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Aldolase A (A-2) (ALD), Kelch-like-ECH associated protein-1 (Keap-1), and Forkhead box O4 (FoxO4) are key regulatory proteins, which have been proven to be involved in tumor development. However, the clinicopathological significance of ALD, Keap-1, and FoxO4 expressions in colorectal (colon) carcinoma (CRC) is not clearly known. We sought to explore the clinicopathological significance of ALD, Keap-1, and FoxO4 in CRC to provide evidences for potential monitoring index of CRC. Cases of 199 CRC patients were analyzed retrospectively. Evaluation of ALD, cAMP response element-binding protein-2, cyclo-oxygenase 2, FoxO4, Keap-1, and p53 expressions in CRC patients was accomplished with immunohistochemical technique. The patients were divided into negative and positive groups in accordance with immunohistochemical result. We compared the clinicopathological characteristics of the patients in the 2 groups, coupled with analysis of the relationship between 6 aforesaid proteins and clinicopathological characteristics. Herein, we confirmed the association of tumor location with the expression of ALD, Keap-1, and FoxO4. Also, tumor differentiation was observed to associate significantly with the expression of Keap-1, FoxO4, and Cox-2. The data also revealed that there was a correlation between smoking and expression of ALD, Keap-1, FoxO4, p53, and Cox-2. Nevertheless, insignificant difference was observed when clinicopathological characteristics were compared with cAMP response element-binding protein-2 expression. These findings suggest that ALD, Keap-1, and FoxO4 reinvolved in CRC development, and thus may be considered as potential monitoring protein for CRC., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Textile pressure sensors capable of withstanding high temperatures have attracted increasing interest due to their potential applications in harsh conditions. In this work, a textile pressure sensor with high-temperature resistance was realized based on multi-wall carbon nanotubes (MWCNTs) and quartz fabrics. The textile pressure sensors exhibited low fatigue over 20 000 cyclic loadings. Owing to the high-temperature resistance of MWCNTs and quartz fabrics, the textile sensor can work at temperatures up to 300 °C and can maintain good sensitivity after calcination at 900 °C in N 2 for 30 min. This work provides a simple, facile, and inexpensive method for fabricating textile pressure sensors with high-temperature resistance., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

In healthy settings, the gut-liver axis allows host-microbiota communications and mediates immune homeostasis through bidirectional regulation. Meanwhile, in diseases, gut dysbiosis, combined with an impaired intestinal barrier, introduces pathogens and their toxic metabolites into the system, causing massive immune alternations in the liver and other extrahepatic organs. Accumulating evidence suggests that these immune changes are associated with the progression of many liver diseases, especially hepatic cirrhosis. Pathogen-associated molecular patterns that originated from gut microbes directly stimulate hepatocytes and liver immune cells through different pattern recognition receptors, a process further facilitated by damage-associated molecular patterns released from injured hepatocytes. Hepatic stellate cells, along with other immune cells, contribute to this proinflammatory and profibrogenic transformation. Moreover, cirrhosis-associated immune dysfunction, an imbalanced immune status characterized by systemic inflammation and immune deficiency, is linked to gut dysbiosis. Though the systemic inflammation hypothesis starts to link gut dysbiosis to decompensated cirrhosis from a clinical perspective, a clearer demonstration is still needed for the role of the gut-liver-immune axis in cirrhosis progression. This review discusses the different immune states of the gut-liver axis in both healthy and cirrhotic settings and, more importantly, summarizes the current evidence about how microbiota-derived immune remodeling contributes to the progression of hepatic cirrhosis via the gut-liver axis., 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 © 2022 Guan, Zhang, Kuang and Yu.)

The effects of digital Cognitive Behavior Therapy for insomnia (dCBT-i) on sleep quality have been previously demonstrated but the spillover effects on fatigue, flow (a state of immersion in activities of interest), and cognitive flexibility remain unclear. The current study examined the effectiveness of dCBT-i. A total of 97 college students (20.96 ± 1.87 years, 73.1% female students) were randomly selected from a shortlist and divided into sleep intervention ( n = 39), conventional education ( n = 37), and healthy control ( n = 21) groups. Task switching paradigm, Fatigue Severity Scale (FSS), Flow Experience Scale (FES), and the Chinese version of the Pittsburgh Sleep Quality Index (CPSQI) were measured pre- and post-intervention. Results show that the sleep quality of the intervention group improved, and fatigue was relieved. Participants in the sleep intervention group had increased flow experience scores post-intervention and improved cognitive flexibility. The control group's sleep quality deteriorated and fatigue level increased. dCBT-i can not only achieve a significant improvement in sleep quality and reduce fatigue, but also improve learning abilities, quality of life, flow, and cognitive flexibility. Future research should pay attention to indicators such as work efficiency, sedative use, and the durability and stability of such effects.

Purposes: To evaluate the postsurgical prognostic implication of contrast-enhanced ultrasound (CEUS) for combined hepatocellular-cholangiocarcinoma (CHC). To build a CEUS-based early recurrence prediction classifier for CHC, in comparison with tumor-node-metastasis (TNM) staging., Methods: The CEUS features and clinicopathological findings of each case were analyzed, and the Liver Imaging Reporting and Data System categories were assigned. The recurrence-free survival associated factors were evaluated by Cox proportional hazard model. Incorporating the independent factors, nomograms were built to estimate the possibilities of 3-month, 6-month, and 1-year recurrence and whose prognostic value was determined by time-dependent receiver operating characteristics, calibration curves, and hazard layering efficiency validation, comparing with TNM staging system., Results: In the multivariable analysis, the levels of carbohydrate antigen 19-9, prothrombin time and total bilirubin, and tumor shape, the Liver Imaging Reporting and Data System category were independent factors for recurrence-free survival. The LR-M category showed longer recurrence-free survival than did the LR-4/5 category. The 3-month, 6-month, and 1-year area under the curves of the CEUS-clinical nomogram, clinical nomogram, and TNM staging system were 0.518, 0.552, and 0.843 versus 0.354, 0.240, and 0.624 (P = .048, .049, and .471) vs. 0.562, 0.545, and 0.843 (P = .630, .564, and .007), respectively. The calibration curves of the CEUS-clinical model at different prediction time pionts were all close to the ideal line. The CEUS-clinical model effectively stratified patients into groups of high and low risk of recurrence in both training and validation set, while the TNM staging system only works on the training set., Conclusions: Our CEUS-clinical nomogram is a reliable early recurrence prediction tool for hepatocellular-cholangiocarcinoma and helps postoperative risk stratification., (© 2021 American Institute of Ultrasound in Medicine.)

Aberrant RNA modifications lead to dysregulated gene expression and cancer progression. Ribosomal RNA (rRNA) accounts for more than 80% of a cell's total RNA, but the functions and molecular mechanisms underlying rRNA modifications in cancers are poorly understood. Here, we show that the 18S rRNA N 6 -methyladenosine (m 6 A) methyltransferase complex METTL5-TRMT112 is upregulated in various cancer types and correlated with poor prognosis. In addition, we demonstrate the critical functions of METTL5 in promoting hepatocellular carcinoma (HCC) tumorigenesis in vitro and in mouse models. Mechanistically, depletion of METTL5-mediated 18S rRNA m 6 A modification results in impaired 80S ribosome assembly and decreased translation of mRNAs involved in fatty acid metabolism. We further reveal that ACSL4 mediates the function of METTL5 on fatty acid metabolism and HCC progression, and targeting ACSL4 and METTL5 synergistically inhibits HCC tumorigenesis in vivo. Our study uncovers mechanistic insights underlying mRNA translation control and HCC tumorigenesis through lipid metabolism remodeling and provides a molecular basis for the development of therapeutic strategies for HCC treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Imaging traits including nonsmooth tumor margins, internal arteries, peritumoral enhancement, and absence of hypodense halos can reflect tumor aggressiveness preoperatively and may affect treatment selection. This study aimed to explore the role of these four imaging traits in treatment selection between surgical resection (SR) and radiofrequency ablation (RFA) for patients with single ≤ 5 cm hepatocellular carcinoma (HCC)., Patients and Methods: Three hundred eight-one patients with single ≤ 5 cm HCC who underwent SR (n = 202) or RFA (n = 179) in the First Affiliated Hospital of Sun Yat-sen University from April 2010 to December 2019 were retrospectively enrolled. The efficacy of SR and RFA in patients with the imaging traits that significantly influenced recurrence-free survival (RFS) or overall survival (OS) was compared and analyzed., Results: Multivariable Cox regression analysis identified that having internal arteries (P = 0.001) was an independent influencing factor for RFS, while internal arteries (P = 0.005) and peritumoral enhancement (P = 0.001) were independent influencing factors for OS. In patients with internal arteries, subgroup analysis based on tumor size demonstrated that both RFS and OS of SR were superior to those of RFA in patients with 3-5 cm HCC (RFS, P = 0.023; OS, P = 0.015). In patients with peritumoral enhancement, both RFS and OS of SR were superior to those of RFA (RFS, P = 0.019; OS, P = 0.042)., Conclusion: SR may be associated with improved survival compared with RFA in patients with single 3-5 cm HCC having internal arteries and patients with single ≤ 5 cm HCC having peritumoral enhancement., (© 2022. Society of Surgical Oncology.)

