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Aims: To investigate immunometabolic associations of CD4 + T cell phenotypes with gestational diabetes mellitus (GDM)., Methods: A nested case-control study was conducted comprising 53 pairs of GDM patients and matched controls within a prospective cohort. Metabolomic signatures related to both CD4 + T cell phenotypes and glycemic traits among pregnant women were investigated by weighted gene co-expression network analysis (WGCNA). Multivariable-adjusted generalized linear models were used to explore the associations of CD4 + T cell phenotypes and selected metabolites with GDM. Mediation analysis was conducted to evaluate the mediating effect of selected metabolites on the relationship between CD4 + T cell phenotypes and glycemic traits., Results: Higher levels of Treg cells (OR per SD increment (95%CI): 0.57 (0.34, 0.95), p = 0.031) and increased expression of Foxp3 (OR per SD increment (95%CI): 0.59 (0.35, 0.97), p = 0.039) and GATA3 (OR per SD increment (95%CI): 0.42 (0.25, 0.72), p = 0.002) were correlated with a decreased risk of GDM. Plasma pyruvaldehyde, S-adenosylhomocysteine (SAH), bergapten, and 9-fluorenone mediated the association between Tregs and fasting plasma glucose (FPG), with mediation proportions of 46.9%, 39.6%, 52.4%, and 56.9%, respectively., Conclusions: Treg cells and Foxp3 expressions were inversely associated with GDM risk, with potential metabolic mechanisms involving metabolites such as pyruvaldehyde and SAH., (© 2024. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Scope: This study aims to identify the gut enterotypes that explain differential responses to intervention with whole grain rye by proposing an "enterotype - metabolic" model., Methods and Results: A 12-week randomized controlled trial is conducted in Chinese adults, with 79 subjects consuming whole grain products with fermented rye bran (FRB) and 77 consuming refined wheat products in this exploratory post-hoc analysis. Responders or non-responders are identified according to whether blood glucose decreased by more than 10% after rye intervention. Compared to non-responders, responders in FRB have higher baseline Bacteroides (p < 0.001), associated with reduced blood glucose (p < 0.001), increased Faecalibacterium (p = 0.020) and Erysipelotrichaceae&#95;UCG.003 (p = 0.022), as well as deceased 7β-hydroxysteroid dehydrogenase (p = 0.033) after intervention. The differentiated gut microbiota and metabolites between responders and non-responders after intervention are enriched in aminoacyl-tRNA biosynthesis., Conclusion: The work confirms the previously suggested importance of microbial enterotypes in differential responses to whole grain interventions and supports taking enterotypes into consideration for improved efficacy of whole grain intervention for preventing type 2 diabetes. Altered short-chain fatty acids and bile acid metabolism might be a potential mediator for the beneficial effects of whole grain rye on glucose metabolism., (© 2024 Wiley‐VCH GmbH.)

Objective: Fostamatinib, an FDA-approved oral small-molecule spleen tyrosine kinase (SYK) inhibitor, is used to treat thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have not responded to previous treatments. However, comprehensive safety data is lacking. This study uses the FDA Adverse Event Reporting System (FAERS) database to explore real-world adverse events (AEs) related to fostamatinib, aiming to inform its clinical use., Methods: The FAERS database was retrospectively queried to extract reports associated with fostamatinib from 2019 to 2023. To identify and evaluate potential AEs in patients receiving fostamatinib, various disproportionality analyses such as the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed., Results: A total of 23 AE signals were included in our analysis. Among them, hypertension, blood pressure increase, blood pressure abnormality, hepatic enzyme increase, and diarrhea were consistent with the common AEs described for fostamatinib in clinical trials. In addition, unexpected serious AEs were detected including cerebral thrombosis and necrotizing soft tissue infection. The median time to onset of fostamatinib-related AEs was 86 days., Conclusion: Our investigation revealed several possibly emergent safety concerns associated with fostamatinib in real-world clinical practice, which might provide essential vigilance evidence for clinicians and pharmacists to manage the safety issues of fostamatinib.

Female urethral caruncle is the most common urethral mass in postmenopausal women, yet there is a lack of studies on its imaging. The aim of this study was to provide a summary of the clinical and ultrasound features as well as the precise location of female urethral caruncle. This study reviewed the clinical and ultrasonographic records of 20 consecutive women with pathologically confirmed urethral caruncle. Data on patient demographics, symptoms, and transperineal and transrectal ultrasound imaging features, including location, shape, margin, size, blood flow, and inner echo of the caruncle, were extracted. Each patient presented with only one mass at the urethral meatus. Most caruncles were located on the posterior lip (75%) of the urethra, presenting as oval (80%), mixed-echoic (50%), or hypo-echoic (40%) nodules with abundant linear (40%) or dendritic (60%) blood flow. The average distance between the bladder neck and the cranial end of the masses was 28 mm. Hyper-echogenic spots, cystic echo areas, and macrocalcifications were detected in thirteen caruncles (70%). This study shows that transperineal combined with transrectal ultrasound can be used to assess female urethral caruncle, and its relative location to the urethra can be accurately described, which is helpful for surgeons making preoperative localization and conversations., (© 2024. The Author(s).)

Background and Aims: Type 2 diabetes (T2D) is a global and complex public health challenge, and dietary management is acknowledged as critical in its prevention. Recent studies have highlighted the involvement of micronutrients in T2D pathophysiology; our study aims to assess the association between B vitamin intake and T2D risks and the mediating role of inflammation., Methods: In a prospective cohort design, data on B vitamins intake, including thiamine (B1), riboflavin (B2), niacin (B3), pyridoxine (B6), folate (B9), and cobalamin (B12), was obtained using a validated food frequency questionnaire (FFQ), and blood inflammatory biomarkers were analyzed according to standard protocol in the local hospitals at baseline from 44,960 adults in the Shanghai Suburban Adult Cohort and Biobank (SSACB). Incident T2D cases were identified according to a physician's diagnosis or medication records from the electronic medical information system. We employed logistic and weighted quantile sum regression models to explore the associations of single and combined levels of B vitamins with T2D and mediation analyses to investigate the effects of inflammation., Results: Negative correlations between B vitamins and T2D were observed in the single-exposure models, except for B3. The analyses of joint exposure (B1, B2, B6, B9, and B12) also showed an inverse association (OR 0.80, 95% CI 0.71 to 0.88), with vitamin B6 accounting for 45.58% of the effects. Further mediation analysis indicated a mediating inflammatory impact, accounting for 6.72% of the relationship., Conclusions: Dietary intake of B vitamins (B1, B2, B6, B9, B12) was associated with a reduced T2D risk partially mediated by inflammation in Shanghai residents.

Resveratrol (RSV) is a polyphenol antioxidant that has been shown to have neuroprotective effects. We sought molecular mechanisms that emphasize the anti-inflammatory activity of RSV in traumatic brain injury (TBI) in mice associated with endoplasmic reticulum stress (ERS). After establishing three experimental groups (sham, TBI, and TBI+RSV), we explored the results of RSV after TBI on ERS and caspase-12 apoptotic pathways. The expression levels of C/EBP homologous protein (CHOP), glucose regulated protein 78kD (GRP78), caspase-3, and caspase-12 in cortical brain tissues were assessed by western blotting. The qPCR analysis was also performed on mRNA expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in cortical brain tissue. In addition, the expression of GRP78 in microglia (ionized calcium binding adaptor molecule 1; Iba-1) and neurons (neuronal nuclei; NeuN) was identified by immunofluorescence staining. The neurological function of mice was assessed by modified neurological severity scores (mNSS). After drug treatment, the expression of CHOP, GRP78, caspase-3 and caspase-12 decreased, and qPCR results showed that TNF-α and IL-1β were down-regulated. Immunofluorescence staining showed down-regulation of Iba-1+/GRP78+ and NeuN+/GRP78+ cells after RSV treatment. The mNSS analysis confirmed improvement after RSV treatment. RSV improved apoptosis by downregulating the ERS signaling pathway and improved neurological prognosis in mice with TBI., Competing Interests: The authors report no conflicts of interest in this work.

Ferroptosis is characterized by the lethal accumulation of lipid reactive oxygen species (ROS), which has great potential for tumor therapy. However, developing new ferroptosis-inducing strategies by combining nanomaterials with small molecule inducers is important. In this study, an enzyme-gated biodegradable natural-product delivery system based on lactate oxidase (LOD)-gated biodegradable iridium (Ir)-doped hollow mesoporous organosilica nanoparticles (HMONs) loaded with honokiol (HNK) (HNK@Ir-HMONs-LOD, HIHL) is designed to enhance ferroptosis in colon tumor therapy. After reaching the tumor microenvironment, the outer LOD dissociates and releases the HNK to induce ferroptosis. Moreover, the released dopant Ir 4+ and disulfide-bridged organosilica frameworks deplete intracellular glutathione (GSH), which is followed by GSH-mediated Ir(IV)/Ir(III) conversion. This leads to the repression of glutathione peroxidase 4 (GPX4) activity and decomposition of intratumoral hydrogen peroxide (H 2 O 2 ) into hydroxyl radicals (•OH) by Ir 3+ -mediated Fenton-like reactions. Moreover, LOD efficiently depletes lactic acid to facilitate the generation of H 2 O 2 and boost the Fenton reaction, which in turn enhances ROS generation. With the synergistic effects of these cascade reactions and the release of HNK, notable ferroptosis efficacy was observed both in vitro and in vivo. This combination of natural product-induced and lactic acid-responsive sequential production of H 2 O 2 as well as the consumption of glutathione may provide a new paradigm for achieving effective ferroptosis-based cancer therapy., 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 Inc. All rights reserved.)

