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Jyh-Ping Chen,1 Pei-Ching Yang,1 Yunn-Hwa Ma,2 Su-Ju Tu,3 Yu-Jen Lu1,41Department of Chemical and Materials Engineering, 2Department of Physiology and Pharmacology, 3Department of Medical Imaging and Radiological Sciences, Chang Gung University, Kwei-San, Taoyuan, Taiwan, Republic of China; 4Department of Neurosurgery, Chang Gung Memorial Hospital, Kwei-San, Taoyuan, Taiwan, Republic of ChinaBackground and methods: Silica-coated magnetic nanoparticle (SiO2-MNP) prepared by the sol-gel method was studied as a nanocarrier for targeted delivery of tissue plasminogen activator (tPA). The nanocarrier consists of a superparamagnetic iron oxide core and an SiO2 shell and is characterized by transmission electron microscopy, Fourier transform infrared spectroscopy, X-ray diffraction, superconducting quantum interference device, and thermogravimetric analysis. An amine-terminated surface silanizing agent (3-aminopropyltrimethoxysilane) was used to functionalize the SiO2 surface, which provides abundant —NH2 functional groups for conjugating with tPA.Results: The optimum drug loading is reached when 0.5 mg/mL tPA is conjugated with 5 mg SiO2-MNP where 94% tPA is attached to the carrier with 86% retention of amidolytic activity and full retention of fibrinolytic activity. In vitro biocompatibility determined by lactate dehydrogenase release and cell proliferation indicated that SiO2-MNP does not elicit cytotoxicity. Hematological analysis of blood samples withdrawn from mice after venous administration indicates that tPA-conjugated SiO2-MNP (SiO2-MNP-tPA) did not alter blood component concentrations. After conjugating to SiO2-MNP, tPA showed enhanced storage stability in buffer and operation stability in whole blood up to 9.5 and 2.8-fold, respectively. Effective thrombolysis with SiO2-MNP-tPA under magnetic guidance is demonstrated in an ex vivo thrombolysis model where 34% and 40% reductions in blood clot lysis time were observed compared with runs without magnetic targeting and with free tPA, respectively, using the same drug dosage. Enhanced penetration of SiO2-MNP-tPA into blood clots under magnetic guidance was confirmed from microcomputed tomography analysis.Conclusion: Biocompatible SiO2-MNP developed in this study will be useful as a magnetic targeting drug carrier to improve clinical thrombolytic therapy.Keywords: magnetic nanoparticles, drug delivery, thrombolysis, tissue plasminogen activator, silica

Yunn-Hwa Ma,1 Si-Yi Chen,1 Shu-Ju Tu,2 Hung-Wei Yang,3 Hao-Li Liu41Department of Physiology and Pharmacology and Healthy Aging Research Center, 2Department of Medical Image and Radiological Sciences, 3Department of Chemical and Material Engineering, 4Department of Electrical Engineering, College of Medicine and College of Engineering, Chang Gung University, Kuei-Shan, Tao-Yuan, Taiwan, ROCAbstract: Magnetic nanoparticles (MNPs) have been proposed for targeted or embolization therapeutics. How MNP retention occurs in circulation may critically determine local hemodynamics, tissue distribution of MNPs, and the therapeutic effects. We attempted to establish a microcirculation model to study the magnetic capture of MNPs in small vessels and to determine the factors affecting MNP retention. Two-dimensional hemodynamic changes in response to magnet-induced MNP retention in the microvessels of the cremaster muscle in vivo were observed in a real-time manner using a laser speckle imaging technique. Changes in tissue perfusion of the cremaster muscle appeared to be closely correlated with the location of the magnet placement underneath the muscle in response to intra-arterial administration of dextran-coated MNPs. Magnet-related retention was observed along the edge of the magnet, as corroborated by the results of histology analysis and microcomputed tomography. In these preparations, tissue iron content almost doubled, as revealed by inductively coupled plasma optical emission spectroscopy. In addition, MNP retention was associated with reduced downstream flow in a dose-dependent manner. Dissipation of MNPs (5 mg/kg) occurred shortly after removal of the magnet, which was associated with significant recovery of tissue flow. However, MNP dissipation did not easily occur after administration of a higher MNP dose (10 mg/kg) or prolonged exposure to the magnetic field. An ultrasound after removal of the magnet may induce the partial dispersion of MNPs and thus partially improve hemodynamics. In conclusion, our results revealed the important correlation of local MNP retention and hemodynamic changes in microcirculation, which can be crucial in the application of MNPs for effective targeted therapeutics.Keywords: targeted delivery, magnetic nanoparticles, hemodynamics, microcirculation

Rotavirus (RV) vaccines have demonstrated substantial effectiveness in reducing the healthcare burden caused by gastroenteritis (RVGE) worldwide. This study aims to understand the differential impact of RV vaccination in reducing RVGE burden in children under 7 years old in China. A Markov Model was used to investigate the health impact of introducing two different RV vaccines into the Chinese population. The analysis was conducted for RV5, a live pentavalent human-bovine reassortant vaccine, and Lanzhou Lamb RV (LLR), a live-attenuated monovalent RV vaccine, separately, by comparing the strategy of each vaccine to no vaccination within a Chinese birth cohort, including 100,000 children modeled until 7 years of age. The vaccination scenario assumed a vaccination coverage of 2.5%, 2.5%, 90% and 5% for doses one, two, three and no vaccine, respectively, for both vaccines. Strategies with RV5, LLR, and no vaccination were associated with 9,895, 49,069, and 64,746 symptomatic RV infections, respectively. RV5 and LLR were associated with an 85% and 24% reduction in the total symptomatic RV infections, respectively, suggesting that the health benefits of RV5 are at least three-fold greater than those associated with the LLR. Further, strategies with RV5 and LLR resulted in an estimated 206 and 59-year increase in quality-adjusted life years (QALYs), respectively. Sensitivity and scenario analyses supported the robustness of the base-case findings. Use of RV vaccine is expected to improve RV-associated health outcomes and its adoption will help alleviate the burden of RVGE in China. RV5 use will result in significantly better health outcomes.

