC patients receiving Atez/Bev therapy.

Mortality in patients with chronic hepatitis B treated with tenofovir or entecavir: A multinational study.

BACKGROUND AND AIM: The benefits of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in reducing the development of chronic hepatitis B (CHB)-related hepatocellular carcinoma remain controversial. Whether mortality rates differ between patients with CHB treated with ETV and those treated with TDF is unclear. METHODS: A total of 2542 patients with CHB treated with either ETV or TDF were recruited from a multinational cohort. A 1:1 propensity score matching was performed to balance the differences in baseline characteristics between the two patient groups. We aimed to compare the all-cause, liver-related, and non-liver-related mortality between patients receiving ETV and those receiving TDF. RESULTS: The annual incidence of all-cause mortality in the entire cohort was 1.0/100 person-years (follow-up, 15 757.5 person-years). Patients who received TDF were younger and had a higher body mass index, platelet count, hepatitis B virus deoxyribonucleic acid levels, and proportion of hepatitis B e-antigen seropositivity than those who received ETV. The factors associated with all-cause mortality were fibrosis-4 index > 6.5 (hazard ratio [HR]/confidence interval [CI]: 3.13/2.15-4.54, P < 0.001), age per year increase (HR/CI: 1.05/1.04-1.07, P < 0.001), alanine aminotransferase level per U/L increase (HR/CI: 0.997/0.996-0.999, P = 0.003), and γ-glutamyl transferase level per U/L increase (HR/CI: 1.002/1.001-1.003, P < 0.001). No significant difference in all-cause mortality was observed between the ETV and TDF groups (log-rank test, P = 0.69). After propensity score matching, no significant differences in all-cause, liver-related, or non-liver-related mortality were observed between the two groups. CONCLUSIONS: Long-term outcomes of all-cause mortality and liver-related and non-liver-related mortality did not differ between patients treated with ETV and those receiving TDF.

Successful management of splenic artery dissection after sigmoid colon perforation in vascular Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a genetic disorder that causes fragility of the systemic connective tissues. Of the 13 subtypes, vascular EDS (vEDS) is associated with abnormalities in collagen production, resulting in arterial rupture and intestinal perforation. Herein, we report the case of a man with confirmed vEDS who survived a ruptured dissected splenic artery aneurysm triggered by perforation of the sigmoid colon. CASE PRESENTATION: A 48-year-old man presented to our hospital with sudden severe lower abdominal pain. The patient was genetically diagnosed with vEDS at the age of 43 years. Abdominal computed tomography (CT) showed fluid and free air surrounding the sigmoid colon. These findings suggested sigmoid colon perforation, and emergency surgery was needed. Hartmann's procedure was performed. The resected specimen showed a 2-cm-sized depression around the perforation. Histopathological findings showed an abscess and exudate in the serosa of the perforation and thinning of the intrinsic muscular layer in the depressed area. The patient was doing well postoperatively; however, on the ninth postoperative day, sudden upper abdominal pain developed. CT revealed an intra-abdominal hemorrhage due to rupture of a dissecting splenic artery aneurysm. The aneurysm was not observed on preoperative CT and was distant from the surgical site. Urgent transcatheter arterial embolization was performed. Although embolization of the splenic artery was attempted during the procedure, the arterial dissection spread to the common hepatic artery. Moreover, the proper hepatic and gastroduodenal arteries were poorly visualized, probably due to vasospasm. Although complications associated with extensive embolization were a concern, embolization of the splenic and common hepatic arteries was necessary to save the patient's life. After embolization, angiography showed that the left hepatic blood flow was maintained from the inferior phrenic artery, and the right hepatic inflow was maintained from the superior mesenteric artery via the peribiliary vascular plexus in the hilar area. The patient recovered well and was discharged on the 19th postoperative day. CONCLUSIONS: vEDS can cause arterial rupture after intestinal surgery. Therefore, careful post-operative management is necessary. Moreover, cooperation with interventional radiologists is important for prompt treatment of vascular complications.

Impact of body mass index on the prognosis of unresectable HCC patients receiving first-line Lenvatinib or atezolizumab plus bevacizumab.

