Ranolazine effects on exercise tolerance and angina frequency in Taiwanese stable angina: A bridging study of the CARISA randomized trial.

BACKGROUND: The effectiveness of Ranolazine on chronic angina had been proved and launched in the United States. This study aimed to determine whether add-on Ranolazine could also be effective in Taiwanese population with persisting angina symptoms despite taking conventional antianginal agents. METHODS: This is a multi-center, randomized, parallel, double-blind comparative study. The endpoint is to compare the change from the baseline of the exercise treadmill test (ETT) performing duration between add-on ranolazine and placebo at week 12. RESULTS: 46 patients were evaluable for the efficacy and safety endpoints. The mean change from baseline in ETT duration at week 12 was increased in the treatment and control group, and their mean difference was 20.8 s. All data in the Taiwanese population was like those in the CARISA study (24.0 s). The safety evaluation revealed that patients were tolerable to the add-on ranolazine therapy. The AE incidence for both ranolazine and placebo was 34.8%. The data were comparable to the past studies despite the limited statistical power. CONCLUSION: The add-on ranolazine therapy shows the potential to raise the exercise performance and tolerance of patients with chronic angina.

Tumour cell-released autophagosomes promote lung metastasis by upregulating PD-L1 expression in pulmonary vascular endothelial cells in breast cancer.

PURPOSE: Establishing an immunosuppressive premetastatic niche (PMN) in distant organs is crucial for breast cancer metastasis. Vascular endothelial cells (VECs) act as barriers to transendothelial cell migration. However, the immune functions of PMNs remain unclear. Tumour cell-released autophagosomes (TRAPs) are critical modulators of antitumour immune responses. Herein, we investigated the mechanism through which TRAPs modulate the immune function of pulmonary VECs in lung PMN in breast cancer. METHODS: Immortalised mouse pulmonary microvascular endothelial cells were incubated with TRAPs in vitro. RNA sequencing, flow cytometry, and western blotting were employed to assess immunosuppressive function and mechanism. In vivo, TRAP-trained and autophagy-deficient tumour mice were used to detect immunosuppression, and high-mobility group box 1 (HMGB1)-deficient TRAP-trained and TLR4 knockout mice were utilised to investigate the underlying mechanisms of pulmonary VECs. Additionally, the efficacy of anti-programmed cell death ligand-1 (PD-L1) immunotherapy was evaluated in early tumour-bearing mice. RESULTS: HMGB1 on TRAPs surfaces stimulated VECs to upregulate PD-L1 via a TLR4-MyD88-p38/STAT3 signalling cascade that depended on the cytoskeletal movement of VECs. Importantly, PD-L1 on TRAP-induced VECs can inhibit T cell function, promote lung PMN immunosuppression, and result in more pronounced lung metastasis. Treatment with anti-PD-L1 reduces lung metastasis in early stage tumour-bearing mice. CONCLUSIONS: These findings revealed a novel role and mechanism of TRAP-induced immunosuppression of pulmonary VECs in lung PMN. TRAPs and their surface HMGB1 are important therapeutic targets for reversing immunosuppression, providing a new theoretical basis for the treatment of early stage breast cancer using an anti-PD-L1 antibody.

A Rare Noncoding Enhancer Variant in SCN5A Contributes to the High Prevalence of Brugada Syndrome in Thailand.

BACKGROUND: Brugada syndrome (BrS) is a cardiac arrhythmia disorder that causes sudden death in young adults. Rare genetic variants in the SCN5A gene encoding the Nav1.5 sodium channel and common noncoding variants at this locus are robustly associated with the condition. BrS is particularly prevalent in Southeast Asia but the underlying ancestry-specific factors remain largely unknown. METHODS: Genome sequencing of BrS probands and population-matched controls from Thailand was performed to identify rare noncoding variants at the SCN5A-SCN10A locus that were enriched in patients with BrS. A likely causal variant was prioritized by computational methods and introduced into human induced pluripotent stem cell (hiPSC) lines using CRISPR-Cas9. The effect of the variant on SCN5A expression and Nav1.5 sodium channel current was then assessed in hiPSC-derived cardiomyocytes (hiPSC-CMs). RESULTS: A rare noncoding variant in an SCN5A intronic enhancer region was highly enriched in patients with BrS (detected in 3.9% of cases with a case-control odds ratio of 45.2). The variant affects a nucleotide conserved across all mammalian species and predicted to disrupt a Mef2 transcription factor binding site. Heterozygous introduction of the enhancer variant in hiPSC-CMs caused significantly reduced SCN5A expression from the variant-containing allele and a 30% reduction in Nav1.5-mediated sodium current density compared with isogenic controls, confirming its pathogenicity. Patients with the variant had severe phenotypes, with 89% experiencing cardiac arrest. CONCLUSIONS: This is the first example of a functionally validated rare noncoding variant at the SCN5A locus and highlights how genome sequencing in understudied populations can identify novel disease mechanisms. The variant partly explains the increased prevalence of BrS in this region and enables the identification of at-risk variant carriers to reduce the burden of sudden cardiac death in Thailand.