Stent-assisted coiling is a main treatment modality for intracranial aneurysms (IAs) in clinics, but critical challenges remain to be overcome, such as exogenous implant-induced stenosis and reliance on antiplatelet agents. Herein, an endovascular approach is reported for IA therapy without stent grafting or microcatheter shaping, enabled by active delivery of thrombin (Th) to target aneurysms using innovative phase-change material (PCM)-coated magnetite-thrombin (Fe 3 O 4 -Th@PCM) FTP nanorobots. The nanorobots are controlled by an integrated actuation system of dynamic torque-force hybrid magnetic fields. With robust intravascular navigation guided by real-time ultrasound imaging, nanorobotic collectives can effectively accumulate and retain in model aneurysms constructed in vivo, followed by controlled release of the encapsulated Th for rapid occlusion of the aneurysm upon melting the protective PCM (thermally responsive in a tunable manner) through focused magnetic hyperthermia. Complete and stable aneurysm embolization is confirmed by postoperative examination and 2-week postembolization follow-up using digital subtraction angiography (DSA), contrast-enhanced ultrasound (CEUS), and histological analysis. The safety of the embolization therapy is assessed through biocompatibility evaluation and histopathology assays. This strategy, seamlessly integrating secure drug packaging, agile magnetic actuation, and clinical interventional imaging, avoids possible exogenous implant rejection, circumvents cumbersome microcatheter shaping, and offers a promising option for IA therapy., (© 2024 Wiley‐VCH GmbH.)

Purpose: Whole grains have recently been promoted as beneficial to diabetes prevention. However, the evidence for the glycemic benefits of whole grains seems to conflict between the cohort studies and randomized control trials (RCTs). To fill the research gap, we conducted a meta-analysis to determine the effects of whole grains on diabetes prevention and to inform recommendations., Methods: We searched PubMed, Clarivate Web of Science, and Cochrane Library until March 2024. We used the risk ratio (RR) of type 2 diabetes to represent the clinical outcomes for cohort studies, while the biomarkers, including fasting blood glucose and insulin, HbA 1C , and HOMA-IR, were utilized to show outcomes for RCTs. Dose-response relationships between whole grain intakes and outcomes were tested with random effects meta-regression models and restricted cubic splines models. This study is registered with PROSPERO, CRD42021281639., Results: Ten prospective cohort studies and 37 RCTs were included. Cohort studies suggested a 50 g/day whole grain intake reduced the risk of type 2 diabetes (RR = 0.761, 95% CI: 0.700 to 0.828, I 2  = 72.39%, P < 0.001) and indicated a monotonic inverse relationship between whole grains and type 2 diabetes rate. In RCTs, whole grains significantly reduced fasting blood glucose (Mean difference (MD) = -0.103 mmol/L, 95% CI: -0.178 to -0.028; I 2  = 72.99%, P < 0.01) and had modest effects on HbA 1C (MD = -0.662 mmol/mol (-0.06%), 95% CI: -1.335 to 0.010; I 2  = 64.55%, P = 0.05) and HOMA-IR (MD = -0.164, 95% CI: -0.342 to 0.013; I 2  = 33.38%, P = 0.07). The intake of whole grains and FBG, HbA 1C , and HOMA-IR were significantly dose-dependent. The restricted spline curves remained flat up to 150 g/day and decreased afterward. Subgroup analysis showed that interventions with multiple whole-grain types were more effective than those with a single type., Conclusion: Our study findings suggest that a daily intake of more than 150 g of whole grain ingredients is recommended as a population approach for diabetes prevention., (© 2024. The Author(s).)

Disulfiram (DSF) can target and kill cancer cells by disrupting cellular degradation of extruded proteins and has therefore received particular attention for its tumor chemotherapeutic potential. However, the uncontrollable Cu 2+ /DSF ratio reduces the efficacy of DSF-mediated chemotherapy. Herein, self-supplying Cu 2+ and oxidative stress synergistically enhanced DSF-mediated chemotherapy is proposed for melanoma-based on PVP-coated CuO 2 nanodots (CPNDs). Once ingested, DSF is broken down to diethyldithiocarbamate (DTC), which is delivered into a tumor via the circulation. Under the acidic tumor microenvironment, CPNDs produce sufficient Cu 2+ and H 2 O 2 . DTC readily chelates Cu 2+ ions to generate CuET, which shows antitumor efficacy. CuET-mediated chemotherapy can be enhanced by H 2 O 2 . Sufficient Cu 2+ generation can guarantee the maximum efficacy of DSF-mediated chemotherapy. Furthermore, released Cu 2+ can be reduced to Cu + by glutathione (GSH) and O 2- in tumor cells, and Cu + can react with H 2 O 2 to generate toxic hydroxyl radicals (·OH) via a Fenton-like reaction, promoting the efficacy of CuET. Therefore, this study hypothesizes that employing CPNDs instead of Cu 2+ ions could enhance DSF-mediated melanoma chemotherapy, providing a simple but efficient strategy for achieving chemotherapeutic efficacy., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Serving as neuromorphic hardware accelerators, memristors play a crucial role in large-scale neuromorphic computing. Herein, two-terminal memristors utilizing amorphous indium-gallium-zinc oxide (a-IGZO) are fabricated through room-temperature sputtering. The electrical characteristics of these memristors are effectively modulated by varying the oxygen flow during the deposition process. The optimized a-IGZO memristor, fabricated under 3 sccm oxygen flow, presents a 5 × 10 3 ratio between its high- and low-resistance states, which can be maintained over 1 × 10 4 s with minimal degradation. Meanwhile, desirable properties such as electroforming-free and self-compliance, crucial for low-energy consumption, are also obtained in the a-IGZO memristor. Moreover, analog conductance switching is observed, demonstrating an interface-type behavior, as evidenced by its device-size-dependent performance. The coexistence of negative differential resistance with analog switching is attributed to the migration of oxygen vacancies and the trapping/detrapping of charges. Furthermore, the device demonstrates optical storage capabilities by exploiting the optical properties of a-IGZO, which can stably operate for up to 50 sweep cycles. Various synaptic functions have been demonstrated, including paired-pulse facilitation and spike-timing-dependent plasticity. These functionalities contribute to a simulated recognition accuracy of 90% for handwritten digits. Importantly, a one-selector one-memristor (1S1M) architecture is successfully constructed at room temperature by integrating a-IGZO memristor on a TaO x -based selector. This architecture exhibits a 10 7 on/off ratio, demonstrating its potential to suppress sneak currents among adjacent units in a memristor crossbar.

Cancer-associated fibroblasts (CAFs) assist in breast cancer (BRCA) invasion and immune resistance by overproduction of extracellular matrix (ECM). Herein, we develop FPC@S, a photodynamic immunomodulator that targets the ECM, to improve the photodynamic immunotherapy for fibrotic BRCA. FPC@S combines a tumor ECM-targeting peptide, a photosensitizer (protoporphyrin IX) and an antifibrotic drug (SIS3). After anchoring to the ECM, FPC@S causes ECM remodeling and BRCA cell death by generating reactive oxygen species (ROS) in situ . Interestingly, the ROS-mediated ECM remodeling can normalize the tumor blood vessel to improve hypoxia and in turn facilitate more ROS production. Besides, upon the acidic tumor microenvironment, FPC@S will release SIS3 for reprograming CAFs to reduce their activity but not kill them, thus inhibiting fibrosis while preventing BRCA metastasis. The natural physical barrier formed by the dense ECM is consequently eliminated in fibrotic BRCA, allowing the drugs and immune cells to penetrate deep into tumors and have better efficacy. Furthermore, FPC@S can stimulate the immune system and effectively suppress primary, distant and metastatic tumors by combining with immune checkpoint blockade therapy. This study provides different insights for the development of fibrotic tumor targeted delivery systems and exploration of synergistic immunotherapeutic mechanisms against aggressive BRCA.

