Text classification algorithm of tourist attractions subcategories with modified TF-IDF and Word2Vec.

Text classification, as an important research area of text mining, can quickly and effectively extract valuable information to address the challenges of organizing and managing large-scale text data in the era of big data. Currently, the related research on text classification tends to focus on the application in fields such as information filtering, information retrieval, public opinion monitoring, and library and information, with few studies applying text classification methods to the field of tourist attractions. In light of this, a corpus of tourist attraction description texts is constructed using web crawler technology in this paper. We propose a novel text representation method that combines Word2Vec word embeddings with TF-IDF-CRF-POS weighting, optimizing traditional TF-IDF by incorporating total relative term frequency, category discriminability, and part-of-speech information. Subsequently, the proposed algorithm respectively combines seven commonly used classifiers (DT, SVM, LR, NB, MLP, RF, and KNN), known for their good performance, to achieve multi-class text classification for six subcategories of national A-level tourist attractions. The effectiveness and superiority of this algorithm are validated by comparing the overall performance, specific category performance, and model stability against several commonly used text representation methods. The results demonstrate that the newly proposed algorithm achieves higher accuracy and F1-measure on this type of professional dataset, and even outperforms the high-performance BERT classification model currently favored by the industry. Acc, marco-F1, and mirco-F1 values are respectively 2.29%, 5.55%, and 2.90% higher. Moreover, the algorithm can identify rare categories in the imbalanced dataset and exhibit better stability across datasets of different sizes. Overall, the algorithm presented in this paper exhibits superior classification performance and robustness. In addition, the conclusions obtained by the predicted value and the true value are consistent, indicating that this algorithm is practical. The professional domain text dataset used in this paper poses higher challenges due to its complexity (uneven text length, relatively imbalanced categories), and a high degree of similarity between categories. However, this proposed algorithm can efficiently implement the classification of multiple subcategories of this type of text set, which is a beneficial exploration of the application research of complex Chinese text datasets in specific fields, and provides a useful reference for the vector expression and classification of text datasets with similar content.

A novel concept for cleavable linkers applicable to conjugation chemistry - design, synthesis and characterization.

Linkers with disulfide bonds are the only cleavable linkers that utilize physiological thiol gradients as a trigger to initiate the intracellular drug release cascade. Herein, we present a novel concept exploiting the thiol gradient phenomena to design a new class of cleavable linker with no disulfide bond. To support the concept, an electron-deficient sulfonamide-based cleavable linker amenable to conjugation of drug molecules with targeting agents, was developed. Modulating the electron-withdrawing nature of the aryl sulfonamide was critical to the balance between the stability and drug release. Favorable stability and payload release in human serum under physiologically relevant thiol concentrations was demonstrated with two potent cytotoxics. Intracellular payload release was further validated in cell-based assay in context of antibody-drug conjugate generated from monoclonal antibody and sulfonamide containing linker. To support the proposed release mechanism, possible downstream by-products formed from the drug-linker adduct were characterized.

Effects of aged biochar additions at different addition ratios on soil greenhouse gas emissions.

Biochar addition is effective in reducing soil greenhouse gas (GHG) emissions, but it's essential to evaluate whether aged biochar retains this capability as its properties change over time. However, research comparing the effects of fresh and aged biochar on soil GHG emissions is limited. Moreover, exploring the priming effect of biochar on native soil organic carbon (SOC) mineralization is crucial for revealing the effect mechanism on soil CO2 emission. However, research investigating the priming effects of aged biochar is limited. In this study, the effects of aged biochar addition on soil physicochemical properties, GHG emissions, and global warming potential (GWP) were examined through an incubation experiment with three treatments: (1) soil only (CK), (2) 1 % aged maize straw biochar addition (HBC1) and (3) 4 % aged maize straw biochar addition (HBC4), and then their effects were compared with those of fresh biochar from our previous research. 13C tracer technology was used to assess the priming effect of aged biochar on native SOC mineralization. Results showed that aged biochar improved soil physicochemical properties. Compared to CK, HBC1 and HBC4 reduced CO2 emissions by 28.02 % and 20.15 %, respectively, and reduced N2O emissions by 61.54 % and 66.39 %. HBC4 significantly increased CH4 emission, whereas HBC1 reduced it. HBC1 and HBC4 reduced GWP by 29.01 % and 21.41 %, respectively. Overall, aged biochar demonstrated a greater reduction effect compared to fresh biochar at the 1 % addition ratio. The CO2 reduction is attributed to the negative priming effect of aged biochar on native SOC mineralization. The reduction in N2O emissions is attributed to aged biochar promoting microbial nitrogen fixation and reducing the ratio of denitrification to nitrification. The variation in CH4 emissions reflects differing dominant factors influencing CH4 emission across varying addition ratios. In conclusion, 1 % aged biochar addition demonstrates a more favorable long-term effect on mitigating GHG emissions.

