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Purpose: In East Asia, the incidence of breast cancer has been increasing rapidly, particularly among premenopausal women. An elevated ratio of estrogen-DNA adducts was linked to a higher risk of breast cancer. The present study explored the influence of the interaction between base excision repair (BER) gene polymorphisms and estrogen-DNA adducts on breast cancer risk. Methods: We conducted a case–control study comprising healthy volunteers and individuals with benign breast disease (control arm, n = 176) and patients with invasive carcinoma or carcinoma in situ (case arm, n = 177). Genotyping for BER-related genes, including SMUG1, OGG1, ERCC5, and APEX1, was performed. A logistic regression model, incorporating interactions between gene polymorphisms, estrogen-DNA adduct ratio, and clinical variables, was used to identify the risk factors for breast cancer. Results: Univariate analysis indicated marginal associations between breast cancer risk and APEX1 rs1130409 T > G (P = 0.057) and APEX1 rs1760944 T > G (P = 0.065). Multivariate regression analysis revealed significant associations with increased breast cancer risk for APEX1_rs1130409 (GT/GG versus TT) combined with a natural logarithmic value of the estrogen-DNA adduct ratio (estimated OR 1.164, P = 0.023) and premenopausal status with an estrogen-DNA adduct ratio > 2.93 (estimated OR 2.433, P = 0.001). Conclusion: APEX1_rs1130409 (GT/GG versus TT) polymorphisms, which are related to decreased BER activity, combined with an increased ratio of estrogen-DNA adducts, increase the risk of breast cancer in East Asian women. [ABSTRACT FROM AUTHOR]

Performing reliability analysis for reinforced concrete structures is a tedious and challenging task because it requires conducting a four-nested loop calculation procedure involving millions of data samples to account for the complex behaviours of the structures and multiple random variables. Therefore, the study proposes a novel, practical, and accurate reliability framework that is applicable for multi-component RC frame structures exhibiting different behaviours ranging from linear elastic and non-linear elastic to non-linear plastic. For this purpose, this study first employs a tree-based boosting ensemble model combined with quantile regression, dubbed as QR-LightGBM to calculate the structures' limit state function and the associated uncertainty estimation at the same time. Next, an active learning process is implemented to improve the computed reliability results progressively. During each active learning step, relevant data samples with potentially high impacts on the model accuracy are determined based on their uncertainty, and then QR-LightGBM is retrained utilizing these samples. By doing so, the prediction performance of the surrogate model is enhanced with a minimized number of actual data samples, thus significantly reducing overall computational resources. The viability and effectiveness of the proposed framework are validated through three case studies involving a simple 1D reinforced concrete beam, a 2D three-story frame, and a 3D five-story building structure. Furthermore, its performance is quantitatively demonstrated via comparison studies with competing methods such as Monte Carlo simulation, Kriging-based models, and an original LightGBM without active learning. [ABSTRACT FROM AUTHOR]

Background: While single-incision laparoscopic cholecystectomy (SILC) has gained more popularity in recent years, its application to elderly patients needs further evaluation. Few SILC studies regarded this rapidly growing vulnerable population, and single-incision laparoscopic common bile duct exploration (SILCBDE) was never mentioned. We conducted an observational study of 146 routine SILCBDE to address this issue. Methods: One hundred forty-six consecutive patients underwent SILCBDE with concomitant cholecystectomies during a period of 6 years (July 2012–June 2016 and July 2018–July 2020). Forty patients with an age of 65 years or older were the study target. Characteristics and operative outcomes were compared with the remaining 106 younger patients by retrospective chart review. The primary outcomes include complications and mortality, while the secondary outcomes contain intraoperative blood loss, operative time, procedural conversions, postoperative length of hospital stay, and bile duct stone recurrence. Results: There was no mortality. The bile duct stone clearance rate was 98.6%. The elderly group had higher American Society of Anesthesiologists (ASA) scores, higher comorbidity rate, higher acute cholangitis rate, lower completion intraoperative cholangiography (IOC) rate, longer operative time, more blood loss, longer postoperative hospital stay (p <.001), longer total hospital stay (p <.001), higher procedural conversion rate (p <.05), higher complication rate (p <.001), and the exclusive open conversion (2.5%). The difference in complications derived from Clavien–Dindo grade I. Conclusion: Routine SILCBDE with concomitant cholecystectomy by experienced surgeons is safe and efficacious for elderly patients as for younger patients. Randomized controlled trials are anticipated. [ABSTRACT FROM AUTHOR]

Background: Adjuvant nivolumab reduces recurrence in patients with locoregional esophageal cancer who had pathological residual disease after neoadjuvant chemoradiotherapy and R0 resection. However, the efficacy of adjuvant anti-PD-1 therapy in patients at higher risk of recurrence remains unclear. Methods: This phase II trial (ClinicalTrials.gov identifier: NCT03322267) enrolled patients with locally advanced esophageal squamous cell carcinoma (ESCC) received neoadjuvant chemoradiotherapy plus esophagectomy but still had various risk factors for recurrence, such as involved or close margins (≤ 1 mm), extranodal extension of the involved lymph nodes, and the ypN2-3 stage. Patients received adjuvant therapy composed of a course of cisplatin-based chemoradiotherapy and pembrolizumab (200 mg, IV every 3 weeks) for 18 cycles. The primary endpoint was 1-year relapse-free survival (RFS) rate. Results: Twenty-five patients were enrolled. The risk factors were tumor margins of ≤ 1 mm (18 patients), extranodal extension of the involved lymph nodes (9 patients), and the ypN2-3 stage (9 patients). The median follow-up duration was 21.6 months (95% CI: 18.7–33.2). The rate of 1-year RFS was 60.0%. The median duration of RFS and overall survival was 14.3 (95% CI: 9.0–19.5) and 21.6 (95% CI: 0.0–45.5) months, respectively. Treatment-emergent adverse events of any grade and those of ≥ 3 grade occurred in 56% and 8% of all patients receiving cisplatin-based chemoradiotherapy and in 79.2% and 12.5% of those receiving pembrolizumab. Conclusions: Adjuvant chemoradiotherapy followed by pembrolizumab is feasible and may be associated with improved 1-year RFS rate in patients at high risk of recurrence after trimodality therapy for locally advanced ESCC. Trial registration number ClinicalTrials.gov (No. NCT03322267). [ABSTRACT FROM AUTHOR]

