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The killer-cell immunoglobulin-like receptor (KIR) gene complex, a highly polymorphic region of the human genome that encodes proteins involved in immune responses, poses strong challenges in genotyping owing to its remarkable genetic diversity and structural intricacy. Accurate analysis of KIR alleles, including their structural variations, is crucial for understanding their roles in various immune responses. Leveraging the high-quality genome assemblies from the Human Pangenome Reference Consortium (HPRC), we present a novel bioinformatic tool, the structural KIR annoTator (SKIRT), to investigate gene diversity and facilitate precise KIR allele analysis. In 47 HPRC-phased assemblies, SKIRT identifies a recurrent novel KIR2DS4/3DL1 fusion gene in the paternal haplotype of HG02630 and maternal haplotype of NA19240. Additionally, SKIRT accurately identifies eight structural variants and 15 novel nonsynonymous alleles, all of which are independently validated using short-read data or quantitative polymerase chain reaction. Our study has discovered a total of 570 novel alleles, among which eight haplotypes harbor at least one KIR gene duplication, six haplotypes have lost at least one framework gene, and 75 out of 94 haplotypes (79.8%) carry at least five novel alleles, thus confirming KIR genetic diversity. These findings are pivotal in providing insights into KIR gene diversity and serve as a solid foundation for understanding the functional consequences of KIR structural variations. High-resolution genome assemblies offer unprecedented opportunities to explore polymorphic regions that are challenging to investigate using short-read sequencing methods. The SKIRT pipeline emerges as a highly efficient tool, enabling the comprehensive detection of the complete spectrum of KIR alleles within human genome assemblies.

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In isolated English word reading, readers have the optimal performance when their initial eye fixation is directed to the area between the beginning and word center, that is, the optimal viewing position (OVP). Thus, how well readers voluntarily direct eye gaze to this OVP during isolated word reading may be associated with reading performance. Using Eye Movement analysis with Hidden Markov Models, we discovered two representative eye movement patterns during lexical decisions through clustering, which focused at the OVP and the word center, respectively. Higher eye movement similarity to the OVP-focusing pattern predicted faster lexical decision time in addition to cognitive abilities and lexical knowledge. However, the OVP-focusing pattern was associated with longer isolated single letter naming time, suggesting conflicting visual abilities required for identifying isolated letters and multi-letter words. In contrast, in both word and pseudoword naming, although clustering did not reveal an OVP-focused pattern, higher consistency of the first fixation as measured in entropy predicted faster naming time in addition to cognitive abilities and lexical knowledge. Thus, developing a consistent eye movement pattern focusing on the OVP is essential for word orthographic processing and reading fluency. This finding has important implications for interventions for reading difficulties.

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Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.

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Introduction: The morbidity and mortality rates of coronary heart disease are significant, with PCI being the primary treatment. The high incidence of ISR following PCI poses a challenge to its effectiveness. Currently, there are numerous studies on ISR risk prediction models after PCI, but the quality varies and there is still a lack of systematic evaluation and analysis. Methods: To systematically retrieve and evaluate the risk prediction models for ISR after PCI. A comprehensive search was conducted across 9 databases from inception to March 1, 2024. The screening of literature and extraction of data were independently carried out by two investigators, utilizing the checklist for critical appraisal and data extraction for systematic reviews of prediction modeling studies (CHARMS). Additionally, the risk of bias and applicability were evaluated using the Prediction Model Risk of Bias Assessment Tool (PROBAST). Results: A total of 17 studies with 29 models were included, with a sample size of 175-10,004 cases, and the incidence of outcome events was 5.79%-58.86%. The area under the receiver operating characteristic curve was 0.530-0.953. The top 5 predictors with high frequency were diabetes, number of diseased vessels, age, LDL-C and stent diameter. Bias risk assessment into the research of the risk of higher bias the applicability of the four study better. Discussion: The overall risk of bias in the current ISR risk prediction model post-PCI is deemed high. Moving forward, it is imperative to enhance study design and specify the reporting process, optimize and validate the model, and enhance its performance.

