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Hung-Hsiang Huang,1,* Chi-Jie Lu,2– 4,* Mao-Jhen Jhou,4 Tzu-Chi Liu,4 Chih-Te Yang,5 Shang-Ju Hsieh,1 Wen-Jen Yang,6 Hsiao-Chun Chang,1 Ming-Shu Chen7 1Department of Urology, Surgery, Far Eastern Memorial Hospital, New Taipei City, 220, Taiwan; 2Artificial Intelligence Development Center, Fu Jen Catholic University, New Taipei City, 242, Taiwan; 3Department of Information Management, Fu Jen Catholic University, New Taipei City, 242, Taiwan; 4Graduate Institute of Business Administration, Fu Jen Catholic University, New Taipei City, 242, Taiwan; 5Department of Business Administration, Tamkang University, New Taipei City, 251, Taiwan; 6Health Screening Center, Chi Hsin Clinic, Taipei City, 104, Taiwan; 7Department of Healthcare Administration, Asia Eastern University of Science and Technology, New Taipei City, 220, Taiwan*These authors contributed equally to this workCorrespondence: Ming-Shu Chen; Hsiao-Chun Chang, Email tree1013@mail.gmail.com; liberalcsc@gmail.comPurpose: Approximately 20% of couples face infertility challenges and struggle to conceive naturally. Despite advances in artificial reproduction, its success hinges on sperm quality. Our previous study used five machine learning (ML) algorithms, random forest, stochastic gradient boosting, least absolute shrinkage and selection operator regression, ridge regression, and extreme gradient boosting, to model health data from 1375 Taiwanese males and identified ten risk factors affecting sperm count.Methods: We employed the CART algorithm to generate decision trees using identified risk factors to predict healthy sperm counts. Four error metrics, SMAPE, RAE, RRSE, and RMSE, were used to evaluate the decision trees. We identified the top five decision trees based on their low errors and discussed in detail the tree with the least error.Results: The decision tree featuring the least error, comprising BMI, UA, ST, T-Cho/HDL-C ratio, and BUN, corroborated the negative impacts of metabolic syndrome, particularly high BMI, on sperm count, while emphasizing the link between good sleep and male fertility. Our study also sheds light on the potentially significant influence of high BUN on spermatogenesis. Two novel risk factors, T-Cho/HDL-C and UA, warrant further investigation.Conclusion: The ML algorithm established a predictive model for healthcare personnel to assess low sperm counts. Refinement of the model using additional data is crucial for improved precision. The risk factors identified offer avenues for future investigations.Keywords: sperm count, metabolic syndrome, sleep time, food metabolite, decision tree

Lei Pi,1,* Di Che,1,* Haifeng Long,2,3,* Zhenzhen Fang,4 Jiawen Li,1 Shuyi Lin,2 Yunfeng Liu,2 Meiai Li,2 Lijuan Bao,2 Wenli Li,2 Yuan Zhang,2 Qiulian Deng,2 Techang Liu,5 Li Zhang,5 Xiaoqiong Gu1,2 1Department of Clinical Biological Resource Bank, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China; 2Department of Clinical Laboratory, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China; 3Department of Clinical Laboratory, The First Clinical Medical College, Jinan University, Guangzhou, China; 4Program of Molecular Medicine, Guangzhou Women and Children’s Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; 5Department of Cardiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China *These authors contributed equally to this work Introduction: Kawasaki disease is a kind of systemic vasculitis that mainly damages moderate and small-sized blood vessels, and is a leading cause of coronary artery lesions (CAL). Antiplatelet therapy is a routine component of Kawasaki disease treatment strategies. So it is important to evaluate the antiplatelet effect of aspirin because of the individual biological variability of antiplatelet effect of aspirin. The immature platelet fraction (IPF) has attracted particular attention as it may influence the antiplatelet effect of aspirin. This study investigated the prognostic factors for evaluating the degree of vasculitis and the effect of antiplatelet therapy in children with Kawasaki disease. Materials and methods: Blood samples were collected from 44 patients with Kawasaki disease before aspirin treatment and 7 to 10 days after treatment. The IPF counts, percentage of the IPF, and highly fluorescent IPF were detected by a Sysmex XE-5000 instrument. The levels of 11-dehydrothromboxane B2 (11-DH-TXB2), soluble CD40 ligand (sCD40L), and soluble P-selectin (sP-selectin) were measured by ELISA. The correlation between the measured factors and the degree of coronary artery damage in Kawasaki disease was analyzed. Results: We found that 11-DH-TXB2, sP-selectin, and sCD40L levels were much more elevated in the CAL group than in the non-coronary artery lesions (NCAL) group before aspirin treatment. The concentrations of 11-DH-TXB2, sCD40L, sP-selectin, and IPF were reduced after aspirin treatment in the NCAL group but not the CAL group. This is related to the degree of coronary artery damage in Kawasaki disease patients. Additionally, 11-DH-TXB2, sCD40L, sP-selectin, and IPF were positively correlated with the degree of coronary artery damage in Kawasaki disease patients. Conclusion: The current study suggests that the presence of high plasma concentrations of 11-DH-TXB2, sCD40L, sP-selectin, and IPF can be considered a risk factor and experimental biomarker for CAL in Kawasaki disease patients. Keywords: Kawasaki disease, coronary artery lesions, aspirin, immature platelet fraction

