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Serum leucine-rich alpha-2 glycoprotein (LRG) can monitor disease activities during biologics treatment in patients with inflammatory bowel disease (IBD). It is unclear whether the pretreatment serum LRG level can predict clinical effectiveness including serum trough levels of ustekinumab in patients with IBD. This multicenter prospective cohort study included 184 patients (Crohn's disease, 104; ulcerative colitis, 80) who received ustekinumab (n = 119) or anti-tumor necrosis factor (n = 65) between January 2019 and March 2023. Multivariate logistic regression analysis revealed serum LRG level at week 0 (0w-LRG, odds ratio 0.12, 95% confidence interval 0.02-0.68) as one of significant factors for clinical remission at week 8. We divided patients into the low- and the high-LRG groups by the median 0w-LRG (18.2 µg/mL) and compared the effectiveness. In patients who received ustekinumab, the proportion of clinical remission at week 8 was significantly different between in the low- (76.9%) and in the high-LRG group (59.3%, P = 0.038), and median serum trough level at week 8 was significantly different between in the low- (10.9 µg/mL, interquartile range 6.7-13.4) and the high-LRG group (5.3 µg/mL, interquartile range 2.4-8.3, P < 0.001). The 0w-LRG can predict the effectiveness including serum trough levels of ustekinumab during induction treatment for patients with IBD., Competing Interests: Declarations. Competing interests: S. Shinzaki received lecture fees from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and lecture fees and grants from AbbVie GK, Sekisui Medical Co., Ltd.; A. Yonezawa: grants from Shimadzu Corporation and Ayumi Pharma Corporation.; H. Iijima: lecture fees from AbbVie GK and Mitsubishi-Tanabe Pharma Corporation; T. Takehara: grants from Mitsubishi-Tanabe Pharma Corporation, and lecture fees and grants from AbbVie GK. None of the aforementioned are related to this study. The remaining authors do not have any conflicts of interest to disclosure. Ethnics approval and consent to participate: This study was carried out in accordance with the Declaration of Helsinki, and approved by the ethics committee of Osaka University Hospital, the ethics committee of National Hospital Organization Osaka National Hospital, the ethics committee of Osaka Rosai Hospital, the ethics committee of Toyonaka Municipal Hospital, the ethics committee of Japan Community Healthcare Organization Osaka Hospital, the ethics committee of Itami City Hospital, the ethics committee of Suita Municipal Hospital, the ethics committee of Ikeda Municipal Hospital, the ethics committee of Otemae Hospital, the ethics committee of Kansai Rosai Hospital, the ethics committee of Higashiosaka City Medical Center, the ethics committee of Osaka General Medical Center, the ethics committee of Osaka Police Hospital, the ethics committee of Yao Municipal Hospital and the ethics committee of Hyogo Prefectural Nishinomiya Hospital. Written informed consent was obtained from all patients., (© 2024. The Author(s).)

Early mortality after hemodialysis (HD) initiation significantly impacts the longevity of HD patients. This study aimed to quantify the effect sizes of risk factors on mortality using various machine learning approaches. A cohort of 3284 HD patients from the CRC-ESRD (2008-2014) was analyzed. Mortality risk models were validated using logistic regression, ridge regression, lasso regression, and decision trees, as well as ensemble methods like bagging and random forest. To better handle missing data and time-series variables, a recurrent neural network (RNN) with an autoencoder was also developed. Additionally, survival models predicting hazard ratios were employed using survival analysis techniques. The analysis included 1750 prevalent and 1534 incident HD patients (mean age 58.4 ± 13.6 years, 59.3% male). Over a median follow-up of 66.2 months, the overall mortality rate was 19.3%. Random forest models achieved an AUC of 0.8321 for first-year mortality prediction, which was further improved by the RNN with autoencoder (AUC 0.8357). The survival bagging model had the highest hazard ratio predictability (C-index 0.7756). A shorter dialysis duration (< 14.9 months) and high modified Charlson comorbidity index scores (7-9) were associated with hazard ratios up to 7.76 (C-index 0.7693). Comorbidities were more influential than age in predicting early mortality. Monitoring dialysis adequacy (KT/V), RAAS inhibitor use, and urine output is crucial for assessing early prognosis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Trace elements, specifically magnesium (Mg), zinc (Zn), and selenium (Se) have been linked with immunomodulatory properties. This research delves into identifying the potential impression of serum levels Mg, Zn, and Se on the protective immunity arisen through Sinopharm COVID-19 vaccine in the vaccinated subjects. Levels of Mg, Zn, and Se, cytokine and antibody production as well as virus neutralization potency were investigated in 75 males and 75 females before and 2 weeks after first and second dose of vaccination. Level of Mg, Zn, and Se did not change significantly before and 2 weeks after first and second dose of vaccine administration. Concentrations of Interleukin (IL)-2, IL-6, and Interferon (IFN)-γ were significantly higher in the supernatant of peripheral blood mononuclear cells (PBMCs) obtained from subjects 2 weeks after both first and second dose of vaccination compared to before vaccination. Serum level IgG was significantly higher 2 weeks after first and second dose of vaccination compared to before vaccination. Serum level IgM was only higher after first dose of vaccination compared with before vaccine. Also, 2 weeks after both first and second dose of vaccination compared to before vaccination, FRNT 50 titer was significantly higher. Levels of Mg, Zn, and Se did not significantly correlate with levels of IL-2, IL-6, IFN-γ, IgM and IgG, and FRNT 50 after first and second dose of vaccination. No severe unwanted clinical symptoms were detected after vaccination. Mg, Zn, and Se do not play a role in modulating protective immunity during Sinopharm COVID-19 vaccine., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study protocol was approved from the local Ethical Review committee located in Rafsanjan University of Medical Sciences (Permission No. IR.RUMS.REC.1400.165) and written informed consent form was taken by all subjects. All methods were carried out in accordance with relevant guidelines and regulations provided by Rafsanjan University of Medical Sciences. Research carried out here were in compliance with the Helsinki Declaration. The protocol of this study was approved by the Human Research Ethics Committee from the Rafsanjan University of Medical Sciences, Rafsanjna, Iran (Permission No. IR.RUMS.REC.1400.165). Written informed consent forms were obtained from all subjects before blood taking., (© 2024. The Author(s).)

YKL-40 is significantly associated with the prevalence and severity of coronary artery disease (CAD). YKL-40 levels are significantly associated with variations in the CHI3L1 and TRIB1 genes. We investigated candidate genes for YKL-40 levels and evaluated the prognostic value of this biomarker and corresponding variants for long-term outcomes in patients with CAD. We included 4664 and 521 participants from the Taiwan Biobank (TWB) and CAD cohorts, respectively. Candidate variants for circulating YKL-40 levels were investigated using genome-wide association study (GWAS) data from the TWB cohort, and the results were validated in the CAD cohort. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiac events (MACEs), which included the composite endpoints of all-cause mortality, nonfatal acute coronary syndrome, hospitalization for heart failure, and nonfatal stroke. According to the GWAS data from the TWB cohort, three CHI3L1 variants (rs4950928, rs10399931, and rs872129) and one TRIB1 variant (rs6982502) were independently associated with YKL-40 levels. These findings were validated in the CAD cohort. The combined CHI3L1 and TRIB1 weighted genetic risk scores (WGRSs) were not associated with the long-term outcomes (median follow-up period of 3.7 years) in patients with CAD. Conversely, patients with YKL-40 levels in the upper tertile had the highest rates of all-cause mortality and MACEs (log-rank p = 9.58 × 10 -8 for all-cause mortality and 1.34 × 10 -7 for MACEs). Furthermore, YKL-40 levels predicted poor clinical outcomes only in patients with multivessel CAD (log-rank p = 3.0 × 10 -6 for all-cause mortality and 1.10 × 10 -5 for MACEs) and not in patients with single-vessel CAD. This study revealed that YKL-40 levels but not the combined CHI3L1 and TRIB1 WGRSs were found to be independent predictors of poor clinical outcomes in patients with multivessel CAD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

