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Ultraviolet (UV) radiation-triggered production of reactive oxygen species (ROS) is a primary contributor to apoptosis in human lens epithelial cells (HLECs), which can ultimately result in cataract formation. The nuclear factor erythroid-2-related factor 2 (Nrf2)-Kelch ECH associating protein 1 (Keap1) pathway, a fundamental oxidative stress regulation mechanism, plays a crucial role in the development of cataracts. Ferulic acid (FA), recognized for its potent antioxidant properties can activate the Nrf2 signaling pathway to mitigate oxidative damage and cell apoptosis. In this study, we have demonstrated the protective effects of FA in reducing UVA-induced oxidative damage and apoptosis in HLECs through the modulation of the Keap1/Nrf2 pathway, as evidenced by both cellular and animal experiments. HLECs and Lens were exposed to 10 J/cm 2 UVA radiation with or without prior treatment with FA. We found that UVA radiation increased oxidative damage and cell apoptosis in HLECs, ultimately leading to opacification of rat lenses, while FA was able to attenuate both oxidative damage and cell apoptosis in HLECs and reduce the degree of lens opacification. FA upregulated the expression of antioxidant response factors of the Keap1/Nrf2 pathway and downregulated the expression of apoptosis-related genes in HLECs, as demonstrated by Western blot and RT-qPCR analyses. We also found that UVA radiation increased the degree of demethylation of the Keap1 promoter in HLECs, whereas FA reduced the level of Keap1 promoter demethylation as determined by DNA sequencing. Additionally, UVA upregulated the expression of DNA active demethylase of the Keap1 promoter in HLECs, Dnmt1, Dnmt3a, and Dnmt3b, as shown by immunofluorescence, Western blot, and RT-qPCR, however, FA attenuated the activity of the passive demethylase TET1 in addition to the active demethylases. These results demonstrated that UVA radiation can cause oxidative damage, cell apoptosis, and rat lens opacification by increasing the demethylation of the Keap1 promoter in lens epithelial cells. Conversely, FA was shown to reduce oxidative damage, inhibit cell apoptosis, and decrease rat lens opacification by increasing the methylation of the Keap1 promoter. These findings suggest that FA could be therapeutically beneficial in preventing and mitigating cataracts induced by UVA radiation., (© 2024 Wiley Periodicals LLC.)

Background: Sleep disturbance (SD) is a common occurrence in individuals with cirrhosis and significantly impacts their quality of life. Datas regarding post transjugular intrahepatic portosystemic shunt (TIPS) SD are scarce. This study aimed to explore the incidence and outcomes of post-TIPS SD., Methods: From August 2018 to November 2019, 73 patients who underwent TIPS were prospectively recruited for the study. Sleep quality was evaluated via the Pittsburgh Sleep Quality Index (PSQI), and the presence of hepatic encephalopathy was evaluated according to the West Haven criteria before and after the TIPS procedure., Results: Nineteen patients (26%) experienced new-onset SD after TIPS, with a median latency of 67 (40-98) days from the procedure. The median time from TIPS creation to occurrence was 67 (40-98) days. Minimal hepatic encephalopathy (MHE) post-TIPS emerged as an independent predictor of SD, with an odds ratio of 3 (95% CI: 1.04-8.78, P = 0.046). Notably, five of the six (83%) patients with SD experienced improvement after being administered eszopiclone. Ten of the thirteen (77%) patients with SD improved spontaneously without treatment. Furthermore, the prevalence of MHE was significantly greater among patients with SD than among those without SD (58% vs. 31%, P = 0.04)., Conclusions: SD is prevalent in patients who undergo TIPS. MHE is an independent risk factor for the development of SD post-TIPS. Eszopiclone may be a safe and effective treatment option for patients with SD after TIPS. The study was registered with ClinicalTrials.gov under the identifier NCT03685994, with a registration date of September 23, 2018., (© 2024. The Author(s).)

Plant intracellular nucleotide-binding and leucine-rich repeat immune receptors (NLRs) play a key role in activating a strong pathogen defense response. Plant NLR proteins are tightly regulated and accumulate at very low levels in the absence of pathogen effectors. However, little is known about how this low level of NLR proteins is able to induce robust immune responses upon recognition of pathogen effectors. Here, we report that, in the absence of effector, the inactive form of the tomato NLR Sw-5b is targeted for ubiquitination by the E3 ligase SBP1. Interaction of SBP1 with Sw-5b via only its N-terminal domain leads to slow turnover. In contrast, in its auto-active state, Sw-5b is rapidly turned over as SBP1 is upregulated and interacts with both its N-terminal and NB-LRR domains. During infection with the tomato spotted wilt virus, the viral effector NSm interacts with Sw-5b and disrupts the interaction of Sw-5b with SBP1, thereby stabilizing the active Sw-5b and allowing it to induce a robust immune response., (© 2024. The Author(s).)

Erythrocytes, also known as red blood cells (RBCs), have garnered considerable attention as potential carriers for drug delivery, owing to their inherent properties such as biocompatibility, biodegradability, and prolonged circulation half-life. This paper presents a comprehensive overview of the role of erythrocytes in drug delivery, elucidating recent advancements in delivering a diverse array of therapeutic agents, including small molecules, nucleic acids, antibodies, protein enzymes, and nanoparticles. Two primary strategies for encapsulating drugs within erythrocytes are systematically discussed: internal loading and surface loading. Each strategy offers distinct advantages in terms of drug stability and release kinetics. Notably, the utilization of erythrocyte membrane camouflaged nanocarriers holds promise for enhancing the biocompatibility of conventional nanoparticles and facilitating targeted drug delivery. Furthermore, the broad spectrum of biomedical applications of erythrocyte-based drug delivery systems are examined, ranging from cancer treatment to diabetes management, thrombosis prevention, and immunotherapy. This review provides a comprehensive evaluation of current technologies in erythrocyte-loaded drug delivery, highlighting the strengths, weaknesses, and future directions for advancing therapeutic interventions in various disease contexts., (© 2024 Wiley‐VCH GmbH.)

Objectives: This study investigates the vocal fold vibratory dynamics of singers, which are postulated to differ from those of normal speakers due to the singers' regular vocal training. The measurement of vocal fold vibration involved the utilization of laryngeal high-speed videoendoscopy (LHSV) and subsequent LHSV-based analysis. The focus of the present study is to characterize and compare the LHSV-based measures derived from the glottal area waveform (GAW), namely fundamental frequency (F0 GAW ), glottal perturbation (jitter GAW and shimmer GAW ), open quotient (OQ GAW ), and Nyquist plots, between singers and normal speakers across genders., Methods: Participants comprised 13 singers from a local cultural and heritage academy and 56 normal speakers from a local university, all were evaluated to have normal voices. Each participant underwent LHSV procedures to capture images of vocal fold vibration, which were subsequently analyzed to generate the LHSV-based measures., Results: Male singers exhibited lower F0 GAW , jitter GAW , shimmer GAW , and OQ GAW than female singers. When compared to normal speakers, male singers demonstrated higher F0 GAW , and lower jitter GAW and shimmer GAW . No difference in OQ GAW was found between male singers and normal speakers. Female singers exhibited lower jitter GAW compared to normal speakers, but no differences were observed in shimmer GAW and OQ GAW . The results of Nyquist plots indicated no gender-related associations between types of rim width and among singers. However, for rim pattern, male singers were associated with a higher percentage of clustered rim, suggesting more regular vocal fold vibration, compared to female singers and normal male speakers., Conclusions: Singers, particularly male singers, demonstrate distinct and potentially superior vocal fold vibrations compared to normal speakers, likely attributed to their regular vocal training, resulting in refined vocal fold configurations even during speaking. Despite the limited sample of singers, the study offers valuable insights into the vocal fold vibratory behaviors in singers analyzed using LHSV., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Obesity induces insulin resistance and chronic inflammation, impacting human health. The relationship between obesity, gut microbiota, and regulatory mechanisms has been studied extensively. Dendrobium officinale polysaccharide (DOP), a traditional Chinese herbal medicine, potentially reduces insulin resistance. However, the mechanism through which DOP affects gut microbiota and alleviates obesity-induced insulin resistance in rats requires further investigation., Results: The current study aimed to assess the impact of DOP on gut microbiota and insulin resistance in rats on a high-fat diet. The results revealed that DOP effectively reduced blood lipids, glucose disorders, oxidative stress, and inflammatory infiltration in the liver of obese Sprague Dawley rats. This was achieved by downregulating SOCS3 expression and upregulating insulin receptor substrate-1 (IRS-1) by regulating the JAK/STAT/SOCS3 signaling pathway. Notably, DOP intervention enhanced the abundance of beneficial gut microbiota and reduced harmful microbiota. Correlation analysis demonstrated significant associations among intestinal microbiota, SOCS3-mediated IRS-1 expression, and inflammatory factors., Conclusion: Dendrobium officinale polysaccharide regulated the gut microbiota, enhanced IRS-1 expression, and mitigated liver injury and insulin resistance due to a high-fat diet. These findings depict the potential anti-insulin resistance properties of DOP and offer further evidence for addressing obesity and its complications. © 2023 Society of Chemical Industry., (© 2023 Society of Chemical Industry.)

