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Background/purpose: Challenges exist regarding the bonding efficiency of polyaryletherketone (PAEK), a high-performance thermoplastic, attributed to its chemical inertness and hydrophobic surface, hindering effective bonding with resin-matrix cement. This research explored the impact of handheld nonthermal plasma (HNP), under varying operational parameters, on PAEK surface wettability and changes in bonding performance with cement. Materials and methods: Three types of disc-shaped PEAK specimens were prepared, with surface treatments categorized as grinding, airborne-particle abrasion (APB), and HNP. Surface wettability was analyzed using a contact angle analyzer (n = 10). Specimens were bonded with resin cement and subjected to artificial aging tests: distilled water bath (NA), thermocycling, and highly accelerated stress tests (n = 10 for each test). Shear bond strength (SBS) was measured, failure modes were analyzed, and statistical analyses were conducted. Results: The HNP markedly improved PAEK surface wettability, achieving superhydrophilicity (P

Abstract Background Lytic Epstein–Barr virus (EBV) infection plays a major role in the pathogenesis of nasopharyngeal carcinoma (NPC). For patients with recurrent or metastatic NPC and resistant to conventional therapies, adoptive cell therapy using EBV-specific cytotoxic T cells (EBV-CTLs) is a promising option. However, the long production period (around 3 to 4 weeks) and low EBV-CTL purity (approximately 40% of total CD8 T cells) in the cell product limits the application of EBV-CTLs in clinics. Thus, this study aimed to establish a protocol for the rapid production of EBV-CTLs. Methods By culturing peripheral blood mononuclear cells (PBMCs) from EBV-seropositive donors with EBV-specific peptides and interleukin (IL)-2, IL-15, and interferon α (IFN-α) for 9 days, we identified that IL-15 can enhance IL-2-mediated CTL activation and significantly increase the yield of CTLs. Results When IFN-α was used in IL-2/IL-15-mediated CTL production from days 0 to 6, the productivity of EBV-CTLs and EBV-specific cytotoxicity significantly were reinforced relative to EBV-CTLs from IL-2/IL-15 treatment. Additionally, IFN-α-induced production improvement of virus-specific CTLs was not only the case for EBV-CTLs but also for cytomegalovirus-specific CTLs. Conclusion We established a novel protocol to rapidly expand highly pure EBV-CTLs from PBMCs, which can produce EBV-CTLs in 9 days and does not require feeder cells during cultivation.

Abstract Two important factors affecting the progress of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the S-protein binding function of ACE2 receptors and the membrane fluidity of host cells. This study aimed to evaluate the effect of static magnetic field (SMF) on S-protein/ACE2 binding and cellular membrane fluidity of lung cells, and was performed in vitro using a Calu-3 cell model and in vivo using an animal model. The ability of ACE2 receptors to bind to SARS-CoV-2 spike protein on host cell surfaces under SMF stimulation was evaluated using fluorescence images. Host lung cell membrane fluidity was tested using fluorescence polarization to determine the effects of SMF. Our results indicate that 0.4 T SMF can affect binding between S-protein and ACE2 receptors and increase Calu-3 cell membrane fluidity, and that SMF exposure attenuates LPS-induced alveolar wall thickening in mice. These results may be of value for developing future non-contact, non-invasive, and low side-effect treatments to reduce disease severity in COVID-19-invaded lungs.

The rapid acceleration of global warming has led to an increased burden of high temperature-related diseases (HTDs), highlighting the need for advanced evidence-based management strategies. We have developed a conceptual framework aimed at alleviating the global burden of HTDs, grounded in the One Health concept. This framework refines the impact pathway and establishes systematic data-driven models to inform the adoption of evidence-based decision-making, tailored to distinct contexts. We collected extensive national-level data from authoritative public databases for the years 2010–2019. The burdens of five categories of disease causes – cardiovascular diseases, infectious respiratory diseases, injuries, metabolic diseases, and non-infectious respiratory diseases – were designated as intermediate outcome variables. The cumulative burden of these five categories, referred to as the total HTD burden, was the final outcome variable. We evaluated the predictive performance of eight models and subsequently introduced twelve intervention measures, allowing us to explore optimal decision-making strategies and assess their corresponding contributions. Our model selection results demonstrated the superior performance of the Graph Neural Network (GNN) model across various metrics. Utilizing simulations driven by the GNN model, we identified a set of optimal intervention strategies for reducing disease burden, specifically tailored to the seven major regions: East Asia and Pacific, Europe and Central Asia, Latin America and the Caribbean, Middle East and North Africa, North America, South Asia, and Sub-Saharan Africa. Sectoral mitigation and adaptation measures, acting upon our categories of Infrastructure & Community, Ecosystem Resilience, and Health System Capacity, exhibited particularly strong performance for various regions and diseases. Seven out of twelve interventions were included in the optimal intervention package for each region, including raising low-carbon energy use, increasing energy intensity, improving livestock feed, expanding basic health care delivery coverage, enhancing health financing, addressing air pollution, and improving road infrastructure. The outcome of this study is a global decision-making tool, offering a systematic methodology for policymakers to develop targeted intervention strategies to address the increasingly severe challenge of HTDs in the context of global warming.