Bibliometric analysis of chondrocyte apoptosis in knee osteoarthritis.

BACKGROUND: Apoptosis, a form of programmed cell death, plays a significant role in osteoarthritis; however, bibliometric studies in this field remain scarce. Bibliometrics provides a visual representation of research outcomes and trends, guiding future investigations. METHOD: Journal data from January 1, 2013, to December 31, 2023, in this field were obtained from the Web of Science (WOS) core database. Analysis was conducted using VOSviewer and CiteSpace. RESULTS: Analysis revealed that over the past decade, 794 articles were published in 299 journals by 4447 authors from 49 countries and 877 institutions. The top contributors were China, the United States, and the United Kingdom. Zhuang Chao emerged as the most prolific author, and "osteoarthritis and cartilage" ranked as the most frequently cited journal. Keyword clustering focused on mechanisms, inflammation, and cartilage. The most-cited article was "chondrocyte apoptosis in the pathogenesis of osteoarthritis" in the "International Journal of Molecular Sciences." Burst word analysis highlighted extracellular matrix, circular RNA, micro RNA, indicating current research hotspots. CONCLUSION: Utilizing bibliometrics and visual analysis, we explored the hotspots and trends in the field of chondrocyte apoptosis in osteoarthritis. Extracellular matrix, Circular RNA, Micro RNA, among others, are likely to become future research focal points and frontiers.

Resilience Development Among Adult Patients With De Novo Acute Leukemia: A Qualitative Study.

OBJECTIVE: This study aimed to explore the development process of psychological resilience among adult patients with de novo acute leukemia. METHODS: This study utilized a descriptive qualitative approach, employing a purposeful sampling method to select a sample of 15 newly diagnosed patients with acute leukemia (AL) who underwent their initial induction chemotherapy treatment at the Hematology Department of the First Affiliated Hospital of Zhejiang University School of Medicine, China. Semi-structured interviews were conducted with the selected patients. Content analysis methodology was used to analyze, summarize, and extract themes from the collected data. RESULTS: Three categories emerged-namely, (1) negative period, (2) adaptive response phase, and (3) growth transformation period. The negative period occurs during the initial diagnosis and throughout the treatment cycle. However, influenced by both internal and external protective factors, including personal characteristics and social support, individuals enhance their psychological resilience through emotional regulation, mental adjustment, and adaptive strategies vis-à-vis healthcare decision-making and disease management. Overall, psychological resilience development follows an upward spiral trajectory. CONCLUSIONS: This study identified that negative emotions and symptom clusters impede the development of patients' psychological resilience. Moreover, it revealed a substantial need for disease-related information among patients. Therefore, healthcare professionals should prioritize addressing the negative emotions of patients, early identification of protective factors, dynamic monitoring of symptom clusters, effective management, and provision of psychological counseling and interventions. Simultaneously, providing personalized, professional, and systematic disease-related information is vital for promoting psychological resilience development.

Bone-targeting engineered milk-derived extracellular vesicles for MRI-assisted therapy of osteoporosis.

The imbalance between osteoblasts and osteoclasts is the cause of osteoporosis. Milk-derived extracellular vesicles (mEVs), excellent drug delivery nanocarriers, can promote bone formation and inhibit bone resorption. In this study, we conjugated bone-targeting peptide (AspSerSer, DSS)6 to mEVs by click chemistry and then loaded with SRT2104, a SIRT1 (silent mating-type information regulation 2 homolog 1) agonist that was proofed to help reduce bone loss. The engineered (DSS)6-mEV-SRT2104 had the intrinsic anti-osteoporosis function of mEVs and SRT2104 to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis. Furthermore, we labelled mEVs with MnB nanoparticles that can be used for the in vivo magnetic resonance imaging (MRI) visualization. The obtained nanocomposites significantly prevented bone loss in osteoporosis mice and increased bone mineral density, exhibiting superior bone accumulation under MRI. We believe the proposed (DSS)6-mEV-SRT2104/MnB provides a novel paradigm for osteoporosis treatment and monitoring.

