Oxygen reserve index versus conventional peripheral oxygen saturation for prevention of hypoxaemia: A randomised controlled trial.

BACKGROUND: Hypoxaemia occurs frequently during paediatric laryngeal microsurgery. OBJECTIVE: The oxygen reserve index is a noninvasive and continuous parameter to assess PaO2 levels in the range of 100 to 200 mmHg. It ranges from 0 to 1.0. We investigated whether monitoring the oxygen reserve index can reduce the incidence of SpO2 90% or less. DESIGN: Randomised controlled trial. SETTING: A tertiary care paediatric hospital. PARTICIPANTS: Paediatric patients aged 18 years or less scheduled to undergo laryngeal microsurgery. INTERVENTION: The patients were randomly allocated to the oxygen reserve index or control groups, and stratified based on the presence of a tracheostomy tube. Rescue intervention was performed when the oxygen reserve index was 0.2 or less and the SpO2 was 94% or less in the oxygen reserve index and control groups, respectively. MAIN OUTCOME MEASURE: The primary outcome was the incidence of SpO2 90% or less during the surgery. RESULTS: Data from 88 patients were analysed. The incidence of SpO2 ≤ 90% did not differ between the oxygen reserve index and control groups [P = 0.114; 11/44, 25% vs. 18/44, 40.9%; relative risk: 1.27; and 95% confidence interval (CI): 0.94 to 1.72]. Among the 128 rescue interventions, SpO2 ≤ 90% event developed in 18 out of 75 events (24%) and 42 out of 53 events (79.2%) in the oxygen reserve index and control groups, respectively (P < 0.001; difference: 55.2%; and 95% CI 38.5 to 67.2%). The number of SpO2 ≤ 90% events per patient in the oxygen reserve index group (median 0, maximum 3) was less than that in the control group (median 0, maximum 8, P = 0.031). CONCLUSION: Additional monitoring of the oxygen reserve index, with a target value of greater than 0.2 during paediatric airway surgery, alongside peripheral oxygen saturation, did not reduce the incidence of SpO2 ≤ 90%.

Systemic Brain Delivery of Oligonucleotide Therapeutics Enhanced by Protein Corona-Assisted DNA Cubes.

The systemic delivery of oligonucleotide therapeutics to the brain is challenging but highly desirable for the treatment of brain diseases undruggable with traditional small-molecule drugs. In this study, a set of DNA nanostructures is prepared and screened them to develop a protein corona-assisted platform for the brain delivery of oligonucleotide therapeutics. The biodistribution analysis of intravenously injected DNA nanostructures reveals that a cube-shaped DNA nanostructure (D-Cb) can penetrate the brain-blood barrier (BBB) and reach the brain tissue. The brain distribution level of D-Cb is comparable to that of other previous nanoparticles conjugated with brain-targeting ligands. Proteomic analysis of the protein corona formed on D-Cb suggests that its brain distribution is driven by endothelial receptor-targeting ligands in the protein corona, which mediate transcytosis for crossing the BBB. D-Cb is subsequently used to deliver an antisense oligonucleotide (ASO) to treat glioblastoma multiforme (GBM) in mice. While free ASO is unable to reach the brain, ASO loaded onto D-Cb is delivered efficiently to the brain tumor region, where it downregulates the target gene and exerts an anti-tumor effect on GBM. D-Cb is expected to serve as a viable platform based on protein corona formation for systemic brain delivery of oligonucleotide therapeutics.

Performance of ChatGPT on Solving Orthopedic Board-Style Questions: A Comparative Analysis of ChatGPT 3.5 and ChatGPT 4.