Abstract The TAROGE-M radio observatory is a self-triggered antenna array on top of the ∼2700 m high Mt. Melbourne in Antarctica, designed to detect impulsive geomagnetic emission from extensive air showers induced by ultra-high energy (UHE) particles beyond 1017 eV, including cosmic rays, Earth-skimming tau neutrinos, and particularly, the “ANITA anomalous events” (AAE) from near and below the horizon. The six AAE discovered by the ANITA experiment have signal features similar to tau neutrinos but that hypothesis is in tension either with the interaction length predicted by Standard Model or with the flux limits set by other experiments. Their origin remains uncertain, requiring more experimental inputs for clarification. The detection concept of TAROGE-M takes advantage of a high altitude with synoptic view toward the horizon as an efficient signal collector, and the radio quietness as well as strong and near vertical geomagnetic field in Antarctica, enhancing the relative radio signal strength. This approach has a low energy threshold, high duty cycle, and is easy to extend for quickly enlarging statistics. Here we report experimental results from the first TAROGE-M station deployed in January 2020, corresponding to approximately one month of livetime. The station consists of six receiving antennas operating at 180-450 MHz, and can reconstruct source directions of impulsive events with an angular resolution of ∼0.3°, calibrated in situ with a drone-borne pulser system. To demonstrate TAROGE-M's ability to detect UHE air showers, a search for cosmic ray signals in 25.3-days of data together with the detection simulation were conducted, resulting in seven identified candidates. The detected events have a mean reconstructed energy of 0.95-0.31+0.46 EeV and zenith angles ranging from 25° to 82°, with both distributions agreeing with the simulations, indicating an energy threshold at about 0.3 EeV. The estimated cosmic ray flux at that energy is 1.2-0.9+0.7 × 10-16 eV-1 km-2 yr-1 sr-1, also consistent with results of other experiments. The TAROGE-M sensitivity to AAEs is approximated by the tau neutrino exposure with simulations, which suggests comparable sensitivity as ANITA's at around 1 EeV energy with a few station-years of operation. These first results verified the station design and performance in a polar and high-altitude environment, and are promising for further discovery of tau neutrinos and AAEs after an extension in the near future.

BACKGROUND: JX-594 is a targeted oncolytic poxvirus designed to selectively replicate in and destroy cancer cells with cell-cycle abnormalities and epidermal growth factor receptor (EGFR)-ras pathway activation. Direct oncolysis plus granulocyte-macrophage colony-stimulating factor (GM-CSF) expression also stimulates shutdown of tumour vasculature and antitumoral immunity. We aimed to assess intratumoral injection of JX-594 in patients with refractory primary or metastatic liver cancer. METHODS: Between Jan 4, 2006, and July 4, 2007, 14 patients with histologically confirmed refractory primary or metastatic liver tumours (up to 10.9 cm total diameter) that were amenable to image-guided intratumoral injections were enrolled into this non-comparative, open-label, phase I dose-escalation trial (standard 3x3 design; two to six patients for each dose with 12-18 estimated total patients). Patients received one of four doses of intratumoral JX-594 (10(8) plaque-forming units [pfu], 3x10(8) pfu, 10(9) pfu, or 3x10(9) pfu) every 3 weeks at Dong-A University Hospital (Busan, South Korea). Patients were monitored after treatment for at least 48 h in hospital and for at least 4 weeks as out-patients. Adverse event-monitoring according to the National Cancer Institute Common Toxicity Criteria (version 3) and standard laboratory toxicity grading for haematology, liver and renal function, coagulation studies, serum chemistry, and urinalysis were done. The primary aims were to ascertain the maximum-tolerated dose (MTD) and safety of JX-594 treatment. Data were also collected on pharmacokinetics, pharmacodynamics, and efficacy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00629759. FINDINGS: Of 22 patients with liver tumours who were assessed for eligibility, eight patients did not meet inclusion criteria. Therefore, 14 patients, including those with hepatocellular, colorectal, melanoma, and lung cancer, were enrolled. Patients were heavily pretreated (5.6 previous treatments, SD 2.8, range 2.0-12.0) and had large tumours (7.0 cm diameter, SD 2.7, range 1.8-10.9). Patients received a mean of 3.4 (SD 2.2, range 1.0-8.0) cycles of JX-594. All patients were evaluable for toxicity. All patients experienced grade I-III flu-like symptoms, and four had transient grade I-III dose-related thrombocytopenia. Grade III hyperbilirubinaemia was dose-limiting in both patients at the highest dose; the MTD was therefore 1x10(9) pfu. JX-594 replication-dependent dissemination in blood was shown, with resultant infection of non-injected tumour sites. GM-CSF expression resulted in grade I-III increases in