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Heavy metal pollution has gained increasing attention over past years, and notably, cadmium (Cd) is a non-essential heavy metal that can be toxic to human and wildlife. Furthermore, selenium (Se) is a component of the selenoproteins and influences the toxicity of Cd in different organisms, and protect organisms as a kind of heavy metal antagonist. This study exposed mud crab to 5.0 mg/L Cd for 28 days, and investigated whether different concentrations (0.1, 0.2, 0.3 mg/kg) of selenite (Na 2 SeO 3 ) or selenomethionine (SeMet) affect the bioaccumulation of Cd, serum biochemical index, antioxidant and stress-response genes of S. paramamosain. The results showed that the Cd concentration in Cd group was significantly higher than the organic or inorganic Se group. Serum biochemical index demonstrated that Se might relieve the damage or dysfunction of hepatopancreas caused by both Cd accumulation and toxicity. Furthermore, Se improved CAT, GPx T-AOC and SOD activity, and decreased MDA concentrations and the lipid peroxidation levels, antagonistic to Cd. Then, this study analyzed the expression of 26 stress-related genes, the results indicated that the inorganic and organic Se might reduce the damage of cell and the toxicity of heavy metals in the hepatopancreas after Cd exposure. Therefore, this study indicated that Se might alleviate Cd toxicity via the different antioxidative mechanisms, and increased the understanding of environmental toxins on estuary crustaceans., 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 © 2022. Published by Elsevier B.V.)

Long non-coding RNA play an importantr role in the differentiation of chondrocytes. This study aims to explore the role of long non-coding RNA in the transcriptional regulation of Notch4. In previous studies, it has been found that Notch signal can be used as the downstream of TGF-β signal to affect the proliferation and differentiation of deer antler chondrocytes, but the specific mechanism remains unclear. Here we found that lncRNA27785.1 was involved in the regulation of TGF-β/ Smad3 signal and Notch4 gene. The overexpression lncRNA27785.1 can negatively regulate the expression of Notch4 to inhibit cell proliferation and differentiation, while interference with lncRNA27785.1 can promote the expression of Notch4 gene to promote the proliferation and differentiation of chondrocytes. Subsequently, through luciferase experiment and CHIP experiment, we found that lncRNA27785.1 is regulated by Smad3 transcription, and Smad3 inhibited the expression of lncRNA27785.1. In addition, activated TGF-β signaling can reduce the inhibitory effect of lncRNA27785.1 on Notch4 signaling. In summary, we found that lncRNA27785.1 and TGF-β/Smad3 play an important role in Notch4 signaling. Our findings provided evidence to explain how TGF-β signaling regulate the Notch signaling pathway to influence chondrocyte proliferation and differentiation by a specific lncRNA27785.1., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Air exposure stress may result in oxidative damage and ultimately disease or death in crustaceans. Using the Procambarus clarkia, one of the main commercial aquaculture species in China, as a study model, the molecular mechanism including histopathological changes, antioxidant capacity and immunity response under the air exposure stress were firstly evaluated. Results showed that the surfaces of gill were wrinkled while the morphologies of the nuclei and mitochondria in the hepatopancreas were altered after 48 h of air exposure stress, and the damage of mitochondria was more serious after additional bacterial infection. Moreover, the activity of antioxidant enzymes increased at first and then decreased along with increasement of air exposure time. The concentration of malondialdehyde (MDA) in hepatopancreas was significantly increased under the air exposure stress, while the bacterial infection further aggravated such oxidative damage. The transcriptome analysis exhibited that the stress- and immunity-related genes in hepatopancreas altered when response to the air exposure stress. This study could help uncover the mechanisms of aerial exposure stress responses in Procambarus clarkii., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro 1-5 , but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells 6-11 . Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis., (© 2022. The Author(s).)

Using orchid mycorrhizal fungi (OMFs) to facilitate orchid proliferation is considered an effective method of orchid conservation. Based on the success of using in situ seedling baiting to obtain plant growth-promoting fungi in our previous study, in this study, we developed the method of using ex situ seedling baiting to capture seedling-associated fungi from Dendrobium officinale . We collected substrates (e.g., litters, barks and mosses) from six original habitats of D. officinale in different geographical locations in China, and then, transplanted in vitro-produced seedlings of D. officinale into the substrates. After cultivation for 75 days, it was obvious that fungi colonized the seedling roots and formed large numbers of pelotons in all six groups. From these seedling roots, a total of 251 fungal strains, which were divided into 16 OMF and 11 non-OMF species, were successfully isolated. The 16 OMFs included 13 Tulasnella and 3 Serendipitaceae species. The fungal species isolated from the different groups (original habitat sources) were not identical, but the dominant OMFs with high isolation frequencies (more than 10 times) were commonly isolated from more than four original sources. Among the 11 non-OMFs, Fusarium oxysporum TP-18 and Muscodor sp. TP-26 were the dominant endophytes. Fusarium oxysporum is a common endophyte associated with many orchid species, including D. officinale . The results suggest that ex situ seedling baiting is an easy and efficient approach to obtaining seedling-associated fungi for this species and could be performed for other over-collected species, especially orchids for which wild plants have disappeared in the field but their original habitats are known. This approach has great potential for application in OMF studies in the future.

Objective: To analyze the disease burden of pancreatic cancer in major Asian countries and forecast the burden of that in China, which helps to provide reference for the prevention and control of pancreatic cancer. Methods: Data on disease burden of pancreatic cancer among global and major Asian countries from on the Global Burden of Disease (GBD) 2019 were collected to describe burden distribution through the absolute numbers or standardized rates of incidence, death and disability adjusted life years (DALY) by year, sex and socio-demographic index. Estimated annual percentage changes (EAPC) was used to assess the trend of standardized rate. The proportion of deaths attributable to risk factors for pancreatic cancer in 2019 was used to compare by age, sex and region. ARIMA model was performed with R language to predict change of age-standardized incidence and death rates of pancreatic cancer from 2020 to 2029. Results: From 1990 to 2019, the standardized incidence rates of pancreatic cancer in China increased from 3.17/100 000 to 5.78/100 000, and the standardized death rate increased from 3.34/100 000 to 5.99/100 000. The increases exceeded other high-income Asia countries. In the past three decades, the standardized incidence, death and DALY rates of pancreatic cancer in global have increased year by year. Among the major countries in Asia, China has the highest growth rate of disease burden (EAPC of standardized incidence rates=2.32%, 95% CI: 2.10%-2.48% and EAPC of standardized death rate=2.25%, 95% CI: 2.03%-2.42%). In addition, incidence and death rates of pancreatic cancer in China are expected to continue on the rise between 2000 and 2029 by ARIMA model. Incidence rate is expected to increase 15.92% and death rate is expected to increase 15.86%. Conclusions: The standardized incidence and death rates of pancreatic cancer in China increase year by year with an increasing trend for the burden of disease. The disease burden of pancreatic cancer is expected to rise due to the increase and aging of the population. Preventive measures should be adopted to decrease the burden of the pancreatic cancer.