Accurate assessment of portacaval pressure gradient (PCG) in patients with portal hypertension (PH) is of great significance both for diagnosis and treatment. This study aims to develop a noninvasive method for assessing PCG in PH patients and evaluate its accuracy and effectiveness. This study recruited 37 PH patients treated with transjugular intrahepatic portosystemic shunt (TIPS). computed tomography angiography was used to create three dimension (3D) models of each patient before and after TIPS. Doppler ultrasound examinations were conducted to obtain the patient's portal vein flow (or splenic vein and superior mesenteric vein). Using computational fluid dynamics (CFD) simulation, the patient's pre-TIPS and post-TIPS PCG was determined by the 3D models and ultrasound measurements. The accuracy of these noninvasive results was then compared to clinical invasive measurements. The results showed a strong linear correlation between the PCG simulated by CFD and the clinical invasive measurements both before and after TIPS (R 2  = 0.998, P < 0.001 and R 2  = 0.959, P < 0.001). The evaluation accuracy of this noninvasive method reached 94 %, and the influence of ultrasound result errors on the numerical accuracy was found to be marginal if the error was less than 20 %. Furthermore, the information about the hemodynamic environment in the portal system was obtained by this numerical method. Spiral flow patterns were observed in the portal vein of some patients. In a conclusion, this study proposes a noninvasive numerical method for assessing PCG in PH patients before and after TIPS. This method can assist doctors in accurately diagnosing patients and selecting appropriate treatment plans. Additionally, it can be used to further investigate potential biomechanical causes of complications related to TIPS in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Transjugular intrahepatic portosystemic shunt (TIPS) relieves cirrhotic complications by reducing portacaval pressure gradient (PCG), but it lacks precision in achieving a targeted post-TIPS PCG simply through diameter adjustment of equal diameter stents. This study aimed to present a controlled-expansion, streamlined, and covered tapered stent, and examined its effects on pressure reduction compared with equal- diameter stents. Twenty-four patients who underwent standardized 8-mm stent TIPS implantation at West China Hospital from December 2017 to February 2021 were included in the current study. Virtual equal-diameter stent graft with different diameter and streamlined tapered stents were created in the post-TIPS 3-dimentional models reconstructed based on computed tomography angiography data. The numerical simulation showed that only two patients achieved targeted post-TIPS PCG consistent with the clinical invasive measurement. When 6-mm and 10-mm equal-diameter stents were employed, simulated post-TIPS PCGs for most patients remained outside the safe range, and recirculating flow was observed at the stent-portal vein anastomosis. In contrast, the use of the new streamlined taper stent resulted in post-TIPS PCGs within the 10-12 mmHg range for 17 out of 24 patients, with no recirculating flow observed at the anastomotic sites. In conclusion, the streamlined tapered stent could pose an effective solution to the problem that the big jump depressurization between two different equal-diameter stents and it would improve the hemodynamics in the region near the PV-stent anchorage. Therefore, the streamlined tapered stent may present a superior alternative for TIPS procedure., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Antibacterial packaging used to control the growth of microorganisms in food is of great value for prolonging the shelf life of food. In this study, a bio-based antibacterial agent PDI based on zwitterionic and stereochemical synergistic antibacterial was designed and synthesized, and it was simultaneously introduced into polylactic acid (PLA) matrix with antioxidant o-vanillin (oVL) and plasticizer glycerol (GL). A series of PLA/oVL/PDI composite membranes with antibacterial, antioxidant and anti-ultraviolet properties were prepared by solution casting method. The results showed that the mechanical properties of the composite film were significantly improved compared with pure PLA (tensile strength increased by 37 %, elongation at break increased by 209 %), which was mainly attributed to the microphase separation structure induced by synthetic bio-based antibacterial agent, which improved the mechanical strength of PLA matrix, and the hydrogen bond formed by glycerol, o-vanillin and carbonyl group in PLA molecules plasticized PLA matrix. At the same time, the antibacterial rate of PLA/oVL/PDI composite membrane against Escherichia coli and Staphylococcus aureus can reach >95 %. Packaging experiments showed that PLA/oVL/PDI series composite films could effectively extend the shelf life of fresh bananas and apples for 5 days, and had great application prospects in preservative food packaging., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: It was still controversial that whether the increase of splenic vein (SV) diameter increased the risk of portal vein thrombosis (PVT), which was a severe disease with high mortality, in the clinic., Purposes: This study, using computational fluid dynamics method, aimed to investigate how the increase of SV diameter affects the portal vein hemodynamics under different anatomical and geometric features of the portal venous system, thus how it induced to PVT., Methods: The ideal models of the portal system, including different anatomical structures according to the location of left gastric vein (LGV) and inferior mesenteric vein (IMV), and different geometric morphological parameters models were established to carry out numerical simulation in this study. In addition, the morphological parameters of real patients were measured to verify the numerical simulation results., Results: First, the wall shear stress (WSS) and helicity intensity, which were closely related to the occurrence of thrombosis, gradually decreased with the increase of SV diameter in all models. However, the degree of decrease was bigger in following models: (1) the models with LGV and IMV linking to SV compared with them linking to PV; (2) the models with big angle of PV and SV compared with small angle. In addition, the morbidity of PVT was higher when LGV and IMV linked to SV rather than them linked to PV in the real patients. Moreover, the angle of PV and SV was also different between PVT and non-PVT patients (125.53° ± 16.90° vs. 115.03° ± 16.10°, p = 0.01)., Conclusion: Whether the increase of SV diameter will result in PVT is depended on the anatomical structure of portal system and the angle between PV and SV, this is also the reason leading to the clinical controversy that the increase of SV diameter is the risk factor of PVT., (© 2023 American Association of Physicists in Medicine.)

Background Some studies have shown that transjugular intrahepatic portosystemic shunt (TIPS) placement within 72 hours of admission improves survival in patients at high risk who present with acute variceal bleeding. However, the role of small-diameter covered TIPS in the secondary prophylaxis of variceal bleeding is still debatable. Purpose To compare the efficacy of 8-mm TIPS and endoscopic variceal ligation (EVL) plus propranolol in the prevention of variceal rebleeding among participants with advanced cirrhosis. Materials and Methods Between June 2015 and December 2018, participants admitted to the hospital for variceal bleeding were considered for enrollment in this randomized controlled trial (ClinicalTrials.gov). Participants with Child-Pugh class B or C cirrhosis were randomly assigned to receive an 8-mm covered TIPS or EVL and propranolol. The primary end point was recurrent variceal bleeding assessed using Kaplan-Meier curve analysis. Secondary end points included survival and overt hepatic encephalopathy (HE) assessed using Kaplan-Meier curve analysis. Results A total of 100 participants were enrolled, with 50 randomly assigned to the EVL plus propranolol group (median age, 54 years; IQR, 45-60 years; 29 male, 21 female) and 50 randomly assigned to the TIPS group (median age, 49 years; IQR, 43-56 years; 32 male, 18 female). The median follow-up period was 43.4 months. In the TIPS group, variceal rebleeding risk was reduced compared with variceal rebleeding risk in the EVL plus propranolol group (hazard ratio [HR], 0.31; 95% CI: 0.14, 0.69; P = .008), but the incidence of overt HE was higher in the TIPS group (30.0% vs 16.0%, P = .03). No differences in survival were observed between the two groups (1-year survival: TIPS, 98.0%; EVL plus propranolol, 92.0%; 3-year survival: TIPS, 94.0%; EVL plus propranolol, 85.7%; HR, 0.52; 95% CI: 0.19, 1.42; P = .22). Conclusion When compared with EVL plus propranolol, 8-mm TIPS led to reduced variceal rebleeding but did not impact overall survival in participants with Child-Pugh class B or C cirrhosis. Clinical trial registration no. NCT02477384 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Barth in this issue.