Combining hyperthermic intraperitoneal chemotherapy with cytoreductive surgery is the main treatment modality for peritoneal metastatic (PM) carcinoma despite the off-target effects of chemotherapy drugs and the ineluctable side effects of total abdominal heating. Herein, a laser-integrated magnetic actuation system that actively delivers doxorubicin (DOX)-grafted magnetic nanorobot collectives to the tumor site in model mice for local hyperthermia and chemotherapy is reported. With intraluminal movements controlled by a torque-force hybrid magnetic field, these magnetic nanorobots gather at a fixed point coinciding with the position of the localization laser, moving upward against gravity over a long distance and targeting tumor sites under ultrasound imaging guidance. Because aggregation enhances the photothermal effect, controlled local DOX release is achieved under near-infrared laser irradiation. The targeted on-demand photothermal therapy of multiple PM carcinomas while minimizing off-target tissue damage is demonstrated. Additionally, a localization/treatment dual-functional laser-integrated magnetic actuation system is developed and validated in vivo, offering a potentially clinically feasible drug delivery strategy for targeting PM and other intraluminal tumors., (© 2023 Wiley‐VCH GmbH.)

Ovarian cancer presents a substantial challenge due to its high mortality and recurrence rates among gynecological tumors. Existing clinical chemotherapy treatments are notably limited by drug resistance and systemic toxic side effects caused by off target drugs. Sonodynamic therapy (SDT) has emerged as a promising approach in cancer treatment, motivating researchers to explore synergistic combinations with other therapies for enhanced efficacy. In this study, we developed magnetic sonodynamic nanorobot (Fe 3 O 4 @SiO 2 -Ce6, FSC) by applying a SiO 2 coating onto Fe 3 O 4 nanoparticle, followed by coupling with the sonosensitizer Ce6. The magnetic FSC nanorobot collectives could gather at fixed point and actively move to target site regulated by magnetic field. In vitro experiments revealed that the magnetic FSC nanorobot collectives enabled directional navigation to the tumor cell area under guidance. Furthermore, under low-intensity ultrasonic stimulation, FSC nanorobot collectives mediated sonodynamic therapy exhibited remarkable anti-tumor performance. These findings suggest that magnetically actuated sonodynamic nanorobot collectives hold promising potential for application in target cancer therapy., 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 © 2024 Zhou, Cao, Jiang, Chen, Cui, Wu, Xie, Wang and Ying.)

Background: Impaired collateral formation is a major factor contributing to poor prognosis in type 2 diabetes mellitus (T2DM) patients with atherosclerotic cardiovascular disease. However, the current pharmacological treatments for improving collateral formation remain unsatisfactory. The induction of endothelial autophagy and the elimination of reactive oxygen species (ROS) represent potential therapeutic targets for enhancing endothelial angiogenesis and facilitating collateral formation. This study investigates the potential of molybdenum disulfide nanodots (MoS 2 NDs) for enhancing collateral formation and improving prognosis., Results: Our study shows that MoS 2 NDs significantly enhance collateral formation in ischemic tissues of diabetic mice, improving effective blood resupply. Additionally, MoS 2 NDs boost the proliferation, migration, and tube formation of endothelial cells under high glucose/hypoxia conditions in vitro. Mechanistically, the beneficial effects of MoS 2 NDs on collateral formation not only depend on their known scavenging properties of ROS (H 2 O 2 , •O 2 - , and •OH) but also primarily involve a molecular pathway, cAMP/PKA-NR4A2, which promotes autophagy and contributes to mitigating damage in diabetic endothelial cells., Conclusions: Overall, this study investigated the specific mechanism by which MoS 2 NDs mediated autophagy activation and highlighted the synergy between autophagy activation and antioxidation, thus suggesting that an economic and biocompatible nano-agent with dual therapeutic functions is highly preferable for promoting collateral formation in a diabetic context, thus, highlighting their therapeutic potential., (© 2024. The Author(s).)

Malignant ventricular arrhythmia (VA) after myocardial infarction (MI) is mainly caused by myocardial electrophysiological remodeling. Brahma-related gene 1 (BRG1) is an ATPase catalytic subunit that belongs to a family of chromatin remodeling complexes called Switch/Sucrose Non-Fermentable Chromatin (SWI/SNF). BRG1 has been reported as a molecular chaperone, interacting with various transcription factors or proteins to regulate transcription in cardiac diseases. In this study, we investigated the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. Myocardial infarction (MI) mice were established by ligating the left anterior descending (LAD) coronary artery, and electrocardiogram (ECG) was monitored. Epicardial conduction of MI mouse heart was characterized in Langendorff-perfused hearts using epicardial optical voltage mapping. Patch-clamping analysis was conducted in single ventricular cardiomyocytes isolated from the mice. We showed that BRG1 expression in the border zone was progressively increased in the first week following MI. Cardiac-specific deletion of BRG1 by tail vein injection of AAV9-BRG1-shRNA significantly ameliorated susceptibility to electrical-induced VA and shortened QTc intervals in MI mice. BRG1 knockdown significantly enhanced conduction velocity (CV) and reversed the prolonged action potential duration in MI mouse heart. Moreover, BRG1 knockdown improved the decreased densities of Na + current (I Na ) and transient outward potassium current (I to ), as well as the expression of Na v 1.5 and K v 4.3 in the border zone of MI mouse hearts and in hypoxia-treated neonatal mouse ventricular cardiomyocytes. We revealed that MI increased the binding among BRG1, T-cell factor 4 (TCF4) and β-catenin, forming a transcription complex, which suppressed the transcription activity of SCN5A and KCND3, thereby influencing the incidence of VA post-MI., (© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Introduction: Radiographic bone age (BA) assessment is widely used to evaluate children's growth disorders and predict their future height. Moreover, children are more sensitive and vulnerable to X-ray radiation exposure than adults. The purpose of this study is to develop a new, safer, radiation-free BA assessment method for children by using three-dimensional ultrasound (3D-US) and artificial intelligence (AI), and to test the diagnostic accuracy and reliability of this method., Methods and Analysis: This is a prospective, observational study. All participants will be recruited through Paediatric Growth and Development Clinic. All participants will receive left hand 3D-US and X-ray examination at the Shanghai Sixth People's Hospital on the same day, all images will be recorded. These image related data will be collected and randomly divided into training set (80% of all) and test set (20% of all). The training set will be used to establish a cascade network of 3D-US skeletal image segmentation and BA prediction model to achieve end-to-end prediction of image to BA. The test set will be used to evaluate the accuracy of AI BA model of 3D-US. We have developed a new ultrasonic scanning device, which can be proposed to automatic 3D-US scanning of hands. AI algorithms, such as convolutional neural network, will be used to identify and segment the skeletal structures in the hand 3D-US images. We will achieve automatic segmentation of hand skeletal 3D-US images, establish BA prediction model of 3D-US, and test the accuracy of the prediction model., Ethics and Dissemination: The Ethics Committee of Shanghai Sixth People's Hospital approved this study. The approval number is 2022-019. A written informed consent will be obtained from their parent or guardian of each participant. Final results will be published in peer-reviewed journals and presented at national and international conferences., Trial Registration Number: ChiCTR2200057236., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Previous studies have postulated that the urethral vasculature (UV) might play an important role in urinary continence for women. The goal of this research was to compare the UV in pre- and post-menopausal women using a super-resolution ultrasound imaging method called Super Ultrasound for Greater Accuracy and Resolution (SUGAR). We found that post-menopausal women exhibited decreased UV parameters such as fractal dimension, vessel proportion, and mean blood vessel diameter than pre-menopausal women. We also discriminated the vascular pattern in several layers of the urethra and its surrounding in vivo , including the urethral mucosa and submucosa, urethral muscle, and anterior vaginal wall. Besides, the statistical analysis of the vasculature pattern showed that most of the UV parameters peaked at mid-urethra. Ultimately, the UV parameters exhibited a tendency of first increasing, then reducing, and finally decreasing with age., Competing Interests: The authors have no disclosures to declare., (© 2024 The Author(s).)

Background: Treating persistent, recurrent, or metastatic cervical cancer remains challenging. Although pembrolizumab, combined with chemotherapy and bevacizumab, offers a promising first-line option, its cost-effectiveness within the Chinese healthcare system has not been established., Methods: A partitioned survival model was constructed using patient data from the KEYNOTE-826 trial. Efficacy, safety, and economic data from both trial and real-world practices were utilized to determine the costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) of the treatment strategies. Comprehensive insights were gained through the sensitivity and subgroup analyses., Results: Over five years, the combination of pembrolizumab, chemotherapy, and bevacizumab offered an additional 1.18 QALYs compared to that provided by standard treatments. This regimen increased the costs by US$ 134,502.57, resulting in an ICER of US$ 114,275.67 per QALY, relative to traditional treatment costs. The ICER for the pembrolizumab regimen was further calibrated to be US$ 52,765.69 per QALY. Both ICER values surpassed China's established willingness-to-pay threshold. Importantly, subgroup analysis revealed enhanced cost-effectiveness in patients presenting with a programmed death-ligand 1 combined positive score (PD-L1 CPS) ≥10., Conclusion: Introducing pembrolizumab alongside chemotherapy and bevacizumab may not be a cost-effective primary strategy for advanced cervical cancer against current standards. However, for patients with a PD-L1 CPS ≥10, the therapeutic and economic outcomes could be improved by adjusting the pembrolizumab price., 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 © 2024 Lin, Wang, He, Yao and Chen.)