Current genome-wide association studies (GWAS) for kidney function lack ancestral diversity, limiting the applicability to broader populations. The East-Asian population is especially under-represented, despite having the highest global burden of end-stage kidney disease. We conducted a meta-analysis of multiple GWASs (n = 244,952) on estimated glomerular filtration rate and a replication dataset (n = 27,058) from Taiwan and Japan. This study identified 111 lead SNPs in 97 genomic risk loci. Functional enrichment analyses revealed that variants associated with F12 gene and a missense mutation in ABCG2 may contribute to chronic kidney disease (CKD) through influencing inflammation, coagulation, and urate metabolism pathways. In independent cohorts from Taiwan (n = 25,345) and the United Kingdom (n = 260,245), polygenic risk scores (PRSs) for CKD significantly stratified the risk of CKD (p < 0.0001). Further research is required to evaluate the clinical effectiveness of PRSCKD in the early prevention of kidney disease. Here the authors present a large genetic study in East Asians that identifies 97 genetic regions linked to kidney function. These findings aim at better understanding chronic kidney disease in diverse populations. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of Astragalus polysaccharides (PG2) on reducing chemotherapy-induced fatigue (CIF) and toxicity, thereby encouraging compliance to chemotherapy. This was a randomized, placebo-controlled, phase 2 study. Patients with stage II/III early breast cancer planning to undergo adjuvant anthracycline-based chemotherapy were randomly assigned to receive PG2 500 mg or placebo on days 1, 3, and 8 every 21 days. The fatigue global score (FGS) was assessed using the brief fatigue inventory (BFI)-Taiwan. The Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 evaluated the health-related quality of life during the first four cycles of adjuvant chemotherapy. Overall, 66 eligible patients were equally randomized into the PG2 and placebo groups between March 01, 2018, and March 09, 2021. The mean change in the FGS and fatigue intensity did not significantly differ between both groups. However, the FGS and fatigue intensity were less aggravated in the first four cycles in the premenopausal-PG2 group than in the placebo group. Our study concluded PG2 combined with adjuvant chemotherapy can reduce CIF, insomnia, the negative effect on future perspectives, and improve global health status, especially for premenopausal patients with breast cancer. Trial registration number: NCT03314805 registered on 19/10/2017. [ABSTRACT FROM AUTHOR]

This study provides an in-depth simulation of the capillary underfill (CUF) process for flip-chip packages using Moldex3D, offering a comprehensive analysis that integrates material properties, process parameters, and structural factors within a unified framework. The material properties explored include viscosity and reaction kinetics, while the process parameters focus on controllable factors such as resin temperature, mold temperature, dispensing start time, dispensing weight, and dispensing end time. Structural parameters like bump pitch and gap height are also studied. The study further validates its findings with experiments conducted on a high bump count of 1530, showing that the experiment and simulation results are consistent. Key findings reveal that a larger die pitch accelerates the filling process, the incorporation of edge channels enhances filling efficiency, and optimizing the dispensing path improves flow uniformity. Adjusting the dispensing weight and intervals can mitigate edge effects and tongue spreading. Regarding material properties, higher surface tension and lower contact angle significantly increase filling speed, though they have a minimal impact on the overall flow pattern during the underfill filling process. These insights are crucial for optimizing the CUF process, ultimately improving the reliability and performance of flip-chip packages. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that empagliflozin (EMPA) therapy effectively protected renal and heart functions via downregulating reactive oxygen species (ROS) and activating AMPK signaling in cardiorenal syndrome (CRS) (induced by doxorubicin-5/6 nephrectomy) rats. In vitro result showed that underwent p-Cresol treatment, the H9C2/NRK-52E cell viabilities, were significantly suppressed, whereas cellular levels of ROS and early/late apoptosis of these cells were significantly increased that were significantly reversed by EMPA treatment (all p < 0.001). The protein levels of the cell-stress/oxidative signaling (p-PI3K/p-Akt/p-mTOR/NOXs/p-DRP1) were significantly activated, whereas the mitochondrial biogenesis signaling (p-AMPK/SIRT-1/TFAM/PGC-1α) was significantly repressed in these two cell lines treated by p-Cresol and all of these were significantly reversed by EMPA treatment (all p < 0.001). Male-adult-SD rats were categorized into groups 1 [sham-operated control (SC)]/2 [SC + high protein diet (HPD) since day 1 after CKD induction]/3 (CRS + HPD)/4 (CRS + HPD+EMPA/20 mg/kg/day) and heart/kidney were harvested by day 60. By day 63, the renal function parameters (creatinine/BUN/proteinuria)/renal artery restrictive index/cellular levels of ROS/inflammation were significantly increased in group 3 than in groups 1/2, whereas heart function exhibited an opposite pattern of ROS among the groups, and all of these parameters were significantly reversed by EMPA treatment (all p < 0.0001). The protein levels of inflammation/ oxidative-stress/cell-stress signalings were highest in group 2, lowest in group 1 and significantly lower in group 4 than in group 2, whereas the AMPK-mitochondrial biogenesis displayed an opposite manner of oxidative-stress among the groups (all p < 0.0001). EMPA treatment effectively protected the heart/kidney against CRS damage via suppressing ROS signaling and upregulating AMPK-mediated mitochondrial biogenesis. [ABSTRACT FROM AUTHOR]

Drought is one of the common natural disasters with a wide range of occurrences in terms of space and time, and with varying levels of severity, that may result in economic damage and health issues to humans. This study focuses on assessing drought severity in the Central Highlands of Vietnam based on ground meteorological stations and multispectral remote sensing data. A Modification of the Normalized Difference Drought Index (MNDDI) was developed to enhance the effectiveness of remote sensing indices in the drought assessment. Results indicate that MNDDI outperforms Normalized Difference Drought Index and other investigated indicators, such as Normalized Difference Vegetation Index, Normalized Difference Latent Heat Index, and Normalized Difference Water Index, in representing the Earth's surface response to drought events. Correlations ranging from 0.85 to 0.63 were identified between MNDDI and various time scales of the commonly used meteorological drought indicator, namely the Standardized Precipitation Index, during the drought year of 2015. This work also reveals the superiority of MNDDI in portraying the response of land cover types to drought situations. The finding of a severe drought phenomenon in critical agricultural zones is highly consistent with the report from the Ministry of Agriculture and Rural Development of Vietnam. This study contributes valuable insights to the preliminary assessment of drought through remote sensing data, offering a foundation for precise drought outlooks and effective risk management strategies. [ABSTRACT FROM AUTHOR]

This population-based study investigated the risk of having had prior herpes zoster within five years preceding a diagnosis of head and neck cancer. We conducted a case-control study that included 9,191 patients with a diagnosis of head and neck cancer in Taiwan's Longitudinal Health Insurance Database 2010 and 36,764 matched controls. We assessed the odds of patients with head and neck cancer having had a diagnosis of herpes zoster during the five years preceding head and neck cancer using multiple logistic regression analysis. The prevalence of prior herpes zoster among the total sample was 4.6%, 7.9% and 3.8% among patients with and without head and neck cancer, respectively (p < 0.001). The odds ratio of herpes zoster among the head and neck cancer- versus control group was 2.198 (95% CI = 2.001 ~ 2.415) after adjusting for sociodemographic characteristics and hypertension, diabetes, hyperlipidemia, tobacco use disorder, HPV infection, and alcohol dependence syndrome. Statistically significant excess odds were observed for all specific subtypes of head and neck cancer except for sinonasal cancer. Herpes zoster infection within the 5 years preceding a diagnosis of head and neck cancer may be a harbinger of developing head and neck cancer. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver damage, highlighting the limitations of current emergency treatments that primarily involve administering the glutathione precursor N-acetylcysteine and supportive therapy. This study highlights the essential protective role of the type II transmembrane serine protease (TTSP), hepsin, in mitigating acetaminophen-induced liver injury, particularly through its regulation of gap junction (GJ) abundance in response to reactive oxygen stress in the liver. We previously reported that reduced levels of activated hepatocyte growth factor and the c-Met receptor tyrosine kinase—both of which are vital for maintaining cellular redox balance—combined with increased expression of GJ proteins in hepsin-deficient mice. Here, we show that hepsin deficiency in mice exacerbates acetaminophen toxicity compared to wild-type mice, leading to more severe liver pathology, elevated oxidative stress, and greater mortality within 6 h after exposure. Administering hepsin had a protective effect in both mouse models, reducing hepatotoxicity by modulating GJ abundance. Additionally, transcriptome analysis and a functional GJ inhibitor have highlighted hepsin's mechanism for managing oxidative stress. Combining hepsin with relatively low doses of N-acetylcysteine had a synergistic effect that was more efficacious than high-dose N-acetylcysteine alone. Our results illustrate the crucial role of hepsin in modulating the abundance of hepatic GJs and reducing oxidative stress, thereby offering early protection against acetaminophen-induced hepatotoxicity and a new, combination approach. Emerging as a promising therapeutic target, hepsin holds potential for combination therapy with N-acetylcysteine, paving the way for novel approaches in managing drug-induced liver injury. 1. Hepsin−/− mice exhibit exacerbated APAP toxicity, resulting in more severe liver damage, elevated oxidative stress, and higher mortality. 2. Hepsin is crucial in protecting against APAP-induced liver injury by regulating gap junctions and reducing oxidative stress. 3. Combining hepsin with low doses of N-acetylcysteine provides greater protection against APAP-induced hepatotoxicity than high-dose NAC alone. [ABSTRACT FROM AUTHOR]