Plant intracellular nucleotide-binding domain, leucine-rich repeat-containing receptors (NLRs) activate a robust immune response upon detection of pathogen effectors. How NLRs induce downstream immune defense genes remains poorly understood. The Mediator complex plays a central role in transducing signals from gene-specific transcription factors to the transcription machinery for gene transcription/activation. In this study, we demonstrate that MED10b and MED7 of the Mediator complex mediate jasmonate-dependent transcription repression, and coiled-coil NLRs (CNLs) in Solanaceae modulate MED10b/MED7 to activate immunity. Using the tomato CNL Sw-5b , which confers resistance to tospovirus , as a model, we found that the CC domain of Sw-5b directly interacts with MED10b. Knockout/down of MED10b and other subunits including MED7 of the middle module of Mediator activates plant defense against tospovirus . MED10b was found to directly interact with MED7, and MED7 directly interacts with JAZ proteins, which function as transcriptional repressors of jasmonic acid (JA) signaling. MED10b-MED7-JAZ together can strongly repress the expression of JA-responsive genes. The activated Sw-5b CC interferes with the interaction between MED10b and MED7, leading to the activation of JA-dependent defense signaling against tospovirus . Furthermore, we found that CC domains of various other CNLs including helper NLR NRCs from Solanaceae modulate MED10b/MED7 to activate defense against different pathogens. Together, our findings reveal that MED10b/MED7 serve as a previously unknown repressor of jasmonate-dependent transcription repression and are modulated by diverse CNLs in Solanaceae to activate the JA-specific defense pathways.

Background and Aims: The selection of appropriate candidates for transjugular intrahepatic portosystemic shunt (TIPS) is important and challenging. To validate the Model for End-Stage Liver Disease (MELD) 3.0 in predicting mortality in patients with cirrhosis after TIPS creation., Methods: A total of 855 consecutive patients with cirrhosis from December 2011 to October 2019 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the MELD 3.0, MELD, MELD-Na, Child-Pugh and FIPS score was assessed using Harrell's C concordance index (c-index). The Hosmer-Lemeshow test was used to test the goodness of fit of all models and the calibration plot was drawn., Results: The c-index of the MELD 3.0 in predicting 3-month mortality was 0.727 (0.645-0.808), which were significantly superior to the MELD (0.663 [0.565-0.761]; P = 0.015), MELD-Na (0.672 [0.577-0.768]; P = 0.008) and FIPS (0.582 [0.477-0.687]; P = 0.015). The Child-Pugh score reached c-indices of 0.754 (0.673-0.835), 0.720 (0.649-0.792), 0.705 (0.643-0.766) and 0.665 (0.614-0.716) for 3-month, 6-month, 1-year, and 2-year mortality, respectively, which seems comparable to MELD 3.0. A MELD 3.0 of 14 could be used as a cut-off point for discriminating between high- and low-risk patients. The MELD 3.0 could stratify patients with Child-Pugh grade B (log-rank P < 0.001). The Child-Pugh score could stratify patients defined as low risk by MELD 3.0 (log-rank P < 0.001)., Conclusions: The MELD 3.0 was significantly superior to the MELD, MELD-Na and FIPS scores in predicting mortality in patients with cirrhosis after TIPS creation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Memristive switching devices with electrically and optically invoked synaptic behaviors show great promise in constructing an artificial biological visual system. Through rational design and integration, 2D materials and their van der Waals (vdW) heterostructures can be applied to realize multifunctional optoelectronic devices. Here, a multifunctional optoelectronic synaptic memtransistor based on a SnSe/MoS 2 vdW p-n heterojunction to simulate the human biological visual system is reported. By employing simple mild UV-ozone treatment, the device exhibits reversible resistive switching (RS) behavior with switching ratio up to 10 3 . The retina-like selective response to different input light wavelengths is activated, as well as programmable multilevel resistance states and long-term synaptic plasticity. Moreover, memory and logic functions analogous to those found in the visual cortex of the brain are performed by controlling the optical and electrical input signals. This work proposes a feasible strategy to modulate RS in vdW heterostructures for memristive devices, which show significant potential for neuromorphic processing., (© 2023 Wiley-VCH GmbH.)

One of the main reasons impeding wound healing is wound infection caused by bacterial colonization with a continuous stage of inflammation. Traditional wound treatments like gauze are being replaced by tissue adhesives with strong wet tissue adhesion and biocompatibility. Herein, a fast-crosslinking hydrogel is developed to achieve both strong antimicrobial properties and excellent biocompatibility. In this study, a simple and non-toxic composite hydrogel was prepared by the Schiff base reaction between the aldehyde group of 2,3,4-trihydroxybenzaldehyde (TBA) and the amino group of ε -Poly- L -lysine (EPL). Subsequently, a succession of experiments toward this new hydrogel including structure characterization, antimicrobial properties, cell experiment and wound healing were applied. The results of the experiments show that the EPL-TBA hydrogel not only exhibited excellent contact-active antimicrobial activities against Gram-negative bacteria Escherichia coli ( E. coil ) and Gram-positive Bacteria Staphylococcus aureus ( S. aureus ), but also inhibited the biofilm formation. More importantly, the EPL-TBA hydrogel promoted the wound healing with low cytotoxicity in vivo . These findings indicate that the EPL-TBA hydrogel has a promising use as a wound dressing in the bacterial infection prevention and wounds healing acceleration., 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 Zhang, Li, Wei, Yan, He, Wang, Chen and Qin.)

Orthotospoviruses, the plant-infecting bunyaviruses, cause serious diseases in agronomic crops and pose major threats to global food security. The family of Tospoviridae contains more than 30 members that are classified into two geographic groups, American-type and Euro/Asian-type orthotospovirus. However, the genetic interaction between different species and the possibility, during mixed infections, for transcomplementation of gene functions by orthotospoviruses from different geographic groups remains underexplored. In this study, minireplicon-based reverse genetics (RG) systems have been established for Impatiens necrotic spot virus (INSV) (an American-type orthotospovirus) and for Calla lily chlorotic spot virus and Tomato zonate spot virus (CCSV and TZSV) (two representative Euro/Asian orthotospoviruses). Together with the earlier established RG system for Tomato spotted wilt virus (TSWV), a type species of the Orthotospovirus American-clade, viral replicase/movement proteins were exchanged and analyzed on interspecies transcomplementation. Whereas the homologous RNA-dependent RNA polymerase (RdRp) and nucleocapsid (N) protein supported the replication of orthotospoviruses from both geographic groups, heterologous combinations of RdRp from one group and N from the other group were unable to support the replication of viruses from both groups. Furthermore, the NSm movement protein (MP), from both geographic groups of orthotospoviruses, was able to transcomplement heterologous orthotospoviruses or a positive-strand Cucumber mosaic virus (CMV) in their movement, albeit with varying efficiency. MP from Rice stripe tenuivirus (RSV), a plant-infecting bunyavirus that is distinct from orthotospoviruses, or MP from CMV also moves orthotospoviruses. Our findings gain insights into the genetic interaction/reassortant potentials for the segmented plant orthotospoviruses. IMPORTANCE Orthotospoviruses are agriculturally important negative-strand RNA viruses and cause severe yield-losses on many crops worldwide. Whereas the emergence of new animal-infecting bunyaviruses is frequently associated with genetic reassortants, this issue remains underexposed with the plant-infecting orthotospovirus. With the development of reverse genetics systems for orthotospoviruses from different geographic regions, the interspecies/intergroup replication/movement complementation between American- and Euro/Asian-type orthotospoviruses were investigated. Genomic RNAs from American orthotospoviruses can be replicated by the RdRp and N from those of Euro/Asia-group orthotospoviruses, and vice versa. However, their genomic RNAs cannot be replicated by a heterologous combination of RdRp from one geographic group and N from another geographic group. Cell-to-cell movement of viral entity is supported by NSm from both geographic groups, with highest efficiency by NSm from viruses belonging to the same group. Our findings provide important insights into the genetic interaction and exchange ability of viral gene functions between different species of orthotospovirus.

We investigate the effectiveness of convex relaxation and nonconvex optimization in solving bilinear systems of equations under two different designs (i.e. a sort of random Fourier design and Gaussian design). Despite the wide applicability, the theoretical understanding about these two paradigms remains largely inadequate in the presence of random noise. The current paper makes two contributions by demonstrating that: (1) a two-stage nonconvex algorithm attains minimax-optimal accuracy within a logarithmic number of iterations, and (2) convex relaxation also achieves minimax-optimal statistical accuracy vis-à-vis random noise. Both results significantly improve upon the state-of-the-art theoretical guarantees.