We explored effective therapeutic targets for systemic sclerosis (SSc) patients with high risk for pulmonary arterial hypertension (PAH) by plasma proteomics analysis. A total of fifty-seven patients with SSc were enrolled in the study and the prevalence of PAH was 19.3%. On the other hand, 75.4% of SSc patients showed the ratio of forced vital capacity percentage/diffusing capacity of the lungs for carbon monoxide percentage> 1.6 and met criteria for high risk of PAH. Identification of elevated plasma proteins in SSc patients with high risk of PAH, followed by upstream regulator analysis, predicted interleukin (IL)-17A as a major upstream molecule. Furthermore, we performed in vitro neutralization study using MT-6194, a bispecific antibody targeting both IL-17A and IL-6 receptor. We found that MT-6194 broadly suppressed the increased expression of downstream molecules of IL-17A including IL-17A-related cytokines/chemokines, IL-17A-driven NFκB pathway and IL-6-driven JAK/STAT pathway which were shown to be increased in SSc patients with high risk of PAH by the proteomics. Consequently, it is revealed that IL-17A is a promising target for early intervention in SSc patients with high risk for PAH., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Previous studies suggest associations between the risk of developing chronic obstructive pulmonary disease (COPD) and adiponectin/leptin (ALR) and apolipoprotein B/A1 (APOR) ratios. This longitudinal observational study, using data from the Korean Genome and Epidemiology Study (KoGES), examined the rate of lung function decline, risk factors for the airflow obstruction (AFO), and the time to first AFO based on ALR and APOR groups. Among 5578 participants, high ALR and low APOR were associated with rapid decline in lung function and a shorter time to the first AFO. The high ALR group and the combined high ALR and low APOR group showed higher risk of experiencing AFO both at least once (RR 1.46, 95% CI 1.12-1.90; RR 1.74, 95% CI 1.23-2.46, respectively) and at the final follow up (RR 1.44, 95% CI 1.05-1.96; RR 1.72, 95% CI 1.14-2.60, respectively). High ALR and the combined high ALR and low APOR were identified as risk factors for earlier time to first AFO. This study highlights the potential of ALR and APOR as makers for predicting the risk of future airflow obstruction., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Somatic mutations of hematopoietic cells in the peripheral blood of normal individuals refer to clonal hematopoiesis of indeterminate potential (CHIP), which is associated with a 0.5-1% risk of progression to hematological malignancies and cardiovascular diseases. CHIP has also been reported in Multiple Myeloma (MM) patients, but its biological relevance remains to be elucidated. In this study, high-depth targeted sequencing of peripheral blood from 76 NDMM patients revealed CHIP in 46% of them, with a variant allele frequency (VAF) ranging from ~ 1 to 34%. The most frequently mutated gene was DNMT3A, followed by TET2. More aggressive disease features were observed among CHIP carriers, who also exhibited higher proportion of high-risk stages (ISS and R-ISS 3) compared to controls. Longitudinal analyses at diagnosis and during follow-up showed a slight increase of VAFs (p = 0.058) for epigenetic (DNMT3A, TET2, and ASXL1) and DNA repair genes (TP53; p = 0.0123). A more stable frequency was observed among other genes, suggesting different temporal dynamics of CH clones. Adverse clinical outcomes, in term of overall and progression-free survivals, were observed in CHIP carriers. These patients also exhibited weakened immune T-cells and enhanced frailty, predicting greater toxicity and consequently shorter event-free survival. Finally, correlation analysis identified platelets count as biomarker for higher VAF among CHIP carriers, regardless of the specific variant. Overall, our study highlights specific biological and clinical features, paving the way for the development of tailored strategies for MM patients carrying CHIP., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Although corticosteroids are an important treatment for inflammatory bowel disease (IBD) patients, many subjects develop dependence, leading to serious long-term side effects. We applied causal inference analyses to investigate the length of steroid use on reoperations in IBD patients. We identified subjects in the UK Biobank general practice dataset with at least one major GI surgery and followed them for at least 5 years to evaluate subsequent operations. We defined steroid dependence as at least 12 weeks of use (vs. acute steroid use) prior to baseline surgery. Of the 363 subjects included in our analyses, 163 (45%) were prescribed steroids on or before baseline surgery, and of these (N = 125 of 163, 77%) were dependent. Additional analyses for time-dependent data on prescriptions found a link between prescription length and reoperation. Among UC subjects with acute use, the odds of reoperation were significantly lower (OR: 0.32, 95% CI: 0.0-0.73). Steroid dependence resulted in a delay of reoperation (median 1.2 vs. 2.3 years, P = 0.01). Our findings indicate that long-term steroid use tends to increase the need for reoperation, whereas short-term use may reduce it., Competing Interests: Declarations. Competing interests: Potential competing interests: The authors declare that this work was conducted free of commercial, financial, or non-financial relationships that could be interpreted as a potential conflict of interest. Uri Kartoun, Akira Koseki, Akira Koseki, Akihiro Kosugi, Eileen Koski, Joao Bettencourt-Silva, Natasha Mulligan, Jianying Hu, and Vibha Anand are employees of IBM. Dr. Julia Liu: Advisory Board Member for Janssen, Takeda, Bristol Myers Squibb, and Pfizer; Consultant to Janssen, Takeda, Bristol Myers Squibb, Eli Lilly, and Pfizer. Dr. Thad Stappenbeck is an advisor for Janssen and Abbvie and is a founder of Mobius Care. The remaining authors have no disclosures., (© 2024. The Author(s).)

Background The stress hyperglycemia ratio (SHR) indicates relative hyperglycemia levels. Research on the impact of SHR on mortality in coronary heart disease (CHD) patients in intensive care is limited. This study explores the predictive accuracy of SHR for the prognosis of CHD patients in the ICU. Methods This study included 2,059 CHD patients from the American Medical Information Mart for Intensive Care (MIMIC-IV) database. SHR was determined using the formula: SHR = (admission glucose) (mmol/L) / (1.59 * HbA1c [%] - 2.59). Subjects were stratified into quartiles based on SHR levels to examine the correlation between SHR and in-hospital mortality. The restricted cubic splines and Cox proportional hazards models were employed to assess this association, while Kaplan-Meier survival analysis was executed to ascertain the mortality rates across the SHR quartiles. Results Among the 2059 participants (1358 men), the rates of in-hospital and ICU mortality were 8.5% and 5.25%, respectively. Analysis showed SHR as a significant predictor of increased risk for both in-hospital (HR,1.16, 95% CI: 1.02-1.32, P = 0.022) and ICU mortality (HR, 1.16, 95% CI: 1.01-1.35, P = 0.040) after adjustments. A J-shaped relationship was noted between SHR and mortality risks (p for non-linearity = 0.002, respectively). Kaplan-Meier analysis confirmed substantial differences in in-hospital and ICU mortality across SHR quartiles. Conclusions SHR significantly predicts in-hospital and ICU mortality in critically ill CHD patients, indicating that higher SHR levels correlate with longer ICU stays and increased mortality. This underscores the potential of SHR as a prognostic marker for ICU CHD patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: Not applicable., (© 2024. The Author(s).)