The IL6-GP130-STAT3 pathway facilitates lung cancer progression and resistance to tyrosine kinase inhibitors. Although glycosylation alters the stability of GP130, its effect on the ligand IL6 remains unclear. We herein find that N-glycosylated IL6, especially at Asn73, primarily stimulates JAK-STAT3 signaling and prolongs STAT3 phosphorylation, whereas N-glycosylation-defective IL6 (deNG-IL6) induces shortened STAT3 activation and alters the downstream signaling preference for the SRC-YAP-SOX2 axis. This signaling shift induces epithelial-mesenchymal transition (EMT) and migration in vitro and metastasis in vivo, which are suppressed by targeted inhibitors and shRNAs against SRC, YAP, and SOX2. Osimertinib-resistant lung cancer cells secrete a large amount of deNG-IL6 through reduced N-glycosyltransferase gene expression, leading to clear SRC-YAP activation. deNG-IL6 contributes to drug resistance, as confirmed by in silico analysis of cellular and clinical transcriptomes and signal expression in patient specimens. Therefore, the N-glycosylation status of IL6 not only affects cell behaviors but also shows promise in monitoring the dynamics of lung cancer evolution. Post-translational modifications regulate tumorigenesis and cancer therapy sensitivity. Here, the authors show that N-glycosylation defective Interleukin-6 (deNG-IL6) switches downstream signalling pathway from JAK-STAT3 to SRC-YAP axis and lung cancer cells secrete deNG-IL6 to promote metastasis and tyrosine kinase inhibitor resistance. [ABSTRACT FROM AUTHOR]

Although prostate cancer is a common occurrence among males, the relationship between existing risk prediction models remains unclear. The objective of this hospital-based retrospective study is to investigate the impact of polygenic risk scores (PRSs) on the incidence and prognosis of prostate cancer in the Han Chinese population. A total of 24,778 male participants including 903 patients with prostate cancer at Taichung Veterans General Hospital were enrolled in the study. PRS was calculated using 269 single nucleotide polymorphisms and their corresponding effect sizes from the polygenic score catalog. The association between PRS and the risk prostate cancer was evaluated using Cox proportional hazards regression model. Among the 24,778 participants, 903 were diagnosed with prostate cancer. The risk of prostate cancer was significantly higher in the highest quartile of PRS distribution compared to the lowest (hazard ratio = 4.770, 95% CI = 3.999–5.689, p < 0.0001), with statistical significance across all age groups. Patients in the highest quartile were diagnosed with prostate cancer at a younger age (66.8 ± 8.3 vs. 69.5 ± 8.8, p = 0.002). Subgroup analysis of patients with localized or stage 4 prostate cancer showed no significant differences in biochemical failure or overall survival. This hospital-based cohort study observed that a higher PRS was associated with increased susceptibility to prostate cancer and younger age of diagnosis. However, PRS was not found to be a significant predictor of disease stage and prognosis. These findings suggest that PRS could serve as a useful tool in prostate cancer risk assessment. [ABSTRACT FROM AUTHOR]

Purpose: To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel. Introduction: Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel. Methods: A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel. Results: 11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC0 − infinity of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC0 − infinity of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m2. The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached. Conclusion: oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted. Trial registration number: U1111-1173-5473. [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. Methods: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. Results: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00–1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34–2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30–2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). Conclusion: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC. [ABSTRACT FROM AUTHOR]

Abstract This article sheds light on the diversity of meanings and connotations that tend to be lost or hidden in translations between different conceptualizations of nature in East and South-East Asia. It reviews the idea of “nature” in Chinese, Japanese, Vietnamese, Filipino, Tagalog, Cebuano, Lumad, Indonesian, Burmese, Nepali, Khmer, and Mongolian. It shows that the conceptual subtleties in the conceptualization of nature often hide wider and deeper cosmological mismatches. It concludes by suggesting that these diverse voices need to be represented in global reports on sustainability, which can be fostered by the direct involvement of experts from diverse traditions of thought who have access and interpretative knowledge of sources in languages other than English. To take into consideration the diversity of conceptualizations of nature can lead to better decisions about sustainability and improve the acceptability and efficiency of environmental policies in each local context, as well as internationally. Solutions and policies on the ground must be designed based on the local conceptual and cultural frames.

Abstract ACE2 on epithelial cells is the SARS‐CoV‐2 entry receptor. Single‐cell RNA‐sequencing data derived from two COVID‐19 cohorts revealed that MAP4K3/GLK‐positive epithelial cells were increased in patients. SARS‐CoV‐2‐induced GLK overexpression in epithelial cells was correlated with COVID‐19 severity and vesicle secretion. GLK overexpression induced the epithelial cell‐derived exosomes containing ACE2; the GLK‐induced exosomes transported ACE2 proteins to recipient cells, facilitating pseudovirus infection. Consistently, ACE2 proteins were increased in the serum exosomes from another COVID‐19 cohort. Remarkably, SARS‐CoV‐2 spike protein‐stimulated GLK, and GLK stabilized ACE2 in epithelial cells. Mechanistically, GLK phosphorylated ACE2 at two serine residues (Ser776, Ser783), leading to the dissociation of ACE2 from its E3 ligase UBR4. Reduction in UBR4‐induced Lys48‐linked ubiquitination at three lysine residues (Lys26, Lys112, Lys114) of ACE2 prevented its degradation. Furthermore, SARS‐CoV‐2 pseudovirus or live virus infection in humanized ACE2 mice induced GLK and ACE2 protein levels, and ACE2‐containing exosomes. Collectively, ACE2 stabilization by SARS‐CoV‐2‐induced MAP4K3/GLK may contribute to the pathogenesis of COVID‐19.