Background: Marked changes in hemodynamics have been suggested to be a potential contributing factor to portal vein thrombosis (PVT) development. This study investigated the effect of portal hemodynamics based on the anatomical structure of the portal venous system on PVT development., Methods: The morphological features of portal venous system in patients with PVT and those without PVT subgroups were compared. In addition, idealized PV models were established to numerically evaluate the effect of the variation in the angulation of superior mesenteric vein (SMV) and splenic vein (SV) on the hemodynamics of portal venous system., Results: The angle α (angulation of SMV and SV) in patients with PVT was lower than that in patients without PVT (p < 0.0001), which was the only independent risk factor (odds ratio (OR), 0.90 (95% CI 0.84-0.95); p < 0.0001) for the presence of PVT. With the change in angle α, the flow pattern of blood flow changed greatly, especially the helical flow. When α = 80°, helical flow only appeared at the local PV near the intersection of SMV and SV. When α = 120°, most regions were occupied by the helical flow. In addition, the h 2 gradually increased with increasing α, when α = 80°, h 2  = 12.6 m/s 2 ; when α = 120°, h 2  = 29.3 m/s 2 ., Conclusions: The angulation of SV and SMV was closely associated with PVT development. Helical flow changed following the varying angulation of SV and SMV. Therefore, angulation of SV and SMV may help to identify high-risk cohorts for future PVT development earlier., (© 2022. The Author(s).)

An electrocardiography system records electrical activities of the heart, and it is used to assist doctors in the diagnosis of cardiac arrhythmia such as atrial fibrillation. This study presents a fast, automated deep-learning algorithm that predicts atrial fibrillation with excellent performance (F-1 score 88.2% and accuracy 97.3%). Our approach involves the pre-processing of ECG signals, followed by an alternative representation of the signals using a spectrogram, which is then fed to a fine-tuned EfficientNet B0, a pre-trained convolution neural network model, for the classification task. Using the transfer learning approach and with fine-tuning of the EfficientNet, we optimize the model to achieve highly efficient and effective classification of the atrial fibrillation.

Background and Aims: It is important and challenging to evaluate the survival of cirrhotic patients undergoing transjugular intrahepatic portosystemic shunt (TIPS). We aimed to validate the Freiburg index of post-TIPS survival (FIPS) score and classic scores for predicting mortality in Chinese patients after TIPS creation., Methods: A total of 709 consecutive patients with cirrhosis from December 2011 to July 2018 who underwent TIPS placement were retrospectively reviewed. The prognostic value of the FIPS score, the model for end-stage liver disease (MELD) score, Child-Pugh score and Chronic Liver Failure Consortium Acute Decompensation score was validated with the receiver operating characteristic (ROC) curve and DeLong et al. test., Results: The MELD-Na score was superior to the FIPS score in predicting 1-month mortality [AUROC, 0.727 (0.692-0.759) vs. 0.588 (0.551-0.625); P = 0.048]. The MELD and MELD-Na scores were significant superior to the FIPS score in predicting 3-month mortality [AUROC, 0.730 (0.696-0.762) vs. 0.598 (0.561-0.634); P = 0.044 and 0.740 (0.706-0.772) vs. 0.598 (0.561-0.634); P = 0.028]. Subgroup analyses revealed that Child-Pugh score was better than FIPS score in predicting 3-month mortality [AUROC, 0.797 (0.745-0.843) vs. 0.578 (0.517-0.637); P = 0.049] in nonviral cirrhosis group., Conclusion: Classic scores still had good risk stratification and predictive ability of post-TIPS mortality. The FIPS score was not superior to the classic scores in the current Chinese cohort. The MELD and MELD-Na scores were significantly superior to the FIPS score in predicting 3-month mortality., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Facilitative playback-based subjective measures offer a more reliable evaluation of the vocal fold vibration than those derived from direct inspection of video playback. One of the measures is a Nyquist plot, which presents the analyzed cycle-to-cycle vibratory information in a graphical form. While the potential is evident, the information of the features of the Nyquist plot, which the evaluation is based on, is still incomplete. The current identified features and their vibratory behaviors may be inadequate to guarantee accurate interpretation of the findings. The present study aims to address this issue by examining the features of the Nyquist plot and their vibratory behaviors. A total of 56 young normophonic speakers, that is, 20 males and 36 females were recruited as the participants. Each of them underwent laryngeal high-speed videoendoscopy to record the images of the vocal fold vibration, which were then analyzed to generate the Nyquist plots. The features were identified by inspecting the properties of the plot points forming the Nyquist plots. For each identified feature, its vibratory behaviors were examined. The results revealed four features: rim contour depicting the longitudinal phase difference; left edge shape signifying the glottal configuration, phase closure, and closed phase duration; rim width and rim pattern visualizing the regularity of glottal areas and the regularity of the intracycle variations, respectively. The findings present a more complete reference of the features and their vibratory behaviors that is pertinent for the Nyquist plot interpretation., (Copyright © 2020 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate the usefulness of the criteria with liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT) for ruling out high-risk varices in patients with compensated advanced chronic liver disease (cACLD)., Methods: A total of 661 patients with cACLD had successfully undergone 2D-SWE and endoscopy screening. We analyzed risk factors for the presence of high-risk varices and compared proportions of patients who were spared endoscopy when used the predicting criteria with LS (ranged from 16 to 25 kPa) and PLT (ranged from 80 × 10 9 /L to 150 × 10 9 /L)., Results: PLT, albumin, LS were found to be independent predictors of high-risk varices. The LS values for ruling out and ruling in high-risk varices were 14.0 kPa and 24.8 kPa, respectively. When the Baveno VI criteria LS < 20 kPa and PLT > 150 × 10 9 /L were used, the high-risk varices miss rate was 2.1%, while the saved endoscopy rate only was 19.2%. The new criteria that LS < 16 kPa and PLT > 100 × 10 9 /L saved 30.4-34.6% endoscopy with 0-3.2% high-risk varices miss rate in the subgroup analysis stratified according to the types of underlying liver disease., Conclusions: The Baveno VI criteria can be applied to LS measurement by 2D-SWE. The new criteria that LS < 16 kPa and PLT > 100 × 10 9 /L could be a potential model to spare more endoscopy screening with < 5% high-risk varices miss rate., Key Points: • LS measured by 2D-SWE is reliable predictive factor for predicting all-size varices and high-risk varices in patients with compensated advanced chronic liver disease. • LS measured by 2D-SWE < 16 kPa and PLT > 100 × 10 9 /L, which can spare more endoscopy than Baveno VI criteria with < 5% high-risk varices miss rate. • The Baveno VI criteria can be applied to LS measurement by 2D-SWE., (© 2021. European Society of Radiology.)

Background: Serum cytokines-reflecting systemic inflammation has been associated with the risk of decompensation and mortality in patients with cirrhosis. However, the role of systemic inflammation in patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt procedure remains unknown., Patients and Methods: Patients with cirrhosis who received transjugular intrahepatic portosystemic shunt between June 2015 and September 2017 were included. Portal and hepatic venous blood samples were obtained intraoperatively; serum cytokine levels (IL-10, IL-17A, IL-1RA, IL-8, and CXCL10) were measured in 105 patients. Associations with survival and other outcomes during long-term follow-up (median: 1,564 days) were assessed using logistic regression., Results: IL-17A and CXCL10 levels were higher in the portal than in the hepatic veins, whereas IL-1RA levels were higher in the hepatic than in the portal veins. However, IL-8 or IL-10 levels between hepatic and portal veins showed no differences. Multivariate analysis demonstrated that Child-Pugh scores ( P = 0.017, HR: 1.484, 95% CI: 1.072-2.055) and IL-8 level in hepatic veins ( P < 0.001, HR: 1.043, 95% CI: 1.019-1.068) were independent predictors for mortality during long-term follow-up, with an optimal cut-off of 5.87 pg/ml for IL-8 in hepatic veins. Patients with hepatic IL-8 levels < 5.87 pg/ml had significantly higher cumulative survival rates (98.4 vs. 72.9% at 1 year, 98.4 vs. 65.3% at 2 years, 96.7 vs. 60.3% at 3 years, 94.2 vs. 60.3% at 4 years; P < 0.0001)., Conclusions: IL-8 levels in hepatic veins may reflect liver cirrhosis severity. Elevated IL-8 levels suggest shorter survival in patients receiving TIPS., 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 Liu, Wang, Yang, Yan, Xiang, Yang and Luo.)

