Allergen specific immunotherapy（AIT）, as an effective treatment for allergic rhinitis, asthma, and other allergic diseases, has received widespread attention in the field of health economic evaluation in recent years. This article reviews the current status and progress of economic research on AIT, mainly discussing the socioeconomic burden of allergic rhinitis, the results of health economic studies from different countries, and the primary methods used in health economic research on allergic rhinitis. Existing studies indicate that, although AIT involves high initial costs, it offers significant long-term economic benefits by reducing healthcare resource utilization, improving patient quality of life, and decreasing medication dependence. Moreover, reducing initial costs, applying standardized assessment tools, and conducting cross-national comparative analyses have become key directions for future research. Overall, AIT demonstrates strong potential in terms of long-term health benefits and cost savings, providing solid economic evidence for the management of allergic diseases.
Humans ; Desensitization, Immunologic/economics* ; Cost-Benefit Analysis ; Rhinitis, Allergic/economics* ; Economics, Medical

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Multiple primary lung cancer(MPLC)refers to patients with two or more primary lesions of lung cancer.It can be divided into synchronous MPLC(sMPLC)and metachronous MPLC(mMPLC)based on the timing of occurrence.In recent years,the detection rate of MPLC has gradually increased.However,considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis(IM),especially when the histopathological types are identical.Given the significant differences in treatment strategies and prognosis in clinical practice currently,accurate diagnosis of MPLC is cru-cial for personalized precision therapy.Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors.There have been reports of coexisting mutations in the epidermal growth factor receptor(EGFR)and anaplastic lymphoma kinase(ALK)fusion genes in non-small cell lung cancer,but case of EGFR mutation following an ALK mutation has not been mentioned.This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery,and reviews the relevant literature.This paper aims to deepen the understanding of mMPLC and provide clinical refer-ences for the diagnosis and treatment of such patients.

Machine learning(ML)technology has been gradually applied in clinical anesthesia,and the application and research in the perioperative period are increasing.ML can warn occurrence of high-risk events,assist the diagnosis of difficult airway and ultrasound imaging in the perioperative period.Intrao-peratively,ML can predict hypotension,hypoxemia,cardiac arrest,and depth of anesthesia to help achieve precise and safe control of anesthesia.Postoperatively,ML can predict anesthesia-related adverse outcomes.This article summarizes the ML models commonly used in the field of anesthesiology,and reviews the rele-vant studies of ML application in all stages of the perioperative period.The application of ML can improve the perioperative anesthesia management,help to warn the occurrence of high-risk events and reduce anes-thesia-related risks.

The intensifying aging of the population has led to a growing severity of multimorbidity,significantly impacting patients'quality of life.Current anesthetic management approaches primarily target individual diseases,which struggle to effectively address the complexity of multimorbidity.This article re-views the concept and research status of multimorbidity,analyzes the interconnections among aging,multi-morbidity,and frailty,and discusses the influence of multimorbidity on perioperative risks.For patients with multimorbidity,the article proposes perioperative management strategies encompassing preoperative assess-ment,multidisciplinary collaboration,personalized anesthesia plans,intraoperative monitoring,and postop-erative care.Furthermore,the article underscores the shift from single-disease assessments to comprehensive multimorbidity assessment frameworks,and explores novel management models utilizing big data and artificial intelligence to enhance surgical safety and improve patient prognosis.