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Age-related macular degeneration (AMD), a leading cause of blindness, is characterized by mitochondrial dysfunction of retinal pigment epithelium (RPE) cells. EUK-134 is a mimetic of SOD2 and catalase, widely used for its antioxidant properties in models of light-induced damage or oxidative stress. However, its effects on the retina are not yet clear. Here, we investigated the capability of EUK-134 in averting AMD using sodium iodate (NaIO3)-induced Balb/c mouse and ARPE-19 cells (adult RPE cell line). In vivo, EUK-134 effectively antagonized NaIO3-induced retinal deformation and prevented outer and inner nuclear layer thinning. In addition, it was found that the EUK-134-treated group significantly down-regulated the expression of cleaved caspase-3 compared with the group treated with NaIO3 alone. Our results found that EUK-134 notably improved cell viability by preventing mitochondrial ROS accumulation-induced membrane potential depolarization-mediated apoptosis in NaIO3-inducted ARPE-19 cells. Furthermore, we found that EUK-134 could inhibit p-ERK, p-p38, p-JNK, p-p53, Bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP by increasing Bcl-2 protein expression. Additionally, we employed MAPK pathway inhibitors by SB203580 (a p38 inhibitor), U0126 (an ERK inhibitor), and SP600125 (a JNK inhibitor) to corroborate the aforementioned observation. The results support that EUK-134 may effectively prevent mitochondrial oxidative stress-mediated retinal apoptosis in NaIO3-induced retinopathy.

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BACKGROUND: Patients with respiratory or cardiovascular diseases often experience higher rates of hospital readmission due to compromised heart-lung function and significant clinical symptoms. Effective measures such as discharge planning, case management, home telemonitoring follow-up, and patient education can significantly mitigate hospital readmissions. OBJECTIVE: This study aimed to determine the efficacy of home telemonitoring follow-up in reducing hospital readmissions, emergency department (ED) visits, and total hospital days for high-risk postdischarge patients. METHODS: This prospective cohort study was conducted between July and October 2021. High-risk patients were screened for eligibility and enrolled in the study. The intervention involved implementing home digital monitoring to track patient health metrics after discharge, with the aim of reducing hospital readmissions and ED visits. High-risk patients or their primary caregivers received education on using communication measurement tools and recording and uploading data. Before discharge, patients were familiarized with these tools, which they continued to use for 4 weeks after discharge. A project manager monitored the daily uploaded health data, while a weekly video appointment with the program coordinator monitored the heart and breathing sounds of the patients, tracked health status changes, and gathered relevant data. Care guidance and medical advice were provided based on symptoms and physiological signals. The primary outcomes of this study were the number of hospital readmissions and ED visits within 3 and 6 months after intervention. The secondary outcomes included the total number of hospital days and patient adherence to the home monitoring protocol. RESULTS: Among 41 eligible patients, 93% (n=38) were male, and 46% (n=19) were aged 41-60 years, while 46% (n=19) were aged 60 years or older. The study revealed that home digital monitoring significantly reduced hospitalizations, ED visits, and total hospital stay days at 3 and 6 months after intervention. At 3 months after intervention, average hospitalizations decreased from 0.45 (SD 0.09) to 0.19 (SD 0.09; P=.03), and average ED visits decreased from 0.48 (SD 0.09) to 0.06 (SD 0.04; P<.001). Average hospital days decreased from 6.61 (SD 2.25) to 1.94 (SD 1.15; P=.08). At 6 months after intervention, average hospitalizations decreased from 0.55 (SD 0.11) to 0.23 (SD 0.09; P=.01), and average ED visits decreased from 0.55 (SD 0.11) to 0.23 (SD 0.09; P=.02). Average hospital days decreased from 7.48 (SD 2.32) to 6.03 (SD 3.12; P=.73). CONCLUSIONS: By integrating home telemonitoring with regular follow-up, our research demonstrates a viable approach to reducing hospital readmissions and ED visits, ultimately improving patient outcomes and reducing health care costs. The practical application of telemonitoring in a real-world setting showcases its potential as a scalable solution for chronic disease management.

