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Background: It remains unclear whether adults with metabolically healthy obesity (MHO) have altered myocardial tissue-level characteristics., Objectives: This study aims to assess the subclinical myocardial tissue-level characteristics of adults with MHO., Methods: The EARLY-MYO-OBESITY (EARLY Assessment of MYOcardial Tissue Characteristics in OBESITY; NCT05277779) registry was a prospective, 3-center, cardiac imaging study of obese nondiabetic individuals without cardiac symptoms who underwent cardiac magnetic resonance. Myocardial tissue-level characteristics, including extracellular volume fraction (ECV) and native T2 values, were measured as indicators of myocardial fibrosis and edema. Global longitudinal peak systolic strain and early diastolic longitudinal strain rate were assessed by tissue tracking analysis to detect subclinical systolic and diastolic dysfunction., Results: A total of 120 participants were included: MHO (n = 32; mean age, 38 years; 41% men), metabolically healthy controls without obesity (n = 32; mean age: 37 years; 41% men), and metabolically unhealthy obesity (MUHO) (n = 56; mean age: 37 years; 55% men). The MHO group had higher ECV and native T2 values than healthy controls (both P < 0.001); furthermore, the ECV was higher in the MUHO group than in the MHO group (P = 0.002). The prevalence of myocardial fibrosis was 44% (14 of 32) in the MHO group and 71% (40 of 56) in the MUHO group. Although there was no intergroup difference in left ventricular ejection fraction, the MHO group had reduced global longitudinal peak systolic and early diastolic longitudinal strain rates, indicating subclinical systolic and diastolic dysfunction. Multivariate regression analysis identified increased body mass index to be an independent risk factor for myocardial fibrosis (OR: 6.28 [95% CI: 3.17-12.47]; P < 0.001)., Conclusions: This study provides the first evidence of subclinical myocardial tissue-level remodeling in adults with obesity, regardless of metabolic health. Early identification of cardiac impairment may facilitate preventive strategies against heart failure in the MHO population. (EARLY Assessment of MYOcardial Tissue Characteristics in OBESITY [EARLY-MYO-OBESITY]; NCT05277779)., Competing Interests: Funding Support and Author Disclosures This study received funding support from National Natural Science Foundation of China (U21A20341, 81971570, 81930007, 82202159, 31900821), Science and Technology Commission of Shanghai Municipality (21XD1432100, 22JC1402100, 22DZ2292400, 20Y11910500, 2022ZZ01008, 201409005200), Shanghai Hospital Development Center (SHDC2020CR2025B, SHDC12022102), Shanghai Municipal Health Commission (2022JC013, SHSLCZDZK06204), Shanghai Pudong New Area Health Commission (PW2019D-11), Shanghai Jiao Tong University (YG2019ZDA13), University of Shanghai for Science and Technology (10-20-302-425), Shanghai Clinical Research Center for Aging and Medicine (19MC1910500), and the Shanghai Cancer Institute (ZZ-20-22SYL). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Purpose: In the past decade, there has been a rapid increase in the development of automatic cardiac segmentation methods. However, the automatic quality control (QC) of these segmentation methods has received less attention. This study aims to address this gap by developing an automatic pipeline that incorporates DL-based cardiac segmentation and radiomics-based quality control., Methods: In the DL-based localization and segmentation part, the entire heart was first located and cropped. Then, the cropped images were further utilized for the segmentation of the right ventricle cavity (RVC), myocardium (MYO), and left ventricle cavity (LVC). As for the radiomics-based QC part, a training radiomics dataset was created with segmentation tasks of various quality. This dataset was used for feature extraction, selection, and QC model development. The model performance was then evaluated using both internal and external testing datasets., Results: In the internal testing dataset, the segmentation model demonstrated a great performance with a dice similarity coefficient (DSC) of 0.954 for whole heart segmentations. Images were then appropriately cropped to 160 × 160 pixels. The models also performed well for cardiac substructure segmentations. The DSC values were 0.863, 0.872, and 0.940 for RVC, MYO, and LVC for 2D masks and 0.928, 0.886, and 0.962 for RVC, MYO, and LVC for 3D masks with an attention-UNet. After feature selection with the radiomics dataset, we developed a series of models to predict the automatic segmentation quality and its DSC value for the RVC, MYO, and LVC structures. The mean absolute values for our best prediction models were 0.060, 0.032, and 0.021 for 2D segmentations and 0.027, 0.017, and 0.011 for 3D segmentations, respectively. Additionally, the radiomics-based classification models demonstrated a high negative detection rate of >0.85 in all 2D groups. In the external dataset, models showed similar results., Conclusions: We developed a pipeline including cardiac substructure segmentation and QC at both the slice (2D) and subject (3D) levels. Our results demonstrate that the radiomics method possesses great potential for the automatic QC of cardiac segmentation.