Introduction: Roux-en-Y gastric bypass surgery can effectively improve steatosis, necroinflammatory activity, and hepatic fibrosis in individuals diagnosed with morbid obesity or nonalcoholic steatohepatitis (NASH). Common methods such as body mass index (BMI) to evaluate the postoperative effect of clinical bariatric surgery cannot differentiate subcutaneous fats from visceral fats and muscles. Several Quantitative ultrasound (QUS)-based approaches have been developed to quantify hepatic steatosis. QUS techniques (tissue attenuation imaging (TAI), tissue scatter distribution imaging (TSI)) from radio frequency (RF) data analysis as a means for the detection and grading of hepatic steatosis has been posited as an objective and noninvasive approach. The implementation and standardization of QUS techniques (TAI, TSI) in assessing hepatic steatosis quantitatively after bariatric surgery is of high-priority. Our study is aimed to assess hepatic steatosis with QUS techniques (TAI, TSI) in morbidly obese individuals before and after bariatric surgery, and to compare with anthropometric measurements, laboratory assessments and other imaging methods., Methods and Analysis: The present investigation, a self-discipline examination of navigational capacity devoid of visual cues, is designed as a single-site, forward-looking evaluation of efficacy with the imprimatur of the institutional review board. The duration of the study has been provisionally determined to span from 1 January 2023 through 31 December 2025. Our cohort shall encompass one hundred participants, who was scheduled to undergo Roux-en-Y gastric bypass (RYGB) at Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. All patients will undergo anthropometric measurements, blood-based biochemical analyses, ultrasonic examination and magnetic resonance imaging proton density fat fraction (MRI-PDFF). The primary endpoint is the analysis of evaluating the efficacy of QUS techniques assessing hepatic steatosis compared to other methods before and after bariatric surgery., Results: Prior to the fomal study, we recruited 21 obese Chinese participants who received ultrasonic examination (TAI, TSI) and MRI-PDFF. AC-TAI showed moderate correlations with MRI-PDFF (adjusted r  = 0.632; P  < 0.05). For MRI-PDFF ≥10%, SC-TSI showed moderate correlations with MRI-PDFF (adjusted r  = 0.677; P  < 0.05)., Conclusion: Our pre-experiment results signified that using QUS techniques for postoperative evaluation of bariatric surgery is promising. QUS techniques will be signed a widespread availability, real-time functionality, and low-cost approach for assessing hepatic steatosis before and after bariatric surgery in obese individuals, thus is capable for subsequent scale-up liver fat quantification., Ethics and Dissemination: The present research endeavor has been bestowed with the imprimatur of the Ethics Committee of the Hospital, as indicated by its Approval Number: 2023-KY-015. In due course, upon completion of the study, we intend to disseminate our findings by publishing them in a suitable academic journal, thereby facilitating their widespread utilization., Registration: The trial is duly registered with the Chinese Clinical Trial Registry, and with a unique Trial Registration Number, ChiCTR2300069892, approved on March 28, 2023., 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., (© 2024 Chen, Lu, Hu, Sun and Ying.)

Objective: This article aims to clarify pitfalls and find strategies for the detecting and diagnosing hyperechoic liver metastases (LMs) using Sonazoid-contrast enhanced ultrasonography (Sonazoid-CEUS)., Methods: This study was a prospective self-controlled study. Patients with hepatic lesions suspected as LMs or benign lesions were included in the study. Baseline ultrasonography (BUS) and Sonazoid-CEUS were performed on every patient. Characteristics of LMs and benign nodules were compared by chi-square test and fisher test. Factors influenced the CEUS were demonstrated by univariate analysis and multivariate logistic regression analysis., Results: 54 patients were included in this study. CEUS found additional 75 LMs from 19 patients in Kupffer phase. We found hyperechoic focal liver lesions and deep seated in liver are main confounding factors in CEUS diagnosis. Sensitivity would be improved from 16.67% to 78.57%, negative predictive value (NPV) would be improved from 28.57% to 76.92% and accuracy would be improved from 37.5% to 87.50% when using rapid "wash-in" and "wash-out" as main diagnostic criteria., Conclusions: Hyperechoic LMs especially deeply seated ones are usually not shown typical "black hole" sign in Kupffer phase. Quickly "wash-in and wash out" shows high accuracy in diagnosing malignant nodules. We highly recommend CEUS as a routing exam to detect and diagnose LMs.

Deep convolutional neural networks (DCNNs) have demonstrated promising performance in classifying breast lesions in 2D ultrasound (US) images. Exiting approaches typically use pre-trained models based on architectures designed for natural images with transfer learning. Fewer attempts have been made to design customized architectures specifically for this purpose. This paper presents a comprehensive evaluation on transfer learning based solutions and automatically designed networks, analyzing the accuracy and robustness of different recognition models in three folds. First, we develop six different DCNN models (BNet, GNet, SqNet, DsNet, RsNet, IncReNet) based on transfer learning. Second, we adapt the Bayesian optimization method to optimize a CNN network (BONet) for classifying breast lesions. A retrospective dataset of 3034 US images collected from various hospitals is then used for evaluation. Extensive tests show that the BONet outperforms other models, exhibiting higher accuracy (83.33%), lower generalization gap (1.85%), shorter training time (66 min), and less model complexity (approximately 0.5 million weight parameters). We also compare the diagnostic performance of all models against that by three experienced radiologists. Finally, we explore the use of saliency maps to explain the classification decisions made by different models. Our investigation shows that saliency maps can assist in comprehending the classification decisions., (© 2023. The Author(s).)

Background: This study evaluated the cost-effectiveness of serplulimab plus chemotherapy versus chemotherapy alone in treating advanced/metastatic esophageal squamous cell carcinoma (ESCC) within the Chinese health care system., Methods: A partitioned survival model based on ASTRUM-007 trial patient characteristics was developed. Efficacy, safety, and medical/economic data were obtained from the trial and real-world clinical practice. Costs, quality-adjusted life years (QALY), and incremental cost-effectiveness ratios (ICERs) were calculated for both treatment strategies. Sensitivity, subgroup, and scenario analyses were performed to assess the uncertainty impact., Results: Serplulimab combined with chemotherapy yielded an ICER of US$ 53,538.27/QALY. Deterministic sensitivity analysis identified patient survival and serplulimab price as influential parameters. Probabilistic sensitivity analysis showed a 47.33% probability of cost-effectiveness at a willingness-to-pay (WTP) threshold of US$ 53,541/QALY and 0.05% at three times China's GDP per capita. Subgroup analysis revealed that patients with a programmed death-ligand 1 (PD-L1) expression combined positive score (CPS) ⩾10 had a lower hazard ratio (0.59) and ICER (US$ 29,935.23/QALY), with a 95.36% probability of cost-effectiveness. Scenario analysis demonstrated that the drug donation discount policy significantly increased the likelihood of cost-effective serplulimab-chemotherapy combinations in Jiangsu, Fujian, and Guangdong at 99.99%, 99.90%, and 94.16%, respectively., Conclusion: Compared to chemotherapy alone, serplulimab combined with chemotherapy is currently not a cost-effective first-line treatment for advanced/metastatic ESCC in China. However, as serplulimab plus chemotherapy regimens evolve and price competition among programmed death 1 (PD-1) inhibitors intensifies, this combination may become a cost-effective treatment option., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Objective: We explored the role of maximum intensity projection (MIP) based on high frame rate contrast-enhanced ultrasound (H-CEUS) for the differentiation of breast tumors., Methods: MIP imaging was performed in patients with breast tumors who underwent H-CEUS examinations. The microvasculature morphology of breast tumors was assessed. The receiver operating characteristic curve was plotted to evaluate the diagnostic performance of MIP., Results: Forty-three breast tumors were finally analyzed, consisting of 19 benign and 24 malignant tumors. For the ≤30-s and >30-s phases, dot-, line-, or branch-like patterns were significantly more common in benign tumors. A tree-like pattern was only present in the benign tumors. A crab claw-like pattern was significantly more common in the malignant tumors. Among the tumors with crab claw-like patterns, three cases of malignant tumors had multiple parallel small spiculated vessels. There were significant differences in the microvasculature morphology for the ≤30-s and >30-s phases between the benign and malignant tumors (all p < 0.001). The area under the curve, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the ≤30-s phase were all higher than those of the >30-s phase for the classification of breast tumors., Conclusion: MIP based on H-CEUS can be used for the differentiation of breast tumors, and the ≤30-s phase had a better diagnostic value. Multiple parallel small spiculated vessels were a new finding, which could provide new insight for the subsequent study of breast tumors., 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 Li, Wei, Ma, Ying, Sun and Zheng.)