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Objective: This study aimed to assess the efficacy of a modified exhaust method in pediatric open-heart surgery involving cardiopulmonary bypass. Method: Data from 303 cases conducted at the Department of Cardiac Surgery, Guizhou Hospital, Shanghai Children's Medical Center, between October 2023 and March 2024 were analyzed. Among these cases, 202 utilized the modified exhaust method, divided into group A (101 cases with median thoracotomy) and group C (101 cases with lateral thoracotomy), while 101 cases used the traditional exhaust method in group B (median thoracotomy). Comparative analysis included general patient data, cardiopulmonary bypass duration, aortic cross-clamp time, time for exhaust and reperfusion upon opening, post-reperfusion ST segment abnormalities on electrocardiogram, intracardiac pneumogram observations via esophageal ultrasound, relevant plasma biochemical indexes on postoperative day one, postoperative drainage volume, duration of ventilator use, and length of stay in the intensive care unit (ICU). Results: There was no difference in between-group comparisons regarding age (27.98 ± 3.57 vs. 34.05 ± 3.96 months; P = 0.401) and weight (12.23 ± 0.55vs. 12.59 ± 0.70 Kg; P = 0.563). Longer Cardiopulmonary bypass times were observed in patients undergoing median thoracotomy than those undergoing lateral thoracotomy (group B: 108.47 ± 2.30 min vs. group C: 117.03 ± 2.82 min, P = 0.002; group A: 108.91 ± 2.63 min vs. group C: 117.03 ± 2.82 min, P = 0.035). Exhaust and rebound times after opening were significantly shorter in the modified exhaust-method group compared with the traditional-method group (Group A: 52.62 ± 1.39 s vs. Group B: 65.20 ± 1.49 s, P < 0.001; Group B: 65.20 ± 1.49 s vs. Group C: 4.31 ± 1.16 s, P < 0.001). There was no statistical difference in terms of postoperative biochemical indexes, drainage volume, ventilator use time, and ICU stay time (all P > 0.05). Conclusions: The modified exhaust method demonstrates overall good immediate results in pediatric congenital heart surgery. It was superior to the traditional exhaust method in terms of reducing exhaust times and potentially minimizing the risk of local aortic injuries. Additionally, it appeared to be suitable for lateral thoracotomy surgery.

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Antibiotic resistance continues to pose significant health challenges. Considering severe limitations in the discovery and supply of new antibiotics, there is an unmet need to design alternative and more effective strategies for addressing this global issue. Use of polymeric nanoparticles with cationic shell surfaces offers a highly promising approach to coupling their inherent bactericidal action with sustained delivery of small lipophilic microbicides. We have utilized this platform for assembling multi-tasking soft core-shell nanoparticles from star polymers with the desired asymmetric arm composition. These stable nanoparticles with low critical micelle concentration imparted intrinsic antimicrobial potency due to high positive charge density in the corona, as well as the loading of active biocidal agents (such as curcumin and terbinafine) for potential dual and coadjuvant inhibition. This strategic combination allows for both immediate (direct contact) and extended (drug delivery) antibacterial activities for better therapeutic efficacy. Micellar nanoparticles with and without therapeutic cargo were highly efficient against both Escherichia coli (E. coli) and Bacillus subtilis (B. subtilis), representative Gram-negative and Gram-positive bacteria, respectively. Interestingly, we observed bacteria- and concentration-dependent effects, in which higher concentrations of charged nanoparticles were more effective against E. coli, whereas B. subtilis was inhibited only at lower concentrations. This work highlights a valuable platform to achieve combination therapy through nanoparticles with charged coronas and delivery of potent therapeutics to overcome antimicrobial resistance.

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Oral squamous cell carcinoma (OSCC) is a prevalent cancer worldwide, exhibiting unique regional prevalence. Despite advancements in diagnostics and therapy, the 5-year survival rate for patients has seen limited improvement. A deeper understanding of OSCC pathogenesis, especially its molecular underpinnings, is essential for improving detection, prevention, and treatment. In this context, noncoding RNAs, such as circular RNAs (circRNAs), have gained recognition as crucial regulators and potential biomarkers in OSCC progression. Our study highlights the discovery of previously uncharacterized circRNAs, including a SNX5 gene-derived circRNA, circSNX5, through deep sequencing of OSCC patient tissue transcriptomes. We established circSNX5's tumor-specific expression and its strong correlation with patient survival using structure-specific and quantitative PCR analyses. In vitro and in vivo experiments underscored circSNX5 RNA's regulatory role in cancer growth and metastasis. Further, our omics profiling and functional assays revealed that ADAM10 is a critical effector in circSNX5-mediated cancer progression, with circSNX5 maintaining ADAM10 expression by sponging miR-323. This novel circRNA-miRNA-mRNA regulatory axis significantly contributes to oral cancer progression and malignancy. Moreover, we discovered that circSNX5 RNA is produced via noncanonical sequential back-splicing of pre-mRNA, a process negatively regulated by the RNA-binding protein STAU1. This finding adds a new dimension to our understanding of exonic circRNA biogenesis in the eukaryotic transcriptome. Collectively, our findings offer a detailed mechanistic dissection and functional interpretation of a novel circRNA, shedding light on the role of the noncoding transcriptome in cancer biology and potentially paving the way for innovative therapeutic strategies.

