Association Between Intrinsic Capacity and Hospital Admission Among Older Adults in the Emergency Department.

This prospective cohort study assessed the impact of intrinsic capacity on hospital admissions among older adults after an Emergency Department (ED) visit. Assessing 1132 patients according to WHO's Integrated Care for Older People guidelines between March 1 and August 30, 2022, we found that 784 (69.26%) were admitted. The admission group demonstrated significantly lower intrinsic capacity scores (mean ± SD, 2.92 ± 1.29) compared to the discharge group (3.44 ± 1.23; p < .001). Multivariable logistic regression showed that higher intrinsic capacity scores were associated with lower odds of admission (adjusted odds ratio [aOR] = 0.81; 95% CI: 0.71-0.92; p < .001). Notably, patients with malnutrition had significantly higher odds of admission (OR = 3.12; 95% CI: 2.16-4.50; p < .001). These findings underscore the importance of integrating the intrinsic capacity assessment with traditional clinical indicators in the emergency care of older adults.

Loss of tyrosine 211 phosphorylation of proliferating cell nuclear antigen (PCNA) enhances postnatal mammary gland development.

The intricately orchestrated progression of mammary tissue development involves the precise coordination of gland differentiation and cellular proliferation. Nevertheless, the understanding of the role and regulatory mechanisms governing the DNA replication machinery in mammary gland development remains limited. Given the essential role of DNA replication in the viability of living cells, any genetic disturbance to its replicative function, in any form, will impede organ development. This circumstance poses a technical challenge in elucidating the potential function of cell proliferation in mammary morphogenesis. PCNA is crucial in DNA replication, playing a pivotal role in the development of complete eukaryotic organisms. The phosphorylation of PCNA at tyrosine 211 (Y211) has been demonstrated to play a significant role in supporting replication forks and, consequently, cell proliferation. Therefore, the utilization of a knock-in mouse model, wherein the Y211 residue of PCNA is replaced with phenylalanine (211F), presents an opportunity to evaluate the impact of reduced cell proliferation potential on mammary gland development. Interestingly, the lack of Y211 phosphorylation did not significantly impact the rates of proliferation or cell death in the mammary gland. In contrast, the absence of Y211PCNA led to an increased, rather than reduced, growth of the mammary gland. This was evident in assessments of gland length and the number of terminal end buds (TEBs) in both postnatal and virgin mammary glands. Notably, this observation correlated with an elevation in tissue stemness within the 211F glands compared to the WT glands. Additionally, it was consistent with the greater body weight gains observed in 211F pups compared to WT pups during the weaning period. Our findings unveil an unexpected aspect that may carry significance for mammary development. This newfound is associated with the regulation of a central component within the DNA replication machinery, providing insights into the intricate interplay governing mammary tissue expansion.

Development and Validation of a Cholesterol-related Gene Signature for Prognostic Assessment in Head and Neck Squamous Cell Carcinoma.

AIM: This study seeks to develop a prognostic risk signature for head and neck squamous cell carcinoma (HNSCC) based on cholesterol-related genes (CholRG), aiming to enhance prognostic accuracy in clinical practice. BACKGROUND: HNSCC poses significant challenges due to its aggressive behavior and limited response to standard treatments, resulting in elevated morbidity and mortality rates.In order to improve prognostic prediction in HNSCC, our study is inspired by the realization that cholesterol metabolism plays a critical role in accelerating the progression of cancer. To this end, we are developing a unique risk signature using CholRG. OBJECTIVE: The aim of this study was to create a CholRG-based risk signature to predict HNSCC prognosis, aiding in clinical decision-making accurately. METHOD: The TCGA HNSCC dataset, along with GSE41613 and GSE65858, was obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. A CholRG-based risk signature was then developed and validated across various independent HNSCC cohorts. Moreover, a nomogram model incorporating CholRG-based risk signature was established. Additionally, functional enrichment analysis was conducted, and the immune landscapes of the high- and low-risk groups were compared. Finally, in vitro experiments were performed using lipid-based transfection to deliver siRNAs targeting ACAT1 to SCC1 and SCC23 cell lines, further examining the effects of ACAT1 knockdown on these cells. RESULTS: Utilizing RNA-seq, microarray, and clinical data from public databases, we constructed and validated a CholRG-based risk signature that includes key genes such as ACAT1, CYP19A1, CYP27A1, FAXDC2, INSIG2, PRKAA2, and SEC14L2, which can effectively predict the clinical outcome of HNSCC. Additionally, our findings were reinforced by a nomogram model that integrates the risk score with clinical variables for more clinically practical prognostic assessment. In addition, patients at high risk show hypoxia and increased oncogenic pathways such as mTORC1 signaling, as well as a suppressed immune microenvironment marked by a reduction in the infiltration of important immune cells. Notably, in vitro experiments showed that ACAT1 depletion significantly suppressed the proliferation, colony formation, and invasion capabilities of HNSCC cells, confirming ACAT1's role in promoting malignancy. CONCLUSION: Collectively, our study not only underscores the importance of cholesterol metabolism in HNSCC pathogenesis but also highlights the CholRG-based risk signature as a promising tool for enhancing prognostic accuracy and personalizing therapeutic strategies.