This study aimed to investigate whether different salinity stresses (0, 2, 4, 6, or 8 ppt NaCl) affect the histoarchitecture, serum biochemical indices, antioxidant responses, and transcriptome analysis of the red swamp crayfish Procambarus clarkii. Transmission electron microscopy results showed that the degree of damage to the nuclei and mitochondria in the hepatopancreas increased with increasing salinity. Scanning electron microscopy results showed that the degree of gill wrinkles was enhanced under salinity stress. Serum biochemical indices demonstrated that the cholesterol significantly decreased while the triglyceride, aspartate transaminase, and alanine transaminase contents significantly increased with increasing salinity. The antioxidant parameters, including catalase, total antioxidant capacity, and glutathione peroxidase, significantly decreased, while the malondialdehyde content significantly increased under salinity stress. Transcriptome analysis revealed that the expression pattern of immune-related genes showed a downward trend. These findings enrich our knowledge about the salinity stress response of farmed organisms and provide a theoretical base for salinity domestication and saline soil cultivation of P. clarkii, which might contribute to income improvement, employment generation, food security, and environmental safety., 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 © 2022. Published by Elsevier B.V.)

Background Fibromyalgia (FM) is a complex disorder characterized by chronic widespread pain and significant patient burden. Patients with chronic hepatitis C are reportedly predisposed to the development of FM. Direct-acting antiviral drugs (DAA) achieved a remarkable therapeutic efficacy in CHC patients. We therefore investigated the impact of DAA on FM symptoms in CHC patients. Methods We enrolled consecutive CHC patients who received DAA. FM symptoms were evaluated based on the 2016 American College of Rheumatology (ACR) fibromyalgia scale at baseline and 12 and 24 weeks after cessation of DAA therapy. Logistic regression was performed to determine the influence of HCV on FM at baseline. We also recruited individuals who underwent a health checkup examination as the control group, and calculated the standardized prevalence ratio of FM in CHC patients. Comparisons of fibromyalgia in different time points were undertaken using the Wilcoxon signed-rank test. Results A total of 33 CHC patients (15 males and 18 females) and 402 controls were recruited. All CHC patients achieved sustained virological response. Two (6%) patients and two (0.5%) controls fulfilled the diagnostic criteria for FM, and the standardized prevalence ratio was 23.9 in CHC patients. Logistic regression also showed increased odds for FM in CHC patients after adjusting for age and sex (OR: 14.4; 95%CI: 1.6, 128.0). In addition, their fibromyalgianess scale decreased at 12 and 24 weeks after DAA therapy. In conclusion, CHC patients were more likely to develop FM. Implementation of DAA therapy might improve FM symptoms in these patients.

Objectives: The effect of previous coronary stenting on subsequent coronary artery bypass graft is inconclusive., Methods: We used Taiwan's National Health Insurance Database to retrospectively evaluate patients with multivessel coronary artery bypass graft between January 2000 and December 2013. Overall, 32,335 patients who received coronary artery bypass graft were included, of whom 3028 had previous coronary stenting. Propensity-score matching yielded 2977 cases each for evaluation under the previous stenting and no stenting groups. The 30-day mortality and major adverse cardiac events, including all-cause mortality, acute myocardial infarction, and revascularization, were considered primary outcomes., Results: The number of coronary artery bypass grafts decreased per year. However, the percentage of patients who had previous coronary stent implantation before coronary artery bypass graft increased steadily (P for trend <.001), and the average number of stents implanted in a patient also increased per year (P for trend <.001). The previous stent group had a significantly greater 30-day mortality rate than did the no-stent group (7.2% vs 5.0%; odds ratio, 1.47; 95% confidence interval, 1.19-1.82). The previous stent group had a greater rate of revascularization (14.4% and 10.0%; subdistribution hazard ratio, 1.50; 95% confidence interval, 1.30-1.74) in the last follow-up at year 13., Conclusions: Previous coronary stenting before coronary artery bypass graft for multivessel coronary artery disease significantly increased 30-day mortality but did not affect late survival. However, patients who had coronary stenting before coronary artery bypass graft experienced more revascularization events during late follow-up., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Mammalian embryos sequentially differentiate into trophectoderm and an inner cell mass, the latter of which differentiates into primitive endoderm and epiblast. Trophoblast stem (TS), extraembryonic endoderm (XEN) and embryonic stem (ES) cells derived from these three lineages can self-assemble into synthetic embryos, but the mechanisms remain unknown. Here, we show that a stem cell-specific cadherin code drives synthetic embryogenesis. The XEN cell cadherin code enables XEN cell sorting into a layer below ES cells, recapitulating the sorting of epiblast and primitive endoderm before implantation. The TS cell cadherin code enables TS cell sorting above ES cells, resembling extraembryonic ectoderm clustering above epiblast following implantation. Whereas differential cadherin expression drives initial cell sorting, cortical tension consolidates tissue organization. By optimizing cadherin code expression in different stem cell lines, we tripled the frequency of correctly formed synthetic embryos. Thus, by exploiting cadherin codes from different stages of development, lineage-specific stem cells bypass the preimplantation structure to directly assemble a postimplantation embryo., (© 2022. The Author(s).)

Background: Patients with colorectal cancer (CRC) are more likely to develop cardiovascular disease (CVD) than those without cancer. Little is known regarding their CV risk after operative chemotherapy. We aimed to compare the risk of CV disease among different fluoropyrimidine derivatives., Methods: We assembled a nationwide cohort of patients with newly diagnosed CRC between 2004 and 2015 who received fluoropyrimidine-based adjuvant chemotherapy for resected CRC by linking the Taiwan Cancer Registry (TCR), National Health Insurance Research Database (NHIRD), and Taiwan Death Registry (TDR). All eligible patients were followed from CRC diagnosis (index date) until a CV event, death, loss to follow-up, or December 31st 2018, whichever came first. CV outcomes included acute myocardial infarction (AMI), life-threatening arrhythmia (LTA), congestive heart failure (CHF), and ischemic stroke (IS). We used stabilized inverse probability of treatment weighting using propensity score (SIPTW) to balance all covariates among the three chemotherapy groups: tegafur-uracil (UFT), non-UFT, and mixed. In addition, survival analysis was conducted to examine the association between study outcomes and chemotherapy groups., Results: From 2004 to 2015, 10,615 (32.8%) patients received UFT alone, 14,511 (44.8%) patients received non-UFT, and 7,224 (22.3%) patients received mixed chemotherapy. After SIPTW, the UFT group had significantly lower all-cause mortality and cancer-related death rates than the other two chemotherapy groups. However, the UFT group had significantly higher rates of cancer death, ischemic stroke, and heart failure than those of the other two chemotherapy groups. The UFT group also had a significantly higher AMI rate than the mixed group. There was no significant difference in LTA among the three groups. Similar findings were observed in the subgroup analysis (stage II and age <70 years, stage II and age ≥70 years, stage III and age <70 years, stage III and age ≥70 years) as the overall population was observed., Conclusion: Higher heart failure and ischemic stroke rates were found in the UFT group than in the other two chemotherapy groups, especially those with stage III CRC and ≥70 years of age. Careful monitoring of this subset of patients when prescribing UFT is warranted., 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, Ho, Hsu, Chang, Chen, Chou, Chang, Chen, Yang and See.)