neutrophil counts in four of six patients at the MTD. Tumour responses were shown in injected and non-injected tumours. Ten patients were radiographically evaluable for objective responses; non-evaluable patients had contraindications to contrast medium (n=2) or no post-treatment scans (n=2). According to Response Evaluation Criteria in Solid Tumors (RECIST), three patients had partial response, six had stable disease, and one had progressive disease. INTERPRETATION: Intratumoral injection of JX-594 into primary or metastatic liver tumours was generally well-tolerated. Direct hyperbilirubinaemia was the dose-limiting toxicity. Safety was acceptable in the context of JX-594 replication, GM-CSF expression, systemic dissemination, and JX-594 had anti-tumoral effects against several refractory carcinomas. Phase II trials are now underway. [ABSTRACT FROM AUTHOR]

Objective: Exercise exerts protective effects against Alzheimer's disease (AD). However, the factors and mechanisms underlying these effects remain largely unknown. This study aims to elucidate the molecular mechanisms by which exercise exerts its protective effects against AD., Methods: Male 7-week-old Sprague-Dawley rats were randomly allocated to four groups (n = 10 per group): control (CON), exercise control (EXE), sedentary AD model induced by intracerebroventricular streptozotocin (STZ) injection, and AD model with treadmill exercise (EXE + STZ). The exercise groups underwent a 13-week treadmill exercise. An intracerebroventricular injection of STZ was used to induce a rat model of AD. The Barnes maze task was employed as an assessment of spatial learning and memory. Hippocampal tissues from three rats per group was collected for proteomic analysis. Immunofluorescence staining, western blot analysis and polymerase chain reaction were performed for the evaluation of Aβ production, tau hyperphosphorylation, differential protein and corresponding signaling pathway., Results: Treadmill exercise could significantly improve STZ-induced cognitive dysfunction and provide neuroprotection by reducing Aβ deposition and tau hyperphosphorylation. Proteomic analysis and further studies demonstrated that treadmill training could significantly increase the expression of tripartite motif-containing 9 (TRIM9). Subsequent research indicated that the upregulation of TRIM9 maybe due, in part,to the inhibition of the NF-κB pathway, thereby reducing the pro-inflammatory factor, and exerting an anti-inflammatory effect., Conclusions: Treadmill exercise attenuates cognitive decline in AD models by upregulating TRIM9 expression, which in turn inhibits NF-κB-mediated neuroinflammation. These findings suggest that TRIM9 may serve as a potential therapeutic target for immunomodulatory strategies against AD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Dementia is a significant medical and social issue in most developed countries. Practical tools for predicting the progression of degenerative dementia are highly valuable. Machine learning (ML) methods facilitate the construction of effective models using real-world data, which may include missing values and various integrated datasets., Method: This retrospective study analyzed data from 679 patients diagnosed with degenerative dementia at Fu Jen Catholic University Hospital, who were evaluated by neurologists, psychologists and followed for over two years. Predictive variables were categorized into demographic (D), clinical dementia rating (CDR), mini-mental state examination (MMSE), and laboratory data value (LV) groups. These categories were further integrated into three subgroups (D-CDR, D-CDR-MMSE, and D-CDR-MMSE-LV). We utilized the extreme gradient boosting (XGB) model to rank the importance of variables and identify the most effective feature combination via a step-wise approach., Result: The D-CDR-MMSE-LV model combination showed robust performance with an excellent area under the receiver operating characteristic curve (AUC) and the highest sensitivity value (84.66). Employing both demographic and neuropsychiatric variables, our prediction model achieved an AUC of 83.74. By incorporating additional clinical information from laboratory data and applying our proposed feature selection strategy, we constructed a model based on eight variables that achieved an AUC of 85.12 using the XGB technique., Conclusion: We established a machine-learning model to monitor the progression of dementia using a limited, real-world clinical dataset. The XGB technique identified eight critical variables across our integrated datasets, potentially providing clinicians with valuable guidance., Competing Interests: Declarations. Ethics approval and consent to participate: This retrospective study involving human participants was in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The Human Investigation Committee (IRB) of Fu Jen Catholic University Hospital approved this study (IRB No. FJUH112280). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Informed consent: This research study was conducted retrospectively from electrical medical data of regularly clinical records. We consulted extensively with the IRB of Fu Jen Catholic University Hospital (IRB No. FJUH112280) who determined that our study did not need informed consent., (© 2024. The Author(s).)