Considerations for widespread implementation of blood-based biomarkers of Alzheimer's disease.

Diagnosing Alzheimer's disease (AD) poses significant challenges to health care, often resulting in delayed or inadequate patient care. The clinical integration of blood-based biomarkers (BBMs) for AD holds promise in enabling early detection of pathology and timely intervention. However, several critical considerations, such as the lack of consistent guidelines for assessing cognition, limited understanding of BBM test characteristics, insufficient evidence on BBM performance across diverse populations, and the ethical management of test results, must be addressed for widespread clinical implementation of BBMs in the United States. The Global CEO Initiative on Alzheimer's Disease BBM Workgroup convened to address these challenges and provide recommendations that underscore the importance of evidence-based guidelines, improved training for health-care professionals, patient empowerment through informed decision making, and the necessity of community-based studies to understand BBM performance in real-world populations. Multi-stakeholder engagement is essential to implement these recommendations and ensure credible guidance and education are accessible to all stakeholders.

Recommendations for clinical implementation of blood-based biomarkers for Alzheimer's disease.

Blood-based biomarkers (BBM) for Alzheimer's disease (AD) are being increasingly used in clinical practice to support an AD diagnosis. In contrast to traditional diagnostic modalities, such as amyloid positron emission tomography and cerebrospinal fluid biomarkers, BBMs offer a more accessible and lower cost alternative for AD biomarker testing. Their unique scalability addresses the anticipated surge in demand for biomarker testing with the emergence of disease-modifying treatments (DMTs) that require confirmation of amyloid pathology. To facilitate the uptake of BBMs in clinical practice, The Global CEO Initiative on Alzheimer's Disease convened a BBM Workgroup to provide recommendations for two clinical implementational pathways for BBMs: one for current use for triaging and another for future use to confirm amyloid pathology. These pathways provide a standardized diagnostic approach with guidance on interpreting BBM test results. Integrating BBMs into clinical practice will simplify the diagnostic process and facilitate timely access to DMTs for eligible patients.

Post-Translational Modifications of RNA-Modifying Proteins in Cellular Dynamics and Disease Progression.

RNA-modifying proteins, classified as "writers," "erasers," and "readers," dynamically modulate RNA by adding, removing, or interpreting chemical groups, thereby influencing RNA stability, functionality, and interactions. To date, over 170 distinct RNA chemical modifications and more than 100 RNA-modifying enzymes have been identified, with ongoing research expanding these numbers. Although significant progress has been made in understanding RNA modification, the regulatory mechanisms that govern RNA-modifying proteins themselves remain insufficiently explored. Post-translational modifications (PTMs) such as phosphorylation, ubiquitination, and acetylation are crucial in modulating the function and behavior of these proteins. However, the full extent of PTM influence on RNA-modifying proteins and their role in disease development remains to be fully elucidated. This review addresses these gaps by offering a comprehensive analysis of the roles PTMs play in regulating RNA-modifying proteins. Mechanistic insights are provided into how these modifications alter biological processes, contribute to cellular function, and drive disease progression. In addition, the current research landscape is examined, highlighting the therapeutic potential of targeting PTMs on RNA-modifying proteins for precision medicine. By advancing understanding of these regulatory networks, this review seeks to facilitate the development of more effective therapeutic strategies and inspire future research in the critical area of PTMs in RNA-modifying proteins.

Optimizing CD8+ T cell-based immunotherapy via metabolic interventions: a comprehensive review of intrinsic and extrinsic modulators.