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AIMS: Previous systematic reviews suggest that deprescribing may improve survival, particularly in frail older people. Evidence is rapidly accumulating, suggesting a need for an updated review of the literature. METHODS: We updated a 2016 systematic review and meta-analysis to include studies published from inception to 26 April 2024 from specified databases. Studies in which older people had at least one medication deprescribed were included and grouped by study designs and targeted medications. The risk of bias was assessed using the Cochrane tool and the Newcastle-Ottawa tool. Odds ratios (OR) or mean differences were calculated as the effect measures using either the Mantel-Haenszel or generic inverse-variance method with fixed- or random-effects meta-analyses. The primary outcome was mortality. Secondary outcomes were adverse drug withdrawal events, physical health, cognitive function, quality of life and effect on medication regimen. Subgroup analyses were performed based on age and intervention types. RESULTS: A total of 259 studies (reported in 286 papers) were included in this updated review. Deprescribing polypharmacy did not result in a significant reduction in mortality in both randomized (OR 0.96, 95% confidence interval [CI] 0.84-1.09) and non-randomized studies (OR 0.70, 95% CI 0.36-1.38). Further subgroup analyses of randomized studies on deprescribing polypharmacy demonstrated a significant reduction in mortality in the young old (aged 65-79) (OR 0.71, 95% CI 0.51-0.99) and when patient-specific interventions were applied (OR 0.79, 95% CI 0.63-0.99). CONCLUSIONS: Deprescribing can be achieved with potentially important benefits in terms of improved survival, particularly when patient-specific interventions are applied and initiated early in the young old.

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INTRODUCTION: Sharing mental models is essential for high-performance teams, and speaking up is key for exchanging critical insights, especially during medical errors. Understanding how health providers and trainees voice their concerns is crucial for improving speaking-up behavior. This study aims to fill a gap in the literature by examining how medical students speak up when they encounter medical errors and assessing the impact of training on their speaking-up patterns. METHOD: A quasi-experimental study involving 146 students, who were divided into two groups, was conducted in Northern Taiwan. One group of students encountered life-threatening scenario before intervention, followed by a faculty-led personalized debriefing session, then a non-life-threatening scenario after the intervention. Another group of students underwent these sessions in the reverse order. Students' Speaking-up patterns, including expression style, form and attitude, and their speaking-up confidence were assessed at pre- and post-intervention scenarios. RESULTS: During pre-intervention scenario, in expression style, 50 students (34.5%) addressed their concerns to medical errors with direct expression and 14 students (9.7%) utilized indirect hint to express their concerns. In expression form, 31 students (21.4%) addressed their concerns to medical errors with affirmative sentences and 33 students (22.8%) asked questions to express their concerns. In speaking-up attitude, 47 students (32.4%) used unoffensive words, while 17 students (11.7%) used offensive words. After intervention, significantly change of speaking-up styles, forms, and attitude were observed along with their speaking-up confidence (p < 0.001). DISCUSSION: Medical students are inclined to speak up in the event of medical errors using more direct expression and affirmative sentences, along with increased speaking-up confidence after simulation scenario learning and faculty-led personalized debriefing. Healthcare educators can focus more on discussing with students the advantages and disadvantages of various approaches of speaking-up in medical errors, helping them to develop effective speaking-up behaviors in a variety of medical contexts.