INTRODUCTION: Overweight is a negative prognostic factor in the general population in the long term. However, the role of body mass index (BMI) in the short-mid term in advanced tumours is unclear. The present analysis investigates the role of BMI weight classes in a large sample of patients affected by HCC and receiving atezolizumab plus bevacizumab or lenvatinib as first-line treatment. METHODS AND MATERIAL: The cohort included consecutive patients affected by BCLC-c and BCLC-B HCC patients from a multicenter international study group who received atezolizumab plus bevacizumab or lenvatinib as first-line therapy. Population was stratified according to the BMI in under-, over- and normal-weight according to the conventional thresholds. The primary objective of the study was to evaluate the prognostic and predictive impact of BMI in patients affected by advanced or intermediate HCC. Survival curves were estimated using the product-limit method of Kaplan-Meier. The role of stratification factors was analysed with log-rank tests. RESULTS: 1292 consecutive patients with HCC were analysed. 466 (36%) patients were treated with lenvatinib and 826 (64%) patients were treated with atezolizumab plus bevacizumab. In the atezolizumab plus bevacizumab arm, 510 (62%) patients were normal-weight, 52 (6%) underweight and 264 (32%) overweight. At the univariate analysis for OS, underweight patients had significantly shorter OS compared to normal-weight patients, whereas no differences were found between normal-weight versus overweight. Multivariate analysis confirmed that underweight patients had significantly shorter OS compared to normal-weight patients (HR: 1.7; 95% CI: 1.0-2.8; p = .0323). In the lenvatinib arm, 26 patients (5.6%) were categorized as underweight, 256 (54.9%) as normal-weight, and 184 (39.5%) as overweight. At the univariate analysis for OS, no significant differences were found between normal-weight versus underweight and between normal-weight versus overweight, which was confirmed at multivariate analysis. CONCLUSION: Our analysis highlighted a prognostic role of BMI in a cohort of patients with advanced HCC who received atezolizumab plus bevacizumab, while no prognostic role for low BMI was apparent in patients who received lenvatinib.

iATT liver fat quantification for steatosis grading by referring to MRI proton density fat fraction: a multicenter study.

BACKGROUND: Several preliminary reports have suggested the utility of ultrasound attenuation coefficient measurements based on B-mode ultrasound, such as iATT, for diagnosing steatotic liver disease. Nonetheless, evidence supporting such utility is lacking. This prospective study aimed to investigate whether iATT is highly concordant with magnetic resonance imaging (MRI)-based proton density fat fraction (MRI-PDFF) and could well distinguish between steatosis grades. METHODS: A cohort of 846 individuals underwent both iATT and MRI-PDFF assessments. Steatosis grade was defined as grade 0 with MRI-PDFF < 5.2%, grade 1 with 5.2% MRI-PDFF < 11.3%, grade 2 with 11.3% MRI-PDFF < 17.1%, and grade 3 with MRI-PDFF of 17.1%. The reproducibility of iATT and MRI-PDFF was evaluated using the Bland-Altman analysis and intraclass correlation coefficients, whereas the diagnostic performance of each steatosis grade was examined using receiver operating characteristic analysis. RESULTS: The Bland-Altman analysis indicated excellent reproducibility with minimal fixed bias between iATT and MRI-PDFF. The area under the curve for distinguishing steatosis grades 1, 2, and 3 were 0.887, 0.882, and 0.867, respectively. A skin-to-capsula distance of ≥ 25 mm was identified as the only significant factor causing the discrepancy. No interaction between MRI-logPDFF and MRE-LSM on iATT values was observed. CONCLUSIONS: Compared to MRI-PDFF, iATT showed excellent diagnostic accuracy in grading steatosis. iATT could be used as a diagnostic tool instead of MRI in clinical practice and trials. Trial registration This study was registered in the UMIN Clinical Trials Registry (UMIN000047411).

Evaluation of Atezolizumab Plus Bevacizumab Versus Modified Lenvatinib Therapy in Child-Pugh A Unresectable Hepatocellular Carcinoma.

Background/Aim: Atezolizumab/bevacizumab (Atez/BV) and lenvatinib (LEN) are the recommended first-line treatments for patients with unresectable hepatocellular carcinoma (HCC). Previous reports have suggested that the tolerability and therapeutic efficacy of LEN could be enhanced by modifying its administration method. Therefore, this study compared the efficacy and safety of Atez/BV, the standard LEN therapy (standard LEN), and modified LEN therapy (modified LEN). Patients and Methods: The overall survival (OS) and the rate of discontinuation due to adverse events (AEs) were compared between groups treated with Atez/BV (n=36), standard LEN (n=30), and modified LEN (n=11). Results: Discontinuation due to AEs was required in 22.2%, 23.3%, and 9.1% of patients in the Atez/BV, standard LEN, and modified LEN groups (p=0.485). The median OS for the Atez/BV, standard LEN, and modified LEN groups was 523 [95% confidence interval (CI)=163-818], 382 (95%CI=330-547), and 604 (95% CI=257-656) days, respectively (log-rank test, p=0.949). Conclusion: Atez/BV and the standard and modified LEN regimens showed comparable efficacy and safety.