Background: Poor results occasionally occur after unicompartmental knee replacement (UKR). It is often difficult, even for experienced surgeons, to determine why patients have poor outcomes from radiographs. The aim was to compare the ability of experienced surgeons and machine learning to predict whether patients had poor or excellent outcomes from radiographs., Methods: 924 one-year anterior-posterior radiographs post-UKR were used to train a machine learning model (ResNet50v2) with a transfer learning approach based on their one-year Oxford Knee Score categories. Two experienced surgeons and the model assessed and categorised 70 radiographs (14 Poor scores; 56 Excellent scores) not used for training according to their expected outcome., Results: The ResNet50v2 model correctly identified 71% (n = 10) of the patients with a poor score and 46 (82%) of those with an excellent score. In contrast, one surgeon could not identify patients with Poor scores (0%) and the other identified one (7%). Both misidentified 3 of those with Excellent scores. The model visualisation method suggested that estimated classifications were made from image features around the implants., Conclusion: The results suggest that there are radiographical features that relate to poor outcomes, which the surgeons are unaware of. Those the model did not identify may have an extra-articular cause for their poor outcome. Further analysis to identify the features associated with poor outcomes could potentially suggest ways that indications or techniques could be improved so as to decrease the incidence of poor results., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:[One or more of the authors have received or will receive benefits for professional use from a commercial party, Zimmer Biomet, related indirectly to the subject of this article. In addition, benefits have been directed to a research fund, foundation, educational institution, or other non-profit organisation with which more of the authors are associated. (Versus Arthritis & Orthopaedic Research UK)]., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: We sought to investigate the association between obesity, metabolic syndrome, and metabolic health with incident primary open-angle glaucoma (POAG)., Methods: We included 103 249 UK Biobank participants without previously diagnosed glaucoma or glaucoma-related procedures at enrolment. The primary outcome was POAG identified from diagnostic coding via linked hospital inpatient and primary care data. We used multivariable Cox regression to evaluate the association of body mass index (BMI), and the interaction with metabolic syndrome (MetS) and a novel definition of metabolic health status with incident POAG. BMI was modelled as a time-varying coefficient. Multivariable analysis was adjusted for age, sex, ethnicity, intraocular pressure, spherical equivalent, polygenic risk score and stratified by the presence of primary care data., Results: There were 647 events of incident POAG over 464 117 580 person-years and a mean follow-up of 12.6 years. At baseline (time = 0), each one unit increase in BMI was associated with a 9% lower hazard of incident glaucoma (HR 0.91, CI 0.86-0.97, p = 0.0066). Further, compared to a normal BMI range of 18.5-24 kg/m 2 , a BMI ≥30 kg/m 2 was associated with a 65% relative hazard reduction (HR 0.35, CI 0.16-0.80, p = 0.012). There was no significant interaction between BMI and metabolic syndrome or metabolic health (all p > 0.05)., Conclusion: The effect of BMI on the risk of incident POAG varied with time. Higher BMI was associated with a decreased risk of incident POAG in this large prospective cohort. There was no significant association with systemic metabolic health., (© 2024 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: Intraoperative ultrasound was used to assess the flow velocity in the marginal vessel arch adjacent to the anastomosis, critical for evaluating the anastomotic blood supply. This technique also enabled us to investigate the potential effects of preserving the left colonic artery on the perfusion of the anastomosis., Methods: This prospective study included 40 rectal cancer patients who underwent laparoscopic anterior resection between January 2021 and January 2023. The length of the inferior mesenteric artery (IMA) was measured from its origin to the first branch, and the diameters of the mesenteric vessel IMA, left colonic artery (LCA), and marginal mesenteric artery (MMA) were recorded. Blood flow velocity and Doppler ultrasound waveforms of the MMA near the anastomosis were collected. Measurements were taken both before and after clamping the IMA using atraumatic forceps. The tardus parvus pattern of the MMA ultrasound waveforms was recorded to evaluate the hypoperfusion status of the anastomosis., Results: The mean velocities of MMA were 47.9 cm/s before clamping and 34.9 cm/s after atraumatic clamping, indicating significant differences (p < 0.05). Thirteen patients (32.5%) exhibited a Tardus parvus pattern after IMA atraumatic clamping. Multivariate analysis revealed older age and LCA diameter as independent clinical predictors of the hypoperfusion status after IMA clamping., Conclusions: Preservation of the LCA may improve perfusion near the anastomosis during rectal cancer surgery. Older age and LCA diameter can be considered useful predictors of the mesenteric hypoperfusion status after IMA ligation. Intraoperative ultrasound can evaluate the perfusion of the MMA near the anastomosis. Chinese Clinical Trial Registry-Registration number: ChiCTR2000041475., Competing Interests: Declarations Conflict of interest I declare that the authors have no competing interests that might be perceived to influence the results and discussion reported in this paper. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent Informed consent was obtained from all participants., (© 2024. The Author(s).)

Previous studies arguing for parental care in dinosaurs have been primarily based on fossil accumulations of adults and hatchlings, perinatal and post-hatchlings in nests and nest areas, and evidence of brooding, the majority of which date to the Late Cretaceous. Similarly, the general body proportions of preserved embryonic skeletons of the much older Early Jurassic Massospondylus have been used to suggest that hatchlings were unable to forage for themselves. Here, we approach the question of parental care in dinosaurs by using a combined morphological, chemical, and biomechanical approach to compare early embryonic and hatchling bones of the Early Jurassic sauropodomorph Lufengosaurus with those of extant avian taxa with known levels of parental care. We compare femora, the main weight-bearing limb bone, at various embryonic and post-embryonic stages in a precocious and an altricial extant avian dinosaur with those of embryonic and hatchling Lufengosaurus, and find that the rate and degree of bone development in Lufengosaurus is closer to that of the highly altricial Columba (pigeon) than the precocious Gallus (chicken), providing strong support for the hypothesis that Lufengosaurus was fully altricial. We suggest that the limb bones of Lufengosaurus hatchlings were not strong enough to forage for themselves and would likely need parental feeding., (© 2024. The Author(s).)

Introduction: The pattern of extraocular muscle involvement in ocular myasthenia gravis varies across different reports, diverging from our own observations. Thus, we employed two novel tools to discern this pattern., Methods: A retrospective analysis was conducted to collect and organize clinical data from 43 patients diagnosed with ocular myasthenia gravis. Each patient underwent both the computerized diplopia test and the Ocular Motor Nerve Palsy Scale assessment to evaluate the involvement of extraocular muscles., Results: Among the patients, there were 30 male and 13 female individuals, with a total of 113 affected extraocular muscles identified. Among all the affected extraocular muscles, the involvement of the levator palpebrae superioris muscle accounted for 35.40%, medial rectus muscle 7.7%, lateral rectus muscle 16.81%, superior rectus muscle 13.27%, inferior rectus muscle 12.39%, superior oblique muscle 1.77%, and inferior oblique muscle 2.65% of the total affected extraocular muscles. The positivity rates of the Neostigmine test were 89.19%, AChR antibody detection was 59.38%, and repetitive nerve stimulation was 34.38%. The AChR antibody positive rate among patients with only diplopia was 100%; among those with only ptosis, it was 80%; and among those with both diplopia and ptosis, it was 86.67%., Conclusion: The involvement of the extraocular muscles is not uniform. The levator palpebrae superioris exhibits the highest incidence rate, followed by the four rectus muscles and two oblique muscles. The inferior oblique involvement typically occurs when four or more EOMs are affected. Moreover, the levator palpebrae superioris and medial rectus show a higher tendency for bilateral involvement compared with other extraocular muscles., 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 Fan, Tu, Liu, Li, Liu and Zhou.)

Background: Appendectomy is an acute abdominal surgery that is often accompanied by severe abdominal inflammation. Oral probiotics are one of the postoperative treatments for rapid rehabilitation. However, there is a lack of prospective studies on this topic after appendectomy., Aim: To investigate whether the postoperative probiotics can modulate the inflammatory response and restore intestinal function in patients following appendectomy., Methods: This was a prospective, randomized trial. A total of 60 emergency patients were randomly divided into a control group ( n = 30) and a probiotic group ( n = 30). Patients in the control group started to drink some water the first day after surgery, and those in the probiotic group were given water supplemented with Bacillus licheniformis capsules for 5 consecutive days postsurgery. The indices of inflammation and postoperative conditions were recorded, and the data were analyzed with RStudio 4.3.2 software., Results: A total of 60 participants were included. Compared with those in the control group, the C-reactive protein (CRP), interleukin 6 and procalcitonin (PCT) levels were significantly lower in the probiotic group at 2 d after surgery ( P = 2.224e-05, P = 0.037, and P = 0.002, respectively, all P < 0.05). This trend persisted at day 5 post-surgery, with CRP and PCT levels remaining significantly lower in the probiotic group ( P = 0.001 and P = 0.043, both P < 0.05). Furthermore, probiotics resulted in a shorter time to first flatus and a greater percentage of gram-negative bacilli in the feces ( P = 0.035, P = 0.028, both P < 0.05)., Conclusion: Postoperative oral administration of probiotics may modulate the gut microbiota, benefit the recovery of the early inflammatory response, and subsequently enhance recovery after appendectomy., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: A high incidence rate of nasopharyngeal carcinoma (NPC) has been observed in Southeast Asia compared to other parts of the world. Radiomics is a computational tool to predict outcomes and may be used as a prognostic biomarker for advanced NPC treated with concurrent chemoradiotherapy. Recently, radiomic analysis of the peripheral tumor microenvironment (TME), which is the region surrounding the gross tumor volume (GTV), has shown prognostic usefulness. In this study, not only was gross tumor volume (GTVt) analyzed but also tumor peripheral regions (GTVp) were explored in terms of the TME concept. Both radiomic features and delta radiomic features were analyzed using CT images acquired in a routine radiotherapy process., Methods: A total of 50 patients with NPC stages III, IVA, and IVB were enrolled between September 2004 and February 2014. Survival models were built using Cox regression with clinical factors (i.e., gender, age, overall stage, T stage, N stage, and treatment dose) and radiomic features. Radiomic features were extracted from GTVt and GTVp. GTVp was created surrounding GTVt for TME consideration. Furthermore, delta radiomics, which is the longitudinal change in quantitative radiomic features, was utilized for analysis. Finally, C-index values were computed using leave-one-out cross-validation (LOOCV) to evaluate the performances of all prognosis models., Results: Models were built for three different clinical outcomes, including overall survival (OS), local recurrence-free survival (LRFS), and progression-free survival (PFS). The range of the C-index in clinical factor models was (0.622, 0.729). All radiomics models, including delta radiomics models, were in the range of (0.718, 0.872). Among delta radiomics models, GTVt and GTVp were in the range of (0.833, 0.872) and (0.799, 0.834), respectively., Conclusions: Radiomic analysis on the proximal region surrounding the gross tumor volume of advanced NPC patients for survival outcome evaluation was investigated, and preliminary positive results were obtained. Radiomic models and delta radiomic models demonstrated performance that was either superior to or comparable with that of conventional clinical models.