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In this study, attention deficit hyperactivity disorder (ADHD), a childhood neurodevelopmental disorder, is being studied alongside its comorbidity, conduct disorder (CD), a behavioral disorder. Because ADHD and CD share commonalities, distinguishing them is difficult, thus increasing the risk of misdiagnosis. It is crucial that these two conditions are not mistakenly identified as the same because the treatment plan varies depending on whether the patient has CD or ADHD. Hence, this study proposes an electroencephalogram (EEG)-based deep learning system known as ADHD/CD-NET that is capable of objectively distinguishing ADHD, ADHD + CD, and CD. The 12-channel EEG signals were first segmented and converted into channel-wise continuous wavelet transform (CWT) correlation matrices. The resulting matrices were then used to train the convolutional neural network (CNN) model, and the model's performance was evaluated using 10-fold cross-validation. Gradient-weighted class activation mapping (Grad-CAM) was also used to provide explanations for the prediction result made by the 'black box' CNN model. Internal private dataset (45 ADHD, 62 ADHD + CD and 16 CD) and external public dataset (61 ADHD and 60 healthy controls) were used to evaluate ADHD/CD-NET. As a result, ADHD/CD-NET achieved classification accuracy, sensitivity, specificity, and precision of 93.70%, 90.83%, 95.35% and 91.85% for the internal evaluation, and 98.19%, 98.36%, 98.03% and 98.06% for the external evaluation. Grad-CAM also identified significant channels that contributed to the diagnosis outcome. Therefore, ADHD/CD-NET can perform temporal localization and choose significant EEG channels for diagnosis, thus providing objective analysis for mental health professionals and clinicians to consider when making a diagnosis. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-10028-2.

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Background: Cardiogenic shock (CS) complicating myocardial infarction is associated with poor outcomes. Data among Asian populations are scarce. We aimed to investigate the long-term outcomes, prognostic factors, and predictors of CS among Asian ST elevation myocardial infarction (STEMI) patients. Methods: This was a retrospective cohort study of consecutive patients undergoing primary percutaneous coronary intervention (PPCI) for STEMI within our regional STEMI network between 2015 and 2019. The long-term outcomes of those with and without CS were compared. Clinical predictors of outcomes and development of CS were investigated. Results: A total of 1791 patients who underwent PPCI were included. Patients completed at least 2 years' follow-up with a median follow-up period of 2.6 years (IQR 1.0, 3,9). Overall, 208/1791 (11.6 %) STEMI patients developed CS. These patients were older (61.1 ± 12.5 vs 57.8 ± 12.2, P < 0.001) and mostly men (87.0 %). All-cause mortality (59.9 % vs 4.7 % P < 0.001), cardiac mortality (43.8 % vs 2.2 %, P < 0.001) and major adverse cardiovascular events (MACE) was significantly higher in the CS group (59.1 % vs 14.0 %, P < 0.001). Independent predictors of survival were higher index LVEF (adjusted hazards ratio [aHR] 0.967, 95 %CI 0.951-0.984, p < 0.001) and higher arterial pH at onset of shock (aHR 0.750, 0.626-0.897, p = 0.002). Increased serum lactate concentration independently predicts poor prognosis (aHR 1.084, 95 % CI 1.046-1.124, p < 0.001). Conclusion: In Asian STEMI patients who underwent PPCI, CS was associated with poor outcomes. Higher LVEF on index admission was associated with better outcomes; while lactic acidosis independently predicted mortality.

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OBJECTIVES: The association between diuretic use and cardiorenal outcomes remains limited in patients with stage 3-5 chronic kidney disease (CKD) and hypertension. To address this gap, we aim to investigate the long-term clinical impact of diuretic use with its pharmacological classification in Taiwanese patients with stage 3-5 CKD and hypertension who were concurrently received angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs). METHODS: Using data from the National Health Insurance Research Database (January 2008 to December 2019), we focused on individuals with stage 3-5 CKD receiving ACEIs/ARBs between 2010 and 2018. We categorized the cohort into non-diuretic, loop diuretic (furosemide), thiazide diuretic, and combination diuretic groups. We used a Cox proportional hazards regression model with propensity score matching to analyze the influence of diuretics on all-cause mortality, cardiovascular (CV) death, and cardiorenal adverse outcomes. RESULTS: The study included 59,719 patients, with 17,585 in the non-diuretic group and 42,134 in the diuretic group. Diuretics including furosemide use was significantly associated the risks of hospitalization for decompensated congestive heart failure (CHF), acute renal failure (ARF), end-stage renal disease (ESRD) requiring dialysis, CV mortality, and all-cause mortality (p-value <0.001). Thiazide diuretics showed no such adverse outcomes associations. The group receiving both thiazide and furosemide was more associated with all-cause mortality than the nondiuretic, thiazide, and furosemide monotherapy groups (all p-value <0.001). CONCLUSION: Among stage 3-5 CKD patients on ACEIs/ARBs, loop diuretics exposure was associated with increased mortality and hospitalization for cardiorenal events, while thiazide diuretics exposure in isolation had no such associations. In the present data, we cannot evaluate the relationship between furosemide-associated adverse outcomes and worse renal function. These findings highlight the need for randomized controlled trials to assess the safety of loop diuretics in this population, urging caution in their prescription without a clear clinical indication.