An Ultrasensitive Molecularly Imprinted Point-Of-Care Electrochemical Sensor for Detection of Glial Fibrillary Acidic Protein.

Accurate assessment of neurological disease through monitoring of biomarkers has been made possible using the antibody-based assays. But these assays suffer from expensive development of antibody probes, reliance on complicated equipments, and high maintenance costs. Here, using the novel reduced graphene oxide/polydopamine-molecularly imprinted polymer (rGO/PDA-MIP) as the probe layer, a robust electrochemical sensing platform is demonstrated for the ultrasensitive detection of glial fibrillary acidic protein (GFAP), a biomarker for a range of neurological diseases. A miniaturized integrated circuit readout system is developed to interface with the electrochemical sensor, which empowers it with the potential to be used as a point-of-care (POC) diagnostic tool in primary clinical settings. This innovative platform demonstrated good sensitivity, selectivity, and stability, with imprinting factor evaluated as 2.8. A record low limit-of-detection (LoD) is down to 754.5 ag mL-1, with a wide dynamic range from 1 to 106 fg mL-1. The sensing platform is validated through the analysis of GFAP in clinical plasma samples, yielding a recovery rate range of 81.6-108.8% compared to Single Molecule Array (Simoa). This cost-effective and user-friendly sensing platform holds the potential to be deployed in primary and resource-limited clinical settings for the assessment of neurological diseases.

Procyanidin B1 Promotes PSMC3-NRF2 Ubiquitination to Induce Ferroptosis in Glioblastoma.

NRF2 signaling is a crucial antioxidant defense mechanism against ferroptosis in tumors, and targeting NRF2 is essential for tumor therapy. However, the effectiveness of NRF2 inhibitors remains unexplored. The active ingredients of traditional Chinese medicine serve as important sources of NRF2 inhibitors. In this study, we established an intracranial glioblastoma (GBM) orthotopic model and observed the effects of procyanidin B1 on tumor growth and ferroptosis. Using protein-small-molecule docking, z-stack assay of laser confocal imaging, surface plasmon resonance assay, immunoprecipitation, mass spectrometry, and western blotting, we detected the binding between procyanidin B1 and NRF2 and the effect of PSMC3 on the ubiquitin-dependent degradation of NRF2 in GBM cells. Our results showed that procyanidin B1 acted as a novel NRF2 inhibitor to suppress GBM cell proliferation and prolonged the survival of GBM-bearing mice; it also mediated the interaction between PSMC3 and NRF2 to promote ubiquitin-dependent protein degradation of NRF2, which induced ferroptosis in GBM cells. In addition, we found that procyanidin B1 enhanced H2O2 accumulation by downregulating NRF2 during ferroptosis in GBM cells. The botanical agent procyanidin B1 induced ferroptosis and exerted anti-tumor effects through PSMC3-mediated ubiquitin-dependent degradation of NRF2 proteins, providing a potential drug candidate for adjuvant therapy in patients with GBM.

Transcriptome sequencing-based analysis of primary vein development in Betula pendula 'Dalecarlica'.

Keymessage The study revealed the major biological processes occurred at three developmental stages and identified candidate genes involved in primary vein development of birch plants. Vascular tissues usually mirror the surrounding leaf shape and its development plays a fundamental role in plant performance. However, the information of vascular development in birch trees, especially primary vein development, remains unclear. Therefore, we conducted the anatomical observation on primary veins from leaves at different development stages in Betula pendula 'Dalecarlica'. With the development of primary vein, dynamic changes in mechanical tissue thickness and primary vein diameter were consistent with each other, and the sum of phloem, xylem and cambium thickness was significantly varied. Transcriptome analysis indicated that primary vein development could be divided into three stages, namely Stage I, II and III, which were in aggreement with anatomical observation. Expression of marker genes associated with vascular tissues revealed that pro-vasculature development occurred at Stage I and II, and phloem development occurred at Stage III. GO enrichment analysis of differentially expressed genes (DEGs) showed that shared DEGs at Stage II were mainly engaged in cell division and cell cycle, and shared DEGs at Stage III were mainly engaged in phosphorylation. Decreased cell division and cell cycle as well as activation of lignin biosynthesis might contribute to primary vein development. Combining phenotypic traits, we performed weighted gene co-expression network analysis and identified a cytochrome P450 84A (CYP84A) family gene (BpF5H1). Based on analyses of gene families, expression patterns and yeast-two hybrid assay results, we proposed a potential electron transfer pathway involving BpF5H1 and three cytochrome b5 proteins during primary vein development in B. pendula 'Dalecarlica'. These results could shed some light on which biological processes occurred during primary vein formation and provide some valuable clues for vascular morphogenesis in woody plants.