Age-related hearing loss is a chronic health condition. This qualitative study applied the Common-Sense Model of Self-Regulation to explore the lived experiences and illness perceptions of older adults with age-related hearing loss. Twenty older adults ≥ 65 years of age with hearing loss were recruited by purposive sampling. Data were collected with face-to-face semi-structured interviews. Interpretive phenomenological analysis analyzed the interview data. Four overarching themes described the experience of hearing loss: 1) awareness, 2) impacts, 3) coping, and 4) appraisal. These highlight of how participants perceived and reacted to progressive hearing loss before adopting hearing aids. The impact of hearing loss was diverse and complex and included fatigue, stress, and interpersonal conflicts. Participants responded with changes in behaviors that were proactive or avoidant. Our findings may help clinicians understand how older adults perceive and manage age-related hearing loss, which could guide the development of effective individual and family-focused interventions., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prolamin-based nanoparticles, particularly those composed of prolamin-polysaccharide composites, have garnered significant interest as oral delivery systems in recent research. This review provides a thorough analysis of the current advancements in these composite nanoparticles with prolamins derived from various cereals, including maize, wheat, sorghum, and millet, with a focus on their applications in oral drug delivery. It discusses the mechanisms by which these composites enhance nanoparticle performance, especially in terms of stability. The review also explores the differences among various prolamins and clarifies the reasons for their performance characteristics as encapsulants for nanoparticles. Additionally, it offers an in-depth examination of various preparation methods for these composite nanoparticles, such as the traditional anti-solvent method, pH-driven method, and several innovative techniques. The study highlights the physicochemical and encapsulation properties of these composite nanoparticles and underscores their novel applications, which hold promise for future use in the food and pharmaceutical sectors. The findings aim to support the integration of prolamin-polysaccharide composites into these industries, ultimately accelerating the development of new applications for these nanoparticles., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Alterations in ileal Paneth cell (PC) density have been described in gut inflammatory diseases such as Crohn's disease (CD) and could be used as a biomarker for disease prognosis. However, quantifying PCs is time-intensive, a barrier for clinical workflow. Deep learning (DL) has transformed the development of robust and accurate tools for complex image evaluation. Our aim was to use DL to quantify PCs for use as a quantitative biomarker., Methods: A retrospective cohort of whole slide images (WSI) of ileal tissue samples from patients with/without inflammatory bowel disease (IBD) was used for the study. A pathologist-annotated training set of WSI were used to train a U-net two-stage DL model to quantify PC number, crypt number, and PC density. For validation, a cohort of 48 WSIs were manually quantified by study pathologists and compared to the DL algorithm, using root mean square error (RMSE) and the coefficient of determination (r 2 ) as metrics. To test the value of PC quantification as a biomarker, resection specimens from patients with CD (n = 142) and without IBD (n = 48) patients were analysed with the DL model. Finally, we compared time to disease recurrence in patients with CD with low versus high DL-quantified PC density using Log-rank test., Findings: Initial one-stage DL model showed moderate accuracy in predicting PC density in cross-validation tests (RMSE = 1.880, r 2  = 0.641), but adding a second stage significantly improved accuracy (RMSE = 0.802, r 2  = 0.748). In the validation of the two-stage model compared to expert pathologists, the algorithm showed good performance up to RMSE = 1.148, r 2  = 0.708. The retrospective cross-sectional cohort had mean ages of 62.1 years in the patients without IBD and 38.6 years for the patients with CD. In the non-IBD cohort, 43.75% of the patients were male, compared to 49.3% of the