Cardiovascular diseases have been closely linked to abnormal epigenetic regulation. In the context of epigenetic regulation, BRG1, a pivotal SWI/SNF chromatin remodeling enzyme, emerges as a key epigenetic regulator with significant impact on the development and progression of cardiovascular disorders. From the perspective of epigenetic regulation of cardiovascular diseases, BRG1 emerges as a pivotal SWI/SNF chromatin remodeling enzyme, functioning as a key epigenetic regulator. It exerts substantial influence on the development and progression of cardiovascular disorders by exerting precise control over gene expression and protein levels. Therefore, a comprehensive understanding of BRG1's epigenetic regulatory role in cardiovascular disease is essential for unraveling its underlying pathophysiological mechanisms. This paper summarizes and discusses the function of BRG1 in the epigenetic regulation of cardiovascular diseases., Competing Interests: Declaration of competing interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The superhydrophobic feature is highly desirable for oil/water separation (OWS) operation to achieve excellent separation efficiency. However, using hazardous materials in fabricating superhydrophobic surfaces is always the main concern. Herein, superhydrophobic filters were prepared via an eco-friendly approach by anchoring silica particles (SiO 2 ) onto the cotton fabric surface, followed by surface coating using natural material-myristic acid via a dip coating method. Tetraethyl orthosilicate (TEOS) was used in the synthesis of SiO 2 particles from the silica sol. In addition, the impact of the drying temperature on the wettability of the superhydrophobic filter was investigated. Moreover, the pristine cotton fabric and as-prepared superhydrophobic cotton filters were characterised based on Fourier-transform infrared (FTIR) spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy coupled with energy dispersive X-ray spectroscopy (SEM-EDX) and contact angle (CA) measurement. The superhydrophobic cotton filter was used to perform OWS using an oil-water mixture containing either chloroform, hexane, toluene, xylene or dichloroethane. The separation efficiency of the OWS using the superhydrophobic filter was as high as 99.9%. Moreover, the superhydrophobic fabric filter also demonstrated excellent durability, chemical stability, self-healing ability and reusability.

The lack of macroscopic magnetic moments makes antiferromagnetic materials promising candidates for high-speed spintronic devices. The 2D ternary V-based chalcogenides (VXYSe 4 ; X, Y = Al, Ga) monolayers are investigated based on the density-functional theory and Monte Carlo simulations. The results reveal that the Néel temperature of the VGa 2 Se 4 monolayer is 18 K with zigzag2-antiferromagnetic (AFM) spin ordering. Also, the magnetic ordering of V ions in VAl 2 Se 4 and VAlGaSe 4 monolayers prefer zigzag1-AFM coupling with Néel temperature of 47 K and 33 K, respectively. The magnetic anisotropy calculations demonstrate that the easy magnetization axis of the VXYSe 4 monolayers is parallel to the y axis. In addition, the VXYSe 4 monolayers can be adjusted from the AFM state to the ferromagnetic (FM) state under biaxial stretching, which can be attributed to the competition between d-p-d superexchange and d-d direct exchange caused by the variation of bond length. The transition temperature of VXYSe 4 monolayers can be elevated above room temperature with the help of compression strain. In particular, the in-plane magnetic anisotropy is a robust characteristic regardless of the magnitude of the applied biaxial strain. These explorations not only enrich the family of AFM monolayers with excellent stability but also provide distinctive ideas for the performance control of AFM materials and their applications in nanodevices.

Background: Recurrence of atrial fibrillation (AF) after catheter ablation (CA) remains a challenge today. Although it is believed that evaluating the structural and functional remodeling of the left atrium (LA) may be helpful in predicting AF recurrence, there is a lack of consensus on prediction accuracy. Ultrasound-based radiomics is currently receiving increasing attention because it might aid in the diagnosis and prognosis prediction of AF recurrence. However, research on LA ultrasound radiomics is limited., Objective: We aim to investigate the incremental predictive utility of LA radiomics and construct a radiomics nomogram to preoperatively predict AF recurrence following CA., Methods: A training cohort of 232 AF patients was designed for nomogram construction, while a validation cohort ( n  = 100) served as the model performance test. AF recurrence during a follow-up period of 3-12 months was defined as the endpoint. The radiomics features related to AF recurrence were extracted and selected to create the radiomics score (rad score). These rad scores, along with other morphological and functional indicators for AF recurrence, were included in the multivariate Cox analysis to establish a nomogram for the prediction of the likelihood of AF recurrence within 1 year following CA., Results: In the training and validation cohorts, AF recurrence rates accounted for 32.3% (75/232) and 25.0% (25/100), respectively. We extracted seven types of radiomics features associated with AF recurrence from apical four-chamber view echocardiography images and established a rad score for each patient. The radiomics nomogram was built with the rad score, AF type, left atrial appendage emptying flow velocity, and peak atrial longitudinal strain. It outperformed the nomogram building without the rad score in terms of the predictive efficacy of CA outcome and showed favorable performance in both cohorts., Conclusion: We revealed the incremental utility of a radiomics signature in the prediction of AF recurrence and preliminarily developed and validated a radiomics nomogram for identifying patients who were at high risk of post-CA recurrence, which contributed to an appropriate management strategy for AF., 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., (© 2023 Zheng, Zhang, Huang, Wang, Guo, Zhu, Zhang and Ying.)

Objectives: The study aimed to observe, measure the size and elastic value of perineal body (PB) and assess its association with levator hiatus., Methods: Datasets were acquired in 45 nulliparous, 66 POP women and 70 postpartum women using ultrasound. The PB was measured in depth, height, and Young's modulus. The datasets were compared to assess whether there are some differences in the morphology, dimension and elastography modulus of PB among women. Pearson correlation analysis was used to evaluate the association between the morphology measurements (ΔValsalva-rest[v-r]), tissue mechanical properties (ΔValsalva-rest[v-r]) of the PB and levator hiatus area (ΔValsalva-rest[v-r]) to preliminarily explore whether PB can influence levator hiatus., Results: Four representative manifestations of PB were presented in our study. Nulliparous women had smaller diameters and bigger Young's modulus while postpartum women had bigger diameters and smaller Young's modulus. POP and postpartum women had bigger levator hiatal distensibility and PB extensibility. There was no statistical association between PB measurements and levator hiatal area., Conclusion: It is feasible to observe the morphology of PB and assess the dimension and elastography modulus by high-frequency ultrasound. The manifestations and measurements of PB are influenced by parity and long-term increased abdominal pressure. Our study preliminarily shows that PB has little effect on levator hiatus area., 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 Zhou, Shui, Bai, Wu and Ying.)

Background: PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent cellular effects, has recently been developed. Although PFI-3 has been reported as a potential therapeutic agent targeting thrombomodulin, its role in the regulation of vascular function remains unknown. Therefore, we aimed to investigate the impact of PFI-3 on arterial vessel tone., Methods: A microvascular tension measurement device (DMT) was utilized to identify alterations in vascular tension within the mesenteric artery. To detect variations in cytosolic [Ca 2+ ] i , a Fluo-3/AM fluorescent probe and fluorescence microscope were employed. Additionally, whole-cell patch clamp techniques were utilized to evaluate the activity of L-type voltage-dependent calcium channels (VDCCs) in cultured arterial smooth muscle cells (A10 cells)., Results: PFI-3 exerted a dose-dependent relaxation effect on rat mesenteric arteries with both intact and denuded endothelium after phenylephrine (PE)- and high-K + -induced constriction. PFI-3-induced vasorelaxation was not affected by the presence of L-NAME/ODQ or K + channel blockers (Gli/TEA). PFI-3 abolished Ca 2+ -induced contraction on endothelium-denuded mesenteric arteries preincubated by PE in Ca 2+ -free solution. Incubation with TG had no impact on PFI-3-induced vasorelaxation pre-contracted by PE. PFI-3 reduced Ca 2+ -induced contraction on endothelium-denuded mesenteric arteries pre-incubated by KCl (60 mM) in Ca 2+ -free solution. PFI-3 declined extracellular calcium influx in A10 cells detected by Fluo-3/AM fluorescent probe and fluorescence microscope. Furthermore, we observed that PFI-3 decreased the current densities of L-type VDCC by whole-cell patch clamp techniques., Conclusions: PFI-3 blunted PE and high K + -induced vasoconstriction independent of endothelium on rat mesenteric artery. The vasodilatory effect of PFI-3 may be attributed to its inhibition of VDCCs and receptor-operated calcium channels (ROCCs) on vascular smooth muscle cells (VSMCs)., Competing Interests: The authors declare there are no competing interests., (©2023 Li et al.)