Objective: To examine the risk and risk factors of mortality in patients with rheumatoid arthritis (RA) with interstitial lung disease (ILD)., Methods: Using the 1997-2013 Taiwanese National Health Insurance Research Database, we identified 32 289 incident patients with RA by using International Classification of Diseases, Ninth Revision codes from 2001 to 2013, and 214 patients developed ILD subsequently. We matched (1:10) RA-ILD with controls for sex, age, time of ILD diagnosis and disease duration. In addition, we conducted propensity score matching (PSM) (1:1) for selected comorbidities to choose RA-ILD patients and controls. Using the Cox proportional hazard model, we estimated the association of mortality with ILD for the two matched populations and assessed factors associated with mortality among 214 RA-ILD patients, shown as adjusted HRs (aHRs) with 95% CIs., Results: In the populations selected before and after PSM, we included 164 and 155 patients with RA-ILD and 1640 and 155 controls, respectively. ILD was associated with mortality in the population before PSM (aHR, 1.73; 95% CI 1.19 to 2.52) and in the PSM population (HR 4.38; 95% CI 2.03 to 9.43). Among 214 patients with RA-ILD, age (aHR 1.04; 95% CI 1.03 to 1.08), chronic obstructive pulmonary disease (COPD) (aHR 2.12; 95% CI 1.25 to 3.58), diabetes mellitus (DM) with end-organ damage and corticosteroid dose (prednisolone equivalent, mg/day) (aHR 1.09; 95% CI 1.07 to 1.11) were associated with mortality in RA-ILD., Conclusion: This population-based cohort study showed that ILD was associated with risk of mortality in patients with RA, and risk factors associated with mortality in patients with RA-ILD included age, COPD, DM with end-organ damage and average daily prednisolone dose., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Smads, part of signaling cascades that represent downstream pathways of the TGF-β super family proteins, are pleiotropic cytokines with important role in mediating cell proliferation, homeostasis, differentiation, apoptosis and immune response. However, the specific functions of Smads remain unknown in crustaceans. In the present study, the drosophila mothers against decapentaplegic protein gene 1 (Smad1) was firstly identified and characterized from the Red Swamp Crayfish Procambarus clarkii. The obtained cDNA sequence of pcSmad1was 2, 503 bp long with a 1, 488 bp open reading fame, which encoded a putative protein of 496 amino acids. Furthermore, pcSmad1 responded to both Aeromonas hydrophila and WSSV challenge, suggesting the involvement of pcSmad1 in innate immune responses. Knockdown of pcSmad1 in vivo dramatically increased the expressions of NF-κB signaling genes and anti-lipopolysaccharide factor genes. Additionally, overexpression of pcSmad1 in HEK293T cells could markedly activate NF-κB signaling. Taken together, these results indicated that pcSmad1 played an immune-regulatory role in crayfish's innate immunity, which may provide a better understanding of TGF-β superfamily members in crustacean., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Cerebrovascular reactivity (CVR) reflects the CBF change to meet different physiological demands. The reference CVR technique is PET imaging with vasodilators but is inaccessible to most patients. DSC can measure transit time to evaluate patients suspected of stroke, but the use of gadolinium may cause side-effects. Arterial spin labeling (ASL) is a non-invasive MRI technique for CBF measurements. Here, we investigate the effectiveness of ASL with single and multiple post labeling delays (PLD) to replace PET and DSC for CVR and transit time mapping in 26 Moyamoya patients. Images were collected using simultaneous PET/MRI with acetazolamide. CVR, CBF, arterial transit time (ATT), and time-to-maximum (Tmax) were measured in different flow territories. Results showed that CVR was lower in occluded regions than normal regions (by 68 ± 12%, 52 ± 5%, and 56 ± 9%, for PET, single- and multi-PLD PCASL, respectively, all p < 0.05). Multi-PLD PCASL correlated slightly higher with PET (CCC = 0.36 and 0.32 in affected and unaffected territories respectively). Vasodilation caused ATT to reduce by 4.5 ± 3.1% (p < 0.01) in occluded regions. ATT correlated significantly with Tmax (R 2  > 0.35, p < 0.01). Therefore, multi-PLD ASL is recommended for CVR studies due to its high agreement with the reference PET technique and the capability of measuring transit time.

Introduction: Adult-onset Still's disease (AOSD) is an autoinflammatory disease driven by the innate immune response. Given the ambiguity in clinical presentation and lack of specific diagnostic biomarkers, AOSD diagnosis is usually delayed in the early stage. Because AOSD is a rare disease with clinical heterogeneity, there is no consensus on its treatment currently. This review summarizes the current research evidence regarding the pathogenic role and the diagnostic or therapeutic potential of interleukin (IL)-18 in AOSD., Areas Covered: We searched the MEDLINE database using the PubMed interface and reviewed English-language literature from 1971 to 2022. This review focusing on IL-18 discusses its pathogenic role and clinical implications in AOSD., Expert Opinion: NLRP3-inflammasome activation with IL-18 overproduction plays a pathogenic role in AOSD. IL-18 is closely linked to the clinical manifestations and disease activity of AOSD and may be a diagnostic biomarker. Given its pathogenic role in AOSD, IL-18 could become a potential therapeutic target. IL-18 binding protein (IL-18BP) negatively regulates the biological activity of IL-18 by inhibiting IL-18 signaling, and a clinical trial revealed that IL-18BP (Tadekinig alfa) treatment was well-tolerated and effective for AOSD. Recently, monoclonal antibodies against IL-18 have been under evaluation in a phase 1b trial.

Using a sample of about 10^{10}  J/ψ events collected at a center-of-mass energy sqrt[s]=3.097  GeV with the BESIII detector, the electromagnetic Dalitz decays J/ψ→e^{+}e^{-}π^{+}π^{-}η^{'}, with η^{'}→γπ^{+}π^{-} and η^{'}→π^{+}π^{-}η, have been studied. The decay J/ψ→e^{+}e^{-}X(1835) is observed with a significance of 15σ, and also an e^{+}e^{-} invariant-mass dependent transition form factor of J/ψ→e^{+}e^{-}X(1835) is presented for the first time. The intermediate states X(2120) and X(2370) are also observed in the π^{+}π^{-}η^{'} invariant-mass spectrum with significances of 5.3σ and 7.3σ. The corresponding product branching fractions for J/ψ→e^{+}e^{-}X, X→π^{+}π^{-}η^{'} [X=X(1835), X(2120), and X(2370)] are reported.

Objective: This study aims to investigate anxiety and its influencing factors in patients with drug-induced liver injury (DILI)., Materials and Methods: Ninety-four patients with DILI were enrolled and evaluated with a self-rating anxiety scale (SAS). According to the anxiety score, they were divided into four groups: the non-anxiety, mild anxiety, moderate anxiety, or severe anxiety groups, and the scores were analyzed based on demographic and biochemical indicators., Results: Of the 94 patients with DILI, 63 did not have anxiety and 31 had anxiety (32.9%), of which 27 had mild, 3 had moderate, and 1 had severe anxiety. There were no statistically significant differences in gender, age, occupation, and level of education between the groups ( F = 1.42, H = 2.361, H = 6.751, H = 1.796, and P > 0.05); anxiety score and degree of anxiety between the types of drugs that led to the liver injury ( H = 0.812, H = 1.712, and P > 0.05); anxiety score between the different degrees of liver injury ( H = 2.836, H = 4.957, P > 0.05); or length of hospital stay or prognosis between the degrees of anxiety ( F = 1.487, H = 0.761, P > 0.05). However, there were statistically significant differences in the degree of anxiety between different degree and types of liver injury ( H = 7.981, H = 8.208, P < 0.05)., Conclusion: Patients with DILI may have anxiety, especially mild anxiety. The occurrence of anxiety in patients with DILI is not related to gender, age, occupation, or level of education but may be related to the degree and type of liver injury. Anxiety has no impact on the length of stay in hospital or the prognosis of the DILI. These findings may contribute to the development of management strategies for patients with DILI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Guo, Xu, Feng and Chen.)