Mastitis, an inflammation of the mammary gland, is a complex disease that affects the health of dairy cows worldwide. Sodium butyrate (SB) is a short-chain fatty acid that has recently been shown to have antioxidant, anti-inflammatory and anti-apoptotic potential in various cells types, although its role in bovine mammary epithelial cells (bMECs) has not been comprehensively reported. Therefore, the aim of this study was to assess the protective effect of sodium butyrate on Lipopolysaccharide (LPS)-induced mastitis model in vitro and to elucidate the possible underlying molecular mechanisms. The in vitro mastitis model was designed to investigate the regulatory effect of SB on LPS-induced inflammatory conditions in bMECs, with particular emphasis on oxidative stress, inflammatory response, apoptosis, and mitochondrial dysfunction. The results showed that SB co-treatment markedly prevented LPS-induced death of bMECs in a concentration-dependent manner. In addition, SB attenuated LPS-induced oxidative stress (OS) (Increased Intracellular ROS, MDA, and decreased SOD, GSH-Px and CAT activity), thereby reduced inflammation (increased expression of IL-6, IL-Iβ, and TNF-α), and apoptosis (Increased the expression of caspases and Bax and decreased Bcl-2) via inhibiting NF-kB and caspase/bax signaling pathways. Furthermore, the protective effect of SB was also associated with the activation of endogenous antioxidant system (Nrf2, Keap1, NQO-1 and HO-1). Nrf2 silencing significantly abolished the protective effect of SB on bMECs. In conclusion, our findings suggest that SB has a significant protective effect on LPS-induced OS, inflammatory responses and apoptosis by activating Nrf2 and inhibiting NF-kB and ROS-mediated mitochondrial dysfunction. These results propose that SB may be an important regulator of OS and its subsequent inflammatory responses, and thus could be used as a therapeutic agent for bovine mastitis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: For unresectable biliary tract cancer (BTC), chemotherapy (CT) alone is associated with poor survival and severe toxicity. Immunotherapy (IO) is potentially effective for BTC, and radiation therapy (RT) may synergize with IO. We investigated CT versus combined RT and anti-programmed cell death-1 (PD-1) IO for unresectable BTC., Methods and Materials: We prospectively observed 117 participants with unresectable BTC either at initial diagnosis or at first recurrence at a single center who chose 1 of 2 treatment options between August 2018 and October 2020. The options were (1) external beam RT combined with anti-PD-1 IO (RT/IO) or (2) CT alone. In the RT/IO group, camrelizumab (200 mg intravenously every 3 weeks) was initiated within 7 days after the completion of RT and continued until progression or intolerable side effects were noted. The median dose per fraction was 55 Gy/25 fractions (range, 50-60 Gy/20-25 fractions). In the CT group, cisplatin and gemcitabine were delivered intravenously every 3 weeks for 8 cycles. We analyzed the adverse events (AEs), overall survival (OS), and disease-free survival (DFS), and performed subgroup analysis according to tumor mutational burden (TMB) and microsatellite status in the combination group., Results: Thirty-nine and 78 participants received RT/IO and CT, respectively. The crude rate of severe AEs (grade ≥3 AEs) was higher in the CT group (79.4% vs 7.7%, P < .001). The OS and DFS after RT/IO were longer than that after CT (median OS: 17.0 vs 11.5 months, P = .01; median DFS: 12.5 vs 7.9 months, P = .008). Participants with low TMB or microsatellite stability had a shorter median OS (13.6 vs 25.7 months, P = .03) and median DFS (9.8 vs 19.3 months, P = .012) than participants with high TMB or microsatellite instability., Conclusions: RT combined with anti-PD-1 IO may be well tolerated and associated with an improved response rate, DFS, and OS compared with CT alone in patients with unresectable BTC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Recently, there has been a rapidly expanding interest in a new nanomaterial, graphene quantum dots (GQDs), owing to its profound potential in various advanced applications. At present, the study of GQDs mainly focuses on the new synthesis methods and surface modification. However, revealing the intracellular distribution of GQDs is currently not available, limiting in-depth understanding of its biological regulatory mechanism. To fill up this gap, the visualization study of red fluorescent graphene quantum dots (Red-GQDs) is helpful to clarify their subcellular distribution and metabolism in living cells system. Here, in this study, two-photon laser confocal microscopy was used to deeply analyze the uptake and subcellular distribution of Red-GQDs by HeLa cells at different concentrations and times through visual observation and discussed the effect of Red-GQDs on the metabolic of HeLa cells. The results indicated that Red-GQDs could be well-absorbed by HeLa cells and further revealed the differential distribution of Red-GQDs in different organelles (lysosomes and mitochondria) in a time-dependent manner. In addition, we confirmed that Red-GQDs significantly affect cell biological functions. Low concentrations of Red-GQDs are related to the autophagy pathway of cells, and high concentrations of Red-GQDs can induce ferroptosis in cells and promote the secretion of cellular exosomes. In the present study, the distribution and metabolic pathways of Red-GQDs in the subcellular structure of cells were characterized in detail through visual analysis, which can bring positive reference for the application of Red-GQDs in the future., 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 © 2022 Hu, Li, Qiu, Zhao, Kuang, Zhang and Wang.)

Systemic treatment for hepatocellular carcinoma (HCC) has been advancing rapidly over the last decade. More novel agents, including both targeted agents and immune checkpoint inhibitors, are available for physicians to use sequentially or concurrently for patients with advanced HCC. Despite more options, only a proportion of patients benefit from each regimen. Therefore, clinicians are facing challenges on how to choose the right regimen for the right patient with HCC, which raises the importance of personalized treatment approach. To advance personalized treatment for HCC, one approach relies on the acquisition of biomarker data from clinical trials to evaluate clinical parameters or genotypes in association with outcomes of selected drugs. This approach has led to finding of high baseline alpha-fetoprotein levels in association with benefits of ramucirumab. Cumulative findings from multiple clinical trials and translational studies also suggest that selected etiology and/or genotype of HCC could predict resistance to immune checkpoint inhibitors. The second approach is to decipher the tumor heterogeneity of HCC with an aim to identify clinically relevant patterns to guide clinical decisions. Tumor heterogeneity could exist within a single tumor (intra-tumoral heterogeneity), among different tumors in the same patient (inter-tumoral heterogeneity) or between primary and recurrent tumors (temporal tumor heterogeneity). The analyses of tumor heterogeneity have also been powered by coverage of tumor immune environment and incorporation of circulating tumor nucleic acid technology. Emerging publications have been reported above tumor heterogeneity exist in HCC, which is potentially clinically impactful., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

BACKGROUND. Contrast-enhanced ultrasound (CEUS) LI-RADS assigns category LR-M to observations that are definitely or probably malignant but that on imaging are not specific for hepatocellular carcinoma (HCC). A high percentage of LR-M observations represent HCC. OBJECTIVE. The purpose of this study was to retrospectively evaluate the utility of additional features, beyond conventional LI-RADS major features, for detecting HCC among LR-M observations on CEUS. METHODS. This retrospective study included 174 patients (145 men, 29 women; mean age, 53 years) at high risk of HCC who underwent CEUS from August 2014 to June 2016 that showed an LR-M observation according to CEUS LI-RADS version 2017. Two radiologists independently assessed CEUS images for major features and four additional features (chaotic vessels, peripheral circular artery, clear boundary of tumor enhancement, clear boundary of intratumoral unenhanced area). The diagnostic performance of four proposed criteria for the detection of HCC among LR-M observations was assessed. The impact of criteria based on the additional findings on detection of HCC was further explored. Histology or composite imaging and clinical follow-up were the reference standards. RESULTS. The 174 LR-M observations included 142 HCCs and 32 non-HCC lesions (20 intrahepatic cholangiocarcinomas, five combined hepatocellular-cholangiocarcinomas, seven benign lesions). Interreader agreement on the additional features ranged from κ = 0.65 to κ = 0.88. Two of the additional features had excellent PPV for HCC: chaotic vessels (94.8%) and peripheral circular arteries (98.1%). The presence of either of these two additional features had sensitivity of 50.7%, specificity of 90.6%, PPV of 96.0%, and NPV of 29.3% for HCC. Three other criteria incorporating variations of major LI-RADS features but not the additional features had sensitivities of 55.6-96.5%, specificities of 49.6-68.8%, PPVs of 87.8-90.6%, and NPVs of 25.0-75.0%. On the basis of criteria that included additional features, 75 of 174 LR-M observations were recategorized LR-5; 72 of the 75 were HCC. CONCLUSION. The presence of chaotic vessels and/or peripheral circular artery had high specificity and PPV for HCC among LR-M observations. Other explored criteria based on major features did not have higher specificity or PPV. CLINICAL IMPACT. Clinical adoption of the additional CEUS features could help establish the diagnosis of HCC noninvasively and avoid the need for biopsy of LR-M observations.