Individuals diagnosed with advanced cancer often experience stress and depression, factors linked to worse survival. Curability belief-defined as the hope and expectation of cure through treatment, based on affective forecasting-may differ from the patient's actual life expectancy (i.e., likelihood estimation) and has shown variable associations with cancer survival. In this study, multivariate Cox regression analyses were used to examine the effect of curability belief and depression on 1-year survival after adjustment for physical factors. Additionally, regularized partial correlations among physical and psychological factors were assessed using mixed graphical models to elucidate their roles in mediating the relationship between curability belief and 1-year survival. This multi-center cohort study, conducted across 13 tertiary hospitals (including four ranked among the 'World's Best Specialized Hospitals 2025' in oncology), involved 382 adults with stage IV advanced cancer and an oncologist-estimated survival of more than 6 months. Baseline data included demographics, primary tumor site, number of metastatic sites, symptom burdens (EORTC QLQ-C15-PAL), performance status (ECOG-PS), depression levels (PHQ-9), anti-cancer treatment type, patient's life expectancy estimation, and curability belief. Follow-up data included 1-year survival and end-of-life care (place of death) for deceased patients. Multivariate Cox proportional hazards models were used to assess adjusted hazard ratios (aHRs) for curability belief, depression, and their interaction on 1-year survival, adjusting for significant demographic and clinical factors from univariate Cox regressions. The Kaplan-Meier method was used to plot survival probability by curability belief and depression interaction. Mixed graphical models estimated regularized partial correlations among 1-year survival, curability belief, patient's life expectancy, depression, primary tumor site, anti-cancer treatment type, performance status, and symptom burden. In terms of healthcare utilization, patients with curability belief were more likely to receive standard or advanced anti-cancer therapy, while those without curability belief tended to suspend or discontinue therapy (P < 0.001). Among patients who did not survive the 1-year follow-up (N = 161), end-of-life care settings differed significantly between those with curability belief (predominantly nursing homes and home settings) and those without (primarily hospice and tertiary/secondary hospitals; P = 0.036). In multivariate Cox regression, curability belief (P = 0.003), depression (PHQ-9 score ≥ 10; P = 0.003), and their interaction (P = 0.040) were significantly associated with 1-year survival, after adjusting for sex, residential area, primary tumor site, performance status, anti-cancer treatment type, and symptom burdens (fatigue and appetite loss). The relationship between curability belief and 1-year survival was significant only in patients without depression [PHQ-9 score < 10; aHR (95% CI) = 2.20 (1.31-3.70); P = 0.003]. In the mixed graphical model, node predictability values for curability belief, depression, and 1-year survival were 0.68, 0.50, and 0.70, respectively, with curability belief showing partial correlations with depression (r = 0.30) and patients' life expectancy (r = 0.20); depression correlated with fatigue (r = 0.53), anorexia (r = 0.16), life expectancy (r = 0.24), performance status (r = 0.23), and curability belief; and 1-year survival correlated with suspended/stopped anti-cancer treatment (r = 0.45), primary tumor site (r = 0.24), and performance status (r = 0.15). Partial correlations of performance status with depression and discontinued treatment mediated the association between curability belief and 1-year survival. Curability belief among stage IV advanced cancer patients with an oncologist-estimated survival of over 6 months was associated with depression levels and patients' perceived life expectancy estimations. Performance status, depression, and anti-cancer treatment status mediate the relationship between curability belief and improved 1-year survival in patients without depression. Further research using longitudinal modeling of depression, performance status, and healthcare utilization, with curability belief and primary tumor site as covariates, is warranted.Trial registration: Clinical Trial Number (ClinicalTrials.gov): NCT03222258; Study Registration Dates (First submitted: 2017-06-05; First submitted following the QC criteria: 2017-07-16; First posted: 2017-07-19)., Competing Interests: Declarations. Ethics approval and consent to participate: The study was performed in accordance with the 1975 Declaration of Helsinki and its 2013 amendment. The study protocol was approved by the Institutional Review Board of Seoul National University College of Medicine and Hospital (approval no.: 1602-142-745). Informed consent was obtained from all participants. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Vascular calcification is the main cause of death in patients with chronic kidney disease (CKD). The study aims to investigate the risk factor affecting coronary artery calcification (CAC), and the relationship between serum hypoxia-inducible factor-1α (HIF-1α) levels and CAC in non-dialysis CKD patients. One hundred and twenty-three patients were selected in the final analysis. Spearman rank correlation analysis assessed the correlation between HIF-1α levels and CAC scores. Logistic regression analysis was utilized to assess potential risk variables associated with CAC. A ROC curve was drawn to analyze the diagnostic value of HIF-1α in non-dialysis CKD patients with CAC. Compared to the non-CAC group, the CAC group was older age, with a higher proportion of males, smokers, hypertension and diabetes, lower eGFR and HDL-C, and higher SBP and HIF-1α levels. As the HIF-1α levels went up, the proportion of patients with VC increased, as well as Agatston scores. Spearman rank correlation analysis showed that HIF-1α levels were positively correlated with VC and Agatston scores. Logistic regression analysis indicated that being male (OR = 0.242, P = 0.036), older age (OR = 1.093, P < 0.001), and increased HIF-1α levels (OR = 1.002, P = 0.025) were risk factors for the occurrence of CAC. Furthermore, ROC curve analysis determined that a HIF-1α cutoff value of 451.177 pg·mL -1 provided the best diagnostic value for non-dialysis CAC, with a sensitivity of 65.8% and a specificity of 80.9%. The prevalence of CAC is high in non-dialysis CKD patients, with old age and male gender being traditional risk factors for CAC occurrence. HIF-1α positively correlate with both CAC and VC, which can provide certain diagnostic values for non-dialysis CAC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis even without distant metastases, necessitating in-depth characterization of primary tumors for survival prediction. We assessed the feasibility of using FDG-PET/CT radiomics to predict overall survival (OS) in PDAC. This retrospective study included PDAC patients without distant metastasis who underwent FDG-PET/CT for initial staging. Primary tumors were segmented from FDG-PET/CT images, extracting 222 radiomics features. A radiomics-based risk score (Rad-score) was developed using Cox proportional hazards regression with LASSO to predict OS. The prognostic performance of the Rad-score was compared with a clinical model (demographics, disease stage, laboratory results) using Harrell's concordance index (C-index) and bootstrapping. 140 patients were included, with a mortality rate was 72.9% during follow-up (total population, 19.5 ± 19.2 months; survivors, 34.4 ± 28.8 months). Eleven radiomics features were significant for survival prediction. The Rad-score predicted OS with a C-index of 0.681 [95% CI, 0.632-0.731]. A model integrating clinical parameters and Rad-score outperformed the clinical-only model in predicting OS (C-index 0.740 [0.715-0.816] vs. 0.673 [0.650-0.766]; C-index difference 0.067 [0.014-0.113]; P < 0.001). These findings suggest that incorporating FDG-PET/CT radiomics into preexisting prognotic stratification paradiagm may enhance survival prediction in PDAC, warranting large-scale studies to confirm its applicability in clinical practice., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

After the Great East Japan Earthquake, planning appropriate healthcare resource allocation was crucial. However, accurately estimating medical care demand was challenging due to substantial population fluctuations caused by extensive evacuations, compounded by the inaccuracy of conventional Resident Resister data in this context. This study employs population data generated from mobile phone network from 2019 to 2020 to conduct a detailed temporal and spatial population estimation in Futaba County, originally a complete evacuation zone. To enhance the precision of population estimates, population data independently collected by each municipality were used as reference data in the estimation process. Further, the utility of the estimated population data for calculating emergency transport rates was assessed. Our findings revealed discrepancies between daytime and nighttime populations within Okuma and Futaba Town, where median day/night population ratio exceeded three across both weekdays and weekends. Additionally, sex-age-adjusted emergency transport rates calculated using the estimated population demonstrated closer alignment with the national average compared to those calculated based on census data. This study demonstrates the importance of considering dynamic population data, such as that generated from mobile phone networks, in enhancing healthcare planning and ensuring that resources are efficiently allocated to meet communities' evolving needs during recovery periods., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Viral infections can be acute or chronic, with the immune system pivotal in immunopathogenesis. The potential reversibility of inflammation post-viral elimination is of current interest. This study compares the dynamics of soluble inflammatory mediators (SIM) during and after respiratory infections with SARS-CoV-2 and blood-borne acute and chronic hepatitis C virus (HCV) infections. The study included patients with acute HCV (n = 29), chronic HCV (n = 54), and SARS-CoV-2 (n = 39 longitudinal, n = 103 cross-sectional), along with 30 healthy controls. Blood samples were collected at baseline, end of treatment/infection, and during follow-up (up to 9 months). SIMs were quantified using the HD-SP-X Imaging and Analysis System™. At baseline, SIM profiles in acute SARS-CoV-2 and HCV infections were significantly elevated compared with controls. During follow-up, SIM decline was less pronounced in acute and chronic HCV infections after successful therapy than in SARS-CoV-2 infections. Most SIM in the SARS-CoV-2 cohort normalized within 3 months. In chronic HCV, SIM were higher in cirrhotic than noncirrhotic patients post-HCV elimination. Dynamics of SIM after viral elimination vary between blood-borne acute and chronic HCV infections and respiratory SARS-CoV-2 infections. Immunological imprints 3-9 months after HCV elimination appear more pronounced than after SARS-CoV-2 infection., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: We explored the changes in metabolic dysfunction-associated steatotic liver disease (MASLD) severity over time by analyzing data from the placebo arms of randomized controlled trials (RCTs), focusing on the presence of diabetes., Methods: RCTs on MASLD that included a placebo arm were identified using a systematic search of the literature. Primary outcomes were changes in hepatic steatosis and fibrosis., Results: The meta-analysis included 8 RCTs involving 386 patients without diabetes and 24 RCTs involving 637 patients with diabetes. The pooled estimate of mean change in steatosis grade was - 0.1 in patients without diabetes, and - 0.37 in patients with diabetes (P = 0.066). The mean change in fibrosis stage was 0.05 in patients without diabetes, and - 0.03 in patients with diabetes (P = 0.359). The mean change in nonalcoholic fatty liver disease activity score was - 0.55 in patients without diabetes, and - 1.50 in patients with diabetes (P = 0.100). The mean change in ALT and AST were significantly larger in patients without diabetes compared to those with diabetes (P < 0.05)., Conclusion: Placebo treatment had a greater effect in improving liver steatosis in patients with diabetes compared to those without. These findings highlight the importance of tailored treatment strategies in MASLD, particularly considering diabetes status., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Conflict of interest: The authors declare that they have no conflicts of interest relevant to this work. Financial support: This research was supported in part by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (grant numbers 2018R1A5A2025286 and 2022R1I1A1A01065244). The sponsors had no role in study design, data collection and analysis, decision to publish, or manuscript preparation. The funding source was not involved in the design or implementation of the study. Trial registration number: This study was registered with PROSPERO (registration number: CRD42023455528)., (© 2024. The Author(s).)

