Search

Hou-Hsun Liao,1– 3 Hsiao-Tien Chen,4 Hanoch Livneh,5 Hua-Lung Huang,6 Ning-Sheng Lai,7,8 Ming-Chi Lu,7,8 Chia-Chou Yeh,1,2,9 Tzung-Yi Tsai3,10,11 1Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 2Department of Chinese Medicine, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan; 3Department of Nursing, Tzu Chi University of Science and Technology, Hualien, Taiwan; 4Department of Chinese Medicine, Chi Mei Medical Center, Tainan, Taiwan; 5Rehabilitation Counseling Program, Portland State University, Portland, OR, USA; 6Department of Rehabilitation, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan; 7School of Medicine, Tzu Chi University, Hualien, Taiwan; 8Division of Allergy, Immunology and Rheumatology, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, Taiwan; 9School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; 10Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan; 11Department of Medical Research, Dalin Tzuchi Hospital, The Buddhist Tzuchi Medical Foundation, Chiayi, TaiwanCorrespondence: Chia-Chou Yeh; Tzung-Yi Tsai, Tel +886-5-2648000-8713 ; +886-5-2648000 ext. 3209, Fax +886-5-2648006, Email yehcc0530@gmail.com; dm732024@tzuchi.com.twObjective: Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as the first-line agents for the symptomatic relief of rheumatoid arthritis (RA), but it may insidiously provoke the onset of renal diseases, especially chronic kidney disease (CKD). While Chinese herbal medicine (CHM) has become an increasingly popular adjunctive therapy among RA groups, there are currently no available data on the effect of CHM use towards risk of CKD. This study aimed to explore on a population-level whether CHM use decreases sequent CKD risk among them.Methods: In this nested case–control study retrieved from the nationwide insurance database of Taiwan from 2000 to 2012, we looked at the association between CHM use and the likelihood of developing CKD, with a focus on usage intensity. Cases with CKD claims were defined and matched to one randomly selected control case. Conditional logistic regression was then applied to estimate odds ratio (OR) of CKD from CHM treatment measured before the index date. For each OR, we calculated a 95% confidence interval for CHM use relative to the matched control.Results: This nested case–control study included 5464 patients with RA, where after matching comprised 2712 cases and 2712 controls. Among them, there were 706 and 1199 cases that ever received CHM treatment, respectively. After the adjustment, CHM use in RA individuals was related to a lower likelihood of CKD, with an adjusted OR of 0.49 (95% CI: 0.44– 0.56). Additionally, a dose-dependent, reverse association was found between the cumulative duration of CHM use and risk of CKD.Conclusion: Integrating CHM into conventional therapy may reduce the likelihood of developing CKD, which could be a reference in instituting novel preventive strategies to improve treatment outcomes and reduce related fatalities for RA subjects.Keywords: rheumatoid arthritis, chronic kidney disease, Chinese herbal medicine, nested case–control study

Hou-Hsun Liao,1– 3 Hanoch Livneh,4 Yu-Jung Chung,1 Ching-Hsing Lin,5,6 Ning-Sheng Lai,6,7 Hung-Rong Yen,2,8– 11 Tzung-Yi Tsai3,12,13 1Department of Chinese Medicine, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Dalin Township, Chiayi, 62247, Taiwan; 2Graduate Institute of Chinese Medicine, School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan; 3Department of Nursing, Tzu Chi University of Science and Technology, Hualien, 62247, Taiwan; 4Rehabilitation Counseling Program, Portland State University, Portland, OR, 97207-0751, USA; 5Department of Orthopedics, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan; 6School of Medicine, Tzu Chi University, Hualien, 97004, Taiwan; 7Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, Taiwan; 8Department of Chinese Medicine, China Medical University Hospital, Taichung, 404, Taiwan; 9Research Center for Traditional Chinese Medicine, Department of Medical Research, China Medical University Hospital, Taichung, 404, Taiwan; 10Chinese Medicine Research Center, China Medical University, Taichung, 404, Taiwan; 11Department of Biotechnology, Asia University, Taichung, 413, Taiwan; 12Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan, 70428, Taiwan; 13Department of Medical Research, Dalin Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, Chiayi, 62247, TaiwanCorrespondence: Hung-Rong Yen; Tzung-Yi Tsai Tel +886-4-22053366-3313; +886-5-2648000-3209Fax +886-4-22037690; +886-5-2648006Email hungrongyen@gmail.com; dm732024@tzuchi.com.twObjective: Patients with rheumatoid arthritis (RA) often suffer from bone complications due to persistent joint inflammation, especially incident fracture. Nowadays, Chinese herbal medicines (CHMs) have provided safe and effective therapy for treating skeletal conditions, but it is unclear whether CHMs can prevent fracture onset among RA individuals. This study aimed to determine the association between the use of CHMs and the risk of fracture among them.Methods: This retrospective, population-based study retrieved administrative health data from the Taiwan National Health Insurance (NHI) database to identify patients with newly diagnosed RA between 2000 and 2009. Of the 6178 incident RA patients, 2495 matched pairs of CHMs users and non-CHMs users were identified by propensity score matching. Enrollees with hip fractures prior to RA onset were excluded. Included subjects were followed until the end of 2013. Incidence and adjusted hazard ratios (HR) of new-onset bone fracture in the multivariable Cox proportional hazard model were measured with 95% confidence interval (CI).Results: Fracture incidence was lower in CHMs users than in the comparison cohort (26.91 vs 32.94 per 1000 person-years, respectively), with an adjusted HR of 0.82 (95% CI: 0.73– 0.92). Subjects receiving CHMs for more than 2 years had a much lower risk of fracture onset by more than 50%. Some CHMs prescriptions (Yan Hu Suo, Bei Mu, Da Huang, Dang Shen, Fu-Zi, Shu-Jing-Huo-Xue-Tang, Dang-Gui-Nian-Tong-Tang, Jia-Wei-Xiao-Yao-San, Gan-Lu-Yin, and Gui-Zhi-Shao-Yao-Zhi-Mu-Tang) were associated with reduced fracture risk.Conclusion: Adding CHMs to routine treatment was found to be related to lower fracture risk in RA patients.Keywords: rheumatoid arthritis, fracture, Chinese herbal medicines, risk

The androgen receptor signaling inhibitor (ARSI) enzalutamide (Enz) has shown critical efficacy in the treatment of advanced prostate cancer (PCa). However, the development of drug resistance is a significant factor contributing to mortality in PCa patients. We aimed to explore the key mechanisms of Enz-resistance. Through analysis of GEO databases, we identified SLC4A4 as a novel driver in Enz resistance. Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-κB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo. Hence, our results suggest that targeting SLC4A4 could be a promising therapeutic strategy for Enz resistance. STATEMENT OF SIGNIFICANCE: SLC4A4 is a novel driver of enzalutamide resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Hearing loss is a frequently observed comorbidity in patients with nasopharyngeal carcinoma (NPC). Accumulating evidence demonstrated that acupuncture can safely manage cancer and its treatment-related symptoms, but its effect in minimizing the likelihood of experiencing sudden sensorineural hearing loss (SSHL) has not been established. So this work aimed to determine the risk of SSHL among NPC persons with or without acupuncture use., Methods: One population-level, nested case-control design within a cohort study is employed. Relevant information on persons aged 20-80 years who were afflicted with NPC between 2000 and 2010 was extracted from a nationwide health claims database. From them, we identified the cases who had the first SSHL diagnosis occurring after NPC, and all of them were randomly matched to two controls without SSHL. Conditional logistic regression was employed to calculate odds ratios (OR) and its respective 95% confidence intervals (CI) for incident SSHL in relation to acupuncture treatment., Results: Eight hundred eleven SSHL cases were randomly matched to 1452 controls. Those receiving conventional care plus acupuncture use had a reduced adjusted OR of 0.39 (95% CI, 0.25-0.60) for SSHL. We further discovered that the longer usage of acupuncture remarkably correlated with reduction of SSHL risk in a dose-dependent manner., Conclusions: Delineation of the benefit from integration of acupuncture into conventional care may be a reference in instituting more appropriate care for NPC subjects., Implications for Cancer Survivors: Patients living with NPC may benefit from a timely integration of acupuncture into routine care to lessen SSHL risk., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Histidine triad nucleotide-binding protein 2 (HINT2) is an enzyme found in mitochondria that functions as a nucleotide hydrolase and transferase. Prior studies have demonstrated that HINT2 plays a crucial role in ischemic heart disease, but its importance in cardiac remodelling remains unknown. Therefore, the current study intends to determine the role of HINT2 in cardiac remodelling. HINT2 expression levels were found to be lower in failing hearts and hypertrophy cardiomyocytes. The mice that overexpressed HINT2 exhibited reduced myocyte hypertrophy and cardiac dysfunction in response to stress. In contrast, the deficiency of HINT2 in the heart of mice resulted in a worsening hypertrophic phenotype. Further analysis indicated that upregulated genes were predominantly associated with the oxidative phosphorylation and mitochondrial complex I pathways in HINT2-overexpressed mice after aortic banding (AB) treatment. This suggests that HINT2 increases the expression of NADH dehydrogenase (ubiquinone) flavoprotein (NDUF) genes. In cellular studies, rotenone was used to disrupt mitochondrial complex I, and the protective effect of HINT2 overexpression was nullified. Lastly, we predicted that thyroid hormone receptor beta might regulate HINT2 transcriptional activity. To conclusion, the current study showcased that HINT2 alleviates pressure overload-induced cardiac remodelling by influencing the activity and assembly of mitochondrial complex I. Thus, targeting HINT2 could be a novel therapeutic strategy for reducing cardiac remodelling., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