Background: The application of artificial intelligence and large language models in the medical field requires an evaluation of their accuracy in providing medical information. This study aimed to assess the performance of Chat Generative Pre-trained Transformer (ChatGPT) models 3.5 and 4 in solving orthopedic board-style questions. Methods: A total of 160 text-only questions from the Orthopedic Surgery Department at Seoul National University Hospital, conforming to the format of the Korean Orthopedic Association board certification examinations, were input into the ChatGPT 3.5 and ChatGPT 4 programs. The questions were divided into 11 subcategories. The accuracy rates of the initial answers provided by Chat GPT 3.5 and ChatGPT 4 were analyzed. In addition, inconsistency rates of answers were evaluated by regenerating the responses. Results: ChatGPT 3.5 answered 37.5% of the questions correctly, while ChatGPT 4 showed an accuracy rate of 60.0% (p < 0.001). ChatGPT 4 demonstrated superior performance across most subcategories, except for the tumor-related questions. The rates of inconsistency in answers were 47.5% for ChatGPT 3.5 and 9.4% for ChatGPT 4. Conclusions: ChatGPT 4 showed the ability to pass orthopedic board-style examinations, outperforming ChatGPT 3.5 in accuracy rate. However, inconsistencies in response generation and instances of incorrect answers with misleading explanations require caution when applying ChatGPT in clinical settings or for educational purposes.

Pharmacoacupuncture for the Treatment of Frozen Shoulder: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Pharmacoacupuncture (PA) is an alternative injection therapy for a broad range of conditions. This meta-analysis evaluates the effectiveness and safety of PA in treating frozen shoulder (FS) and aims to standardise PA characteristics in clinical practice. METHODS: Randomized controlled trials (RCTs) assessing PA for FS were systematically reviewed from seven electronic databases up to August 31, 2023. Outcomes measured included the visual analogue scale (VAS) or numerical rating scale (NRS), effective rate, Constant-Murley Score (CMS), Shoulder Pain and Disability Index (SPADI), ROM, quality of life (QoL), and adverse events. Data analysis was conducted using RevMan 5.3, with the risk of bias in each trial evaluated using Cochrane's risk of bias tool. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool assessed the quality of evidence. RESULTS: Thirteen RCTs involving 1034 patients met the inclusion criteria, with eleven RCTs and 872 patients included in the meta-analysis. PA showed low-quality evidence of improvement in VAS, effective rate, CMS Total, and CMS Pain. Moderate-quality evidence indicated improvement in CMS ADL and CMS Mobility. PA was effective in four SF-36 subscales: physical function, social role function, mental health, and emotional role function. No significant difference in CMS strength was observed. One trial reported mild anaphylaxis reaction to bee venom as an adverse event. CONCLUSION: PA may offer potential benefits as an alternative injection therapy for FS patients. Further well-designed RCTs with rigorous methodology are required to substantiate its therapeutic efficacy and clinical utility. REGISTRATION: PROSPERO (CRD42023445708).

Decreased Serum Cocaine- and Amphetamine-Regulated Transcript Level in Internet Gaming Disorder.

OBJECTIVE: Vulnerability to internet gaming disorder (IGD) has increased as internet gaming continues to grow. Cocaine- and amphetamine-regulated transcript (CART) is a hormone that plays a role in reward, anxiety, and stress. The purpose of this study was to identify the role of CART in the pathophysiology of IGD. METHODS: The serum CART levels were measured by enzyme-linked immunosorbent assay, and the associations of the serum CART level with psychological variables were analyzed in patients with IGD (n=31) and healthy controls (HC) (n=42). RESULTS: The serum CART level was significantly lower in the IGD than HC group. The IGD group scored significantly higher than the HC group on the psychological domains of depression, anxiety, the reward response in the Behavioral Activation System and Behavioral Inhibition System. There were no significant correlations between serum CART level and other psychological variables in the IGD group. CONCLUSION: Our results indicate that a decrease in the expression of the serum CART level is associated with the vulnerability of developing IGD. This study supports the possibility that CART is a biomarker in the pathophysiology of IGD.

Evaluation of NAD+ precursors for improved metabolism and productivity of antibody-producing CHO cell.

