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Background/Purpose: Shared decision-making (SDM) promotes patient awareness about medical conditions and treatments, facilitating patient involvement in care decisions. This two-stage multicenter study evaluated impacts of SDM in Taiwanese adults with atrial fibrillation (AF) eligible for novel oral anticoagulant (NOAC) therapy. Methods: Participants were NOAC-naïve (part I) or dabigatran-experienced (part II). During Stage I, part I participants (n = 124) completed a semi-structured survey (understanding evaluation sections only) before and after viewing SDM materials on stroke prevention for AF. Surveys collected data on anxiety about AF, confidence in healthcare professionals, usefulness of the SDM materials, and perception of different NOACs. During Stage II, part I participants after being prescribed NOACs, and part II participants completed another survey to compare impacts of SDM. Results: During Stage I, dabigatran was the preferred NOAC after viewing the SDM materials among 90% of part I participants. During Stage II, both part I (n = 87) and part II participants (n = 104) completed another survey. Fewer part I participants were anxious about AF (p

Background Latency in transferring patients from intensive care units (ICUs) to general wards impedes the optimal allocation of ICU resources, underscoring the urgency of initiatives to reduce it. This study evaluates the extent of ICU transfer latency and assesses the potential benefits of minimizing it. Methods Transfer latency was measured as the time between the first transfer request and the actual ICU discharge at a single-center tertiary hospital in 2021. Computer-based simulations and cost analyses were performed to examine how reducing transfer latency could affect average hourly ICU bed occupancy, the proportion of time ICU occupancy exceeds 80%, and hospital costs. The first analysis evaluated all ICU admissions, and the second analysis targeted a subset of ICU admissions with longer transfer latency, those requiring infectious precautions. Results A total of 7,623 ICU admissions were analyzed, and the median transfer latency was 5.7 hours. Eliminating transfer latency for all ICU admissions would have resulted in a 32.8% point decrease in the proportion of time ICU occupancy exceeded 80%, and a potential annual savings of $6.18 million. Eliminating transfer latency for patients under infectious precautions would have decreased the time ICU occupancy exceeded 80% by 13.5% points, and reduced annual costs by a potential $1.26 million. Conclusions Transfer latency from ICUs to general wards might contribute to high ICU occupancy. Efforts to minimize latency for all admissions, or even for a subset of admissions with particularly long transfer latency, could enable more efficient use of ICU resources.

Abstract Background Blunt spleen injuries (BSI) present significant diagnostic and management challenges in trauma care. Current guidelines recommend arterial-phase contrast-enhanced multidetector computed tomography (CT) for a detailed assessment. However, the direct impact of add-on arterial phase CT on clinical outcomes remains unclear. This study investigated the impact of early arterial-phase imaging via multidetector CT on the clinical outcomes of patients with blunt splenic injuries. Methods A retrospective case-control study was conducted to analyze the data of adult patients with BSI treated at a single institution between 2019 and 2022. Patients were divided based on the CT phase performed: portal vein phase only or add-on arterial phase. Management methods were divided according to the initial treatment intent: nonoperative management observation (NOM-Obs), transarterial embolization (TAE), and splenectomy. NOM failure refers to either NOM-Obs or TAE failure leading to splenectomy. NOM-Obs failure refers to cases initially managed with observation only, but later requiring either TAE or splenectomy. Transarterial embolization (TAE) failure refers to cases initially treated with TAE, but subsequently requiring splenectomy. Inverse probability of treatment weighting (IPTW) was used to balance baseline differences and compare outcomes between the two groups. Results Of 170 patients assessed, 147 met the inclusion criteria and were divided into two groups: those receiving portal vein phasic-only CT (N = 104) and those receiving add-on arterial phasic CT (N = 43). The overall NOM failure rate was 3.0% (4/132), the NOM-OBS failure rate was 6.7% (4/60), and the TAE failure rate was 4.1% (3/73). After adjusting for covariates using inverse probability of treatment weighting (IPTW), the comparison between the add-on arterial phase and portal phase CT groups revealed similar overall NOM failure rates (3.0% vs. 2.2%, p = 0.721), NOM-OBS failure rates (3.8% vs. 6.2%, p = 0.703), and intra-abdominal bleeding-related mortality rates (4.8% vs. 2.1%, p = 0.335). Among the 43 patients who underwent add-on arterial CT, only one was diagnosed with a tiny pseudoaneurysm (0.7 cm) attributable to the inclusion of the arterial phase. Conclusion Dual-phase CT within 24 h of presentation offers no added value over single-phase CT in managing blunt splenic injuries in terms of clinical outcomes.

Abstract Background Particulate matter less than 2.5 microns in aerodynamic diameter (PM2.5) is a significant air pollutant known to adversely affect respiratory health and increase the incidence of chronic obstructive pulmonary disease (COPD). Furthermore, climate change exacerbates these impacts, as extreme temperatures and relative humidity (RH) levels can intensify the effects of PM2.5. This study aims to examine the joint effects of PM2.5, temperature, and RH on the risk of COPD. Methods A case–control study was conducted among 1,828 participants from 2017 to 2022 (995 COPD patients and 833 controls). The radial basis function interpolation was utilized to estimate participants' individual mean and differences in PM2.5, temperature, and RH in 1-day, 7-day, and 1-month periods. Logistic regression models examined the associations of environmental exposures with the risk of COPD adjusting for confounders. Joint effects of PM2.5 by quartiles of temperature and RH were also examined. Results We observed that a 1 µg/m3 increase in PM2.5 7-day and 1-month mean was associated with a 1.05-fold and 1.06-fold increase in OR of COPD (p 23.5 °C) and both extremely low (69.3%) and high (80.9%) RH levels generally exacerbate the effects of PM2.5 on OR for COPD, especially over longer exposure durations. Conclusion The joint effects of PM2.5, temperature, and RH on the risk of COPD underscore the importance of air pollution control and comprehensive research to mitigate COPD risk in the context of climate change.

Respiratory syncytial virus (RSV) is the most common pathogen for young children hospitalized with bronchiolitis and pneumonia. Most infections occur below 1 year of age. RSV is also a significant viral pathogen for adults with respiratory tract infection.Vaccines targeting the pre-fusion protein of RSV, including recombinant and mRNA vaccines, are now available. A committee of experts from related fields was convened by the Taiwan Immunization Vision and Strategy to develop recommendations for RSV vaccination in the elderly and pregnant women.The recommendation is not intended as a sole source of guidance in the prevention of RSV infection in children. The provisions listed in this recommendation are comprehensive suggestions made by experts in Taiwan based on existing medical evidence. This recommendation should be subject to modification in light of additional medical research findings in the future, and these provisions should not be cited as a basis for dispute resolution.

An AI-assisted algorithm has been developed to improve the detection of significant coronary artery disease (CAD) in high-risk individuals who have normal electrocardiograms (ECGs). This retrospective study analyzed ECGs from patients aged ≥ 18 years who were undergoing coronary angiography to obtain a clinical diagnosis at Chang Gung Memorial Hospital in Taiwan. Utilizing 12-lead ECG datasets, the algorithm integrated features like time intervals, amplitudes, and slope between peaks, a total of 561 features, with the XGBoost model yielding the best performance. The AI-enhanced ECG algorithm demonstrated high sensitivity (0.82–0.84) when detecting CAD in patients with normal ECGs and gave remarkably high prediction rates among those with abnormal ECGs, both with and without ischemia (92 %-95 % and 80 %-83 %, respectively). Notably, the algorithm's top features, mostly related to slope and amplitude differences, are challenging for clinicians to discern manually. Additionally, the study highlights significant sex differences regarding feature prediction and ranking. Comparatively, the AI-enhanced ECG's detection capability matched that of myocardial perfusion scintigraphy, which is a costly nuclear medicine test, and offers a more accessible alternative for identifying significant CAD, especially among patients with atypical ECG readings.