A mild, facile, and metal-free approach via the N -heterocyclic carbene-catalyzed S N Ar reaction between aryl aldehydes with perfluoroarenes to obtain the coveted functional perfluorinated diarylmethanones is disclosed. This method accommodates a diverse substrate range and exhibits notable tolerance toward various functional groups. Our success in modifying biologically relevant molecules, crafting a fully fluorinated bioisosteric analogue of drug candidate D1 , and highlighting the potential of these ketones as valuable electrolyte additives for lithium-ion batteries (LIBs) underscores the versatility of our methodology.

Objective: To demonstrate that acupuncture is beneficial for decreasing the risk of ischaemic stroke in patients with rheumatoid arthritis (RA)., Design: A propensity score-matched cohort study., Setting: A nationwide population-based study., Participants: Patients with RA diagnosed between 1 January 1997 and 31 December 2010, through the National Health Insurance Research Database in Taiwan., Interventions: Patients who were administered acupuncture therapy from the initial date of RA diagnosis to 31 December 2010 were included in the acupuncture cohort. Patients who did not receive acupuncture treatment during the same time interval constituted the no-acupuncture cohort., Primary Outcome Measures: A Cox regression model was used to adjust for age, sex, comorbidities, and types of drugs used. We compared the subhazard ratios (SHRs) of ischaemic stroke between these two cohorts through competing-risks regression models., Results: After 1:1 propensity score matching, a total of 23 226 patients with newly diagnosed RA were equally subgrouped into acupuncture cohort or no-acupuncture cohort according to their use of acupuncture. The basic characteristics of these patients were similar. A lower cumulative incidence of ischaemic stroke was found in the acupuncture cohort (log-rank test, p<0.001; immortal time (period from initial diagnosis of RA to index date) 1065 days; mean number of acupuncture visits 9.83. In the end, 341 patients in the acupuncture cohort (5.95 per 1000 person-years) and 605 patients in the no-acupuncture cohort (12.4 per 1000 person-years) experienced ischaemic stroke (adjusted SHR 0.57, 95% CI 0.50 to 0.65). The advantage of lowering ischaemic stroke incidence through acupuncture therapy in RA patients was independent of sex, age, types of drugs used, and comorbidities., Conclusions: This study showed the beneficial effect of acupuncture in reducing the incidence of ischaemic stroke in patients with RA., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Dihydroquinazolinone (DHQZ) has recently been harnessed as a ketone-derived pro-aromatic reagent extensively employed in (metalla)photoredox reactions as versatile group transfer agents. In this work, we outline a column chromatography-free protocol for the multigram-scale synthesis of pro-aromatic DHQZs as well as its use in a gram-scale nickel/photoredox dual-catalyzed cross-coupling in single-batch, photoflow, and simultaneous multiple smaller batches. While the single-batch approach leveraged moderate yields, a simple plug-flow photoreactor also exhibited amenable productivity (up to 45 % yield) despite the use of a heterogeneous base. Meanwhile, performing the metallaphotoredox-catalyzed reaction in multiple smaller batches in an improvised photoreactor facilitated high yields of up to 59 % and good reproducibility, implying a convenient alternative in the absence of photoflow setups., (© 2023 Wiley-VCH GmbH.)

Parapharyngeal infection is a well-known disease of otorhinolaryngologists. Rapid onset, short duration, severe symptoms, and manifestations such as sore throat and dysphagia are common characteristics treated primarily by surgical incision and drainage. Traditional surgical approaches encompass endoscopic transoral/nasal, transparotid, transcervical, or a combination thereof. We report a novel technique of nasal endoscopic incision and drainage transnasal retropterygoid approach to an upper parapharyngeal abscess. This report presents a case of a 14-year-old man presented with severe right neck and head pain, who was found to have an upper parapharyngeal abscess during a nasal endoscopic parapharyngeal exploration via a retropterygoid approach. The intraoperative frozen section revealed chronic mucosal inflammation and mild to moderate dysplasia of the squamous epithelium, but no carcinoma., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Dementia is a prevalent condition in type 2 diabetes mellitus (T2DM) patients. While Chinese herbal medicine (CHM) is often employed as complementary therapy for glycemic control, its effect in controlling likelihood of dementia has not yet been fully elucidated., Aim: To compare the risk of dementia between T2DM patients with and without CHM treatment., Methods: We undertook a nested case-control study and obtained data on patients 20-70 years of age who received medical care for T2DM between 2001 and 2010 from the National Health Insurance Research database in Taiwan. Cases, defined as those with dementia that occurred at least one year after the diagnosis of T2DM, were randomly matched to controls without dementia from the study cohort at a 1:1 ratio. We applied conditional logistic regression to explore the associations between CHM treatment and dementia., Results: A total of 11699 dementia cases were matched to 11699 non-dementia controls. We found that adding CHM to conventional care was related to a lower risk of dementia [adjusted odds ratio (OR) = 0.51], and high-intensity CHM treatment was associated with an adjusted OR of 0.22., Conclusion: This study shows that the cumulative CHM exposure was inversely associated with dementia risk in an exposure-response manner, implying that CHM treatment may be embraced as a disease management approach for diabetic patients to prevent dementia., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: The early detection of clinically significant prostate cancer (csPCa) through the integration of multidimensional parameters presents a promising avenue for improving survival outcomes for this fatal disease. This study aimed to assess the contribution of prostate transition zone (TZ) to predictive models based on the prostate health index (PHI), with the goal of enhancing early detection of csPCa in the prostate-specific antigen (PSA) gray zone., Methods: In this observational cross-sectional study, a total of 177 PSA gray zone patients (total prostate-specific antigen [tPSA] level ranging from 4.0 to 10.0 ng/mL) were recruited and received PHI detections from August 2020 to March 2022. Prostatic morphologies especially the TZ morphological parameters were measured by transrectal ultrasound (TRUS)., Results: Univariable logistic regression indicated prostatic morphological parameters including total prostate volume (PV) indexes and transitional zone volume indexes were all associated with csPCa ( P  < .05), while the multivariable analysis demonstrated that C-reactive protein (CRP), PHI, PHI density (PHID), and PHI transition zone density (PHI-TZD) were the 4 independent risk factors. The receiver-operating characteristic (ROC) curve analysis suggested that integrated predictive models (PHID, PHI-TZD) yield area under the curves (AUCs) of 0.9135 and 0.9105 in csPCa prediction, which shows a relatively satisfactory predictive capability compared with other predictors. Moreover, the PHI-TZD outperformed PHID by avoiding 30 patients' unnecessary biopsies while maintaining 74.36% specificity at a sensitivity of 90%. Decision-curve analysis (DCA) confirmed the comparable performance of the multivariable full-risk prediction models, without the inclusion of the net benefit, thereby highlighting the superior diagnostic efficacy of PHID and PHI-TZD in comparison with other diagnostic models, in both univariable and multivariable models., Conclusion: Our data confirmed the value of prostate TZ morphological parameters and suggested a significant advantage for the TZ-adjusted PHI predictive model (PHI-TZD) compared with PHI and PHID in the early detection of gray zone csPCa under specific conditions., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile synthesis of the elusive all-carbon quaternary-center-bearing azetidines. By adopting a well-orchestrated polar-radical relay strategy, ring strain release of bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed for nickel-catalyzed Suzuki Csp 2 -Csp 3 cross-coupling with commercially available boronic acids in broad scope (>50 examples), excellent functional group tolerance, and gram-scale utility. Preliminary mechanistic studies provided insights into the underlying mechanism, wherein the ring opening of ABB with a catalytic quantity of bromide accounts for the conversion of ABB into a redox-active azetidine, which subsequently engages in the cross-coupling reaction through a radical pathway. The synergistic bromide and nickel catalysis could intriguingly be derived from a single nickel source (NiBr 2 ). Application of the method to modify natural products, biologically relevant molecules, and pharmaceuticals has been successfully achieved as well as the synthesis of melanocortin-1 receptor (MC-1R) agonist and vesicular acetylcholine transporter (VAChT) inhibitor analogues through bioisosteric replacements of piperidine with azetidine moieties, highlighting the potential of the method in drug optimization studies. Aside from the synthesis of azetidines, we demonstrate the ancillary utility of our nickel catalytic system toward the restricted Suzuki cross-coupling of tertiary alkyl bromides with aryl boronic acids to construct all-carbon quaternary centers.