External Validation and Comparison of Statistical and Machine Learning-Based Models in Predicting Outcomes Following Out-of-Hospital Cardiac Arrest: A Multicenter Retrospective Analysis.

BACKGROUND: The aim of this study was to validate and compare the performance of statistical (Utstein-Based Return of Spontaneous Circulation and Shockable Rhythm-Witness-Age-pH) and machine learning-based (Prehospital Return of Spontaneous Circulation and Swedish Cardiac Arrest Risk Score) models in predicting the outcomes following out-of-hospital cardiac arrest and to assess the impact of the COVID-19 pandemic on the models' performance. METHODS AND RESULTS: This retrospective analysis included adult patients with out-of-hospital cardiac arrest treated at 3 academic hospitals between 2015 and 2023. The primary outcome was neurological outcomes at hospital discharge. Patients were divided into pre- (2015-2019) and post-2020 (2020-2023) subgroups to examine the effect of the COVID-19 pandemic on out-of-hospital cardiac arrest outcome prediction. The models' performance was evaluated using the area under the receiver operating characteristic curve and compared by the DeLong test. The analysis included 2161 patients, 1241 (57.4%) of whom were resuscitated after 2020. The cohort had a median age of 69.2 years, and 1399 patients (64.7%) were men. Overall, 69 patients (3.2%) had neurologically intact survival. The area under the receiver operating characteristic curves for predicting neurological outcomes were 0.85 (95% CI, 0.83-0.87) for the Utstein-Based Return of Spontaneous Circulation score, 0.82 (95% CI, 0.81-0.84) for the Shockable Rhythm-Witness-Age-pH score, 0.79 (95% CI, 0.78-0.81) for the Prehospital Return of Spontaneous Circulation score, and 0.79 (95% CI, 0.77-0.81) for the Swedish Cardiac Arrest Risk Score model. The Utstein-Based Return of Spontaneous Circulation score significantly outperformed both the Prehospital Return of Spontaneous Circulation score (P<0.001) and the Swedish Cardiac Arrest Risk Score model (P=0.007). Subgroup analysis indicated no significant difference in predictive performance for patients resuscitated before versus after 2020. CONCLUSIONS: In this external validation, both statistical and machine learning-based models demonstrated excellent and fair performance, respectively, in predicting neurological outcomes despite different model architectures. The predictive performance of all evaluated clinical scoring systems was not significantly influenced by the COVID-19 pandemic.

Fecal microbiota transplantation alleviates food allergy in neonatal mice via the PD-1/PD-L1 pathway and change of the microbiota composition.

Background: Food allergy (FA) is a common disorder in children and affects the health of children worldwide. The gut microbiota is closely related to the occurrence and development of FA. Fecal microbiota transplantation (FMT) is a way to treat diseases by reconstituting the microbiota; however, the role and mechanisms of FA have not been validated. Methods: In this study, we established an ovalbumin (OVA)-induced juvenile mouse model and used 16S RNA sequencing, pathological histological staining, molecular biology, and flow-through techniques to evaluate the protective effects of FMT treatment on FA and to explore the mechanisms. Results: OVA-induced dysregulation of the gut microbiota led to impaired intestinal function and immune dysregulation in FA mice. FMT treatment improved the structure, diversity, and composition of the gut microbiota and restored it to a near-donor state. FMT treatment reduced levels of Th2-associated inflammatory factors, decreased intestinal tissue inflammation, and reduced IgE production. In addition, FMT reduced the number of mast cells and eosinophils and suppressed OVA-specific antibodies. Further mechanistic studies revealed that FMT treatment induced immune tolerance by inducing the expression of CD103+DCs and programmed cell death ligand 1 (PD-L1) in mesenteric lymph nodes and promoting the production of Treg through the programmed cell death protein 1 (PD-1)/PD-L1 pathway. Meanwhile, Th2 cytokines, OVA-specific antibodies, and PD-1/PD-L1 showed a significant correlation with the gut microbiota. Conclusions: FMT could regulate the gut microbiota and Th1/Th2 immune balance and might inhibit FA through the PD-1/PD-L1 pathway, which would provide a new idea for the treatment of FA.

Reset-Voltage Controlled Resistance-State and Applications of Forming-Free Fe-Doped SrTiO3 Thin-Film Memristor.