Prognostic significance of growth differentiation factor-15 across age in chronic heart failure.

AIMS: Growth differentiation factor-15 (GDF15), a cytokine in the transforming growth factor family, is up-regulated in stress and inflammatory conditions and is elevated in patients with heart failure (HF). However, the age-specific attributes and prognostic significance of GDF15 across age remain unknown in chronic HF (CHF). METHODS AND RESULTS: Serum levels of GDF15 were examined in 942 hypertensive patients (median 68 years) with CHF from the SUPPORT trial across the four age groups [under 50 (n = 73), 51-59 (n = 158), 60-69 (n = 296), and 70-79 years (n = 415)] and in the continuous spectrum. Clinical correlates of GDF15 were explored using the classic stepwise and LASSO (least absolute shrinkage and selection operator) regression approaches. Interaction terms with age were tested in the LASSO regression approach. The associations with the composite outcome of HF hospitalization or all-cause death were investigated across ages. Median GDF15 levels (pg/mL) increased along with aging, from 691 in under 50 years to 855 in 51-59 years, 1114 in 60-69 years, and 1516 in 70-79 years (trend P < 0.001). Age, sex, systolic blood pressure, history of diabetes, ischaemic heart disease, left ventricular (LV) end-systolic dimension, LV ejection fraction, estimated glomerular filtration rate, haemoglobin, N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin, C-reactive protein, and the use of angiotensin-converting enzyme inhibitors, diuretics, and statins were mutually selected as clinical covariates of GDF15. The LASSO regression analysis identified significant interactions between age and the history of diabetes and NT-proBNP, with particularly robust associations in patients aged between 60 and 70 years. During the mean follow-up of 8.6 years, 474 composite endpoints of HF hospitalization or death occurred. GDF15 was associated with a higher risk of HF hospitalization or all-cause death [adjusted hazard ratio 1.84 (95% confidence interval 1.45-2.33)], with a particularly heightened risk in patients aged around 70 years (Pinteraction  = 0.0008). The model with GDF15 on top of other established risk factors yielded marginally higher C-statistics compared with the model without GDF15 (0.803 and 0.796, P = 0.045). The additive value of GDF15 on top of other established risk factors appeared similar across ages. A universal cut-off value of 1400 pg/mL performed well in discriminating between those with and without HF hospitalization or death. CONCLUSIONS: Some clinical correlates of GDF15 have an interaction with age. GDF15 is an important determinant of cardiovascular endpoints, particularly in patients aged around 70 years. The additive value of GDF15 appeared consistent across ages, suggesting the use of a universal cut-off value.

Underuse of heart failure medications and poor long-term prognosis in chronic heart failure patients with polypharmacy - A report from the CHART-2 study.

Background: In patients with chronic heart failure (CHF), comorbidities are often managed with multiple medications, characterized by polypharmacy, leading to increased risk of potentially inappropriate medication and adverse effects. Methods: We studied 4,876 consecutive patients with CHF (Stage C/D, age 69.0 ± 12.3 years) in the CHART-2 study to evaluate the association among polypharmacy, underuse of HF medications, and all-cause death. Polypharmacy was defined as the daily use of ≥ 8 medications for the survival classification and regression tree analysis. Results: The average number of medications was 10 in the polypharmacy group and 5 in the non-polypharmacy group, respectively. Over a median of 8.3 (4.1-11.7) years, the incidence rate of all-cause death was significantly higher in the polypharmacy group (n = 2,108) than in the non-polypharmacy group (57.3 % vs. 40.6 %; adjusted hazard ratio [aHR] 1.34 (95 %CI, 1.22-1.48), P < 0.001), even in age < 55 years (26.6 % vs. 14.3 %; adjusted hazard ratio [aHR] 1.61 (95 %CI, 1.04-2.50), P = 0.033). In patients with polypharmacy, those without renin-angiotensin system inhibitors (RAS-I) and/or beta-blockers (N = 1,023) were associated with increased incidence of all-cause death as compared with those with both medications (aHR 1.18; 95 %CI 1.04-1.35, P = 0.012). Conclusions: Polypharmacy was associated with poor long-term prognosis, even in younger patients with CHF. Among 4,876 patients with CHF, 1023 (20.9%) with polypharmacy and underuse of RAS-I and/or beta-blocker were associated with increased risk of all-cause death.