In the previous study, the culture medium was treated with nicotinamide adenine dinucleotide (NAD+) under the hypothesis that NAD+ regeneration is a major factor causing excessive lactate accumulation in Chinese hamster ovary (CHO) cells. The NAD+ treatment improved metabolism by not only reducing the Warburg effect but also enhancing oxidative phosphorylation, leading to enhanced antibody production. Building on this, four NAD+ precursors - nicotinamide mononucleotide (NMN), nicotinic acid (NA), nicotinamide riboside (NR), and nicotinamide (NAM) - were tested to elevate intracellular NAD+ levels more economically. First, the ability of CHO cells to utilize both the salvage and Preiss-Handler pathways for NAD+ biosynthesis was verified, and then the effect of NAD+ precursors on CHO cell cultures was evaluated. These precursors increased intracellular NAD+ levels by up to 70.6% compared to the non-treated group. Culture analysis confirmed that all the precursors induced metabolic changes and that NMN, NA, and NR improved productivity akin to NAD+ treatment, with comparable integral viable cell density. Despite the positive effects such as the increase in the specific productivity and changes in cellular glucose metabolism, none of the precursors surpassed direct NAD+ treatment in antibody titer, presumably due to the reduction in nucleoside availability, as evidenced by the decrease in ATP levels in the NAD+ precursor-treated groups. These results underscore the complexity of cellular metabolism as well as the necessity for further investigation to optimize NAD+ precursor treatment strategies, potentially with the supplementation of nucleoside precursors. Our findings suggest a feasible approach for improving CHO cell culture performances by using NAD+ precursors as medium and feed components for the biopharmaceutical production.

The effect of aroma lymphatic tressage on taxane-induced lower-extremity edema in breast cancer patients.

BACKGROUND: Taxanes are effective chemotherapy drugs for breast cancer care, but adverse effects pose a significant challenge in cancer treatment. Taxane-induced fluid retention and lower-extremity edema are two of the important dose-limiting toxicity and result in decreased quality of life (QoL). However, there is no standard of care to alleviate the symptoms. We conducted a clinical study to assess the efficacy of short-term aroma lymphatic tressage therapy (ALTT) in reducing taxane-induced edema in breast cancer patients. METHODS: In this phase 2 clinical trial, patients with edema of CTCAE grade 2 or higher were enrolled and conducted 8 sessions of ALTT. The primary endpoint was to determine the proportion of patients with a reduction in lower extremity circumference of 3% or more before and 6 weeks after starting ALTT. The change in QoL was assessed as the secondary endpoint using QoL questionnaires. RESULTS: A total of 37 breast cancer patients completed the protocol and were analyzed. The median sum of the 3-point circumference (thigh, calf, and ankle) was 230.8 cm (IQR 218-243) in the baseline and 220.2 cm (IQR 212-236) at the end of the study. The average decrease of circumference was 3.8%. About, 23 patients (62%) experienced a circumference decrease of 3% or more. An improvement in every scale of FACT-TAXANE and EORTC-QLQ-C30 was observed when comparing questionnaire results before and at the end of the intervention (P < 0.0001). CONCLUSION: Eight sessions of ALTT over 4 weeks were effective in reducing lower-extremity edema and resulted in improvement of QoL in patients with breast cancer.

Efficacy and safety of a new torque-controlled angiographic catheter in cerebral angiography: A multicenter, randomized, open-label trial.

Objective: We aimed to examine the effectiveness and safety of a novel torque-controlled catheter for cerebral angiography. Methods: A total of 417 patients who underwent routine transfemoral cerebral angiography were enrolled in a randomized controlled study to compare the new torque-controlled and control group catheters. Device success was assessed on parameters such as the assessment of the common carotid artery, device rotation force, and success rate with the crossover group after the failed procedure. Four neurointerventionalists investigated the degree of satisfaction of using the new device. Superiority and non-inferiority tests of satisfaction scores were estimated for the new torque-controlled and the control group catheters. Results: The new torque-controlled catheter showed improved performance in terms of technical device success (92.79 vs. 98.09 %, P = 0.010), crossover after technical device failure (0 vs. 86.67 %, P = 0.004), and common carotid artery access (92.79 vs. 98.56 %, P = 0.004). The flexibility and rotational force of the new torque-controlled catheter were higher than those of the control group catheters (75.48 vs. 100 %, P < 0.001). No marked adverse cerebrovascular accidents or vessel damage occurred in either group during the procedure. The differences between the two groups in terms of the device rotational force and operator satisfaction were 1.836 (1.765-1.907) and 2.092 (2.000-2.183), respectively. The new torque-controlled catheter showed superior device rotational force satisfaction, operator satisfaction, and manufacturer satisfaction, with statistical significance. Conclusion: The new torque-controlled catheter was effective, safe, and convenient compared to the control group catheters for diagnostic cerebrovascular angiography.