Background: We introduced an adapted Lyman normal-tissue complication probability (NTCP) model, incorporating clinical risk factors and censored time-to-event data, to estimate the risk of major adverse cardiac events (MACE) following left breast cancer radiotherapy (RT). Materials and methods: Clinical characteristics and MACE data of 1100 women with left-side breast cancer receiving postoperative RT from 2005 to 2017 were retrospectively collected. A modified generalized Lyman NTCP model based on the individual left ventricle (LV) equivalent uniform dose (EUD), accounting for clinical risk factors and censored data, was developed using maximum likelihood estimation. Subgroup analysis was performed for low-comorbidity and high-comorbidity groups. Results: Over a median follow-up 7.8 years, 64 patients experienced MACE, with higher mean LV dose in affected individuals (4.1 Gy vs. 2.9 Gy). The full model accounting for clinical factors identified D50 = 43.3 Gy, m = 0.59, and n = 0.78 as the best-fit parameters. The threshold dose causing a 50 % probability of MACE was lower in the high-comorbidity group (D50 = 30 Gy) compared to the low-comorbidity group (D50 = 45 Gy). Predictions indicated that restricting LV EUD below 5 Gy yielded a 10-year relative MACE risk less than 1.3 and 1.5 for high-comorbidity and low-comorbidity groups, respectively. Conclusion: Patients with comorbidities are more susceptible to cardiac events following breast RT. The proposed modified generalized Lyman model considers nondosimetric risk factors and addresses incomplete follow-up for late complications, offering comprehensive and individualized MACE risk estimates post-RT.

Background: Given the established association between sarcopenia and cognitive impairment was mainly in the older and oldest-old population or people with relatively limited education, this study extends the investigation to community-dwelling middle-to-old age adults in urban communities, emphasizing the need for preventive intervention for muscle health and healthy longevity. Methods: Data of 712 participants from the Gan-Dau Healthy Longevity Plan were retrieved for analysis, and all participants were stratified by age (50–64, 65–74 and 75+ years old). Possible sarcopenia was defined by 2019 consensus report of the Asian Working Group for Sarcopenia (AWGS). This study used four neuropsychological tests for analysis, i.e., Mini-Mental Status Examination (MMSE), California Verbal Learning Test II (CVLT-SF), Digital Symbol Substitution Test (DSST) and Verbal fluency (VF) for global and domain-specific cognitive function. Multivariate generalized linear models (GLMs) were employed to investigate the associations between possible sarcopenia and cognitive function in each age-specific groups. Results: The prevalence of possible sarcopenia increased with age, with 31.8 %, 37.7 %, and 55.6 % in participants aged 5064, 65–74 and, 75+ years, respectively. On the other hand, cognitive performance declined with age. In particular, among participants aged 75+ years with possible sarcopenia, their cognitive performance were poorer than robust counterparts, including MMSE (26.6 [3.4] vs. 27.4 [2.6]), CVTL-SF (total score: 21.5 [5.4] vs. 23.8 [5.5]; 30-second delayed recall: 6.0 [1.7] vs. 6.5 [1.6]), DSST (32.8 [14.3] vs. 41.3 [18.7]), and VF (12.8 [5.1] vs. 14.8 [4.9]). Multivariate generalized linear model indicated that possible sarcopenia was associated with lower MMSE (β: −0.70, p = 0.014) and lower DSST (β: −7.00, p = 0.010) in those aged 50–64 years. Moreover, possible sarcopenia was associated with lower CVLT-SF (total score β:-1.90, p = 0.028), lower DSST (β: −6.45, p

Abstract Colorectal cancer (CRC) patients who receive cancer surgeries from higher-volume providers may have better outcomes. However, the definitions of surgical volume may affect the results. We aim to analyze the effects of different definitions of surgical volume on patient outcomes. We conducted a nationwide population-based study in Taiwan that enrolled all patients who underwent definitive surgery for newly diagnosed CRC. We used three common definitions of surgical volume: total volume means the total surgical number conducted by the same provider during the study period; cumulative volume was calculated as the number of operations the surgeon performed before the index procedure; annual volume was calculated as the number of times the surgeon had been responsible for surgery during the index year. In this study, we included 100,009 newly diagnosed CRC patients, including 55.8% males, of median age 66 years at diagnosis (range 20–105 years). After adjustment for the patient and provider characteristics, we found that CRC patients receiving definitive surgery by higher-volume providers had better outcomes, especially where surgeon volume may play a more important role than hospital volume. The cumulative volume could predict the 5-year mortality of the study cohort better than the total and annual volume.