Background: The risk for major adverse cardiovascular events (MACE) with targeted therapies for patients with advanced renal cell carcinoma (RCC) in real-world practice remains unclear., Objectives: The aim of this study was to compare the risk for MACE associated with targeted cancer therapies with that associated with cytokine treatment in patients with advanced RCC., Methods: Using Taiwan's National Health Insurance Research Database, a retrospective nationwide cohort study was conducted involving patients with advanced RCC who had received targeted therapy (sunitinib, sorafenib, pazopanib, everolimus, or temsirolimus) or cytokine therapy (interleukin-2 or interferon gamma) from 2007 to 2018. Cox proportional hazards models were used to estimate the risk for MACE (a composite of myocardial infarction, ischemic stroke, heart failure, and cardiovascular death) in the cohort using the propensity score method of stabilized inverse probability of treatment weighting., Results: In this cohort of 2,785 patients with advanced RCC, 2,257 (81%) and 528 (19%) had received targeted and cytokine therapy, respectively. After stabilized inverse probability of treatment weighting, the incidence rates of MACE were 6.65 and 3.36 per 100 person-years in the targeted and cytokine therapy groups, respectively (HR: 1.80; 95% CI: 1.19-2.74). Baseline history of heart failure (HR: 3.88; 95% CI: 2.25-6.71), atrial fibrillation (HR: 3.60; 95% CI: 2.16-5.99), venous thromboembolism (HR: 2.50; 95% CI: 1.27-4.92), ischemic stroke (HR: 1.88; 95% CI: 1.14-3.11), and age ≥ 65 years (HR: 1.81; 95% CI: 1.27-2.58) were independent risk factors for targeted therapy-associated MACE., Conclusions: Among patients with advanced RCC, the risk for MACE associated with targeted cancer therapy is higher than that associated with cytokine therapy., Competing Interests: This study was supported by Chang Gung Memorial Hospital (CMRPG3K0032). The funding sources had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Psoriasis is an immune-mediated skin disease with a worldwide prevalence of 2-4% that causes scaling erythematous skin lesions. It is a chronic relapsing and complex multifactorial disease that often necessitates long-term therapy. Despite various novel therapies, psoriasis remains a treatable but non-curable disease. Because the antitussive medication dextromethorphan (DXM) can inhibit murine bone marrow and human monocytes and slow the progression of arthritis in mice with type II collagen-induced arthritis, we explored whether the oral administration of DXM to mice with imiquimod (IMQ)-induced psoriasis can effectively alleviate psoriasis symptoms and improve immune regulation. Herein, we examined the therapeutic effects of DXM on psoriasis and its potential mechanisms of action in an IMQ-induced psoriasis mice model. We found that an oral dose of DXM (10 mg/kg) could more significantly reduce psoriasis symptoms compared with intraperitoneal injection. Seven days after the oral administration of DXM, the Psoriasis Area and Severity Index (PASI) score was significantly decreased compared with that in the vehicle group. Furthermore, DXM treatment also significantly ameliorated the psoriasis symptoms and the histopathological features of psoriasis, including stratum corneum thickening, desquamation, and immune cell infiltration. Additionally, DXM reduced the mRNA levels of the cytokines TNF-α, IL-6, IL-17A, and IL-22 in skin and the percentage of IL-17A and IL-22 producing T cell receptor γδ T cells (TCRγδT). Taken together, our research demonstrated that DXM could inhibit keratinocyte proliferation and alleviate psoriasis symptoms, which suggests the potential application of DXM in the treatment of chronic inflammation and autoimmune diseases.

Cerebrovascular reactivity (CVR), the capacity of the brain to increase cerebral blood flow (CBF) to meet changes in physiological demand, is an important biomarker to evaluate brain health. Typically, this brain "stress test" is performed by using a medical imaging modality to measure the CBF change between two states: at baseline and after vasodilation. However, since there are many imaging modalities and many ways to augment CBF, a wide range of CVR values have been reported. An understanding of CVR reproducibility is critical to determine the most reliable methods to measure CVR as a clinical biomarker. This review focuses on CVR reproducibility studies using neuroimaging techniques in 32 articles comprising 427 total subjects. The literature search was performed in PubMed, Embase, and Scopus. The review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We identified 5 factors of the experimental subjects (such as sex, blood characteristics, and smoking) and 9 factors of the measuring technique (such as the imaging modality, the type of the vasodilator, and the quantification method) that have strong effects on CVR reproducibility. Based on this review, we recommend several best practices to improve the reproducibility of CVR quantification in neuroimaging studies.

Objectives: Both bullying and psychosis-like experiences (PLEs) have gained much attention in recent years, but their interactions are not fully unraveled. The aim of the current study was to validate the Chinese version of Bullying Scale for Adults (C-BSA), and to investigate whether past bullying experiences independently predict the presence of PLEs in university students., Methods: The validity and reliability of the C-BSA were determined in two independent samples. A battery of psychological inventories was also administered to assess the presence of PLEs, maltreatment history in the family, and current depression and anxiety, including the 15-item positive subscale of the community assessment of psychic experiences (CAPE-p15), the Chinese version of the Childhood Trauma Questionnaire (CTQ), Self-Rating Depression Scale (SDS), and Self-Rating Anxiety Scale (SAS)., Results: In the construction sample ( N = 629), a Cronbach's α of 0.921 indicated a good internal consistency of C-BSA. The exploratory factor analysis (EFA) yielded a four-factor model and a three-factor model, and both were verified by using the confirmatory factorial analysis (CFA) in the validation sample ( N = 629). The total scores of C-BSA were significantly correlated with that of CTQ, CAPE-p15, SDS, and SAS. Multivariate logistic regression revealed that bullying was associated with 2.0 or 3.7 times of risk for the presence of PLEs (numbers of bullying types < = 3 or > 3, respectively) after controlling for CTQ, SDS, and SAS scores., Conclusions: C-BSA has shown good psychometric properties in college students. The contribution of past bullying experiences to the present PLEs seems to be independent of other childhood trauma, current depression, and anxiety., 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 Zhao, Lu, Liu, Wang, Chen, Lin, Li, Zhou and Wang.)

Patients with immune-mediated inflammatory diseases (IMID) were seldom enrolled in the studies of SARS-CoV-2 vaccines, and real-world data regarding the immunogenicity of different types of vaccines is limited. We aimed to assess the immunogenicity and safety of three types of vaccines (AZD1222, mRNA-1273, and BNT162b2) in 253 patients with IMID and 30 healthcare workers (HCWs). Plasma levels of IgG-antibody against SARS-CoV-2 targeting the receptor-binding domain of spike protein (anti-S/RBD-IgG) were determined by chemiluminescent immunoassay 3-4 weeks after the first-dose and second-dose vaccination. The positive rate and titers of anti-S/RBD-IgG were significantly higher in mRNA-1273 or BNT162b2 than in the AZD1222 vaccine. Immunogenicity was augmented after the second dose of any vaccine type in all IMID patients, suggesting that these patients should complete the vaccination series. Anti-S/RBD-IgG titers after first-dose vaccination were significantly lower in RA patients than pSS patients, but there was no significant difference after second-dose vaccination among five groups of IMID patients. The positive rate and titers of anti-S/RBD-IgG were significantly lower in patients receiving abatacept/rituximab therapy than in those receiving other DMARDs. All three SARS-CoV-2 vaccines showed acceptable safety profiles, and the common AEs were injection site reactions. We identified SLE as a significant predictor of increased autoimmunity and would like to promote awareness of the possibility of autoimmunity following vaccination.