Association between carbohydrate to protein or fat ratio and mortality: A prospective cohort study.

BACKGROUND & AIMS: The effect of dietary macronutrient balance on longevity and metabolic health remains a subject of considerable interest. We aimed to investigate the association of carbohydrate-to-protein and carbohydrate-to-fat ratios with all-cause and cardiovascular mortalities. METHODS: In this population-based study, data from the Korean Genome and Epidemiology Study were integrated with those from national data sources, including mortality records from the Korea National Statistical Office. The primary outcomes were all-cause and cardiovascular mortalities. Carbohydrate-to-protein and carbohydrate-to-fat ratios were evaluated based on dietary habits assessed through a food frequency questionnaire. Harrell's C-index was employed to determine optimal cut-off points for carbohydrate-to-protein and carbohydrate-to-fat ratios. Cox proportional hazards regression models were used to assess associations. RESULTS: A total of 143,050 participants aged ≥40 years were included in the analyses. Compared with individuals with non-elevated carbohydrate-to-protein ratios (<5.2), those with elevated carbohydrate-to-protein ratios (>9.9) exhibited a higher all-cause mortality (hazard ratio 1.09, 95% confidence interval 1.01-1.17); however, no correlation between carbohydrate-to-protein ratio and cardiovascular mortality (hazard ratio 1.13, 95% confidence interval 0.96-1.32) was observed. Compared with those with non-elevated carbohydrate-to-fat ratios (<5.1), those with higher carbohydrate-to-fat ratios (>7.1) exhibited increased all-cause (hazard ratio 1.08, 95% confidence interval 1.00-1.16) and cardiovascular (hazard ratio 1.27, 95% confidence interval 1.06-1.52) mortalities. CONCLUSIONS: Our findings regarding macronutrient ratios and their association with mortality suggest that reducing excessive carbohydrate intake and increasing the consumption of protein and fats may have beneficial effects on longevity and cardiovascular health. Further studies are needed to understand the underlying mechanisms of these effects.

Studying the Pulmonary Endothelium in Health and Disease. An Official American Thoracic Society Workshop Report.

Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. Endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the arterial-to-capillary-to-vein axis. While our understanding of mechanisms that contribute to endothelial cell injury and repair in acute and chronic vascular disease have advanced, pathophysiological mechanisms that underlie site-specific vascular disease remain incompletely understood. In an effort to improve the translatability of mechanistic studies of the endothelium, the American Thoracic Society convened a workshop to optimize rigor, reproducibility, and translation of discovery to advance our understanding of endothelial cell function in health and disease.

Impact of the COVID-19 pandemic on the financial performance of hospitals according to hospital characteristics in Korea: An observational study.

The coronavirus disease-19 (COVID-19) pandemic had a profound effect on society and various industries. Moreover, hospitals experienced huge financial losses owing to COVID-19 prevention efforts. This study aims not only to comprehensively inspect the financial impact of the pandemic on Korean hospitals but also to consider financial performance by hospital characteristics. Data were collected from 255 general hospitals that uploaded their income statements on the website, and 1530 data points were collected from 2016 to 2021. We used the paired t-test, linear mixed-effects (LME) model in R software (Ver. 4.3.2). We then selected operating margin ratio (OMR) and total margin ratio (TMR) to measure financial performance and used location, type of hospital, and ownership as hospital characteristics. We found that OMR and TMR worsened after COVID-19 breakout, and the labor and management cost ratios increased. According to the LME model with hospital characteristics, the OMR of hospitals located in the capital area worsened more than that of hospitals in noncapital areas (ß5 = -6.3, P < .01). Regarding type of hospitals, tertiary general hospitals maintained a surplus and recorded a better OMR than general hospitals during the pandemic (ß6 = 9.5, P < .01). The OMR of public hospitals worsened more than that of private hospitals during the pandemic (ß7 = -25.4, P < .01), but the TMR of public hospitals increased compared to that of private hospitals (ß7 = 3.9, P < .01). We confirmed that the COVID-19 pandemic had a negative impact on the financial status of hospitals. Considering hospital characteristics, the impact of the pandemic on hospital financial performance differed based on location, type of hospital, and ownership. As the contributions of this study, the government could establish support policies such as government subsidies based on hospital characteristics and hospital administrators could set a contingency plan to mitigate national disasters.