patients with CD. Analysis by the DL model showed significantly higher PC density in non-IBD controls compared to the patients with CD (4.04 versus 2.99 PC/crypt). Finally, the algorithm quantification of PCs density in patients with CD showed patients with the lowest 25% PC density (Quartile 1) have significantly shorter recurrence-free interval (p = 0.0399)., Interpretation: The current model performance demonstrates the feasibility of developing a DL-based tool to measure PC density as a predictive biomarker for future clinical practice., Funding: This study was funded by the National Institutes of Health (NIH)., Competing Interests: Declaration of interests The authors have no conflict of interest to declare in relation to the work presented., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Perianal fistulizing Crohn's disease (PCD) is a common and debilitating complication with elusive pathophysiology. We examined mucosal cells from patients with PCD and related conditions using a multi-omics approach., Methods: We recruited patients with PCD (n = 24), CD without perianal disease (NPCD, n = 10), and idiopathic perianal fistulas (IPF, n = 29). Biopsies were taken from fistula tracts, fistula opening, and rectal mucosa. Single-cell RNA-sequencing (scRNA-seq), mass cytometry (CyTOF), spatial transcriptomics (ST), immunohistochemistry, and integrated analysis were performed., Results: ScRNA-seq, CyTOF, and ST unraveled immune and non-immune cell compartments in PCD and IPF fistula tracts. PCD fistulas showed hyperactivated pathogenic pathways including interferon (IFN)G response and TNF signaling in myeloid and stromal cells. Intestinal cells from PCD patients also expressed greater levels of IFNG-responsive and EMT genes compared to NPCD patients. Furthermore, both fistula tracts and ileal mucosa from PCD patients harbored expanded IFNG+ pathogenic Th17 cells, which expressed elevated inflammatory mediators. CyTOF also identified skewed immune cell phenotypes in the fistula tracts, fistula opening, and rectum in PCD patients including expanded Th17 cells, increased pathogenic myeloid cells, and altered T cell exhaustion markers. Further analysis also revealed cellular modules associated with anti-TNF therapy in PCD patients., Conclusion: Multi-omics analysis revealed immune, stromal, and epithelial cell landscapes of PCD, which highlight the pathogenic role of hyperactivated IFNG signaling in both fistula tracts and luminal mucosa. This study identified IFNG as a potential therapeutic target for PCD.

Molecular studies have shown ALT to be an important prognostic biomarker of shorter relapse-free survival (RFS) for patients with pancreatic neuroendocrine tumors (PanNETs) and other neoplasms. However, the preferred method of detecting ALT in tissue is by fluorescence in situ hybridization (FISH), which has several clinical limitations. These issues necessitate the creation of a chromogenic ALT assay that can be easily implemented into routine practice. A CISH assay was developed using genetically modified osteosarcoma cell lines, 20 normal pancreata, 20 ALT-positive PanNETs, and 20 ALT-negative PanNETs. Thereafter, it was validated on a multi-institutional cohort of 360 surgically resected PanNETs and correlated with multiple clinicopathologic features, RFS, and FISH results. Separately, 109 leiomyosarcomas (LMS) were evaluated by both CISH and FISH, and, similarly, the prognostic significance of ALT status was assessed. Upon optimization, ALT-CISH was identified in 112 of 360 (31%) primary PanNETs and was 100% concordant with FISH testing. ALT correlated with several adverse prognostic findings and distant metastasis (all p<0.004). The 5-year RFS for patients with ALT-positive PanNETs was 35% as compared to 94% for ALT-negative PanNETs. By multivariate analysis, ALT was an independent prognostic factor for shorter RFS. Similarly, ALT was associated with shorter RFS in LMS patients and, analogous to PanNETs, a negative, independent prognostic factor. ALT-CISH was developed and validated in not only PanNETs, but also sarcomas, specifically LMS. CISH testing has multiple advantages over FISH that facilitate its widespread clinical use in the detection of ALT and prognostication of patients with diverse neoplasms., (Copyright © 2024. Published by Elsevier Inc.)

LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.