ObjectiveTo investigate the effects of Tongluo Juanbi granules on chondrocyte apoptosis and Toll-like receptor 4 （TLR4）/myeloid differentiation factor 88 （MyD88）/nuclear factor-κB （NF-κB） signaling pathway of rabbits with knee osteoarthritis （KOA） and study the mechanism of Tongluo Juanbi granules in the prevention and treatment of KOA. MethodThirty New Zealand rabbits were randomly assigned to the following five groups （n=6）： sham group， model group， low-dose and high-dose groups of Tongluo Juanbi granules （4.1 and 8.2 g·kg^-1·d^-1）， and celecoxib group （10.9 mg·kg^-1·d^-1）. The KOA model was established by destabilization of the medial meniscus （DMM） for six weeks. Six weeks after the modeling， the drug was given once a day for eight weeks. The pathological changes of cartilago articularis were observed by hematoxylin-eosin （HE） staining and Safranin O-Fast Green staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） staining was performed to detect chondrocyte apoptosis. Enzyme-linked immunosorbent assay （ELISA） was used to detect the contents of interleukin-1β （IL-1β） and tumor necrosis factor-α （TNF-α） in synovial fluid. The mRNA and protein expression levels of genes related to the TLR4/MyD88/NF-κB signaling pathway were detected by real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） and Western blot， respectively. ResultCompared with the sham group， the cartilago articularis of the model group significantly degenerated. Mankin's score was increased （P<0.01）， and the contents of IL-1β and TNF-α in synovial fluid were increased （P<0.01）. The number of apoptosis of chondrocytes was increased （P<0.01）. The mRNA and protein expressions of TLR4， MyD88， and NF-κB p65 in cartilage tissue were up-regulated （P<0.01）， while the mRNA and protein expressions of Bcl-2 were down-regulated （P<0.01）. Compared with the model group， chondrocyte degeneration in both low-dose and high-dose groups of Tongluo Juanbi granules was improved， and Mankin's score was decreased （P<0.01）. The contents of IL-1β and TNF-α were decreased （P<0.01）， and the number of apoptosis of chondrocytes was decreased （P<0.01）. The mRNA and protein expressions of TLR4， MyD88， and NF-κB p65 in cartilage tissue were down-regulated （P<0.01）， while the mRNA and protein expressions of Bcl-2 were up-regulated （P<0.01）. In addition， in the above observation indicators， the high-dose group of Tongluo Juanbi granules was significantly superior to the low-dose group of Tongluo Juanbi granules. ConclusionTongluo Juanbi granules could inhibit chondrocyte apoptosis in rabbits with KOA and improve cartilage degeneration， which may be related to inhibiting inflammatory responses mediated by TLR4/MyD88/NF-κB signaling pathway.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

Background An association between atmospheric fine particulate matter (PM_2.5) exposure and Parkinson's disease (PD) has been suggested by previous studies, but the results of current epidemiological studies are still inconclusive. Objective To systematically evaluate the relationship between exposure to ambient PM_2.5 and the risk of PD, as well as to explore potential influencing factors, aiming to provide scientific evidence for formulating early prevention strategies for PD. Methods Cochrane Library, PubMed, Web of Science, Medline, Embase, China National Know-ledge Infrastructure (CNKI), Wanfang Database, and VIP Chinese Science and Technology Journal Database were queried. The search terms included Parkinson's disease, particulate matter 2.5, and PM_2.5 in both Chinese and English. Cohort studies examining the association between atmospheric PM_2.5 exposure and the risk of PD were collected and searched from the inception of each database to June 26, 2023. The identified literature was screened, and the basic information of the included studies and their research subjects, outcome indicators, quantitative results of each study, as well as the information required by bias risk assessment were extracted. The Newcastle-Ottawa Scale was employed to assess the risk of literature bias. Meta-analysis, subgroup analysis, sensitivity analysis, and publication bias analysis were conducted in Stata 15.0 software. Results Twelve cohort studies were identified. A total of 17443136 participants with follow-up periods ranging from 3.5 to 22 years were included in the analysis. The meta-analysis, utilizing a random-effects model, revealed that PD risk was elevated by 6% after exposure to PM_2.5 [HR=1.06 (95%CI: 1.02, 1.11), P=0.006]. The subgroup analysis demonstrated that exposure to PM_2.5 increased PD risk by 6% in North America [HR=1.06 (95%CI: 1.00, 1.12), P=0.033] and by 17% in East Asia [HR=1.17 (95%CI: 1.02, 1.33), P=0.020]. However, the effect was not statistically significant in Europe. PD risk exhibited a 7% rise [HR=1.07 (95%CI: 1.02, 1.14), P=0.011] in individuals aged 60 years and older, which was different from that in individuals younger than 60 years. Exposure to various concentrations of PM_2.5 was observed to associate with an elevated risk of PD. The inclusion of adjustments for PD-related comorbidities did not alter the conclusion that ambient PM_2.5 exposure might elevate the risk of PD. The studies with a follow-up duration exceeding 5 years and reporting more than 1000 PD cases suggested a significant increase in the risk of PD due to ambient PM_2.5 exposure [HR=1.06 (95%CI: 1.01, 1.12), P=0.012; HR=1.06 (95%CI: 1.01, 1.11), P=0.027, respectively]. Conversely, no significant association was identified between ambient PM_2.5 exposure and the risk of PD within the cohorts with a follow-up duration of less than 5 years and reporting fewer than 1000 PD cases [HR=1.09 (95%CI: 0.95, 1.26), P=0.214; HR=1.12 (95%CI: 0.98, 1.02), P=0.092, respectively]. The sensitivity analysis showed that the results were stable. The publication bias analysis and the combined trim-and-fill method showed that the results were robust. Conclusion The risk of PD could be increased by ambient PM_2.5 exposure and influenced by age and area. The research results might be affected by the duration of follow-up and the quantity of PD cases reported.