Impact of permanent pacemaker for iatrogenic atrioventricular block on outcomes after congenital heart surgery.

OBJECTIVE: The need for permanent pacemaker (PPM) for iatrogenic atrioventricular block (AVB) after congenital heart surgery is about 1%. We aim to evaluate the long-term outcomes of patients with PPM for iatrogenic AVB and compare them to patients with an optimal repair (trivial/no residua)- Residual Lesion Score (RLS) Class-1 repair without PPM need. METHODS: We reviewed 183 patients discharged with PPM for iatrogenic AVB from 2011 to 2022. Patients who survived to discharge with >30 days of follow-up were matched 1:1 with a cohort of RLS Class-1 patients based on fundamental diagnosis and primary procedure. RESULTS: Median age at PPM placement was 1.4 years (IQR: 4.3 months - 3.9 years). The cumulative incidence of moderate or greater ventricular dysfunction at 1 year and 5 years was 11% and 18% in PPM patients, respectively, compared to 3% and 7% in RLS Class-1 patients (subdistribution HR, 2.6; 95% CI, 1.2-6.1; P =0.022). Independently, PPM patients with hypoplastic left heart syndrome (P =0.027) and who had undergone STAT Mortality Category 5 procedures (P =0.033) were at higher risk of ventricular dysfunction. Transplant-free survival at 1 year and 5 years was 94% and 89% in PPM patients, respectively, compared to 98% and 97% in RLS Class-1 patients (P =0.044). Additionally, PPM patients with palliated circulation had significantly lower transplant-free survival (P <0.001). CONCLUSIONS: Compared to patients with an optimal repair without PPM, patients with PPM for iatrogenic AVB are at higher risk of developing moderate or greater ventricular dysfunction and have lower transplant-free survival.

Development of a media cell-free DNA direct digital PCR method for cell viability estimation.

BACKGROUND: Accurate estimation of cell viability is crucial in various applications such as cytotoxicity testing and routine cell culture on both industrial and laboratory scales. For this, the real-time monitoring of cell status would be beneficial. Conventional cell-based assays for cell viability have limitations in sensitivity and time-effectiveness. Analysis of cell-free DNA (cfDNA) in (culture) media is a good alternative as cfDNA release are a well-known phenomenon during cell death. RESULTS: We demonstrate a direct digital PCR (dPCR) method to estimate cell viability by analyzing cfDNA in media during induced cell death. After validating the duplex dPCR method for short and long amplicons of the SMAD4 and RPP30 loci, we determined that a media volume of 2 µL is feasible to measure the target DNA copy number with minimal negative effects on amplification. dPCR inhibition was evident with a higher media volume per reaction targeting long amplicons. Next, we applied our dPCR method using media cfDNA and other conventional methods to the monitoring of camptothecin (CPT)-induced cell death. Copy numbers increased significantly after 4 h of CPT treatment, showing a fold change of approximately 4-6 compared to the controls. Cell-based assays such as the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay and annexin V/7-AAD assay also indicated increased cell death at 4 h, but the trypan blue exclusion assay did not. SIGNIFICANCE: The developed media cfDNA direct dPCR method allows for efficient measurements of the degree of cell viability. Unlike other conventional cell-based assays, our method has advantages of no loss of cultured cells and the ability to implement online analysis. Accurate and sensitive media cfDNA analysis using dPCR can be adopted in various applications such as determining cytotoxicity levels in large-scale bioreactors or screening for effective anticancer drugs.

Genetic Deletion of Skeletal Muscle Inositol Polyphosphate Multikinase Disrupts Glucose Homeostasis and Impairs Exercise Tolerance.