Two moderately halotolerant bacterium strains, designated PJ-16 T and PJ-38, were isolated from a tidal flat of the red beach in Panjin City, Liaoning Province, PR China. Cells were found to be Gram-stain-negative, aerobic, motile, rod-shaped with a single polar flagellum. Optimum growth of strain PJ-16 T occurred at 30 °C, pH 7.0 and 0.2-8.0  % (w/v) NaCl, and strain PJ-38 at 30 °C, pH 6.0-7.0 and 0.2-8.0  % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain PJ-16 T was most closely related to Marinobacter denitrificans KCTC 62941 T (99.2 % 16S rRNA gene sequence similarity), Marinobacter algicola DSM 16394 T (98.6 %), Marinobacter salarius JCM 19399 T (98.4 %) and Marinobacter confluentis KCTC 42705 T (98.2 %), and strain PJ-38 was most closely related to M. denitrificans KCTC 62941 T (99.1 %), M. algicola DSM 16394 T (98.6 %), M. salarius JCM 19399 T (98.4 %) and M. confluentis KCTC 42705 T (98.1 %). The G+C content of the genomic DNA of strain PJ-16 T based on its draft genomic sequence was 57.4 mol%. The major cellular fatty acids of strain PJ-16 T were C 16 : 0 , C 16 : 1  ω 7 c /C 16 : 1  ω 6 c and C 18 : 1  ω 9 c . The major respiratory quinone of PJ-16 T was ubiquinone-9 and the major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. The results of the phenotypic, phylogenetic and genomic analyses revealed that strains PJ-16 T and PJ-38 represent a novel species of the genus Marinobacter , and the name Marinobacter panjinensis sp. nov. is proposed. The type strain is PJ-16 T (= CGMCC 1.13694 T = KCTC 72023 T ).

Objectives: Cardiovascular diseases are the common cause of death in patients with idiopathic inflammatory myopathies (IIMs). Diabetes mellitus was associated with higher cardiovascular mortality, but few studies focused on the risk of diabetes mellitus in IIMs patients. Our study is aimed at developing a predictive model of diabetes mellitus in IIMs patients., Methods: A total of 354 patients were included in this study, of whom 35 (9.9%) were diagnosed as new-onset diabetes mellitus. The predictive nomogram was drawn based on the features selected by least absolute shrinkage and selection operator (LASSO) regression, univariate logistic regression, multivariable logistic regression, and clinical relationship. The discriminative capacity of the nomogram was assessed by C-index, calibration plot, and clinical usefulness. The predictive model was verified by the bootstrapping validation., Results: The nomogram mainly included predictors such as age, gender, hypertension, uric acid, and serum creatinine. This predictive model demonstrated good discrimination and calibration in primary cohort (C-index=0.762, 95% CI: 0.677-0.847) and validation cohort (C-index=0.725). Decision curve analysis indicated that this predictive model was clinically useful., Conclusions: Clinicians can assess the risk of diabetes mellitus in IIMs patients by using this prediction model, and preventive measures should be taken early for high-risk patients, ultimately reducing the adverse cardiovascular prognosis., 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 Nie, Qin, Yan, Luo, Ying, Wang and Wu.)

Mechanochemically activated magnesium(0) metal as a highly active mediator driving direct C-4-H alkylation of pyridines with alkyl halides has been developed. Excellent regioselectivity and substrate scope, including those containing reducible functionalities, free amines, and alcohols, as well as biologically relevant molecules were achieved to access 4-alkylpyridine products. Preliminary mechanistic studies suggested a radical-radical coupling pathway.

Ferroptosis-based treatment strategies display the potential to suppress some malignant tumors with intrinsic apoptosis resistance. However, current related cancer treatments are still hampered by insufficient intracellular reactive oxygen species (ROS) levels and Fe 2+ contents, posing considerable challenges for their clinical translation. Herein, an intracellular acid-biodegradable iridium-coordinated nanosheets (Ir-Hemin) with sonodynamic therapy (SDT) properties to effectively induce ferroptosis in tumor cells through multiple regulatory pathways are proposed. Under ultrasound (US) irradiation, Ir-Hemin nanosheets act as nanosonosensitizers to effectively generate ROS, subsequently causing the accumulation of lipid peroxides (LPO) and inducing ferroptotic cell death. Furthermore, these Ir-Hemin nanosheets decompose quickly to release hemin and Ir(IV), which deplete intracellular glutathione (GSH) to deactivate the enzyme glutathione peroxidase 4 (GPX4) and initiate the ferroptosis pathway. Specifically, the released hemin enables heme oxygenase 1 (HO-1) upregulation for endogenous ferrous ion supplementation, which compensates for the toxicity concerns brought about by the large uptake of exogenous iron. Surprisingly, Ir-Hemin nanosheets exhibit high tumor accumulation and trigger effective ferroptosis for tumor therapy. These Ir-Hemin nanosheets display pronounced synergistic anticancer efficacy under US stimulation both in vitro and in vivo, providing a strong rationale for the application of ferroptosis in cancer treatment., (© 2023 Wiley-VCH GmbH.)

The breaking of the out-of-plane symmetry makes a two-dimensional (2D) Janus monolayer a new platform to explore the coupling between ferroelectricity and ferromagnetism. Using density functional theory in combination with Monte Carlo simulations, we report a novel phase-switchable 2D multiferroic material VInSe 3 with large intrinsic out-of-plane spontaneous electric polarization and a high Curie temperature ( T c ). The structural transition energy barrier between the two phases is determined to be 0.4 eV, indicating the switchability of the electric polarizations and the potential ferroelectricity. Carrier doping can boost the Curie temperature above room temperature, attributing to the enhanced magnetic exchange interaction. A transition from the ferromagnetic (FM) state to the antiferromagnetic (AFM) state can be induced by carrier doping in octahedra-VInSe 3 , while FM coupling is well-preserved in tetrahedron-VInSe 3 , which can be regulated to be either an XY or Ising magnet at an appropriate carrier concentration. These findings not only enrich the family of high -T c low-dimensional monolayers but also offer a new direction for the design and multifunctional application of multiferroic materials.

Safe and effective strategies are urgently needed to fight against the life-threatening diseases of various cancers. However, traditional therapeutic modalities, such as radiotherapy, chemotherapy and surgery, exhibit suboptimal efficacy for malignant tumors owing to the serious side effects, drug resistance and even relapse. Phototherapies, including photodynamic therapy (PDT) and photothermal therapy (PTT), are emerging therapeutic strategies for localized tumor inhibition, which can produce a large amount of reactive oxygen species (ROS) or elevate the temperature to initiate cell death by non-invasive irradiation. In consideration of the poor bioavailability of phototherapy agents (PTAs), lots of drug delivery systems have been developed to enhance the tumor targeted delivery. Nevertheless, the carriers of drug delivery systems inevitably bring biosafety concerns on account of their metabolism, degradation, and accumulation. Of note, carrier-free nanomedicine attracts great attention for clinical translation with synergistic antitumor effect, which is characterized by high drug loading, simplified synthetic method and good biocompatibility. In this review, the latest advances of phototherapy with various carrier-free nanomedicines are summarized, which may provide a new paradigm for the future development of nanomedicine and tumor precision therapy., (© 2022 Wiley-VCH GmbH.)

Background: Remimazolam is a novel ultra-short-acting sedative, but its safety and adverse events (AEs) in high-risk patients in the intensive care unit (ICU) setting remain unknown., Methods: This was a single-center, retrospective study that compared remimazolam to propofol and midazolam in patients undergoing upper gastrointestinal endoscopy. The primary outcome was the incidence of treatment-related AEs. The secondary outcomes were the time to extubation, the length of ICU stay, and the average cost of sedative per case., Results: Of the 88 patients analyzed, 47 were treated with remimazolam (mean dose, 7.90±4.84 mg), and 41 were treated with propofol (21.19±17.98 mg) or midazolam (3.08±2.17 mg). There was no statistically significant difference in the average duration of the endoscopic procedure (35.89±13.37 min vs. 44.51±21.68 min, P=0.133) or the time to extubation (15.00±9.75 h vs. 20.59±18.71 h, P =0.211) in the remimazolam group (group I) compared to the propofol or midazolam group (group II). ICU stays (5.40±2.93 d vs. 4.63±3.31 d, P =0.072) and treatment-related AEs (48.61% vs. 51.38%, P =0.056) were similar between groups. The average cost of sedative per case was significantly lower in the group I than in the group II (RMB 16.07±10.58 yuan vs. RMB 24.37±15.46 yuan, P =0.016)., Conclusion: Remimazolam-based sedation was noninferior to the classic sedatives and had lower average cost per case, indicating that it may be used as a promising sedative for high-risk patients during endoscopic procedures in the ICU setting., Competing Interests: Conflicts of interest: The authors declare that they have no competing interests., (Copyright: © World Journal of Emergency Medicine.)