Fundamental changes in intracellular processes, such as overactive growth signaling pathways, are common in carcinomas and are targets of many cancer therapeutics. GRIP and coiled-coil containing 2 (GCC2) is a trans-Golgi network (TGN) golgin maintaining Golgi apparatus structure and regulating vesicle transport. Here, we found an aberrant overexpression of GCC2 in non-small cell lung cancer (NSCLC) and conducted shRNA-mediated gene knockdown to investigate the role of GCC2 in NSCLC progression. shRNA-mediated GCC2 knockdown suppressed NSCLC cell growth, migration, stemness, and epithelial-mesenchymal transition (EMT) in vitro and tumor growth in vivo. In addition, GCC2 knockdown suppressed cancer cell exosome secretion and the oncogenic capacity of cancer cell-derived exosomes. Mechanistically, GCC2 inhibition decreased epidermal growth factor receptor (EGFR) expression and downstream growth and proliferation signaling. Furthermore, GCC2 inhibition compromised Golgi structural integrity in cancer cells, indicating a functional role of GCC2 in regulating intracellular trafficking and signaling to promote lung cancer progression. Together, these findings suggest GCC2 as a potential therapeutic target for the treatment of NSCLC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Heart failure (HF) constitutes a substantial burden on healthcare systems worldwide, contributing to elevated rates of mortality and morbidity. Iron deficiency (ID), both with and without concurrent anemia, has been identified in up to half of all patients with CHF and is associated with an increased risk of HF exacerbations, higher rates of hospitalization, and diminished quality of life. However, data from resource-limited settings remain limited. In this study, we reviewed 108 adult Yemeni patients with HF who also had concomitant ID, defined as serum ferritin concentrations of < 100 ng/mL or 100-299 ng/mL with transferrin saturation < 20%. The prevalence of ID among HF patients was determined, and independent predictors of ID were assessed using univariate and multivariate regression analyses. Anemia was present in 64 (59.3%), ID was observed in 65 (60.2%), and both anemia and ID were concurrently present in 44 (40.7%) patients. The mean ejection fraction among the study cohort was 34.2 ± 6.3%. Multivariate regression analysis identified New York Heart Association class III (OR: 4.46; 95% CI: 1.65-12.90, p = 0.004), presence of anemia (OR: 3.95; 95% CI: 1.51-11.23, p = 0.007), and an EF < 30% (OR: 9.42; 95% CI: 1.97-54.64, p = 0.007) as independent predictors of ID. These findings highlight the potential under-recognition of ID in patients with congestive HF, suggesting the need for routine assessment of iron status in this patient population., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics declarations: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This study was approved by Ibb University’s Ethics Committee (Code number: IBBUNI.AC.YEM.2023.117). Consent to participate/Consent to publish: All patients provided written informed consent to be involved in this study., (© 2024. The Author(s).)

Inhaled corticosteroids (ICS) are commonly used for airway disease, but concerns about adrenal insufficiency (AI) have arisen. This retrospective observational study investigated the link between ICS use and AI risk using data from the National Health Insurance Service-National Sample Cohort, analyzing 66,631 patients with COPD (Korean Standard Classification of Diseases [KCD] codes J42-J44) or asthma (KCD codes J45-J46). ICS use, daily dosage, and AI cases (hospitalization or ≥ 2 outpatient visits with KCD code E27) were identified via diagnostic codes. Cox proportional hazard survival analysis and inverse probability of treatment weighting (IPTW) addressed baseline differences between ICS and non-ICS users. In total 66,631 patients, the mean age was 57.3 years, 42.6% were male, and 42.2% had a Charlson comorbidity index (CCI) of 2 or higher. Among the patients, 15.5% used ICS, with a mean daily dose of 404.2 µg/day. The incidence of AI was higher in ICS users (1.69 per 1000) than in non-users (0.54 per 1000). ICS use independently increased AI risk (HR: 3.06, 95% CI: 1.82-5.14, p < 0.001). Each 100 µg/day increase in ICS was associated with a 3% increase in AI incidence (HR: 1.03, 95% CI: 1.02-1.04, p < 0.001). Quartile analysis indicated a significant AI risk increase across all ICS dosage quartiles compared with non-users. Subgroup analysis showed consistent associations with age, sex, and smoking, with stronger links in systemic steroid users (HR: 3.54, 95% CI: 2.10-5.96, p < 0.001) and those with higher CCI (HR: 2.61, 95% CI: 1.64-4.12, p < 0.001). ICS may use increases AI risk in chronic airway disease patients, particularly among systemic steroid users and those with higher CCI. Close monitoring of high-risk patients is advised, and further research is needed to clarify mechanisms and optimize safe ICS use., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study protocol was approved by the Institutional Review Board of the Soonchunhyang University Seoul Hospital (2023-06-008), and the requirement for informed consent was waived due to the de-identified nature of the NHIS-NSC dataset. Consent for publication: Not applicable., (© 2024. The Author(s).)

Age-related macular degeneration (AMD) is a progressive chronic disease causing visual impairment or central vision loss in the elderly. We hypothesized that successful rheopheresis would be associated with positive changes in soluble endoglin (sENG), PSCK9, alpha-2-macroglobulin (A2M), and hs-CRP levels. 31 elderly patients with the dry form of AMD, treated with rheopheresis with a follow-up period of at least 5 years and an average age of 68 ± 4 years, were evaluated. Each treated patient received a series of 8 procedures in 10 weeks and, after the 2-year period, another 2 procedures within 1 week. Then, the patients were followed up every 6 months and divided into the successfully treated and therapeutic failure group according to best-corrected visual acuity (BCVA), size of the drusen area, and the drusenoid pigment epithelium detachment (DPED). Based on the ophthalmological assessment, rheopheresis treatment was successful in 73% of AMD patients. The therapy was associated with a significant decrease in total cholesterol, LDL-C, HDL-C, apoprotein B, lipoprotein (a) levels, and rheologically important parameters, irrespective of the therapy's success or failure. The success of rheopheresis therapy was exclusively related to a significant decrease in sENG and A2M levels. Over the long term, rheopheresis prevented the decline of BCVA, reduced the DPED and area of macular drusen, and improved the preservation of an intact photoreceptor ellipsoid zone in most patients. Moreover, we showed for the first time that sENG and A2M could be potentially sensitive biomarkers of successful rheopheresis procedure, irrespective of lipid parameters changes., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The protocol was carried out according to the Declaration of Helsinki. All participants gave written informed consent, which, together with the protocol of the study, were approved by the institute’s ethics committee (approval number 201607 S03P). The study has been registered under Clinical Trial Registration number NCT01943396 (17/09/2013). https://classic.clinicaltrials.gov/ct2/show/NCT01943396?cond=Age-Related+Macular+Degeneration&cntry=CZ&draw=2&rank=1, (© 2024. The Author(s).)

Helicobacter pylori infection is a major risk factor for gastric adenocarcinomas. In the case of the intestinal subtype, chronic gastritis and intestinal metaplasia are well-known sequential steps in carcinogenesis. H. pylori has high genetic diversity that can modulate virulence and pathogenicity in the human host as a cag Pathogenicity Island (cagPAI). However, bacterial gene combinations do not always explain the clinical presentation of the disease, indicating that other factors associated with H. pylori may play a role in the development of gastric disease. In this context, we characterized the microbial composition of patients with chronic gastritis (inactive and active), intestinal metaplasia, and gastric cancer as well as their potential association with H. pylori. To this end, 16 S rRNA metagenomic analysis was performed on gastric mucosa samples from patients with different types of lesions and normal gastric tissues. Our main finding was that H. pylori virulence status can contribute to significant differences in the constitution of the gastric microbiota between the sequential steps of the carcinogenesis cascade. Differential microbiota was observed in inactive and active gastritis dependent of the H. pylori presence and status (p = 0.000575). Pseudomonades, the most abundant order in the gastritis, was associated the presence of non-virulent H. pylori in the active gastritis. Notably, there are indicator genera according to H. pylori status that are poorly associated with diseases and provide additional evidence that the microbiota, in addition to H. pylori, is relevant to gastric carcinogenesis., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: The study was approved by Ethics Committee (COMEP) of the Federal University of Ceará (protocol 071002/10) and conducted in accordance with the Declaration of Helsinki. All participants of the study signed individual informed consent forms., (© 2024. The Author(s).)