Ideally, an analysis method for laryngeal high-speed videoendoscopy (LHSV) based on the glottal area waveforms (GAW) requires images of a complete view of the glottis to ensure findings that are representatives of the vibratory behaviors of the whole vocal folds. However, in practice, the preferred images may not be obtained at all times. Often, the only available images that a clinician has to work with consist of a partial view of the glottis. This study aims to examine the effects of using images of a partial view of the glottis (ie, posterior-middle, anterior-middle, or middle) on the LHSV-based measures (ie, fundamental frequency (F0 GAW) , frequency perturbation (jitter GAW) , amplitude perturbation (shimmer GAW) , open quotient (OQ GAW) , and Nyquist plot). The participants consisted of 9 young normophonic females. The procedures involved LHSV recording of the vibration of the vocal folds. The images of the complete view of the glottis were analyzed to obtain the LHSV-based measures. The same images were used to simulate the images of partial views of the glottis by changing the outline of the region of interest to include only either the posterior-middle, anterior-middle, or middle parts of the glottis. The LHSV-based measures from the images of the partial views were then compared to those with the complete view . The results showed that all LHSV-based measures from the images of the posterior-middle view were similar to those of the complete view. However, only the F0 GAW , jitter GAW , and shimmer GAW from the images of the anterior-middle and middle views were similar to those of the complete view. Lower OQ GAW and different Nyquist plots than those of the complete view were generated by the images of the anterior-middle and middle views. In conclusion, all LHSV-based measures from the images of the posterior-middle view of the glottis, and only the F0 GAW , jitter GAW, and shimmer GAW from the images of the anterior-middle and middle views of the glottis reflect the vibratory behaviors of the whole vocal folds. The same conclusion could not be applied to the OQ GAW and Nyquist plots of the images of the anterior-middle and middle views of the glottis. A possible effect of the presence or absence of a posterior glottal gap on the findings warrants further confirmation., (Copyright © 2020 The Voice Foundation. All rights reserved.)

Objectives: To investigate the diagnostic performance of liver stiffness (LS) measured by 2D-SWE for predicting esophageal varices (EV) and high-risk varices (HRV) in patients with hepatitis B virus (HBV)-related compensated advanced chronic liver disease (cACLD)., Methods: In total, 268 patients with HBV-related cACLD who underwent 2D-SWE and esophagogastroduodenoscopy (EGD) were retrospectively evaluated. The new criteria for ruling out HRV were tested in the training cohort with 175 patients and validated in the validation cohort with 93 patients., Results: The AUROCs of LS for predicting EV and HRV were 0.90(0.86-0.95) and 0.93(0.89-0.96) respectively. LS (OR, 1.64 (95% CI: 1.31-2.07); P < 0.0001), PLT (OR, 0.94 (95% CI: 0.91-0.97); P < 0.0001) and albumin (OR, 0.75 (95% CI: 0.62-0.90); P = 0.02) were independent factors for the presence of HRV. The Baveno VI criteria of LS < 20 kPa and PLT > 150 × 10 9 /L saved 15.1%-17.1% EGD screening with 0-4.3% HRV miss rate. LS < 16 kPa and PLT > 60 × 10 9 /L spared 51.4%-52.7% EGD screening with 3.8%-4.3% HRV miss rate., Conclusion: Baveno VI criteria is suitable for 2D-SWE to rule out HRV. LS < 16 kPa and PLT > 60 × 10 9 /L could be a reliable model for ruling out HRV in patients with HBV-related cACLD.

The curse of dimensionality is a widely known issue in reinforcement learning (RL). In the tabular setting where the state space S and the action space A are both finite, to obtain a nearly optimal policy with sampling access to a generative model, the minimax optimal sample complexity scales linearly with | S | × | A | , which can be prohibitively large when S or A is large. This paper considers a Markov decision process (MDP) that admits a set of state-action features, which can linearly express (or approximate) its probability transition kernel. We show that a model-based approach (resp. Q-learning) provably learns an ε -optimal policy (resp. Q-function) with high probability as soon as the sample size exceeds the order of K ( 1 - γ ) 3 ε 2 ( resp . K ( 1 - γ ) 4 ε 2 ) , up to some logarithmic factor. Here K is the feature dimension and γ ∈ (0, 1) is the discount factor of the MDP. Both sample complexity bounds are provably tight, and our result for the model-based approach matches the minimax lower bound. Our results show that for arbitrarily large-scale MDP, both the model-based approach and Q-learning are sample-efficient when K is relatively small, and hence the title of this paper.

Background: A large portion of patients with compensated advanced chronic liver disease (cACLD) do not have varices or only have low risk varices., Aims: To create and validate an easy-to-use risk scoring system to identify high-risk varices (HRV) and spare esophagogastroduodenoscopy (EGD) in patients with hepatitis B virus (HBV)-related cACLD., Methods: In total, 334 patients with HBV-related cACLD who had undergone routine laboratory tests and ultrasound examination were enrolled. Multivariate logistic regression analysis was used to determine which variables were the independent risk factors for the presence of HRV, so as to establish the scoring system for screening HRV. The criteria were tested in a training cohort with 221 patients and validated in a validation cohort with 113 patients., Results: In the training cohort, the prevalence of HRV was 29.5%. Albumin (ALB) [OR 0.83; 95% confidence index (CI) 0.77-0.90; P < 0.0001], platelet count (PLT) (OR 0.96, 95% CI 0.96-0.99; P < 0.0001) and portal vein diameter (OR 1.40; 95% CI 1.15-1.71; P = 0.001) were independent risk factors for the presence of HRV. The negative predictive value was > 95%, when albumin-platelet-portal vein diameter varices scores (APP score) were < 0.24. One hundred twenty-five of 221 (56.6%) patients met an APP score < 0.24 with a 4.8% HRV miss rate. In the validation cohort, 59 of 113 (51.3%) patients met the APP score < 0.24 with a 1.7% HRV miss rate., Conclusions: APP score is a potential model for safely screening HRV and sparing EGDs in patients with HBV-related cACLD., (© 2021. The Author(s).)

Background and Aims: The optimal treatment for gastric varices (GVs) is a topic that remains open for study. This study compared the efficacy and safety of endoscopic cyanoacrylate injection and balloon-occluded retrograde transvenous obliteration (BRTO) to prevent rebleeding in patients with cirrhosis and GVs after primary hemostasis., Approach and Results: Patients with cirrhosis and history of bleeding from gastroesophageal varices type 2 or isolated gastric varices type 1 were randomized to cyanoacrylate injection (n = 32) or BRTO treatment (n = 32). Primary outcomes were gastric variceal rebleeding or all-cause rebleeding. Patient characteristics were well balanced between two groups. Mean follow-up time was 27.1 ± 12.0 months in a cyanoacrylate injection group and 27.6 ± 14.3 months in a BRTO group. Probability of gastric variceal rebleeding was higher in the cyanoacrylate injection group than in the BRTO group (P = 0.024). Probability of remaining free of all-cause rebleeding at 1 and 2 years for cyanoacrylate injection versus BRTO was 77% versus 96.3% and 65.2% versus 92.6% (P = 0.004). Survival rates, frequency of complications, and worsening of esophageal varices were similar in both groups. BRTO resulted in fewer hospitalizations, inpatient stays, and lower medical costs., Conclusions: BRTO is more effective than cyanoacrylate injection in preventing rebleeding from GVs, with similar frequencies of complications and mortalities., (© 2021 by the American Association for the Study of Liver Diseases.)

This paper delivers improved theoretical guarantees for the convex programming approach in low-rank matrix estimation, in the presence of (1) random noise, (2) gross sparse outliers, and (3) missing data. This problem, often dubbed as robust principal component analysis (robust PCA) , finds applications in various domains. Despite the wide applicability of convex relaxation, the available statistical support (particularly the stability analysis vis-à-vis random noise) remains highly suboptimal, which we strengthen in this paper. When the unknown matrix is well-conditioned, incoherent, and of constant rank, we demonstrate that a principled convex program achieves near-optimal statistical accuracy, in terms of both the Euclidean loss and the ℓ ∞ loss. All of this happens even when nearly a constant fraction of observations are corrupted by outliers with arbitrary magnitudes. The key analysis idea lies in bridging the convex program in use and an auxiliary nonconvex optimization algorithm, and hence the title of this paper.