The abnormal structure of tumor vascular seriously hinders the delivery and deep penetration of drug in tumor therapy. Herein, an integrated and tumor microenvironment (TME)-responsive nanocarrier is designed, which can dilate vessle and improve the drug penetration by in situ releasing nitric oxide (NO). Briefly, S-nitroso-glutathione (GSNO) and curcumin (Cur) were encapsulatd into the Cu-doped zeolite imidazole framework-8 (Cu-ZIF-8) and modified with hyaluronic acid. The nanocarrier degradation in the weakly acidic of TME releases Cu 2+ , then deplete overexpressed intratumourally glutathione and transformed into Cu + , thus disrupting the balance between nicotinamide adenine dinucleotide phosphate and flavin adenine dinucleotide (NADPH/FAD) during the metabolism homeostasis of tumor. The Cu + can generate highly toxic hydroxyl radical through the Fenton-like reaction, enhancing the chemodynamic therapeutic effect. In addition, Cu + also decomposes GSNO to release NO by ionic reduction, leading to vasodilation and increased vascular permeability, significantly promoting the deep penetration of Cur in tumor. Afterwards, the orderly operation of cell cycle is disrupted and arrested in the S-phase to induce tumor cell apoptosis. Deep-hypothermia potentiated 2D/3D fluorescence imaging demonstrated nanocarrier regulated endogenous metabolism homeostasis of tumor. The cascade-catalysed multifunctional nanocarrier provides an approach to treat orthotopic tumor., (© 2024. The Author(s).)

Background: The efficacy and safety of 40 Hz gamma transcranial alternating current stimulation (γ-tACS) in Alzheimer's disease (AD) are still uncertain., Objective: This meta-analysis was conducted to investigate the therapeutic potential and safety of 40 Hz γ-tACS for AD., Methods: The meta-analysis was conducted by systematically searching four databases from their start to 28 December 2023. Subgroup analyses were performed to identify the intervention effects of γ-tACS., Results: Of the 7 included studies, γ-tACS has a notable impact on improving overall cognition [standardized mean difference (SMD): 0.49, 95% CI: 0.09 to 0.89], memory (SMD: 0.79, 95% CI: 0.18 to 1.41), and cholinergic transmission (weighted mean difference: -0.40, 95% CI: -0.43 to -0.37). Furthermore, subgroup analysis revealed that γ-tACS treatment had a substantial impact on enhancing memory targeting the left angular gyrus in both home (SMD: 3.12, 95% CI: 1.54 to 4.70) and non-home settings (SMD: 0.53, 95% CI: 0.24 to 0.82). However, γ-tACS had a positive effect on overall cognition in non-home settings (SMD: 0.55, 95% CI 0.11 to 0.98), but not in home settings (SMD: 0.22, 95% CI -0.76 to 1.20). Additionally, targeting temporo-frontal or bitemporal γ-tACS treatment resulted in improvement in overall cognition (SMD: 0.61, 95% CI: 0.06 to 1.16), but not targeting the left angular gyrus (SMD: 0.22, 95% CI: -0.76 to 1.20)., Conclusions: γ-tACS could be beneficial in enhancing cognition, memory and restoring cholinergic dysfunction in AD. The different selection of stimulation sites plays distinct roles. Meanwhile, AD patients are recommended to receive γ-tACS treatment at home., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mutations in various type II transmembrane serine protease (TMPRSS) family members are associated with non-syndromic hearing loss, with some mechanisms still unclear. For instance, the mechanism underlying profound hearing loss and tectorial membrane (TM) malformations in hepsin/TMPRSS1 knockout (KO) mice remains elusive. In this study, we confirmed significantly elevated hearing thresholds and abnormal TM morphology in hepsin KO mice, characterized by enlarged TM with gaps and detachment from the spiral limbus. Transgenic mouse lines were created to express either wild-type or a serine protease-dead mutant of human hepsin in the KO background. The Tg68;KO line, expressing moderate levels of wild-type human hepsin in the cochlea, showed partial restoration of hearing function. Conversely, the Tg5;KO or TgRS;KO lines, with undetectable hepsin or protease-dead hepsin, did not show such improvement. Histological analyses revealed that Tg68;KO mice, but not Tg5;KO or TgRS;KO mice, had a more compact TM structure, partially attached to the spiral limbus. These results indicate that hepsin expression levels correlate with improvements in hearing and TM morphology, and its protease activity is critical for these effects. Hepsin's role was further examined by studying its relationship with α-tectorin (TECTA) and β-tectorin (TECTB), non-collagenous proteins crucial for TM formation. Hepsin was co-expressed with TECTA and TECTB in the developing cochlear epithelium. Immunostaining showed decreased levels of TECTA and TECTB in hepsin KO TM, partially restored in Tg68;KO mice. These findings suggest that hepsin is essential for proper TM morphogenesis and auditory function, potentially by proteolytic processing/maturation of TECTA and TECTB and their incorporation into the TM., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The poor prognosis of relatively undifferentiated cancers has long been recognized, suggesting that selection against differentiation and in favor of uncontrolled growth is one of the most powerful drivers of cancer progression. Goblet cells provide the mucous surface of the gut, and when present in colorectal cancers (CRC), the cancers are called mucinous. We have used the presence of MUC2, the main mucous product of goblet cells, and an associated gene product, TFF3, to classify a large panel of nearly 80 CRC-derived cell lines into five categories based on their levels of MUC2 and TFF3 expression. We have then shown that these five patterns of expression can be easily identified in the direct analysis of tumor specimens allowing a much finer characterization of CRCs with respect to the presence of goblet cell differentiation. In particular, about 30% of all CRCs fall into the category of expressing TFF3 but not MUC2, which has not previously been acknowledged. Using the cell line data, we suggest that there are up to 12 genes ( MUC2, TFF3, ATOH1, SPDEF, CDX1, CDX2, GATA6, HES1, ETS2, OLFM4, TOX3, and LGR5 ) that may be involved in selection against goblet cell differentiation in CRC by changes in methylation rather than mutations. Of these, LGR5 , which is particularly associated with lack of goblet cell features, may function in the control of differentiation rather than direct control of cell growth, as has so far mostly been assumed. These results emphasize the importance of methylation changes in driving cancer progression., Competing Interests: Competing interests statement:The authors declare no competing interest.