The ordered coassembly of mixed-dimensional species-such as zero-dimensional (0D) nanocrystals and 2D microscale nanosheets-is commonly deemed impracticable, as phase separation almost invariably occurs. Here, by manipulating the ligand grafting density, we achieve ordered coassembly of 0D nanocrystals and 2D nanosheets under standard solvent evaporation conditions, resulting in macroscopic, freestanding hybrid-dimensional superlattices with both out-of-plane and in-plane order. The key to suppressing the notorious phase separation lies in hydrophobizing nanosheets with molecular ligands identical to those of nanocrystals but having substantially lower grafting density. The mismatched ligand density endows the two mixed-dimensional components with a molecular recognition-like capability, driving the spontaneous organization of densely capped nanocrystals at the interlayers of sparsely grafted nanosheets. Theoretical calculations reveal that the intercalation of nanocrystals can substantially reduce the short-range repulsions of ligand-grafted nanosheets and is therefore energetically favorable, while subsequent ligand-ligand van der Waals attractions induce the in-plane order and kinetically stabilize the laminate superlattice structure.

Aims/introduction: Overweight and obesity in adults are strongly associated with an increased risk of prediabetes, and this study set out to gain a better understanding of the optimal body mass index (BMI) range for assessing the risk of prediabetes in the Chinese population., Materials and Methods: The cohort study included 100,309 Chinese adults who underwent health screening. Participants were divided into six groups based on the cut-off point for BMI recommended by the World Health Organization (underweight: <18.5 kg/m 2 , normal-weight: 18.5-24.9 kg/m 2 , pre-obese: 25.0-29.9 kg/m 2 , obese class I: 30.0-34.9 kg/m 2 , obese class II: 35.0-39.9 kg/m 2 , and obese class III ≥40 kg/m 2 ). The association of BMI with prediabetes and the shape of the correlation were modeled using multivariate Cox regression and restricted cubic spline regression, respectively., Results: In the multivariate Cox regression model, with normal weight as the control group, underweight people had a lower risk of developing prediabetes, whereas obese and pre-obese people had a higher risk of prediabetes. Additionally, in the restricted cubic spline model, we found that the association of BMI with prediabetes follows a positive dose-response relationship, but does not conform to the pattern of obesity paradox. Among the general population in China, a BMI of 23.03 kg/m 2 might be a potential intervention threshold for prediabetes., Conclusions: The national cohort study found that the association of BMI with prediabetes follows a positive dose-response relationship, rather than a pattern of obesity paradox. For Chinese people with normal weight, more attention should be paid to glucose metabolism when BMI exceeds 23.03 kg/m 2 ., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Objective: Sepsis remains a major cause of neonatal death. To better characterize the inflammatory response during neonatal sepsis, we compared the differences in serum cytokines and chemokines between full-term neonates with sepsis and without infection., Methods: We enrolled 40 full-term neonates with sepsis and 26 full-term neonates without infection as controls between October 2016 and June 2018. Forty cytokines /chemokines in serum were analyzed using the Luminex Bead Immunoassay System., Results: Our results showed that serum IL-6, IL-8, TNF-α, IL-1β, MIF, CXCL13, CXCL1, CXCL2, CXCL5, CXCL6, CXCL16, CCL27, CCL2, CCL8, CCL3, CCL20, CCL23, and CX3CL1 levels were significantly increased in neonates with sepsis compared to those in the control group (all p <0.05). The levels of serum CCL20, and IL-17 were higher in late-onset sepsis (LOS) than those in early-onset sepsis (EOS) (all p <0.05). Conversely, serum CXCL16 was lower in LOS than that in EOS ( p <0.05)., Conclusion: Our findings revealed that excessive pro-inflammatory cytokines might be involved in neonatal sepsis. In addition, chemokines significantly increased the recruitment of immune cells after infection to participate in the anti-infection defense of neonates, but this could lead to damage., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Chen et al.)

Aims: With prevalence of hepatocellular carcinoma (HCC) in low-risk population (LRP), establishing a non-invasive diagnostic strategy becomes increasingly urgent to spare unnecessary biopsies in this population. The purposes of this study were to find characterisics of HCC and to establish a proper non-invasive method to diagnose HCC in LRP., Methods: A total of 681 patients in LRP (defined as the population without cirrhosis, chronic HBV infection or HCC history) were collected from 2 institutions. The images of computed tomography (CT) and magnetic resonance imaging (MRI) were manually analysed. We divided the patients into the training cohort (n = 324) and the internal validating cohort (n = 139) by admission time in the first institution. The cohort in the second institution was viewed as the external validation (n = 218). A multivariate logistic regression model incorporating both imaging and clinical independent risk predictors was developed. C-statistics was used to evaluate the diagnostic performance., Results: Besides the major imaging features of HCC (non-rim enhancement, washout and enhancing capsule), tumor necrosis or severe ischemia (TNSI) on imaging and two clinical characteristics (gender and alpha fetoprotein) were also independently associated with HCC diagnosis (all P < 0.01). A clinical model (including 3 major features, TNSI, gender and AFP) was built to diagnose HCC and achieved good diagnostic performance (area under curve values were 0.954 in the training cohort, 0.931 in the internal validation cohort and 0.902 in the external cohort)., Conclusions: The clinical model in this study developed a satisfied non-invasive diagnostic performance for HCC in LRP., (© 2022. The Author(s).)

The study aims to build a model that predicts the behavior of the use of blended learning by English teachers of basic education in China in the environment of repeated lockdowns during the COVID-19 pandemic. It examines the relationships between ICT self-efficacy, organizational support for blended learning, attitudes toward blended learning, and the use of blended learning. Data were collected from 562 teachers using a survey questionnaire. Employing partial least squares structural equation modeling (PLS-SEM), a hypothesized model was tested for path coefficients and predictive power. This study found that ICT self-efficacy and organizational support for blended learning are sound predictors of teachers' use of blended learning and that the former appeared to be a stronger determinant. In addition, attitudes toward blended learning can directly influence teachers' use of blended learning and mediate the relationship between ICT efficacy and the use of blended learning and between organizational support for blended learning and the use of blended learning. These three variables account for 54.7% of the variance in teachers' use of blended learning., 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 © 2022 Ye, Kuang and Liu.)

Background: The diversity of obesity-related metabolic characteristics generates different obesity phenotypes and corresponding metabolic diseases. This study aims to explore the correlation of different abdominal obesity phenotypes with non-alcoholic fatty liver disease (NAFLD)., Methods: The current study included 14,251 subjects, 7411 males and 6840 females. Abdominal obesity was defined as waist circumference ≥ 85 cm in males and ≥ 80 cm in females; according to the diagnostic criteria for metabolic syndrome recommended by the National Cholesterol Education Program Adult Treatment Panel III, having more than one metabolic abnormality (except waist circumference criteria) was defined as metabolically unhealthy. All subjects were divided into 4 abdominal obesity phenotypes based on the presence ( +) or absence (- ) of metabolically healthy/unhealthy (MH) and abdominal obesity (AO) at baseline: metabolically healthy + non-abdominal obesity (MH - AO - ); metabolically healthy + abdominal obesity (MH - AO + ); metabolically unhealthy + non-abdominal obesity (MH + AO - ); metabolically unhealthy + abdominal obesity (MH + AO + ). The relationship between each phenotype and NAFLD was analyzed using multivariate logistic regression., Results: A total of 2507 (17.59%) subjects in this study were diagnosed with NAFLD. The prevalence rates of NAFLD in female subjects with MH - AO - , MH - AO + , MH + AO - , and MH + AO + phenotypes were 1.73%, 24.42%, 7.60%, and 59.35%, respectively. Among male subjects with MH - AO - , MH - AO + , MH + AO - , and MH + AO + phenotypes, the prevalence rates were 9.93%, 50.54%, 25.49%, and 73.22%, respectively. After fully adjusting for confounding factors, with the MH - AO - phenotype as the reference phenotype, male MH - AO + and MH + AO + phenotypes increased the risk of NAFLD by 42% and 47%, respectively (MH - AO + : OR 1.42, 95%CI 1.13,1.78; MH + AO + : OR 1.47, 95%CI 1.08,2.01); the corresponding risks of MH - AO + and MH + AO + in females increased by 113% and 134%, respectively (MH - AO + : OR 2.13, 95%CI 1.47,3.09; MH + AO + : OR 2.34, 95%CI 1.32,4.17); by contrast, there was no significant increase in the risk of NAFLD in the MH + AO - phenotype in both sexes., Conclusions: This first report on the relationship of abdominal obesity phenotypes with NAFLD showed that both MH - AO + and MH + AO + phenotypes were associated with a higher risk of NAFLD, especially in the female population. These data provided a new reference for the screening and prevention of NAFLD., (© 2022. The Author(s).)