N6-methyladenosine demethylase FTO regulates neuronal oxidative stress via YTHDC1-ATF3 axis in arsenic-induced cognitive dysfunction.

Excessive exposure to metals in daily life has been proposed as an environmental risk factor for neurological disorders. Oxidative stress is an inevitable stage involved in the neurotoxic effects induced by metals, nevertheless, the underlying mechanisms are still unclear. In this study, we used arsenic as a representative environmental heavy metal to induce neuronal oxidative stress and demonstrated that both in vitro and in vivo exposure to arsenic significantly increased the level of N6-methyladenosine (m6A) by down-regulating its demethylase FTO. Importantly, the results obtained from FTO transgenic mice and FTO overexpressed/knockout cells indicated that FTO likely regulated neuronal oxidative stress by modulating activating transcription factor 3 (ATF3) in a m6A-dependent manner. We also identified the specific m6A reader protein, YTHDC1, which interacted with ATF3 and thereby affecting its regulatory effects on oxidative stress. To further explore potential intervention strategies, cerebral metabolomics was conducted and we newly identified myo-inositol as a metabolite that exhibited potential in protecting against arsenic-induced oxidative stress and cognitive dysfunction. Overall, these findings provide new insights into the importance of the FTO-ATF3 signaling axis in neuronal oxidative stress from an m6A perspective, and highlight a beneficial metabolite that can counteract the oxidative stress induced by arsenic.

MFG-E8 Ameliorates Nerve Injury-Induced Neuropathic Pain by Regulating Microglial Polarization and Neuroinflammation via Integrin ß3/SOCS3/STAT3 Pathway in Mice.

Spinal microglial polarization plays a crucial role in the pathological processes of neuropathic pain following peripheral nerve injury. Accumulating evidence suggests that milk fat globule epidermal growth factor-8 (MFG-E8) exhibits anti-inflammatory effect and regulates microglial polarization through the integrin ß3 receptor. However, the impact of MFG-E8 on microglial polarization in the context of neuropathic pain has not yet been investigated. In this study, we evaluated the effect of MFG-E8 on pain hypersensitivity and spinal microglial polarization following spared nerve injury (SNI) of the sciatic nerve in mice. We determined the molecular mechanisms underlying the effects of MFG-E8 on pain hypersensitivity and spinal microglial polarization using pain behavior assessment, western blot (WB) analysis, immunofluorescence (IF) staining, quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA), and small interfering RNA (siRNA) transfection. Our findings indicate that SNI significantly increased the levels of MFG-E8 and integrin ß3 expressed in microglia within the spinal cord of mice. Additionally, we observed that intrathecal injection of recombinant human MFG-E8 (rhMFG-E8) alleviated SNI induced-mechanical allodynia and thermal hyperalgesia. Furthermore, the results suggested that rhMFG-E8 facilitated M2 microglial polarization and ameliorated neuroinflammation via integrin ß3/SOCS3/STAT3 pathway in the spinal cord of mice with SNI. Importantly, these effects were negated by integrin ß3 siRNA, or SOCS3 siRNA. These results demonstrate that MFG-E8 ameliorates peripheral nerve injury induced-mechanical allodynia and thermal hyperalgesia by driving M2 microglial polarization and mitigating neuroinflammation mediated by integrin ß3/SOCS3/STAT3 pathway in the spinal cord of mice. MFG-E8 may serve as a promising target for the treatment of neuropathic pain.

FOSL1-mediated LINC01566 negatively regulates CD4+ T-cell activation in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined. METHODS: Using microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter. RESULTS: Based on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566. CONCLUSIONS: In summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.

Single-cell sequencing reveals glial cell involvement in development of neuropathic pain via myelin sheath lesion formation in the spinal cord.