Abstract Objective Long-acting triptorelin (LAT) (22.5 mg) is a gonadotropin-releasing hormone (GnRH) agonist used in men with prostate cancer. This study investigated the prescription pattern of LAT in a real-world setting and its efficacy. Patients & methods This was a retrospective review of patients in a tertiary center who were prescribed LAT for prostate cancer from January 2018 to March 2023 after the introduction of LAT in the territory. Demographic data were collected, and LAT prescription patterns were reviewed. These patterns included the indication and duration of prescription, testosterone suppression and characteristics of the primary prostate cancer. Results A total of 237 prostate cancer patients were prescribed LAT in the study period. The indications for LAT included metastatic prostate cancer (50.6%), neoadjuvant/adjuvant therapy for radiotherapy (28.7%) and neoadjuvant therapy for radical prostatectomy (5.1%). Among the cohort, 41.4% of the patients were receiving short-acting triptorelin (11.25 mg) before LAT initiation, 15.2% were receiving other GnRH agonists, and 15.6% were receiving GnRH antagonists. The median age at the first dose of LAT and the median treatment duration were 72 (53–94) years and 30 (6–72) months, respectively. During the study period, 92.0% of the patients did not receive another form of hormonal treatment other than LAT. A total of 121 (51.1%) patients had their testosterone level checked after LAT initiation. The median time interval of testosterone measurement after LAT initiation was 8 (1–47) months, with 98.3% of the patients having a testosterone level

Abstract This study investigated alterations in the foveal microvasculature following the administration of 0.125% atropine in myopic children. In this prospective study, 63 eyes from 36 individuals aged 5–18 years with myopia were administered 0.125% atropine for myopia control. After administration, foveal microvascular parameters such as the area and perimeter of the foveal avascular zone (FAZ), the acircularity index (AI) of FAZ, and foveal vessel density were evaluated longitudinally. The effect of atropine on foveal microvasculature was analyzed using a linear mixed model. One month after atropine application, the area and perimeter of FAZ significantly decreased (p = 0.014 and 0.041). A significant decrease in vessel density within the 300-µm wide annulus around FAZ and an increase in the AI of the FAZ were observed in the initial 3-month period (p = 0.035 and p = 0.047, respectively). However, changes in the FAZ area, perimeter, AI and foveal vessel density throughout the follow-up were not significant. These findings suggest that 0.125% atropine may induce transient changes in FAZ size and foveal vessel density, but its overall safety in managing myopia is supported by the stability of foveal parameters over time.

Abstract Background Out-of-hospital traumatic cardiac arrest (TCA), a sudden loss of heart function caused by severe trauma such as blunt, penetrating, or other injuries, presents significant public health challenges due to its high severity and extremely low survival rates. Approximately 2.7% of trauma patients experience cardiac arrest at the scene, with an overall survival rate of less than 5%. The correlations of prognosis with various transport approach, such as hospital level with different distance, are yet to be clarified. Thus, we conducted this study to assess the association of transporting TCA patients to hospitals of different levels and distances on critical outcomes, including the return of spontaneous circulation (ROSC), survival to admission, and 30-day survival. Methods This retrospective study included adults with TCA who were admitted to various emergency departments in Taoyuan City between January 2016 and December 2022. The patients were stratified by destination hospital into three groups: those transported to a trauma center (TC; TC group), those transported to the nearest non-TC (non-TC group), and those cross-regionally transported to a TC (cross-region TC group). Geographic information system (GIS) data were utilized to determine hospital locations and distances. The associations between various factors and key outcomes—any return of spontaneous circulation (ROSC), survival to admission, 24-h survival and 30-day survival—were analyzed. Multivariable logistic regression was used to determine the association of these outcomes based on transportation to hospitals of different levels. Results This study included 557 patients with TCA (TC: 190 [direct transport: 72; cross-region transport: 118]; non-TC: 367). The TC and cross-region TC groups demonstrated significantly higher rates of ROSC at 30.6% and 30.5%, respectively, as well as lower mortality rates (95.8% for both), compared to the non-TC group, which had a ROSC rate of 12.0% and a mortality rate of 99.5%. Multivariable analysis revealed significant associations between favorable outcomes and transportation to a trauma center, either directly (aOR 2.91, 95% CI 1.54–5.49) or via cross-region transfer (aOR 2.05, 95% CI 1.01–4.15). Furthermore, blunt trauma was significantly associated with a poorer survival prognosis (aOR 0.31, 95% CI 0.08–0.78). Discussion This study highlights the positive associations of direct or cross-region transportation to a TC on the outcomes of TCA. Our findings challenge the current EMT transport approach in Taiwan, which prioritizes transporting TCA patients to the nearest hospital regardless of its level, potentially leading to worse outcomes. Transport time and TC distance may not significantly influence prognosis. Conclusion Bypassing and directly transporting to a TC within the observed (10 km) distances are associated with better survival rates in patients with TCA. Furthermore, blunt TCA is associated with a poorer survival prognosis compared to other mechanisms of trauma-induced cardiac arrest.

Background: The role of systemic tumor immune environment (STIE) is unclear in hepatocellular carcinoma (HCC). This study aimed to exam the cells in the STIE, their changes after transarterial chemoembolisation (TACE), stereotactic body radiotherapy (SBRT), and immunotherapy (IO) and explore their significance in the treatment response of patients with unresectable HCC. Methods: This is a prospective biomarker study of patients with unresectable HCC. The treatment was sequential TACE, SBRT (27.5–40 Gy/5 fractions), and IO. The treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) by magnetic resonance imaging (MRI) after 6 months of treatment. Longitudinal data of STIE cells was extracted from laboratory results of complete blood cell counts, including leukocytes, lymphocytes, neutrophils, monocytes, eosinophils, basophils, and platelets. Peripheral blood samples were collected at baseline and after TACE, SBRT, and IO for T-lymphocyte subtyping by flow cytometry. Generalized estimation equation was employed for longitudinal analyses. Results: A total of 35 patients with unresectable HCC were enrolled: 23 patients in the exploratory cohort and 12 in the validation cohort. STIE circulating cells, especially lymphocytes, were heterogenous at baseline and changed differentially after TACE, SBRT, and IO in both cohorts. SBRT caused the greatest reduction of 0.7 × 109/L (95 % CI: 0.3 × 109/L–1.0 × 109/L, P < 0.001) in lymphocytes; less reduction was associated with significantly better treatment response. The analysis of T-lymphocyte lineage revealed that the baseline levels of CD4+ T cells (P = 0.010), type 1 T helper (Th1) cells (P = 0.007), and Th1/Th17 ratios (P = 0.001) were significantly higher in responders, while regulatory T (Treg) cells (P = 0.002), Th17 cells (P = 0.047), and Th2/Th1 ratios (P = 0.028) were significantly higher in non-responders. After treatment with TACE, SBRT and IO, T-lymphocyte lineage also changed differentially. More reductions were observed in CD25+CD8+ T cells and CD127+CD8+ T cells after SBRT in non-responders, while increases in natural killer T (NKT) cells after SBRT (10.4% vs. 3.4 %, P = 0.001) and increases in the lymphocyte counts were noted during IO in responders. Conclusions: STIE cells are significant for treatment response, can be reshaped differentially after TACE, SBRT, and IO. The most significant changes of T-lymphocyte lineage are SBRT associated modulations in CD25+CD8+ T cells, CD127+CD8+ T cells, and NKT cells, which also have significant effects on the ultimate treatment response after TACE-SBRT-IO (ClinicalTrails.gov identifier: GCOG0001/NCT05061342).

The study presented a green and benign approach via mechanochemistry for rapidly preparing a typical cobalt-based zeolitic imidazolate framework, namely ZIF-9. The structural, morphological and textural properties of the obtained material were confirmed by X-ray diffraction (XRD), scanning electron microscopy (SEM), and nitrogen sorption at 77 K. The prepared material was then employed as an efficient adsorbent to remove Congo red (CR) from the aqueous solution. Intensive experiments were then conducted with the removal of CR to investigate the effect of adsorption conditions, including contacting time, pH value, and initial concentration of organic dye solution. The adsorption process follows the pseudo-second-order kinetic model, indicating that the adsorption of the CR dye is primarily chemical adsorption. The Langmuir model fitted the experimental data with a maximum adsorption quantity of 248.22 mg/g. Besides, the adsorption capacity of prepared ZIF-9 still remained stable after three cycles. This strategy was a simple method compared to conventional methods in terms of reducing the amount of used solvents, energy requirements, and the duration of the synthetic process.

Abstract Background Orchids are well-known for their rich diversity of species as well as wide range habitats. Their floral structures are so unique in angiosperms that many of orchids are economically and culturally important in human society. Orchids pollination strategy and evolutionary trajectory are also fantastic human for centuries. Previously, OrchidBase was created not only for storage and management of orchid genomic and transcriptomic information including Apostasia shenzhenica, Dendrobium catenatum, Phalaenopsis equestris, and two species of Platanthera that belong to three different subfamilies of Orchidaceae, but explored orchid genetic sequences for their function. The OrchidBase offers an opportunity for the plant science community to compare orchid genomes and transcriptomes, and retrieve orchid sequences for further study. Description Recently, three whole-genome sequences of the Epidendroideae species, Cymbidium sinense, C. ensifolium and C. goeringii, were sequenced de novo, assembled, and analyzed. In addition, the systemic transcriptomes of these three species have been established. We included these datasets to develop a new version of OrchidBase 6.0. Furthermore, four new analytical methods, namely regulation, updated transcriptome, advanced BLAST, and domain search, were developed for orchid genome analyses. Conclusion OrchidBase 6.0 extended genetic information to that of eight orchid species and created new tools for an expanded community curation in response to the ever-increasing volume and complexity of data.