Objective: To perform a meta-analysis of published randomized controlled trials (RCTs) to assess the effects of curcumin supplementation with different formulations on anthropometric and cardiometabolic indices in patients with metabolism-related diseases (MRDs). Methods: Six databases, including PubMed, Embase, Web of Science, China national knowledge internet (CNKI), Wanfang and China Biology Medicine (CBM), were systematically searched to find relevant articles from 2011 to July 2021. The effect sizes were expressed as weighted mean difference (WMD) with 95% confidence intervals (CI). Between-study heterogeneity was assessed using I 2 . Subgroup analysis was conducted to find possible sources of heterogeneity. Curcumin formulations in this study were divided as low bioavailability, high bioavailability and nanocurcumin. Results: Of the retrieved 1585 articles, 31 were included in the final analysis. Combined effect sizes suggested a significant effect of curcumin supplementation on reduced body weight (BW) (WMD: -0.94 kg, 95% CI: -1.40, -0.47) and body mass index (BMI) (WMD: -0.40 kg/m 2 , 95% CI: -0.60, -0.19), respectively. The results also showed significant improvements of fasting plasma glucose (FPG) (WMD: -0.50 mg/dL, 95% CI: -0.72, -0.28), glycosylated hemoglobin (Hb1Ac) (WMD: -0.42%, 95% CI: -0.57, -0.26), insulin (INS) (WMD: -1.70 μIU/mL, 95%CI: -2.03, -1.38), homeostasis model assessment-insulin resistance (HOMA-IR) (WMD: -0.71, 95%CI: -1.11, -0.31), high-density lipoprotein cholesterol (HDL-C) (WMD: 1.73 mg/dL, 95%CI: 0.78, 2.68) and high sensitivity C-reactive protein (Hs-CRP) (WMD: -1.11, 95%CI: -2.16, -0.05). Nanocurcumin showed a greater reduction in FPG (WMD: -1.78 mg/dL, 95% CI: -2.49, -1.07), INS (WMD: -1.66 μIU/mL, 95% CI: -3.21, -0.11), TC (WMD: -12.64 mg/dL (95% CI: -23.72, -1.57) and LDL-C (WMD: -8.95 mg/dL, 95% CI: -16.51, -1.38). The dose-effect analysis showed that there were trends of first rising and then falling between the supplemented curcumin dose and BW, BMI, LDL-C, Hb1Ac, which were clearly distinguished at 80 mg/d due to the strong effect of nanocurcumin on outcomes. A slow upward trend between the dose of curcumin supplementation and HDL-C. No relationships between dose and outcomes were found for FPG and insulin, except for nanocurcumin at 80 mg/d. Conclusions: Our study showed some significant beneficial effects of curcumin supplementation on improving BW, BMI, and the levels of FPG, Hb1Ac, HOMA-IR, HDL-C and Hs-CRP in patients with MRDs. Nanocurcumin may have a greater effect on the reduction of FPG, INS, TC and LDL-C than other curcumin formulations. Considering the potential bias and limitations of studies included, further quality studies with larger sample sizes are needed to confirm these results.

Kallmann syndrome (KS) is a congenital disorder characterized by idiopathic hypogonadotropic hypogonadism and olfactory dysfunction. KS is linked to variants in >34 genes, which are scattered across the human genome and show disparate biological functions. Although the genetic basis of KS is well studied, the mechanisms by which disruptions of these diverse genes cause the same outcome of KS are not fully understood. Here we show that disruptions of KS-linked genes affect the same biological processes, indicating convergent molecular mechanisms underlying KS. We carried out machine learning-based predictions and found that KS-linked mutations in heparan sulfate 6-O-sulfotransferase 1 (HS6ST1) are likely loss-of-function mutations. We next disrupted Hs6st1 and another KS-linked gene, fibroblast growth factor receptor 1 (Fgfr1), in mouse neuronal cells and measured transcriptome changes using RNA sequencing. We found that disruptions of Hs6st1 and Fgfr1 altered genes in the same biological processes, including the upregulation of genes in extracellular pathways and the downregulation of genes in chromatin pathways. Moreover, we performed genomics and bioinformatics analyses and found that Hs6st1 and Fgfr1 regulate gene transcription likely via the transcription factor Sox9/Sox10 and the chromatin regulator Chd7, which are also associated with KS. Together, our results demonstrate how different KS-linked genes work coordinately in a convergent signaling pathway to regulate the same biological processes, thus providing new insights into KS., (© The Author(s) 2022. Published by Oxford University Press.)

Objective: Insulin is a principal metabolic hormone. It regulates a plethora of metabolic pathways in peripheral tissues. The highly homologous insulin-like growth factor 1 (IGF-1), on the other hand, is important for development and growth. Recent studies have shown that insulin and IGF-1 signaling plays fundamental roles in the brain. Loss of insulin or IGF-1 receptors in astrocytes leads to altered glucose handling, mitochondrial metabolism, neurovascular coupling, and behavioral abnormalities in mice. Here, we aim to investigate molecular mechanisms by which insulin and IGF-1 signaling regulates astrocyte functions., Methods: IR-flox and IRKO primary astrocytes were treated with 100 nM insulin or IGF-1 for 6 h, and their transcriptomes were analyzed. Astrocytes with either IR deletion, IGF1R deletion or both were used to examine receptor-dependent transcriptional regulations using qPCR. Additional immunoblotting and confocal imaging studies were performed to functionally validate pathways involved in protein homeostasis., Results: Using next-generation RNA sequencing, we show that insulin significantly regulates the expression of over 1,200 genes involved in multiple functional processes in primary astrocytes. Insulin-like growth factor 1 (IGF-1) triggers a similar robust transcriptional regulation in astrocytes. Thus, over 50% of the differentially expressed genes are regulated by both ligands. As expected, these commonly regulated genes are highly enriched in pathways involved in lipid and cholesterol biosynthesis. Additionally, insulin and IGF-1 induce the expression of genes involved in ribosomal biogenesis, while suppressing the expression of genes involved in autophagy, indicating a common role of insulin and IGF-1 on protein homeostasis in astrocytes. Insulin-dependent suppression of autophagy genes, including p62, Ulk1/2, and several Atg genes, is blunted only when both IR and IGF1R are deleted., Conclusions: In summary, insulin and IGF-1 potently suppress autophagy in astrocytes through transcriptional regulation. Both IR and IGF1R can elicit ligand-dependent transcriptional suppression of autophagy. These results demonstrate an important role of astrocytic insulin/IGF-1 signaling on proteostasis. Impairment of this regulation in insulin resistance and diabetes may contribute to neurological complications related to diabetes., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Ferroptosis is a regulated form of necrotic cell death that involves the accumulation of lipid peroxide (LPO) species in an iron- and reactive oxygen species (ROS)-dependent manner. Previous investigations have reported that ferroptosis-based cancer therapy can overcome the limitations of traditional therapeutics targeting the apoptosis pathway. However, it is still challenging to enhance the antitumor efficacy of ferroptosis due to intrinsic cellular regulation. In this study, a ferroptosis-inducing agent, i.e., chlorin e6 (Ce6)-conjugated human serum albumin-iridium oxide (HSA-Ce6-IrO 2 , HCIr) nanoclusters, is developed to achieve sonodynamic therapy (SDT)-triggered ferroptosis-like cancer cell death. The sonosensitizing role of both Ce6 and IrO 2 within the HCIr nanoclusters exhibits highly efficient 1 O 2 generation capacity upon ultrasound stimulation, which promotes the accumulation of LPO and subsequently induces ferroptosis. Meanwhile, the HCIr can deplete glutathione (GSH) by accelerating Ir (IV)-Ir (III) transition, which further suppresses the activity of glutathione peroxidase 4 (GPX4) to enhance the ferroptosis efficacy. Through in vitro and in vivo experiments, it is demonstrated that HCIr possesses tremendous capacity to reduce the intracellular GSH content, which enhances SDT-triggered ferroptosis-like cancer cell death. Thus, an iridium-nanoclusters-based ferroptosis-inducing agent is developed, providing a promising strategy for inducing ferroptosis-like cancer cell death., (© 2022 Wiley-VCH GmbH.)

Two-dimensional (2D) ferro-type materials have received great attention owing to the remarkable polarization effect in optoelectronics and spintronics. Using the first-principles method, the coupling between ferromagnetism and ferroelectricity is investigated in a multiferroic Janus 1T-FeSSe monolayer, which has a strong Stoner ferromagnetic ground state. The magnetic anisotropy energy (MAE) is apparently impacted by the out-of-plane asymmetry donated ferroelectricity, which is reflected by the asymmetry of the Z-MAE image. The easy magnetization axis of Janus FeSSe is the + y axis with a large MAE of 0.59 meV, rooting in unpaired d electrons of Fe atoms. The transformation of band splitting and Fermi surface can be effectively engineered by different magnetic polarization directions. The ferromagnetic (FM) coupling of the FeSSe monolayer is very robust under external strain within the range of -6% to 6%, while the strength of magnetic moment of Fe atoms and polarization are easily strain-engineered, the intrinsic mechanism of which can be elaborated by the GKA rules that depend on angles and distances. This multiferroic FeSSe monolayer provides a new platform for exploring the coupling of 2D ferromagnetism and ferroelectricity and designing low-dimensional multiferroic electronics.

Magnesium alloys with high strength and excellent corrosion resistance are always sought-after in light-weighting structural components for automotive and aerospace applications. However, for most magnesium alloys that have a high specific strength, they usually have an inferior corrosion resistance and vice versa. In this work, we successfully develop a Mg-11Y-1Al (wt. %) alloy through conventional casting, solution treatment followed by extrusion. The overall properties of this alloy feature with a corrosion rate lower than 0.2 mm y -1 , high yield strength of 350 MPa and moderate tensile elongation of 8%, the combination of which shows competitive advantage over other comparative magnesium alloys in the literature. It is found that a thin and dense protective film of Y 2 O 3 /Y(OH) 3 can be fast developed with the aid of Al 2 O 3 /Al(OH) 3 deposition to isolate this alloy from further attack of corrosion medium. Meanwhile, the refined grains, weak texture and activation of non-basal slip systems co-contribute to the high strength and good ductility. Our findings are expected to inspire the design of next-generation high performance magnesium alloys., (© 2022. The Author(s).)