Background: Coronary perfusion pressure (CPP) and coronary artery stenosis are responsible for myocardial perfusion. However, how CPP-related survival outcome affects revascularization is unclear., Objective: The aim of this study is to investigate the prognostic role of CPP in patients with left ventricular systolic dysfunction (LVSD) undergoing percutaneous coronary intervention (PCI) with complete revascularization (CR) or reasonable incomplete revascularization (RIR)., Methods: We retrospectively screened 6,076 consecutive patients in a registry. The residual synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) score (rSS) was used to define CR (rSS = 0) and RIR (0 42 mmHg. Moreover, 101 pairs of RIR and CR were present in patients with CPP ≤ 42 mmHg. In patients with CPP > 42 mmHg, RIR was not significantly different from CR in long-term mortality [hazard ratio (HR) 1.20; 95% confidence interval (CI):0.70-2.07; p = 0.513]; However, in patients with CPP≤42 mmHg, RIR had a significantly higher mortality risk than CR (HR 2.39; 95% CI: 1.27-4.50; p = 0.007)., Conclusions: The CPP had a risk stratification role in selecting different revascularization strategies in patients with LVSD. When patients with LVSD had CPP > 42 mmHg, RIR was equivalent to CR in survival. However, when patients with LVSD had CPP ≤ 42 mmHg, RIR had a significantly higher mortality risk than CR., 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 Hsieh, Chen, Chen, Lee, Ho, Yeh, Huang, Lu, Chang, Wang, Chang and Hsieh.)

The singly Cabibbo-suppressed decay Λ&#95;{c}^{+}→nπ^{+} is observed for the first time with a statistical significance of 7.3σ by using 3.9  fb^{-1} of e^{+}e^{-} collision data collected at center-of-mass energies between 4.612 and 4.699 GeV with the BESIII detector at BEPCII. The branching fraction of Λ&#95;{c}^{+}→nπ^{+} is measured to be (6.6±1.2&#95;{stat}±0.4&#95;{syst})×10^{-4}. By taking the upper limit of branching fractions of Λ&#95;{c}^{+}→pπ^{0} from the Belle experiment, the ratio of branching fractions between Λ&#95;{c}^{+}→nπ^{+} and Λ&#95;{c}^{+}→pπ^{0} is calculated to be larger than 7.2 at the 90% confidence level, which disagrees with most predictions of the available phenomenological models. In addition, the branching fractions of the Cabibbo-favored decays Λ&#95;{c}^{+}→Λπ^{+} and Λ&#95;{c}^{+}→Σ^{0}π^{+} are measured to be (1.31±0.08&#95;{stat}±0.05&#95;{syst})×10^{-2} and (1.22±0.08&#95;{stat}±0.07&#95;{syst})×10^{-2}, respectively, which are consistent with previous results.

Background: Vaccination is one of the most important measures worldwide to halt the spread of the corona virus disease 2019 (COVID-19). However, the efficacy and safety of these vaccines in rheumatic patients are not well explored. Therefore, we conducted a systematic review and meta-analysis., Methods: We performed a literature search of the PubMed and EMBASE databases on 17 November 2021. Forty-seven studies relevant to the immunogenicity, efficacy/effectiveness, and safety of COVID-19 vaccines were selected., Results: Our results demonstrated that COVID-19 vaccination is effective in protecting rheumatic patients from severe illness caused by the virus. Both the humoral and cellular immunogenicity of vaccines were impaired in rheumatic patients, which were greatly enhanced after the second vaccine dose. Receiving anti-CD20 therapy was associated with impaired humoral immunogenicity. Adverse events due to COVID-19 vaccines in rheumatic patients were similar to those in healthy controls, except for an increased incidence of arthralgia. The incidence of disease flares after COVID-19 vaccination was low., Conclusion: Our systematic review indicated the importance of full vaccination in rheumatic patients. Withholding anti-CD20 therapy was found to be potentially beneficial for the immunogenicity. Furthermore, the vaccines were found to be safe in general. Despite significant heterogeneity between studies, we recommend that rheumatic patients receive these vaccines amidst the global pandemic.

Background: Autonomic nervous dysfunction is a shared clinical feature in Alzheimer's disease (AD) and heart failure (HF). Cholinesterase inhibitors (ChEIs) are widely used autonomic modulators in patients with AD, but their primary preventive benefit on new-onset HF is still uncertain., Objective: This study examined whether ChEIs have a primary preventive effect on new-onset HF in patients with AD., Methods: This propensity score matching (PSM) study was conducted using data from the National Health Insurance Research Database of Taiwan for 1995 to 2017. Certificated patients with AD and without a history of HF were divided into ChEI (donepezil, rivastigmine, or galantamine) users or nonusers. The primary endpoint was new-onset HF, and the secondary endpoints were myocardial infarction and cardiovascular death after 10-year follow-up., Results: After screening 16,042 patients, 7,411 patients were enrolled, of whom 668 were ChEI users and 1,336 were nonusers after 1:2 PSM. Compared with nonusers, ChEI users exhibited a significantly lower incidence of new-onset HF (HR 0.48; 95% CI 0.34-0.68, p < 0.001) and cardiovascular death (HR 0.55; 95% CI 0.37-0.82, p = 0.003) but not of myocardial infarction (HR 1.09; 95% CI 0.52-1.62, p = 0.821) after 10-year follow-up. The preventive benefit of ChEI use compared with Non-use (controls) was consistent across all exploratory subgroups without statistically significant treatment-by-subgroup interactions., Conclusions: Prescription of ChEIs may provide a preventive benefit associated with lower incidence of new-onset HF in patients with AD after 10-year follow-up., 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 Hsieh, Chen, Lee, Wu, Chen, Huang and Chang.)

Mutations in the gene encoding DNA methyltransferase 3A ( DNMT3A ) are the most common cause of clonal hematopoiesis and are among the most common initiating events of acute myeloid leukemia (AML). Studies in germline and somatic Dnmt3a knockout mice have identified focal, canonical hypomethylation phenotypes in hematopoietic cells; however, the kinetics of methylation loss following acquired DNMT3A inactivation in hematopoietic cells is essentially unknown. Therefore, we evaluated a somatic, inducible model of hematopoietic Dnmt3a loss, and show that inactivation of Dnmt3a in murine hematopoietic cells results in a relatively slow loss of methylation at canonical sites throughout the genome; in contrast, remethylation of Dnmt3a deficient genomes in hematopoietic cells occurs much more quickly. This data suggests that slow methylation loss may contribute, at least in part, to the long latent period that characterizes clonal expansion and leukemia development in individuals with acquired DNMT3A mutations in hematopoietic stem cells., Competing Interests: A.M.S. is an employee of Incyte Corporation, A.M.V. is an employee of Vitalant Corporation, and E.R.L. is the owner of Leight Medical Communications, LLC. All studies in the manuscript were performed before the authors joined these companies. The other authors declare no competing interests., (© 2022 The Authors.)