Background: Current guidelines advocate for maintaining BP level below 180/105 mmHg during EVT, determining the safe lower boundary remains primarily consensus-driven by experts. This study aims to delve into the correlation between various targets of lower boundary for systolic and diastolic BP (SBP and DBP) during EVT and 3-month functional outcomes. Methods: A cohort study was conducted across two EVT-capable centers, enrolling patients with large artery occlusion undergoing EVT within 8 h of stroke onset. Mean BP values during EVT were meticulously recorded, and logistic regression models were utilized to evaluate the correlation between outcomes and diverse lower boundary targets for SBP and DBP. Additionally, logistic regression models investigated the relationship between periprocedural BP variability and subsequent outcomes. Results: Among the 201 patients included, having a SBP higher than 130 or 140 mmHg showed an independent association with increased good functional outcomes at 3 months (adjusted odds ratio, aOR 2.80, 95% Cis, 1.26–6.39 for 140 mmHg; aOR 2.34, 95% Cis, 1.03–5.56 for 130 mmHg). Additionally, an SBP exceeding 130 mmHg was correlated with decreased 3-month mortality (aOR, 0.24, 95% CI 0.07–0.74). No significant relationship was observed between DBP and functional outcomes. Patients with higher periprocedural SBP coefficient variance exhibited a decreased rate of good functional outcomes at 3 months (aOR, 0.42, 95% CI, 0.18–0.96). Conclusion: A SBP range above 130–140 mmHg could potentially serve as a safe lower boundary during EVT, while minimizing BP fluctuations may correlate with improved post-EVT functional outcomes.

Background/aims: The study is to analyze the clinical characteristics and identify prognostic factors as well as evaluate predictive models in patients with acute-on-chronic liver failure (ACLF) from Southern Taiwan. Methods: The cohort study was conducted using the Chang Gung Research Database. We included patients with ACLF based on the definition provided by the Asian-Pacific Association for the Study of the Liver ACLF Research Consortium (AARC). Results: A total of 231 patients diagnosed with ACLF were included in this study, out of which 26 patients underwent liver transplantation (LT). The primary cause of ACLF was acute exacerbation of hepatitis B virus (HBV) in 68.4% of cases and followed by severe alcoholic hepatitis (20.8%). Among LT-free patients, the 28-day mortality rate was observed to be 31%. Older age, higher INR and ammonia levels, and the presence of severe hepatic encephalopathy on 3–6 days of treatment were independent predictors of 28-day mortality. The CLIF-C ACLF and COSSH-ACLF scores, evaluated on 3–6 days, demonstrated the highest predictive performance for 28-day mortality. The optimal cut-off values for the CLIF-C ACLF and COSSH-ACLF scores were determined to be 47 and 6.3, respectively. Patients with CLIF-C ACLF score >63 or COSSH-ACLF score >8.1 experienced 100% mortality by day 28. Conclusion: The CLIF-C ACLF and COSSH-ACLF scores, evaluated within one week after treatment, exhibit strong predictive capabilities for short-term mortality in ACLF patients. These models are valuable tools for guiding timely decision-making, including the consideration of liver transplantation or withdrawal from treatment.

Abstract Evaluating the prognosis of ARDS patients using grading systems can enhance treatment decisions. This retrospective observational study evaluated the predictive accuracy of the SOFA score, APACHE II score, SpO2/FiO2 ratio, and PaO2/FiO2 ratio for mortality in ARDS patients in Vietnam. The study included 335 adult ARDS patients admitted to a central hospital from August 2015 to August 2023. Among them, 66.9% were male, the median age was 55 years, and 61.5% died in the hospital. The SOFA (AUROC: 0.651) and APACHE II scores (AUROC: 0.693) showed poor discriminatory ability for hospital mortality. The SpO2/FiO2 (AUROC: 0.595) and PaO2/FiO2 ratios (AUROC: 0.595) also displayed poor discriminatory ability. In multivariable analyses, after adjusting for the same set of confounding variables, the APACHE II score (adjusted OR: 1.152), SpO2/FiO2 ratio (adjusted OR: 0.985), and PaO2/FiO2 ratio (adjusted OR: 0.989) were independently associated with hospital mortality. Although the SOFA score (adjusted OR: 1.132) indicated a potential association with hospital mortality, it did not reach statistical significance (p = 0.081). However, a SOFA score of ≥ 10 emerged as an independent predictor (adjusted OR: 3.398) of hospital mortality. These findings emphasize the need for further studies to develop more accurate scoring systems for predicting outcomes in ARDS patients.

Abstract Background Colorectal cancer (CRC) poses a significant clinical challenge because of drug resistance, which can adversely impact patient outcomes. Recent research has shown that abnormalities within the tumor microenvironment, especially hyperglycemia, play a crucial role in promoting metastasis and chemoresistance, and thereby determine the overall prognosis of patients with advanced CRC. Methods This study employs data mining and consensus molecular subtype (CMS) techniques to identify pitavastatin and atorvastatin as potential agents for targeting high glucose-induced drug resistance in advanced CRC cells. CRC cells maintained under either low or high glucose conditions were established and utilized to assess the cytotoxic effects of pitavastatin and atorvastatin, both with and without 5-fluorouracil (5-FU). CRC 3D spheroids cultured were also included to demonstrate the anti-drug resistance of pitavastatin and atorvastatin. Results A bioinformatics analysis identified pitavastatin and atorvastatin as promising drug candidates. The CMS4 CRC cell line SW480 (SW480-HG) was established and cultured under high glucose conditions to simulate hyperglycemia-induced drug resistance and metastasis in CRC patients. Pitavastatin and atorvastatin could inhibit cell proliferation and 3D spheroid formation of CMS4 CRC cells under high glucose conditions. In addition, both pitavastatin and atorvastatin can synergistically promote the 5-FU-mediated cytotoxic effect and inhibit the growth of 5-FU-resistant CRC cells. Mechanistically, pitavastatin and atorvastatin can induce apoptosis and synergistically promote the 5-FU-mediated cytotoxic effect by activating autophagy, as well as the PERK/ATF4/CHOP signaling pathway while decreasing YAP expression. Conclusion This study highlights the biomarker-guided precision medicine strategy for drug repurposing. Pitavastatin and atorvastatin could be used to assist in the treatment of advanced CRC, particularly with CMS4 subtype CRC patients who also suffer from hyperglycemia. Pitavastatin, with an achievable dosage used for clinical interventions, is highly recommended for a novel CRC therapeutic strategy.

Objective: This study aimed to investigate whether platelet-rich plasma (PRP) obtained from the blood of rats preconditioned with hyperbaric oxygen (HBOP) would enhance the biological activity of PRP and accelerate the healing process of femur fractures in a rat model. Design: PRP was derived from blood samples of healthy rats subjected to either hyperbaric oxygen (hPRP) or normobaric air (nPRP). A closed femur fracture model was established in male Wistar rats, with treatments of hPRP or nPRP administered around the fracture site immediately post-fracture and on days 7, 14, 21, and 28. Growth factor concentrations in hPRP and nPRP were biochemically quantified. Bone healing was assessed weekly by X-ray, while histological and immunofluorescence analyses evaluated inflammatory status, osteoprotegerin (OPG), receptor activator of nuclear factor kappa-B ligand (RANKL) expression, and the presence of osteoblasts, osteoclasts, and osteocytes during healing. The effects of hPRP and nPRP on MC3T3-E1 preosteoblast migration and proliferation were also tested in vitro. Results: hPRP showed significantly higher concentrations of growth factors such as activin-A, brain-derived neurotrophic factor, nerve growth factor, Flt-3 Ligand, granulocyte-macrophage colony-stimulating factor, hepatocyte growth factor, and platelet-derived growth factor, compared to nPRP. In vitro, hPRP demonstrated more significant effects on preosteoblast migration and proliferation. In vivo, hPRP treatment resulted in enhanced bone healing, higher OPG levels in osteoblasts and osteoclasts, and an elevated OPG/RANKL ratio compared to nPRP. Conclusions: HBOP enhances the biological activity of PRP and accelerates bone healing in a closed femur fracture model in rats. This study highlights the regenerative potential of PRP when preconditioned with hyperbaric oxygen for use in bone fracture therapy. Significance statement: PRP is widely used in treating bone defects and fractures, but its enhancement through HBOP remains underexplored. Our findings demonstrate that HBOP potentiates the biological activity of PRP, offering promising therapeutic potential for bone fracture healing. The translational potential of this article: Enriching growth factors in PRP through HBOP could significantly improve tissue regeneration, especially in bone healing. The potential of hPRP in clinical applications is highly promising, particularly in orthopaedic surgery, trauma care, sports medicine, and managing bone healing in compromised patients.