BACKGROUND: Neuropathic pain (NP), which results from injury or lesion of the somatosensory nervous system, is intimately associated with glial cells. The roles of microglia and astrocytes in NP have been broadly described, while studies on oligodendrocytes have largely focused on axonal myelination. The mechanisms of oligodendrocytes and their interactions with other glial cells in NP development remain uncertain. METHODS: To explore the function of the interaction of the three glial cells and their interactions on myelin development in NP, we evaluated changes in NP and myelin morphology after a chronic constriction injury (CCI) model in mice, and used single-cell sequencing to reveal the subpopulations characteristics of oligodendrocytes, microglia, and astrocytes in the spinal cord tissues, as well as their relationship with myelin lesions; the proliferation and differentiation trajectories of oligodendrocyte subpopulations were also revealed using pseudotime cell trajectory and RNA velocity analysis. In addition, we identified chemokine ligand-receptor pairs between glial cells by cellular communication and verified them using immunofluorescence. RESULTS: Our study showed that NP peaked on day 7 after CCI in mice, a time at which myelin lesions were present in both the spinal cord and sciatic nerve. Oligodendrocytes, microglia, and astrocytes subpopulations in spinal cord tissue were heterogeneous after CCI and all were involved in suppressing the process of immune defense and myelin production. In addition, the differentiation trajectory of oligodendrocytes involved a unidirectional lattice process of OPC-1-Oligo-9, which was arrested at the Oligo-2 stage under the influence of microglia and astrocytes. And the CADM1-CADM1, NRP1-VEGFA interactions between glial cells are enhanced after CCI and they had a key role in myelin lesions and demyelination. CONCLUSIONS: Our study reveals the close relationship between the differentiation block of oligodendrocytes after CCI and their interaction with microglia and astrocytes-mediated myelin lesions and NP. CADM1/CADM1 and NRP-1/VEGFA may serve as potential therapeutic targets for use in the treatment of NP.

Essential and multifunctional mpox virus E5 helicase-primase in double and single hexamer.

An outbreak of mpox virus in May 2022 has spread over 110 nonpandemic regions in the world, posing a great threat to global health. Mpox virus E5, a helicase-primase, plays an essential role in DNA replication, but the molecular mechanisms are elusive. Here, we report seven structures of mpox virus E5 in a double hexamer (DH) and six in single hexamer in different conformations, indicating a rotation mechanism for helicase and a coupling action for primase. The DH is formed through the interface of zinc-binding domains, and the central channel density indicates potential double-stranded DNA (dsDNA), which helps to identify dsDNA binding residues Arg249, Lys286, Lys315, and Lys317. Our work is important not only for understanding poxviral DNA replication but also for the development of novel therapeutics for serious poxviral infections including smallpox virus and mpox virus.

Immune checkpoint reprogramming via sequential nucleic acid delivery strategy optimizes systemic immune responses for gastrointestinal cancer immunotherapy.

Monoclonal antibodies targeting immune checkpoints have been widely applied in gastrointestinal cancer immunotherapy. However, systemic administration of various monoclonal antibodies does not often result in sustained effects in reversing the immunosuppressive tumor microenvironment (TME), which may be due to the spatiotemporal dynamic changes of immune checkpoints. Herein, we reported a novel immune checkpoint reprogramming strategy for gastrointestinal cancer immunotherapy. It was achieved by the sequential delivery of siPD-L1 (siRNA for programmed cell death ligand 1) and pOX40L (plasmid for OX40 ligand), which were complexed with two cationic polymer brush-grafted carbon nanotubes (dense short (DS) and dense long (DL)) designed based on the structural characteristics of nucleic acids and brush architectures. Upon administrating DL/pOX40L for the first three dosages, then followed by DS/siPD-L1 for the next three dosages to the TME, it upregulated the stimulatory checkpoint OX40L on dendritic cells (DCs) and downregulated inhibitory checkpoint PD-L1 on tumor cells and DCs in a sequential reprogramming manner. Compared with other combination treatments, this sequential strategy drastically boosted the DCs maturation, and CD8+ cytotoxic T lymphocytes infiltration in tumor site. Furthermore, it could augment the local antitumor response and improve the T cell infiltration in tumor-draining lymph nodes to reverse the peripheral immunosuppression. Our study demonstrated that sequential nucleic acid delivery strategy via personalized nanoplatforms effectively reversed the immunosuppression status in both tumor microenvironment and peripheral immune landscape, which significantly enhanced the systemic antitumor immune responses and established an optimal immunotherapy strategy against gastrointestinal cancer.