Purpose: To investigate the ability of extracellular vesicles (EVs) to deliver oxaliplatin to epidermal growth factor receptor (EGFR+) colorectal cancer cells and increase oxaliplatin's cytotoxicity. Method: Oxaliplatin was passively loaded into a stable cell line expressing cetuximab in membranes. EVs were collected and characterized for size, and their ability to target EGFR+ cells was tested. Cytotoxicity experiments were performed, and a xenograft cancer animal model was used to confirm the specific accumulation of oxaliplatin-loaded EVs with cetuximab-expressing membranes in EGFR+ cells. Results: EVs with cetuximab-expressing membranes were successfully produced and used to encapsulate oxaliplatin, resulting in consistently sized oxaliplatin-loaded EVs with cetuximab-expressing membranes. The oxaliplatin-loaded EVs with cetuximab-expressing membranes were specifically accumulated by EGFR+ cells, leading to significant cytotoxic effects on these cells. In the animal model, the oxaliplatin-loaded EVs with cetuximab-expressing membranes accumulated specifically in EGFR+ cells and significantly enhanced oxaliplatin's therapeutic efficacy against EGFR+ cancer cells. Conclusion: EVs with membrane-expressed bioactive molecules are a promising strategy for delivering therapeutic agents to EGFR+ colorectal cancer cells. Highlights: EVs with cetuximab-expressing membranes were used to encapsulate oxaliplatin and target EGFR+ cells. Oxaliplatin-loaded EVs with cetuximab-expressing membranes exhibited significant cytotoxic effects on EGFR+ cells. In a xenograft cancer animal model, oxaliplatin-loaded EVs with cetuximab-expressing membranes accumulated specifically in EGFR+ cells and significantly enhanced oxaliplatin's therapeutic efficacy against EGFR+ cancer cells. EVs with targeted membrane expression of drugs are a promising strategy for delivering therapeutic agents to specific cell populations. [ABSTRACT FROM AUTHOR]

The Vietnam sugarcane industry faces to many challenges during the last few years since Covid-19 pandemic. However, the industry has a significant increase in the last 2 years thanks to many factors that make a remarkable transformation of the industry. This paper reviews the factors affecting this significant transformation of the sugarcane industry and toward the trend of net zero and sustainable transformation of sugarcane value chain and sugar industry in Vietnam such as digitalization of the supply chain, research and development of co-products from sugar processing, application of big data and AI in consumer insight of the R&D process. [ABSTRACT FROM AUTHOR]

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. Methods: A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined—the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. Results: The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. Conclusion: The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen. [ABSTRACT FROM AUTHOR]

Remotely sensed evapotranspiration (ETRS) shows promise for enhancing hydrological models, especially in regions lacking in situ streamflow observations. However, model calibration studies showed conflicting results regarding the ability of ETRS products to improve streamflow simulation. Rather than relying on model calibration, here we produce the first randomized experiment that explores the full streamflow–ET skill distribution, and also the first probabilistic assessment of the value of different global ETRS products for streamflow simulation. Using 280,000 randomized SWAT (Soil and Water Assessment Tool) model runs across seven catchments and four ETRS products, we show that the relationship between ET and streamflow skills is complex, and simultaneous improvement in both skills is only possible in a limited range. Parameter sensitivity analysis indicates that the most sensitive parameters can have opposite contributions to ET and streamflow skills, leading to skill trade-offs. Conditional probability assessment reveals that models with good ET skills are likely to produce good streamflow skills, but not vice versa. We suggest that randomized experiments such as ours should be performed before model calibration to determine whether using ETRS is worthwhile, and to help in interpreting the calibration results. [ABSTRACT FROM AUTHOR]

Medical advances prolonging life have led to more permanent pacemaker implants. When pacemaker implantation (PMI) is commonly caused by sick sinus syndrome or conduction disorders, predicting PMI is challenging, as patients often experience related symptoms. This study was designed to create a deep learning model (DLM) for predicting future PMI from ECG data and assess its ability to predict future cardiovascular events. In this study, a DLM was trained on a dataset of 158,471 ECGs from 42,903 academic medical center patients, with additional validation involving 25,640 medical center patients and 26,538 community hospital patients. Primary analysis focused on predicting PMI within 90 days, while all-cause mortality, cardiovascular disease (CVD) mortality, and the development of various cardiovascular conditions were addressed with secondary analysis. The study's raw ECG DLM achieved area under the curve (AUC) values of 0.870, 0.878, and 0.883 for PMI prediction within 30, 60, and 90 days, respectively, along with sensitivities exceeding 82.0% and specificities over 81.9% in the internal validation. Significant ECG features included the PR interval, corrected QT interval, heart rate, QRS duration, P-wave axis, T-wave axis, and QRS complex axis. The AI-predicted PMI group had higher risks of PMI after 90 days (hazard ratio [HR]: 7.49, 95% CI: 5.40-10.39), all-cause mortality (HR: 1.91, 95% CI: 1.74–2.10), CVD mortality (HR: 3.53, 95% CI: 2.73–4.57), and new-onset adverse cardiovascular events. External validation confirmed the model's accuracy. Through ECG analyses, our AI DLM can alert clinicians and patients to the possibility of future PMI and related mortality and cardiovascular risks, aiding in timely patient intervention. [ABSTRACT FROM AUTHOR]

The current technologies to place new DNA into specific locations in plant genomes are low frequency and error-prone, and this inefficiency hampers genome-editing approaches to develop improved crops1,2. Often considered to be genome ‘parasites’, transposable elements (TEs) evolved to insert their DNA seamlessly into genomes3–5. Eukaryotic TEs select their site of insertion based on preferences for chromatin contexts, which differ for each TE type6–9. Here we developed a genome engineering tool that controls the TE insertion site and cargo delivered, taking advantage of the natural ability of the TE to precisely excise and insert into the genome. Inspired by CRISPR-associated transposases that target transposition in a programmable manner in bacteria10–12, we fused the rice Pong transposase protein to the Cas9 or Cas12a programmable nucleases. We demonstrated sequence-specific targeted insertion (guided by the CRISPR gRNA) of enhancer elements, an open reading frame and a gene expression cassette into the genome of the model plant Arabidopsis. We then translated this system into soybean—a major global crop in need of targeted insertion technology. We have engineered a TE ‘parasite’ into a usable and accessible toolkit that enables the sequence-specific targeting of custom DNA into plant genomes.Fusion of rice Pong transposase to the Cas9 or Cas12a programmable nucleases provides sequence-specific targeted insertion of enhancer elements, an open reading frame and gene expression cassette into the genome of the model plant Arabidopsis and crop soybean. [ABSTRACT FROM AUTHOR]

We present a method for modification of silicon nitride (Si3N4) waveguide resonators using femtosecond laser annealing. The quality (Q) factor of the waveguide resonators can be improved by approximately 1.3 times after annealing. Notably, waveguides that originally had a high Q value maintained their quality after the annealing process. However, those with a lower initial Q value experienced a noticeable improvement post-annealing. To characterize the annealing effect, the surface morphologies of Si3N4 films, both pre- and post-annealing, were analyzed using atomic force microscopy. The findings suggest a potential enhancement in surface refinement. Furthermore, Raman spectroscopy confirmed that the Si3N4 film's composition remains largely consistent with its original state within the annealing power range of 0.6–1.6 W. This research underscores the potential of femtosecond laser annealing as an efficient, cost-effective, and localized technique for fabricating low-loss integrated photonics. [ABSTRACT FROM AUTHOR]