Abstract Background Dengue fever (DF) in older patients is associated with higher mortality, but optimal mortality prediction approaches remain unclear. We assessed the utility of the quick Sequential Organ Failure Assessment (qSOFA) as a predictive tool in older DF patients. Methods We retrospectively included DF patients aged ≥ 65 years who visited our study hospital between September 1, 2015, and December 31, 2015. Demographics, vital signs, comorbidities, laboratory data, and mortality were collected. Accuracy of qSOFA score ≥ 2 in predicting 30-day mortality was evaluated. Results 626 older DF patients were recruited (mean age: 74.1 years, nearly equal sex distribution). Mean ± standard deviation of qSOFA score was higher in mortality group vs. survival group (0.6 ± 0.8 vs. 0.1 ± 0, p

Abstract Background Neurological outcomes after out-of-hospital cardiac arrest (OHCA) depend on multiple factors, including the patient’s baseline condition and post-arrest management. The SLANT, developed specifically for OHCA survivors treated with targeted temperature management (TTM), requires further validation, particularly in Asian populations. Methods This multicenter retrospective cohort study analyzed data from 2016 to 2023, examining demographics, pre-arrest conditions, resuscitation events, and laboratory biomarkers following TTM. The primary outcome was defined as a poor neurological outcome at hospital discharge. Model performance was assessed using the area under the receiver operating characteristic curve. Multivariate logistic regression analysis was used to analyze the included variables. Results A total of 448 eligible adult patients were included, of whom 77.9% experienced poor neurological outcomes at discharge. The performance of the current cohort was comparable to that of the original SLANT cohort, achieving an area under the curve of 0.797 (95% confidence interval: 0.746–0.849). All five factors of the SLANT score remained statistically significant in predicting poor neurological outcomes. At a cutoff of ≥ 6.5, the SLANT score demonstrated a specificity of 53.5% and positive predictive value (PPV) of 86.9%. Increasing the cutoff value to 8.5 improved the specificity to 66.7% and the PPV to 89.6%. Conclusion The SLANT showed high PPV for predicting poor neurological outcomes at discharge in patients with OHCA undergoing TTM across a multicenter Asian cohort. Combining the score with other neurological assessments is recommended for improved neuroprognostication. Graphical Abstract

Abstract Background The relative risk of ischemic stroke (IS) in head and neck cancer (HNC) patients developing carotid artery stenosis (CAS) or vertebral artery stenosis (VAS) after radiation therapy (RT) remains uncertain due to limited studies, complicating vascular follow-ups and preventive strategies. Methods We included HNC patients who received RT between 2010 and 2023. The patients were divided into nasopharyngeal carcinoma (NPC) and non-NPC groups. The primary outcome was the occurrence of IS after RT, and the secondary outcomes included the development of > 50% CAS or > 50% VAS after RT. Results Of the 1,423 HNC patients, there were 19% of patients developed > 50% CAS, 6.8% of patients developed > 50% VAS, and 2.3% of patients developed IS. In patients with HNC, > 50% CAS (adjusted hazard ratio [HR] = 3.21, 95% confidence interval [CI] = 1.53–6.71), and > 50% VAS (adjusted HR = 2.89, 95% CI = 1.28–6.53) were both the independent predictors of IS. In the patients with NPC, > 50% CAS was an independent predictor of anterior circulation IS (adjusted HR = 4.39, 95% CI = 1.17–16.47). By contrast, > 50% VAS emerged as a predictor of posterior circulation IS in both the NPC (adjusted HR = 15.02, 95% CI = 3.76–60.06) and non-NPC groups (adjusted HR = 13.59, 95% CI = 2.21–83.46). Conclusion HNC patients with > 50% CAS or > 50% VAS after RT had an increased risk of IS within their corresponding vascular territory. CAS could be an important predictor of IS in NPC patients, whereas VAS might also be a significant predictor of IS in both NPC and non-NPC patients. Evaluation both the carotid and vertebral arteries after RT might be necessary. Trial registration ClinicalTrials.gov identifier No.: NCT06111430.

We review the epidemiology, policies, and control programs of HIV infection in Taiwan in the past 40 years since the first case of HIV infection was diagnosed in 1984. With the introduction of combination antiretroviral therapy (ART) in Taiwan in 1997, the incidences of HIV-related opportunistic illnesses and mortality have significantly declined. However, despite improved access to HIV testing and treatment, late presentation of HIV infection remains common. Unprotected sex, particularly among men who have sex with men, continues to be the leading risk for HIV transmission after implementation of harm reduction program to control an outbreak of HIV infection among people who inject drugs that occurred in 2003–2007. The sequential introduction of well-tolerated, effective, single-tablet antiretroviral regimens has facilitated the implementation of “treat-all” policy in 2016, rapid ART initiation within 7 days of diagnosis in 2018, and same-day ART initiation in 2021 when immunochromatography was used for rapid confirmation of HIV infection. Government-funded pilot program of pre-exposure prophylaxis for HIV infection, which was launched in 2016 followed by wider enrollment of people at high risk for HIV acquisition in 2018, have contributed to sustained declines of the incidence of HIV infection since 2018, along with high rates of linkage to HIV care, ART initiation, viral suppression, and retention in care in Taiwan. Challenges remain to achieve HIV elimination and long-term successful management of HIV infection, which include stigma and discrimination, late presentation of HIV infection, and accelerated ageing with increasing rates of co-morbidities among people with HIV.

Background: Cigarette smoking remains a leading cause of mortality worldwide. Streptococcus pneumoniae, also known as pneumococcus, is one of the most common pathogens that colonizes the human respiratory tract, causing life-threatening infections. Several studies have reported that cigarette smoke (CS) exposure promotes pneumococcal infectivity; however, the underlying mechanisms remain to be illustrated. Methods: In this study, we prepared cigarette smoke extract (CSE) from tobacco containing nicotine (0.8 mg/cigarette) and tar (10 mg/cigarette) to investigate the effects of CSE on innate immune response using murine macrophage models. Results: The results from the cytokine array showed that the production of C-C Motif Chemokine Ligand 2 (CCL2), CCL4, CCL3, C-X-C Motif Chemokine Ligand 2 (CXCL2), and CXCL-10, in pneumococcus-infected cells was reduced upon 5 % CSE treatment. Our results further demonstrated that 5 % CSE exposure, followed by pneumococcal challenge, significantly decreased CCL2 and type I interferon (IFN) production in macrophages by inhibiting nuclear factor (NF)-κB and IFN regulatory factor 3 (IRF3) signaling pathways. Moreover, CSE disrupts macrophage polarization and impedes innate immune signaling to suppress pneumococcal phagocytosis by macrophages. Conclusion: Our results provide evidence that CS manipulates the signaling molecules to subvert macrophage functions, thereby hindering the innate response against pneumococcal infection.

Abstract Alzheimer's disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder marked by cognitive decline and memory loss. Early diagnosis is the most effective strategy to slow the disease's progression. Mild Cognitive Impairment (MCI) is frequently viewed as a crucial stage before the onset of AD, making it the ideal period for therapeutic intervention. AD is marked by the buildup of amyloid-beta (Aβ) plaques and tau neurofibrillary tangles (NFTs), which are believed to cause neuronal loss and cognitive decline. Both Aβ plaques and NFTs accumulate for many years before the clinical symptoms become apparent in AD. As a result, in this study, CerebroSpinal Fluid (CSF) biomarker information is combined with hippocampal volumes to differentiate between MCI and AD. For this, a novel two-stage hybrid learning model that leverages 3D CNN and the notion of a Fuzzy and Machine learning model is proposed. A 3D-CNN architecture is employed to segment the hippocampus from the structural brain 3D-MR images and quantify the hippocampus volume. In stage 1, the hippocampus volume is passed through thirteen machine learning models and fuzzy clustering for classifying symptomatic AD and healthy brain (Normal Control - NC). The CSF data is fuzzified to capture the inherent uncertainty and overlap in clinical data. The identified symptomatic AD data in the stage1 are further classified into MCI and AD with the aid of a fuzzified CSF biomarker in stage 2. The experimental work presented in this study utilized the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. The proposed hybrid model achieved an average accuracy of 93.6% for distinguishing between NC and symptomatic AD and 93.7% for discriminating between MCI and AD. This approach enhances diagnostic accuracy and provides a more comprehensive assessment, allowing for earlier and more targeted therapeutic interventions.

ABSTRACT Introduction The early detection of high‐risk individuals is crucial to delay and reduce the incidence of type 2 diabetes. In this study, we aimed to explore the performance of a novel subgroup‐specific biomarker strategy in the prediction of incident diabetes. Materials and Methods In the Taiwan Lifestyle Cohort Study, adult subjects without diabetes were included and followed for the incidence of diabetes in 2006–2019. The biomarkers measured included blood secretogranin III (SCG3), vascular adhesion protein‐1 (VAP‐1), fibrinogen‐like protein 1 (FGL1), angiopoietin‐like protein 6 (ANGPTL6), and angiopoietin‐like protein 4 (ANGPTL4). Results Among the 1,287 subjects, 12.2% developed diabetes during a 6 year follow‐up. Blood VAP‐1 was significantly associated with incident diabetes in the overall population (HR = 0.724, P

Abstract Background Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient. This study highlights the interaction between histamine N-methyltransferase (HNMT) and HER2 as an adjunct predictor for trastuzumab response. Furthermore, modulation of HER2 expression by HNMT may explain why those with low HER2 expression still respond to T-Dxd. Methods We investigated the impact of HNMT protein expression on the efficacy of anti-HER2 therapy in both in vivo and ex vivo models of patient-derived xenografts and cell line-derived xenografts. Our analysis included Förster resonance energy transfer (FRET) to assess the interaction strength between HNMT and HER2 proteins in trastuzumab-resistant and sensitive tumor tissues. Additionally, we used fluorescence lifetime imaging microscopy (FLIM), cleaved luciferase, and immunoprecipitation to study the interaction dynamics of HNMT and HER2. Furthermore, we evaluated the influence of HNMT activity on the binding of anti-HER2 antibodies to their targets through flow cytometry. We also observed the nuclear translocation of HNMT/HER2-ICD cells using fluorescent double staining and DeltaVision microscopy. Finally, ChIP sequencing was employed to identify target genes affected by the HNMT/HER2-ICD complex. Results This study highlights HNMT as a potential auxiliary biomarker for diagnosing HER2 + breast cancer. FRET analysis demonstrated a significant interaction between HNMT and HER2 protein in trastuzumab-sensitive tumor tissue (n = 50), suggesting the potential of HNMT as a predictor of treatment response. Mechanistic studies revealed that the interaction between HNMT and HER2 contributes to increased HER2 protein expression at the transcriptional level, thereby impacting the efficacy of anti-HER2 therapy. Furthermore, a subset of triple-negative breast cancers characterized by HNMT overexpression was found to be sensitive to HER2 antibody–drug conjugates such as T-Dxd. Conclusions These findings offer crucial insights for clinicians evaluating candidates for anti-HER2 therapy, especially for HER2-low breast cancer patients who could gain from T-Dxd treatment. Identifying HNMT expression could help clinicians pinpoint patients who would benefit from anti-HER2 therapy.