Developing novel luminescent materials with ideal properties is an endless project, urged by growing requirements of advances in energy saving, healthy lighting and environmental friendliness. Herein, a series of ScCaOBO 3 :Ce 3+ ,Mn 2+ phosphors with excellent luminescence properties were synthesized by the high temperature solid state method. X-ray diffraction was applied to analyse the phase composition of the obtained phosphors. The morphology and dopant distribution were observed by scanning electron microscopy (SEM) and energy dispersive spectrometry (EDS), respectively. The Rietveld refinements and luminescence spectra indicate that Ce 3+ preferentially occupies the Sc 3+ site and produces a blue emission band at around 460 nm, which originates from the characteristic 5d-4f transitions, while Mn 2+ preferentially occupies the Ca 2+ site and emits red light due to its characteristic 4 T 1 ( 4 G)- 6 A 1 ( 6 S) transitions. Upon excitation at 354 nm, both Ce 3+ and Mn 2+ emissions can be obtained and further investigations evidenced that the broad and intense light emission of Mn 2+ located in the red spectral region is the result of energy transfer from Ce 3+ to Mn 2+ . Theoretical calculations reveal that the energy transfer process from Ce 3+ to Mn 2+ is of the resonance type and is governed by electric dipole-dipole interactions. Since the ScCaOBO 3 :Ce 3+ ,Mn 2+ phosphors are capable of producing broadband emissions that widely cover the blue and red spectral regions, the introduction of a green light-emitting phosphor CMA:Tb 3+ can conveniently generate high quality white light. Therefore, a white light-emitting diode device with extremely high color rendering indices, R a = 93.7 and R 9 = 91.9, was successfully obtained.

Background: Zinc is an essential trace element involved in multiple metabolic processes. Acute kidney injury (AKI) is associated with low plasma zinc, but outcomes with zinc supplementation in critically ill patients with AKI remain unknown. Our objective was to investigate the effectiveness of zinc supplementation in this patient population., Methods: Critically ill patients with AKI were identified from the Medical Informative Mart for Intensive Care IV database. Prosperity score matching (PSM) was applied to match patients receiving zinc treatment to those without zinc treatment. The association between zinc sulfate use and in-hospital mortality and 30-day mortality, need for renal replacement therapy (RRT), and length of stay was determined by logistic regression and Cox proportional hazards modeling., Results: A total of 9,811 AKI patients were included in the study. PSM yielded 222 pairs of patients who received zinc treatment and those who did not. Zinc supplementation was associated with reduced in-hospital mortality (HR = 0.48 (95% CI: 0.28, 0.83) P = 0.009) and 30-day mortality (HR = 0.51 (95% CI, 0.30, 0.86) P = 0.012). In the subgroup analysis, zinc use was associated with reduced in-hospital mortality in patients with stage 1 AKI and those with sepsis., Conclusions: Zinc supplementation was associated with improved survival in critically ill patients with AKI. The supplementation was especially effective in those with stage 1 AKI and sepsis. These results need to be verified in randomized controlled trials., 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 © 2022 Xia, Li, Zhao, Xu, Kuang, Yao and Hu.)

Background: Conventional and unconventional lipid parameters are associated with diabetes risk, the comparative studies on lipid parameters for predicting future diabetes risk, however, are still extremely limited, and the value of conventional and unconventional lipid parameters in predicting future diabetes has not been evaluated. This study was designed to determine the predictive value of conventional and unconventional lipid parameters for the future development of diabetes., Methods: The study was a longitudinal follow-up study of 15,464 participants with baseline normoglycemia. At baseline, conventional lipid parameters such as low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) were measured/calculated, and unconventional lipid parameters such as non-HDL-C, remnant cholesterol (RC), LDL/HDL-C ratio, TG/HDL-C ratio, non-HDL/HDL-C ratio, TC/HDL-C ratio and RC/HDL-C ratio were calculated. Hazard ratio (HR) and 95% confidence interval (CI) were estimated by Cox proportional hazard regression adjusting for demographic and diabetes-related risk factors. The predictive value and threshold fluctuation intervals of baseline conventional and unconventional lipid parameters for future diabetes were evaluated by the time-dependent receiver operator characteristics (ROC) curve., Results: The incidence rate of diabetes was 3.93 per 1000 person-years during an average follow-up period of 6.13 years. In the baseline non-diabetic population, only TG and HDL-C among the conventional lipid parameters were associated with future diabetes risk, while all the unconventional lipid parameters except non-HDL-C were significantly associated with future diabetes risk. In contrast, unconventional lipid parameters reflected diabetes risk better than conventional lipid parameters, and RC/HDL-C ratio was the best lipid parameter to reflect the risk of diabetes (HR: 6.75, 95% CI 2.40-18.98). Sensitivity analysis further verified the robustness of this result. Also, time-dependent ROC curve analysis showed that RC, non-HDL/HDL-C ratio, and TC/HDL-C ratio were the best lipid parameters for predicting the risk of medium-and long-term diabetes., Conclusions: Unconventional lipid parameters generally outperform conventional lipid parameters in assessing and predicting future diabetes risk. It is suggested that unconventional lipid parameters should also be routinely evaluated in clinical practice., (© 2022. The Author(s).)

A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment., (©2022 American Association for Cancer Research.)

Background: Hypertriglyceridemic-waist (HTGW) phenotype has been proposed as a practical tool for screening the risk of cardiovascular diseases and glycemic metabolic disease. This study sought to investigate the relationship between HTGW phenotype and non-alcoholic fatty liver disease (NAFLD)., Methods: A total of 14,251 subjects who took part in health screening were enrolled in the study and NAFLD was diagnosed by abdominal ultrasound. According to triglyceride (TG) and waist circumference, the study population was divided into four phenotypes, in which HTGW phenotype was defined as TG ≥ 1.7 mmol/L and male waist circumference ≥ 90 cm or female waist circumference ≥ 80 cm. Multivariate logistic regression analysis was used to evaluate the relationship between HTGW phenotype and NAFLD., Results: In the current study, 2.43% of the subjects had HTGW phenotype, while the prevalence of NAFLD in subjects with HTGW phenotype was 77.81%. After full adjustment for covariates, compared with people with normal waist circumference and TG levels, the risk of NAFLD in people with normal TG levels but enlarged waist circumference increased by 39% [OR:1.39, 95%CI: 1.15, 1.68], in people with normal waist circumference but elevated TG levels increased by 96% [OR:1.96, 95%CI: 1.65, 2.33], and in subjects with HTGW phenotype increased by 160% [OR:2.60, 95%CI: 1.88, 3.58]. Additionally, further analysis suggested that there were significant interactions between age, height, BMI and NAFLD risk associated with TGW phenotypes. Receiver operating characteristic curves analysis suggested that the combination of TG and waist circumference further improved the diagnostic value for NAFLD., Conclusions: HTGW phenotype is associated with NAFLD risk in the general population, which may be a novel and accessible indicator for NAFLD screening., (© 2022. The Author(s).)

Background and Aims: Radiological prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC) is essential but few models were clinically implemented because of limited interpretability and generalizability., Methods: Based on 2096 patients in three independent HCC cohorts, we established and validated an MVI predicting model. First, we used data from the primary cohort to train a 3D-ResNet network for MVI prediction and then optimised the model with "expert-inspired training" for model construction. Second, we implemented the model to the other two cohorts using three implementation strategies, the original model implementation, data sharing model implementation and skeleton sharing model implementation, the latter two of which used part of the cohorts' data for fine-tuning. The areas under the receiver operating characteristic curve (AUCs) were calculated to compare the performances of different models., Results: For the MVI predicting model, the AUC of the expert-inspired model was 0.83 (95% CI: 0.77-0.88) compared to 0.54 (95% CI: 0.46-0.62) of model before expert-inspiring. Taking this model as an original model, AUC on the second cohort was 0.76 (95% CI: 0.67-0.84). The AUC was improved to 0.83 (95% CI: 0.77-0.90) with the data-sharing model, and further improved to 0.85 (95% CI: 0.79-0.92) with the skeleton sharing model. The trend that the skeleton sharing model had an advantage in performance was similar in the third cohort., Conclusions: We established an expert-inspired model with better predictive performance and interpretability than the traditional constructed model. Skeleton sharing process is superior to data sharing and direct model implementation in model implementation., (© 2022 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.)