MFN2-dependent mitochondrial dysfunction contributes to Relm-ß-induced pulmonary arterial hypertension via USP18/Twist1/miR-214 pathway.

Induction of resistin-like molecule ß (Relm-ß) and mitofusin 2 (MFN2) mediated aberrant mitochondrial fission have been found to be involved in the pathogenesis of pulmonary arterial hypertension (PAH). However, the molecular mechanisms underlying Relm-ß regulation of MFN2 therefore mitochondrial fission remain unclear. This study aims to address these issues. Primary cultured PASMCs and monocrotaline (MCT)-induced PAH rats were applied in this study. The results showed that Relm-ß promoted cells proliferation in PASMCs, this was accompanied with the upregulation of USP18, Twist1 and miR-214, and downregulation of MFN2. We found that Relm-ß increased USP18 expression which in turn raised Twist1 by suppressing its proteasome degradation. Elevation of Twist1 increased miR-214 expression and then reduced MFN2 expression and mitochondrial fragmentation leading to PASMCs proliferation. In vivo study, we confirmed that Relm-ß was elevated in MCT-induced PAH rat model, and USP18/Twist1/miR-214/MFN2 axis was altered similar as in vitro. Targeting this cascade by Relm-ß receptor inhibitor Calhex231, proteasome inhibitor MG-132, Twist1 inhibitor Harmine or miR-214 antagomiR prevented the development of pulmonary vascular remodeling and therefore PAH in MCT-treated rats. In conclusion, we demonstrate that Relm-ß promotes PASMCs proliferation and vascular remodeling by activating USP18/Twist1/miR-214 dependent MFN2 reduction and mitochondrial fission, suggesting that this signaling pathway might be a promising target for management of PAH.

Electronic Health Record-Based Nudge Intervention and Axillary Surgery in Older Women With Breast Cancer: A Nonrandomized Controlled Trial.

Importance: Choosing Wisely recommendations advocate against routine use of axillary staging in older women with early-stage, clinically node-negative (cN0), hormone receptor-positive (HR+), and HER2-negative breast cancer. However, rates of sentinel lymph node biopsy (SLNB) in this population remain persistently high. Objective: To evaluate whether an electronic health record (EHR)-based nudge intervention targeting surgeons in their first outpatient visit with patients meeting Choosing Wisely criteria decreases rates of SLNB. Design, Setting, and Participants: This nonrandomized controlled trial was a hybrid type 1 effectiveness-implementation study with subsequent postintervention semistructured interviews and lasted from October 2021 to October 2023. Data came from EHRs at 8 outpatient clinics within an integrated health care system; participants included 7 breast surgical oncologists. Data were collected for female patients meeting Choosing Wisely criteria for omission of SLNB (aged ≥70 years with cT1 and cT2, cN0, HR+/HER2- breast cancer). The study included a 12-month preintervention control period; baseline surveys assessing perceived acceptability, appropriateness, and feasibility of the designed intervention; and a 12-month intervention period. Intervention: A column nudge was embedded into the surgeon's schedule in the EHR identifying patients meeting Choosing Wisely criteria for potential SLNB omission. Main Outcomes and Measures: The primary outcome was rate of SLNB following nudge deployment into the EHR. Results: Similar baseline demographic and tumor characteristics were observed before (control period, n = 194) and after (intervention period, n = 193) nudge deployment. Patients in both the control and intervention period had a median (IQR) age of 75 (72-79) years. Compared with the control period, unadjusted rates of SLNB decreased by 23.1 percentage points (46.9% SLNB rate prenudge to 23.8% after; 95% CI, -32.9 to -13.8) in the intervention period. An interrupted time series model showed a reduction in the rate of SLNB following nudge deployment (adjusted odds ratio, 0.26; 95% CI, 0.07 to 0.90; P = .03). The participating surgeons scored the intervention highly on acceptability, appropriateness, and feasibility. Dominant themes from semistructured interviews indicated that the intervention helped remind the surgeons of potential Choosing Wisely applicability without the need for additional clicks or actions on the day of the patient visit, which facilitated use. Conclusions and Relevance: This study showed that a nudge intervention in the EHR significantly decreased low-value axillary surgery in older women with early-stage, cN0, HR+/HER2- breast cancer. This user-friendly and easily implementable EHR-based intervention could be a beneficial approach for decreasing low-value care in other practice settings or patient populations. Trial Registration: ClinicalTrials.gov Identifier: NCT06006910.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis.

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.