The co-infection of dengue and COVID-19 has been regarded as a public health issue for dengue-endemic countries during the COVID-19 pandemic. Travel restrictions might decrease the chance of mosquitoes biting and, thus, reduce the risk of dengue transmission. However, the spread of dengue was reported to increase with the policies of lockdowns and social distancing in specific areas due to delayed interventions in dengue transmission. Of cases experiencing dengue and COVID-19 co-infection, most recovered after receiving supportive care and/or steroid therapy. However, some episodes of severe or fatal diseases in specific individuals, such as pregnant women, have been reported, and the clinical course of this co-infection is unrecognized or unpredictable. Accordingly, it is crucial to promptly identify predictors of developing severe viral diseases among co-infection patients.

Background: Neuronal apoptosis and inflammation are two critical factors that impede functional recovery post spinal cord injury (SCI). Previous studies have demonstrated the inhibitory effects of integrated stress response inhibitor (ISRIB) on neuroinflammation in brain injury. However, whether ISRIB can regulate neuron death and neuroinflammation in the context of SCI remains elusive. Methods: We employed an oxygen-glucose deprivation/reperfusion (OGD/R) model to simulate spinal cord ischemia-reperfusion injury and utilized lipopolysaccharide (LPS) to activate microglia. We assessed cell viability and death to demonstrate the neuroprotective effect of ISRIB against neuron death, while evaluating cytokine levels and the expression of Arg1 and iNOS to elucidate the regulatory role of ISRIB in neuroinflammation. Bulk RNA-seq analysis was employed to investigate the global transcriptional changes in neurons and microglia induced by ISRIB treatment. Additionally, we validated the promoting effects of ISRIB on motor and sensory recovery in a mouse model of SCI. Results: We observed that ISRIB exerted a suppressive effect on neuron death and neuroinflammation. RNA-seq data revealed that the ISRIB exhibited regulation of neuron apoptosis through the P53 signaling pathway, as well as modulation of neuroinflammation by the JAK2/STAT3 signaling pathway. Western blotting and immunofluorescence analyses demonstrated that ISRIB reduced P53 expression in neuronal nuclei and inhibited the phosphorylation of JAK2 and STAT3 in microglia. In addition, we validated the capacity of ISRIB to promote locomotor function recovery in a mouse model of SCI. Conclusion: Our study confirmed the ability of ISRIB to regulate neuron apoptosis and neuroinflammation in SCI via the P53 signaling pathway and the JAK2/STAT3 signaling pathway, respectively. Treatment with ISRIB in mice with SCI promoted the recovery of neural function. This research provides new evidence and options for therapeutic strategies of SCI. The translational potential of this article: Our study provides experimental evidence to support the application of ISRIB in the repair of spinal cord injury.

Abstract Background Inflammation significantly influences thrombosis development, with venous thromboembolism (VTE) risk linked to various systemic inflammatory diseases, but not fully established in inflammatory bowel disease (IBD). Using a population-based cohort study conducted in Taiwan, we investigated the impact of IBD on the risk of VTE, deep vein thrombosis (DVT), and pulmonary embolism (PE), as well as the impact of anti-IBD treatments. Methods A study was conducted on a cohort of patients with IBD diagnosed between 2010 and 2019 using the National Health Insurance database. The risks of VTE, DVT, and PE, as well as anti-IBD treatment use, were examined using Cox proportional hazard regression analysis. Results The overall number of person-years recorded for 12,126 patients with IBD (mean age: 49.18 years; 55.31% male) and 12,126 controls (mean age: 49.19 years; 55.31% male) was 64,057 and 72,056, with a follow-up duration for the two cohorts was 5.28 and 5.94 years, respectively. After adjusting for age, gender, and comorbidities, the adjusted hazard ratios (aHRs) of VTE, DVT, and PE in patients with IBD were 5.58 [95% confidence interval (CI) = 3.97–7.87], 5.48 (95% CI = 3.83–7.86), and 4.96 (95% CI = 2.00-12.35) times higher, respectively, than those in the control cohort. Male patients with IBD and those under the age of 50 were more likely to develop VTE (aHR = 8.54, 95% CI = 2.00-12.35; aHR = 15.75, 95% CI = 5.73–43.26, respectively). Compared to the cohort of patients with IBD receiving no treatment, patients receiving anti-IBD treatments did not show a significant change in the risk of developing VTE. Additionally, compared to the IV steroid cohort, patients with IBD who only used oral steroids had a substantially lower incidence of VTE, particularly with average doses of ≤ 80 mg (aHR = 0.24, 95% CI = 0.10–0.59). Conclusion Patients with IBD are at an increased risk of developing VTE, particularly DVT and PE. While our study found that anti-IBD treatments did not significantly alter this risk, proactive management of associated factors and close monitoring remains essential for preventing VTE in this population. Identifying and addressing specific associated factors should be prioritized in clinical practice to mitigate the heightened risk of VTE in IBD patients.

Abstract Background Retinal vein occlusion (RVO) is a significant retinal vascular disorder that has been hypothesized to increase the risk of cerebrovascular accidents (CVA). Given the shared vascular pathology between the retina and cerebral circulation, understanding the association between RVO and stroke incidence is critical for early intervention and risk management. This systematic review and meta-analysis aim to evaluate the risk of CVA, including ischemic and hemorrhagic subtypes, in patients with RVO. Methods This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in PROSPERO (CRD42024557820). A systematic search of PubMed, Cochrane Library, Scopus, Web of Science, and Embase was conducted from inception to February 2025. Studies assessing the incidence of CVA post-RVO in adult patients (≥ 18 years) were included. Two independent reviewers performed study selection, data extraction, and quality assessment using the Cochrane Risk of Bias tool for Non-Randomized studies (ROBINS-I) was used for observational cohort studies. Meta-analysis was conducted using Comprehensive Meta-Analysis (CMA) software version 3.7, applying a fixed-effects model for low heterogeneity. Subgroup and sensitivity analyses were performed based on RVO type (BRVO vs. CRVO) and stroke subtype (ischemic vs. hemorrhagic CVA). Publication bias was evaluated using Egger’s test and funnel plots. Results A total of 14 studies (n = 97,812 patients) were included. The pooled event rate for CVA post-RVO was 37.5% (95% CI: 37.3%–37.8%), with no significant heterogeneity (I2 = 0%, p = 0.97). Subgroup analysis showed that both ischemic CVA (37.8%; 95% CI: 37.3%–38.3%) and hemorrhagic CVA (32.7%; 95% CI: 32.3%–33.1%) occurred at similar rates across branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). The mortality rate post-CVA in RVO patients was 69.0% (95% CI: 68.4%–69.5%), highlighting the severity of stroke outcomes in this population. The incidence of ischemic cardiovascular events, including myocardial infarction, was 15.7% (95% CI: 15.4%–16.0%), reinforcing the need for cardiovascular monitoring in RVO patients. The incidence of deep vein thrombosis (DVT) was relatively low (0.05%) but still warrants clinical attention in high-risk populations. Publication bias was minimal, as confirmed by Egger’s test (p > 0.24) and funnel plot symmetry. Sensitivity analyses confirmed the robustness of the pooled estimates. Conclusion This meta-analysis provides strong evidence linking RVO to an increased risk of CVA and mortality. Given the high incidence of stroke (37.5%) and mortality post-CVA (69%), early cardiovascular risk assessment and intervention are crucial. Patients with RVO should undergo comprehensive vascular risk evaluation, including blood pressure control, lipid regulation, and anticoagulation therapy when indicated. The findings support a multidisciplinary approach involving ophthalmologists, neurologists, and cardiologists for proactive stroke prevention strategies in RVO patients. Future research should explore genetic predispositions, inflammatory markers, and AI-based predictive models to improve early risk stratification and intervention.