Fluid overload is common in patients with advanced chronic kidney disease (CKD) due to their decreased ability to excrete water. Diuretic therapy is often used to manage this condition. However, prolonged use of diuretics may activate harmful bodily systems, including the renin-angiotensin-aldosterone system and the sympathetic nervous system. Our study, focusing on Taiwanese patients with stage 3­5 CKD and hypertension, found that loop diuretics, such as furosemide, were linked to higher risks of hospitalization, mortality, and serious heart and kidney complications. Thiazide diuretics did not show these adverse effects, suggesting they may be safer for these patients. More research is needed to clarify the long-term impact of diuretics on this population.

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Breast cancer remains the most prevalent cancer in women globally, posing significant challenges in treatment due to the inevitable development of resistance to targeted therapies like everolimus, an mTOR inhibitor. While several mechanisms of resistance have been proposed, the role of snoRNAs in this context remains inadequately explored. Our study unveils a novel connection between snoRNAs and everolimus resistance, focusing on the snoRNA U50A. We discovered that U50A negatively regulates mTOR signaling by transcriptionally downregulating mTOR gene expression, which consequently leads to decreased sensitivity to everolimus treatment. Through RNA sequencing, gene set enrichment analyses, and experimental validations, we established that U50A overexpression in breast cancer cells results in mTOR downregulation and subsequently, everolimus desensitization. Clinical results further supported our findings, showing a higher prevalence of everolimus resistance in tumors with elevated U50A expression. Moreover, our results suggest that U50A's effect on mTOR is mediated through the suppression of the transcription factors c-Myc, with a notable impact on cancer cell viability under everolimus treatment. This study not only highlights the complex role of snoRNAs in cancer drug resistance but also proposes U50A as a potential biomarker for predicting everolimus efficacy in breast cancer treatment.

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OBJECTIVES: This research elucidates the correlation between solar radiation insolation, polygenic risk score (PRS), and systemic lupus erythematosus (SLE) diagnosis, utilizing genomic, environmental, and clinical data. METHODS: We included 1,800 SLE participants and 1,800 controls from the Taiwan Precision Medicine Initiative, genotyped via the Affymetrix Genome-Wide TWB 2.0 SNP Array. The study employed a SLE-PRS tailored for individuals of Taiwanese ancestry, comprising 27 single nucleotide polymorphisms (SNPs). QGIS computed solar radiation insolation from participants' residences. We employed logistic regression to investigate the associations between SLE-PRS, solar insolation susceptibility, and SLE. Additive and multiplicative interactions were utilized to assess the interactions between solar insolation and SLE-PRS regarding the risk of SLE. RESULTS: SLE patients showed decreased solar insolation (p < 0.001). The highest decile of SLE-PRS exhibited a statistically significant lower solar insolation 1, 3, 6, and 12 months prior to diagnosis as compared to the lowest decile. Specifically, there were significant differences observed at 1 and 12 months (p = 0.025 and p = 0.004, respectively). It suggests that higher SLE-PRS correlated with reduced solar insolation tolerance. We observed an increase in SLE risk across ascending SLE-PRS percentiles exclusively in the high solar insolation group, not in the low solar insolation group. However, the interaction effect of SLE-PRS and solar insolation on SLE risk is not statistically significant. Compared to the lowest decile, the highest SLE-PRS decile showed a 10.98-fold increase in SLE risk (95 % CI, 3.773-31.952, p < 0.001). High SLE-PRS scores in conjunction with high solar insolation contribute to SLE incidence. CONCLUSIONS: Our study unveils the intertwined nature of UV insolation and polygenic risks in SLE. Future studies should explore the preventative potential of robust solar radiation protection for high-risk individuals before the disease onset.