Abstract Background Frailty often coexists with heart failure (HF), which significantly aggravates the clinical outcomes of older adults. However, studies investigating the interplay between frailty and HF in older adults are scarce. We aimed to assess the prevalence of frailty using the cumulative deficit approach and evaluate the impacts of frailty on health utilization, use of HF‐related medications and adverse clinical outcomes (all‐cause mortality, all‐cause readmissions and HF readmissions) among older HF patients. Methods A total of 38 843 newly admitted HF patients were identified from Taiwan's National Health Insurance Research Database and categorized into three frailty subgroups (fit, mild frailty and severe frailty) based on the multimorbidity frailty index. Cox regression models and Fine and Gray subdistribution hazard models were used to estimate the impacts of frailty on clinical outcomes at 1 and 2 years of follow‐up. Generalized estimating equation models were further conducted to evaluate the associations between longitudinal and time‐varying use of HF‐related medications and clinical outcomes among distinct frailty subgroups. Results Of 38 843 older HF patients (mean age 80.4 ± 8.5 years, 52.3% females) identified, 68.3% were categorized as frail (47.5% of mild frailty and 20.8% of severe frailty). The median number of readmissions (fit: 1 [inter‐quartile range—IQR 2], mild frailty: 1 [IQR 2] and severe frailty: 2 [IQR 3]) increased with the severity of frailty. Only 27.3% of HF patients died of cardiovascular diseases regardless of their frailty status. Compared with the fit group, the severe frailty group was associated with increased risk of all‐cause mortality (adjusted hazard ratio 1.16, 95% confidence interval [CI] 1.11–1.21), all‐cause readmissions (subdistributional hazard ratio (sHR) 1.21, 95% CI 1.16–1.25) and HF‐related readmissions (sHR 1.14, 95% CI 1.09–1.20) at 2 years of follow‐up. Those who used triple or more HF‐related medications were at lower risk for all‐cause readmissions (adjusted odds ratio [aOR] 0.49, 95% CI 0.44–0.54) and HF‐related readmissions (aOR 0.42, 95% CI 0.37–0.47) at 2 years of follow‐up even in the severe frailty group. Conclusions Frailty is highly prevalent and associated with increased risk of all‐cause mortality, all‐cause readmissions and HF readmissions among older HF patients. Those who were using triple or more HF‐related medications were at lower risk of adverse clinical outcomes across distinct frailty subgroups. Further studies are needed to optimize the treatment strategies for older HF patients with distinct frailty status.

Tobacco fields have been continuously cropped for several years because of the high demand for tobacco leaves and limited land resources. To explore the effects of continuous cropping on tobacco growth and soil microecological community structure, this study compared the agronomic traits and physiological resistance characteristics of tobacco plants grown in noncontinuous cropping soil and soil with different continuous cropping years. High-throughput sequencing technology was used to analyze and predict the microbial community structure and functional gene variation patterns of tobacco soil. The results demonstrated that continuous cropping significantly impacted the average height, leaf area, and stem diameter of tobacco plants, as well as the contents of malondialdehyde, hydrogen peroxide, and glutathione in tobacco leaves that were continuously cropped. The relative abundances of Proteobacteria, Bacteroidetes, and Gemmatimonadetes in tobacco soil decreased with an increase in continuous cropping years, while relative abundance of Acidobacteria increased. The biodiversity index of tobacco soil samples showed a decreasing trend with an increase in continuous cropping years, with the sample with the longest continuous cropping year (33 years) having the lowest biodiversity index. Prediction of the potential functions of soil samples with different continuous cropping years revealed that the Z-scores of each pathway in noncontinuous cropping soil samples ranged from 1.12 to 0.078, while those in 33-year continuous cropping samples decreased from −0.10 to −1.41. Our findings indicate that continuous cropping has negative impacts on soil health and microecology, leading to a reduction in beneficial microbial population and microbial diversity.