Abstract Background Polyploids in citrus are generally used to improve crop varieties. Changshan Huyou (Citrus changshan-huyou) is a native citrus species in China that is highly adaptable and has pharmaceutical value. However, the influence in Changshan Huyou following polyploidization remains unclear. Here we evaluated the adult tetraploid scions of Changshan Huyou with contemporary diploid scions as the control in the phenotypic variations, metabolic alterations of fruits and associated transcriptomic changes. Result The tetraploid scions had rounder and thicker leaves, larger floral organs and fruits, and satisfactory viability of pollen grains and ovules. The tetraploid fruits accumulated lower levels of soluble solids but similar levels of organic acids. Metabolic profiling of three tissues of fruits revealed that most of 2064 differentially accumulated metabolites (DAMs), including flavonoids, lignans, and coumarins, were downregulated. In contrast, the upregulated DAMs mainly included alkaloids (clausine K and 2-(1-pentenyl)quinoline), amino acids (L-asparagine and L-ornithine), and terpenoids (deacetylnomilin and evodol) in tetraploid peels, as well as, flavonoids (neohesperidin and quercetin-5-O-β-D-glucoside) and organic acids (2-methylsuccinic acid and dimethylmalonic acid) in juice sacs. The upregulated genes were associated with phenylpropanoid biosynthesis, secondary metabolite biosynthesis, and the biosynthesis of various alkaloid pathways. Pearson Correlation Analysis showed that the upregulated genes encoding PEROXIDASE and CYTOCHROME P450 (CYP450) were closely related to the higher accumulation of amino acids and alkaloids in tetraploid peels, and up-regulated neohesperidin and quercetin glucoside were positively associated with FERULATE-5-HYDROXYLASE (F5H), CYP450 81Q32, FLAVONOID 3'-MONOOXYGENASE (F3'H), 4-COUMARATE–CoA LIGASE 1 (4CL1), and UDP-GLUCOSE FLAVONOID 3-O-GLUCOSYLTRANSFERASE (UFOG), as well as, some transcription factors in tetraploid juice sacs. Conclusion The tetraploid Changshan Huyou investigated here may be used in triploids breeding to produce seedless citrus, and for fruit processing on pharmaceutical purpose due to the alteration of metabolites following polyploidization.

Abstract To evaluate influence of total antioxidant capacity expression (TAC) on outcome of kerato-lenticule extraction (KLEx). A prospective non-randomized trial was conducted and patients received KLEx were categorized via TAC concentration. A total of 56 and 36 eyes were enrolled into the low TAC and high TAC groups. The main outcomes are the postoperative un-corrected visual acuity (UCVA), refraction and superficial keratitis between groups. The generalized liner model was applied for statistical analysis. One month after the KLEx surgery, the UCVA was significantly higher in the high TAC group (P = 0.028), and low TAC group associated with superficial keratitis risk compared to high TAC group (P = 0.035). The trends of TAC and ascorbic acid (AA) decrements were more significant in the low TAC group (both P

Abstract Despite considerable work in recent years, pinpointing the time when angiosperms originated has been challenging. However, the rapid development of molecular clock methodology has provided new tools to resolve this conundrum. In particular, the fossilized birth-death model establishes a rich interplay between molecules and stratigraphy by incorporating fossils explicitly into dating analyses. In this study, we apply Bayesian node dating and the skyline fossilized birth-death model, which differ in how the calibration is applied, to estimate the crown age of angiosperms. Node dating analyses with different calibration strategies show that the posterior distribution is strongly constrained by the effective prior at the node of crown angiosperms, dominated by the maximum age constraint. Using the skyline fossilized birth-death model, we reveal that assigning different priors for origin time resulted in similar crown ages for angiosperms. Moreover, the oldest fossils play a significant role in time estimates, and the dating results are robust to sampling assumptions of extant taxa. Our dating analyses indicate a largely Triassic crown age (255–202 Ma) for angiosperms, the period when mammals, dinosaurs, and squamate reptiles first appeared, and highlight the potential of morphological data to redefine the timeline of angiosperms.

Abstract Background Hearing loss, a major public health issue, affects 1.33 per 1,000 live births worldwide. Genetic factors contribute to over half of congenital cases, with X-linked inheritance accounting for 1–5%. POU3F4 mutations are associated with approximately 50% of X-linked non-syndrome hearing loss cases. POU3F4 plays a critical role in cochlear development by regulating otic mesenchyme cell differentiation. The study investigates the impact of a novel POU3F4 p.E294G mutation on cochlear structure and function using cellular and animal model. Methods The study utilized immortalized lymphoblastoid cell lines, POU3F4 overexpressed HEK293 cells and generated Pou3f4 knock-in (Pou3f4KI) mice via CRISPR/Cas9 to introduce the p.E294G mutation. Alterations in expression and subcellular localization of POU3F4 were detected at the cellular level. Auditory function was assessed using auditory brainstem response testing. Cochlear structure was analyzed through histology, immunohistochemistry, scanning electron microscopy, and transmission electron microscopy. RNA sequencing, qPCR and Western blot were conducted to evaluate gene expression and mitochondrial function. Results The transcription of POU3F4 was abnormal and the expression was normal in lymphoblastoid cell lines. Abnormal nuclear localization of POU3F4 p.E294G was found in overexpressed HEK293 cells. Pou3f4KI mice exhibited cochlear malformations, including modiolus hypoplasia and reduced stria vascularis cell populations. Auditory testing revealed progressive hearing loss. Pou3f4 affect mitochondrial protein expression by affecting the expression of TFAM. Mitochondrial dysfunction was evident, with reduced oxidative phosphorylation (OXPHOS) complex assembly and activity, decreased ATP levels. The level of reactive oxygen species, mitochondrial fission and apoptosis in cochlea were elevated. Conclusions The POU3F4 p.E294G resulted in abnormal nuclear localization. Pou3f4 mutant disrupts cochlear development and function, impairs mitochondrial integrity, induces oxidative stress, and promotes apoptosis, leading to progressive hearing loss. The findings enhance the understanding of POU3F4-related hearing loss mechanisms and highlight the importance of early genetic screening and audiological monitoring.

Abstract Policosanols, found in relatively large amounts in rice bran and sugarcane wax, are of interest due to their cholesterol-lowering bioactivity. Many dietary supplements and functional foods containing policosanols are available globally. The amount and stability of policosanols affect the health benefits; however, while many products claim to contain policosanols, data on the amounts and stability, including in dietary supplements and rice bran oil, are limited. This study examined the policosanol contents of commercial rice bran cooking oil and commercial dietary supplements. The policosanol stability was investigated through a model of rice bran oil enriched with policosanols extracted from defatted rice bran. The highest and lowest policosanol content of commercial rice bran cooking oil were 73.99 ± 2.96 and 18.65 ± 2.21 mg/100 g, respectively, with the major policosanols being tetracosanol (C24) and hexacosanol (C26). Functional oil products containing rice bran oil had the highest policosanol levels (215.72 ± 2.49 mg/100 g), with the rice content of the rice bran oil affecting the policosanol content. Some dietary supplements contained lower amounts of policosanol than the claimed 5 and 20 mg/serving. Policosanol was stable to heat treatment at 150 and 180 °C, with heat treatment transiently increasing the policosanol level, and was stable during 6 months of storage. Graphical Abstract

Objective: We present a rare case of trisomy 18 of maternal origin in a pregnancy with omphalocele, craniorachischisis, and ectopia cordis. Case report: A 38-year-old woman, G3P1A1, was diagnosed with fetal anencephaly, an extrathoracic heart (ectopic cordis), deformity of spine and a stomach-and-intestine-containing omphalocele by prenatal ultrasound at 12 weeks of gestation. The patient's husband was 39 years old and healthy. The patient had no significant past medical history. She was a nonsmoker, with a pre-pregnancy BMI of 23.7 and was not diabetic. There was no family history of malformations, diseases, or teratogenic medication. The patient had not received assisted reproductive technology during this pregnancy. The pregnancy was terminated in the 13th gestational week. Additional anomalies detected after termination of the pregnancy included small and triangular face, abnormal posturing of hands, clubfoot and craniorachischisis. Crown-heel length was 5.5 cm consistent with a 12–13-week gestational age. Postnatal cytogenetic analysis of chorionic villi obtained by placental sampling revealed a karyotype of 47, XX + 18. Polymorphic DNA marker analysis by quantitative fluorescent polymerase chain reaction (QF-PCR) assays showed a maternal origin of the extra chromosome 18. Conclusion: The concomitant omphalocele, ectopia cordis and craniorachischisis may be related to trisomy 18. Genetic analysis of the postmortem tissue and the analysis of the parental origin of the extra chromosome 18 using QF-PCR, provide valuable information for genetic counseling.