Background: Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNA Lys gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease., Methods: MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients., Results: We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients' skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities., Conclusions: We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNA Lys gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome., (© 2023. National Science Council of the Republic of China (Taiwan).)

Ferroptosis has been suggested to involve in doxorubicin (DOX)-induced cardiotoxicity. However, the underlying mechanisms and regulatory targets of cardiomyocyte ferroptosis remains to be understood. This study demonstrated that the up-regulation of ferroptosis associated proteins genes were accompanied with the down-regulation of AMPKα2 phosphorylation in DOX treated mouse heart or neonatal rat cardiomyocytes (NRCMs). AMPKα2 knockout (AMPKα2-/-) significantly exacerbated mouse cardiac dysfunction, increased mortality, promoting ferroptosis associated mitochondrial injuries, enhanced ferroptosis associated proteins and genes expression, and lead to accumulation of lactate dehydrogenase (LDH) and malondialdehyde (MDA) in mouse serum and hearts respectively. Ferrostatin-1 administration markedly improved cardiac function, decreased mortality, inhibited mitochondrial injuries and ferroptosis associated proteins and genes expression, and depressed accumulation of LDH and MDA in DOX treated AMPKα2-/- mouse. Moreover, Adeno-associated virus serotype 9 AMPKα2 (AAV9-AMPKα2) or AICAR treatment mediated AMPKα2 activation could significantly improve cardiac function and depress ferroptosis in mouse. AMPKα2 activation or silence could also inhibit or promote ferroptosis associated injuries in DOX treated NRCMs respecitively. Mechanistically, AMPKα2/ACC mediated lipid metabolism has been suggested to involve in regulating DOX-treatment induced ferroptosis other than mTORC1 or autophagy dependent pathway. The metabolomics analysis exhibited that AMPKα2-/- significantly enhanced accumulation of polyunsaturated fatty acids (PFAs), oxidized lipid, and phosphatidylethanolamine (PE). Finally, this study also demonstrated that metformin (MET) treatment could inhibit ferroptosis and improve cardiac function via activating AMPKα2 phosphorylation. The metabolomics analysis exhibited that MET treatment significantly depressed PFAs accumulation in DOX treated mouse hearts. Collectively, this study suggested that AMPKα2 activation might protect against anthracycline chemotherapeutic drugs mediated cardiotoxicity via inhibiting ferroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The interactions among agar, gellan gum, gelatin, and modified waxy corn starch in the formation of mixed gels were examined in five different ratios. Binary hydrocolloid gels were prepared using three ingredients: two hydrocolloids (total hydrocolloid concentration: 0.5 wt%, ratios of mixture: 0/0.5, 0.1/0.4, 0.2/0.3, 0.3/0.2, 0.4/0.1, and 0.5/0) and water. The textural properties of the hydrocolloid gels were studied by measuring the gel strength, rigidity, breaking force, breaking point, and syneresis as functions of the mixing ratio. The higher syneresis percentage of binary modified waxy corn starch and gum gels than that of mixed gum gels after cold storage was mainly due to the retrogradation of amylopectin. Agar was shown be the most influential with regards to increasing the gel strength, breaking force, and rigidity among the three kinds of gum, while gellan gum was more effective against syneresis than agar and gelatin for storage periods of 7 and 14 days. In the mixed gels, a dramatic increase in the breaking point from 0 to 0.5% was only exhibited for gellan gum. The results provided useful information, including gel strength, rigidity, breaking force, breaking point, and syneresis, for gum and modified corn starch ingredients selected from refrigerated binary gum gels such as pudding for food product development.

Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients often respond to EGFR tyrosine kinase inhibitors (TKIs) initially but eventually develop resistance to TKIs. The switch of EGFR downstream signaling from TKI-sensitive to TKI-insensitive is a critical mechanism-driving resistance to TKIs. Identification of potential therapies to target EGFR effectively is a potential strategy to treat TKI-resistant LUADs. In this study, we developed a small molecule diarylheptanoid 35d, a curcumin derivative, that effectively suppressed EGFR protein expression, killed multiple TKI-resistant LUAD cells in vitro, and suppressed tumor growth of EGFR-mutant LUAD xenografts with variant TKI-resistant mechanisms including EGFR C797S mutations in vivo. Mechanically, 35d triggers heat shock protein 70-mediated lysosomal pathway through transcriptional activation of several components in the pathway, such as HSPA1B, to induce EGFR protein degradation. Interestingly, higher HSPA1B expression in LUAD tumors associated with longer survival of EGFR-mutant, TKI-treated patients, suggesting the role of HSPA1B on retarding TKI resistance and providing a rationale for combining 35d with EGFR TKIs. Our data showed that combination of 35d significantly inhibits tumor reprogression on osimertinib and prolongs mice survival. Overall, our results suggest 35d as a promising lead compound to suppress EGFR expression and provide important insights into the development of combination therapies for TKI-resistant LUADs, which could have translational potential for the treatment of this deadly disease., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: RIP2 is a member of the receptor-interacting protein family that has been associated with various pathophysiological processes, including immunity, apoptosis, and autophagy. However, no studies have hitherto reported the role of RIP2 in lipopolysaccharide (LPS)-induced septic cardiomyopathy (SCM). This study was designed to illustrate the role of RIP2 in LPS-induced SCM., Methods: C57 and RIP2 knockout mice received intraperitoneal injections of LPS to establish models of SCM. Echocardiography was used to assess the cardiac function of the mice. Real-time-PCR, cytometric bead array and immunohistochemical staining were used to detect the inflammatory response. Immunoblotting was used to determine the protein expression of relevant signaling pathways. Our findings were validated by treatment with a RIP2 inhibitor. Neonatal rats cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) were transfected with Ad-RIP2 to further explore the role of RIP2 in vitro., Results: RIP2 expression was upregulated in our mice models of septic cardiomyopathy and LPS-stimulated cardiomyocytes and fibroblasts. RIP2 knockout or RIP2 inhibitors attenuated LPS-induced cardiac dysfunction and reduced the inflammatory response in mice. Overexpression of RIP2 in vitro enhanced the inflammatory response, and TAK1 inhibitors attenuated the inflammatory response caused by overexpression of RIP2., Conclusion: Our findings substantiate that RIP2 induces an inflammatory response by regulating the TAK1/IκBα/NF-κB signaling pathway. RIP2 inhibition by genetic or pharmacological approaches has huge prospects for application as a potential treatment strategy for inhibiting inflammation, alleviating cardiac dysfunction, and improving survival., Competing Interests: Declaration of competing interest The authors report no conflicts of interest in this work., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objectives : Sjögren's Syndrome (SS) is a common extra-articular feature among subjects with rheumatoid arthritis (RA). While Chinese herbal medicine (CHM) has been used to treat symptoms of RA for many years, few studies have examined its efficacy in guarding against the SS onset. This study aimed to compare risk of SS for RA patients with and without use of CHM. Materials and Methods : Data obtained for this nested case-control study were retrieved from Taiwanese nationwide insurance database from 2000-2013. Cases with SS claims were defined and matched to two randomly selected controls without SS from the recruited RA cohorts. Risk of SS in relation to CHM use was estimated by fitting multiple conditional logistic regression. Results : Patients aged between 20 and 80 years were included and 916 patients with incident SS were matched to 1832 non-SS controls by age, sex and index year. Among them, 28.1% and 48.4% cases ever received CHM therapy, respectively. After adjusting for baseline characteristics, CHM use was found to be related to a lower risk of SS among them (adjusted odds ratio = 0.40, 95% confidence interval: 0.34-0.47). A dose-dependent, reverse association, was further detected between the cumulative duration of CHM use and SS risk. Those receiving CHM therapy for more than 730 days showed a significantly reduced risk of SS by 83%. Conclusions : Findings of this study indicated that the add-on CHM formula, as part of RA care, may be a beneficial treatment for prevention against the incident SS.