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Coxsackievirus A24 (CV-A24) is a human enterovirus that causes acute flaccid paralysis. However, a Coxsackievirus A24 variant (CV-A24v) is the most common cause of eye infections. The causes of these variable pathogenicity and tissue tropism remain unclear. To elucidate the phylodynamics of CV-A24 and CV-A24v, we analyzed a dataset of 66 strains using Bayesian phylodynamic approach, along with detailed sequence variation and epistatic analyses. Six CV-A24 strains available in GenBank and 60 CV-A24v strains, including 11 Taiwanese strains, were included in this study. The results revealed striking differences between CV-A24 and CV-A24v exhibiting long terminal branches in the phylogenetic tree, respectively. CV-A24v presented distinct ladder-like clustering, indicating immune escape mechanisms. Notably, 10 genetic recombination events in the 3D regions were identified. Furthermore, 11 missense mutation signatures were detected to differentiate CV-A24 and CV-A24v; among these mutations, the F810Y substitution may significantly affect the secondary structure of the GH loop of VP1 and subsequently affect the epitopes of the capsid proteins. In conclusion, this study provides critical insights into the evolutionary dynamics and epidemiological characteristics of CV-A24 and CV-A24v, and highlights the differences in viral evolution and tissue tropism.

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Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

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Breast cancer is the most frequent malignancy in women, constituting 15.2% of all new cancers diagnosed in the United States. Distant breast cancer metastasis accounts for the majority of breast cancer-related deaths; brain metastasis is the third most common site for metastatic breast cancer but is associated with worst prognosis of approximately eight months of survival. Current treatment options for breast cancer brain metastasis (BCBM) are limited and ineffective. To help identify new and effective therapies for BCBM, it is important to investigate the mechanisms by which breast cancer cells metastasize to the brain and thrive in the brain microenvironment. To this end, studies have reported that primary breast tumor cells can prime brain microenvironmental cells, including, astrocytes and microglia, to promote the formation of BCBM through the release of extracellular vesicle-microRNAs (miRNAs). Breast tumor-derived miRNAs can also promote breast cancer cell invasion through the blood-brain barrier by disrupting the integrity of the brain microvascular endothelial cells. In this review, we summarize current literature on breast cancer-derived BCBM-promoting miRNAs, cover their roles in the complex steps of BCBM particularly their interactions with microenvironmental cells within the brain metastatic niche, and finally discuss their therapeutic applications in the management of BCBM.

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BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is characterized by rapid, unexplained loss of hearing within a 72-hour period and exhibits a high incidence globally. Despite this, the outcomes of therapeutic interventions remain largely unpredictable, especially for those with profound hearing loss. Extracellular vesicles (EVs), nano-sized entities containing biological materials, are implicated in the development of numerous diseases. The specific relationship between EVs and both the severity and treatment effectiveness of SSNHL, however, is not well understood. METHODS: This study involved the analysis of medical records from the Department of Otolaryngology (September 1, 2020 - December 31, 2022) of patients diagnosed with SSNHL according to the 2015 Guidelines for Diagnosis and Treatment of Sudden Deafness in China. Peripheral blood samples from patients with various types of SSNHL before and after treatment were collected, alongside samples from healthy volunteers serving as controls. Plasma EVs were isolated using gel rejection chromatography and analyzed for concentration, marker presence, and morphology using Nanosight, Western blot, and transmission electron microscopy (TEM), respectively. Proteomics and miRNA assessments were conducted to identify differentially expressed proteins and miRNAs in the plasma EVs of SSNHL patients and healthy volunteers. Key proteins were further validated through Western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was utilized to determine the levels of complement C3 in plasma EVs, and correlation analyses were performed with audiological data pre- and post-treatment. RESULTS: Plasma from SSNHL patients of varying types was collected and their EVs were successfully isolated and characterized. Proteomic analysis revealed that complement C3 levels in the plasma EVs of patients with profound SSNHL were significantly higher compared to healthy controls. Differential expression of miRNAs in plasma EVs and their related functions were also identified. The study found that the level of complement C3 in plasma EVs, but not the total plasma complement C3, positively correlated with the severity of SSNHL in patients exhibiting positive therapeutic responses, particularly in those with initially lower levels of EV-associated complement C3. After treatment, complement C3 level was decreased in patients with initially higher levels of EV-associated complement C3. No significant correlation was observed between changes in plasma EV-derived complement C3 levels and the degree of hearing loss in either responders or non-responders among patients with profound SSNHL. CONCLUSION: Differential profiles of proteins and miRNAs were identified in patients with profound SSNHL. Notably, plasma EV-derived complement C3 was linked to both the severity and early treatment effectiveness of patients with profound SSNHL.

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