Assessing programmed death ligand 1 (PD-L1) expression through immunohistochemistry (IHC) is the golden standard in predicting immunotherapy response of non-small cell lung cancer (NSCLC). However, observation of heterogeneous PD-L1 distribution in tumor space is a challenge using IHC only. Meanwhile, immunofluorescence (IF) could support both planar and three-dimensional (3D) histological analyses by combining tissue optical clearing with confocal microscopy. We optimized clinical tissue preparation for the IF assay focusing on staining, imaging, and post-processing to achieve quality identical to traditional IHC assay. To overcome limited dynamic range of the fluorescence microscope's detection system, we incorporated a high dynamic range (HDR) algorithm to restore the post imaging IF expression pattern and further 3D IF images. Following HDR processing, a noticeable improvement in the accuracy of diagnosis (85.7%) was achieved using IF images by pathologists. Moreover, 3D IF images revealed a 25% change in tumor proportion score for PD-L1 expression at various depths within tumors. We have established an optimal and reproducible process for PD-L1 IF images in NSCLC, yielding high quality data comparable to traditional IHC assays. The ability to discern accurate spatial PD-L1 distribution through 3D pathology analysis could provide more precise evaluation and prediction for immunotherapy targeting advanced NSCLC. [ABSTRACT FROM AUTHOR]

The rapid progress of industrial development, urbanization, and traffic has caused air quality degradation that negatively affects human health and environmental sustainability, especially in developed countries. However, due to the limited number of sensors available, the air quality index at many locations is not monitored. Therefore, many research, including statistical and machine learning approaches, have been proposed to tackle the problem of estimating air quality value at an arbitrary location. Most of the existing research perform interpolation process based on traditional techniques that leverage distance information. In this work, we propose a novel deep-learning-based model for air quality value estimation. This approach follows the encoder–decoder paradigm, with the encoder and decoder trained separately using different training mechanisms. In the encoder component, we proposed a new self-supervised graph representation learning approach for spatio-temporal data. For the decoder component, we designed a deep interpolation layer that employs two attention mechanisms and a fully connected layer using air quality data at known stations, distance information, and meteorology information at the target point to predict air quality at arbitrary locations. The experimental results demonstrate significant improvements in estimation accuracy achieved by our proposed model compared to state-of-the-art approaches. For the MAE indicator, our model enhances the estimation accuracy from 4.93% to 34.88% on the UK dataset, and from 6.89% to 31.94% regarding the Beijing dataset. In terms of the RMSE, the average improvements of our method on the two datasets are 13.33% and 14.37%, respectively. The statistics for MAPE are 36.05% and 13.25%, while for MDAPE, they are 24.48% and 36.33%, respectively. Furthermore, the value of R 2 score attained by our proposed model also shows considerable improvement, with increases of 5.39% and 32.58% compared to that of comparison benchmarks. Our source code and data are available at https://github.com/duclong1009/Unsupervised-Air-Quality-Estimation. [ABSTRACT FROM AUTHOR]

3-Bromofluoranthene (3-BrFlu) is the secondary metabolite of fluoranthene, which is classified as a polycyclic aromatic hydrocarbon, through bromination and exists in the fine particulate matter of air pollutants. Endothelial dysfunction plays a critical role in the pathogenesis of cardiovascular and vascular diseases. Little is known about the molecular mechanism of 3-BrFlu on endothelial dysfunction in vivo and in vitro assay. In the present study, 3-BrFlu included concentration-dependent changes in ectopic angiogenesis of the sub-intestinal vein and dilation of the dorsal aorta in zebrafish. Disruption of vascular endothelial integrity and up-regulation of vascular endothelial permeability were also induced by 3-BrFlu in a concentration-dependent manner through pro-inflammatory responses in vascular endothelial cells, namely, SVEC4-10 cells. Generation of pro-inflammatory mediator PGE2 was induced by 3-BrFlu through COX2 expression. Expression of COX2 and generation of pro-inflammatory cytokines, including TNFα and IL-6, were induced by 3-BrFlu through phosphorylation of NF-κB p65, which was mediated by phosphorylation of MAPK, including p38 MAPK, ERK and JNK. Furthermore, generation of intracellular ROS was induced by 3-BrFlu, which is associated with the down-regulated activities of the antioxidant enzyme (AOE), including SOD and catalase. We also found that 3-BrFlu up-regulated expression of the AOE and HO-1 induced by 3-BrFlu through Nrf-2 expression. However, the 3-BrFlu-induced upregulation of AOE and HO-1 expression could not be revised the responses of vascular endothelial dysfunction. In conclusion, 3-BrFlu is a hazardous substance that results in vascular endothelial dysfunction through the MAPK-mediated-NFκB pro-inflammatory pathway and intracellular ROS generation. [ABSTRACT FROM AUTHOR]

In this study, the evolution of grain and ripple structures on the surface of 6061 aluminum alloy (AA6061) parts fabricated by a laser-foil-printing (LFP) additive manufacturing process at different preheated temperatures were characterized and compared. Results indicated that the preheated temperature of the substrate plays a crucial role in the formation of grain structures, the shape of ripples, and the surface quality of aluminum parts fabricated by LFP. As the preheated temperature of the substrate elevated from room temperature to 300 °C, the grain and ripple structures formed coarser and flatter, respectively, due to the reduction in the thermal gradient and cooling rate. The grain structure was coarsened with an increasing average grain size from 74.96 to 150.5 μm measured by the electron backscattered diffraction (EBSD) technique. Meanwhile, the ripple structure was stretched and transformed from short and curved shapes to smoother, which improved the surface roughness significantly and reduced the Sa value from 21.7 to 8.5 μm in three-dimensional (3D) surface morphologies. However, when the preheated temperature reached 500 °C in LFP, the grain structure experienced a recrystallization process, resulting in the formation of finer grains compared to those observed at 300 °C. Furthermore, the surface quality was improved to a Sa value of 5.2 μm because the flowability of the melt pool was enhanced from the extended solidification time by the smallest temperature gradient and cooling rate at the highest preheat temperature, which was estimated using the finite element method (FEM). In the X-ray diffraction (XRD) patterns, the ratio of the main peak (200) to the secondary peak was gradually increased when preheated temperature elevated; however, the ratio decreased at 500 °C due to the recrystallization. [ABSTRACT FROM AUTHOR]