We investigated the high energy spin excitations in electron-doped La&#95;{2-x}Ce&#95;{x}CuO&#95;{4}, a cuprate superconductor, by resonant inelastic x-ray scattering (RIXS) measurements. Efforts were paid to disentangle the paramagnon signal from non-spin-flip spectral weight mixing in the RIXS spectrum at Q&#95;{∥}=(0.6π,0) and (0.9π,0) along the (1 0) direction. Our results show that, for doping level x from 0.07 to 0.185, the variation of the paramagnon excitation energy is marginal. We discuss the implication of our results in connection with the evolution of the electron correlation strength in this system.

A base-promoted olefin skeletal rearrangement strategy from para -quinone methides ( p -QMs) and N -fluoroarenesulfonamides is reported, enabling direct nitrogen insertion of olefins to produce a series of multiarylated ( Z )- N -sulfonyl amidines with complete stereoselectivity and generally good yields. Using p -QMs without o -hydroxy substituents gave triarylated N -sulfonyl amidines, whereas tetraarylated N , N '-disulfonyl amidines were synthesized with the existence of o -hydroxy groups.

Background and Purpose: We aimed to investigate the prognostic value of peritumoral and intratumoral computed tomography (CT)-based radiomics during the course of radiotherapy (RT) in patients with laryngeal and hypopharyngeal cancer (LHC)., Materials and Methods: A total of 92 eligible patients were 1:1 randomly assigned into training and validation cohorts. Pre-RT and mid-RT radiomic features were extracted from pre-treatment and interim CT. LASSO-Cox regression was used for feature selection and model construction. Time-dependent area under the receiver operating curve (AUC) analysis was applied to evaluate the models' prognostic performances. Risk stratification ability on overall survival (OS) and progression-free survival (PFS) were assessed using the Kaplan-Meier method and Cox regression. The associations between radiomics and clinical parameters as well as circulating lymphocyte counts were also evaluated., Results: The mid-RT peritumoral (AUC: 0.77) and intratumoral (AUC: 0.79) radiomic models yielded better performance for predicting OS than the pre-RT intratumoral model (AUC: 0.62) in validation cohort. This was confirmed by Kaplan-Meier analysis, in which risk stratification depended on the mid-RT peritumoral (p = 0.009) and intratumoral (p = 0.003) radiomics could be improved for OS, in comparison to the pre-RT intratumoral radiomics (p = 0.199). Multivariate analysis identified mid-RT peritumoral and intratumoral radiomic models as independent prognostic factors for both OS and PFS. Mid-RT peritumoral and intratumoral radiomics were correlated with treatment-related lymphopenia., Conclusion: Mid-RT peritumoral and intratumoral radiomic models are promising image biomarkers that could have clinical utility for predicting OS and PFS in patients with LHC treated with RT., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chien-Yu Lin reports that this study was supported by grants from Chang Gung Memorial Hospital, Taiwan [grant numbers CIRPG3I0011-3, CMRPG3M0681-2, CORPG3N0081]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: To examine the associations between specific dietary patterns and incident atrial fibrillation (AF)., Methods: Using data from the UK Biobank, dietary intakes were calculated from 24-hour diet recall questionnaires. Indices representing adherence to dietary patterns (Mediterranean-style, Dietary Approaches to Stop Hypertension (DASH) and plant-based diets) were scored, and ultra-processed food consumption was studied as a percentage of total food mass consumed. Incident AF hospitalisations were assessed in Cox regression models., Results: A total of 121 300 individuals were included, with 4 579 incident AF cases over a median follow-up of 8.8 years. Adherence to Mediterranean-style or DASH diets was associated with a lower incidence of AF in minimally adjusted analyses (HR for highest vs lowest quintile 0.87 (95% CI 0.80-0.96) and HR 0.78 (95% CI 0.71-0.86), respectively). However, associations were no longer significant after accounting for lifestyle factors (HR 0.95 (95% CI 0.87-1.04) and 0.94 (95% CI 0.86-1.04) respectively), with adjustment for body mass index responsible for approximately three-quarters of the effect size attenuation. Plant-based diets were not associated with AF risk in any models. Greatest ultra-processed food consumption was associated with a significant increase in AF risk even in fully adjusted models (HR 1.13 (95% CI 1.02-1.24)), and a 10% increase in absolute intake of ultra-processed food was associated with a 5% increase in AF risk (HR 1.05 (95% CI 1.01-1.08))., Conclusion: With the possible exception of reducing ultra-processed food consumption, these findings suggest that attention to other modifiable risk factors, particularly obesity, may be more important than specific dietary patterns for the primary prevention of AF., Competing Interests: Competing interests: GMM has received research funding from Baylis Medical, is a consultant for Johnson and Johnson and InCarda and holds equity in InCarda. DHL reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Biotronik, Medtronic and MicroPort CRM. JH is an International Advisory Board member for BMJ Heart and reports that Flinders University has received on his behalf lecture and/or consulting feels from Biotronik. PS reports having served on the Advisory Board of Boston Scientific, CathRx, Medtronic, PaceMate and Abbott Medical. PS also reports that the University of Adelaide has received on his behalf lecture, consulting fees and/or research funding from Medtronic, Boston Scientific, Abbott Medical and LivaNova. CXW reports that the University of Adelaide has received on his behalf lecture, travel and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical and Vifor Pharma., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The incidence of early-onset colorectal cancer (CRC), which affects people under 50, is increasing for unknown reasons. Additionally, no underlying genetic cause is found in 20%-30% of patients suspected of having familial CRC syndrome. Whole exome sequencing (WES) has generated evidence for new genes associated with CRC susceptibility, but many patients remain undiagnosed. This study applied WES in five early-onset CRC patients from three unrelated families to identify novel genetic variants that could be linked to rapid disease development. Furthermore, the candidate variants were validated using Sanger sequencing. Two heterozygote variations, c.1077-2A>G and c.199G>A, were found in the MSH2 and the MLH1 genes, respectively. Sanger sequencing analysis confirmed that these (likely) pathogenic mutations segregated in all the affected families' members. In addition, we identified a rare heterozygote variant (c.175C>T) with suspected pathogenic potential in the MAP3K1 gene; formally the variant is of uncertain significance (VUS). Our findings support the hypothesis that CRC onset may be oligogenic and molecularly heterogeneous. Larger and more robust studies are needed to understand the genetic basis of early-onset CRC development, combined with novel functional analyses and omics approaches., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Background: Human endogenous retroviruses (HERVs) play an important role in the development of cancer and many diseases. Here, we comprehensively explored the impact of HERVs on hepatocellular carcinomas (HCCs)., Methods: We employed Telescope to identify HERVs and quantify their expression in the total RNA sequencing data obtained from 254 HCC samples, comprising 254 tumor tissues and 34 matched normal tissues., Results: In total, 3357 locus-specific activations of HERVs were differentially expressed, and 180 were correlated with patient survival. Using these 180 HERVs for classification, we found four subgroups with survival correlation. Higher expression levels of the 180 HERVs were correlated with poorer survival, while age, AFP, some mutations, and copy and structural variants differed among subgroups. The differential expression of host genes in high expression of these 180 HERVs primarily involved the activation of pathways related to immunity and infection, lipid and atherosclerosis, MAPK and NF-kB signaling, and cytokine-cytokine receptor interactions. Conversely, there was a suppression of pathways associated with RNA processing, including nucleocytoplasmic transport, surveillance and ribosome biogenesis, and transcriptional misregulation in cancer pathways. Almost all genes involved in HERV activation restriction, KRAB zinc finger proteins, RNA nucleocytoplasmic transport, stemness, HLA and antigen processing and presentation, and immune checkpoints were overexpressed in cancerous tissues, and many over-expressed HERV-related nearby genes were correlated with high HERV activation and poor survival. Twenty-three immune and stromal cells showed higher expression in non-cancerous than cancerous tissues, and seven were correlated with HERV activation. Small-molecule modulation of alternative splicing (AS) altered the expression of survival-related HERVs and their activation-related genes, as well as nearby genes., Conclusion: Comprehensive and integrated approaches for evaluating HERV expression and their correlation with specific pathways have the potential to provide new companion diagnostics and therapeutic strategies for HCC.