Baicalin is a flavonoid glycoside obtained from the dried root of Scutellaria baicalensis Georgi, which belongs to the Labiatae family. Accumulating evidence indicates that baicalin has favorable therapeutic effects on cardiovascular diseases. Previous studies have revealed the therapeutic effects of baicalin on atherosclerosis, myocardial ischemia/reperfusion injury, hypertension, and heart failure through anti-inflammatory, antioxidant, and lipid metabolism mechanisms. In recent years, some new ideas related to baicalin in ferroptosis, coagulation and fibrinolytic systems have been proposed, and new progress has been made in understanding the mechanism by which baicalin protects cardiomyocytes. However, many relevant underlying mechanisms remain unexplained, and much experimental data is lacking. Therefore, further research is needed to determine these mechanisms. In this review, we summarize the mechanisms of baicalin, which include its anti-inflammatory and antioxidant effects; inhibition of endothelial cell apoptosis; modulation of innate immunity; suppression of vascular smooth muscle cells proliferation, migration, and contraction; regulation of coagulation and fibrinolytic systems; inhibition of myocardial hypertrophy; prevention of myocardial fibrosis; and anti-apoptotic effects on cardiomyocytes.

The urgency of environmental sustainability has catalyzed a thorough reconsideration of traditional workspaces and their environmental impact, particularly concerning carbon footprint stemming from business-related travel and daily commutes. In response to these concerns, the innovative notion of the “Phygital Workspace” has arisen. Moreover, the advent of the COVID-19 pandemic has accelerated the proliferation of this technology. In a Phygital Workspace, physical and digital elements coexist and interact to enhance productivity, collaboration, and overall work experience. This integration is often facilitated using advanced digital technologies, such as Augmented Reality (AR), Virtual Reality (VR), Mixed Reality (MR), and other immersive or interactive tools. This conceptual framework sets the stage for the seamless integration of both physical and digital dimensions, empowered by the potential of Extended Reality (XR) technology. An integral part of this review involves the analysis of various workspace scenarios, and further examines the role of a Phygital Workspace plays in reducing carbon footprint within each context. The scenarios under examination include flexible workspace scenarios, field work scenarios, and hybrid work scenarios. XR technology’s contributions to reducing carbon footprint are evaluated by minimizing the need for physical travel, enabling remote collaboration, and enhancing workspace efficiency within these scenarios. Employing a systematic review methodology, this review considers the status of XR technology adoption in diverse business environments, pinpointing its strengths and limitations. The aim is to provide a solid foundation for the framework of a new typological work environment that leverages XR technology to effectively reduce the carbon footprint associated with travel. The framework comprises four key dimensions: XR Infrastructure, Collaborative Work Environment, Social Interaction Enhancement, and Environmental Impact Assessment. These dimensions collectively guide the development and implementation of sustainable Phygital Workspaces, catering to technological, social, and ecological considerations. It is an impassioned call for collaborative efforts among researchers, policymakers, and organizations to converge their expertise for a more environmentally conscious future of work.

Idiopathic cholangiopathies are diseases that affect cholangiocytes, and they have unknown etiologies. Currently, orthotopic liver transplantation is the only treatment available for end-stage liver disease. Limited access to the bile duct makes it difficult to model cholangiocyte diseases. In this study, by mimicking the embryonic development of cholangiocytes and using a robust, feeder- and serum-free protocol, we first demonstrate the generation of unique functional 3D organoids consisting of small and large cholangiocytes derived from human pluripotent stem cells (PSCs), as opposed to traditional 2D culture systems. At day 28 of differentiation, the human PSC–derived cholangiocytes expressed markers of mature cholangiocytes, such as CK7, CK19, and cystic fibrosis transmembrane conductance regulator (CFTR). Compared with the 2D culture system–generated cholangiocytes, the 3D cholangiocyte organoids (COs) showed higher expression of the region-specific markers of intrahepatic cholangiocytes YAP1 and JAG1 and extrahepatic cholangiocytes AQP1 and MUC1. Furthermore, the COs had small-large tube-like structures and functional assays revealed that they exhibited characteristics of mature cholangiocytes, such as multidrug resistance protein 1 transporter function and CFTR channel activity. In addition to the extracellular matrix supports, the epidermal growth factor receptor (EGFR)-mediated signaling regulation might be involved in this cholangiocyte maturation and differentiation. These results indicated the successful generation of intrahepatic and extrahepatic cholangiocytes by using our 3D organoid protocol. The results highlight the advantages of our 3D culture system over the 2D culture system in promoting the functional differentiation and maturation of cholangiocytes. In summary, in advance of the previous works, our study provides a possible concept of small-large cholangiocyte transdifferentiation of human PSCs under cost-effective 3D culture conditions. The study findings have implications for the development of effective cell-based therapy using COs for patients with cholangiopathies.