Objectives: To determine the bidirectional relationship between macrophage activation syndrome (MAS) and SLE., Methods: Using the 1997-2013 Taiwan National Health Insurance Research Database, we identified patients with newly diagnosed SLE from 2001 to 2013 and selected individuals without SLE from a 1 million representative population. Propensity score (PS) matching was performed to balance incident SLE patients and individuals without SLE according to age, sex, comorbidities and medical utilization. The association between a history of MAS and SLE was studied using conditional logistic regression analysis shown as an adjusted odds ratio (aOR). The risk of MAS associated with SLE was analysed using Cox proportional regression analysis, shown as an adjusted hazard ratio (aHR), and we conducted a sensitivity analysis using various definitions of MAS., Results: We included 10 481 SLE patients and 20 962 PS-matched (1:2) non-SLE individuals. The correlation between a history of MAS and SLE did not reach statistical significance after adjustment for potential confounders [aOR 1.18 (95% CI, 0.80, 1.75)] in the age-/sex-matched populations. In the 1:2 PS-matched populations, the risk of MAS markedly increased in patients with SLE [aHR 7.18 (95% CI 4.97, 10.36)]. Other risk factors for MAS included female gender, age ≥65 years, low income, a history of inflammatory bowel disease and a history of MAS., Conclusion: This nationwide, population-based study revealed that a history of MAS was not significantly associated with SLE risk. However, the risk of MAS was markedly associated with SLE and a history of MAS., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Molecular self-assembly is widely used in the fields of biosensors, molecular devices, efficient catalytic materials, and medical biomaterials. As the carrier of genetic information, DNA is a kind of biomacromolecule composed of deoxyribonucleotide units. DNA nanotechnology extends DNA of its original properties as a molecule that stores and transmits genetic information from its biological environment by taking advantage of its unique base pairing and inherent biocompatibility to produce structurally-defined supramolecular structures. With the continuously development of DNA technology, the assembly method of DNA nanostructures is not only limited on the basis of DNA hybridization but also other biochemical interactions. In this review, we summarize the latest methods used to construct higher-order DNA structures. The problems of DNA nanostructures are discussed and the future directions in this field are provided., (© 2022 Wiley-VCH GmbH.)

Aim: Results from various studies are controversial regarding long-term hepatic effects of tumor necrosis factor (TNF)-α inhibitors. Here we aimed to investigate the development of liver cirrhosis with TNF-α inhibitors use in patients with rheumatoid arthritis (RA)., Method: This nested case-control study was based on the National Health Insurance Research Database (January 1, 2000 to December 31, 2008) of Taiwan. We identified 559 adult RA patients who developed liver cirrhosis, and 1055 matched control RA patients. TNF-α inhibitors of interest in the study period included adalimumab and etanercept. Multivariate logistic regression analysis for the development of liver cirrhosis with respect to use of TNF-α inhibitors was performed., Results: The incidence rate of liver cirrhosis was 274 per 100 000 person-years in newly diagnosed RA patients. We found the use of TNF-α inhibitors was not associated with the development of liver cirrhosis in RA patients (odds ratio 1.02, 95% confidence interval 0.61, 1.70) after adjustment for potential confounders. In addition, the finding was robust to an unobserved confounder., Conclusion: We found no association between the use of TNF-α inhibitors and development of liver cirrhosis in RA patients., (© 2022 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

MicroRNAs (miRNAs) are a class of small, endogenous, noncoding RNAs. Recent research has proven that miRNAs play an essential role in the occurrence and development of ischemic stroke. Our previous studies confirmed that 20(R)-ginsenosideRg3 [20(R)-Rg3] exerts beneficial effects on cerebral ischemia-reperfusion injury (CIRI), but its molecular mechanism has not been elucidated. In this study, we used high-throughput sequencing to investigate the differentially expressed miRNA and mRNA expression profiles of 20(R)-Rg3 preconditioning to ameliorate CIRI injury in rats and to reveal its potential neuroprotective molecular mechanism. The results show that 20(R)-Rg3 alleviated neurobehavioral dysfunction in MCAO/R-treated rats. Among these mRNAs, 953 mRNAs were significantly upregulated and 2602 mRNAs were downregulated in the model group versus the sham group, whereas 437 mRNAs were significantly upregulated and 35 mRNAs were downregulated in the 20(R)-Rg3 group in contrast with those in the model group. Meanwhile, the expression profile of the miRNAs showed that a total of 283 differentially expressed miRNAs were identified, of which 142 miRNAs were significantly upregulated and 141 miRNAs were downregulated in the model group compared with the sham group, whereas 34 miRNAs were differentially expressed in the 20(R)-Rg3 treatment group compared with the model group, with 28 miRNAs being significantly upregulated and six miRNAs being significantly downregulated. Furthermore, 415 (391 upregulated and 24 downregulated) differentially expressed mRNAs and 22 (17 upregulated and 5 downregulated) differentially expressed miRNAs were identified to be related to 20(R)-Rg3's neuroprotective effect on stroke recovery. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that 20(R)-Rg3 could modulate multiple signaling pathways related to these differential miRNAs, such as the cGMP-PKG, cAMP and MAPK signaling pathways. This study provides new insights into the protective mechanism of 20(R)-Rg3 against CIRI, and the mechanism may be partly associated with the regulation of brain miRNA expression and its target signaling pathways.

No study has evaluated the effect of dexmedetomidine in patients who received surgery for type A aortic dissection. This is the first study to evaluate the effect of dexmedetomidine in aortic dissection patients. This study was executed using data from the Chang Gung Research Database in Taiwan. The CGRD contains the multi-institutional standardized electronic medical records from seven Chang Gung Memorial hospitals, the largest medical system in Taiwan. We retrospectively evaluate patients who received surgery for acute type A aortic dissection between January 2014 and December 2018. Overall, 511 patients were included, of whom 104 has received dexmedetomidine infusion in the postoperative period. One-to-two propensity score-matching yielded 86 cases in the dexmedetomidine group and 158 cases in the non-dexmedetomidine group. The in-hospital mortality and composite outcome including all-cause mortality, acute kidney injury, delirium, postoperative atrial fibrillation, and respiratory failure, were considered primary outcomes. The in-hospital mortality and composite outcome were similar between groups. The risk of Acute Kidney Injury Network stage 3 acute kidney injury was significantly lower in the dexmedetomidine group than in the non-dexmedetomidine group (8.1% vs 19.0%; OR, 0.38; 95% CI, 0.17-0.86; p = 0.020. The risk of newly-onset dialysis was also significantly lower in the dexmedetomidine group than in the non-dexmedetomidine group (4.7% vs 13.3%; OR, 0.32; 95% CI, 0.11-0.90; p = 0.031). Post-operative dexmedetomidine infusion significantly reduced the rate of severe acute kidney injury and newly-onset dialysis in patients who received surgery for acute type A aortic dissection., (© 2022. The Author(s).)

Based on electron-positron collision data collected with the BESIII detector operating at the Beijing Electron-Positron Collider II storage rings, the value of R≡σ(e^{+}e^{-}→hadrons)/σ(e^{+}e^{-}→μ^{+}μ^{-}) is measured at 14 center-of-mass energies from 2.2324 to 3.6710 GeV. The resulting uncertainties are less than 3.0% and are dominated by systematic uncertainties.