Objectives : The presence of varices affects the survival of patients with primary biliary cholangitis (PBC). The aim of this study is to assess the criteria based on liver stiffness (LS) measured by two-dimensional shear wave elastography (2D-SWE) and platelet count (PLT), and recently published noninvasive models for triaging PBC patients. Methods : 231 patients with PBC who underwent EGD and 2D-SWE examination were enrolled. Areas under the receiver-operating characteristic curve (AUROC) were used to assess the performance of 2D-SWE for predicting all-size varices and high-risk varices. All-size varices and high-risk varices miss rate < 10% and <5%, respectively, were acceptable for screening varices. Results : The AUROCs of LS for predicting all-size varices and high-risk varices were 0.87 (95%CI: 0.82-0.91) and 0.84 (95%CI: 0.74-0.86), respectively. LS <25 kPa and PLT >110 × 10 9 /L spared 46.3% EGD screening, with 3.7% high-risk varices miss rate and 8.4% all-size varices miss rate. One hundred and sixteen (50.2%) patients met the Newcastle varices in PBC score (cutoff, 0.5), with 4.3% high-risk varices miss rate and 11.2% all-size varices miss rate. Conclusion : The criteria based on LS and PLT are useful for triaging PBC patients. LS <25 kPa and PLT >110 × 10 9 /L could be the optimal criteria for screening varices.

Background: COVID-19 is a global pandemic. The prevention of SARS-CoV-2 infection and the rehabilitation of survivors are currently the most urgent tasks. However, after patients with COVID-19 are discharged from the hospital, how long the antibodies persist, whether the lung lesions can be completely absorbed, and whether cardiopulmonary abnormalities exist remain unclear. Methods: A total of 56 COVID-19 survivors were followed up for 12 months, with examinations including serum virus-specific antibodies, chest CT, and cardiopulmonary exercise testing. Results: The IgG titer of the COVID-19 survivors decreased gradually, especially in the first 6 months after discharge. At 6 and 12 months after discharge, the IgG titer decreased by 68.9 and 86.0%, respectively. The IgG titer in patients with severe disease was higher than that in patients with non-severe disease at each time point, but the difference did not reach statistical significance. Among the patients, 11.8% were IgG negative up to 12 months after discharge. Chest CT scans showed that at 3 and 10 months after discharge, the lung opacity had decreased by 91.9 and 95.5%, respectively, as compared with that at admission. 10 months after discharge, 12.5% of the patients had an opacity percentage >1%, and 18.8% of patients had pulmonary fibrosis (38.5% in the severe group and 5.3% in the non-severe group, P < 0.001). Cardiopulmonary exercise testing showed that 22.9% of patients had FEV1/FVC%Pred <92%, 17.1% of patients had FEV1%Pred <80%, 20.0% of patients had a VO 2 AT <14 mlO 2 /kg/min, and 22.9% of patients had a VE/VCO 2 slope >30%. Conclusions: IgG antibodies in most patients with COVID-19 can last for at least 12 months after discharge. The IgG titers decreased significantly in the first 6 months and remained stable in the following 6 months. The lung lesions of most patients with COVID-19 can be absorbed without sequelae, and a few patients in severe condition are more likely to develop pulmonary fibrosis. Approximately one-fifth of the patients had cardiopulmonary dysfunction 6 months after discharge., 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 Xiao, Yang, Liu, Pang, Du, Liu, Liu, Jing, Chen, Deng, Zhou, Du, Yin, Yan, Mou and She.)

Despite its clear advantages, laryngeal high-speed videoendoscopy (LHSV) has not yet been accepted as a routine imaging tool for the evaluation of vocal fold vibration due to the unavailability of methods to effectively analyze the huge number of images from the LHSV recording. Recently, a promising LHSV-based analysis method has been introduced. The ability of this analysis method in studying the vocal fold vibratory behaviors had been substantially demonstrated. However, some practical aspects of its clinical applications still require further attention. Most fundamental is that the criteria for the measurement input ie, a segment of interest (SOI), which has not been fully defined. Particularly, the length of the SOI and the location along the sample, where it needs to be selected require further confirmation. Meanwhile, the analysis using any options of a well-delineated glottal area demands verification. Without clear criteria for the SOI, it is difficult to demonstrate the relevance of this analysis method in clinical voice assessment. Therefore, the aim of the present study is to establish the criteria for the SOI, which involved the investigations on the length of the SOI and the location along the sample, where it needs to be selected, as well as the use of any options of a well-delineated glottal area for analysis. The participants in the present study consisted of 36 young normophonic females. The methods involved LHSV recording of the images of the vibrating vocal folds. The captured images were then analyzed using the method. The LHSV-based measures from the analyses were compared according to the specified procedures of each investigation. Results indicated that 2000 frames should be used as the SOI length. The SOI could be selected at any location along the sample as long as well-delineated glottal areas were observed. With the current findings, a more conclusive measurement protocol is available to ensure reliable LHSV-based measures. The findings further support this analysis method for clinical application, which in turn promote LHSV as a reliable laryngeal imaging tool in clinical setting., (Copyright © 2019 The Voice Foundation. All rights reserved.)

Aims: This study aimed to determine the effects of sodium-glucose cotransporter-2 inhibitor (SGLT2i) in heart failure with reduced ejection fraction (HFrEF), compare the effect of SGLT2i with angiotensin receptor neprilysin inhibitor (ARNI), and find whether combination of SGLT2i and ARNI is better than monotherapy., Methods and Results: Embase, Medline, and Cochrane Central Registry of Controlled Trials were searched for randomized controlled trials evaluating SGLT2i or ARNI in HFrEF. And a total of six trials were included. SGLT2i was found to significantly reduce the risk of cardiovascular death or hospitalization for heart failure by 27% [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.67-0.80], hospitalization for heart failure by 31% (HR 0.69, 95% CI 0.62-0.77), cardiovascular death by 16% (HR 0.84, 95% CI 0.74-0.95), and all-cause death by 16% (HR 0.84, 95% CI 0.75-0.94) in HFrEF only with a statistically higher risk of genital infection (risk ratio (RR) 2.78, 95% CI 1.46-5.29). The reduction in cardiovascular death or hospitalization for heart failure was of similar magnitude in patients with or without diabetes mellitus (HR 0.71, 95% CI 0.64-0.80 vs. HR 0.75, 95% CI 0.65-0.87) using SGLT2i. Indirect treatment comparison showed that SGLT2i and ARNI had similar effects on primary outcome (HR 0.93, 95% CI 0.82-1.06). And combination of SGLT2i and ARNI achieved a better prognosis performance (HR 0.68, 95% CI 0.53-0.89) compared with ARNI monotherapy., Conclusions: SGLT2i could safely reduce cardiovascular death or hospitalization for heart failure in HFrEF regardless of diabetes mellitus status. SGLT2i and ARNI demonstrate similar effects, while combination of SGLT2i and ARNI results in a better cardiovascular protective effect., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Two-dimensional shear-wave elastography (2D-SWE) is an ultrasound-based real-time 2D-SWE imaging technique for noninvasive assessment of liver fibrosis. The diagnostic performance of 2D-SWE for assessing liver fibrosis in patients with autoimmune hepatitis (AIH) has not been reported., Aims: To evaluate the diagnostic performance of 2D-SWE and serologic tests including the aspartate amino transferase-to-platelet ratio index (APRI) and fibrosis-4 index (FIB-4) for liver fibrosis staging in patients with AIH., Methods: 103 patients were retrospectively collected. Liver fibrosis was staged according to the Scheuer scoring system. The areas under the receiver operating characteristic curves (AUROCs) were used to assess the accuracy of 2D-SWE and serum fibrosis models for staging liver fibrosis., Results: Liver stiffness measured by 2D-SWE had a strong correlation with histological fibrosis stage (r = 0.71, P < 0.0001). The AUROCs of liver stiffness in detecting significant fibrosis, severe fibrosis, and cirrhosis were 0.84, 0.84, and 0.94, respectively. The AUROCs of liver stiffness for detecting significant fibrosis and severe fibrosis were higher than those of APRI (0.57, 0.56) and FIB-4 (0.63, 0.66), respectively. The cut-off liver stiffness values for predicting significant fibrosis, severe fibrosis, and cirrhosis were 10.0, 15.8, and 19.3 kPa, respectively., Conclusions: 2D-SWE shows promising diagnostic performance for staging liver fibrosis in patients with AIH.