Abstract Group A Streptococcus (GAS) is a significant human pathogen that poses a global health concern. However, the development of a GAS vaccine has been challenging due to the multitude of diverse M-types and the risk of triggering cross-reactive immune responses. Our previous research has identified a critical role of PrsA1 and PrsA2, surface post-translational molecular chaperone proteins, in maintaining GAS proteome homeostasis and virulence traits. In this study, we aimed to further explore the potential of PrsA1 and PrsA2 as vaccine candidates for preventing GAS infection. We found that PrsA1 and PrsA2 are highly conserved among GAS isolates, demonstrating minimal amino acid variation. Antibodies specifically targeting PrsA1/A2 showed no cross-reactivity with human heart proteins and effectively enhanced neutrophil opsonophagocytic killing of various GAS serotypes. Additionally, passive transfer of PrsA1/A2-specific antibodies conferred protective immunity in infected mice. Compared to alum, immunization with CFA-adjuvanted PrsA1/A2 induced higher levels of Th1-associated IgG isotypes and complement activation and provided approximately 70% protection against invasive GAS challenge. These findings highlight the potential of PrsA1 and PrsA2 as universal vaccine candidates for the development of an effective GAS vaccine.

Abstract Background This study aims to analyze the longitudinal variation of occlusal force distribution prior to and after fixed restoration for molar full-crowns with T-SCAN III which provide reference for occlusal adjustment and long-term maintenance. Methods We enrolled a total of 20 patients who received conventional restorative treatment for molars. The occlusion examination was conducted in 3 stages (before placement, immediately after placement, and 3 months after placement) using T-SCAN III (Tekscan South Boston, MA, USA, 10.0) to examine and measure the occlusal contact areas of the full dentition. Results The results indicated that the occlusal force distribution in the molar region of the patients changed before and after the fixed restoration, but the percentages of occlusal force in the dental arch of the molar did not differ significantly before and after the restoration (P > 0.05). Three months after the fixed restoration, the percentage of occlusal force in the restored dental arches of lateral teeth increased significantly (P

With the popularization of intelligent cars, users’ understanding of the value of cars gradually changes from a travel tool to a “third living space”, and cabin comfort is becoming a criterion for evaluating the goodness of cars. In this paper, we start from the physical environment and human-computer interaction environment that affect the comfort of the intelligent cockpit of a car and establish a comprehensive comfort evaluation model of the intelligent cockpit of a car based on the support vector machine (SVM) algorithm in machine learning by conducting experiments on the comfort evaluation of the intelligent cockpit of a car and compare it with several classical machine learning algorithms. The mean square error ( $MSE$ ) of the model based on the SVM algorithm is 0.00096, and the coefficient of determination ( $R^{2}$ ) reaches 0.966, which is better than several other algorithms. The results show that the established evaluation model has good generalization ability and can evaluate the comprehensive comfort of the intelligent cockpit of the car, thus helping the cockpit to make timely and accurate comfort adjustments to ensure the occupant’s riding experience. This project provides a reference direction for the comprehensive evaluation of cockpit comfort, which is of great significance for the future development of intelligent cockpit comfort. In addition, the comfort model can be applied to a variety of comfort evaluation scenarios, which has great practical value.

Purpose: Obstructive sleep apnea (OSA) is a chronic disease that affects 1%–6% of children. Our study aims to explore the effectiveness and clinical characteristics of integrative Traditional Chinese Medicine (ITCM) for pediatric OSA. Materials and methods: In this retrospective cohort study, we assessed differences of polysomnography (PSG) parameters and clinical characteristics between 2009 and 2020. Children

The prediction of equilibrium components for chemical reactions is a considerable section in the metallurgical industry. According to the ion and molecule coexistence theory (IMCT), a modified mass action concentration model based on a thermodynamic database is proposed in this paper, which complys with the law of mass conservation and can be applied in the batching process for Al-Ti-Ca-oxide system that originates from SHS (Self-propagating High-temperature Synthesis) metallurgy. The trend for slag and alloy component under different batching conditions are in good agreement with experiment, while the difference between the theoretical calculation and experiment can be attributed to the deviation from the thermodynamic equilibrium. The modified mass action concentration model with melts and slag can be used to predict the composition and content of the system when equilibrium is achieved at a certain temperature under a specific material ratio, which is conducive to reducing the cost of the experiment and predicting the operability of the actual process. Moreover, it is believed that this thermodynamic insight may has certain application prospects in these metallurgical procedure based on the equilibrium process.