Objectives: We presented an unreported T96R mutation induced transthyretin cardiac amyloidosis (ATTR). The biochemical and biophysical properties were explored to support its pathogenicity., Background: Understanding the biochemical and biophysical nature of genetically mutated transthyretin (TTR) proteins is key to provide precise medical cares for ATTR patients., Results: Genetic testing showed heterozygosity for the T96R pathogenic variant c.347C > G (ATTR p.T116R ) after myocardial biopsy confirmed amyloid deposition. Biochemical characterizations revealed slight perturbation of its thermodynamic stability (C m =3.7 M for T96R, 3.4 M for WT and 2.3 M for L55P (commonly studied TTR mutant)) and kinetic stability (t 1/2 =39.8 h for T96R, 42 h for WT and 4.4 h in L55P). Crosslinking experiment demonstrated heterozygous subunit exchange between wild-type and TTR T96R protein destabilized the tetramer. Inhibitory effect of tafamidis and diflunisal on TTR T96R fibril formation was slightly less effective compared to WT and L55P., Conclusions: A novel T96R mutation was identified for TTR protein. Biochemical and biophysical analyses revealed slightly destabilized kinetic stability. T96R mutation destabilized heterozygous protein but not proteolytic degradation, explaining its pathogenicity. Inhibitory effect of small molecule drugs on T96R mutation was different, suggesting personalized treatment may be required.

Purpose : This study aimed to assess the value of radiomic features derived from the myocardium (MYO) and papillary muscle (PM) for left ventricular hypertrophy (LVH) detection and hypertrophic cardiomyopathy (HCM) versus hypertensive heart disease (HHD) differentiation. Methods : There were 345 subjects who underwent cardiovascular magnetic resonance (CMR) examinations that were analyzed. After quality control and manual segmentation, the 3D radiomic features were extracted from the MYO and PM. The data were randomly split into training (70%) and testing (30%) datasets. Feature selection was performed on the training dataset. Five machine learning models were evaluated using the MYO, PM, and MYO+PM features in the detection and differentiation tasks. The optimal differentiation model was further evaluated using CMR parameters and combined features. Results : Six features were selected for the MYO, PM, and MYO+PM groups. The support vector machine models performed best in both the detection and differentiation tasks. For LVH detection, the highest area under the curve (AUC) was 0.966 in the MYO group. For HCM vs. HHD differentiation, the best AUC was 0.935 in the MYO+PM group. Comparing the radiomics models to the CMR parameter models for the differentiation tasks, the radiomics models achieved significantly improved the performance ( p = 0.002). Conclusions : The radiomics model with the MYO+PM features showed similar performance to the models developed from the MYO features in the detection task, but outperformed the models developed from the MYO or PM features in the differentiation task. In addition, the radiomic models performed better than the CMR parameters' models.