Consider a graph G with vertex set V(G) and edge set E(G). A subset D of V(G) is said to be a dominating set of G if every vertex not in D is adjacent to at least one vertex in D. If, in addition, every vertex not in a dominating set R of G is adjacent to at least one vertex in V (G) - R , then R is called a restrained dominating set of G. A paired restraint dominating set S of a graph G is a restrained dominating set of G satisfying that the induced subgraph by S contains a perfect matching. The problems of computing the dominating set, restrained dominating set, and paired restraint dominating set with minimum cardinality are referred to as the domination, restrained domination, and paired restraint domination problems, respectively. The paired restraint domination problem and its applications are first proposed here. Our focus is on examining the complexity of the proposed problem on extended supergrid graphs and their subclasses, which include grid, diagonal supergrid, and (original) supergrid graphs. The domination problem is known to be NP-complete on grid graphs and, therefore, also on extended supergrid graphs. Our previous research demonstrated that the domination and restrained domination problems on diagonal and original supergrid graphs are NP-complete. However, the complexity of the paired restraint domination problem on grid, diagonal supergrid, and original supergrid graphs remains unknown. The NP-completeness of the paired restraint domination problem on diagonal supergrid graphs is demonstrated in this paper, and this finding is also applicable to the original supergrid graphs and planar graphs with maximum degree 4. We then examine a subclass of diagonal and original supergrid graphs known as rectangular supergrid graphs. These graphs are distinguished by a rectangular shape consisting of m rows and n columns of vertices. Specifically, we address the paired restraint domination problem on R m × n and develop a linear time algorithm for 3 ⩾ m ⩾ 1 and n ⩾ m . Then, when n ⩾ m ⩾ 4 , we obtain a tight upper bound on the minimum size of the paired restraint dominating set of R m × n and then use this upper bound to establish one lower bound. [ABSTRACT FROM AUTHOR]

Precision systems have extensively employed compliant mechanisms. Nevertheless, its utilization in vibration-assisted polishing has not garnered much interest. Therefore, this study presents a novel framework for a mechanism that adheres to two degrees of freedom. The mechanism that has been constructed exhibits a symmetrical design, enabling it to extract comparable performances in two directions. The proposed construction incorporates a novel combination of a three-lever amplification mechanism and a parallelogram to improve both the stroke and resonant frequency. The output amplification ratio is calculated by the graphical scheme method. The pseudo-rigid-body model, the free-body diagram, and the Lagrange method are all used together in this study to look into kinetostatics and dynamics. The water cycle algorithm is used to conduct structural optimization based on mathematical models. The prototype is fabricated by CNC milling, and physical tests are conducted. According to the findings for the resonant frequency, the analytical results well match the finite element analysis (FEA) results with an error of 8.44%. Besides, the measured resonant frequency was determined approximately 486 Hz, while the FEA yielded a result of 460.4 Hz. The discrepancy between the FEA and experimental results is 5.26%. The utilization of the design mechanism holds promise for the application of vibration-assisted polishing. [ABSTRACT FROM AUTHOR]

This phase 3 trial compared safety, tolerability, immunogenicity and efficacy of the self-amplifying mRNA COVID-19 vaccine, ARCT-154, with ChAdOx1-S adenovirus-vector vaccine. In four centers in Vietnam adult participants aged 18‒85 years were randomly assigned to receive two doses, 28 days apart, of either ARCT-154 (n = 1186) or ChAdOx1-S (n = 1180). Both vaccines were well tolerated with similar safety and reactogenicity profiles consisting of mainly mild-to-moderate solicited adverse events and few related serious adverse events. Higher neutralizing antibody responses persisting to one-year post-vaccination after ARCT-154 compared with ChAdOx1-S were associated with a generally higher efficacy against COVID-19. In an exploratory analysis relative vaccine efficacy of ARCT-154 vs. ChAdOx1-S against any COVID-19 from Day 36 to Day 394 was 19.8% (95% CI: 4.0–33.0). Self-amplifying mRNA vaccine offers potential immunological advantages in terms of immunogenicity and efficacy over adenovirus-vector vaccine without compromising safety. [ABSTRACT FROM AUTHOR]

Perovskite solar cells (PSCs) offer an efficient, inexpensive alternative to current photovoltaic technologies, with the potential for manufacture via high-throughput coating methods. However, challenges for commercial-scale solution-processing of metal-halide perovskites include the use of harmful solvents, the expense of maintaining controlled atmospheric conditions, and the inherent instabilities of PSCs under operation. Here, we address these challenges by introducing a high volatility, low toxicity, biorenewable solvent system to fabricate a range of 2D perovskites, which we use as highly effective precursor phases for subsequent transformation to α-formamidinium lead triiodide (α-FAPbI3), fully processed under ambient conditions. PSCs utilising our α-FAPbI3 reproducibly show remarkable stability under illumination and elevated temperature (ISOS-L-2) and "damp heat" (ISOS-D-3) stressing, surpassing other state-of-the-art perovskite compositions. We determine that this enhancement is a consequence of the 2D precursor phase crystallisation route, which simultaneously avoids retention of residual low-volatility solvents (such as DMF and DMSO) and reduces the rate of degradation of FA+ in the material. Our findings highlight both the critical role of the initial crystallisation process in determining the operational stability of perovskite materials, and that neat FA+-based perovskites can be competitively stable despite the inherent metastability of the α-phase. The use of harmful solvents to fabricate stable devices hampers the commercialization of perovskite solar cells. Here, the authors introduce a biorenewable solvent system and precursor-phase engineering to realize stable formamidinium lead triiodide-based solar cells. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) shares common risk factors with cardiovascular (CV) disease, such as a sedentary lifestyle, obesity, and metabolic syndrome. However, the relationship between ED and CV risk in Vietnam remains unknown. To investigate this, we conducted a multi-center observational study, randomly selecting 2,936 men aged 40 to 69 years in Vietnam, with 385 participants included after exclusions. The study evaluated the 10-year CV risk using the Systematic Coronary Risk Evaluation 2-Diabetes (SCORE2-Diabetes) score and assessed ED using the International Index of Erectile Function (IIEF-5) score. Results showed that men with diabetes mellitus and hypertension had significantly lower IIEF-5 scores compared to healthy individuals (18 [15–22] vs. 23 [20–24], p < 0.001). Additionally, the IIEF-5 score proved effective in identifying patients at very high CV risk, with an area under the curve (AUC) of 0.747, a cutoff point of 18.5, sensitivity of 69.6%, and specificity of 69.9%. Furthermore, we found a significant inverse correlation between SCORE2-Diabetes and IIEF-5 (ρ = -0.45 and p < 0.001). These findings establish a significant connection between ED and CV risk in men with diabetes, underscoring the need for integrated screening and management strategies to address both conditions concurrently. [ABSTRACT FROM AUTHOR]

A ready-to-use numerical model has been developed for the atomic ladder (cascade) systems which are widely exploited in Rydberg Radio Frequency (RF) sensors. The model has been explicitly designed for user convenience and to be extensible to arbitrary N-level non-thermal systems. The versatility and adaptability of the model is validated up to 4-level atomic systems by direct comparison with experimental results from the prior art. The numerical model provides a good approximation to the experimental results and provides experimentalists with a convenient ready-to-use model to optimise the operation of an N-level Rydberg RF sensor. Current sensors exploit the 4-level atomic systems based on alkali metal atoms which require visible frequency lasers and these can be expensive and also suffer from high attenuation within optical fiber. The ability to quickly and simply explore more complex N-level systems offers the potential to use cheaper and lower-loss near-infrared lasers. [ABSTRACT FROM AUTHOR]