Previously reported oropharyngeal exercises are long and difficult to perform. Therefore, we created a 10-min daily oropharyngeal exercise program and conducted a study to confirm its effectiveness. Twenty-five participants whose apnoea-hypopnoea index (AHI) values were greater than 5 were enrolled. All of the participants performed 10 min of exercise per day for 12 weeks and were evaluated for AHI values, tongue pressure, lip closure pressure, snoring, and Mallampati scores before and after the exercise. Twenty-two participants (88% of all participants) completed the oropharyngeal exercise. Another patient was unable to attend the last evaluation session due to illness. The AHI value improved significantly from an average of 20.9 to 16.9 times/hour in patients with a pre-exercise AHI of 5 to 30 (P = 0.0317). The AHI improvement group included younger participants than did the AHI deterioration group (P = 0.0498). Although the tongue pressures in the AHI improvement group did not improve significantly (P = 0.354), the lip closure pressures tended to increase from a median of 17.6 N to 21.3 N with oropharyngeal exercises (P = 0.0677). This novel oropharyngeal exercise may be appropriate for younger SAS patients with an AHI less than 30., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

AI-based methods to generate images have seen unprecedented advances in recent years challenging both image forensic and human perceptual capabilities. Accordingly, these methods are expected to play an increasingly important role in the fraudulent fabrication of data. This includes images with complicated intrinsic structures such as histological tissue samples, which are harder to forge manually. Here, we use stable diffusion, one of the most recent generative algorithms, to create such a set of artificial histological samples. In a large study with over 800 participants, we study the ability of human subjects to discriminate between these artificial and genuine histological images. Although they perform better than naive participants, we find that even experts fail to reliably identify fabricated data. While participant performance depends on the amount of training data used, even low quantities are sufficient to create convincing images, necessitating methods and policies to detect fabricated data in scientific publications., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The onset of degenerative joint diseases such as post-traumatic osteoarthritis (PTOA) are associated with joint injury, biomechanical changes, and synovial biochemical anomalies. Sex and reproductive endocrinology have been emerging as potential risk factors, with epidemiological evidence revealing that female's exhibit higher PTOA risk and poorer outcomes post-injury compared to males. Sex hormones, including estradiol, progesterone, and testosterone, have been shown to regulate inflammatory signaling in immune and synovial cells, yet their collective impact on injury-induced joint inflammation and catabolism is poorly understood. Using an in silico kinetic model, we investigated the effects of sex-specific endocrine states on post-injury mechanisms in the human synovial joint. Our model results reveal that heightened estradiol levels in pre-menopausal females during the peri-ovulatory phase increase interleukin (IL)-1β expression and suppress IL-10 expression within the synovium after a simulated injury. Conversely, elevated testosterone levels in males decrease post-injury IL-1β, tumor necrosis factor alpha (TNF)-α, and stromelysin (MMP)-3 expression while increasing IL-10 production compared to females. Gaining insight into the effects of sex hormones on injury-induced inflammation and cartilage degradation provides a basis for designing future experimental and clinical studies to explore their effects on the synovial system, with a particular focus on the female sex., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

House dust mites (HDM) are common aeroallergens linked to airway inflammation and remodeling in asthma. Protease-activated receptor 2 (PAR2) and thymic stromal lymphopoietin (TSLP) may mediate these immune responses. However, how the epithelium influences fibroblasts toward airway remodeling remains unclear. We hypothesize that HDM stimulates human bronchial epithelial cells (HBECs) to produce TSLP via PAR2 activation, driving fibroblasts toward remodeling processes. HBECs were treated with HDM, with or without the PAR2 antagonist FSLLRY-NH2 (FSL), and TSLP expression was measured by qPCR and ELISA. Phosphorylation of MAPKs was assessed by western blotting. Human lung fibroblasts (HLFs) were exposed to recombinant TSLP or conditioned medium (CM) from HDM-stimulated HBECs, with or without anti-TSLP antibodies. Fibroblast proliferation and collagen production were assessed as remodeling markers. HDM increased ERK phosphorylation (not p38 or JNK) and TSLP expression at mRNA and protein levels. FSL preincubation significantly reduced ERK phosphorylation and TSLP production: HDM-stimulated CM induced fibroblast proliferation and collagen production, effects suppressed by anti-TSLP or FSL. Direct treatment with recombinant TSLP also promoted fibroblast proliferation and collagen synthesis. These findings suggest that HDM promotes HBEC-to-HLF paracrine interactions via PAR2-ERK-TSLP axis, participating in airway remodeling. PAR2 antagonists may represent potential therapeutic targets for HDM-induced remodeling processes., Competing Interests: Declarations Conflict of interest All authors declare that they have no conflict of interest. Ethics approval This study was approved by the Institutional Review Board of Taipei Veterans General Hospital (ID 2019-08-004B)., (© 2024. The Author(s).)

Despite remarkable improvements in the survival of pediatric acute lymphoblastic leukemia (ALL), sensitive detection and clinical management of central nervous system leukemia (CNSL) are still immensely challenging. Blast cells residing in the CNS but not circulating in the cerebrospinal fluid (CSF) remain undetected by current diagnostic methods, preventing a truly risk-adapted anti-leukemic treatment in this compartment. We examined the clinical applicability of the molecular marker microRNA (miR)-181a quantified in the cell-free CSF to evaluate the level of CNS involvement and to optimize patient stratification based on CNS status. Normalized copy number of miR-181a was longitudinally profiled using droplet digital PCR, and the results were compared with the degree of leukemic involvement of the CNS. After combining cytospin- and flow cytometry (FCM) data with miR-181a expression, we could stratify previously ambiguous cases and reclassify patients into a CNS-positive/miR-significant group (mean ± SE for miR-181a copies: 3300.70 ± 809.69) bearing remarkable infiltration as well as into CNS-minimal/miR-significant and CNS-minimal/miR-minimal groups differentiating putative, clinically significant occult CNSL cases (2503.50 ± 275.89 and 744.02 ± 86.81 copies, respectively, p = 1.13 × 10 -6 ). In summary, miR-181a expression is a promising biomarker for CNSL detection, facilitating the robust identification of patients who could benefit from intensified CNS-directed therapy., Competing Interests: Ethics approval and consent to participate All procedures performed in this study, involving human participants were in accordance with the ethical standards of the Medical Research Council of Hungary, and with the 1964 Helsinki declaration and its later amendments. The study was approved by the central ethical committee (institute: National Scientific and Ethical Committee of the Medical Research Council of Hungary (ETT-TUKEB), approval numbers: 60106–1/2015/EKU and 6886/2019/EKU). The study is compliant with all relevant ethical regulations for human research participants, and informed consent was obtained from all patients or legal guardians. Consent for publication The study is compliant with all relevant ethical regulations for human research participants, and informed consent was obtained from all patients or legal guardians. Data availability The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Fetal microchimerism, the presence of fetal cells in maternal tissues, has garnered interest for its potential role in maternal physiology. In this study, we aimed to explore the impact of fetal microchimeric cells on maternal lung health following term and preterm delivery, particularly in the context of infection-induced preterm birth and subsequent allergic challenges. We characterized the immune cells in maternal lungs using a transgenic mouse model (mT+ Ve, Td Tomato) and high dimensional mass cytometry (CyTOF) techniques. We evaluated their influence on lung function and inflammation. Our findings revealed distinct differences in the immune cell composition of maternal lungs between term and preterm deliveries. Mice delivered preterm significantly increased in fetal-specific cells, such as activated macrophages and Tbet + Ve memory B-cells, compared to term-delivered mice. Conversely, term deliveries showed elevated levels of CD4 cells. Furthermore, preterm-delivered dams demonstrated heightened airway hyperresponsiveness, pro-inflammatory cytokine expression, cellular infiltration, and lung mucous production compared to term-delivered dams. Co-culture experiments demonstrated that microchimeric cells from preterm births stimulated the production of inflammatory cytokines IL-6 and TNF-α in lung epithelial cells. These findings shed light on the complex immune dynamics postpartum and their role in lung complications after preterm birth. Understanding these mechanisms could provide insights for targeted interventions to improve maternal lung health in at-risk populations., Competing Interests: Competing interests The authors state that there are no conflicts of interest regarding this study., (© 2024. The Author(s).)

High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood-brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation., Competing Interests: Competing interests Davalos, Aycock, Dervisis, and Rossmeisl have pending and issued patents related to electroporation. Murphy, Marsh, Hay, Athanasiadi, Bracha, Chang, and Gourdie declare no potential conflicts of interest., (© 2024. The Author(s).)