This paper proposed the forecasting model of Influenza-like Illness (ILI) and respiratory disease. The dataset was extracted from the Taiwan Environmental Protection Administration (EPA) for air pollutants data and the Centers for Disease Control (CDC) for disease cases from 2009 to 2018. First, this paper applied the ARIMA method, which trained based on the weekly number of disease cases in time series. Second, we implemented the Long short-term memory (LSTM) method, which trained based on the correlation between the weekly number of diseases and air pollutants. The models were also trained and evaluated based on five and ten years of historical data. Autoregressive integrated moving average (ARIMA) has an excellent model in the five-year dataset of ILI at 2564.9 compared to ten years at 8173.6 of RMSE value. This accuracy is similar to the Respiratory dataset, which gets 15,656.7 in the five-year dataset and 22,680.4 of RMSE value in the ten-year dataset. On the contrary, LSTM has better accuracy in the ten-year dataset than the five-year dataset. For example, on average of RMSE in the ILI dataset, LSTM has 720.2 RMSE value in five years and 517.0 in ten years dataset. Also, in the Respiratory disease dataset, LSTM gets 4768.6 of five years of data and 3254.3 of the ten-year dataset. These experiments revealed that the LSTM model generally outperforms ARIMA by three to seven times higher model performance.

Objectives: Outcomes of sex differences in major cardiac surgery remain controversial. A comprehensive understanding of sex differences in major adult cardiac surgery could provide better knowledge of risk factors, management strategy and short-term or long-term outcomes. The present study aimed to investigate sex differences in the risks of outcomes of major cardiac surgeries and subgroup analyses of different valve types., Design: Population-based nationwide cohort study., Setting: Data were obtained from National Health Insurance Research Database (NHIRD) in Taiwan., Participants: A total of 66 326 adult patients (age ≥20 years; 30.3% women) who underwent a first major cardiac surgery (isolated coronary artery bypass graft (CABG), isolated valve or concomitant bypass/valve) from 2000 to 2013 were identified via Taiwan NHIRD., Main Outcome Measures: Outcomes of primary interest were in-hospital death and all-cause mortality during follow-up period. Propensity score matching was conducted as a secondary analysis for the sensitivity test., Results: Women who underwent isolated CABG tended to have greater risks of both in-hospital (OR 1.37; 95% CI 1.26 to 1.49) and late outcomes (HR 1.26; 95% CI 1.22 to 1.31). Women after concomitant CABG/valve also had a greater in-hospital (OR 1.19; 95% CI 1.01 to 1.40) and long-term mortality (HR 1.14; 95% CI 1.05 to 1.24). Women after isolated mitral valve repair have a non-favourable outcome of in-hospital mortality (OR 1.70; 95% CI 1.01 to 2.87). Women who did not receive an isolated aortic valve replacement had more favourable all-cause mortality outcome (HR 0.90; 95% CI 0.84 to 0.96). Secondary analysis in the propensity score-matching cohort demonstrated results similar to the primary analysis., Conclusions: Female patients who underwent procedures involving CABG (with or without concurrent valvular intervention) had generally worse outcomes. However, the results of isolated valve surgery were variable on the basis of the type of intervened valve., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Severe immune-related adverse events (irAEs) occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). However, it is unknown whether a common baseline immunological state precedes irAE development. Here we applied mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing and bulk T cell receptor (TCR) sequencing to study peripheral blood samples from patients with melanoma treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination ICIs. By analyzing 93 pre- and early on-ICI blood samples and 3 patient cohorts (n = 27, 26 and 18), we found that 2 pretreatment factors in circulation-activated CD4 memory T cell abundance and TCR diversity-are associated with severe irAE development regardless of organ system involvement. We also explored on-treatment changes in TCR clonality among patients receiving combination therapy and linked our findings to the severity and timing of irAE onset. These results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder with clinical heterogeneity. Although tocilizumab (TCZ), an interleukin (IL)-6 receptor inhibitor, is an effective treatment for AOSD, the evidence regarding its efficacy on systemic or articular subtypes is conflicting. Furthermore, the predictors of therapeutic response are still elusive and worthy of exploration., Methods: This two-center retrospective study analyzed the effectiveness and safety profile of TCZ treatment in 28 patients with refractory AOSD. The 28-joint disease activity score (DAS28) and systemic activity score were assessed before and during TCZ treatment period at weeks 12, 24, 36, and 48. Plasma levels of proinflammatory cytokines at baseline were determined using ELISA method., Results: Among the systemic subtype patients, 10 (58.8%), 13 (76.5%), 14 (82.4%), and 15 (88.2%) patients achieved complete remission at week 12, 24, 36, and 48, respectively, in comparison to 2 (22.2%), 5 (55.6%), 6 (66.7%), and 7 (77.8%) who achieved disease remission (DAS28 < 2.6) at weeks 12, 24, 36, and 48, respectively, among articular subtype patients. The systemic activity scores and inflammatory parameters were significantly decreased after 12-week TCZ therapy, and TCZ could significantly reduce corticosteroid dose in AOSD patients. Multivariate analysis reveals that baseline IL-18 level is a significant predictor of poor therapeutic response at week 24 (odds ratio 7.86, p < 0.05)., Conclusion: AOSD patients refractory to high-dose corticosteroids and methotrexate may respond well to TCZ treatment with a steroid-sparing effect and an acceptable safety. A high baseline IL-18 level may be a predictor of poor therapeutic response. Key Points • Tocilizumab may be effective and well-tolerated in refractory AOSD patients regardless of disease subtypes. • High plasma levels of IL-18 may predict poor response to tocilizumab in AOSD patients., (© 2021. International League of Associations for Rheumatology (ILAR).)

Importance: Current international normalized ratio (INR) guidelines are based on trials involving European and US populations. To our knowledge, no adequate study involving Asian patients has been conducted to date., Objective: To evaluate the association between INR and anticoagulation-related outcomes in an Asian population after mechanical aortic valve replacement (AVR) or mitral VR (MVR)., Design, Setting, and Participants: This retrospective cohort study was conducted between 2001 and 2018, with follow-up until December 31, 2018, among patients who underwent AVR, MVR, or combined AVR-MVR at 3 medical centers and 4 regional hospitals and contributed electronic medical records to the Chang Gung Research Database. Exclusion criteria were missing demographic characteristics, younger than 20 years, fewer than 2 INR records, and having died during the hospitalization of the index surgery., Main Outcomes and Measures: Bleeding and thromboembolic complications were analyzed. The possibility of nonlinearity and cutoff potential for the INR were explored using a logistic regression model, which considered the INR a restricted cubic spline (RCS) variable., Results: The study population consisted of 900 patients, with 525 (58.3%) men and 375 (41.7%) women and a mean (SD) age of 52.0 (12.5) years. Overall, 474 (52.7%) received AVR alone, 329 (36.6%) received MVR alone, and 97 (10.8%) received combined AVR-MVR. All patients had at least 2 INR examinations after discharge, providing 16 676 INR records for the AVR group and 18 207 for the MVR and combined AVR-MVR groups. In the AVR group, the RCS model showed that higher risks of composite thromboembolic events were associated with an INR of less than 2.0 or greater than 2.6 vs an INR of 2.0, and a higher risk of bleeding events was associated with an INR of less than 1.8 or greater than 2.4 vs an INR of 2.0. When treating the INR as a categorical variable, the risk of composite thromboembolic and composite bleeding events was significantly higher among patients with INRs less than 1.5 (adjusted odds ratio [aOR], 2.55; 95% CI, 1.37-4.73) and with INRs of 3.0 or greater (aOR, 3.48; 95% CI, 1.95-6.23) vs those with INRs between 2.0 and 2.5.In the MVR and combined AVR-MVR groups, higher risks of composite thromboembolic events were associated with an INR of less than 2.1 or greater than 2.7 vs an INR of 2.5, and a higher risk of bleeding events was associated with an INR of less than 2.1 or greater than 2.8 vs an INR of 2.5. When treating the INR as a categorical variable, the risk of a composite bleeding events was significantly higher among patients with INRs of 3.5 or greater (aOR, 2.25; 95% CI, 1.35-3.76) vs those with INRs between 2.5 and 3.0., Conclusions and Relevance: Among Asian patients in this study, the incidence of thromboembolic events in the MVR group with INRs in the range of 2.0 to 2.5 was not significantly higher than that among those with INRs in the range of 2.5 to 3.0; in the AVR group, the incidence for those with INRs in 1.5 to 2.0 range was not significantly higher than for those with INRs in the range of 2.0 to 2.5.