Purpose: Gd-encapsulated carbonaceous dots (Gd@C-dots) have excellent stability and magnetic properties without free Gd leakage, therefore they can be considered as a safe alternative T1 contrast agent to commonly used Gd complexes. To improve their potential for cancer diagnosis and treatment, affibody-modified Gd@C-dots targeting non-small-cell lung cancer (NSCLC) EGFR-positive tumors with enhanced renal clearance were developed and synthesized., Materials and Methods: Gd@C-dots were developed and modified with Ac-Cys-Z EGFR:1907 through EDC/NHS. The size, morphology, and optical properties of the Gd@C-dots and Gd@C-dots-Cys-Z EGFR:1907 were characterized. Targeting ability was evaluated by in vitro and in vivo experiments, respectively. Residual gadolinium concentration in major organs was detected with confocal imaging and inductively coupled plasma mass spectrometry (ICP-MS) ex vivo. H&E staining was used to assess the morphology of these organs., Results: Gd@C-dots with nearly 20 nm in diameter were developed and modified with Ac-Cys-Z EGFR:1907 . EGFR expression in HCC827 cells was higher than NCI-H520. In cell uptake assays, EGFR-expressing HCC827 cells exhibited significant MR T1WI signal enhancement when compared to NCI-H520 cells. Cellular uptake of Gd@C-dots-Cys-Z EGFR:1907 was reduced, when Ac-Cys-Z EGFR:1907 was added. In vivo targeting experiments showed that the probe signal was significantly higher in HCC827 than NCI-H520 xenografts at 1 h after injection. In contrast to Gd@C-dots, Gd@C-dots-Cys-Z EGFR:1907 nanoparticles can be efficiently excreted through renal clearance. No morphological changes were observed by H&E staining in the major organs after injection of Gd@C-dots-Cys-Z EGFR:1907 ., Conclusion: Gd@C-dots-Cys-Z EGFR:1907 is a high-affinity EGFR-targeting probe with efficient renal clearance and is therefore a promising contrast agent for clinical applications such as diagnosis and treatment of NSCLC EGFR-positive malignant tumors., Competing Interests: The authors have declared that no competing interest exists and that they have no conflicts of interest in this work., (© 2020 Wu et al.)

Background: Two-dimensional shear-wave elastography (2D-SWE) is an ultrasound-based technique used to stage liver fibrosis by measuring liver stiffness (LS). The diagnostic performance of 2D-SWE for assessing liver fibrosis in patients with primary biliary cholangitis (PBC) has not been reported before., Aims: To investigate the diagnostic performance of 2D-SWE for staging liver fibrosis in patients with PBC by using histologic analysis as a reference standard., Methods: Patients with PBC who underwent liver biopsy and 2D-SWE were retrospectively collected. Liver fibrosis was staged according to the Scheuer scoring system. Areas under receiver operating characteristic curve (AUROC) was constructed to assess the accuracy of 2D-SWE and serum fibrosis models for staging liver fibrosis., Results: The diagnostic performance characteristics were determined for 157 patients with PBC. The AUROCs of LS measured by 2D-SWE for significant fibrosis, severe fibrosis, and cirrhosis were 0.88, 0.97 and 0.99, respectively. The cutoff values of LS measured by 2D-SWE in discriminating significant fibrosis, severe fibrosis, and cirrhosis were 10.7 kPa, 12.2 kPa and 14.1 kPa, respectively. The diagnostic accuracy of 2D-SWE for staging liver fibrosis was 73.9%., Conclusions: 2D-SWE is an efficient noninvasive method for the assessment of liver fibrosis in patients with PBC., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

This paper studies noisy low-rank matrix completion: given partial and noisy entries of a large low-rank matrix, the goal is to estimate the underlying matrix faithfully and efficiently. Arguably one of the most popular paradigms to tackle this problem is convex relaxation, which achieves remarkable efficacy in practice. However, the theoretical support of this approach is still far from optimal in the noisy setting, falling short of explaining its empirical success. We make progress towards demystifying the practical efficacy of convex relaxation vis-à-vis random noise. When the rank and the condition number of the unknown matrix are bounded by a constant, we demonstrate that the convex programming approach achieves near-optimal estimation errors - in terms of the Euclidean loss, the entrywise loss, and the spectral norm loss - for a wide range of noise levels. All of this is enabled by bridging convex relaxation with the nonconvex Burer-Monteiro approach, a seemingly distinct algorithmic paradigm that is provably robust against noise. More specifically, we show that an approximate critical point of the nonconvex formulation serves as an extremely tight approximation of the convex solution, thus allowing us to transfer the desired statistical guarantees of the nonconvex approach to its convex counterpart.

Sinusoidal obstruction syndrome (SOS) is a rare liver disorder due to hepatic vascular injury. Its rapid and accurate diagnosis is crucial for patient survival. SOS is often established clinically, based on Baltimore, modified Seattle, or European Society for Blood and Marrow Transplantation (EBMT) criteria. Unfortunately, such criteria are not highly specificity and fail to provide a timely, reliable differential diagnosis. The use of noninvasive imaging techniques, such as ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), has recently grown in this setting, some key imaging features offering diagnostic improvement. This review provides a synopsis of current noninvasive imaging techniques used for this purpose, summarizing accurate and reliable diagnostic features of SOS.

Noisy matrix completion aims at estimating a low-rank matrix given only partial and corrupted entries. Despite remarkable progress in designing efficient estimation algorithms, it remains largely unclear how to assess the uncertainty of the obtained estimates and how to perform efficient statistical inference on the unknown matrix (e.g., constructing a valid and short confidence interval for an unseen entry). This paper takes a substantial step toward addressing such tasks. We develop a simple procedure to compensate for the bias of the widely used convex and nonconvex estimators. The resulting debiased estimators admit nearly precise nonasymptotic distributional characterizations, which in turn enable optimal construction of confidence intervals/regions for, say, the missing entries and the low-rank factors. Our inferential procedures do not require sample splitting, thus avoiding unnecessary loss of data efficiency. As a byproduct, we obtain a sharp characterization of the estimation accuracy of our debiased estimators in both rate and constant. Our debiased estimators are tractable algorithms that provably achieve full statistical efficiency., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Increased epicardial adipose tissue (EAT) has been proposed as a risk factor for non-alcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the association of EAT with NAFLD., Methods: The PubMed, EMBASE, and Cochrane databases were systematically reviewed by two independent investigators to identify relevant studies assessing the association of EAT thickness (EAT-t) and volume (EAT-v) with NAFLD. Comparisons between NAFLD subjects and controls were performed with meta-analysis and trial sequential analysis (TSA)., Results: A total of thirteen case-control studies (n = 2260 patients) were included in the final analysis. The EAT was significantly increased in NAFLD patients compared with the controls (EAT, SMD: 0.73, 95% CI 0.51-0.94, p < 0.001; TSA-adjusted 95% CI 0.07-0.18; p < 0.001). When comparing the subgroups of NAFLD, the EAT-t in the severe-hepatic steatosis subgroup was thicker than that in the moderate subgroup (SMD: 1.43, 95% CI 0.15-2.71, p = 0.029). This study indicated that the EAT-t in the F3-4 fibrosis subgroup was thicker than that in the F0-2 fibrosis subgroup (SMD: 0.72, 95% CI 0.30-1.14, p = 0.001). The proportion of hypertension (OR = 1.64, 95% CI = 1.24-2.18, p = 0.001) and atherosclerotic cardiovascular disease (ASCVD) (OR = 1.66, 95% CI = 1.21-2.28, p = 0.002) was higher in the high-EAT-t group compared with the low-EAT-t group in NAFLD patients., Conclusions: The EAT was increased in the NAFLD subjects compared to the controls. The increase in the EAT was associated with the severity of steatosis, fibrosis and cardiovascular disease in patients with NAFLD. These findings provide new information regarding the development and progression of NAFLD.