Osteoarthritis (OA) is a chronic degenerative joint disease whose main characteristic is the destruction of articular cartilage, causing pain and disability in patients and seriously affecting their quality of life. OA can be induced by a variety of causes, and pathological changes in articular cartilage are considered to be one of the key driving factors for the occurrence of OA. High mobility group box-1 protein (HMGB1), as a non-histone protein in eukaryotic cells, can participate in regulating the inflammation and apoptosis process of OA chondrocytes, thus leading to the occurrence of OA. This article reviews the research on the mechanism of HMGB1 in OA chondrocytes, with a view to providing new ideas for the clinical prevention and treatment of OA.

Objective To investigate the relationship of miRNA gene polymorphisms with blood pressure(BP)responses to the sodium and potassium diet intervention.Methods In 2004,we recruited 514 participants from 124 families in seven villages of Baoji,Shaanxi Province,China.All subjects were given a three-day normal diet,followed by a seven-day low-salt diet,a seven-day high-salt diet,and finally a seven-day high-salt and potassium supplementation.A total of 19 miRNA single nucleotide polymorphisms(SNPs)were selected for analysis.Results Throughout the sodium-potassium dietary intervention,the BP of the subjects fluctuated across all phases,showing a decrease during the low-salt period and an increase during the high-salt period,followed by a reduction in BP subsequent to potassium supplementation during the high-salt diet.MiR-210-3p SNP rs 12364149 was significantly associated with systolic BP(SBP),diastolic BP(DBP)and mean arterial pressure(MAP)responses to low-salt diet.MiR-4638-3p SNP rs6601178 was significantly associated with SBP while miR-26b-3p SNP rs115254818 was significantly associated with MAP responses to low-salt intervention.In addition,miR-26b-3p SNP rs115254818 was significantly correlated with SBP,DBP and MAP responses to high-salt intervention.MiR-1307-5p SNPs rs1 1191676 and rs2292807 were associated with SBP and MAP responses to high-salt diet.MiR-4638-3p SNP rs6601178,miR-210-3p SNP rs12364149,miR-382-5p SNP rs4906032 and rs4143957 were significantly associated with SBP response to high-salt diet.In addition,miR-26b-3p SNP rs115254818 was significantly associated with SBP,DBP and MAP responses to potassium supplementation.MiR-1307-5p SNPs rs11191676,rs2292807,and miR-19a-3p SNP rs4284505 were significantly associated with SBP responses to high-salt and potassium supplementation.Conclusion miRNA gene polymorphisms are associated with BP response to sodium and potassium,suggesting that miRNA genes may be involved in the pathophysiological process of salt sensitivity and potassium sensitivity.