Background: Comprehensive and integrative analysis of hepatocellular carcinoma (HCC) is important. In this study, we explored Taiwanese HCCs using multi-omics analyses., Methods: We analyzed 254 HCCs by whole genome sequencing and total RNA sequencing, and then used bioinformatic tools to analyze genomic and transcriptomic alterations in coding and non-coding sequences to explore the clinical importance of each sequence., Results: The frequencies of the five most commonly mutated cancer-related genes were TERT, TP53, CTNNB1, RB1, and ARID1A. Genetic alteration frequencies influenced the etiology of HCC; some alterations were also correlated with clinicopathological conditions. Many cancer-related genes had copy number alterations (CNAs) and structure variants (SVs) that changed according to etiology and exhibited potential associations with survival. We also identified several alterations in histone-related genes, HCC-related long non-coding RNAs, and non-coding driver genes that may contribute to the onset and progression of HCC. Transcriptomic analysis revealed that 229 differentially expressed and 148 novel alternative splicing (AS) genes, as well as the presence of fusion genes, were associated with patient survival. Moreover, somatic mutations, CNAs, and SVs were associated with immune checkpoint gene expression and tumor microenvironment. Finally, we identified relationships among AS, immune checkpoint gene expression and tumor microenvironment., Conclusions: This study shows that genomic alterations are associated with survival, including DNA-based and RNA-based data. Moreover, genomic alterations and their associations with immune checkpoint genes and the tumor microenvironment may provide novel insights for the diagnosis and treatment of HCC., (© 2023. The Author(s).)

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy. Definitive biomarkers for disease diagnosis and activity remain elusive, making the exploration of molecular markers paramount. We conducted single-cell sequencing on peripheral blood mononuclear cells from 13 aHUS patients, 3 unaffected family members of aHUS patients, and 4 healthy controls. We identified 32 distinct subpopulations encompassing 5 B-cell types, 16 T- and natural killer (NK) cell types, 7 monocyte types, and 4 other cell types. Notably, we observed a significant increase in intermediate monocytes in unstable aHUS patients. Subclustering analysis revealed seven elevated expression genes, including NEAT1 , MT-ATP6 , MT-CYB , VIM , ACTG1 , RPL13 , and KLRB1 , in unstable aHUS patients, and four heightened expression genes, including RPS27 , RPS4X , RPL23 , and GZMH genes, in stable aHUS patients. Additionally, an increase in the expression of mitochondria-related genes suggested a potential influence of cell metabolism on the clinical progression of the disease. Pseudotime trajectory analysis revealed a unique immune cell differentiation pattern, while cell-cell interaction profiling highlighted distinctive signaling pathways among patients, family members, and controls. This single-cell sequencing study is the first to confirm immune cell dysregulation in aHUS pathogenesis, offering valuable insights into molecular mechanisms and potential new diagnostic and disease activity markers.

Background: As more than 500,000 neonates participate in newborn congenital hypothyroidism (CH) screening in Guangxi Zhuang Autonomous Region each year, the overall number of false-positive (FP) cases has increased. We aim to assess the parental stress in parents of neonates with FP CH results in Guangxi, find out the influence factors related to demographics, and provide the basis for personalized health education., Methods: The parents of neonates with FP CH results were invited to participate in the FP group, and the parents of neonates with all negative results were invited to participate in the control group. The parents completed a questionnaire on demographics, knowledge of CH, and the parental stress index (PSI) in the hospital for the first time. The follow-up visits for PSI were conducted 3, 6, and 12 months afterward through telephone and online., Results: A total of 258 and 1,040 parents participated in the FP and control groups, respectively. The parents in the FP group had better knowledge of CH and higher PSI scores than the parents in the control group. The result of logistic regression showed that the major influence factors related to the knowledge of CH were FP experience and source of knowledge. The parents in the FP group who were well-informed during the recall phone call had lower PSI scores than the other parents. The parents in the FP group showed decreasing PSI scores gradually in follow-up visits., Conclusion: The results suggested that FP screening results may affect parental stress and parent-child relationship. FP results increased the stress on the parents and increased their knowledge of CH passively., 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 Tu, Wei, Chen, Zhang, Luo and Dong.)

A novel gold(I)/Brønsted acid relay catalysis enabling azofuran activation to induce annulative rearrangement from 3-yne-1,2-diols and aryldiazonium tetrafluoroborates is reported, producing a series of furan-2-yl-substituted pyrrol-2-ones bearing a quaternary carbon center with good yields. Exchanging aryldiazonium tetrafluoroborate for azofuran led to skeletally identical but substituent-diverse furan-2-yl-containing pyrrol-2-ones with good yields, supporting the key azofuran activation and annulative rearrangement by gold/Brønsted acid relay catalysis.

Background: There is a paucity of data on the association between respiratory function and atrial fibrillation (AF). This study aimed to assess the relationship between forced expiratory volume (FEV1), forced vital capacity (FVC), and FEV1/FVC and incident AF., Methods: We performed an analysis of prospectively collected data from the UK Biobank. We included all participants with available spirometry and excluded those with prior AF. Incident AF was ascertained through hospitalisation and death records, and dose-response associations were assessed by means of multivariable Cox regression analysis with adjustment for known AF risk factors., Results: We studied 348,219 white individuals (54.1% female) with a median age of 58.1 years (interquartile range [IQR] 50.8-63.5 years). Over a median follow-up time of 11.5 years (IQR 11.0-12.6 years), a total of 18,188 incident AF events occurred. After standardisation to sex, age, and height, the risk of AF consistently increased with decreasing FEV1 percentage predicted, FEV1 z score, and FVC z score. The risk of AF linearly increased with decreasing FEV1/FVC ratio, and those that had airway obstruction as defined by FEV1/FVC ratio < 0.70 had a 23% greater risk of incident AF (adjusted hazard ratio [aHR] 1.23, 95% confidence interval [CI] 1.19-1.28) compared with those without airway obstruction. Patients with known chronic obstructive pulmonary disease and asthma were at 40% (aHR 1.40, 95% CI 1.29-1.51) and 17% (aHR 1.17, 95% CI 1.12-1.22) increased risk of incident AF respectively., Conclusions: These findings indicate that reduced ventilatory function is associated with increased risk of AF independently from age, sex, smoking, and other known AF risk factors., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

A new gold(I) self-relay catalysis reaction enabling the annulative oxygenation of propargylic alcohols with various O-nucleophiles, such as carboxylic acids, alcohols and TBHP, is reported, producing a series of functionalized benzofurans in moderate to good yields under mild conditions. This protocol benefits from the π- and σ-Lewis acid capability of gold complexes, demonstrating high molecular convergence, broad substrate flexibility, high functional group compatibility and mild conditions.