The assessment of vascular permeability of malignant tumor plays an important role in the diagnosis and treatment of cancer. Dynamic contrast-enhanced magnetic resonance image (DCE-MRI) using Gd-encapsulated carbonaceous dots and Gd-DTPA-BMA as contrast agents was performed in 4T1 mouse breast cancer and HCC827 human non-small-cell lung cancer (NSNLC) xenograft models. Histopathological parameters of tumor vascularity microvessel density (MVD), microvessel area (MVA), endothelial area (EA) and α-SMA CD31 Co-expression (α-SMA/CD31%) were compared with the DCE-MRI parameters. Results demonstrated that DCE-MRI with the new nanoparticle Gd@C-dots can noninvasively evaluate vascular permeability. K trans measured by DCE-MRI with Gd@C-dots is an accurate parameter for the characterization of tumor permeability. EA is a reliable microvessel parameter to evaluate vessel permeability., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Clarifying the mechanisms via which pacemaker- like cells are generated is critical for identifying novel targets for arrhythmia-associated disorders and constructing pacemakers with the ability to adapt to physiological requirements. T-box 18 (Tbx18) + epicardial progenitor cells (EPCs) have the potential to differentiate into pacemaker cells. Although bone morphogenetic protein 4 (Bmp4) is likely to contribute, its role and regulatory mechanisms in the differentiation of Tbx18 + EPCs into pacemaker-like cells have remained to be fully elucidated. In the present study, the association between Bmp4, GATA binding protein 4 (Gata4) and hyperpolarization- activated cyclic nucleotide gated potassium channel 4 (Hcn4) to regulate NK2 homeobox 5 (Nkx2.5), which is known to be required for the differentiation of Tbx18 + EPCs into pacemaker-like cells, was assessed. Tbx18 + EPCs were isolated from Tbx18:Cre/Rosa26R enhanced yellow fluorescence protein (EYFP) murine embryos at embryonic day 11.5 and divided into the following four treatment groups: Control, Bmp4, Bmp4+LDN193189 (a Bmp inhibitor) and LDN193189. In vitro Bmp4 promoted the expression of Hcn4 in Tbx18 + EPCs via lineage tracing of Tbx18:Cre/Rosa26R EYFP mice, which was likely due to upregulation of Gata4 expression. Gata4 knockdown experiments were then performed using the following five treatment groups: Control, control small interfering RNA (siRNA), Bmp4, Bmp4+siRNA targeting Gata4 (siGata4) and siGata4 group. Knockdown of Gata4 caused a downregulation of Hcn4 and an upregulation of Nkx2.5, but had no effect on Bmp4 expression. In conclusion, it was indicated that in Tbx18 + EPCs, the expression of Nkx2.5 was regulated by Bmp4 via Gata4. Taken together, these results provide important information on regulatory networks of pacemaker cell differentiation and may serve as a basis for further studies.

Brain-Machine Interface (BMI) has been considered as an effective way to help and support both the disabled rehabilitation and healthy individuals' daily lives to use their brain activity information instead of their bodies. In order to reduce costs and control exoskeleton robots better, we aim to estimate the necessary torque information for a subject from his/her electroencephalography (EEG) signals when using an exoskeleton robot to perform the power assistance of the upper limb without using external torque sensors nor electromyography (EMG) sensors. In this paper, we focus on extracting the motion-relevant EEG signals' features of the shoulder joint, which is the most complex joint in the human's body, to construct a power assistance system using wearable upper limb exoskeleton robots with BMI technology. We extract the characteristic EEG signals when the shoulder joint is doing flexion and extension movement freely which are the main motions of the shoulder joint needed to be assisted. Independent component analysis (ICA) is used to extract the source information of neural components, and then the average method is used to extract the characteristic signals that are fundamental to achieve the control. The proposed approach has been experimentally verified. The results show that EEG signals begin to increase at 300⁻400 ms before the motion and then decrease at the beginning of the generation of EMG signals, and the peaks appear at about one second after the motion. At the same time, we also confirmed the relationship between the change of EMG signals and the EEG signals on the time dimension, and these results also provide a theoretical basis for the delay parameter in the linear model which will be used to estimate the necessary torque information in future. Our results suggest that the estimation of torque information based on EEG signals is feasible, and demonstrate the potential of using EEG signals via the control of brain-machine interface to support human activities continuously.

Background: Folate receptors (FRs) hold great potential as important diagnostic and prognostic biological marker for cancer., Purpose: To assess the targeted capability of the FR-targeted perfluorocarbon (PFC) nanoparticles and to assess in vivo the relationship between FR expression and tumor proliferation with fluorine-19 ( 19 F) MR molecular imaging., Study Type: Prospective animal cancer model., Animal Model: H460 (n = 14) and A549 (n = 14) nude mice subcutaneous tumor models., Field Strength: 9.4T, 1 H and 19 F RARE sequences., Assessment: Intracellular uptake of the PFC nanoparticles was tested in H460 and A549 cell lines. 19 F MRI of H460 and A549 subcutaneous tumors was performed following intravenous injection of PFC nanoparticles. The concentration of PFC in tumors were compared. 3'-Deoxy-3'- 18 F-fluorothymidine ( 18 F-FLT) positron emission tomography / computed tomography (PET/CT) imaging, Ki-67, and proliferating cell nuclear antigen (PCNA) staining were performed to confirm tumor proliferation., Statistical Tests: One-way or two-way analysis of variance. P < 0.05 was considered a significant difference., Results: The diameter of the FR-targeted nanoparticles was 108.8 ± 0.56 nm, and the zeta potential was -58.4 ± 10.8 mV. H460 cells incubated with FR-targeted nanoparticles showed ∼59.87 ± 3.91% nanoparticles-labeled, which is significantly higher than the other groups (P < 0.001). The PFC concentration in H460 tumors after injection with FR-targeted nanoparticles was 4.64 ± 1.21, 8.04 ± 1.38, and 9.16 ± 2.56 mmol/L at 8 hours, 24 hours, and 48 hours, respectively (P < 0.05 compared to others). The ratio of 18 F-FLT uptake for H460 and A549 tumors was 3.32 ± 0.17 and 1.48 ± 0.09 (P < 0.05), and there was more Ki-67 and PCNA in H460 tumor than A549. DATA CONCLUSION: 19 F MRI with FR-targeted PFC nanoparticles can be used in differentiating of FR-positive and FR-negative tumors, and further, in evaluation of the two cancer models proliferation., Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1617-1625., (© 2018 International Society for Magnetic Resonance in Medicine.)

Embryonic epicardial cells (EPCs) can facilitate cardiomyocyte growth through secreting several essential growth factors, and participate in cardiac development through auto-differentiating into many cardiac cell lineages. Proper proliferation of EPCs is the precondition of these functions, so it is quite necessary to explore the mechanisms involving in EPC proliferation. In this study, we aimed to explore whether insulin-like growth factor 1 receptor (IGF1R) signaling participated in regulating the proliferation of EPCs. Our results showed that the expressions of IGF1R and its ligands IGF1 and IGF2 can be clearly spotted on the epicardium layer from E11.5d to E17.5d. Inhibition of IGF1R signaling using picropodophyllin or NVP-AEW541 significantly decreased the proliferation activity and blocked the cell cycle progression of epicardial cells in vitro. On the contrary, activating IGF1R with recombinant IGF1 and IGF2 promoted epicardial cell proliferation and cell cycle. We also found that decreased expression and phosphorylation of FAK in IGF1R inhibitor-treated cells and use of FAK inhibitor Y15 could significantly inhibit the IGFs-induced EPC proliferation. In conclusion, our results suggest that IGF1R signaling plays an important role in regulating EPC proliferation, and this effect may be mediated by FAK pathway.

Dormant tumor cells (DTCs) serve a crucial role in the pathogenesis of metastasis and may compromise the efficacy of existing therapeutic modalities aimed at fully eradicating cancer. However, the mechanisms underlying the dormant-to-proliferating switch of DTCs remain largely unknown. The lung is one of the most common sites of metastatic recurrence. The transdifferentiation of alveolar epithelial cells II (AEC IIs) to AEC Is is a hallmark of alveolar epithelial stimulation. However, the role of AEC II transdifferentiation during the reactivation of DTCs has not been fully elucidated. In the present study, we found that tumor cells promoted the transdifferentiation of AEC IIs. Furthermore, the supernatant of the transdifferentiation of AEC IIs to AEC Is (Super-TDA) promoted the dormant-to-proliferating switch of DTCs via the autocrine effect of TGF-β1 on the 3D BME culture system in vitro. Monensin and LY2109761 blocked the dormant-to-proliferating switch of DTCs induced by Super-TDA. Although lipopolysaccharide did not directly stimulate the reactivation of DTCs, it promoted DTC reactivation by increasing the secretion of TGF-β1 in the Super-TDA. We further demonstrated that the upregulation of SNAI2 expression was required for Super-TDA facilitating the DTC dormant-to‑proliferating switch. Taken together, our findings demonstrated that tumor cells may promote AEC II transdifferentiation. Furthermore, the transdifferentiation of AEC IIs may, in turn, induce the reactivation of 3D-established DTCs by promoting TGF-β1/SNAI2 signaling. Targeting this process may provide novel therapeutic strategies for the inhibition of the dormant‑to-proliferating switch.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive method to assess angiogenesis, which is widely used in clinical applications including diagnosis, monitoring therapy response and prognosis estimation in cancer patients. Contrast agents play a crucial role in DCE-MRI and should be carefully selected in order to improve accuracy in DCE-MRI examination. Over the past decades, there was much progress in the development of optimal contrast agents in DCE-MRI. In this review, we describe the recent research advances in this field and discuss properties of contrast agents, as well as their advantages and disadvantages. Finally, we discuss the research perspectives for improving this promising imaging method.