CD8+ T cells are integral to the effective management of cancer and infectious diseases due to their cytotoxic functions. The efficacy of these cells is profoundly influenced by their metabolic state, which regulates their activation, differentiation, and longevity. Accordingly, the modulation of metabolic pathways within CD8+ T cells is crucial for enhancing the effectiveness of T cell-based immunotherapy. Precise metabolic control is paramount in optimizing therapeutic outcomes and minimizing potential toxicities associated with treatment. Importantly, the potential of exogenous metabolites to augment CD8+ T cell responses is critically evaluated, especially through in vivo evidence that underscores their therapeutic promise. This review also addresses current challenges, including the need for precise control of metabolic modulation to avoid adverse effects, the development of targeted delivery systems to ensure efficient metabolite delivery to CD8+ T cells, and the inherent variability of metabolic states among patients that may influence treatment outcomes. Addressing these hurdles will be crucial for the successful integration of metabolic interventions into established immunotherapeutic regimens.

Modeling the Population Equity of Alzheimer Disease Treatments in the US.

Importance: The arrival of new medications for Alzheimer disease (AD) has prompted efforts to measure their value using conventional cost-effectiveness analyses; however, these analyses focus on how much health improvement new medications generate per dollar spent. As AD disproportionately affects older adults, women, racial and ethnic minority individuals, and individuals with lower socioeconomic and educational levels, it is critical to also examine the health equity outcomes of treatment. Objective: To estimate the health equity impact of a hypothetical disease-modifying treatment for early AD in the US and to examine targeted policies to mitigate health care disparities. Design, Setting, and Participants: This economic evaluation, which used a distributional cost-effectiveness analysis, was conducted from June 16, 2022, to January 11, 2024. The study included subgroups defined by race and ethnicity and by social vulnerability quintiles in the US. Exposures: A hypothetical disease-modifying treatment compared with best supportive care. Main Outcomes and Measures: The main outcomes were population-level quality-adjusted life-years (QALYs), lifetime costs, and net health benefits. The social welfare impact and change in health inequality were estimated using the Atkinson index. Results: The distributional cost-effectiveness analysis simulated 316 037 100 individuals from the US population, including 25 subgroups defined by 5 categories of race and ethnicity and population quintiles of social vulnerability, with the fifth quintile representing the most socially vulnerable group. At an opportunity cost benchmark of $150 000 per QALY, treatment was associated with improved population health, adding 28 197 QALYs per year to the US population. Accounting for health inequality preferences (using an aversion level of 11, based on an Atkinson inequality aversion parameter that can range from 0 to infinity, with higher values assigning greater weight to health gains that accrue to the population with the lowest lifetime quality-adjusted life expectancy), treatment was associated with a 0.009% reduction in existing population health inequalities annually. Scenario analyses examining earlier and expanded treatment access suggested a population health improvement of up to 221 358 QALYs. Conclusions and Relevance: The findings of this economic evaluation suggest that treatment for AD could improve population health and health equity. Policies to enable earlier diagnosis and treatment initiation, as well as expanded access to treatment, may further improve treatment and health equity impacts.

Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.

The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.

Effects of multilevel OSA surgery on patients with poor cardiopulmonary performance: A prospective pilot study.

OBJECTIVE: Multilevel airway surgery for obstructive sleep apnea/hypopnea syndrome (OSA) has benefits in improving sleep quality, but its effect on polysomnography (PSG) and 6-minute walk test (6MWT) parameters, including walking distance and cardiopulmonary performance, in patients with poor pre-operative cardiopulmonary performance remains understudied, which should be further investigated. METHODS: This prospective pilot study enrolled 27 consecutive OSA patients with poor pre-operative 6MWT results. All patients received multilevel OSA surgery, and the alterations of sleep parameters and 6MWT profiles were studied. The pre- and post-operative values of polysomnographic data and 6MWT profiles were analyzed using the Wilcoxon signed-rank tests. The relationships among changes of the indices of PSG and 6MWT were further investigated with the Spearman's correlations. RESULTS: After surgery, the sleep parameters and certain cardiopulmonary indices improved. When analyzing the correlations among changes of the indices of PSG and 6MWT, the improvement of daytime sleepiness (with ESS) was found related to farther walking distance (ρ=-0.414, p = 0.032) and higher percentage of "distance/target distance" (ρ=-0.435, p = 0.023). Moreover, the change of maximal expiratory pressure was the only index associated with the changes of AHI (apnea/hypopnea index, /hr.; ρ=-0.407, p = 0.035) and AHI in REM (ρ=-0.502, p = 0.009) among the cardiopulmonary performance parameters. CONCLUSION: This pilot study showed that OSA patients with poor pre-operative cardiopulmonary status undergoing multilevel sleep surgery could experience improvement in the sleep study and 6MWT to some extent. The relatively better walking distance and cardiopulmonary performance after the operation might potentially result from the improvement of daytime sleepiness and better respiration.