In endometrial cancer (EC) and colorectal cancer (CRC), in addition to microsatellite instability, tumor mutational burden (TMB) has gradually gained attention as a genomic biomarker that can be used clinically to determine which patients may benefit from immune checkpoint inhibitors. High TMB is characterized by a large number of mutated genes, which encode aberrant tumor neoantigens, and implies a better response to immunotherapy. Hence, a part of EC and CRC patients associated with high TMB may have higher chances to receive immunotherapy. TMB measurement was mainly evaluated by whole-exome sequencing or next-generation sequencing, which was costly and difficult to be widely applied in all clinical cases. Therefore, an effective, efficient, low-cost and easily accessible tool is urgently needed to distinguish the TMB status of EC and CRC patients. In this study, we present a deep learning framework, namely Ensemble Transformer-based Multiple Instance Learning with Self-Supervised Learning Vision Transformer feature encoder (ETMIL-SSLViT), to predict pathological subtype and TMB status directly from the H&E stained whole slide images (WSIs) in EC and CRC patients, which is helpful for both pathological classification and cancer treatment planning. Our framework was evaluated on two different cancer cohorts, including an EC cohort with 918 histopathology WSIs from 529 patients and a CRC cohort with 1495 WSIs from 594 patients from The Cancer Genome Atlas. The experimental results show that the proposed methods achieved excellent performance and outperforming seven state-of-the-art (SOTA) methods in cancer subtype classification and TMB prediction on both cancer datasets. Fisher's exact test further validated that the associations between the predictions of the proposed models and the actual cancer subtype or TMB status are both extremely strong (p<0.001). These promising findings show the potential of our proposed methods to guide personalized treatment decisions by accurately predicting the EC and CRC subtype and the TMB status for effective immunotherapy planning for EC and CRC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential., Objective: To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC., Design, Setting, and Participants: This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9)., Main Outcomes and Measures: The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping., Results: Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects., Conclusion and Relevance: The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

The prevalence of obesity in the United States has continued to increase over the past several decades. Understanding how diet-induced obesity modulates mucosal immunity is of clinical relevance. We previously showed that consumption of a high fat, high sugar "Western" diet (WD) reduces the density and function of small intestinal Paneth cells, a small intestinal epithelial cell type with innate immune function. We hypothesized that obesity could also result in repressed gut adaptive immunity. Using small intestinal intraepithelial lymphocytes (IEL) as a readout, we found that in non-inflammatory bowel disease (IBD) subjects, high body mass index correlated with reduced IEL density. We recapitulated this in wild type (WT) mice fed with WD. A 4-week WD consumption was able to reduce IEL but not splenic, blood, or bone marrow lymphocytes, and the effect was reversible after another 2 weeks of standard diet (SD) washout. Importantly, WD-associated IEL reduction was not dependent on the presence of gut microbiota, as WD-fed germ-free mice also showed IEL reduction. We further found that WD-mediated Farnesoid X Receptor (FXR) activation in the gut triggered IEL reduction, and this was partially mediated by intestinal phagocytes. Activated FXR signaling stimulated phagocytes to secrete type I IFN, and inhibition of either FXR or type I IFN signaling within the phagocytes prevented WD-mediated IEL loss. Therefore, WD consumption represses both innate and adaptive immunity in the gut. These findings have significant clinical implications in the understanding of how diet modulates mucosal immunity., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Stappenbeck advises Janssen, Boehringer Ingelheim, Kallyope, Takada, and Roche. T.C. Liu has research contracts with Denali Therapeutics and Interline Therapeutics. All other authors declare no relevant competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteoarthritis (OA) is one of the most prevalent musculoskeletal diseases in Taiwan, posing a significant public health challenge. In recent years, outdoor air pollution has become an increasingly critical