Objectives: To construct a preoperative model for survival prediction in intrahepatic cholangiocarcinoma (ICC) patients using ultrasound (US) based radiographic-radiomics signatures., Methods: Between April 2010 and September 2015, 170 patients with ICC who underwent curative resection were retrospectively recruited. Overall survival (OS)-related radiographic signatures and radiomics signatures based on preoperative US were built and assessed through a time-dependent receiver operating characteristic curve analysis. A nomogram was developed based on the selected predictors from the radiographic-radiomics signatures and clinical and laboratory results of the training cohort (n = 127), validated in an independent testing cohort (n = 43) by the concordance index (C-index), and compared with the Tumor Node Metastasis (TNM) cancer staging system as well as the radiographic and radiomics nomograms., Results: The median areas under the curve of the radiomics signature and radiographic signature were higher than that of the TNM staging system in the testing cohort, although the values were not significantly different (0.76-0.82 versus 0.62, P = .485 and .264). The preoperative nomogram with CA 19-9, sex, ascites, radiomics signature, and radiographic signature had C-indexes of 0.72 and 0.75 in the training and testing cohorts, respectively, and it had significantly higher predictive performance than the 8th TNM staging system in the testing cohort (C-index: 0.75 versus 0.67, P = .004) and a higher C-index than the radiomics nomograms (0.75 versus 0.68, P = .044)., Conclusions: The preoperative nomogram integrated with the radiographic-radiomics signature demonstrated good predictive performance for OS in ICC and was superior to the 8th TNM staging system., (© 2021 American Institute of Ultrasound in Medicine.)

Background: Microvascular invasion (MVI) is essential for the management of hepatocellular carcinoma (HCC). However, MVI is hard to evaluate in patients without sufficient peri-tumoral tissue samples, which account for over a half of HCC patients., Methods: We established an MVI deep-learning (MVI-DL) model with a weakly supervised multiple-instance learning framework, to evaluate MVI status using only tumor tissues from the histological whole slide images (WSIs). A total of 350 HCC patients (2917 WSIs) from the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU cohort) were divided into a training and test set. One hundred and twenty patients (504 WSIs) from Dongguan People's Hospital and Shunde Hospital of Southern Medical University (DG-SD cohort) formed an external test set. Unsupervised clustering and class activation mapping were applied to visualize the key histological features., Results: In the FAHSYSU and DG-SD test set, the MVI-DL model achieved an AUC of 0.904 (95% CI 0.888-0.920) and 0.871 (95% CI 0.837-0.905), respectively. Visualization results showed that macrotrabecular architecture with rich blood sinus, rich tumor stroma and high intratumor heterogeneity were identified as the key features associated with MVI ( +), whereas severe immune infiltration and highly differentiated tumor cells were associated with MVI (-). In the simulation of patients with only one WSI or biopsies only, the AUC of the MVI-DL model reached 0.875 (95% CI 0.855-0.895) and 0.879 (95% CI 0.853-0.906), respectively., Conclusion: The effective, interpretable MVI-DL model has potential as an important tool with practical clinical applicability in evaluating MVI status from the tumor areas on the histological slides., (© 2022. The Author(s).)

Objective: Altered metabolites are important for the tumourigenicity of hepatocellular carcinoma (HCC). We performed integrative metabolomics analysis of the metabolites changes in portal venous blood and in comparison with the metabolites changes in liver tissues and stool samples of HCC patients and healthy liver donors., Design: Serum (portal and central vein), liver tissue (HCC tumour and adjacent non-tumour, normal liver) and stool samples were collected from 102 subjects (52 HCC patients and 50 healthy controls) in the discovery cohort; and 100 subjects (50 HCC patients and 50 healthy controls) in an independent validation cohort. Untargeted metabolomic profiling was performed using high-performance liquid chromatography-mass spectrometry. The function of candidate metabolites was validated in hepatocyte cell lines., Results: Detailed metabolomic evaluation showed distinct clusters of metabolites in serum, liver tissue and stool samples from patients with HCC and control individuals (p<0.001). HCC patients had significantly higher levels of portal vein serum and HCC tissue metabolites of DL-3-phenyllactic acid, L-tryptophan, glycocholic acid and 1-methylnicotinamide than healthy controls, which were associated with impaired liver function and poor survival. On the other hand, HCC patients had lower levels of linoleic acid and phenol in portal vein and stool samples than healthy controls. Linoleic acid and phenol significantly inhibited HCC proliferation, inferring their anti-HCC function as protective metabolites., Conclusions: The integrative metabolome analysis of serum, tissue and stool metabolites revealed unreported metabolic alterations in HCC patients. In portal vein, we identified elevated and depleted metabolites signifying that they might play a role in HCC development., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aim: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive disease with the underlying mechanisms poorly understood. YTHDF1, an N 6 -methyladenosine (m 6 A) reader protein, has important physiological functions in regulation of tumor development. However, the effect of YTHDF1 on ICC progression remains unknown yet., Methods: The expression level of YTHDF1 in human ICC tissue was examined in The Cancer Genome Atlas database and our cohort. The role of YTHDF1 was detected using two human ICC cell lines in vitro. An ICC tumorigenesis mouse model was established via hydrodynamic transfection of AKT/YAP plasmids. m 6 A sequencing, RNA immunoprecipitation sequencing, and RNA sequencing were carried out to explore the mechanism of YTHDF1 modulating ICC progression., Results: Here, we find that YTHDF1 is upregulated in ICC and associated with shorter survival of ICC patients. Depletion of YTHDF1 inhibits cell proliferation, migration, and invasion, while overexpression of wild-type YTHDF1, but not m 6 A reader domain mutant YTHDF1, significantly enhances tumor cell growth and aggressive abilities in vitro. Moreover, overexpression of YTHDF1 promotes the AKT/YAP transfection-induced orthotopic ICC tumorigenesis and progression in vivo. Mechanistically, we identify that YTHDF1 regulates the translation of epidermal growth factor receptor (EGFR) mRNA via binding m 6 A sites in the 3'-UTR of EGFR transcript, thus leading to aberrant activities of downstream signal pathways that impact tumor progression., Conclusions: Our data uncover the oncogenic function and m 6 A reader-dependent mechanism of YTHDF1 in regulation of ICC progression. Restricting abnormal oncogenic mRNA translation by targeting YTHDF1 may be a novel and promising strategy for ICC treatment., (© 2022 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: Diabetes is one of the most prevalent chronic diseases in the world, and its prevalence is expected to rise further. To help understand the utility of the ratio of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) in diabetes prevention, this large-scale longitudinal cohort study aims to explore the association of NHHR with diabetes risk and compare it as a risk predictor with conventional lipid parameters., Patients and Methods: This observational study extracted data from the NAGALA longitudinal cohort study conducted in Japan between 2004 and 2015. Multivariate Cox regression analysis was used to evaluate the association between NHHR and the risk of diabetes. The dose-response relationship was analyzed by restricted cubic spline (RCS) regression and the potential risk threshold was estimated. The receiver operator characteristic curve (ROC) was used to analyze and calculate the predictive value and optimal threshold of NHHR and other conventional lipids for new-onset diabetes., Results: Of the 15,464 people aged 18-79, 373 (2.41%) were diagnosed with new-onset diabetes during the study period, with a median age of 46 years. The sensitivity analysis based on multivariate adjustment showed that the independent positive correlation between diabetes and NHHR was stable in different populations. RCS and ROC analysis indicated that the association between NHHR and diabetes was non-linear, and the NHHR was a better marker for predicting diabetes risk than other conventional lipid parameters; Additionally, it is worth noting that an NHHR of approximately 2.74 may be the optimal threshold for intervention in diabetes risk., Conclusion: In the general population, NHHR is a better marker for predicting diabetes risk than conventional lipid parameters, and an NHHR of about 2.74 may be the optimal threshold for assessing diabetes risk., Competing Interests: The authors report no conflicts of interest in this work., (© 2022 Sheng et al.)

Purpose: The contrast-enhanced ultrasound (CEUS) Liver Imaging Reporting and Data System (LI-RADS) treatment response algorithm (TRA) is still in development. The aim of this study was to explore whether the CT/MRI LI-RADS TRA features were applicable to CEUS in evaluating the liver locoregional therapy (LRT) response., Patients and Methods: This study was a retrospective review of a prospectively maintained database of patients with hepatocellular carcinoma undergoing ablation between July 2017 and December 2018. The standard criteria for a viable lesion were a histopathologically confirmed or typical viable appearance in the follow-up CT/MRI. Performance of the LI-RADS TRA assessing tumor viability was then compared between CEUS and CT/MRI. Inter-reader association was calculated., Results: A total of 244 patients with 389 treated observations (118 viable) were evaluated. The sensitivity and specificity of the CEUS TRA and CT/MRI LI-RADS TRA viable categories for predicting viable lesions were 55.0% (65/118) versus 56.8% (67/118) ( P = 0.480) and 99.3% (269/271) versus 96.3% (261/271) ( P = 0.013), respectively. The PPV of CEUS was higher than that of CT/MRI (97.0% vs 87.0%). Subgroup analysis showed that the sensitivity was low in the 1-month assessment for both CEUS (38.1%, 16/42) and CT/MR (47.6%, 20/42) and higher in the 2-6-month assessment for both CEUS (65.7%, 23/35) and CT/MR (62.9%, 22/35). Interobserver agreements were substantial for both CEUS TRA and CT/MRI LI-RADS TRA (κ, 0.74 for both)., Conclusion: The CT/MRI LI-RADS TRA features were applicable to CEUS TRA for liver locoregional therapy. The CEUS TRA for liver locoregional therapy has sufficiently high specificity and PPV to diagnose the viability of lesions after ablation., Competing Interests: The authors have no relevant financial or non-financial interests to disclose in this work., (© 2022 Ruan et al.)