Inositol phosphates are critical signaling messengers involved in a wide range of biological pathways in which inositol polyphosphate multikinase (IPMK) functions as a rate-limiting enzyme for inositol polyphosphate metabolism. IPMK has been implicated in cellular metabolism, but its function at the systemic level is still poorly understood. Since skeletal muscle is a major contributor to energy homeostasis, we have developed a mouse model in which skeletal muscle IPMK is specifically deleted and examined how a loss of IPMK affects whole-body metabolism. Here, we report that mice in which IPMK knockout is deleted, specifically in the skeletal muscle, displayed an increased body weight, disrupted glucose tolerance, and reduced exercise tolerance under the normal diet. Moreover, these changes were associated with an increased accumulation of triglyceride in skeletal muscle. Furthermore, we have confirmed that a loss of IPMK led to reduced beta-oxidation, increased triglyceride accumulation, and impaired insulin response in IPMK-deficient muscle cells. Thus, our results suggest that IPMK mediates the whole-body metabolism via regulating muscle metabolism and may be potentially targeted for the treatment of metabolic syndromes.

Impact of the Korea Early Childhood Home-visiting Intervention (KECHI) on child health and development and maternal health: a randomised controlled trial protocol.

INTRODUCTION: Randomised controlled trials (RCTs) of early childhood home-visiting interventions led by nurses have been conducted mainly in Western countries, whereas such trials have been limited in non-Western cultures, including Asia. In South Korea, a national nurse home visit programme (Korea Early Childhood Home-visiting Intervention (KECHI)) was developed in 2020 and launched throughout the country. We designed a pragmatic RCT to evaluate the effectiveness of KECHI on child health and development and maternal health. METHODS AND ANALYSIS: Eligible participants will be pregnant women at <37 weeks of gestation with risk factor scores of 2 or over, who are sufficiently fluent in Korean to read and answer the questionnaire written in Korean and live in districts where the KECHI services are available. Eight hundred participants will be recruited from the general community and through the District Public Health Centres. The participants will be randomised 1:1 to KECHI plus usual care or usual care. KECHI encompasses 25-29 home visits, group activities and community service linkage. Participants will complete assessments at baseline (<37 weeks gestation), 6 weeks, 6 months, 12 months, 18 months and 24 months post partum. The six primary outcomes will be (1) home environment (assessed by Infant/Toddler Home Observation for Measurement of the Environment), (2) emergency department visits due to injuries, (3) child development (assessed using Korean Bayley Scales of Infant and Toddler Development-III), (4) breastfeeding duration, (5) maternal self-rated health and (6) community service linkage. ETHICS AND DISSEMINATION: This trial has received full ethical approval from the Institutional Review Board of the Seoul National University Hospital. Written consent will be obtained from the participants. The results will be reported at conferences, disseminated through peer-reviewed publications and used by the Korean government to expand the KECHI services. TRIAL REGISTRATION NUMBER: NCT04749888.

Enhanced phagocytosis associated with multinucleated microglia via Pyk2 inhibition in an acute ß-amyloid infusion model.

Multinucleated microglia have been observed in contexts associated with infection, inflammation, and aging. Though commonly linked to pathological conditions, the larger cell size of multinucleated microglia might enhance their phagocytic functions, potentially aiding in the clearance of brain debris and suggesting a reassessment of their pathological significance. To assess the phagocytic capacity of multinucleated microglia and its implications for brain debris clearance, we induced their formation by inhibiting Pyk2 activity using the pharmacological inhibitor PF-431396, which triggers cytokinesis regression. Multinucleated microglia demonstrate enhanced phagocytic function, as evidenced by their increased capacity to engulf ß-amyloid (Aß) oligomers. Concurrently, the phosphorylation of Pyk2, induced by Aß peptide, was diminished upon treatment with a Pyk2 inhibitor (Pyk2-Inh, PF-431396). Furthermore, the increased expression of Lamp1, a lysosomal marker, with Pyk2-inh treatment, suggests an enhancement in proteolytic activity. In vivo, we generated an acute Alzheimer's disease (AD) model by infusing Aß into the brains of Iba-1 EGFP transgenic (Tg) mice. The administration of the Pyk2-Inh led to an increased migration of microglia toward amyloid deposits in the brains of Iba-1 EGFP Tg mice, accompanied by morphological activation, suggesting a heightened affinity for Aß. In human microglia, lipopolysaccharide (LPS)-induced inflammatory responses showed that inhibition of Pyk2 signaling significantly reduced the transcription and protein expression of pro-inflammatory markers. These results suggest that Pyk2 inhibition can modulate microglial functions, potentially reducing neuroinflammation and aiding in the clearance of neurodegenerative disease markers. This highlights Pyk2 as a promising target for therapeutic intervention in neurodegenerative diseases.