The association between alcohol consumption and abnormalities of heart rate and rhythm has long been recognized. Significant attention has focused on the risk of atrial fibrillation (AF) and sudden cardiac death (SCD) with excessive alcohol intake. Recent studies have advanced our understanding of these relationships and provided additional insights into potentially arrhythmogenic mechanisms. However, considerable uncertainty remains, such as the level of consumption at which harm begins and whether alcohol plays a role in other arrhythmias. This review characterizes the spectrum of conduction abnormalities and heart rhythm disorders in relation to alcohol consumption. In addition, it discusses the latest epidemiologic and experimental evidence, the potential importance of beverage type and constituent ingredients, and conflicting information on drink definitions, thresholds, and recommendations., Competing Interests: Funding Support and Author Disclosures Dr Wong has received support from a Mid-Career Fellowship from the Hospital Research Foundation and a Postdoctoral Fellowship from the National Heart Foundation of Australia; and has reported that the University of Adelaide has received on his behalf lecture, travel, and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical, and Vifor Pharma. Dr Tu has received support from a Postgraduate Scholarship from the National Health and Medical Research Council of Australia. Dr Marcus has received support from the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (grant R01AA022222); has received research funding from Baylis Medical; has served as a consultant for Johnson & Johnson and InCarda; and has holding equity in InCarda., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Genomic alterations play important roles in the development of cancer. We explored the impact of protein-coding genes and transcriptomic changes on clinical and molecular alterations in Taiwanese hepatocellular carcinoma (HCC) patients., Methods: We analyzed 147 whole-exome sequencing and 100 RNA sequencing datasets of HCC and compared them with The Cancer Genome Atlas (TCGA)-Liver Hepatocellular Carcinoma cohort and develop a panel of 81 apoptosis-related genes for molecular classification., Results: TERT (50%), TP53 (25%), CTNNB1 (14%), ARID1A (12%), and KMT2C (11%) were the most common genetic alterations of cancer-related genes. ALDH2 and KMT2C mutated at much higher frequencies in our cohort than in TCGA, whereas CTNNB1 was found only in 14% of our Taiwanese patients. A high germline mutation rate of ALDH2 in the APOBEC mutational signature and herb drug-related aristolochic acid-associated signature was also observed. Groups A and B of HCC were identified when we used apoptosis-related genes for molecular classification. The latter group, which had poorer survival outcomes, had significantly more aDC, CD4+ Tem, macrophages M2, NKT, plasma cells, and Th1 cells, and less CD4+ memory T cells, CD8+ Tcm, cDC, iDC, and Th2 cells, as well as more inter-chromosome fusion genes. Metatranscriptomic analysis revealed 54 cases of HBV infection. Moreover, we found that the main target gene of HBV integration is ALB., Conclusions: Unique genomic alterations were observed in our Taiwanese HCC patients. Molecular classification using apoptosis-related genes could lead to new therapeutic approaches for HCC., (© 2022. Asian Pacific Association for the Study of the Liver.)

Objective: Prior data have shown rising acute myocardial infarction (MI) trends in Australia; whether these increases have continued in recent years is not known. This study thus sought to characterise contemporary nationwide trends in MI hospitalisations and coronary procedures in Australia and their associated economic burden., Methods: The primary outcome measure was the incidence and time trends of total MI, ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) hospitalisations from 1993 to 2017. The incidence and time trends of coronary procedures were additionally collected, alongside MI hospitalisation costs., Results: Adjusted for population changes, annual MI incidence increased from 216.2 cases per 100 000 to a peak of 270.4 in 2007 with subsequent decline to 218.7 in 2017. Similarly, NSTEMI incidence increased from 68.0 cases per 100 000 in 1993 to a peak of 192.6 in 2007 with subsequent decline to 162.6 in 2017. STEMI incidence decreased from 148.3 cases per 100 000 in 1993 to 56.2 in 2017. Across the study period, there were annual increases in MI hospitalisations of 0.7% and NSTEMI hospitalisations of 5.6%, and an annual decrease in STEMI hospitalisations of 4.8%. Angiography and percutaneous coronary intervention increased by 3.4% and 3.3% annually, respectively, while coronary artery bypass graft surgery declined by 2.2% annually. MI hospitalisation costs increased by 100% over the study period, despite a decreased average length of stay by 45%., Conclusions: The rising incidence of MI hospitalisations appear to have stabilised in Australia. Despite this, associated healthcare expenditure remains significant, suggesting a need for continual implementation of public health policies and preventative strategies., Competing Interests: Competing interests: DHL reports that the University of Adelaide received on his behalf lecture and/or consulting fees from Abbott Medical, Boehringer Ingelheim, Biotronik, Medtronic, MicroPort CRM and Pfizer. PS reports having served on the advisory board of Medtronic, Abbott Medical, Boston Scientific, CathRx and PaceMate. PS reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Abbott Medical and Boston Scientific. PS reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific and Microport. CXW reports that the University of Adelaide has received on his behalf lecture, travel and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical and Vifor Pharma. The other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Cell subpopulations in the blood and joint fluid of patients with gout are poorly understood. Single-cell RNA sequencing and bioinformatic tools were used to identify cell subsets and their gene signatures in blood and synovial fluid (SF) cells, determine their relationships, characterize the diversity, and evaluate interactions among specific cell types. We identified 34 subpopulations (5 types of B cells, 16 types of T and natural killer cells, 9 types of monocytes, and 4 other cell types) in the blood of five healthy subjects and seven patients with acute gouty, and the SF of three patients with acute gout. We found that naïve CD4 T cells and classical monocytes cell populations were enriched in patients with gout, whereas plasmacytoid dendritic cells and intermediate monocytes were more abundant in healthy subjects. SF was enriched in Th1/Th17 cells, effector memory CD8 T cells, mucosal-associated invariant T cells, and macrophages. Subclusters of these cell subpopulations showed different compositions between healthy subjects and those with acute gout, according to blood and SF samples. At the cellular level, the inflammation score of a subpopulation or subcluster was highest in SF, following by the blood of acute gout patients and healthy person, whereas energy score showed the opposite trend. We also detected specific cell-cell interactions for interleukin-1, tumor necrosis factor-α, and transforming growth factor-β1 expression in the cells of patients with acute gout. Our study reveals cellular and molecular insights on inflammatory responses to hyperuricemia or uric crystal and may provide therapeutic guidance to improve treatments for gout., (© 2022. The Author(s).)

Purpose: To investigate the association of systemic blood pressure and incident primary open-angle glaucoma (POAG) using a large open-access database., Methods: Prospective cohort study included 484,268 participants from the UK Biobank without glaucoma at enrollment. Incident POAG events were recorded through assessment visits, hospital inpatient admissions, and primary care data. Blood pressure measures included systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Repeated measurements throughout the study period were analyzed as time-varying covariables. The parameters were modeled as both categorical and continuous nonlinear variables. The primary outcome measure was the relative hazard of incident POAG., Results: There were 2390 incident POAG events over 5,715,480 person-years of follow-up. Median follow-up was 12.08 years. In multivariable analyses, compared to SBP and PP in the normal range (SBP, 120-130 mmHg; PP, 40-50 mmHg), higher SBP and PP were associated with an increased risk of incident POAG (linear trend P = 0.038 for SBP, P < 0.001 for PP). Specifically, SBP of 130 to 140 mmHg or 140 to 150 mmHg was associated with a 1.16 higher hazard of incident POAG (95% CI, 1.01-1.32 and 1.01-1.33, respectively), whereas a PP of greater than 70 mmHg was associated with a 1.13 higher hazard of incident glaucoma (95% CI, 1.00-1.29). In multivariable models, no statistically significant associations were found for DBP or MAP with incident glaucoma. These findings were similar when blood pressure measures were modeled as continuous variables., Conclusions: Higher SBP and PP were associated with an increased risk of incident POAG. Further studies are required to characterize these relationships better.

The Schmidt rearrangement, a reaction that enables C-C or C-H σ bond cleavage and nitrogen insertion across an aldehyde or ketone substrate, is one of the most important and widely used synthetic tools for the installation of amides and nitriles. However, such a reaction frequently requires volatile, potentially explosive, and highly toxic azide reagents as the nitrogen donor, thus limiting its application to some extent. Here, we show a Schmidt-type reaction where aryldiazonium salts act as the nitrogen precursor and in-situ-generated cyclopenta-1,4-dien-1-yl acetates serve as pronucleophiles from gold-catalyzed Nazarov cyclization of 1,3-enyne acetates. Noteworthy is that cycloketone-derived 1,3-enyne acetates enabled ring-expansion relay to access a series of 2-pyridone-containing fused heterocycles, in which nonsymmetric cycloketone-derived counterparts demonstrated high regioselectivity. Aside from investigating the scope of this Schmidt-type reaction, mechanistic details of this transformation are provided by performing systematic theoretical calculations., (© 2022. The Author(s).)