Stingers, evolved from ovipositors, are an important defense organ for the Apidae, Vespidae, and Formicidae species. However, the molecular mechanism of stinger development remains unclear. Here, we show that the earliest time point for the appearance of stingers in Apis mellifera is at the 1-day-old worker pupal stage based on morphological observations and anatomy from the pre-pupal to adult stages. To discover the genes related to stinger development, we first comprehensively compared the stinger transcriptome at different stages and screened 1282, 186, and 166 highly expressed genes in the stingers of 1- and 5-day-old worker pupae and newly emerged worker bees (NEBs), respectively, then identified 25 DEGs involved in the early stage of stinger development. We found that Dll was a key candidate gene in the early development of A. mellifera stingers by combining analyses of the protein–protein interaction network and spatiotemporal expression patterns. An RNAi experiment showed that about 20% of individuals exhibited tip bending in the piercing parts of their stingers in the Dll-dsRNA-treated group, with the morphology presenting as side–side or front–back tip bending. This indicates that Dll plays a vital role in the early development of A. mellifera stingers. Together, our study provides insight into the molecular mechanism of Hymenoptera stinger development and an inspiration for the molecular breeding of gentle honeybee species with stinger abnormalities.

BackgroundAntiretroviral therapy has led to AIDS being a chronic disease. Nevertheless, the presence of constantly emerging drug resistance mutations poses a challenge to clinical treatment. A systematic analysis to summarize the advancements and uncharted territory of drug resistance mutations is urgently needed and may provide new clues for solving this problem.MethodsWe gathered 3,694 publications on drug resistance mutations from the Web of Science Core Collection with CiteSpace software and performed an analysis to visualize the results and predict future new directions and emerging trends. Betweenness centrality, count, and burst value were taken as standards.ResultsThe number of papers on HIV medication resistance mutations during the last 10 years shows a wave-like trend. In terms of nation, organization, and author, the United States (1449), University of London (193), and Mark A. Wainberg (66) are the most significant contributors. The most frequently cited article is “Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.” Hot topics in this field include “next-generation sequencing,” “tenofovir alafenamide,” “children,” “regimens,” “accumulation,” “dolutegravir,” “rilpivirine,” “sex,” “pretreatment drug resistance,” and “open label.” Research on drug resistance in teenagers, novel mutation detection techniques, and drug development is ongoing, and numerous publications have indicated the presence of mutations related to current medications. Therefore, testing must be performed regularly for patients who have used medications for a long period. Additionally, by choosing medications with a longer half-life, patients can take fewer doses of their prescription, increasing patient compliance.ConclusionThis study involved a bibliometric visualization analysis of the literature on drug resistance mutations, providing insight into the field’s evolution and emerging patterns and offering academics a resource to better understand HIV drug resistance mutations and contribute to the field’s advancement.

BackgroundScrub typhus, caused by the Orientia tsutsugamushi (Ot), is a widespread vector-borne disease transmitted by chigger mites. Hemophagocytic lymphohistiocytosis (HLH) is considered to be one of the potentially severe complications. The diagnosis of scrub typhus-associated HLH may be overlooked due to the non-specific clinical characteristics and the absence of pathognomonic eschar.Case presentationWe obtained clinical data from two patients in the South of Sichuan, China. The first case involved a 6-year-old girl who exhibited an unexplained fever and was initially diagnosed with sepsis, HLH, and pulmonary infection. The other patient presented a more severe condition characterized by multiple organ dysfunction and was initially diagnosed with septic shock, sepsis, HLH, acute kidney injury (AKI), and pulmonary infection. At first, a specific examination for scrub typhus was not performed due to the absence of a characteristic eschar. Conventional peripheral blood cultures yielded negative results in both patients, and neither of them responded to routine antibiotics. Fortunately, the causative pathogen Orientia tsutsugamushi (Ot) was detected in the plasma samples of both patients using metagenomics next-generation sequencing (mNGS) and further confirmed by polymerase chain reaction. Subsequently, they both were treated with doxycycline and recovered quickly.ConclusionThe unbiased mNGS provided a clinically actionable diagnosis for an uncommon pathogen-associated infectious disease that had previously evaded conventional diagnostic approaches.

Methylene blue (MB) was found to exert neuroprotective effect on different brain diseases, such as ischemic stroke. This study assessed the MB effects on ischemia induced brain edema and its role in the inhibition of aquaporin 4 (AQP4) and metabotropic glutamate receptor 5 (mGluR5) expression. Rats were exposed 1 h transient middle cerebral artery occlusion (tMCAO), and MB was injected intravenously following reperfusion (3 mg/kg). Magnetic resonance imaging (MRI) and 2,3,5-triphenyltetrazolium chloride (TTC) staining was performed 48 h after the onset of tMCAO to evaluate the brain infarction and edema. Brain tissues injuries as well as the glial fibrillary acidic protein (GFAP), AQP4 and mGluR5 expressions were detected. Oxygen and glucose deprivation/reoxygenation (OGD/R) was performed on primary astrocytes (ASTs) to induce cell swelling. MB was administered at the beginning of reoxygenation, and the perimeter of ASTs was measured by GFAP immunofluorescent staining. 3,5-dihydroxyphenylglycine (DHPG) and fenobam were given at 24 h before OGD to examine their effects on MB functions on AST swelling and AQP4 expression. MB remarkably decreased the volumes of T2WI and ADC lesions, as well as the cerebral swelling. Consistently, MB treatment significantly decreased GFAP, mGluR5 and AQP4 expression at 48 h after stroke. In the cultivated primary ASTs, OGD/R and DHPG significantly increased ASTs volume as well as AQP4 expression, which was reversed by MB and fenobam treatment. The obtained results highlight that MB decreases the post-ischemic brain swelling by regulating the activation of AQP4 and mGluR5, suggesting potential applications of MB on clinical ischemic stroke treatment.