Background: This study aimed to validate self-reported medical conditions in the Taiwan Biobank (TWBB), in which participants were inquired about 30 disease conditions, by comparing them with claims records from Taiwan’s National Health Insurance (NHI) claims database. Methods: We identified 30 clinical diagnoses using International Classification of Diseases - Clinical Modification codes from ambulatory and hospital claims within the NHI claims database, matching diseases included in the TWBB. The concordance between self-reports and claims records was evaluated using tetrachoric correlation to assess the correlation between binary variables. Results: A total of 131,834 participants aged 30–70 years with data from the TWBB and NHI records were included. Concordance analysis revealed tetrachoric correlations ranged from 0.420 (chronic obstructive pulmonary disease) to 0.970 (multiple sclerosis). However, several disorders exhibited lower tetrachoric correlations. The concordance was higher among those with higher education attainment, and lower among married individuals. Conclusion: The concordance between self-reports in the TWBB and NHI claims records varied across clinical diagnoses, showing inconsistencies depending on participant characteristics. These findings underscore the need for further investigation, especially when these variables are crucial to research objectives. Integrating complementary databases, such as clinical diagnoses, prescription records, and medical procedures, can enhance accuracy through customized algorithms based on disease categories and participant characteristics and optimize sensitivity or positive predictive values to align with specific research objectives.

Qingquan Wei,1 Lifang Chi,2 Meiling Li,3 Qinghua Qiu,1 Qing Liu1 1Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Anesthesia and Operating Room, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 3Department of Ophthalmology, Shigatse People’s Hospital, Shigatse, Xizang, People’s Republic of ChinaCorrespondence: Qinghua Qiu; Qing Liu, Department of Ophthalmology, Tong Ren Hospital, Shanghai Jiao Tong University School of Medicine, 1111 Xianxia West Road, Shanghai, People’s Republic of China, Email QQH4948@shtrhospital.com; LQ1098@shtrhospital.comPurpose: This study aims to evaluate the performance of a deep learning-based artificial intelligence (AI) diagnostic system in the analysis of retinal diseases, assessing its consistency with expert diagnoses and its overall utility in screening applications.Methods: A total of 3076 patients attending our hospital underwent comprehensive ophthalmic examinations. Initial assessments were performed using the AI, the Comprehensive AI Retinal Expert (CARE) system, followed by thorough manual reviews to establish final diagnoses. A comparative analysis was conducted between the AI-generated results and the evaluations by senior ophthalmologists to assess the diagnostic reliability and feasibility of the AI system in the context of ophthalmic screening.Results: : The AI diagnostic system demonstrated a sensitivity of 94.12% and specificity of 98.60% for diabetic retinopathy (DR); 89.50% sensitivity and 98.33% specificity for age-related macular degeneration (AMD); 91.55% sensitivity and 97.40% specificity for suspected glaucoma; 90.77% sensitivity and 99.10% specificity for pathological myopia; 81.58% sensitivity and 99.49% specificity for retinal vein occlusion (RVO); 88.64% sensitivity and 99.18% specificity for retinal detachment; 83.33% sensitivity and 99.80% specificity for macular hole; 82.26% sensitivity and 99.23% specificity for epiretinal membrane; 94.55% sensitivity and 97.82% specificity for hypertensive retinopathy; 83.33% sensitivity and 99.74% specificity for myelinated fibers; and 75.00% sensitivity and 99.95% specificity for retinitis pigmentosa. Additionally, the system exhibited notable performance in screening for other prevalent conditions, including DR, suspected glaucoma, suspected glaucoma, pathological myopia, and hypertensive retinopathy.Conclusions: : The AI-assisted screening system exhibits high sensitivity and specificity for a majority of retinal diseases, suggesting its potential as a valuable tool for screening practices. Its implementation is particularly beneficial for grassroots and community healthcare settings, facilitating initial diagnostic efforts and enhancing the efficacy of tiered ophthalmic care, with important implications for broader clinical adoption.Keywords: artificial intelligence, retinal diseases, screening

Developing ultra-high strength and high toughness maraging steel requires an effective route of a well-designed heat treatment regimen to control the precipitates. In this study, we regulated the heterogeneous nucleation sites through Mo-enriched particles to increase the nucleation rate of Ni3Ti. The Mo-enriched particles as Ni3Ti precursors decrease the lattice mismatch between α-Fe and Ni3Ti, reducing crack formation at the interface. We tailored the maraging steel utilizing duplex aging treatment (DAT) to break the conventional precipitation pathway. The DAT comprises a solid solution treatment followed by a two-step aging treatment at 370 °C and 480 °C. The Mo-enriched particles precipitated after solid solution treatment due to the low solubility and diffusion rate at low temperatures. The aging treatment conducted at 370 °C enhances the density of the Mo-enriched particles and inhibits the formation of Ni3Ti. The pre-formed precipitates act as heterogeneous nucleation sites for Ni3Ti during aging at 480 °C, increasing the nucleation rate and reducing the size. As aging continues, Mo segregates to the interface of Ni3Ti and the matrix, inhibiting the growth of Ni3Ti and forming Fe7Mo2 precipitates. The DAT steel exhibits an excellent yield strength of 2093 MPa and fracture toughness of 77 MPa∙m1/2 at room temperature. The well-regulated precipitates increase crack nucleation energy, forming a curved primary crack and multiple secondary cracks, which reduce stress concentrations and increase fracture toughness. The DAT strategy provides a new avenue for improving fracture toughness while maintaining high strength in maraging steel.

Abstract Pathogenesis of periodontitis is marked by microbiota dysbiosis and disrupted host responses. Porphyromonas gingivalis is a keystone pathogen of periodontitis which expresses various crucial virulence factors. This study aimed to clarify the role and mechanisms of P. gingivalis tryptophan-indole metabolic pathway in the pathogenesis of periodontitis. This study showed that periodontitis patients exhibited elevated tryptophan metabolism and salivary pathogen abundance. Tryptophanase gene-deficiency altered proteome and metabolome of P. gingivalis , inhibited P. gingivalis virulent factors expression, biofilm growth, hemin utilization, cell adhesion/invasion and pro-inflammation ability. Tryptophan-indole pathway of P. gingivalis stimulated periodontitis biofilm formation and induced oral microbiota dysbiosis. In periodontitis mice, this pathway of P. gingivalis aggravated alveolar bone loss and gingival tissue destruction, causing oral and gut microbiota dysbiosis. This study indicates that the tryptophan-indole pathway serves as a significant regulator of P. gingivalis virulence and oral microbiota dysbiosis, which is also associated with gut dysbiosis.

Abstract Chimeric antigen receptor (CAR) T cell therapy has demonstrated significant clinical efficacy in patients with hematologic cancers. However, long-term follow-up studies indicate that only 50% of patients remain in complete remission after three years. To overcome these limitations, we investigated a strategy to enhance the antitumor activity of CAR T cells through gene modification. Based on previous research results demonstrating that CAR T cells with disrupted TET2, a methylcytosine dioxygenase, exhibit enhanced antitumor effects compared to conventional CAR T, we developed CAR T cells in which TET2 is downregulated by TET2 shRNA. Among the screened TET2-specific shRNAs, TET2-shRNA-1 was identified as the most effective sequence for gene silencing. Using this sequence, we constructed an all-in-one vector co-expressing CD19 CAR and TET2 shRNA. In vitro studies demonstrated that TET2 knockdown CD19 CAR T cells exhibited comparable cytolytic activity against CD19-positive cancer cells compared to conventional CD19 CAR T cells. However, interestingly, in xenograft mouse model using NSG mice, TET2 knockdown CAR T cells showed significantly improved antitumor activity compared to conventional CAR T cells. Our study demonstrates that shRNA-mediated knockdown of TET2 is a promising strategy to enhance the antitumor activity of CD19 CAR T cells in a preclinical model.

Abstract Background Spontaneous intracerebral hemorrhage (sICH) is a critical and disabling form of stroke and accounts for an obvious number of stroke-related deaths and disabilities globally. Hematoma growth is a key target for therapeutic intervention because of its association with poor outcomes. Recently, the STOP–MSU trial showed that intravenous tranexamic acid (TA) did not reduce hematoma growth or improve clinical outcomes when administered within 2 h of intracerebral hemorrhage symptom onset. This study aims to evaluate the efficacy of TA in reducing hematoma growth and improving clinical outcomes in patients with spontaneous sICH by incorporating the findings from the latest STOP–MSU trial and consolidating past research to clarify the overall efficacy and safety of TA on sICH. Methods A systematic review and meta-analysis were conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and PRISMA guidelines. We included randomized controlled trials (RCTs) comparing TA to placebo in adult patients with sICH. Databases such as PubMed, Medline, and Cochrane were searched up to May 2024. Key outcomes analyzed included hematoma expansion, mortality within 90 days, thromboembolic events, and favorable functional outcomes. Data were pooled using a random-effects model and analyzed using the “metafor” package in RStudio. Results Five RCTs involving 1419 patients were included. The meta-analysis showed no significant difference in hematoma expansion (odds ratio [OR] 0.87, 95% confidence interval [CI] 0.74–1.03), mortality within 90 days (OR 1.03, 95% CI 0.86–1.24), thromboembolic events (OR 1.07, 95% CI 0.69–1.64), and favorable functional outcomes (modified Rankin Scale of 0–2 at 90 days; OR 1.04, 95% CI 0.88–1.22) between the TA and placebo groups. Conclusions TA does not significantly reduce hematoma growth or improve clinical outcomes in patients with sICH. Despite its affordability and availability, the routine use of TA in sICH is not supported by current evidence.