Polyfluoroaryl sulfide is one of the prevalent motifs ubiquitous in materials and pharmaceutical chemistry. We herein describe a simple yet efficient procedure for their synthesis from readily available thiols and polyfluoroarenes via an S N Ar step. We detail specific steps for a gram-scale preparation of 2-((perfluoropyridin-4-yl)thio)benzo[d]thiazole 3 from mercaptobenzothiazole 1 and pentafluoropyridine 2. For complete details on the use and execution of this protocol, please refer to Liao et al. (2022). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Polyketide natural products often contain common repeat motifs, for example, propionate, acetate and deoxypropionate, and so can be synthesized by iterative processes. We report here a highly efficient iterative strategy for the synthesis of polyacetates based on boronic ester homologation that does not require functional group manipulation between iterations. This process involves sequential asymmetric diboration of a terminal alkene, forming a 1,2-bis(boronic ester), followed by regio- and stereoselective homologation of the primary boronic ester with a butenyl metallated carbenoid to generate a 1,3-bis(boronic ester). Each transformation independently controls the stereochemical configuration, making the process highly versatile, and the sequence can be iterated prior to stereospecific oxidation of the 1,3-polyboronic ester to yield the 1,3-polyol. This methodology has been applied to a 14-step synthesis of the oxopolyene macrolide bahamaolide A, and the versatility of the 1,3-polyboronic esters has been demonstrated in various stereospecific transformations, leading to polyalkenes, -alkynes, -ketones and -aromatics with full stereocontrol., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: Cardiac remodeling has been demonstrated to be the early stage and common pathway for various types of cardiomyopathy, but no specific treatment has been suggested to prevent its development and progress. This study was aimed at assessing whether Cryptotanshinone (CTS) treatment could effectively attenuate cardiac remodeling in vivo and in vitro ., Methods: Aortic banding (AB) surgery was performed to establish a pressure-overload-induced mouse cardiac remodeling model. Echocardiography and pressure-volume proof were used to examine mouse cardiac function. Hematoxylin and eosin (HE) and Picro-Sirius Red (PSR) staining were used to assess cardiac remodeling in vivo. Mouse hearts were collected to analysis signaling pathway and cardiac remodeling markers, respectively. Furthermore, neonatal rat cardiomyocyte (NRCMs) and cardiac fibroblast (CF) were isolated to investigate the roles and mechanisms of CTS treatment in vitro ., Results: CTS administration significantly alleviated pressure-overload-induced mouse cardiac dysfunction, inhibited cardiac hypertrophy, and reduced cardiac fibrosis. Mechanically, CTS treatment significantly inhibited the STAT3 and TGF- β /SMAD3 signaling pathways. In vitro experiments, CTS treatment markedly inhibited AngII-induced cardiomyocyte hypertrophy and TGF- β -induced myofibroblast activation via inhibiting STAT3 phosphorylation and its nuclear translocation. Finally, CTS treatment could not protect against pressure overload-induced mouse cardiac remodeling after adenovirus-associated virus (AAV)9-mediated STAT3 overexpression in mouse heart., Conclusion: CTS treatment might attenuate pathological cardiac remodeling via inhibiting STAT3-dependent pathway., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wen-jing Li et al.)

Background: Dual antiplatelet therapy (DAPT) with potent P2Y12 inhibitor is the cornerstone of acute coronary syndrome (ACS) management. Balancing the effects of different strategies of antiplatelet therapy including DAPT de-escalation, potent P2Y12 inhibitor monotherapy, and conventional DAPT is a hot topic., Methods: A systematic search was conducted from the MEDLINE, PubMed, and Embase through October 2021 to identify various DAPT strategies in randomized controlled trials (RCTs) for treatment of ACS patients after undergoing PCI with drug-eluting stent (DES). The network meta-analysis was performed to investigate the net clinic benefit of the DAPT de-escalation, potent P2Y12 inhibitor monotherapy, as well as conventional DAPT. The primary outcome was net adverse clinical events, defined as a composite of major bleeding and cardiac death, myocardial infarction, stroke, stent thrombosis, or target-vessel revascularization. The secondary outcomes include major adverse cardiac events and trial-defined major or minor bleeding., Results: A total of 14 RCTs with 63,982 patients were included. The DAPT de-escalation was associated with a lower risk of the primary outcome compared with potent P2Y12 inhibitor monotherapy (De-escalation vs monotherapy odds ratio (OR): 0.72 95% confidence interval (CI): 0.55-0.96), and other antiplatelet strategies (De-escalation vs clopidogrel + aspirin OR: 0.49 95% CI: 0.39-0.63; De-escalation vs prasugrel + aspirin OR: 0.76 95% CI: 0.59-0.98; De-escalation vs ticagrelor + aspirin OR: 0.76 95% CI: 0.55-0.90). There were no statistical differences in the incidence of bleeding (DAPT de-escalation vs P2Y12 inhibitor monotherapy OR: 0.73 95% CI: 0.47-1.12) and major adverse cardiac events (DAPT de-escalation vs P2Y12 inhibitor monotherapy OR: 0.79 95% CI: 0.59-1.08) between DAPT de-escalation and potent P2Y12 inhibitor monotherapy., Conclusions: This network meta-analysis showed that DAPT de-escalation would reduce the net adverse clinical events, compared with potent P2Y12 inhibitor monotherapy, for ACS patients undergone PCI treatment., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2022 The Author(s). Published by IMR Press.)

The aza-ortho-quinone methide (aza-o-QM) chemistry has overwhelmingly progressed in the past few decades. This review aims to integrate various transition metal-catalyzed and organocatalytic strategies in taming aza-o-QM intermediates, including the aza-ortho-vinylidene quinone methide (aza-o-VQM), aza-ortho-alkynyl quinone methide (aza-o-AQM), aza-para-quinone methide (aza-p-QM), and indole-based aza-o-QM analog. These transient species are often utilized for the direct and enantioselective synthesis of complex (hetero)polycyclic or fused-ring molecular scaffolds such as tetrahydroquinoline and indoline, among others, which are abundant in many natural products, bioactive compounds, and pharmaceuticals., (© 2022 Wiley-VCH GmbH.)

Background: Liquiritin (LQ) is one of the main flavonoids extracted from the roots of Glycyrrhiza spp., which are widely used in traditional Chinese medicine. Studies in both cellular and animal disease models have shown that LQ attenuates or prevents oxidative stress, inflammation, and apoptosis. However, the potential therapeutic effects of LQ on pressure overload-induced cardiac hypertrophy have not been so far explored. Therefore, we investigated the cardioprotective role of LQ and its underlying mechanisms in the aortic banding (AB)-induced cardiac hypertrophy mouse model. Methods and Results: Starting 3 days after AB surgery, LQ (80 mg/kg/day) was administered daily over 4 weeks. Echocardiography and pressure-volume loop analysis indicated that LQ treatment markedly improved hypertrophy-related cardiac dysfunction. Moreover, hematoxylin and eosin, picrosirius red, and TUNEL staining showed that LQ significantly inhibited cardiomyocyte hypertrophy, interstitial fibrosis, and apoptosis. Western blot assays further showed that LQ activated LKB1/AMPKα2/ACC signaling and inhibited mTORC1 phosphorylation in cardiomyocytes. Notably, LQ treatment failed to prevent cardiac dysfunction, hypertrophy, and fibrosis in AMPKα2 knockout (AMPKα2 -/- ) mice. However, LQ still induced LKB1 phosphorylation in AMPKα2 -/- mouse hearts. In vitro experiments further demonstrated that LQ inhibited Ang II-induced hypertrophy in neonatal rat cardiomyocytes (NRCMs) by increasing cAMP levels and PKA activity. Supporting the central involvement of the cAMP/PKA/LKB1/AMPKα2 signaling pathway in the cardioprotective effects of LQ, inhibition of Ang II-induced hypertrophy and induction of LKB1 and AMPKα phosphorylation were no longer observed after inhibiting PKA activity. Conclusion: This study revealed that LQ alleviates pressure overload-induced cardiac hypertrophy in vivo and inhibits Ang II-induced cardiomyocyte hypertrophy in vitro via activating cAMP/PKA/LKB1/AMPKα2 signaling. These findings suggest that LQ might be a valuable adjunct to therapeutic approaches for treating pathological cardiac remodeling., 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 Aiyasiding, Liao, Feng, Zhang, Lin, Ding, Yan, Zhou and Tang.)