Abstract Organic electrochemical transistors (OECTs) are recognized for their ability to combine electronic and ionic transport in the channel, resulting in improved transconductance and reduced operation voltage compared to organic field‐effect transistors (OFETs). Nevertheless, the hydrophobic nature of conjugated polymers remains a hindrance to ion drift, thereby causing slow switching speed and limiting their practical application. This study introduces the ionic liquid 1‐ethyl‐3‐methylimidazolium bis(trifluoromethylsulfonyl)imide ([EMIM][TFSI]) adsorbed in a metal–organic framework (MOF‐525) as an ion reservoir within a conjugated polymer, for the first time, to serve as the active channel in OECTs. Due to shortened ionic drift time, in the poly[2,5‐bis(3‐tetradecylthiophen‐2‐yl)thieno[3,2‐b]thiophene] (PBTTT‐C14) system, the original polymer membrane without MOF‐525/[EMIM][TFSI] exhibits a characteristic ON time (τON) of 28.75 s, whereas the PBTTT‐C14/MOF‐525/[EMIM][TFSI] composite film significantly reduces the τON to 2.56 s with ON/OFF current ratio of 102. Enhancing response speed through facile physical blending of MOF‐525/[EMIM][TFSI] in conjugated polymer film can also be realized on flexible substrate and in poly(3‐hexylthiophene‐2,5‐diyl) (P3HT) system which provide a general strategy to broaden the selection of conjugated polymers in accumulation mode OECTs.

Background: It has recently been determined that N6-methyladenosine (m6A) RNA methylation regulators have prominent effects on several cancers. However, the potential role of m6A modification in lung squamous cell carcinoma (LUSC) remains unclear. Methods: We evaluated the modification pattern of m6A and studied the biological function of m6A regulators in LUSC. Then, we constructed the m6Ascore to predict the prognosis of LUSC and analyzed the relationship between the m6Ascore and tumor mutation burden, immune cell infiltration, and immunotherapy. Result: In the unsupervised consensus cluster analysis, three different m6Aclusters were identified, which correspond to an immune activation state, a moderate immune activation state, and an immune tolerance state. Forty-two genes related to the m6A phenotype were used to construct the m6Ascore; subsequently, multiple validations of the m6Ascore were carried out to determine the relationship between the score and immune cell infiltration and response to CTLA-4/PD-1 inhibitor treatment. Further analysis revealed that the m6Ascore could effectively predict the prognosis of LUSC and that the m6A phenotype-related genes, FAM162A and LOM4, might be potential biomarkers. Conclusion: These findings highlight the potential role of m6A modification in the prognosis, TME, and immunotherapy of LUSC and have profound implications for developing more effective personalized treatment strategies for LUSC.

In 2019, the coronavirus pandemic was caused by severe acute respiratory syndrome coronavirus 2. In Taiwan, an inflatable negative pressure isolation chamber (INPIC) was applied into the emergency air medical transport (EAMT) in 2020. The standard operating procedure of the INPIC as infection control was developed and practiced in the UH-60M helicopter. There were five cases moved by the EAMT from the Lanyu Township and Ludao Township to Taiwan's mainland. After they were screened positive for coronavirus disease 2019 (COVID-19) with a rapid test, the medical staff completed the INPIC preparation and loaded the patients into it before the EAMT. This study reported that none of the crewmembers were infected with COVID-19 during the transfers. However, some restrictions of the INPIC could be improved in the future, e.g. limited space, thermal stress, equipment immobilization, and communication barrier. The medical team should assess the efficiency and safety using the INPIC based on each patient's condition before the flight.