Highly conductive, stretchable, and biocompatible graphene oxide biocomposite hydrogel for advanced tissue engineering.

The importance of hydrogels in tissue engineering cannot be overemphasized due to their resemblance to the native extracellular matrix (ECM). However, natural hydrogels with satisfactory biocompatibility exhibit poor mechanical behavior, which hampers their application in stress-bearing soft tissue engineering. Here, we describe the fabrication of a double methacrylated gelatin bioink covalently linked to graphene oxide (GO) via a zero-length crosslinker, digitally light-processed (DLP) printable into 3D complex structures with high fidelity. The resultant natural hydrogel (GelGOMA) exhibits a conductivity of 15.0 S m-1 as a result of the delocalization of the π-orbital from the covalently linked GO. Furthermore, the hydrogel shows a compressive strength of 1.6 MPa, and a 2.0 mm thick GelGOMA can withstand a 1.0 kg ms­1 momentum. The printability and mechanical properties of GelGOMA were demonstrated by printing a fish heart with a functional fluid pumping mechanism and tricuspid valves. Its biocompatibility, electroconductivity, and physiological relevance enhanced the proliferation and differentiation of myoblasts and neuroblasts and the contraction of hiPSC-derived cardiomyocytes. GelGOMA demonstrates the potential for the tissue engineering of functional hearts and wearable electronic devices. .

Association of TP53 Mutation Status and Sex with Clinical Outcome in NSCLC Treated with Immune Checkpoint Inhibitors: A Retrospective Cohort Study.

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC. Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed. Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT. Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Broad-Spectrum Antiviral Agents against SARS-CoV-2 Variants Inhibit the Conserved Viral Protein Nsp1-RNA Interaction.

The ongoing global threats posed by COVID-19 pandemic, catalyzed by SARS-CoV-2, underscores the pressing need for effective antiviral strategies. The viral non-structural protein 1 (Nsp1) significantly influences pathogenicity by impeding host protein expression and enhancing viral RNA translation through its interaction with the stem-loop 1 (SL1) in the 5' untranslated region (UTR). We have developed a novel dual-luciferase reporter assay, designed to investigate the critical Nsp1-SL1 interaction, and identified P23E02 as a potential inhibitor. Our investigation, combining molecular docking studies and alanine mutagenesis, has unveiled that P23E02 disrupts Nsp1-40S ribosomal subunit interaction, liberating translational inhibition and empowering host antiviral responses. P23E02 exhibits antiviral efficacy against various sarbecoviruses, making it a promising candidate for combatting COVID-19 and related diseases. This study underscores the therapeutic potential of targeting the Nsp1/SL1 axis and lays the foundation for innovative antiviral interventions, ultimately fortifying global preparedness against future viral threats.

Corrosion behavior of Ti-Pt-coated stainless steel for bipolar plates in polymer electrolyte membranes under water electrolysis conditions.

In this study, the corrosion behavior and degradation mechanism of Ti-Pt-coated stainless steel bipolar plates were investigated through electrochemical tests and surface analysis in a polymer electrolyte membrane water electrolysis (PEMWE) operating environment. The coated bipolar plate has a corrosion current density of only 1.68 × 10-8 A/cm2, which is an order of magnitude lower than that of the bare SS316L substrate (1.94 × 10-7 A/cm2), indicating that its corrosion resistance is superior to that of bare SS316L substrate. However, in the PEMWE operating environment, the protection efficiency of the coating and the corrosion resistance of the coated bipolar plate decreased. The degradation of the coated bipolar plate can be attributed to electrolyte penetration into the blistering areas of the coating layer with micro voids. Defects in the coating layer occur because of the pressure of oxygen gas generated within the coating layer under high-potential conditions, thereby exposing the substrate to the electrolyte and corrosion.