Abstract Background Pasteurella multocida causes progressive atrophic rhinitis and suppurative bronchopneumonia in pigs, which results in severe economic losses in swine industry. This study aimed to determine the serovar, genotype and prevalence of toxA virulence gene of Pasteurella multocida isolates collected in Taiwan. A total of 164 Pasteurella multocida isolates from 161 diseased pigs were characterized by serotyping, multilocus sequence typing (MLST), antimicrobial susceptibility testing, and the presence of virulence gene (toxA) and antibiotic resistance gene (floR). Results The majority of Pasteurella multocida strains were serovar D:L6 (48.2%; 79/164) followed by A:L6 (28.7%; 47/164) and A:L3 (19.5%; 32/164). More than 80% of strains carrying toxA gene belonged to serovar A:L6 (82.6%; 19/23). The MLST data showed five sequence types (STs), where multi-host ST10 was the most dominant. Most Pasteurella multocida strains of multi-host ST10 were serovar A:L6 (93.9%; 31/33), which suggested that STs were highly associated with specific serovars. Most of the floR-carrying Pasteurella multocida strains belonged to serovar D:L6 with significantly high resistance to some antimicrobial agents, especially florfenicol. Conclusions This study demonstrated that serovar D:L6 and multi-host ST10 was the most prevalent Pasteurella multocida strain in Taiwan. A:L6 accounted for the majority of toxA-positive strains and the presence of floR gene may be responsible for the antimicrobial resistance to florfenicol.

Abstract Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Histone deacetylase (HDAC) inhibitors (HDACi) have shown clinical benefit in HR ( +) breast cancer patients. The Hippo pathway is an important cellular pathway involving proliferation, cell contact, and cancer. Hippo pathway proteins YAP/TAZ are often viewed as pro-tumorigenic; however, recent studies support a role of YAP as a tumor suppressor in HR ( +) breast cancer. Few studies have investigated the link between HDACi and the Hippo pathway. In our study, we demonstrate that HDACi induces transcriptional downregulation of YAP expression, while conversely activating a TEAD-mediated transcriptional program with upregulation of canonical Hippo pathway genes. We subsequently identified four Hippo canonical genes (CCDC80, GADD45A, F3, and TGFB2) that were upregulated by HDACi and associated with significantly improved survival in a HR ( +) breast cancer cohort. We further validated experimentally that HR ( +) breast cancer cells treated with HDACi resulted in upregulation of CCDC80 and GADD45A. A pan-cancer analysis of TCGA database demonstrated lower CCDC80 and GADD45A expression in tumor tissue compared to non-tumor samples in BRCA (breast cancer), LAML (acute myeloid leukemia), and UCS (uterine carcinosarcoma). Further analysis of HR ( +) breast cancer patients in the METABRIC dataset revealed high CCDC80 and/or GADD45A expression associated with significantly better survival outcomes compared to patients with low expression. Our study provides evidence for a novel mechanism of HDACi clinical activity, as well as a potential role for CCDC80 and GADD45A in HR ( +) breast cancer.

Abstract Background Metabolic syndrome (MetS) encompasses a collection of metabolic abnormalities. This study aims to determine which combination of MetS components has the highest mortality risk, and to investigate the causal relationships between MetS components and longevity. Methods Prospective analyses were conducted on 340,196 participants from the MJ cohort at baseline, and 121,936 participants had follow-up MetS information. We defined MetS according to the NCEP ATP III criteria. The study’s outcomes included mortality from cardiovascular disease (CVD), cancer, and all causes combined. We employed Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals. Multivariable Mendelian randomization (MVMR) was employed to infer causality using the genetic data of MetS components and longevity. Results Elevated blood pressure (BP) was the initial split for all-cause mortality, cancer mortality, and CVD mortality. Participants with MetS, especially those with elevated BP and elevated fasting plasma glucose (FPG), had higher mortality risks than those with other types of MetS. In the MJ cohort, participants with elevated BP and FPG (BG-type MetS) had a 44% (HR = 1.44, 95% CI = 1.37–1.51), 73% (HR = 1.73, 95% CI = 1.62–1.84), and 34% (HR = 1.34, 95% CI = 1.27–1.42) increased risk of all-cause mortality, cancer mortality, and CVD mortality, respectively, compared with non-BG-type MetS (12%, 24%, 5%). The highest mortality rate and mortality risk were observed in participants with BG-type MetS at baseline and follow-up (mortality rate/1000 person years = 9.73, 95% CI = 8.81–10.74; HR = 1.52, 95% CI = 1.35–1.72). SBP and FPG increases that were genetically proxied to a 1-standard deviation higher level decreased the probabilities of living to the 90th percentile age by 41% (OR = 0.59, 95% CI = 0.40–0.86) and 32% (OR = 0.68, 95% CI = 0.48–0.98) in MVMR, respectively. Conclusions Individuals with BG-type MetS are at a higher risk of death than those with other types of MetS. Therefore, these individuals should be targeted to improve MetS outcomes.

A novel approach to α-fluoroamides bearing a C–F quaternary stereocenter is reported herein. With sulfone installed as the activating group, an alkyl group as well as a fluorine atom was introduced successively under mild conditions. Subsequently, heterolytic fission of the C–S bond occurred smoothly under photoredox conditions to afford a tertiary radical, which then engaged in varied intramolecular cyclizations depending on substrate structure and condition applied, rendering sulfone an overall traceless activating group.

Abstract Background Although the implementation of a hierarchical medical system (HMS) has been shown to improve the allocation of medical resources and patient health-seeking behaviour, its role in patient’s perceived quality of primary care remains unexplored. This study aimed to assess the impact of HMS implementation on rural and urban residents’ perceived quality of primary care. Methods Data were obtained from the China Family Panel Study for 2012, 2014, 2016, and 2018. A total of 40,011 rural and 22,482 urban residents were included in the research participants for analysis. This study adopted a quasi-natural experimental design, and the multiple-period difference-in-differences method was used to capture changes in patient’s perceived quality of primary care before and after the introduction of HMS. Results We found that HMS implementation declined the perceived quality of primary care by an average of 18% among rural residents (OR: 0.82, 95% CI 0.68–0.99), while there was no significant change among urban residents (OR: 1.13, 95% CI 0.87–1.46). There was a 24% reduction in the perceived quality of primary care (OR: 0.76, 95% CI 0.61–0.96) one year after HMS among rural residents, and there was no statistically significant difference two years after HMS. After HMS implementation, the level of perceived quality of primary care by rural patients with chronic diseases decreased by 72% (OR: 0.28, 95% CI 0.11–0.78). Conclusions HMS has a limited effect on improving residents’ perceived quality of primary care, especially for those living in rural areas. Policymakers are suggested to establish a quality monitoring system that incorporates patient experience as an essential standard to systematically evaluate the impacts of the HMS, with more efforts being put into helping vulnerable groups such as residents under 60 years old and patients with chronic diseases.

Abstract Background Differences in overall survival (OS) between pediatric and adult patients diagnosed with osteosarcoma are poorly understood. The objective of this study is to compare the OS of pediatric and adult patients with osteosarcoma, identify prognostic factors associated with OS, and explore factors specifically associated with pediatric osteosarcoma using data gathered from the National Cancer Database (NCDB). Methods Patients > = 1 years old and diagnosed with osteosarcoma between 2004 and 2017 were included in the study. Multivariable Cox regression analysis adjusted for gender, race, income, education, place of living, health insurance status, year of diagnosis, stage of cancer, surgery, chemotherapy, and radiation therapy (RT) was used to assess the association of age with the OS of the patients. Results The analysis included 8,458 patients among whom 3,027 (35.8%) were between 1 and 17 years old. In the multivariable Cox regression analysis, adult patients had worse OS compared with pediatric patients (HR: 1.84; p

Abstract In contrast to mammals, adult zebrafish achieve complete heart regeneration via proliferation of cardiomyocytes. Surprisingly, we found that regenerating cardiomyocytes experience DNA replication stress, which represents one reason for declining tissue regeneration during aging in mammals. Pharmacological inhibition of ATM and ATR kinases revealed that DNA damage response signaling is essential for zebrafish heart regeneration. Manipulation of Bone Morphogenetic Protein (BMP)-Smad signaling using transgenics and mutants showed that BMP signaling alleviates cardiomyocyte replication stress. BMP signaling also rescues neonatal mouse cardiomyocytes, human fibroblasts and human hematopoietic stem and progenitor cells (HSPCs) from replication stress. DNA fiber spreading assays indicate that BMP signaling facilitates re-start of replication forks after replication stress-induced stalling. Our results identify the ability to overcome replication stress as key factor for the elevated zebrafish heart regeneration capacity and reveal a conserved role for BMP signaling in promotion of stress-free DNA replication.