Adults with cancer may perceive cannabis as beneficial for managing their cancer-related symptoms, but the evidence supporting its medical use is varied and inconclusive. This study characterized associations of cannabis use with cancer-related symptom trajectories. Participants were adults undergoing cancer treatment at the Stephenson Cancer Center (SCC; n = 218) in Oklahoma; they were 71% female, 10% minoritized race, and 45% had stage III or IV cancer. Participants completed surveys at baseline and 2-, 4-, and 6-months post-baseline. Assessments queried about cannabis use behavior, physical and psychological distress via the Rotterdam Symptoms Checklist (RSCL), respiratory symptoms via the American Thoracic Society Questionnaire (ATSQ), and quality of life indices (physical and social functioning, pain interference, sleep quality, fatigue) via the Patient Reported Outcomes Measurement Information System (PROMIS-29). Cannabis use status was categorized based on self-reported past 30-day cannabis use at each assessment as non-use [no use at any assessment], occasional-use [use at 1-2 assessments], or consistent-use [use at 3-4 assessments]. Longitudinal hierarchical linear modeling evaluated associations of cannabis use status with average symptoms and symptom trajectories across all four assessments. One-third (33%) of participants reported past 30-day cannabis use at ≥ 1 assessment. Participants who reported cannabis use (occasional-use and consistent-use) had more severe symptoms overall across assessments. While most cancer symptom trajectories did not differ by cannabis use status, participants who reported consistent cannabis use uniquely showed worsening physical function over time. Cannabis use was associated with greater cancer-related symptom severity over time., Competing Interests: Declarations Competing interests Kendzor and Businelle are inventors of the Insight Mobile Health Platform (not used or evaluated in the current study) and receive royalties for the external use of the platform outside of the University of Oklahoma Health Sciences Center. Kendzor is a member of the Scientific Advisory Board of Qnovia. Inc., which is a drug development company focused on inhaled therapies including prescription inhaled nicotine replacement therapy for smoking cessation (no medications provided or evaluated in the current study). Kendzor previously received medication (varenicline) at no cost from Pfizer to support a now completed pilot study (no medications provided or evaluated in the current study). The authors declare no competing interests., (© 2024. The Author(s).)

Bioinformatics software tools are essential to identify informative molecular features that define different phenotypic sample groups. Among the most fundamental and interrelated tasks are missing value imputation, signature gene detection, and differential pattern visualization. However, many commonly used analytics tools can be problematic when handling biologically diverse samples if either informative missingness possess high missing rates with mixed missing mechanisms, or multiple sample groups are compared and visualized in parallel. We developed the ABDS tool suite specifically for analyzing biologically diverse samples. Collectively, a mechanism-integrated group-wise pre-imputation scheme is proposed to retain informative missingness associated with signature genes, a cosine-based one-sample test is extended to detect group-silenced signature genes, and a unified heatmap is designed to display multiple sample groups. We describe the methodological principles and demonstrate the effectiveness of three analytics tools under targeted scenarios, supported by comparative evaluations and biomedical showcases. As an open-source R package, ABDS tool suite complements rather than replaces existing tools and will allow biologists to more accurately detect interpretable molecular signals among phenotypically diverse sample groups., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Extracellular vesicles (EVs) are involved in the progression of various diseases. Tumor cell-derived EVs (TEVs) are a particular concern, as they can induce fatty liver by promoting liver macrophages to secrete tumor necrosis factor (TNF), thus enhancing the toxicity of chemotherapy. Therefore, reducing pathogenic EV production is a potential strategy for treating EV-related diseases. However, there are currently no effective clinical reagents to obtain this purpose. In addition, EVs are also natural and ideal drug-delivery vehicles. Improving the delivery efficiency of EVs remains a challenge. Proton pump inhibitors (PPIs) have been demonstrated to promote cell uptake of EVs by inducing micropinocytosis. Here, we show that PPIs can accelerate TEV clearance, reduce TEV uptake by liver macrophages and decrease the mRNA expression of TNF in liver macrophages of tumor-bearing mice. Correspondingly, the fatty liver phenotypes are alleviated, and the tolerance to chemotherapy is improved in these mice. Furthermore, our findings indicate that PPIs facilitate the uptake of red blood cell-derived EVs (RBC-EVs) loaded with antisense oligonucleotides of Trim21 (Trim21-ASOs) by the liver macrophages of obesity. Consequently, the inhibition of macrophage inflammatory responses in obese mice mediated by RBC-EVs/Trim21-ASOs was further enhanced by PPIs, resulting in a more profound improvement in obesity and related metabolic disorders. In conclusion, our findings demonstrated that PPIs can effectively clear pathogenic EVs and enhance the delivery efficacy of EV vehicles, making them a highly promising clinical prospect., Competing Interests: Declarations Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

The molecular mechanisms linking obstructive sleep apnea syndrome (OSA) to obesity and the development of metabolic diseases are still poorly understood. The role of hypoxia (a characteristic feature of OSA) in excessive fat accumulation has been proposed. The present study investigated the possible effects of hypoxia (4% oxygen) on de novo lipogenesis by tracking the major carbon sources in differentiating 3T3-L1 adipocytes. Gas-permeable cultuware was employed to cultivate 3T3-L1 adipocytes in hypoxia (4%) for 7 or 14 days of differentiation. We investigated the contribution of glutamine, glucose or acetate using 13 C or 14 C labelled carbons to the newly synthesized lipid pool, changes in intracellular lipid content after inhibiting citrate- or acetate-dependent pathways and gene expression of involved key enzymes. The results demonstrate that, in differentiating adipocytes, hypoxia decreased the synthesis of lipids from glucose (44.1 ± 8.8 to 27.5 ± 3.0 pmol/mg of protein, p < 0.01) and partially decreased the contribution of glutamine metabolized through the reverse tricarboxylic acid cycle (4.6% ± 0.2-4.2% ± 0.1%, p < 0.01). Conversely, the contribution of acetate, a citrate- and mitochondria-independent source of carbons, increased upon hypoxia (356.5 ± 71.4 to 649.8 ± 117.5 pmol/mg of protein, p < 0.01). Further, inhibiting the citrate- or acetate-dependent pathways decreased the intracellular lipid content by 58% and 73%, respectively (p < 0.01) showing the importance of de novo lipogenesis in hypoxia-exposed adipocytes. Altogether, hypoxia modified the utilization of carbon sources, leading to alterations in de novo lipogenesis in differentiating adipocytes and increased intracellular lipid content., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The present study was designed to identify the preoperative clinical and imaging findings influencing adverse clinical outcomes in patients with chronic constrictive pericarditis after pericardiectomy. Patients with constrictive pericarditis who underwent pericardiectomy between January 2009 and September 2023 were retrospectively analyzed. Preoperative evaluations included assessments of clinical symptoms, comorbidities, laboratory tests, cardiac computed tomography (CT), and transthoracic echocardiography. The volume of pericardial calcifications was quantified on calcium scoring CT. Adverse clinical events were defined as cardiovascular death or hospitalization due to cardiac causes, and all-cause mortality was assessed. Univariable and multivariable Cox proportional hazard model analysis were performed to find factors associated with adverse clinical events. Among the 91 patients with available preoperative CT scans, 26 (28.6%) experienced adverse clinical events after pericardiectomy, with 19 (20.9%) experiencing cardiovascular deaths. On multivariable Cox analysis, larger pericardial calcium volume hazard ratio [HR], 1.004 (95% confidence interval [CI], 1.001-1.006) per 1cm 3 increase; p = 0.005), higher E/E' ratio (HR, 1.059, 95% CI, 1.015-1.105, p = 0.008), and lower albumin level (HR, 0.476, 95% CI, 0.229-0.986, p = 0.046) were significant factors associated with the adverse clinical events after pericardiectomy. The amount of pericardial calcification could be associated with the efficacy of pericardiectomy and potentially have implications for postoperative outcomes. Additionally, a high E/E ratio on echocardiography is indicative of unfavorable postoperative prognosis., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate This retrospective study was approved by the institutional review board of Asan Medical Center. Patients’ informed consent was waived due to retrospective nature of the study., (© 2024. The Author(s).)

Impulse oscillometry (IOS) is a sensitive tool for assessing small airway function in patients with chronic obstructive pulmonary disease (COPD). This study aimed to differentiate between COPD, small airway disease (SAD), and normal groups using IOS, and to evaluate the clinical applicability of IOS. This retrospective cohort study was conducted from January 2020 to February 2022. The eligible population comprised adult patients who simultaneously underwent IOS and pulmonary function tests. The diagnostic value of IOS in differentiating SAD and/or COPD from control was analyzed, and the correlations among IOS parameters, lung function, and radiological assessment results were determined. Among the enrolled 306 patients, 38 (12.4%) had SAD and 134 (43.8%) had COPD. The remainder comprised the control group without COPD and/or SAD. Abnormal airway resistance according to IOS parameters was detected in 17.2% of the patients in the control group, 47.2% of those in the SAD group, and 55.2% of those in the COPD group. Airway resistance estimated by IOS were significantly higher in the SAD and COPD groups than in the control group and correlated with lung function and radiological airway wall thickness. We developed a composite index called the IOS severity index (IOSsi) using IOS parameters that can predict SAD and COPD, and IOSsi showed significantly differentiation of SAD and/or COPD from control. Especially, IOSsi value ≥ 4 was associated with an increased risk of SAD and/or COPD and also with risk for moderate-to-severe exacerbation in patients with COPD. IOS may be a useful tool to differentiate disease status and evaluate disease severity and prognosis in patients with SAD and/or COPD, and a prognostic factor of COPD., Competing Interests: Declarations Ethics approval and consent to participate The Institutional Review Board of Seoul Metropolitan Government–Seoul National University Boramae Medical Center approved this study (no: 10-2022-37) and waived the requirement for informed consent due to the retrospective study design without participant intervention or interaction, and this study was conducted in accordance with the principles stated in the Declaration of Helsinki. Competing interests The authors declare no competing interests. Confidentiality The interim findings of this paper were presented in a poster discussion at the 26th Congress of the Asian Pacific Society of Respirology on November 2022., (© 2024. The Author(s).)