Myocardial infarction (MI) is one of the most common cardiac emergencies with high morbidity and is a leading cause of death worldwide. Since MI could develop into a life-threatening emergency and could also seriously affect the life quality of patients, continuous efforts have been made to create an effective strategy to prevent the occurrence of MI and reduce MI-related mortality. Numerous studies have confirmed that neutrophils play important roles in inflammation and innate immunity, which provide the first line of defense against microorganisms by producing inflammatory cytokines and chemokines, releasing reactive oxygen species, and degranulating components of neutrophil cytoplasmic granules to kill pathogens. Recently, researchers reported that neutrophils are closely related to the severity and prognosis of patients with MI, and neutrophil to lymphocyte ratio in post-MI patients had predictive value for major adverse cardiac events. Neutrophils have been increasingly recognized to exert important functions in MI. Especially, granule proteins released by neutrophil degranulation after neutrophil activation have been suggested to involve in the process of MI. This article reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Video abstract Neutrophils played a crucial role throughout the process of MI, and neutrophil degranulation was the crucial step for the regulative function of neutrophils. Both neutrophils infiltrating and neutrophil degranulation take part in the injury and repair process immediately after the onset of MI. Since different granule subsets (e g. MPO, NE, NGAL, MMP-8, MMP-9, cathelicidin, arginase and azurocidin) released from neutrophil degranulation show different effects through diverse mechanisms in MI. In this review, we reviewed the current research progress of neutrophil granules in MI and discusses neutrophil degranulation associated diagnosis and treatment strategies. Myeloperoxidase (MPO); Neutrophil elastase (NE); Neutrophil gelatinase-associated lipocalin (NGAL); Matrix metalloproteinase 8 (MMP-8); Matrix metalloproteinase 9 (MMP-9)., (© 2022. The Author(s).)

As an important mechanism to maintain cellular homeostasis, autophagy exerts critical functions via degrading misfolded proteins and damaged organelles. Recent years, alternative autophagy, a new type of autophagy has been revealed, which shares similar morphology with canonical autophagy but is independent of Atg5/Atg7. Investigations on different diseases showed the pivotal role of alternative autophagy during their physio-pathological processes, including heart diseases, neurodegenerative diseases, oncogenesis, inflammatory bowel disease (IBD), and bacterial infection. However, the studies are limited and the precise roles and mechanisms of alternative autophagy are far from clear. It is necessary to review current research on alternative autophagy and get some hint in order to provide new insight for further study. Video Abstract., (© 2022. The Author(s).)

The C-S activation and sulfur removal from native thiols is challenging, which limits their application as feedstock materials in organic synthesis despite their natural abundance. Herein, we introduce a per-/polyfluoroaryl moiety, which serves as a redox-active scaffold, into sp 3 -hybridized thiols to activate the C-S bond. Using a Ni catalyst with MgBr 2 as an additive, the S group can be removed to yield an aliphatic radical that can react with an aryl halide in a reductive cross-coupling.

Herein we report ketones as feedstock materials in radical cross-coupling reactions under Ni/photoredox dual catalysis. In this approach, simple condensation first converts ketones into prearomatic intermediates that then act as activated radical sources for cross-coupling with aryl halides. Our strategy enables the direct benzylation/benzoylation of (hetero)arenes under mild reaction conditions with high functional group tolerance.

Screening for cancer and improved treatments have not only improved treatment outcomes and patient survival but have also led to an increase in the number of second primary cancers (SPCs). Hepatocellular carcinoma has been a common occurrence in Taiwan over the past decade. The mortality rate is second only to malignant tumors of lung cancer, and it also represents the fourth highest cancer medical expenditure. This study aimed to use machine learning to identify the risk factors for Hepatocellular carcinoma survivors. Of 378,445 datasets, including 15,251 from patients with SPCs, were collected; 18 predictive variables were considered risk factors for SPCs based on the physician panel discussion. The machine learning techniques employed included support vector machine, C5 decision tree, and random forest. SMOTE (Synthetic Minority Oversampling Technique) sampling method was used to resolve the imbalance problem. The results showed that the top 5 risk factors for SPCs were tumor size, clinical stage, surgery, total bilirubin, and BCLC Stage. The support vector machine method had the highest predicted accuracy (0.7673). The risk factors extracted from the classification models and association rules will be used to provide valuable information for HCC therapy.

In contrast to conventional digital images, high-dynamic-range (HDR) images have a broader range of intensity between the darkest and brightest regions to capture more details in a scene. Such images are produced by fusing images with different exposure values (EVs) for the same scene. Most existing multi-scale exposure fusion (MEF) algorithms assume that the input images are multi-exposed with small EV intervals. However, thanks to emerging spatially multiplexed exposure technology that can capture an image pair of short and long exposure simultaneously, it is essential to deal with two-exposure image fusion. To bring out more well-exposed contents, we generate a more helpful intermediate virtual image for fusion using the proposed Optimized Adaptive Gamma Correction (OAGC) to have better contrast, saturation, and well-exposedness. Fusing the input images with the enhanced virtual image works well even though both inputs are underexposed or overexposed, which other state-of-the-art fusion methods could not handle. The experimental results show that our method performs favorably against other state-of-the-art image fusion methods in generating high-quality fusion results.

Amyloid-β (Aβ) peptides play a key role in Alzheimer's disease (AD), the most common type of dementia. In this study, a polysaccharide from Bletilla striata (BSP), with strong antioxidant and anti-inflammatory properties, was extracted using a low-temperature method and tested for its efficacy against AD, in vitro using N2a and BV-2 cells, and in vivo using an AD rat model. The characterization of the extracted BSP for its molecular structure and functional groups demonstrated the effectiveness of the modified method for retaining its bioactivity. In vitro, BSP reduced by 20% reactive oxygen species (ROS) levels in N2a cells ( p = 0.0082) and the expression levels of inflammation-related genes by 3-fold TNF-α ( p = 0.0048), 4-fold IL-6 ( p = 0.0019), and 2.5-fold IL-10 ( p = 0.0212) in BV-2 cells treated with Aβ fibrils. In vivo, BSP recovered learning memory, ameliorated morphological damage in the hippocampus and cortex, and reduced the expression of the β-secretase protein in AlCl 3 -induced AD rats. Collectively, these findings demonstrated the efficacy of BSP for preventing and alleviating the effects of AD.