Traumatic neuromuscular injury to the pudendal nerve and urethra during childbirth does not regenerate well and contributes to stress urinary incontinence in women. Mesenchymal stem cells (MSCs) can improve neuroregeneration via their secretions, or secretome, which includes brain-derived neurotrophic factor (BDNF). In this study, we investigated whether BDNF is a key factor in the secretome of MSCs for the facilitation of functional recovery following a dual simulated childbirth injury. BDNF knockdown (KD) MSCs were created using an anti-BDNF shRNA lentivirus vector. A scrambled sequence was used as a transduction control (scrambled). Cells were cultured for 24 h before media was concentrated 50x to create concentrated conditioned media (CCM) containing MSC secretome. CCM of unmanipulated MSCs was screened for high BDNF expression (high BDNF CCM). Concentrated control media (CM) was created by concentrating media not conditioned by cells. Female Sprague-Dawley rats underwent bilateral pudendal nerve crush and vaginal distension (Injury) or sham injury. One hour and 1 week after injury, sham injured rats received CM, and injured rats received CM, high BDNF CCM, KD CCM, or scrambled CCM (300 μl intraperitoneally). Three weeks after injury, rats underwent leak point pressure (LPP) and pudendal nerve sensory branch potential (PNSBP) recordings. The urethra and pudendal nerve were harvested for anatomical assessment. ANOVA followed by the Student-Newman-Keuls test determined significant differences between groups ( p < 0.05). BDNF KD CCM had significantly decreased BDNF concentration compared to scrambled CCM, while the concentration in high BDNF CCM was significantly increased. LPP was significantly decreased in CM and KD CCM treated animals compared to sham injury, but not with scrambled or high BDNF CCM. PNSBP firing rate showed a significant decrease with CM treatment compared to sham injury. Neuromuscular junctions in the urethral sphincter in KD CCM, scrambled CCM, and high BDNF CCM were healthier than CM treated rats. While anatomical and nerve function tests demonstrate regeneration of the pudendal nerve with any CCM treatment, LPP results suggest it takes longer to recover continence with reduced BDNF in CCM. BDNF in MSC CCM is an important factor for the acceleration of recovery from a dual nerve and muscle injury., Competing Interests: MD has an issued patent on MSC CCM treatment for genitourinary disorders, which is currently optioned for licensing. This study was performed with grant funding prior to optioning the intellectual property and involved no corporate input or influence. The remaining 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 © 2022 Yuan, Balog, Lin, Hanzlicek, Kuang, Yan, Majerus and Damaser.)

Background: Low-density lipoprotein:high-density lipoprotein cholesterol ratio (LDL:HDL ratio) has a good performance in identifying diabetes mellitus (DM) and insulin resistance. However, it is not yet clear whether the LDL:HDL ratio is associated with a high-risk state of prediabetes., Methods: This cohort study retrospectively analyzed the data of 100,309 Chinese adults with normoglycemia at baseline. The outcome event of interest was new-onset prediabetes. Using multivariate Cox regression and smoothing splines to assess the association of LDL:HDL ratio with prediabetes., Results: During an average observation period of 37.4 months, 12,352 (12.31%) subjects were newly diagnosed with prediabetes. After adequate adjustment for important risk factors, the LDL:HDL ratio was positively correlated with the prediabetes risk, and the sensitivity analysis further suggested the robustness of the results. Additionally, in stratified analysis, we discovered significant interactions between LDL:HDL ratio and family history of DM, sex, body mass index and age (all P-interaction < 0.05); among them, the LDL:HDL ratio-related prediabetes risk decreased with the growth of body mass index and age, and increased significantly in women and people with a family history of DM., Conclusions: The increased LDL:HDL ratio in the Chinese population indicates an increased risk of developing prediabetes, especially in women, those with a family history of DM, younger adults, and non-obese individuals., (© 2022. The Author(s).)

Introduction: Secondhand smoke exposure in many countries decreased dramatically after the implementation of smoke-free legislation in public places, but the exposure at home did not change to the same degree. The aim of this study was to describe the status and correlates of a home smoking ban in Chongqing, China., Methods: From June to August 2021, we selected two healthcare centers in the East, West, North, South and Middle regions of Chongqing. We investigated the family smoke-free situation in the selected region using a stratified random sampling method. A chi-squared test was performed to compare the totally and partially smoke-free homes, and a binary logistic regression model was used to analyze the correlates of smoke-free rules at home., Results: The study investigated 2121 families, among which 884 (41.7%) implemented a total ban on smoking at home. The covariates included age (OR=1.54; 95% CI: 1.18-2.01), living with children aged <14 years (OR=1.51; 95% CI: 1.20-1.90), no smokers in the family (OR=2.37; 95% CI: 1.78-3.17), awareness of the hazards of secondhand smoke (OR=1.30; 95% CI: 1.07-1.59), worrying about the impact of smoking in the presence of children on health (OR=1.92; 95% CI: 1.25-2.95), no difficulty (OR=1.34; 95% CI: 1.07-1.67) and confidence (OR=1.73; 95% CI: 1.41-2.13) in stopping others from smoking, no smoking rules in cars (OR=3.67; 95% CI: 2.58-5.22), and frequency of entertaining guests with cigarettes (OR=0.41; 95% CI: 0.28-0.59)., Conclusions: It is common for households in Chongqing to have smoking bans, especially those with children. If a family has members that are smokers, education researchers should pay more attention to the hazards of secondhand smoke on the health of family members, and to adopt more tobacco control measures and enhance the self-efficacy of implementing a home smoking ban. Helping smokers to quit is a vital way to decrease the hazards of cigarettes., Competing Interests: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none was reported., (© 2022 Zhang L. et al.)

Purpose: Targeted therapy and immunotherapy are transforming the treatment approach for intrahepatic cholangiocarcinoma (ICC). However, little is known about the intertumor heterogeneity (ITH) of multifocal ICC and its impacts on patient response to these treatments. We aimed to characterize the immunogenomic and epigenomic heterogeneity of multifocal ICC to guide treatment decision making., Experimental Design: We obtained 66 tumor samples from 16 patients with multifocal ICC and characterized the tumor and immune heterogeneity using whole-exome sequencing, bulk and single-cell RNA sequencing, methylation microarray, and multiplex immunostaining. Patients were divided into high- or low-ITH groups according to the median ITH index. Two independent cohorts were used to validate findings. Responses to anti-PD-1 therapy were assessed., Results: Multifocal ICC presented considerable intertumor genomic, transcriptional, and epigenomic heterogeneity within a patient in high ITH group. The immune profile among multiple tumors within a patient was relatively less heterogeneous in high- or low-ITH group, and consistent responses of multiple tumors to anti-PD-1 immunotherapy were observed. Unsupervised clustering of immune markers identified one low and one high immune subtype, with higher immune cell infiltration, closer tumor-immune cell interactions, and upregulated IFN-signature expression in high-immune subtype. Determining expression levels of CD8B and ICOS facilitated this immune classification and prediction of patient prognosis. Finally, promoter DNA methylation contributed to different immune profiles of two subtypes by regulating immune-gene expression., Conclusions: There is comprehensive heterogeneity in the genome, transcriptome, and epigenome of multifocal ICC. On the basis of the less heterogeneous immune profile of ICC, we suggest an immune classification that stratifies patients' prognosis and may support personalized immunotherapy., (©2021 American Association for Cancer Research.)