Abstract Background The hypoxia-responsive long non-coding RNA, RP11-367G18.1, has recently been reported to induce histone 4 lysine 16 acetylation (H4K16Ac) through its variant 2; however, the underlying molecular mechanism remains poorly understood. Methods RNA pull-down assay and liquid chromatography-tandem mass spectrometry were performed to identify RP11-367G18.1 variant 2-binding partner. The molecular events were examined utilizing western blot analysis, real-time PCR, luciferase reporter assay, chromatin immunoprecipitation, and chromatin isolation by RNA purification assays. The migration, invasion, soft agar colony formation, and in vivo xenograft experiments were conducted to evaluate the impact of RP11-367G18.1 variant 2–YY1 complex on tumor progression. Results In this study, RNA sequencing data revealed that hypoxia and RP11-367G18.1 variant 2 co-regulated genes were enriched in tumor-related pathways. YY1 was identified as an RP11-367G18.1 variant 2-binding partner that activates the H4K16Ac mark. YY1 was upregulated under hypoxic conditions and served as a target gene for hypoxia-inducible factor-1α. RP11-367G18.1 variant 2 colocalized with YY1 and H4K16Ac in the nucleus under hypoxic conditions. Head and neck cancer tissues had higher levels of RP11-367G18.1 and YY1 which were associated with poor patient outcomes. RP11-367G18.1 variant 2–YY1 complex contributes to hypoxia-induced epithelial–mesenchymal transition, cell migration, invasion, and tumorigenicity. YY1 regulated hypoxia-induced genes dependent on RP11-367G18.1 variant 2. Conclusions RP11-367G18.1 variant 2–YY1 complex mediates the tumor-promoting effects of hypoxia, suggesting that this complex can be targeted as a novel therapeutic strategy for cancer treatment.

Background: Enterobacterales carrying blaNDM represent an emerging challenge in treating infectious diseases. In this study, we aimed to investigate the characteristics of blaNDM-producing Enterobacterales from three hospitals in southern Taiwan. Methods: Enterobacterales strains that were nonsusceptible to more than one carbapenem (ertapenem, meropenem, imipenem, or doripenem) were collected from hospitalized patients. Molecular typing for New Delhi metallo-β-lactamase (NDM) and antibiotic susceptibility tests were performed, followed by multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), and plasmid analysis by PCR-based replicon typing. Results: A total of 1311 carbapenem-nonsusceptible Enterobacterales were isolated from 2017 to 2021. blaNDM-encoding genes were detected in 108 isolates, with 53 (49.1%) harboring blaNDM-1 and 55 (50.9%) harboring blaNDM-5. The rate of blaNDM-1 detection among isolates decreased to 2% in 2021. However, the rate of E. coli harboring blaNDM-5 increased from 1% to 12% of total isolates during the study period. Of 47 NDM-5-positive E. coli isolates, 44 (93.6%) were ST8346 with high genetic relatedness. E. coli ST8346 isolates showed high-level resistance to both carbapenems and aminoglycosides. Most (38 out of 47, 80.9%) blaNDM-5-harboring E. coli isolates co-harbored blaOXA-181. We analyzed the regions harboring blaNDM-5 in E. coli ST8346 via PCR amplification. blaNDM-5 and blaOXA-181 were located on two separate plasmids, IncF and IncX3, respectively. Conclusion: The dissemination of E. coli ST8346 caused an increase in blaNDM-5 and blaOXA-181 co-harboring Enterobacterales in southern Taiwan, which show high-level resistance to both carbapenems and aminoglycosides. We identified a distinct IncF plasmid encoding blaNDM-5 that has the potential for rapid spread and needs further surveillance.

Background and Objectives: Frailty in older adults is associated with adverse health outcomes. This study aimed to analyze the frailty status of community-dwelling older adults in Taiwan using the Kihon Checklist (KCL) and explore associations with demographic, physiological, and functional factors. Materials and Methods: In this cross-sectional study, 278 community-dwelling older adults were classified as robust, prefrail, or frail based on their KCL scores. Participants underwent physical fitness assessments including muscle strength and endurance tests, walking speed tests, and flexibility tests. One-way ANOVA and logistic regression analyses were used to examine differences and associations between frailty status and physical fitness indicators. Results: 36% of participants were robust, 47.1% prefrail, and 16.9% frail. The robust group significantly outperformed the prefrail and frail groups in the 30 s sit-to-stand test, 2.44 m sit-to-walk test, and walking speed (p < 0.001). The 2.44 m sit-to-walk test was a significant predictor of prefrailty (OR = 1.18, 95% CI = 1.02–1.36) after adjusting for other physical fitness indicators. Conclusions: Lower limb functional capacity, particularly in the 2.44 m sit-to-walk test, was significantly associated with pre-frailty among community-dwelling older adults in Taiwan. Early screening, the classification of frailty by the Kihon Checklist, and targeted interventions focusing on lower limb strength, endurance, and mobility are crucial for preventing and delaying frailty progression in older populations.