Developing on-site earthquake early warning systems has been a challenging problem because of time limitations and the amount of information that can be collected before the warning needs to be issued. A potential solution that could prevent severe disasters is to predict the potential strong motion using the initial P-wave signal and provide warnings before serious ground shaking starts. In practice, the accuracy of prediction is the most critical issue for earthquake early warning systems. Traditional methods use certain criteria, selected through intuition or experience, to make the prediction. However, the criteria thresholds are difficult to select and may significantly affect the prediction accuracy. This paper investigates methods based on artificial intelligence for predicting the greatest earthquake ground motion early, when the P-wave arrives at seismograph stations. A neural network model is built to make the predictions using a small window of the initial P-wave acceleration signal. The model is trained by seismic waves collected from 1991 to 2019 in Taiwan and is evaluated by events in 2020 and 2021. From these evaluations, the proposed scheme significantly outperforms the threshold-based method in terms of its accuracy and average leading time.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in more than 235 million cases worldwide and 4.8 million deaths (October 2021), with various incidences and mortalities among regions/ethnicities. The coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize the angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells. We hypothesized that the genetic variability in ACE2 may contribute to the variable clinical outcomes of COVID-19. To test this hypothesis, we first conducted an in silico investigation of single-nucleotide polymorphisms (SNPs) in the coding region of ACE2. We then applied an integrated approach of genetics, biochemistry, and virology to explore the capacity of select ACE2 variants to bind coronavirus spike proteins and mediate viral entry. We identified the ACE2 D355N variant that restricts the spike protein-ACE2 interaction and consequently limits infection both in vitro and in vivo . In conclusion, ACE2 polymorphisms could modulate susceptibility to SARS-CoV-2, which may lead to variable disease severity. IMPORTANCE There is considerable variation in disease severity among patients infected with SARS-CoV-2, the virus that causes COVID-19. Human genetic variation can affect disease outcome, and the coronaviruses SARS-CoV, SARS-CoV-2, and HCoV-NL63 utilize human ACE2 as the receptor to enter cells. We found that several missense ACE2 single-nucleotide variants (SNVs) that showed significantly altered binding with the spike proteins of SARS-CoV, SARS-CoV-2, and NL63-HCoV. We identified an ACE2 SNP, D355N, that restricts the spike protein-ACE2 interaction and consequently has the potential to protect individuals against SARS-CoV-2 infection. Our study highlights that ACE2 polymorphisms could impact human susceptibility to SARS-CoV-2, which may contribute to ethnic and geographical differences in SARS-CoV-2 spread and pathogenicity.

Background: Rheumatoid arthritis (RA)-related comorbidities, including cardiovascular disease (CVD), osteoporosis (OP), and interstitial lung disease (ILD), are sub-optimally managed. RA-related comorbidities affect disease control and lead to impairment in quality of life. We aimed to develop consensus recommendations for managing RA-related comorbidities., Methods: The consensus statements were formulated based on emerging evidence during a face-to-face meeting of Taiwan rheumatology experts and modified through three-round Delphi exercises. The quality of evidence and strength of recommendation of each statement were graded after a literature review, followed by voting for agreement. Through a review of English-language literature, we focused on the existing evidence of management of RA-related comorbidities., Results: Based on experts' consensus, eleven recommendations were developed. CVD risk should be assessed in patients at RA diagnosis, once every 5 years, and at changes in DMARDs therapy. Considering the detrimental effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on CVD risks, we recommend using the lowest possible dose of corticosteroids and prescribing NSAIDs cautiously. The OP/fragility fracture risk assessment includes dual-energy X-ray absorptiometry and fracture risk assessment (FRAX) in RA. The FRAX-based approach with intervention threshold is a useful strategy for managing OP. RA-ILD assessment includes risk factors, pulmonary function tests, HRCT imaging and a multidisciplinary decision approach to determine RA-ILD severity. A treat-to-target strategy would limit RA-related comorbidities., Conclusions: These consensus statements emphasize that adequate control of disease activity and the risk factors are needed for managing RA-related comorbidities, and may provide useful recommendations for rheumatologists on managing RA-related comorbidities., Competing Interests: The authors have no conflicts of interests to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Using a data sample corresponding to an integrated luminosity of 2.93  fb^{-1} collected at a center-of-mass energy sqrt[s]=3.773  GeV by the BESIII detector, the decay D^{0}→ωϕ is observed for the first time. The branching fraction is measured to be (6.48±0.96±0.40)×10^{-4} with a significance of 6.3σ, where the first and second uncertainties are statistical and systematic, respectively. An angular analysis reveals that the ϕ and ω mesons from the D^{0}→ωϕ decay are transversely polarized. The 95% confidence level upper limit on longitudinal polarization fraction is set to be less than 0.24, which is inconsistent with current theoretical expectations and challenges our understanding of the underlying dynamics in charm meson decays.

Background: Poststroke cognitive impairment (PSCI) is a prevalent cause of disability in people with stroke. PSCI results from either lesion-dependent loss of cognitive function or augmentation of Alzheimer's pathology due to vascular insufficiency. The lack of prestroke cognitive assessments limits the clear understanding of the impact of PSCI on cognition., Objective: The present study aims to make a direct comparison of longitudinal cognitive assessment results to clarify the impact of ischemic stroke on PSCI and assess the cognitive decline in PSCI compared to people with Alzheimer's disease (AD)., Methods: All study participants had their Mini-Mental State Examination (MMSE) at the chronic poststroke stage (≥6 months after stroke), which was compared with prestroke or acute poststroke (<6 months after stroke) MMSE to investigate the two aspects of PSCI. A group of patients with AD was used to reference the speed of neurodegenerative cognitive deterioration. Repeated measures analysis of variance was used to compare the longitudinal change of MMSE., Results: MMSE score between acute and chronic poststroke revealed a 1.8 ± 6.49 decline per year (n=76), which was not significantly different from the AD patients who underwent cholinesterase inhibitors treatment (-1.11 ± 2.61, p=0.35, n=232). MMSE score between prestroke and chronic poststroke (n=33) revealed a significant decline (-6.52 ± 6.86, p < 0.001). In addition, their cognitive deterioration was significantly associated with sex, age, and stroke over the white matter or basal ganglia., Conclusion: Ischemic stroke substantially affects cognition with an average six-point drop in MMSE. The rate of cognitive decline in PSCI was similar to AD, and those with white matter or basal ganglia infarct were at greater risk of PSCI., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)