Background and Study Aims: Post-hepatectomy liver failure (PHLF) is the main cause of perioperative death after hepatocellular carcinoma (HCC) resection. PHLF occurrence is related to both the hepatectomy volume and the degree of cirrhosis. Accurate preoperative assessment of the degree of cirrhosis may aid in reducing the incidence of PHLF. Several studies have shown that the liver stiffness measurement (LSM) is well correlated with cirrhosis. This study explored the relationship between LSM and PHLF occurrence after radical HCC resection and the effect on long-term prognosis., Patients and Methods: We retrospectively analyzed the clinical data of 164 patients who underwent radical HCC resection at our center from January 2017 to January 2020. The related postoperative PHLF factors were analyzed. The LSM threshold in postoperative PHLF was calculated through receiver operating characteristic (ROC) curve analysis. Patients were grouped according to different LSM thresholds and survival analysis was performed., Results: Forty-six patients experienced PHLF, of whom 19, 21, and 6 were classified as grades A, B, and C, respectively. Multivariate analysis indicated that LSM was an independent risk factor for PHLF after HCC surgery (OR = 1.174, P < 0.000). LSM (OR = 1.219, P < 0.000) and intraoperative bleeding (OR = 1.001, P = 0.047) were risk factors for grade B-C PHLF. The LSM threshold that predicted PHLF occurrence was 17.9 kPa (AUC = 0.831, P < 0.000) and 24.5 kPa (AUC = 0.867, P < 0.000) for grade B-C PHLF. LSM was correlated with PHLF severity (r = 0.439, P < 0.001). The median survival times were 32 vs 26 months (P = 0.016) for patients with LSM ≤ 17.9 kPa vs those with LSM > 17.9 kPa and 28 vs 24 months (P = 0.004) for patients with LSM ≤ 24.5 kPa vs those with LSM > 24.5 kPa., Conclusion: LSM is related to PHLF occurrence in patients undergoing HCC resection; a higher LSM is associated with the occurrence of more severe PHLF after surgery. In addition, LSM may aid in predicting long-term survival after liver resection in patients with HCC., (Copyright © 2022 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the diagnostic performance of LR-5 for diagnosing poorly differentiated hepatocellular carcinoma (p-HCC). To build a contrast-enhanced ultrasound (CEUS) signature for improving the differential diagnostic performance between p-HCC and intrahepatic cholangiocarcinoma (ICC)., Methods: The B-mode ultrasound (BUS) and CEUS features of 60 p-HCCs and 56 ICCs were retrospectively analyzed. The CEUS LI-RADS category was assigned according to CEUS LI-RADS v2017. A diagnostic CEUS signature was built based on the independent significant features. An ultrasound (US) signature combining both BUS and CEUS features was also built. The diagnostic performances of the CEUS signature, US signature, and LR-5 were evaluated by receiver operating characteristic (ROC) analysis., Results: One (1.7%) p-HCC and 26 (46.4%) ICC patients presented cholangiectasis or cholangiolithiasis (P < .001). Fifty-four (90.0%) p-HCCs and 8 (14.3%) ICCs showed clear boundaries in the artery phase (P < .001). The washout times of p-HCCs and ICCs were 81.0 ± 42.5 s and 34.7 ± 8.6 s, respectively (P < .001). The AUC, sensitivity, and specificity of the CEUS signature, US signature, and LR-5 were 0.955, 91.67%, and 90.57% versus 0.976, 96.67%, and 92.45% versus 0.758, 51.67%, and 100%, respectively. The AUC and sensitivity of CEUS LI-RADS were much lower than those of the CEUS and US signatures (P < .001)., Conclusion: LR-5 had high specificity but low sensitivity in diagnosing p-HCC. When the washout time and tumor boundary were included in the CEUS signature, the sensitivity and AUC were remarkably increased in the differentiation between p-HCC and ICC., (© 2021 American Institute of Ultrasound in Medicine.)

Herein, an improved method for detecting the endocrine-disrupting chemicals in milk is presented, which is based on high performance liquid chromatography tandem mass spectrometry, coupled with a quick, effective, and safe method. The linearity of the proposed method was in the range of 0.05-100 μg/L, and all correlation coefficients were ≥0.9973. At three concentration levels, the spiked recoveries ranged from 77.7 to 107.5%, relative standard deviations ranged from 0.2 to 14.6%, limits of quantitation ranged from 0.1 to 40 μg/kg, limits of detection ranged from 0.03 to 13.3 μg/kg. The proposed method for the identification and quantitation of 26 endocrine disruptors present in milk is not only easy, fast, and cost-efficient but also provides a reference for the detection of various endocrine disruptors in milk and other dairy products., (© 2022 Wiley-VCH GmbH.)

Background: Albumin to fibrinogen ratio (AFR) is a demonstrated predictor of mortality in various diseases. The aim of this study was to evaluate the prognostic value of AFR to predict mortality in peritoneal dialysis (PD) patients., Methods: We retrospectively analyzed 212 incident PD patients from January 2010 to December 2017 and followed them until December 2019. We used receiver operating curve (ROC) analysis to determine the optimal cut-off point for AFR at baseline to predict overall and cardiovascular mortality during the follow-up period. Kaplan-Meier curve and Cox regression analysis were applied to evaluate the association between AFR and all-cause and cardiovascular mortality., Results: The optimal threshold for AFR to predict mortality was 8.48. A low AFR was strongly correlated with worse all-cause and cardiovascular mortality in PD patients. Multivariate analysis revealed that elevated AFR was an independent marker predicting reduced all-cause and cardiovascular mortality (HR 2.41, 95% CI 1.11-5.22, P = 0.026; and HR 2.18, 95% CI 1.21-3.95, P = 0.010, respectively)., Conclusions: Patients with a high AFR had reduced all-cause and cardiovascular mortality. AFR is a potential prognostic biomarker in PD patients., 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 © 2022 Xia, Kuang, Li, Yao, Chen, Lin and Hu.)

Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense (Foc), has been considered as the most devastating disease affecting bananas (Musa spp.) worldwide. A highly virulent strain of Foc, known as tropical race 4 (TR4), has been detected in the southeast Asia in the 1990s, and has since spread to western Asia, Australia, the Middle East, southern Africa, and South America (Viljoen et al. 2020). Foc TR4 can cause severe yield losses in Cavendish (AAA), Gros Michel (AAA), Silk (AAB), Pisang Awak (ABB) and Bluggoe (ABB) bananas (Ploetz et al. 2006). However, cooking bananas such as plantain (AAB) and Matooke (AAA) bananas, appear to be resistant (Zuo et al. 2017). Iholena bananas (AAB), a subgroup of varieties related to plantains (also known as Pacific plantains), is an important staple food in the Pacific Islands where it was domesticated. It is also popular in Peru, probably due to its nutritional value (Kepler et al. 2011) and is wildly cultivated in other South American countries (Dita et al. 2013). In December 2019, typical symptoms of banana Fusarium wilt were observed on Iholena accession 'Pacific Plantain' (ITC0210) in experimental fields located in Dongguan, Guangdong Province of China. The symptoms included leaf yellowing and pseudostem splitting. The vascular tissue inside the pseudostems was dark red to brown, and the inner rhizomes yellowish-brown. Vascular tissues from three diseased plants were sampled aseptically and placed on potato dextrose agar (PDA) containing 0.05 g/liter kanamycin. Fungal colonies typical of F. oxysporum developed rapidly, with purple-tinged white aerial mycelia and an abundance of microconidia borne in false heads on short microconidia (Nelson et al. 1983). Chlamydospores were produced singly or in pairs in hyphae and macroconidia. Molecular identification was performed using Foc race 4-specific primers (Lin et al. 2009), Foc TR4-specific primers (Dita et al. 2010), Foc race 1 and Foc STR4-specific primers (Ndayihanzamaso et al. 2020). Amplicons of expected sizes were obtained for Foc TR4 and race 4, but not for Foc race 1 and STR4. Sequencing of the ITS and 18S rDNA from the three Iholena isolates and BLAST result showed a 100% similarity to the Foc TR4 reference sequences in GenBank (Foc II5, PRJNA73539 and PRJNA56513) to prove that the isolates were Foc TR4. Pathogenicity of the three isolates from Iholena bananas was determined by infecting 4-month-old Cavendish cv. 'Grand Nain' bananas and three Iholena accessions, 'Pacific Plantain' 'Tigua' and 'Uzakan', under greenhouse conditions by root immersion in a Foc conidial suspension and soil drenching at 106 conidia/ml (Dita, 2010). Control plants were treated with sterile distilled water. Three replications of five plantlets were used for each accession. After 35 days, the inoculated plantlets developed typical Fusarium wilt symptoms such as yellowing of the older leaves and discoloration of the inner rhizome. The control plants did not develop symptoms. To complete Koch's postulates, the fungus was re-isolated from inoculated plants and identified as Foc TR4 by PCR (Dita et al, 2010). The susceptibility of 'Tigua' and 'Uzakan' was also confirmed in Foc TR4-infested field trials, with both accessions developing severe Fusarium wilt symptoms. The susceptibility of Iholena bananas to Foc TR4 is of significant concern to all countries where this subgroup is cultivated for major food source, including Peru and other South American countries.

As total joint replacement is widely applied for severe arthropathy, peri-prosthetic aseptic loosening as one of the main causes of implant failure has drawn wide attention. Wear particles such as titanium particles (TiPs) derived from prosthesis can initiate macrophages inflammation and sequentially activate osteoclasts, which results in bone resorption and osteolysis for long-term. Therefore, inhibiting wear particles induced macrophages inflammation is considered as a promising therapy for AL. In this research, we found that the inhibition of p110δ, a member of class IA PI3Ks family, could significantly dampen the TiPs-induced secretion of TNFα and IL-6. By the transfection of siRNA targeting p110δ, we confirmed that p110δ was responsible for TNFα and IL-6 trafficking out of Golgi complex without affecting their expression in TiPs-treated macrophages. As the upstream transcription-repressor of p110δ, Krüppel-like factor 4 (KLF4), targeted by miR-92a, could also attenuate TiPs-induced inflammation by mediating NF-κB pathway and M1/M2 polarization. To further ascertain the roles of KLF4/p110δ, TiPs-induced mice cranial osteolysis model was established and vivo experiments validated that KLF4-knockdown could exacerbate TiPs-induced osteolysis, which was strikingly ameliorated by knockdown of p110δ. In summary, our study suggests the key role of miR-92a/KLF4/p110δ signal in TiPs-induced macrophages inflammation and osteolysis., (© 2022. The Author(s).)