Background and Aim: Cardiotoxicity has become the most common cause of non-cancer death among breast cancer patients. Pyrotinib, a tyrosine kinase inhibitor targeting HER2, has been successfully used to treat breast cancer patients but has also resulted in less well-understood cardiotoxicity. This prospective, controlled, open-label, observational trial was designed to characterize pyrotinib's cardiac impacts in the neoadjuvant setting for patients with HER2-positive early or locally advanced breast cancer., Patients and Methods: The EARLY-MYO-BC study will prospectively enroll HER2-positive breast cancer patients who are scheduled to receive four cycles of neoadjuvant therapy with pyrotinib or pertuzumab added to trastuzumab before radical breast cancer surgery. Patients will undergo comprehensive cardiac assessment before and after neoadjuvant therapy, including laboratory measures, electrocardiography, transthoracic echocardiography, cardiopulmonary exercise testing (CPET), and cardiac magnetic resonance (CMR). To test the non-inferiority of pyrotinib plus trastuzumab therapy to pertuzumab plus trastuzumab therapy in terms of cardiac safety, the primary endpoint will be assessed by the relative change in global longitudinal strain from baseline to completion of neoadjuvant therapy by echocardiography. The secondary endpoints include myocardial diffuse fibrosis (by T1-derived extracellular volume), myocardial edema (by T2 mapping), cardiac volumetric assessment by CMR, diastolic function (by left ventricular volume, left atrial volume, E/A, and E/E') by echocardiography, and exercise capacity by CPET., Discussion: This study will comprehensively assess the impacts of pyrotinib on myocardial structural, function, and tissue characteristics, and, furthermore, will determine whether pyrotinib plus trastuzumab is a reasonable dual HER2 blockade regimen with regard to cardiac safety. Results may provide information in selecting an appropriate anti-HER2 treatment for HER2-positive breast cancer., Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04510532., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chai, Jiang, Wang, Liu, Lu, Tao, Wu, Yin, Lu and Pu.)

Introduction and Objectives: The aging population is expected to reach 2 billion by 2050, but the impact of somatic symptom disorder (SSD) on the elderly has been insufficiently addressed. We aimed to clarify the prevalence of SSD in China and to identify physical and psychological differences between the elderly and non-elderly., Methods: In this prospective multi-center study, 9020 participants aged (2206 non-elderly adults and 6814 elderly adults) from 105 communities of Shanghai were included (Assessment of Somatic Symptom in Chinese Community-Dwelling People, clinical trial number NCT04815863, registered on 06/12/2020). The Somatic Symptom Scale-China (SSS-CN) questionnaire was used to measure SSD. Depressive and anxiety disorders were assessed by the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively., Results: The prevalence of SSD in the elderly was higher than that in the non-elderly (63.2% vs. 45.3%). The elderly suffered more severe SSD (20.4% moderate and severe in elderly vs. 12.0% in non-elderly) and are 1.560 times more likely to have the disorder (95%CI: 1.399-1.739; p < .001) than the non-elderly. Comorbidity of depressive or anxiety disorders was 3.7 times higher than would be expected in the general population. Additionally, the results of adjusted multivariate analyses identified older age, female sex, and comorbid physical diseases as predictive risk factors of SSD in the elderly group., Conclusions: With higher prevalence of common physical problems (including hypertension, diabetes mellitus and cardio/cerebrovascular disease), the elderly in Shanghai are more vulnerable to have SSD and are more likely to suffer from comorbid depressive and anxiety disorders. SSD screening should be given more attention in the elderly, especially among older females with several comorbid physical diseases., (© 2022. The Author(s).)

Cholesterol gallstone disease is a worldwide common disease. Cholesterol supersaturation in gallbladder bile is the prerequisite for its pathogenesis, while the mechanism is not completely understood. In this study, we find enrichment of gut microbiota (especially Desulfovibrionales) in patients with gallstone disease. Fecal transplantation of gut microbiota from gallstone patients to gallstone-resistant strain of mice can induce gallstone formation. Carrying Desulfovibrionales is associated with enhanced cecal secondary bile acids production and increase of bile acid hydrophobicity facilitating intestinal cholesterol absorption. Meanwhile, the metabolic product of Desulfovibrionales, H 2 S increase and is shown to induce hepatic FXR and inhibit CYP7A1 expression. Mice carrying Desulfovibrionales present induction of hepatic expression of cholesterol transporters Abcg5/g8 to promote biliary secretion of cholesterol as well. Our study demonstrates the role of gut microbiota, Desulfovibrionales, as an environmental regulator contributing to gallstone formation through its influence on bile acid and cholesterol metabolism., (© 2022. The Author(s).)