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1 H -indol-2-yl)methyl]malonates with ( E )-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2- a ]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Aims: There is a paucity of epidemiological evidence on alcohol and the risk of bradyarrhythmias. We thus characterized associations of total and beverage-specific alcohol consumption with incident bradyarrhythmias using data from the UK Biobank., Methods and Results: Alcohol consumption reported at baseline was calculated as UK standard drinks (8 g alcohol)/week. Bradyarrhythmia events were defined as sinus node dysfunction (SND), high-level atrioventricular block (AVB), and permanent pacemaker implantations. Outcomes were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias. We studied 407 948 middle-aged individuals (52.4% female). Over a median follow-up time of 11.5 years, a total of 8 344 incident bradyarrhythmia events occurred. Increasing total alcohol consumption was not associated with an increased risk of bradyarrhythmias. Beer and cider intake were associated with increased bradyarrhythmia risk up to 12 drinks/week; however, no significant associations were observed with red wine, white wine, or spirit intake. When bradyarrhythmia outcomes were analysed separately, a negative curvilinear was observed for total alcohol consumption and risk of SND, but no clear association with AVB was observed., Conclusion: In this predominantly White British cohort, increasing total alcohol consumption was not associated with an increased risk of bradyarrhythmias. Associations appeared to vary according to the type of alcoholic beverage and between different types of bradyarrhythmias. Further epidemiological and experimental studies are required to clarify these findings., Competing Interests: Conflict of interest: J.M.L.H. reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic and Pfizer/BMS. D.H.L. reports the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, Boehringer Ingelheim, Medtronic, Microport, and Pfizer/BMS. P.S. reports having served on the advisory board of Medtronic, Abbott Medical, Boston Scientific, CathRx, and PaceMate. P.S. reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Abbott Medical, and Boston Scientific. P.S. reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and Microport. C.X.W. reports that the University of Adelaide has received on his behalf lecture, travel, and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical, and Vifor Pharma. The other authors have nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Prediction of treatment response to androgen deprivation therapy (ADT) prior to treatment initiation remains difficult. This study was undertaken to investigate whether 68Ga-PSMA-11 PET/CT features extracted from different radiomic zones within the prostate gland might predict response to ADT in patients with advanced prostate cancer (PCa). Methods: A total of 35 patients with prostate adenocarcinoma underwent two 68Ga-PSMA-11 PET/CT scans—termed PET-1 and PET-2—before and after 3 months of ADT, respectively. The prostate was divided into three radiomic zones, with zone-1 being the metabolic tumor zone, zone-2 the proximal peripheral tumor zone, and zone-3 the extended peripheral tumor zone. Patients in the response group were those who showed a reduction ratio > 30% for PET-derived parameters measured at PET-1 and PET-2. The remaining patients were classified as non-responders. Results: Seven features (glcm&#95;idmn, glcm&#95;idn, glcm&#95;imc1, ngtdm&#95;Contrast, glrlm&#95;rln, gldm&#95;dn, and shape&#95;MeshVolume) from zone-1, two features (gldm&#95;sdlgle and shape&#95;MinorAxisLength) from zone-2, and two features (diagnostics&#95;Mask-interpolated&#95;Minimum and shape&#95;Sphericity) from zone-3 successfully distinguished responders from non-responders to ADT. One predictive feature (shape&#95;SurfaceVolumeRatio) was consistently identified in all of the three zones. Conclusions: this study demonstrates the potential usefulness of radiomic features extracted from different prostatic zones in distinguishing responders from non-responders prior to ADT initiation., Competing Interests: The authors have no conflict of interest to declare that are relevant to the content of this article.

Objective: To analyze the research hot spots and frontiers of studies on of the fusion of sports and medicine (FSM) in China in recent decade via CiteSpace., Methods: Relevant publications related FSM published from January 1, 2012 to December 31, 2021 were obtained from the China National Knowledge Infrastructure (CNKI) database. CiteSpace software was used to analyze the amount of publications, institutions and keywords using standard bibliometric indicators., Results: A total of 729 publications on FSM were identified, and 688 qualified records were included in the final analysis. Between 2012 to 2021, the number of publications showed a trend of growth, albeit with certain fluctuations. The authors of these publications were mainly from universities or colleges with sports background. The institution leading the study was the Beijing Sport University ( n = 20), the most prolific ( n =12) and most-cited (224 times) author was Guo JJ from Capital University of Physical Education Sports. The journal with most publications on FSM was Contemporary Sports Technology ( n =74). The analysis of keywords showed that the "FSM" had the highest frequency ( n = 269), "integration of sports and medicine" had the strongest citation bursts (4.82), "national fitness" had the highest centrality (0.97) in recent decade, and 15 clusters of keywords were produced by log-likelihood ratio (all silhouette value >0.9)., Conclusion: The findings of this bibliometric study analyse the current status and trends in the FSM in China, which may help to identify hot topics, explore new study directions for scholars and policymakers in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tu, Jin, Chen, Xu, Luo and Wang.)

A new electrochemical selective annulative amino-ketalization and amino-oxygenation of 1,6-enynes with disulfonimides and alcohols is reported, producing a series of functionalized benzofurans under catalyst- and oxidant-free conditions. The annulative aminoketalization proceeds with simple short-chain alcohols such as methanol, ethanol and n -propanol as O -nucleophilic reagents, while the reaction occurs in the annulative aminooxygenation direction in the presence of water and large steric sec -butyl alcohol (SBA).

Hyperuricemia and gout are two of the most common metabolic disorders worldwide; their incidence is increasing with changes in lifestyle, and they are correlated with many diseases, including renal and cardiovascular diseases. The majority of studies on hyperuricemia and gout have focused on the discovery of the associated genes and their functions and on the roles of monocytes and neutrophils in the development of gout. Virtually no studies investigating the epigenomics of gout disease or exploring the clinical significance of such research have been conducted. In this study, we observed that the expression of enzymes involved in RNA modifications or RNA editing was affected in uric acid (UA)- or monosodium urate (MSU)-treated cell lines. RNA alternative splicing and splicing factors were also affected by UA or MSU treatment. We used transcriptome sequencing to analyze genome-wide RNA splicing and RNA editing and found significant changes in RNA splicing and RNA editing in MSU- or UA-treated THP-1 and HEK293 cells. We further found significant changes of RNA modifications, editing, and splicing in patients with gout. The data indicate that RNA modifications, editing, and splicing play roles in gout. The findings of this study may help to understand the mechanism of RNA splicing and modifications in gout, facilitating the development of new diagnostic and therapeutic strategies., 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 Huang, Chen, Lai, Chen, Huang, Tu, Lee, Yen, Lin, Liu and Chang.)

Atrial fibrillation (AF) is the most common cardiac tachyarrhythmia and has a rising global prevalence. Given the increasing burden of AF-related symptoms and complications, new approaches to management are required. Anemia and iron deficiency are common conditions in patients with AF. Furthermore, emerging evidence suggests that the presence of anemia may be associated with worse outcome in these patients. The role of anemia and iron deficiency has been extensively explored in other cardiovascular states, such as heart failure and ischemic heart disease. In particular, the role of iron repletion amongst patients with heart failure is now an established treatment modality. However, despite the strong bidirectional inter-relationship between AF and heart failure, the implications of anemia and iron-deficiency in AF have been scarcely studied. This area is of mechanistic and clinical relevance given the potential that treatment of these conditions may improve symptoms and prognosis in the increasing number of individuals with AF. In this review, we summarise the current published literature on anemia and iron deficiency in patients with AF. We discuss AF complications such as stroke, bleeding, and heart failure, in addition to AF-related symptoms such as exercise intolerance, and the potential impact of anemia and iron deficiency on these. Finally, we summarize current research gaps on anemia, iron deficiency, and AF, and underscore potential research directions., (© 2022. The Author(s).)