Objective: To overview the colonoscopy adherence in cascade screening of colorectal cancer (CRC) and evaluate potential influence of the initial tests based on an ecological evaluation., Methods: The performance of the initial screening tests and adherence to subsequent colonoscopy were extracted from relevant studies published up to 16 October 2020. The age-standardised incidence (ASRi) of CRC in populations in the year of screening was derived from the Cancer Statistics., Results: One hundred sixty-six observational studies and 60 experimental studies were identified. Most studies applied cascade screening with faecal occult blood tests (FOBTs) as an initial test. The adherence to colonoscopy varied greatly across populations by continents, gross national income and type of initial tests, with a median (interquartile range) of 79.8% (63.1%-87.8%) in observational studies and 82.1% (66.7%-90.4%) in randomised trials. The adherence was positively correlated with the ASRi of CRC (r = 0.145, p = 0.023) and positive predictive value (PPV) of the initial tests (r = 0.206, p = 0.002) in observational studies and correlated with ASRi of CRC (r = 0.309, p = 0.002) and sensitivity of the initial tests (r = -0.704, p = 0.003) in experimental studies., Conclusions: Adherence to colonoscopy varies greatly across populations and is related with performance of the initial tests, indicating the importance to select appropriate initial tests., (© 2022 John Wiley & Sons Ltd.)

Purpose: The aim was to explore the clinical efficacy of ranibizumab combined with surgical treatment of neovascular glaucoma with vitreous hemorrhage., Materials and Methods: A total of 15 patients (17 affected eyes) who had neovascular glaucoma (NVG) with vitreous hemorrhage in our hospital were enrolled. After admission, the patient was given levofloxacin eye drops, 4 times a day. Three days later, the patients received intravitreal injection of ranibizumab. Then, trabeculectomy and vitrectomy were performed. The detailed clinical data, such as type of diseases, intraocular pressure (IOP), and best corrected visual acuity (BCVA), were collected before and after surgery., Results: Visual acuity remained stable or improved in thirteen effected eyes and decreased in effected three eyes. Within 30 days after discharge, one effected eye recurred iris neovascularization with slightly higher IOP; then, the patient received intravitreal injection of ranibizumab again and neodymium-doped yttrium aluminum garnet (YAG) therapy. One patient (one effected eye) was given intravitreal ranibizumab injection again because of uncontrollable IOP and recurrence of neovascularization on iris surface and angle after operation; then, the patient received cyclophotocoagulation. Vitreous cavity hemorrhage occurred again in 3 patients after operation; then, these patients received the vitreous cavity lavage again. After trabeculectomy, inflammatory exudation or a small amount of bleeding could be seen in the anterior chamber of 6 young patients., Conclusion: Intravitreal injection of ranibizumab can effectively promote the rapid regression of intraocular neovascularization and help to control the IOP and improve postoperative visual acuity., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: As the presence of hepatic metastases is very important to cancer patients' clinical stage which would directly affect the selection and application of anti-cancer treatments. Although conventional ultrasound is commonly performed as a screening tool, most of the examinations have relatively poor sensitivity and specificity for detecting liver metastases. Contrast-enhanced ultrasound (CEUS) with Sonazoid has been reported to have the advantage of the diagnosis and therapeutic support of focal hepatic lesions and its specific Kupffer phase whole liver scan (KPWLS) is believed to be sensitive to detect liver metastases. And the purpose of this study is to determine the number, size, location and diagnosis of metastatic lesions, and to compare the results with conventional ultrasound and contrast-enhanced computed tomography (CECT), thus to clarify the application value, indications of Sonazoid-CEUS in screening liver metastasis., Methods and Analysis: Kupffer phase whole liver scan for metastases (KPWLSM) is a self-control, blind map-reading, single-center, prospective superiority trial. Approved by the institutional review committee, the study period is planned to be from 1 January 2022 to 31 December 2025. Our study will include 330 patients with history of malignant tumors that cling to metastasize to liver. All patients will undergo the examinations of conventional ultrasound, Sonazoid-CEUS, and contrast-enhanced magnetic resonance imaging (CEMRI), and 65 of them should have additional CECT scans. The primary endpoint is the comparative analysis of the numbers of detected liver metastatic lesions among Sonazoid-CEUS, conventional ultrasound and CECT in screening liver metastases. Subjective conditions of patient after injection of Sonazoid will be followed up 3 and 30 days after KPWLSM, and any short-term and long-term adverse events are to be recorded with telephone interviews., Ethics and Dissemination: This study has been granted by the Ethics Committee of Shanghai Jiao Tong University Affiliated Sixth People's Hospital (Approval No: 2021-197). When the KPWLSM is completed, we will publish it in an appropriate journal to promote further widespread use., Registration: Trial Registration Number and Date of Registration: Chinese Clinical Trial Registry, ChiCTR2100054385, December 16, 2021., 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 Wu, Liu, Sun, Wang, Wei, Li, Liu, Wang, Zhou, Hu, Zhang, Jiao, Li and Ying.)

Multiciliated cells (MCCs) in the brain reside in the ependyma and the choroid plexus (CP) epithelia. The CP secretes cerebrospinal fluid that circulates within the ventricular system, driven by ependymal cilia movement. Tumors of the CP are rare primary brain neoplasms mostly found in children. CP tumors exist in three forms: CP papilloma (CPP), atypical CPP, and CP carcinoma (CPC). Though CPP and atypical CPP are generally benign and can be resolved by surgery, CPC is a particularly aggressive and little understood cancer with a poor survival rate and a tendency for recurrence and metastasis. In contrast to MCCs in the CP epithelia, CPCs in humans are characterized by solitary cilia, frequent TP53 mutations, and disturbances to multiciliogenesis program directed by the GMNC-MCIDAS transcriptional network. GMNC and MCIDAS are early transcriptional regulators of MCC fate differentiation in diverse tissues. Consistently, components of the GMNC-MCIDAS transcriptional program are expressed during CP development and required for multiciliation in the CP, while CPC driven by deletion of Trp53 and Rb1 in mice exhibits multiciliation defects consequent to deficiencies in the GMNC-MCIDAS program. Previous studies revealed that abnormal NOTCH pathway activation leads to CPP. Here we show that combined defects in NOTCH and Sonic Hedgehog signaling in mice generates tumors that are similar to CPC in humans. NOTCH-driven CP tumors are monociliated, and disruption of the NOTCH complex restores multiciliation and decreases tumor growth. NOTCH suppresses multiciliation in tumor cells by inhibiting the expression of GMNC and MCIDAS, while Gmnc-Mcidas overexpression rescues multiciliation defects and suppresses tumor cell proliferation. Taken together, these findings indicate that reactivation of the GMNC-MCIDAS multiciliogenesis program is critical for inhibiting tumorigenesis in the CP, and it may have therapeutic implications for the treatment of CPC., (© 2022. The Author(s).)

Context: The comparative effectiveness of drugs and surgical therapy for women with obesity and polycystic ovary syndrome (PCOS) has not been systematically compared., Objective: We aimed to determine the difference in efficacy between drug and bariatric surgery therapy for women with obesity and PCOS., Methods: This prospective nonrandomized trial enrolled 90 women aged 18 to 40 years with body mass index (BMI) ≥ 27.5 kg/m2 and waist circumference ≥ 85 cm and fulfilling the 2011 Chinese diagnostic criteria for PCOS; 81 subjects completed the study. In the drug group, patients were administered metformin and an oral contraceptive containing ethinyl-estradiol and cyproterone acetate for the first 6 months, and metformin alone for the second 6 months. In the surgical group, patients underwent laparoscopic sleeve gastrectomies. The follow-up period was 12 months. The main outcome was the complete remission of PCOS, requiring 6 consecutive regular menstruation cycles or spontaneous pregnancy., Results: Median BMI at endpoint was 30.1 kg/m2 in the drug group and 23.7 kg/m2 in the surgical group; complete remission rate was 15% and 78%, respectively. Except endpoint BMI, no difference was observed in free androgen index, ovarian morphology, homeostasis model assessment for insulin resistance, and total weight loss between remission and nonremission patients. Logistic regression analyses also revealed that the final BMI was the major factor influencing the remission of PCOS. The cutoff points for the final BMI were 27.5 kg/m2 for the drug group and 26 kg/m2 for the surgical group. Overall, nearly 95% of patients with an endpoint BMI below the cutoff values achieved complete remission., Conclusion: Complete remission of PCOS in patients with obesity depends on the final BMI after weight loss. Thus, bariatric surgery should be prioritized for these patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)