This meta-analysis investigated therapeautic effects of laser therapies in patients with Bell's palsy (BP). The authors performed the literature search in the PubMed, Embase, and Cochrane Library databases using the following search terms: (facial paralysis OR Bell's palsy OR facial palsy OR idiopathic facial paralysis) AND (laser OR low-level laser OR photobiomodulation OR phototherapy). Relevant studies published before October 29th 2024 were identified. Randomized trials comparing the outcomes of laser therapies with other interventions, including electrical stimulation and control or usual care in patients with BP were included. The mean difference (MD) was determined as the effect size for continuous outcomes, and outcome accuracy was determined using 95% confidence intervals (CIs). Twelve studies were included, with a total of 597 patients. Nine studies were further included in the quantitative analysis. Our meta-analysis revealed that laser therapy significantly improved disease severity (House-Brackmann facial paralysis scale) (MD = −1.51, 95% CI = −2.43 to −0.59), facial asymmetry (Sunnybrook facial grading system) (MD = 20.63, 95% CI = 10.33 to 30.94), and facial function and disability (Facial disability index) (MD = 17.91, 95% CI = 5.60 to 30.22) when compared with control care in adult patients. Moreover, laser therapy significantly improved facial severity (MD = 21.05, 95% CI = 16.77 to 25.33) when compared with electrical stimulation. In addition, no adverse effects of laser therapy were reported. Laser therapy has favorable effects on disease severity, facial asymmetry, and facial function and disability for patients with BP. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type-Ia patients, deficient in the G6PC1 gene encoding glucose-6-phosphatase-α, lack blood glucose control, resulting in life-threatening hypoglycemia. Here we show our humanized mouse model, huR83C, carrying the pathogenic G6PC1-R83C variant displays the phenotype of glycogen storage disease type-Ia and dies prematurely. We evaluate the efficacy of BEAM-301, a formulation of lipid nanoparticles containing a newly-engineered adenine base editor, to correct the G6PC1-R83C variant in huR83C mice and monitor phenotypic correction through one year. BEAM-301 can correct up to ~60% of the G6PC1-R83C variant in liver cells, restores blood glucose control, improves metabolic abnormalities of the disease, and confers long-term survival to the mice. Interestingly, just ~10% base correction is therapeutic. The durable pharmacological efficacy of base editing in huR83C mice supports the development of BEAM-301 as a potential therapeutic for homozygous and compound heterozygous glycogen storage disease type-Ia patients carrying the G6PC1-R83C variant. In this mouse study, an adenine base editor shows potential as a durable therapy for glycogen storage disease type-Ia, correcting both the life-threatening lack of blood glucose control and metabolic abnormalities of this orphan disease. [ABSTRACT FROM AUTHOR]

This study examined the effectiveness of various electrical stimulation methods in alleviating symptoms and enhancing the quality of life for women with urinary incontinence. We conducted a systematic search of PubMed, Cochrane Library, PEDro, EMBASE, and ClinicalTrials.gov from inception to August 2024. Randomized controlled trials (RCTs) that meet following criteria were included, urinary continence in women, using various electric stimulation treatments and evaluated outcomes related to symptoms, quality of life. Thirty RCTs were subjected to risk of bias assessment, certainty of evidence, and network meta-analysis. Statistical analysis was performed using a random-effects model, with continuous variables expressed as standardized mean difference (SMD) and 95% confidence interval (CI). Percutaneous tibial stimulation (SMD − 1.86, 95% CI − 2.77 to − 0.96) and intravaginal stimulation (SMD − 0.97, 95% CI − 1.55 to − 0.38) significantly reduced symptom severity. Additionally, percutaneous tibial, intravaginal, transcutaneous tibial, and trans-sacral stimulations improved quality of life. Percutaneous tibial stimulation was the most effective, followed by intravaginal stimulation. Despite moderate to low confidence in the evidence, large-scale RCTs are needed to evaluate long-term benefits of these treatment. [ABSTRACT FROM AUTHOR]

Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including those linked to its formation, such as tobacco exposure, and progression, such as homologous recombination repair deficiency. Clinically, ecDNA detection was associated with tumour stage, more prevalent after targeted therapy and cytotoxic treatments, and associated with metastases and shorter overall survival. These results shed light on why ecDNA is a substantial clinical problem that can cooperatively drive tumour growth signals, alter transcriptional landscapes and suppress the immune system.A study examines the diversity of extrachromosomal DNA elements in cancer, and provides details on the frequency and origin of extrachromosomal DNA and its role in the development of different types of cancer. [ABSTRACT FROM AUTHOR]

The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently1. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division2,3. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells4. How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.Cooperative species of extrachromosomal DNAs are coordinately inherited through mitotic co-segregation. [ABSTRACT FROM AUTHOR]

Introduction: The comparison between the cementless taper wedge stem and fit-and-fill stem in total hip arthroplasty (THA) for various proximal femoral morphological types has not been thoroughly assessed. This study aimed to compare the risk of leg length discrepancy (LLD) ≥ 10 mm between these two stem types in Dorr type A, B, and C femurs. Materials and methods: From April 2015 through April 2021, we analyzed 1178 unilateral primary cementless THA procedures. We categorized all procedures into three groups: Dorr type A (N = 220, 18.7%), B (N = 875, 74.3%), and C (N = 83, 7.0%). Within each Dorr type, we compared the incidence and risk of postoperative LLD ≥ 10 mm between the two stem types. The factors considered in the multivariate regression analyses included stem type, age, sex, body mass index, diagnosis, canal flare index, femoral cortical index and stem alignment. Results: The taper wedge stem group had a higher overall incidence of LLD ≥ 10 mm (12.8% vs. 7.4%, P = 0.012) and in Dorr type A femurs (22.2% vs. 7.6%, P = 0.014), compared with the fit-and-fill stem group. In multivariate analysis, the taper wedge stem exhibited an increased risk of LLD ≥ 10 mm only in Dorr type A femurs (aOR: 3.449, 95% CI: 1.325–8.794). The incidence and risk of LLD ≥ 10 mm were not different between the two stems in Dorr type B and C femurs. Conclusions: The taper wedge stem demonstrated an elevated risk of LLD ≥ 10 mm in Dorr type A femurs compared with the fit-and-fill stem, necessitating meticulous preoperative templating and intraoperative femoral canal preparation. [ABSTRACT FROM AUTHOR]

This study introduces the fractional stochastic diffusion particle tracking model (FSD-PTM), a novel Lagrangian particle tracking model (PTM) designed to simulate stochastic suspended sediment transport by incorporating fractional Brownian motion (FBM). This FBM-based approach introduces memory into particle movements, particularly when particles are influenced by coherent turbulent structures near boundaries, such as ejection and sweep events. These coherent structures exhibit consistent motion over time, leading to correlated increments in particle movements. In scenarios unaffected by coherent structures, the FBM reverts to the Wiener process, preserving the independent increments. The FSD-PTM is applied to a steady, incompressible, fully developed two-dimensional open channel flow, and Monte Carlo simulations yield ensemble statistics results, including mean, variance, skewness of particle positions, particle velocity, and concentrations. These simulation results validate the FSD-PTM against experimental data, demonstrating its superior performance when considering correlated increments. Without such consideration, concentration profiles generated by previous PTMs fail to reach long-term equilibrium. A key innovation of the FSD-PTM is its integration of correlated motion directly within the governing stochastic differential equation (SDE), eliminating the need for additional terms. This model's flexibility also allows for the incorporation of various particle dynamic models, enhancing its utility for sediment transport analysis. The FSD-PTM represents a substantial advancement in modeling stochastic suspended sediment transport, particularly when particles' movements exhibit correlations due to surrounding turbulence. [ABSTRACT FROM AUTHOR]