Objective: To investigate the clinical features, distribution of pathogenic bacteria, and drug resistance of bloodstream infection in children with acute leukemia., Methods: Clinical data of 93 blood culture-positive children with acute leukemia from January 2015 to December 2019 in Department of Pediatrics, The Second Hospital of Anhui Medical University were analyzed retrospectively., Results: In these 93 cases, 78 cases were in the period of neutrophil deficiency. There were 54 Gram-negative bacteria (G - ) (58.1%) found through blood culture, and the top 4 strains were Escherichia coli (15.1%), Klebsiella pneumoniae (13.9%), Pseudomonas aeruginosa (6.5%), and Enterobacter cloacae (6.5%). There were 39 Gram-positive bacteria (G + ) (41.9%) detected, and the top 4 strains were Staphylococcus epidermidis (10.8%), Streptococcus pneumoniae (6.5%), Staphylococcus hemolyticus (5.4%), and Staphylococcus human (5.4%). Among 74 strains of pathogenic bacteria from acute lymphoblastic leukemia (ALL) children, there were 29 strains of G + bacteria (39.2%) and 45 strains of G - bacteria (60.8%). While in 19 strains from acute myeloblastic leukemia (AML) patients, G - bacteria accounted for 47.4% and G + bacteria accounted for 52.6%. In 15 ALL children without neutropenia, G + bacteria made up the majority of the strains (66.7%). In the 93 strains of pathogenic bacteria, 13 (13.9%) strains were multidrug-resistant. Among them, extended-spectrum β-lactamases accounted for 42.9%, carbapenemase-resistant enzyme Klebsiella pneumoniae 15.4%, and carbapenemase-resistant enzyme Enterobacter cloacae strains 33.3%, which were detected from G - bacteria. While, 13.3% of methicillin-resistant coagulase-negative Staphylococci accounted for 13.3% detected from G + bacteria, but linezolid, vancomycin, teicoplanin Staphylococcus and Enterococcus resistant were not found. The average procalcitonin (PCT) value of G - bacteria infection was (11.02±20.282) ng/ml, while in G + infection it was (1.81±4.911) ng/ml, the difference was statistically significant (P<0.05). The mean value of C-reactive protein (CRP) in G - infection was (76.33±69.946) mg/L, and that in G + infection was (38.34±57.951) mg/L. The prognosis of active treatment was good, and only one case died of septic shock complicated with disseminated intravascular coagulation (DIC) and gastrointestinal bleeding caused by carbapenemase-resistant enzyme enterobacteriaceae., Conclusion: G - is the major bacteria in acute leukemia children with bloodstream infection, but the distribution of ALL and AML strains is different. G - bacteria dominates in ALL, while G + bacteria and G - bacteria are equally distributed in AML. Non-agranulocytosis accompanied by bloodstream infections is dominant by G + bacteria. The mean value of PCT and CRP are significantly higher in G - bacteria infection than in G + bacteria.

A novel metal-free nitrative bicyclization of 1,7-diynes with t BuONO in the presence of H 2 O is reported, producing three types of skeletally diverse tricyclic pyrroles, namely pyrrolo[3,4- c ]quinolines, chromeno[3,4- c ]pyrroles and benzo[ e ]isoindoles, with moderate to good yields by simply tuning the linkers of the 1,7-diynes. This domino protocol demonstrates remarkable compatibility regarding 1,7-diynes with different linkers, such as nitrogen and oxygen atoms and a hydroxymethyl group, and t BuONO plays dual roles as a nitro precursor as well as a nitrogen atom source.

Background: Although previous studies have demonstrated a U-shaped relationship between alcohol and sudden cardiac death (SCD), there is a paucity of evidence on the role of alcohol specifically on incident ventricular arrhythmias (VAs)., Objective: The purpose of this study was to characterize associations of total and beverage-specific alcohol consumption with incident VA and SCD using data from the UK Biobank., Methods: Alcohol consumption reported at baseline was calculated as UK standard drinks (8 g of alcohol) per week. Outcomes were assessed through hospitalization and death records. Alcohol consumption was modeled as restricted cubic splines in multivariate Cox regression models and corrected for regression dilution bias., Results: We studied 408,712 middle-aged individuals (52.1% female) over a median follow-up time of 11.5 years. A total of 1733 incident VA events and 2044 SCDs occurred. For incident VA, no clear association was seen with total alcohol consumption. Although consumption of greater amounts of spirits was associated with increased VA risk, no other significant beverage-specific associations were observed. For SCD, a U-shaped association was seen for total alcohol consumption, such that consumption of <26 drinks per week was associated with lowest risk. Consumption of greater amounts of beer, cider, and spirits was potentially associated with increasing SCD risk, whereas increasing red and white wine intake was associated with reduced risk., Conclusion: In this predominantly white cohort, no association of total alcohol consumption was observed with VA, whereas a U-shaped association was present for SCD. Additional studies utilizing accurately defined VA and SCD events are required to provide further insights into these contrasting findings., (Copyright © 2021 Heart Rhythm Society. All rights reserved.)

Objectives: This study sought to characterize associations of total and beverage-specific alcohol consumption with incident atrial fibrillation (AF)., Background: Although binge drinking and moderate to high consumption of alcohol are both established risk factors for AF, comparatively less is known about the effect of low alcohol consumption and whether associations differ by specific alcoholic beverages., Methods: Using data from the UK Biobank, total and beverage-specific alcohol consumption was calculated as UK standard drinks (8 g alcohol) per week. Past drinkers and those with a history of AF were excluded. Incident AF events were assessed through hospitalization and death records, and dose-response associations were characterized using Cox regression models with correction for regression dilution bias., Results: We studied 403,281 middle-aged individuals (52.4% female). Over a median follow-up time of 11.4 years (IQR: 10.7-12.3 years), a total of 21,312 incident AF events occurred. A J-shaped association of total alcohol consumption was observed, with lowest risk of AF with fewer than 7 drinks/week. Beverage-specific analyses demonstrated harmful associations of beer/cider consumption with any consumption. In contrast, consumption of red wine, white wine, and spirits up to 10, 8, and 3 drinks/week, respectively, was not associated with increased risk., Conclusions: In this predominantly White population, low levels of alcohol consumption (<7 U.K. standard drinks [56 g alcohol]/week) were associated with lowest AF risk. Low consumption of red and white wine and very low consumption of spirits may not be associated with increased AF risk, whereas any consumption of beer/cider may be associated with harm. These findings may have important implications for the primary prevention of AF that should be explored in future studies., Competing Interests: Funding Support and Author Disclosures Dr Gallagher is supported by a Postdoctoral Fellowship from the University of Adelaide. Dr Elliott is supported by an Early Career Fellowship from the National Heart Foundation of Australia. Dr Linz is supported by the Beacon Research Fellowship from the University of Adelaide. Mr Pitman is supported by a Postgraduate Scholarship from the Hospital Research Foundation. Dr Hendriks is supported by an Early Career Fellowship from the National Heart Foundation of Australia and the Derek Frewin Lectureship from the University of Adelaide. Dr Lau is supported by the Robert J. Craig Lectureship from the University of Adelaide. Dr Sanders is supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia and by the National Heart Foundation of Australia. Dr Wong is supported by a Mid-Career Fellowship from the Hospital Research Foundation and a Postdoctoral Fellowship from the National Heart Foundation of Australia. Dr Hendriks reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic and Pfizer/Bristol Myers Squibb. Dr Lau reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Abbott Medical, Bayer, Biotronik, Boehringer Ingelheim, Medtronic, Microport, and Pfizer/Bristol Myers Squibb. Dr Sanders has served on the Advisory Boards of Medtronic, Abbott Medical, Boston Scientific, CathRx, and PaceMate; reports that the University of Adelaide has received on his behalf lecture and/or consulting fees from Medtronic, Abbott Medical, and Boston Scientific; and reports that the University of Adelaide has received on his behalf research funding from Medtronic, Abbott Medical, Boston Scientific, and Microport. Dr Wong reports that the University of Adelaide has received on his behalf lecture, travel, and/or research funding from Abbott Medical, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Servier, St Jude Medical, and Vifor Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. All rights reserved.)

Tunable electrocatalytic annulation reactions of o -arylalkynylanilines have been established, leading to green and divergent syntheses of skeletally diverse indoles by adjusting the electrolytes and the solvents. The presence of ammonium halides as the electrolytes enabled the halogenation of o -arylalkynylanilines to give C3-halogenated indoles whereas naphtho[1',2':4,5]furo[3,2- b ]indoles could be obtained by changing the electrolyte from ammonium halides to KI. Interestingly, by combining acetone as the solvent and both NH 4 I and NH 4 Cl as the electrolytes, the reaction worked through an intramolecular annulation and [5 + 1] cyclization cascade to form naphtho[1',2':5,6][1,3]oxazino[3,4- a ]indoles.

A concise copper catalysis strategy for the addition-cyclization of cyclic oxime esters across 1,6-enynes with high stereoselectivity to generate 1-indanones bearing an all-carbon quaternary center is reported. In this process, single-electron reduction of cyclic oxime esters enables deconstructive carbon-carbon cleavage to provide a key cyanopropyl radical poised for the addition-cyclization. This reaction is redox-neutral, exhibits good functional group compatibility, and features 100% atomic utilization. This process driven by copper catalyst makes readily available cyclic oxime esters as bifunctional reagents to demonstrate convergent synthesis.