Background: Hepatic lipid metabolism regulates biliary composition and influences the formation of cholesterol gallstones. The genes Hmgcr and Cyp7a1 , which encode key liver enzymes, are regulated by circadian rhythm-related transcription factors. We aimed to investigate the effect of circadian rhythm disruption on hepatic cholesterol and bile acid metabolism and the incidence of cholesterol stone formation., Methods: Adult male C57BL/6J mice were fed either a lithogenic diet (LD) only during the sleep phase (time-restricted lithogenic diet feeding, TRF) or an LD ad libitum (non-time-restricted lithogenic diet feeding, nTRF) for 4 weeks. Food consumption, body mass gain, and the incidence of gallstones were assessed. Circulating metabolic parameters, lipid accumulation in the liver, the circadian expression of hepatic clock and metabolic genes, and the gut microbiota were analyzed., Results: TRF caused a dysregulation of the circadian rhythm in the mice, characterized by significant differences in the circadian expression patterns of clock-related genes. In TRF mice, the circadian rhythms in the expression of genes involved in bile acid and cholesterol metabolism were disrupted, as was the circadian rhythm of the gut microbiota. These changes were associated with high biliary cholesterol content, which promoted gallstone formation in the TRF mice., Conclusion: Disordered circadian rhythm is associated with abnormal hepatic bile acid and cholesterol metabolism in mice, which promotes gallstone formation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 He, Shen, Chen, Wang, Lu, Shao, Jiang and Hu.)

Gallstone disease is a worldwide common disease. However, the knowledge concerning the gallbladder in the pathogenesis of cholesterol gallstone formation remains limited. In this study, using single-cell RNA sequencing (scRNA-seq) to obtain the transcriptome of gallbladder cells, we showed cellular heterogeneity and transcriptomic dynamics in murine gallbladder cells during the process of lithogenesis. Our results indicated gallbladder walls were subjected to remodeling during the process of lithogenesis. The major molecular events that happened included proliferation of epithelial cells, infiltration of immune-cells, activation of angiogenesis, and extracellular matrix modulation. Furthermore, we observed partial reversal of gallbladder cell transcriptomes by ursodeoxycholic acid treatment. This work thus provides novel and integral knowledges on the cellular changes during lithogenesis, which is of great significance to the understanding of pathogenesis and treatment of cholesterol gallstone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liang, Shao, Liu, Lu, Gu and Jiang.)

Background: Decreased spikelet fertility is often responsible for reduction in grain yield in rice (Oryza sativa L.). In this study, two varieties with different levels of heat tolerance, Liangyoupeijiu (LYPJ, heat susceptible) and Shanyou63 (SY63, heat tolerant) were subjected to two temperature treatments for 28 days during the panicle initiation stage in temperature/relative humidity-controlled greenhouses: high temperature (HT; 37/27 °C; day/night) and control temperature (CK; 31/27 °C; day/night) to investigate changes in anther development under HT during panicle initiation and their relationship with spikelet fertility., Results: HT significantly decreased the grain yield of LYPJ by decreasing the number of spikelets per panicle and seed setting percentage. In addition, HT produced minor adverse effects in SY63. The decreased spikelet fertility was primarily attributed to decreased pollen viability and anther dehiscence, as well as poor pollen shedding of the anthers of LYPJ under HT. HT resulted in abnormal anther development (fewer vacuolated microspores, un-degraded tapetum, unevenly distributed Ubisch bodies) and malformation of pollen (obscure outline of the pollen exine with a collapsed bacula, disordered tectum, and no nexine of the pollen walls, uneven sporopollenin deposition on the surface of pollen grains) in LYPJ, which may have lowered pollen viability. Additionally, HT produced a compact knitted anther cuticle structure of the epidermis, an un-degraded septum, a thickened anther wall, unevenly distributed Ubisch bodies, and inhibition of the confluent locule, and these malformed structures may be partially responsible for the decreased anther dehiscence rate and reduced pollen shedding of the anthers in LYPJ. In contrast, the anther wall and pollen development of SY63 were not substantially changed under HT., Conclusions: Our results suggest that disturbed anther walls and pollen development are responsible for the reduced spikelet fertility and grain yield of the tested heat susceptible variety, and noninvasive anthers and pollen formation in response to HT were associated with improved heat tolerance., (© 2021. The Author(s).)