Add-on perceptual learning on refractive amblyopia in children.

AIM: To evaluate the visual outcomes of standard amblyopic treatment add-on training via perceptual learning in refractive amblyopic children and to identify the risk factors for treatment failure. METHODS: Retrospective charts were reviewed in children with refractive amblyopia who received standard treatment and add-on Cambridge Visual Stimulator (CAM) training. The add-on CAM group that was enrolled had worn full-corrected glasses for at least 2mo before training. A control group received only the standard treatment. Treatment success was defined as best-corrected visual acuity (BCVA) ≥20/25. The age, sex, initial BCVA, refractive errors, sessions and duration of training, and final BCVA were recorded. RESULTS: A total of 209 children (129 children in add-on CAM group and 80 children in control group) were enrolled. Seventy-six percent of unilateral and 87% of bilateral amblyopic children achieved treatment success. In children with unilateral or bilateral moderate amblyopia, the duration to reach BCVA ≥20/25 was significantly shorter in add-on CAM group than in control group. Poor initial BCVA (P<0.001) and high astigmatism (P=0.007) were risk factors for treatment failure after add-on CAM training. Age, sex, and types of refractive error were not associated with treatment success. CONCLUSION: Add-on CAM training is an effective strategy for visual improvement and can shorten the treatment course when the effect of standard treatment is limited in amblyopic children.

Femtogram-Sensitive Cantilever Platform for Dynamic Graphene Oxide Nanosheet Monitoring.

This study introduces a new approach to optimizing graphene oxide (GO) properties using liquid-phase plasma treatment in a microenvironment. Our innovation exploits atomic force microscopy (AFM) cantilever frequency tracking to monitor mass variations in GO, which are indicative of surface oxidation-reduction processes or substituent doping (boron/nitrogen). Complementary in situ Raman spectroscopy has observed D/G band shifts, and X-ray photoelectron spectroscopy (XPS) determined the C/O ratio and B/N doping levels pre- and post-treatment, confirming chemical tuning to GO. We can achieve femtogram-level precision in detecting nanomaterial mass changes by correlating elemental ratios with AFM cantilever frequency measurements. This multifaceted approach not only enhances our understanding of the chemical properties of GO but also establishes a new, versatile method for monitoring, modifying, and optimizing the properties of nanomaterials.

Flow cytometric immunophenotypic features of acute myeloid leukemia with mast cell differentiation.

OBJECTIVES: Acute myeloid leukemia (AML) with mast cell (MC) differentiation was recently described as an aggressive subgroup of AML cases. The objectives of this study were to assess the flow cytometric immunophenotypic features of AML-MC cases. METHODS: We characterized the immunophenotypic features of 21 AML-MC cases by flow cytometry and compared them to 20 reactive/regenerating bone marrow specimens. RESULTS: The number of MCs detected by flow cytometry in AML-MC cases ranged from 0.4% to 21.1%, with a median of 3.5%, significantly higher than that of normal/reactive bone marrow (BM) (median, 0.01%; range, 0.000%-0.396%; P < .0001). Immunophenotypically, MCs in AML-MC cases demonstrated immaturity, differing from MCs in normal/reactive BMs, including dimmer CD45 (100% vs 0%), lower side scatter (100% vs 0%), more frequent CD34 (81% vs 20%), and CD123 (100% vs 10%) positivity, and more frequent uniform/increased CD38 expression (95% vs 20%) (all P ≤ .0001). CD2 (0/5) and CD25 (2/6, 1 uniform and 1 partial) were assessed in a subset of cases. The myeloblasts in AML-MC were typically CD34+CD117+HLA-DR+ with unusually frequent expression of CD56 (57%, all partial) and CD25 (63%, mostly partial), increased CD117 (62%), and decreased CD38 (86%). The MC percentage determined by flow cytometry correlated well with MCs detected by tryptase immunohistochemistry (r = 0.76, P < .001). CONCLUSIONS: The MCs in AML-MC cases are characterized by dim CD45, low side scatter, CD34 and CD123 positivity, and uniform and increased CD38 expression. Flow cytometry is an excellent tool for identifying AML-MC cases.