Objectives: Sestrin2 (Sesn2) has been demonstrated to be a cysteine sulfinyl reductase and protects cells from multiple stress insults, including hypoxia, endoplasmic reticulum stress, and oxidative stress. However, the roles and mechanisms of Sesn2 in pressure overload-induced mouse cardiac hypertrophy have not been clearly clarified. This study intended to investigate whether sestrin2 (Sesn2) overexpression could prevent pressure overload-induced cardiac hypertrophy via an AMPKα2 dependent pathway through conditional knockout of AMPKα2. Methods and results: Sesn2 expression was significantly increased in mice hearts at 2 and 4 weeks after aortic banding (AB) surgery, but decreased to 60-70% of the baseline at 8 weeks. Sesn2 overexpression (at 3, 6, and 9 folds) showed little cardiac genetic toxicity in transgenic mice. Cardiac dysfunctions induced by pressure overload were attenuated by cardiomyocyte-specific Sesn2 overexpression when measured by echocardiography and hemodynamic analysis. Results of HE and PSR staining showed that Sesn2 overexpression significantly alleviated cardiac hypertrophy and fibrosis in mice hearts induced by pressure overload. Meanwhile, adenovirus-mediated-Sesn2 overexpression markedly suppressed angiotensin II-induced neonatal rat cardiomyocyte hypertrophy in vitro . Mechanistically, Sesn2 overexpression increased AMPKα2 phosphorylation but inhibited mTORC1 phosphorylation. The cardiac protections of Sesn2 overexpression were also via regulating oxidative stress by enhancing Nrf2/HO-1 signaling, restoring SOD activity, and suppressing NADPH activity. Particularly, we first proved the vital role of AMPKα2 in the regulation of Sesn2 with AMPKα2 knockout (AMPKα2-/-) mice and Sesn2 transgenic mice crossed with AMPKα2-/-, since Sesn2 overexpression failed to improve cardiac function, inhibit cardiac hypertrophy and fibrosis, and attenuate oxidative stress after AMPKα2 knockout. Conclusion: This study uniquely revealed that Sesn2 overexpression showed little genetic toxicity in mice hearts and inhibited mTORC1 activation and oxidative stress to protect against pressure overload-induced cardiac hypertrophy in an AMPKα2 dependent pathway. Thus, interventions through promoting Sesn2 expression might be a potential strategy for treating pathological cardiac hypertrophy and heart failure., 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 Zhang, Liao, Feng, Mou, Li, Aiyasiding, Lin, Ding, Zhou, Yan, Chen and Tang.)

Objective: The aim of this study is to examine the pathways by which work-life balance influences safety climate in hospital settings., Design: A national cross-sectional survey on patient safety culture., Settings: Healthcare workers from 56 hospitals in Taiwan, covering three work settings: intensive care units, operation rooms and emergency departments., Participants: 14 345 healthcare workers took part in the survey and were included in the present analysis., Primary and Secondary Outcome Measures: The Safety Attitudes, Maslach's Burn-out Inventory and Work-life balance questionnaires were used to measure patient safety culture, teamwork, leadership, emotional exhaustion and work-life balance. Path analysis was conducted to determine the relationship between work-life balance and safety climate. We tested for mediating and moderating factors influencing this relationship., Results: The path between work-life balance and safety climate was found to be significant (b=0.32, p<0.001) and explained through a serial mediation. This relationship was found to be mediated by emotional exhaustion followed by teamwork climate in a full mediation. Leadership factors such as identifying as a manager, moderated the indirect pathway between work-life balance and safety climate through teamwork climate (index of moderation: b=0.083, bias corrected 95% CI 0.044 to 0.120) but not through emotional exhaustion or the serial pathway. Subgroup analysis from non-managers on their perception of management was also found to moderate this relationship., Conclusion: We found work-life balance to be associated with safety climate through a fully mediated model. The mediation pathways are moderated by self-identified leadership and perceptions of leadership. Understanding the pathways on how work-life balance influences safety climate provides an explanatory model that can be used when designing effective interventions for implementation in system-based approaches to improve patient safety culture in hospital settings., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aimed to investigate the role and mechanisms of Receptor interacting protein kinase 2 (RIP2) in pressure overload-induced cardiac remodeling. Human failing or healthy donor hearts were collected for detecting RIP2 expression. RIP2 cardiomyocyte-specific overexpression, RIP2 global knockout, or wild-type mice were subjected to sham or aortic banding (AB) surgery to establish pressure overload-induced cardiac remodeling in vivo . Phenylephrine (PE)-treated neonatal rat cardiomyocytes (NRCMs) were used for further investigation in vitro . The expression of RIP2 was significantly upregulated in failing human heart, mouse remodeling heart, and Ang II-treated NRCMs. RIP2 overexpression obviously aggravated pressure overload-induced cardiac remodeling. Mechanistically, RIP2 overexpression significantly increased the phosphorylation of TAK1, P38, and JNK1/2 and enhanced IκBα/p65 signaling pathway. Inhibiting TAK1 activity by specific inhibitor completely prevented cardiac remodeling induced by RIP2 overexpression. This study further confirmed that RIP2 overexpression in NRCM could exacerbate PE-induced NRCM hypertrophy and TAK1 silence by specific siRNA could completely rescue RIP2 overexpression-mediated cardiomyocyte hypertrophy. Moreover, this study showed that RIP2 could bind to TAK1 in HEK293 cells, and PE could promote their interaction in NRCM. Surprisingly, we found that RIP2 overexpression caused spontaneous cardiac remodeling at the age of 12 and 18 months, which confirmed the powerful deterioration of RIP2 overexpression. Finally, we indicated that RIP2 global knockout attenuated pressure overload-induced cardiac remodeling via reducing TAK1/JNK1/2/P38 and IκBα/p65 signaling pathways. Taken together, RIP2-mediated activation of TAK1/P38/JNK1/2 and IκBα/p65 signaling pathways played a pivotal role in pressure overload-induced cardiac remodeling and spontaneous cardiac remodeling induced by RIP2 overexpression, and RIP2 inhibition might be a potential strategy for preventing cardiac remodeling., 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 Yang, Zhang, Zhou, Ni, Feng, Li, Mou, Wu, Deng, Liao and Tang.)

Diabetic cardiomyopathy (DCM) significantly increased the morbidity of heart failure in diabetic patients. Long-time oxidative stress is an indisputable contributor for DCM development. Apocynin (APO) has been suggested to be a potential drug against oxidative stress. The study aims to find out the effects of APO on DCM and the related mechanisms. Mice were randomly divided into four groups: control (CON), APO, DCM and DCM + APO. Echocardiography analyses, histological analyses, Western blot and RT-PCR were used to explore the roles and mechanisms of APO in DCM. Isolated neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (CFs) were used for further confirming the APO treatment effects in vitro. Deteriorated cardiac function, enlarged cardiomyocytes, excess cardiac fibrosis and significant cardiac oxidative stress were observed in DCM group. However, APO treatment successfully improved cardiac function, decreased cardiac hypertrophy and fibrosis, and depressed oxidative stress. Mechanistically, APO treatment markedly suppressed apoptosis signal regulating kinase 1(ASK1)-p38/c-jun N-terminal kinase (JNK) signaling and reduced apoptosis. It also inhibited NRCM apoptosis and CF activation via depressing ASK1-p38/JNK signaling in vitro. Moreover, adenovirus-mediated ASK1 overexpression completely removed the protection of APO in vitro. In conclusion, APO treatment could effectively attenuate DCM-associated injuries in vivo and protect against high glucose-induced NRCM and CF injuries in vitro via suppressing ASK1-p38/JNK signaling. APO might be a potential ASK1 inhibitor for treating DCM., (Copyright © 2021. Published by Elsevier B.V.)

This study compared the effects of the sulfate dry-wet cycle on the properties of ordinary concrete and nano-TiO 2 -modified concrete, including the mass loss rate, ultrasonic wave velocity, compressive strength, and XRD characteristics. In addition, a series of compression simulations carried out using the PFC2D software are also presented for comparison. The results show the following: (1) with an increase in dry-wet cycles, the damage to the concrete gradually increased, and adding nano-TiO 2 into ordinary concrete can improve the material's sulfate resistance; (2) after 50 sulfate dry-wet cycles, the mass loss rate of ordinary concrete was -3.744%, while that of nano-TiO 2 -modified concrete was -1.363%; (3) the compressive strength of ordinary concrete was reduced from 41.53 to 25.12 MPa (a reduction of 39.51%), but the compressive strength of nano-TiO 2 -modified concrete was reduced from 49.91 to 32.12 MPa (a reduction of 35.64%); (4) after a sulfate dry-wet cycle, the nano-TiO 2 -modified concrete surface produced white crystalline products, considered to be ettringite based on the XRD analysis; (5) when considering the peak stress and strain of the concrete samples, the numerical results agreed well with the test results, indicating the reliability of the method.

Pyogenic liver abscess (PLA) is a major life-threatening disease with varied clinical features. This study aimed to determine predictors of mortality in patients with PLA using criteria determined upon admission. We retrospectively examined the data of 324 hospitalized adults in whom liver abscesses were confirmed using abdominal ultrasound and/or computed tomography. The relationship between various risk factors was assessed using multivariate analysis. A total of 109 (33.6%) patients were admitted to the intensive care unit (ICU). The overall mortality rate was 7.4% and was higher among ICU patients than non-ICU patients (21.1% vs. 0.5%, p < 0.001). PLA patients with an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥18 had a 19.31-fold increased risk, and those with concomitant infections had a 34.33-fold increased risk of 30-day mortality according to multivariate analysis. The estimated area under the receiver operating characteristic curve for predicting 30-day mortality revealed that APACHE II score ≥18 (sensitivity of 75% and specificity of 84%, p < 0.0001) had better discriminative power than Sequential Organ Failure Assessment (SOFA) ≥6 (sensitivity of 81% and specificity of 66%, p < 0.0001). APACHE II has shown better discrimination ability than SOFA in predicting mortality in PLA patients. To improve outcomes in patients with PLA, future management strategies should focus on high-risk patients.