Ulcerative colitis (UC) is a refractory, chronic inflammatory bowel disease of unknown etiology. Although platelets are activated in UC, their relevance in pathophysiology remains unclear. We analyzed the correlation of platelet activation and platelet-monocyte complexes (PMCs) with severity of mucosal inflammation using the Mayo endoscopic subscore (MES). Platelet activation marker, CD62P was upregulated in patients with UC compared with that in healthy controls (P < 0.05). CD62P expression was significantly higher in patients with MES3 (severe inflammation) than in those with MES ≤ 2 (endoscopic remission to moderate inflammation) (P < 0.001). The concentration of sCD62P in patients with MES0 (endoscopic remission) was significantly higher than in those with MES ≥ 1 (P < 0.01). The expression of CD40L, CD63, PAC-1, annexin V, and CD36, and the concentrations of sCD40L, PF4, and RANTES did not correlate with MES. The proportion of PMCs in patients with MES3 was higher than in those with MES ≤ 2 (P < 0.05). CD16 expression on monocytes with platelets was significantly higher than in monocytes without platelets (P < 0.001). Patients with complete remission after treatment showed significant reduction in PMCs 3 months after treatment (P < 0.05) but had no change in CD62P and sCD62P. Our data suggest that platelet activation via the CD62P-PMC axis is involved in UC pathophysiology., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Various scoring systems have been developed to predict outcomes in patients with non-variceal upper gastrointestinal bleeding (NVUGIB). However, their accuracy remains unclear. This study aimed to compare and validate the predictive performance of several established scoring systems in patients with NVUGIB: Glasgow-Blatchford score (GBS) and the age, blood tests, and comorbidities (ABC), mental status-anesthesiologist score-pulse-albumin-systolic blood pressure-hemoglobin (MAP(ASH)), Japanese, and Charlson comorbidity index-in-hospital onset-albumin-mental status-Eastern Cooperative Oncology Group performance status-steroids (CHAMPS) scores. We retrospectively reviewed the records of 1,241 patients who presented to the emergency department with NVUGIB and subsequently required hospitalization. Each scoring system was evaluated for its ability to predict in-hospital mortality, rebleeding, and the need for radiological or surgical intervention. The ABC score showed the highest accuracy in predicting in-hospital mortality. The MAP(ASH) score was the most effective predictor of rebleeding and the need for interventions. Different scoring systems have been optimized for various clinical outcomes. The ABC score was the best for predicting mortality, whereas the MAP(ASH) score excelled in identifying rebleeding risks and intervention needs. The selection of an appropriate scoring tool based on specific clinical scenarios can improve patient management and resource allocation in NVUGIB., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval This retrospective chart review study was approved by the Institutional Review Board (IRB) of Chungnam National University Hospital (IRB number: CNUH 2024-05-017). All procedures performed in studies involving participants were conducted in accordance with the ethical standards of the Association, National Research Council, and the 1964 Helsinki Declaration, as amended or equivalent thereto. Consent to participate The requirement for written informed consent was waived due to the retrospective study design., (© 2024. The Author(s).)

In light of research indicating that normal TSH levels do not necessarily reflect clinical euthyroidism in hypothyroid patients, and given the patient dissatisfaction with levothyroxine (LT4) monotherapy, we evaluate the response to weight loss treatment in patients with obesity and primary hypothyroidism who are euthyroid under LT4 therapy, with a focus on weight and metabolic parameters. The retrospective study included 138 subjects with obesity (BMI ≥ 30 kg/m 2 ), 69 women with hypothyroidism on levothyroxine, and 69 age- and BMI-matched women without thyroid disease. Secondary causes of obesity, medications that may affect thyroid functions and metabolic parameters, chronic and oncological disease, pregnancy, TSH outside the reference range, follow-up periods of less than one year, and bariatric surgery were the exclusion criteria. Patients' characteristics and metabolic responses to weight reduction treatment consisting of calorie restriction, moderate exercise, and metformin if needed were evaluated. TSH and fT4 levels were higher, and fT3 and T3/T4 ratios were lower all within the reference ranges in hypothyroid women. They were less insulin resistant. Both patient' groups experienced a significant decrease in body weight, BMI, and atherogenic index of plasma (AIP) during the follow-up (p = 0.001). Insulin resistance was not changed. The groups' body weight, BMI, HOMA-IR, and AIP changes were similar at the end of the study (p = 0.876, p = 0.850, p = 0.555, p = 0.293). The results suggest that achieving euthyroid status via levothyroxine monotherapy in hypothyroid women leads to weight loss responses comparable to those in women with normal thyroid. This supports the effectiveness of current hypothyroidism treatment strategies, emphasizing TSH level normalization, in achieving clinical euthyroidism concerning weight loss outcomes., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The 5' cap, catalyzed by RNA guanylyltransferase and 5'-phosphatase (RNGTT), is a vital mRNA modification for the functionality of mRNAs. mRNA capping occurs in the nucleus for the maturation of the functional mRNA and in the cytoplasm for fine-tuning gene expression. Given the fundamental importance of RNGTT in mRNA maturation and expression there is a need to further investigate the regulation of RNGTT. N6-methyladenosine (m 6 A) is one of the most abundant RNA modifications involved in the regulation of protein translation, mRNA stability, splicing, and export. We sought to investigate whether m 6 A could regulate the expression and activity of RNGTT. In this short report, we demonstrated that the 3'UTR of RNGTT mRNA is methylated with m 6 a by the m 6 A writer methyltransferase 3 (METTL3). Knockdown of METTL3 resulted in reduced protein expression of RNGTT. Sequencing of capped mRNAs identified an underrepresentation of ribosomal protein mRNA overlapping with 5' terminal oligopyrimidine (TOP) mRNAs, and genes are dysregulated when cytoplasmic capping is inhibited. Pathway analysis identified disruptions in the mTOR and p70S6K pathways. A reduction in RPS6 mRNA capping, protein expression, and phosphorylation was detected with METTL3 knockdown., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Prior research has demonstrated an association between sodium-glucose cotransporter 2 (SGLT2) inhibitor and a reduced incidence of atrial fibrillation (AF). Given the established link between mitochondrial dysfunction and AF, this study aimed to explore the impact of SGLT2 inhibitors on AF burden and plausible antiarrhythmic mechanisms in patients with cardiovascular implantable electronic devices (CIEDs). Patients with atrial high-rate episodes (AHREs) detected by CIEDs were randomized to receive either 10 mg of dapagliflozin or a placebo for 3 months. AF burdens were quantified via CIEDs interrogations as AHREs duration, percentage, and number of episodes at baseline and after 3 months of treatment. Mitochondrial parameters, cellular oxidative stress, and norepinephrine levels were measured in peripheral blood mononuclear cells (PBMCs). A total of 54 patients with CIEDs were enrolled in the study. Among them, 36 patients (66.7%) had a history of clinical AF, and 9 patients (16.7%) had diabetes mellitus. After 3 months of the assigned treatment, the median longest AHRE duration decreased similarly in both the dapagliflozin and placebo groups (-77.0 vs. -162.0 min, p = 0.442). Clinical AF, as opposed to subclinical AF, was independently linked to decreased basal respiration and adenosine triphosphate (ATP) production. Although the changes in AHREs burden over the 3 months did not significantly differ between the dapagliflozin and placebo groups, dapagliflozin significantly decreased the number of AHREs per month by 2.2 episodes among patients with clinical AF, whereas the placebo group experienced an increase of 0.6 episodes (p = 0.048). Additionally, dapagliflozin significantly reduced cellular oxidative stress (from 26840 to 18164 arbitrary units, p = 0.049) and improved mitochondrial spare respiratory capacity (SRC) percentage (from 166 to 202%, p = 0.016) in patients with clinical AF. Dapagliflozin did not significantly reduce the longest AHRE duration in patients with CIED. However, in the subgroup of patients with clinical AF, dapagliflozin reduced the number of AHREs potentially via reduction of cellular oxidative stress and enhancement of mitochondrial function.The study protocol was registered at the Thai Clinical Trials Registry (TCTR identification number TCTR20210315003) on March 15, 2021., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics approval and consent to participate The study protocol was approved by the Research Ethics Committee, Chiang Mai University (certificate of approval No.041/2021). The investigations were carried out in accordance with the Declaration of Helsinki. The informed consent was obtained from all subjects and/or their legal guardian(s)., (© 2024. The Author(s).)