Green wearable electronics are attracting increasing attention to eliminate harmful byproducts generated by traditional devices. Although various degradable materials have been explored for green wearable electronics, the development of degradable elastomers with integrated characteristics of low modulus, self-adhesion, high resilient, and low hysteresis remains challenging. In this work, a degradable elastomer poly(1,8-octanediol- co -citrate- co -caprolactone) (POCL) is reported, in which a loosely cross-linked network contains plenty of entangled flexible chains. The coexistence of covalent cross-links and entanglements of long polymer chains endows the elastomer with good resilience and low hysteresis, in addition to low modulus and self-adhesion. Taking advantage of the unique mechanical properties, epidermal strain sensors based on the POCL elastomer were prepared, which exhibited good adhesion to human skin, high sensitivity, high response rate, and excellent fatigue resistance. We also fabricated stretchable electroluminescent devices using this degradable elastomer and demonstrated the recyclability of the nondegradable materials in the electronic device.

In 2020, the National Center for Cardiovascular Diseases with National Committee on Hypertension Management in Primary Health Care in China issued revised national clinical practice guidelines on the management of hypertension in primary health care based on the 2018 Chinese guidelines for the management of hypertension. To evaluate adherence to the guidelines, this retrospective study assessed the real-world status of antihypertensive drug prescribing for Chinese patients with hypertension, classified by comorbidity: coronary heart disease, diabetes mellitus, heart failure, stroke, and renal disease. About 1088212 hypertensive patients who received their first prescription for antihypertensive therapy between January 2021 to June 2021, were obtained from a database of Hangzhou Kang Sheng Health Consulting CO., Ltd. Calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs) were the most common drugs prescribed for each comorbidity subgroup. Whereas diabetes mellitus or renal disease is a compelling indication for use of renin-angiotensin system inhibitors, CCBs were often administered in these subgroups. The treatment pattern for patients with coronary heart disease was closely similar to that for the overall patient population. Beta-blockers (BBs) were prescribed more frequently for patients with heart failure than for those with other comorbidities. Although antihypertensive drug prescription varied by comorbidity, pharmacological decisions were largely made under Chinese recommendations while physicians could select antihypertensive drugs based on the patients' comorbidities. However, educational initiatives are still necessary to inspire clinicians to better familiarize themselves with the guidelines and manage hypertension comorbid diseases.

Purpose: To improve noninvasive diagnosis of HCC using a combination of CE US LI-RADS and alpha-fetoprotein (AFP)., Methods: 757 solitary liver nodules from 757 patients at risk of HCC with CE US and serum AFP test were categorized as LR-1 to LR-5 through LR-M according to CE US LI-RADS version 2017. In LR-3, LR-4, and LR-M nodules, those with AFP > 200 ng/ml were reclassified as mLR-5. Nodules with LR-5 and mLR-5 were reclassified as definitely HCC to modify CE US LI-RADS. Diagnostic performance was assessed with specificity, sensitivity, and PPV., Results: The sensitivity, specificity, and PPV of LR-5 as a predictor of HCC were 64.7%, 97.8%, and 98.9%, respectively. 32.1% patients with solitary liver nodule had AFP greater than 200 ng/ml, of which 98.8% were HCC (25.8%, 7.5%, 2.5% assigned to LR-M, LR-4, LR-3, respectively) and 1.2% were Combined Hepatocellular Cholangiocarcinoma. After modification, the sensitivity increased to 79.6% (P < 0.001), while specificity and PPV remained high (96.6% and 98.7%, P > 0.050)., Conclusion: The combination of CE US LI-RADS and AFP for diagnosing HCC improved diagnostic sensitivity significantly, while maintaining high PPV and specificity in patients with the solitary liver nodule., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Gut microbiota and microbe-derived metabolites are involved in the development of HCC. Bile acids (BAs) are the most important gut microbiota-modulated endogenous signaling molecules., Methods: We tested serum bile acid levels and gut microbiome compositions in patients with HCC, chemical-induced HCC mouse models (DEN-HCC mice) and mouse orthotopic implanted liver tumor models with vancomycin treatment (vancomycin-treated mice). Then, we screened an important kind of HCC-related BAs, and verified its effect on the growth of HCC in vivo and in vitro., Results: We found that the remarkably decreasing percentages of serum secondary BAs in the total bile acids of patients and DEN-HCC mice, especially, conjugated deoxycholic acids (DCA). The relative abundance of the bile salt hydrolase (BSH)-rich bacteria (Bifidobacteriales, Lactobacillales, Bacteroidales, and Clostridiales) was decreased in the feces of patients and DEN-HCC mice. Then, in vancomycin-treated mice, vancomycin treatment induced a reduction in the BSH-rich bacteria and promoted the growth of liver tumors. Similarly, the percentage of conjugated DCA after vancomycin treatment was significantly declined. We used a kind of conjugated DCA, Glyco-deoxycholic acid (GDCA), and found that GDCA remarkably inhibited the growth of HCC in vivo and in vitro., Conclusions: We conclude that the remarkably decreasing percentages of serum conjugated DCA may be closely associated with HCC, which may be induced by the reducing gut BSH-rich bacteria. The mechanisms may be correlated with conjugated DCA directly inhibiting the growth and migration of HCC cells., (© 2022. The Author(s).)

Aseptic loosening (AL), secondary to particle-caused periprosthetic osteolysis, is one of the main reasons of artificial joint failure. Suppressing the macrophage inflammatory response caused by wear particles extends the life of prosthesis, and the long noncoding RNAs (lncRNAs) may play a predominant part in it. Here, titanium particles' (TiPs') stimulation increases both the cytoplasmic and nuclear levels of lncRNA Neat1 in bone marrow derived macrophages (BMDMs), which further induces the inflammatory response. Mechanically, Neat1 facilitates Bruton's tyrosine kinase (BTK) transcription by reducing the transcriptional factor KLF4, which further activates the NF-κB pathway, NLRP3 inflammation, and M1 polarization in BMDMs. Cytoplasmic Neat1 also works as an miRNA sponge in miR-188-5p-regulated BTK expression in the post-transcriptional stage. In vivo, Neat1 downregulation can reduce the TiP-induced pro-inflammatory factors and reverse the osteolysis induced by BTK overexpression. In addition, the PLGA-based microparticles loaded with si-Neat1 are developed for the treatment of the mouse calvarial osteolysis model via local injection, presenting satisfactory anti-osteolysis efficacy. These findings indicate that Neat1 is a key regulator of AL. STATEMENT OF SIGNIFICANCE: Due to released particles, aseptic loosening (AL) is the most common reason for prosthesis failure and surgical revision and represents a substantial economic burden worldwide. Herein, we reported that lncRNA Neat1 is a key regulator in regulating wear particles-induced osteolysis by activating NF-κB pathway, NLRP3 inflammation and M1 polarization via BTK, and the underlying mechanisms of Neat1-BTK interaction were further portrayed. For potential clinical application, the microparticles are developed for effective si-Neat1 delivery, leading to a dramatically enhanced effect for the treatment of osteolysis, which might be a novel strategy to extend the life of the implant., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Remnant cholesterol/high-density lipoprotein cholesterol (RC/HDL-C) ratio has been shown to be a good predictor of metabolic disease risk, but no studies have further investigated the role of RC/HDL-C ratio in non-alcoholic fatty liver disease (NAFLD) patients., Methods: The participants were 14,251 adults who underwent a physical examination, all of whom underwent abdominal ultrasonography to determine whether they had NAFLD. Receiver operating characteristic curve analysis and multivariate logistic regression models were used to assess the association between the RC/HDL-C ratio and the risk of NAFLD., Results: Multivariate logistic regression analysis showed that after fully adjusting the confounding factors, the higher RC/HDL-C ratio was independently positively correlated with the risk of NAFLD. Interaction tests suggested that the effect of RC/HDL-C ratio on NAFLD was significantly affected by sex. Additionally, receiver operating characteristic curve analysis showed that the area under the curve of RC/HDL-C ratio for identifying NAFLD was 0.82, which was significantly higher than that of other conventional lipid parameters., Conclusions: This study indicates for the first time that the higher RC/HDL-C ratio in the general population may be closely related to the increased risk of NAFLD., (© 2022. The Author(s).)

By virtue of a calcium(II)/hexafluoroisopropanol cocatalytic system, the efficient and practical coupling of 3-aminobenzoic acids with alkynes has been realized, giving direct and regioselective access to the phthalide framework with good substrate/functional group compatibility. Mechanistic studies identified 3-amino-2-vinylbenzoic acid species as the active intermediate, thereby revealing an ortho -C-alkenylation/hydroacyloxylation cascade for this transformation.