Objectives: Incident reporting is one of the tools used to improve patient safety that has been widely used in health facilities in many countries. Incident reporting systems provide functionality to collect, analyze, and disseminate lessons learned to the wider community, whether at the hospital or national level. The aim of this study was to compare the patient safety incident reporting systems of Taiwan, Malaysia, and Indonesia to identify similarities, differences, and areas for improvement., Methods: We searched the official Web sites and homepages of the responsible leading patient safety agencies of the three countries. We reviewed all publicly available guidelines, regulatory documents, government reports that included policies, guidelines, strategy papers, reports, evaluation programs, as well as scientific articles and gray literature related to the incident reporting system. We used the World Health Organization components of patient safety reporting system as the guidelines for comparison and analyzed the documents using descriptive comparative analysis., Results: Taiwan had the most incidents reported, followed by Malaysia and Indonesia. Taiwan Patient Safety Reporting (TPR) and the Malaysian Reporting and Learning System had similar attributes and followed the World Health Organization components for incident reporting. We found differences between the Indonesian system and both of TPR and the Malaysian system. Indonesia did not have an external reporting deadline, analysis and learning were conducted at the national level, and there was a lack of transparency and public access to data and reports. All systems need to establish a clear and structured incident reporting evaluation framework if they are to be successful., Conclusions: Compared with TPR and Malaysian system, the Indonesian patient safety incident reporting system seemed to be ineffective because it failed to acquire adequate national incident reporting data and lacked transparency; these deficiencies inhibited learning at the national level. We suggest further research on the implementation at the hospital level to see how far national guidelines and policy have been implemented in each country., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Liver injury seriously threatens the health of people. Meanwhile, dexmedetomidine hydrochloride (DEX) can protect against liver injury. However, the mechanism by which Dex mediates the progression of liver injury remains unclear. Thus, this study aimed to investigate the function of DEX in oxygen and glucose deprivation (OGD)-treated hepatocytes and its underlying mechanism., Methods: In order to investigate the function of DEX in liver injury, WRL-68 cells were treated with OGD. Cell viability was measured by MTT assay. Cell apoptosis was detected by flow cytometry. Inflammatory cytokines levels were measured by ELISA assay. The interaction between miR-194 and TUG1 or SIRT1 was detected by dual-luciferase reporter. Gene and protein levels were measured by qPCR or western blotting., Results: DEX notably reversed OGD-induced inflammation and apoptosis in WRL-68 cell. Meanwhile, the effect of OGD on TUG1, SIRT1 and miR-194 expression in WRL-68 cells was reversed by DEX treatment. However, TUG1 knockdown or miR-194 overexpression reversed the function of DEX in OGD-treated WRL-68 cells. Moreover, TUG1 could promote the expression of SIRT1 by sponging miR-194. Furthermore, knockdown of TUG1 promoted OGD-induced cell growth inhibition and inflammatory responses, while miR-194 inhibitor or SIRT1 overexpression partially reversed this phenomenon., Conclusions: DEX could suppress OGD-induced hepatocyte apoptosis and inflammation by mediation of TUG1/miR-194/SIRT1 axis. Therefore, this study might provide a scientific basis for the application of DEX on liver injury treatment.

Background: Liquiritin (LIQ) is a traditional Chinese medicine that has been reported to regulate inflammation, oxidative stress and cell apoptosis. However, the beneficial effects of LIQ in lipopolysaccharides (LPS)-induced septic cardiomyopathy (SCM) has not been reported. The primary goal of this study was to investigate the effects of LIQ in LPS-induced SCM model. Methods: Mice were pre-treated with LIQ for 7 days before they were injected with LPS (10 mg/kg) for inducing SCM model. Echocardiographic analysis was used to evaluate cardiac function after 12 h of LPS injection. Thereafter, mice were sacrificed to collect hearts for molecular and histopathologic assays by RT-PCR, western-blots, immunohistochemical and terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) staining analysis respectively. AMPKα2 knockout (AMPKα2 -/- ) mice were used to elucidate the mechanism of LIQ Neonatal rat cardiomyocytes (NRCMs) treated with or without LPS were used to further investigate the roles and mechanisms of LIQ in vitro experiments. Results: LIQ administration attenuated LPS-induced mouse cardiac dysfunction and reduced mortality, based upon the restoration of EF, FS, LVEDs, heart rate, dp/dt max and dp/dt min deteriorated by LPS treatment. LIQ treatment also reduced mRNA expression of TNFα, IL-6 and IL-1β, inhibited inflammatory cell migration, suppressed cardiac oxidative stress and apoptosis, and improved metabolism. Mechanistically, LIQ enhanced the phosphorylation of AMP-activated protein kinase α2 (AMPKα2) and decreased the phosphorylation of mTORC1, IκBα and NFκB/p65. Importantly, the beneficial roles of LIQ were not observed in AMPKα2 knockout model, nor were they observed in vitro model after inhibiting AMPK activity with an AMPK inhibitor. Conclusion: We have demonstrated that LIQ exerts its protective effects in an SCM model induced by LPS administration. LIQ reduced inflammation, oxidative stress, apoptosis and metabolic alterations via regulating AMPKα2 dependent signaling pathway. Thus, LIQ might be a potential treatment or adjuvant for SCM treatment., 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 Mou, Zhou, Feng, Zhang, Lin, Aiyasiding, Li, Ding, Liao, Bian and Tang.)

It is well known that information technology (IT) can play a pivotal role in enhancing healthcare quality and patient safety. The use of computational science to enhance the capabilities of hospital information systems helps deliver enhanced healthcare quality. "Smart healthcare" has become a popular term, reflecting the level of IT involvement in healthcare services. However, each hospital has a different level of IT development, and no clear definition of smart healthcare exists. In this study, we aimed to develop and validate a survey standard to evaluate the level of IT involvement in hospitals. The quality improvement task force of the Joint Commission of Taiwan (QITF-JCT) conducted a systematic literature review to identify the key elements of major healthcare IT functions. The modified Delphi technique was used to review the importance and appropriateness of these elements through an expert panel, and the JCT Smart Healthcare Standard version 1.0 (JCT-SHS 1.0) was drafted. A total of 40 healthcare quality improvement campaign (HQIC) application projects in 2018 were selected for evaluating nine key dimensions of hospital functions: security, digitization, automation, interconnection, connectivity, interoperability, mobility, computation, and artificial intelligence. The standard can be used smart hospital evaluation and executed by two experts by on-site evaluation and rating as three-level scale (norm, excellent, and innovative). The internal consistency and inter-rater reliability were investigated using Cronbach's α and kappa statistics, respectively. This standard was evaluated by using 40 HQIC application projects. The Cronbach's α values were in the range of 0.74-0.92, indicating the good internal consistency of the JCT-SHS 1.0 among the nine IT dimensions. The kappa correlation coefficients were 0.68 for security (p = 0.027), 0.47 for digitization (p = 0.042), 0.21 for automation (p = 0.048), 0.82 for interconnection (p = 0.014), 0.35 for connectivity (p = 0.036), 0.28 for interoperability (p = 0.042), 0.71 for mobility (p = 0.016), 0.47 for computation (p = 0.029), and 0.34 for artificial intelligence (p = 0.033), revealing moderate inter-rater reliability. The validation data indicated that the JCT-SHS 1.0 is a consistent and reliable instrument for evaluating the levels of IT development in the hospitals. Healthcare providers, external accreditation bodies, and policymakers may use the JCT-SHS 1.0 to assess and plan their organizational and system-wise IT strategy.