global health issue. Asian Dust Storms (ADS) are known to exacerbate various health conditions due to elevated levels of particulate matter and other pollutants. However, the relationship between ADS and knee OA remains insufficiently explored. This study investigates the association between ADS occurrences and knee OA outpatient visits from January 2006 to December 2012, aiming to understand the potential health impacts of dust storms on OA patients. Using data from the National Health Insurance Research Database (NHIRD), the Taiwan Environmental Protection Agency (TEPA), and the Taiwan Central Weather Bureau, we conducted a time-series analysis employing the autoregressive moving average with exogenous variables (ARMAX) model. This approach accounted for daily outpatient visits related to knee OA, ADS events, and various environmental and meteorological factors. The results revealed a significant increase in knee OA outpatient visits on days immediately following ADS events, with peaks observed one to two days after the event. This increase was most pronounced among females, individuals aged 61 and above, and residents in the western regions. The study demonstrates an association between ADS and increased knee OA outpatient visits, highlighting the need for public health strategies to mitigate the health impacts of dust storms., (© 2024. The Author(s).)

We refresh the design of zero-mode waveguides (ZMWs) by introducing metamaterials that makes the zeroth order resonant mode existence. Of particular importance, the resulting electromagnetic field exhibits nearly constant distribution but not a trivial solution of Maxwell's equation, showing great advantage to equalize the excitation rate of molecules throughout the waveguides. A closed form expression for the wave impedance is derived which is verified by the finite-difference time-domain simulations. Benefitted from the cavity Purcell effect which is lacking in existing ZMWs, fluorescence amplification and lifetime reduction are simultaneously enhanced. A practical design where the excitation volume reduced down to sub-zeptoliter and the fluorescence lifetime shortened to picosecond scale is illustrated. This result makes single molecule real time (SMRT) sensing of biochemical reactions at biophysically relevant concentrations (~ μM) possible, combining off-the-shelf ultrafast lasers., (© 2024. The Author(s).)

Background: Environmental enteric dysfunction (EED) is an asymptomatic intestinal disorder associated with growth impairment, delayed neurocognitive development, and impaired oral vaccine responses., Objectives: We set out to develop and validate a histopathologic scoring system on duodenal biopsies from a cohort study of children with growth failure in Bangladesh, Pakistan, and Zambia ("EED") with reference to biopsies from United States children with no clinically reported histologic pathology (referred to hereafter as "normal") or celiac disease., Methods: Five gastrointestinal pathologists evaluated 745 hematoxylin and eosin slide images from 291 children with EED (mean age: 1.6 y) and 66 United States children (mean age: 6.8 y). Histomorphologic features (i.e., villus/crypt architecture, goblet cells, epithelial and lamina propria acute/chronic inflammation, Brunner's glands, Paneth cells, epithelial detachment, enterocyte injury, and foveolar metaplasia) were used to score each histopathologic slide. Generalized estimating equations were used to determine differences between EED, normal, and celiac disease, and receiver operating characteristic curves were used to assess predictive value., Results: Biopsies from the duodenal bulb showed higher intramucosal Brunner's gland scores and lower intraepithelial lymphocyte scores than from the second or third parts of the duodenum (D2/3), so only D2/3 were included in the final analysis. Although 7 parameters differed significantly between EED and normal biopsies in regression models, only 5 (blunted villus architecture, increased intraepithelial lymphocytosis, goblet cell depletion, Paneth cell depletion, and reduced intramucosal Brunner's glands) were required to create a total score percentage (TSP-5) that correctly identified EED against normal biopsies (AUC: 0.992; 95% CI: 0.983, 0.998). Geographic comparisons showed more severe goblet cell depletion in Bangladesh and more marked intraepithelial lymphocytosis in Pakistan., Conclusions: This scoring system involving 5 histologic parameters demonstrates very high discrimination between EED and normal biopsies, indicating that this scoring system can be applied with confidence to studies of intestinal biopsies in EED., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)