Mitochondrial dysfunction with oxidative stress contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) progression. We aimed to evaluate the fibrosis predictive efficacy of a novel non-invasive diagnostic panel using metabolic stress biomarkers. From a population-based general cohort, 144 subjects with MASLD were recruited in the development group and underwent magnetic resonance imaging-based liver examinations, anthropometric and laboratory tests. As an external validation group, 41 patients enrolled in a biopsy-evaluated MASLD cohort participated in this study. Liver fat content and stiffness were measured by magnetic resonance (MR) imaging-proton density fat fraction and MR elastography (MRE), respectively. Serologic stress biomarkers were quantitated by ELISA. Multivariate regression showed that waist-to-height ratio, growth differentiation factor-15 (GDF15), γ-glutamyltransferase, decorin, and alkaline-phosphatase were independent predictors of hepatic fibrosis (rank-ordered by Wald). The area under receiver-operator characteristics curve [AUROC (95% CI)) of the metabolic stress index for fibrosis (MSI-F) was 0.912 (0.85‒0.98) and 0.977 (0.92‒1.00) in development and validation groups, respectively. MSI-F also had better diagnostic accuracy (82.6‒92.4%) than other fibrosis indices in the both study cohorts. MSI-F consistently differentiated fibrosis severities across cohorts of MRE-evaluated general population and biopsy-proven patients with MASLD, while other indices showed no or less discrimination. MSI-F, as a novel non-invasive index based on a stress-stimulated protective hormone GDF15 and decorin, effectively predicted hepatic fibrosis. Furthermore, MSI-F may serve as pre-screening tool to increase the population that could be excluded from further evaluation, reducing unnecessary invasive investigations more effectively than other indices., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethics statement All aspects of this study, including research methods were conducted in strict accordance with relevant guidelines and regulations. This study was conducted in compliance with the ethical principles outlined in the Declaration of Helsinki. All data were de-identified, and all study protocols and procedures were reviewed and approved by the Institutional Review Board of Wonju Severance Christian Hospital (approval No. CR317131). Informed consent Written informed consent was obtained from all participants, who have consented to the publication of any data included in the study., (© 2024. The Author(s).)

This study examined the sex-specific mortality risk and causes of death soon after hip fracture in Taiwan. The objective of this study was to evaluate the 30-day mortality risk and cause of death in patients with hip fracture and identify its associated risk factors. We conducted a retrospective cohort study using data from the National Health Insurance Research Database in Taiwan from 2000 to 2015. This study included patients aged 50 years or older who were admitted to a hospital with a hip fracture diagnosis for the first time. Of 285,891 patients hospitalized for their first hip fracture, 8,505 (2.98%) died within 30 days. The mortality risk of hip fracture declined from 3.76% in 2000 to 2.92% in 2015. Circulatory system diseases like ischemic heart disease and cerebrovascular disease were the most common cause of death and accounted for 22% of deaths within 30 days after fracture. Accidents and unintentional injuries caused 18% of deaths, followed by malignant neoplasms in 10% of deaths. Multivariate Cox regression identified older age, male sex, higher Charlson Comorbidity Index (CCI), suburban or rural residence, and lower income as risk factors for hip fracture mortality. The 30-day mortality risk of hip fractures has decreased but remains correlated with male sex, older age, and comorbidities. Circulatory diseases were the main cause of death. Early identification and treatment by experienced clinicians may optimize outcomes, minimize complications, and reduce mortality risk in the 30 days following hip fracture., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Chronic kidney disease-mineral and bone disorder (CKD-MBD) are recognized as a systemic disease affecting the prognosis of patients with CKD. Proper management of CKD-MBD is important to improve the prognosis of patients with CKD. Although proteinuria is recognized as a poor prognostic factor in these patients, few reports have examined its association with CKD-MBD. We examined the association between proteinuria and CKD-MBD using data from the Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex). Among the patients registered in the J-CKD-DB-Ex, 30,977 with CKD stages G2-G5 who had serum creatinine, albumin, calcium, and phosphate concentrations measured at least once and urinalysis performed were included. The patients were divided into four groups (negative, 1+, 2+, and 3+) according to the degree of proteinuria. The association between proteinuria and CKD-MBD was examined by a logistic regression analysis. In a model adjusted for age, sex, diabetes, and the estimated glomerular filtration rate (eGFR), the odds ratio of the 3 + group compared with the negative group significantly increased to 2.67 (95% confidence interval, 2.29-3.13) for hyperphosphatemia, 2.68 (1.94-3.71) for hypocalcemia, and 1.56 (1.24-1.98) for hypomagnesemia. Proteinuria is associated with hyperphosphatemia, hypocalcemia, and hypomagnesemia in patients with CKD independently of eGFR., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Given the limited head-to-head comparison of cardiovascular and renal outcomes between liraglutide and dulaglutide, our study aimed to investigate the clinical outcomes between dulaglutide and liraglutide in a real-world setting. In this new-user design, comparative and retrospective cohort study, patients with type 2 diabetes mellitus with prescription for GLP-1RAs from January 1, 2016 to December 31, 2022 (n = 8,278) were included. Primary outcome was composite cardiovascular outcomes which was composed of cardiovascular death, non-fatal myocardial infarction, and non-fatal ischemic stroke. The composite renal outcome was also interested, including new macroalbuminuria, doubling of serum creatinine, worsening of estimated glomerular filtration rate (eGFR), and progression to dialysis. A total of 3,210 subjects receiving liraglutide and 5,068 subjects receiving dulaglutide were identified. In the adjusted cohort by applying inverse probability of treatment weighting, the incidence of composite cardiovascular outcomes was 18.4 and 18.7 events per 1000 person-years in the liraglutide and dulaglutide groups, respectively. The risk of cardiovascular outcomes did not significantly differ between groups (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.85-1.15). Moreover, the risk of composite renal outcomes was also comparable between groups (subdistribution HR 1.07, 95% CI 0.995-1.16). Liraglutide and dulaglutide demonstrated comparable cardiovascular and renal outcomes in a real-world setting., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Metabolic dysfunction-associated steatohepatitis (MASH) is a form of chronic liver inflammation associated with metabolic syndrome, such as obesity and a major cause of hepatocellular carcinoma (HCC). Multi-biotics, a soymilk fermented with lactic acid bacteria, are known to alleviate obesity by lowering lipid profile. This study aimed to establish and characterize mouse organoids derived from MASH-related HCC models to evaluate drug responses, particularly focusing on Lenvatinib resistance. Organoids were developed using mouse liver tissues subjected to a choline-deficient L-amino acid-defined high-fat diet (CDAHFD) to mimic MASH-related HCC. The study evaluated the effect of multi-biotics, a fermented product, on tumor regression and drug sensitivity. While multi-biotics did not reduce tumor burden, they enhanced the response to Lenvatinib. Additionally, repeated treatment with Lenvatinib led to the development of drug-resistant organoids. Transcriptomic analysis of these resistant organoids identified key pathways related to KRAS signaling, inflammation, and epithelial-mesenchymal transition (EMT), revealing potential targets for overcoming Lenvatinib resistance. This study provides valuable insights into MASH-related HCC progression and drug resistance, offering a model for further therapeutic research., Competing Interests: Declarations Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

The combination of aminophylline and salbutamol is frequently used in clinical practice in the treatment of obstructive lung diseases. While the side effects (including arrhythmias) of the individual bronchodilator drugs were well described previously, the side effects of combined treatment are almost unknown. We aimed to study the arrhythmogenic potential of combined aminophylline and salbutamol treatment in vitro. For this purpose, we used the established atomic force microscopy (AFM) model coupled with cardiac organoids derived from human pluripotent stem cells (hPSC-CMs). We focused on the chronotropic, inotropic, and arrhythmogenic effects of salbutamol alone and aminophylline and salbutamol combined treatment. We used a method based on heart rate/beat rate variability (HRV/BRV) analysis to detect arrhythmic events in the hPSC-CM based AFM recordings. Salbutamol and aminophylline had a synergistic chronotropic and inotropic effect compared to the effects of monotherapy. Our main finding was that salbutamol reduced the arrhythmogenic effect of aminophylline, most likely mediated by endothelial nitric oxide synthase activated by beta-2 adrenergic receptors. These findings were replicated and confirmed using hPSC-CM derived from two cell lines (CCTL4 and CCTL12). Data suggest that salbutamol as an add-on therapy may not only deliver a bronchodilator effect but also increase the cardiovascular safety of aminophylline, as salbutamol reduces its arrhythmogenic potential., (© 2024. The Author(s).)