Tumor Microenvironment-Derived Exosomes: A Double-Edged Sword for Advanced T Cell-Based Immunotherapy.

The tumor microenvironment (TME) plays a crucial role in cancer progression and immune evasion, partially mediated by the activity of the TME-derived exosomes. These extracellular vesicles are pivotal in shaping immune responses through the transfer of proteins, lipids, and nucleic acids between cells, facilitating a complex interplay that promotes tumor growth and metastasis. This review delves into the dual roles of exosomes in the TME, highlighting both their immunosuppressive functions and their emerging therapeutic potential. Exosomes can inhibit T cell function and promote tumor immune escape by carrying immune-modulatory molecules, such as PD-L1, yet they also hold promise for cancer therapy as vehicles for delivering tumor antigens and costimulatory signals. Additionally, the review discusses the intricate crosstalk mediated by exosomes among various cell types within the TME, influencing both cancer progression and responses to immunotherapies. Moreover, this highlights current challenges and future directions. Collectively, elucidating the detailed mechanisms by which TME-derived exosomes mediate T cell function offers a promising avenue for revolutionizing cancer treatment. Understanding these interactions allows for the development of targeted therapies that manipulate exosomal pathways to enhance the immune system's response to tumors.

A de novo int22h-1/int22h-2-flanked Xq28 deletion-associated preferential X-inactivation in a female with severe hemophilia B.

A 5-year-old female diagnosed with severe hemophilia B began experiencing frequent muscular and joint bleeds at 19 months old. Molecular studies, including Sanger sequencing, Giemsa banding, human androgen receptor (HUMARA) assay, array-based comparative genomic hybridization (aCGH), whole-exome sequencing (WES), and multiplex ligation-dependent probe amplification (MLPA), revealed a heterozygous factor IX (F9) intron 3 substitution (c.277+1G>T) inherited from her mother and a de novo heterozygous 441 kb deletion in the Xq28 region, which flanked intron 22 homologous regions 1 (int22h1) and 2 (int22h2). This rare genetic profile explains her severe phenotype and guides hereditary consultation for family planning.

Immune mRNA Expression and Fecal Microbiome Composition Change Induced by Djulis (Chenopodium formosanum Koidz.) Supplementation in Aged Mice: A Pilot Study.

Background and Objectives: The aging process has always been associated with a higher susceptibility to chronic inflammatory lung diseases. Several studies have demonstrated the gut microbiome's influence on the lungs through cross-talk or the gut-lungs axis maintaining nutrient-rich microenvironments. Taiwan djulis (Chenopodium formosanum Koidz.) provides antioxidant and anti-inflammatory characteristics that could modulate the gut microbiome. This could induce the gut-lung axis through microbial cross-talk, thus favoring the modulation of lung inflammation. Materials and Methods: Here, we investigate the immune mRNA expression in the spleen, fecal microbiome composition, and hyperplasia of the bronchial epithelium in aged 2-year-old BALB/c mice after 60 days of supplementation of djulis. Results: The pro-inflammatory cytokines IFN-γ, TNF-α, and IL-1ß, T; cells CD4 and CD8; and TLRs TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9 were reduced in their mRNA expression levels, while the anti-inflammatory cytokines IL-2, IL-4, and IL-10 were highly expressed in the C. formosanum-treated group. Interestingly, the fecal microbiome composition analysis indicated higher diversity in the C. formosanum-treated group and the presence of butyrate-producing bacteria that are beneficial in the gut microbiome. The histopathology showed reduced hyperplasia of the bronchial epithelium based on the degree of lesions. Conclusions: Our findings suggest that Taiwan djulis can modulate the gut microbiome, leading to microbial cross-talk; reducing the mRNA expression of pro-inflammatory cytokines, T cells, and TLRs; and increasing anti-inflammatory cytokines in the spleen, as cytokines migrate in the lungs, preventing lung inflammation damage in aged mice or the gut-lung axis. Thus, Taiwan djulis could be considered a beneficial dietary component for the older adult population. The major limitation includes a lack of protein validation of cytokines and TLRs and quantification of the T cell population in the spleen as a marker of the gut-lung axis.

Genetic Basis of Hearing Loss in Mongolian Patients: A Next-Generation Sequencing Study.

BACKGROUND/OBJECTIVE: The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients. METHODS: We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. RESULTS: We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns. CONCLUSIONS: Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.