Background: Patients with chronic schizophrenia present cognitive impairment, which affects their social function and prevents them from reintegrating into society. Yijinjing is a traditional Chinese aerobic exercise that has a putative psychosomatic effect on improving cognitive function. Methods: From January to May 2021, 40 patients with chronic schizophrenia were recruited and randomly divided into a control group and a Yijinjing group. In the 12-week intervention, the patients in the control group received conventional treatment, whereas patients in the Yijinjing group performed Yijinjing exercise (40 min/session, twice a week) in addition to receiving conventional treatment. The Positive and Negative Syndrome Scale (PANSS), the Insight and Treatment Attitude Questionnaire (ITAQ), the Rosenberg Self-esteem Scale (SES), and the Mini Mental State Examination (MMSE) were used to measure clinical symptoms and cognitive function at 0, 6, and 12 weeks. Results: The demographic information was not significantly different between groups. At baseline, the scores of all the scales were not statistically different between groups. After 12 weeks of intervention, compared to those at baseline, the scores of the negative scale ( t = 19.00, p < 0.0001), general psychopathology scale ( t = 15.98, p < 0.0001), and total score ( t = 15.47, p < 0.0001) of the PANSS and SES ( t = 5.378, p < 0.0001) had significantly decreased, and the scores of the ITAQ ( t = 7.984, p < 0.0001) and MMSE ( t = 6.750, p < 0.0001) had significantly increased in Yijinjing group; the score of the MMSE increased in the control group as well ( t = 2.491, p = 0.0222). Compared to the respective scores in the control group, the negative scale score ( t = 2.953, p = 0.0054) significantly decreased, and the ITAQ ( t = 3.043, p = 0.0042) and MMSE ( t = 2.2.68, p = 0.0291) scores significantly increased in the Yijinjing group after 12 weeks of intervention. Conclusion: These results provide a preliminary indication that Yijinjing exercise had the potential to improve cognitive function and negative symptoms in patients with chronic schizophrenia. A larger-scale study to determine the trajectory of change in the longer term should be undertaken., 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 Gao, Luo, Tu, Lu, Jiang, Qiao, Lin, Li and Chen.)

A new and green route to skeletally diverse oxo -heterocyclic architectures such as pyrano[3,4- c ]chromen-2-ones and pyrano[3,4- c ]quinolin-2-ones is reported via an unprecedented photocatalytic Kharasch-type cyclization/1,5-(S N ″)-substitution/elimination/6π-electrocyclization/double nucleophilic substitution cascade starting from easily available heteroatom-linked 1,7-diynes and low-cost CBrCl 3 . During this reaction process, the full scission of carbon-halogen bonds of BrCCl 3 was realized to directly build two new rings, including a lactone scaffold, using H 2 O as the oxygen source of the ester group.

Objectives: Quantum noise is a random process in X-ray-based imaging systems. We addressed and measured the uncertainty of radiomics features against this quantum noise in computed tomography (CT) images., Methods: A clinical multi-detector CT scanner, two homogeneous phantom sets, and four heterogeneous samples were used. A solid tumor tissue removed from a male BALB/c mouse was included. We the placed phantom sets on the CT scanning table and repeated 20 acquisitions with identical imaging settings. Regions of interest were delineated for feature extraction. Statistical quantities-average, standard deviation, and percentage uncertainty-were calculated from these 20 repeated scans. Percentage uncertainty was used to measure and quantify feature stability against quantum noise. Twelve radiomics features were measured. Random noise was added to study the robustness of machine learning classifiers against feature uncertainty., Results: We found the ranges of percentage uncertainties from homogeneous soft tissue phantoms, homogeneous bone phantoms, and solid tumor tissue to be 0.01-2138%, 0.02-15%, and 0.18-16%, respectively. Overall, it was found that the CT features ShortRunHighGrayLevelEmpha (SRHGE) (0.01-0.18%), ShortRunLowGrayLevelEmpha (SRLGE) (0.01-0.41%), LowGrayLevelRunEmpha (LGRE) (0.01-0.39%), and LongRunLowGrayLevelEmpha (LRLGE) (0.02-0.66%) were the most stable features against the inherent quantum noise. The most unstable features were cluster shade (1-2138%) and max probability (1-16%). The impact of random noise to the prediction accuracy by different machine learning classifiers was found to be between 0 and 12%., Conclusions: Twelve features were used for uncertainty measurements. The upper and lower bounds of percentage uncertainties were determined. The quantum noise effect on machine learning classifiers is model dependent., Key Points: • Quantum noise is a random process and is intrinsic to X-ray-based imaging systems. This inherent quantum noise creates unpredictable fluctuations in the gray-level intensities of image pixels. Extra cautions and further validations are strongly recommended when unstable radiomics features are selected by a predictive model for disease classification or treatment outcome prognosis. • We addressed and used the statistical quantity of percentage uncertainty to measure the uncertainty of radiomics features against the inherent quantum noise in computed tomography (CT) images. • A clinical multi-detector CT scanner, two homogeneous phantom sets, and four heterogeneous samples were used in the stability measurement. A solid tumor tissue removed from a male BALB/c mouse was included in the heterogeneous sample., (© 2021. European Society of Radiology.)

This study was designed to characterize the microbiomes of the lung tissues of lung cancer patients. RNA-sequencing was performed on lung tumor samples from 49 patients with lung cancer. Metatranscriptomics data were analyzed using SAMSA2 and Kraken2 software. 16S rRNA sequencing was also performed. The heterogeneous cellular landscape and immune repertoires of the lung samples were examined using xCell and TRUST4, respectively. We found that nine bacteria were significantly enriched in the lung tissues of cancer patients, and associated with reduced overall survival (OS). We also found that subjects with mutations in the epidermal growth factor receptor gene were less likely to experience the presence of Pseudomonas. aeruginosa . We found that the presence of CD8+ T-cells, CD4+ naive T-cells, dendritic cells, and CD4+ central memory T cells were associated with a good prognosis, while the presence of pro B-cells was associated with a poor prognosis. Furthermore, high clone numbers were associated with a high ImmuneScore for all immune receptor repertoires. Clone numbers and diversity were significantly higher in unpresented subjects compared to presented subjects. Our results provide insight into the microbiota of human lung cancer, and how its composition is linked to the tumor immune microenvironment, immune receptor repertoires, and OS.

Purpose: In most radiomic studies related to cancer research, the traditional tumor-centric view has predominated. In this retrospective study, we go beyond the single-tumor region and investigate the utility of proposed radiomic zones for risk classification and clinical outcome predictions using radiomic features extracted from 11 C-choline positron emission tomography (PET) imaging and supervised machine learning in prostate tumors., Materials and Methods: Seventy-seven prostate tumors were selected and delineated. The prostate organ was divided into three radiomic zones, with zone-1 being the metabolic tumor zone, zone-2 the proximal peripheral tumor zone, and zone-3 the extended peripheral tumor zone. LIFEx was used for PET-radiomic feature extraction. Risk groups were created using Gleason scores (GS), prostate-specific antigen (PSA) levels, clinical TNM staging, and progression-free survival (PFS). Random forest (RF) and AdaBoost advanced machine learning algorithms were used for supervised machine learning. Accuracy, positive predictive value, area under the receiver operating characteristic curve (AreaROC), and other metrics were calculated for comparisons of predictive performance between zones., Results: For the GS risk classification group, the accuracies of risk classification predictions were 71%, 71%, and 67% using RF and 65%, 64%, and 63% using AdaBoost for zones -1, -2, and -3, respectively. For the PSA group, the accuracies of risk classification predictions were 74%, 65%, and 64% using RF and 76%, 66%, and 67% using AdaBoost for zones -1, -2, and -3, respectively. For the TNM group, the accuracies of risk classification predictions were 68%, 76%, and 78% using RF and 66%, 75%, and 80% using AdaBoost for zones -1, -2, and -3, respectively. For the PFS group, the accuracies of clinical outcome predictions were 77%, 75%, and 83% using RF and 77%, 74%, and 83% using AdaBoost in zones -1, -2, and -3, respectively., Conclusions: We proposed three radiomic zones with different standard uptake value characteristics and created four risk groups of prostate cancer patients for testing this idea. We showed that these radiomic zones have different predicting strengths in classifying risk groups and might allow us to identify a radiomic zone with higher accuracy for patient outcome prediction., (© 2021 American Association of Physicists in Medicine.)