Background and Purpose: In-hospital cardiac arrest (IHCA) has high mortality rate, which needs more research. This multi-center study aims to evaluate potential risk factors for mortality in patients after IHCA. Methods: Data for this study retrospectively enrolled IHCA patients from 14 regional hospitals, two district hospitals, and five medical centers between 2013 June and 2018 December. The study enrolled 5,306 patients and there were 2,871 patients in subgroup of intensive care unit (ICU) and emergency room (ER), and 1,894 patients in subgroup of general wards. Results: As for overall IHCA patients, odds ratio (OR) for mortality was higher in older patients (OR = 1.69; 95% CI:1.33-2.14), those treated with ventilator (OR = 1.79; 95% CI:1.36-2.38) and vasoactive agents (OR = 1.88; 95% CI:1.45-2.46). Whereas, better survival was reported in IHCA patients with initial rhythm as ventricular tachycardia (OR = 0.32; 95% CI: 0.21-0.50) and ventricular fibrillation (OR = 0.26; 95% CI: 0.16-0.42). With regard to ICU and ER subgroup, there was no mortality difference among different nursing shifts, whereas for patients in general wards, overnight shift (OR = 1.83; 95% CI: 1.07-3.11) leads to poor outcome. Conclusion: For IHCA patients, old age, receiving ventilator support and vasoactive agents reported poor survival. Overnight shift had poor survival for IHCA patients in general wards, despite no significance in overall and ICU/ER subgroups., 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 Wang, Huang, Yen, Yeh, Wu and Liao.)

Magnesium alloys can work as biomedical materials due to their Young's modules similar to that of bone. Nevertheless, in a human plasma, one of the major drawbacks of these materials is the low corrosion resistance. Here, AZ80 corrosion in the solutions containing chloride, bicarbonate, sulphate and hydrogen phosphate ions were investigated by a short-term immersion test and electrochemical techniques. The results showed that bicarbonate and hydrogen phosphate could retard corrosion rate, while chloride and sulphate accelerated corrosion rate. During the early immersion stage, the corrosion rate increased with the presence of bicarbonate. It was caused by the reaction of bicarbonate and hydroxide promoting the dissolution of magnesium and accelerating corrosion. In the later stage, the reduced corrosion rate was due to the formation of various protective films. The sample formed a new sparse porous MgSO 4 ·5H 2 O compounds in the sulphate ion solution, which could not effectively prevent chloride ions from entering the matrix and thus accelerated the dissolution of magnesium. With the presence of hydrogen phosphate, magnesium phosphate with a much lower solubility was formed, preferentially precipitated on the surface and was not influenced by the chloride ions. The corrosion mechanisms of magnesium alloys in above ions were proposed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cardiac remodeling is a common pathological process in various heart diseases, such as cardiac hypertrophy, diabetes-associated cardiomyopathy and ischemic heart diseases. The inhibition of cardiac remodeling has been suggested to be a potential strategy for preventing heart failure. However, the mechanisms involved in cardiac remodeling are quite complicated. Recent studies have reported a close correlation between autophagy and energy homeostasis in cardiac remodeling associated with various heart diseases. In this review, we summarize the roles of autophagy and energy homeostasis in cardiac remodeling and discuss the relationship between these two processes in different conditions to identify potential targets and strategies for treating cardiac remodeling by regulating autophagy., 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 © 2020 Ding, Feng, Li, Liao and Tang.)

Collision carcinoma is a rare malignancy that generally occurs in cervical, esophageal, pulmonary, and squamous cell cancers. Few studies have been reported involving endometrial adenocarcinoma and fallopian tube carcinoma. We reported the case of a 58-year-old woman who presented because of irregular vaginal bleeding for more than 1 month. Cervical biopsy suggested moderately differentiated cervical adenocarcinoma, and the patient underwent radical hysterectomy under general anesthesia. However, postoperative pathology and immunohistochemical results indicated a collision tumor comprising endometrial adenocarcinoma (grade I) and primary serous fallopian tube carcinoma. According to the treatment principle of multiple primary tumors, a regimen of paclitaxel combined with carboplatin was administered. The patient also underwent local pelvic radiotherapy to treat lymph node metastasis. One month later, the patient developed brain metastases and died.

Given that evidence supporting chronic hepatitis C (CHC) infection developed chance for hepatocellular carcinoma (HCC) following antiviral agents therapy is controversial. We conducted a meta-analysis to examine the risk.We evaluated 20 retrospective and prospective cohort studies published up to 31 December 2017 which investigated the association between sustained virological response (SVR) and incidence of HCC patients treated with monotherapy interferon (IFN) or IFN plus ribavirin (RBV) therapy. The primary outcome of the study was the cumulative incidence of HCC. Odds ratio (OR) was used to evaluate the index of effect size for the association between SVR and treatment with IFN alone or IFN/RBV in CHC patients.SVR patients demonstrated a lower incidence of HCC compared to non-SVR patients. Non-SVR patients had greater odds of HCC incidence compared to SVR patients in the treatment of IFN plus RBV (pooled OR = 7.405, 95% CI = 4.689 to 11.694, P < .001). Non-SVR patients had greater odds of HCC incidence compared to SVR patients in the treatment of IFN monotherapy (pooled OR = 4.135, 95% CI = 3.009 to 5.682, P < .001). Lack of SVR to IFN therapy was significantly associated with greater risk of HCC incidence (pooled OR = 5.035, 95% CI = 3.915 to 6.474, P < .001).SVR could be as a predictor of HCC in CHC patients treated with IFN or IFN plus RBV, and have important implications during HCC screening, whereby patients who fail to achieve SVR need to be screened more rigorously.

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. In this study, we investigated the role of miR-346 in RCC cells under hypoxia. OS-RC-2 and 786-O cells were cultured in 1% O2 or normal oxygen. Cell proliferation, migration, and invasion abilities were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, transwell migration, and invasion assays, respectively. Quantitative real-time PCR (qRT-PCR) was performed to detect the expression of miR-346 and N-myc downstream-regulated gene 2 (NDRG2). Then bioinformatics analysis, dual-luciferase reporter assay, and RNA immunoprecipitation were carried out to determine the relationship between miR-346 and NDRG2. The protein expression of NDRG2 was detected by western blot assay. Hypoxia promoted cell proliferation, migration, and invasion in OS-RC-2 and 786-O cells. Meanwhile, we found that miR-346 was upregulated in RCC cells under hypoxia as relative to normoxia. miR-346 deletion could decrease the viability, migration, and invasion abilities of RCC cells under hypoxia. Besides, our data demonstrated that NDRG2 was a target gene of miR-346. The expression of NDRG2 in OS-RC-2 and 786-O cells was lower under hypoxia than under normal oxygen conditions. Moreover, NDRG2 overexpression could inhibit cell proliferation, migration, and invasion in RCC cells under hypoxia. And NDRG2 silencing reversed the inhibitory effects of the miR-346 inhibitor on the viability, migration, and invasion abilities of RCC cells in hypoxia conditions. miR-346 promoted the viability, migration, and invasion of RCC cells under hypoxia by targeting NDRG2.

Objective: Menopausal women appear to report a higher risk of Sjögren syndrome (SS). Although Chinese herbal medicines (CHMs) are proven to lower SS risk, the scientific evidence of whether it can lessen the occurrence of SS among menopausal women is limited. This longitudinal cohort study aimed to clarify the relationship between CHMs use and SS risk in menopausal women., Methods: Using a nationwide claims data, we enrolled 31,917 women with first-time diagnosed menopause who simultaneously were free of SS between 2000 and 2007. Among them, we randomly selected 12,757 CHMs users and 12,757 non-CHMs users using propensity scores matching. All participants were followed until the end of 2012 to record SS incidence. The hazard ratio of SS with regard to CHMs use was estimated using the Cox proportional hazards regression model., Results: In the follow-up period, 589 CHMs users and 644 non-CHMs users developed SS, representing incidence rates of 5.12 and 6.40, respectively, per 1,000 person-years. CHMs use was associated with a 21% lower subsequent risk of SS (adjusted hazard ratio, 0.79; 95% CI, 0.71-0.89). Six commonly prescribed CHMs were discovered to be associated with lower SS risk: Ge-Gen-Tang, Zhi-Gan-Cao-Tag, Da-Huang, Ye-Jiao-Teng, Tian-Hua-Fen, and Bo-Zi-Ren., Conclusions: A statistically significant association was found between CHMs use and lower risk of SS onset in menopausal women, suggesting that CHMs could be considered to integrate it into conventional therapy to reduce subsequent SS risk for menopausal women., Competing Interests: Financial disclosure/conflicts of interest: None reported., (Copyright © 2020 by The North American Menopause Society.)