Background: Limited reports have discussed the risk factors for contralateral inguinal hernia (CIH) repair. We generated a risk factor scoring system to predict CIH within 3 years after unilateral inguinal hernia repair. Methods: We extracted the admission data of patients aged ≥ 18 years who underwent primary unilateral inguinal hernia repair without any other operation from the National Health Insurance Research Database. Patients were randomly divided into 80% and 20% validation cohorts. Multivariate analysis with a logistic regression model was used to generate the scoring system, which was used in the validation group. Results: Overall, 170,492 adult men were included, with a median follow-up of 87 months. The scoring system ranged from 0–5 points, composited with age (< 45 years, 0 points; 45–65 years, 2 points; 65–80 years, 3 points; > 80 years, 2 points) and two comorbidities (cirrhosis and prostate disease: 1 point each). The areas under receiver operating characteristic (ROC) curves were 0.606 and 0.551 for the derivation and validation groups, respectively. The rates and adjusted odds ratios (OR) of CIH repair in the derivation group were 3.0% at 0–2 points, 5.5% (1.854, p < 0.001) at 3, 6.7% (2.279, p < 0.001) at 4, and 6.9% (2.348, p < 0.001) at 5, with similar results in the validation group [2.3% at 0–2 points, 3.8% (1.668, p < 0.001) at 3, 5.4% (2.386, p < 0.001) at 4, and 6.8% (3.033, p < 0.001) at 5]. Conclusions: The CIH scoring system effectively predicted CIH repair within three years of primary unilateral inguinal hernia repair. Surgeons could perform laparoscopic surgery with CIH scores > 2 points which enables easier contralateral exploration and repair during the same surgery, without additional incisions, to minimize the need for future surgeries. However, further prospective validation of this scoring system is required. [ABSTRACT FROM AUTHOR]

Background: For patients with psoriasis, discontinuation of biologics following remission has become more common in daily practice. Objective: We aimed to identify predictors and construct a predictive model for time to relapse following withdrawal from biologics. Methods: This 12-year, multicenter, observational cohort study was performed in six dermatology centers between February 2011 and February 2024. We identified biological treatment episodes in patients with moderate-to-severe psoriasis and included only treatment episodes in which a clinical response (≥ 50% reduction in Psoriasis Area and Severity Index score [PASI 50] from baseline) was achieved and the patient withdrew from biological therapy with a well-controlled status (PASI < 10 and ≥ 50% improvement in PASI from baseline). The primary outcome was time to relapse, which was defined as the period from the last biologic administration to relapse. An extended multivariate Cox proportional hazards analysis (Prentice–Williams–Peterson Gap time model) was used to predict relapse and generate a predictive model. Results: This study screened 1613 biological treatment episodes, and 991 treatment episodes were enrolled. The time to relapse decreased significantly as the number of previous withdrawals from biological treatment increased (p < 0.001). Similarly, the time to relapse decreased significantly as the number of previous biologics used increased (p < 0.001). The maximum PASI improvement during biological treatment decreased and the PASI score at withdrawal of biological treatment increased in parallel as the number of prior withdrawals from biologics increased. The time to relapse following withdrawal was longest for interleukin (IL)-23 inhibitors (IL-23i), followed by the IL-12/23i, IL-17 inhibitors (IL-17i), and tumor necrosis factor-α inhibitors. After adjustment, multivariate Cox regression identified the following significant predictors of relapse following withdrawal: the mechanisms of action of biologics (hazard ratio [HR] for IL-17i vs IL-12/23i, 1.59; HR for IL-23i vs IL-12/23i, 0.60), number of previous withdrawals from biological treatment (HR 1.23; 95% confidence interval [CI] 1.13‒1.33), time to achieve PASI 50 (HR 1.01; 95% CI 1.00‒1.02), maximum PASI improvement on biologics (HR 0.98; 95% CI 0.98‒0.99), and PASI at the end of therapy (HR 1.03; 95% CI 1.01‒1.05). The model had good predictive and discriminative ability. Conclusions: These results have the potential to help physicians and patients make individualized treatment decisions; information on the risk of relapse of psoriasis at specific timepoints following the withdrawal of biologics is particularly valuable for patients considering discontinuation of biologics or as-needed biologic therapy. However, the benefit and risk of repeated withdrawals of biologics should be carefully weighed, as the treatment efficacy and duration of remission decline as the number of withdrawals increases. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) are rarely used to treat advanced pancreatic ductal adenocarcinoma (PDAC) due to marginal efficacy. Patients and methods: This study included 92 consecutive patients diagnosed with advanced or recurrent PDAC who received nivolumab-based treatment. Univariate and multivariate analyses were used to identify prognostic factors. A control group of 301 patients with PDAC who achieved disease control with palliative chemotherapy but without ICIs was selected for comparison using propensity score matching (PSM). Results: The median overall survival (OS) since nivolumab treatment was 15.8 (95% confidence interval [CI], 12.5–19.0), 2.4 (95% CI 1.2–3.6), and 1.1 (95% CI 1.0–1.2) months in patients who received add-on nivolumab after achieving disease control with chemotherapy, in those who received concomitant nivolumab and chemotherapy without prerequisite confirmation of disease control, and in those who received nivolumab without concomitant chemotherapy, respectively (P < 0.001). After PSM, the median overall survival (OS) since initiation of the concomitant chemotherapy that achieved disease control was significantly longer (P = 0.026) in patients who received add-on nivolumab (19.8 months; 95% CI 14.5–25.1) than in those who received chemotherapy alone (13.8 months; 95% CI 10.8–16.9). The immune profiling of the tumors in resected patients revealed higher scores of CD8+ T cells to Tregs in patients with add-on nivolumab comparing to those who received chemotherapy alone. Conclusion: Adding-on nivolumab was associated with improved OS in patients with advanced PDAC who achieved disease control following chemotherapy. [ABSTRACT FROM AUTHOR]

This paper aims to propose a more efficient control algorithm for improving the control performance of uncertain nonlinear systems. A novel improved Takagi–Sugeno–Kang (TSK) wavelet type-2 fuzzy brain emotional learning controller (ITSKWT2FBC) is proposed. The proposed ITSKWT2FBC contains a brain emotional learning controller (BELC) combined with an improved TSK wavelet type-2 fuzzy system. By taking the advantages of BELC and the improved wavelet type-2 TSK fuzzy system, the control performance of this controller can be improved. The adaptive laws of controller parameters are derived from the defined Lyapunov function and gradient descent method. Moreover, the system stability can be guaranteed based on the Lyapunov stability theory. Finally, three nonlinear systems, a double inverted pendulum system, a Mackey–Glass time series prediction (TSP) and a four dimensional (4D) chaotic system synchronization are simulated to illustrate the effectiveness of the proposed method. The simulation results have demonstrated the effectiveness of the developed method. [ABSTRACT FROM AUTHOR]