Increasing evidence suggests that cholecystectomy is an independent risk factor for non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms that lead to hepatic lipid deposition after cholecystectomy are unclear. In this study, adult male C57BL/6J mice that underwent a cholecystectomy or sham operation were fed either a high-fat diet (HFD) or a chow diet for 56 days. Significantly increased steatohepatitis, liver/body weight ratio, hepatic triglycerides, and glucose intolerance were observed in postcholecystectomy mice fed the HFD. Notable alterations in the composition of gut microbiota after cholecystectomy were observed in both HFD- and chow-diet-fed mice. Our results indicate that cholecystectomy alters the gut microbiota profile, which might contribute to the development of NAFLD in mice., (© 2021 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Introduction and Objectives: The incidence of gallstone-related disease steadily increased in the last few years. Here, we aimed to investigate the effect of tauroursodeoxycholic acid 1 (TUDCA) on preventing cholesterol gallstones formation in high-fat fed (HFD) mice., Material and Methods: Specific pathogen-free male C57Bl/6 mice were fed a lithogenic diet 2 (LD group) alone or in combination with TUDCA (5g/kg diet) for 8 weeks. Upon sacrifice, serum, gallbladder, liver and small intestine were collected and the formation of gallstones or crystals in the gallbladder was analyzed. Additionally, the intestinal microbiota, and bile acid composition, serum lipids and hepatic lipids were studied., Results: Cholesterol gallstones with cholesterol crystals formed in mice of the LD-fed group (15/15, 100%). However, only cholesterol crystals were found in three mice without the presence of any gallstone in the TUDCA-treated group. Both serum and hepatic total cholesterol levels in the TUDCA group were significantly decreased compared with the LD group. Concomitantly, mRNA expression of Abcg5 and Abcg8 was significantly lower in the liver of the TUDCA group whilst mRNA transcripts for Abcb11, Acat2, and Cyp27 were significantly increased compared with the LD group. Additionally, the gallbladder cholesterol saturation index (1.06±0.15) in the TUDCA group was significantly decreased compared with the LD group. Interestingly, the ratio of Firmicutes/Bacteroides in the TUDCA group was increased 3x fold., Conclusions: TUDCA can inhibit the absorption and synthesis of lipids in the small intestine by improving the intestinal microbiota in HFD-fed mice, thus reducing gallstone formation., (Copyright © 2020. Published by Elsevier España, S.L.U.)

Trimethylamine-N-oxide (TMAO) is a metabolite derived from trimethylamine (TMA), which is first produced by gut microbiota and then oxidized by flavin-containing monooxygenase 3 (FMO3) in the liver. TMAO may contribute to the development of diseases such as atherosclerosis because of its role in regulating lipid metabolism. In this study, we found that high plasma TMAO levels were positively associated with the presence of gallstone disease in humans. We further found increased hepatic FMO3 expression and elevated plasma TMAO level in a gallstone-susceptible strain of mice C57BL/6J fed a lithogenic diet (LD), but not in a gallstone-resistant strain of mice AKR/J. Dietary supplementation of TMAO or its precursor choline increased hepatic FMO3 expression and plasma TMAO levels and induced hepatic canalicular cholesterol transporters ATP binding cassette (Abc) g5 and g8 expression in mice. Up-regulation of ABCG5 and ABCG8 expression was observed in hepatocytes incubated with TMAO in vitro. Additionally, in AKR/J mice fed a LD supplemented with 0.3% TMAO, the incidence of gallstones rose up to 70% compared with 0% in AKR/J mice fed only a LD. This was associated with increased hepatic Abcg5 and g8 expression induced by TMAO. Our study demonstrated TMAO could be associated with increased hepatic Abcg5/g8 expression, biliary cholesterol hypersecretion and gallstone formation., (Copyright © 2019 Elsevier B.V. All rights reserved.)