In this study, we prepared a strontium ferrite titanate (STF) thin film using a sol-gel process to insulate resistive random-access memory (RRAM) applications. Compared to the typical strontium titanate (STO) RRAM, the improvement in the resistive switching characteristics in STF RRAM is obvious. The Al/STO/ITO/Glass RRAM set/reset voltages of -1.4 V/+3.3 V and the Al/STF/ITO/Glass RRAM set/reset voltages of -0.45 V/+1.55 V presented a memory window larger than 103, a low operating voltage and device stability of more than 104 s. In this study, the influence of Fe on the conducting paths and the bipolar resistive switching properties of Al/STF/ITO/Glass RRAM devices is investigated.

Analgesic effect of dance movement therapy: An fNIRS study.

OBJECTIVE: This study aims to explores the physiological and psychological mechanisms of exercise-induced hypoalgesia (EIH) by combining the behavioral results with neuroimaging data on changes oxy-hemoglobin (HbO) in prefrontal cortex (PFC). METHODS: A total of 97 healthy participants were recruited and randomly divided into three groups: a single dance movement therapy (DMT) group, a double DMT group, and control group. Evaluation indicators included the pressure pain threshold (PPT) test, the color-word stroop task (CWST) for wearing functional near-infrared spectroscopy (fNIRS), and the self-assessment manikin (SAM). The testing time is before intervention, after intervention, and one hour of sit rest after intervention. RESULTS: 1) Repeated measures ANOVA revealed that, there is a time * group effect on the PPT values of the three groups of participants at three time points. After 30 min of acute dance intervention, an increase in the PPT values of 10 test points occurred in the entire body of the participants in the experimental group with a significant difference than the control group. 2) In terms of fNIRS signals, bilateral DLPFC and left VLPFC channels were significantly activated in the experimental group. 3) DMT significantly awakened participants and brought about pleasant emotions, but cognitive improvement was insignificant. 4) Mediation effect analysis found that the change in HbO concentration in DLPFC may be a mediator in predicting the degree of improvement in pressure pain threshold through dance intervention (total effect ß = 0.7140). CONCLUSION: In healthy adults, DMT can produce a diffuse EIH effect on improving pressure pain threshold, emotional experience but only showing an improvement trend in cognitive performance. Dance intervention significantly activates the left ventrolateral and bilateral dorsolateral prefrontal cortex. This study explores the central nervous system mechanism of EIH from a physiological and psychological perspective.

Coping strategies of intensive care units nurses in alarm management: a qualitative research study.

BACKGROUND: Intensive care units are critical environments where various alarm systems play a pivotal role in patient monitoring and safety. Alarm fatigue can lead to slower response times and missed alarms, compromising patient safety and increasing stress and burnout among intensive care unit nurses. Understanding how intensive care unit nurses respond to and manage these alarms is crucial in evaluating their impact on patient care and nursing well-being. METHODS: This descriptive qualitative study explored the experiences of intensive care unit nurses in alarm management. Conducted in the medical and surgical intensive care units of a Northern Taiwan medical center, the study involved 15 nurses. Semi-structured interviews were utilized to investigate the working experiences of ICU nurses in alarm management and to identify their coping strategies for dealing with the constant inundation of medical device alarms. The interviews were transcribed, and content analysis was applied to identify key themes in the responses. RESULTS: The study revealed five main themes in intensive care unit nurses' strategies for managing alarms: (1) Mastering alarm signals and acting; (2) Team monitoring for life preservation; (3) Enhancing senses and distinguishing carefully; (4) Learning from the lessons of incidents for vigilant reflection; and (5) Detach alarms' influence on daily life. These coping strategies are effective in alarm management, safeguarding patients' lives, enhancing the serenity of the clinical environment, and mitigating the physical and mental exhaustion caused by alarm fatigue. CONCLUSIONS: Intensive Care Unit nurses develop various coping strategies to manage medical device alarms, based on their experience. These strategies are crucial in maintaining patient safety and reducing nurse alarm fatigue. They can also be used for nursing education and clinical training.

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma.

BACKGROUND: Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG. METHODS: In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy. RESULTS: Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT. CONCLUSIONS: As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.

Augmenting dermal collagen synthesis through hyaluronic acid-based microneedle-mediated delivery of poly(l-lactic acid) microspheres.

Poly(L-lactic acid) (PLLA) can stimulate collagen synthesis through a foreign body response. However, inappropriate injection techniques and localized PLLA clustering can lead to complications and adverse events. This study developed a composite microneedle (MN) device comprising an array of PLLA microsphere (PLLA MP)-loaded hyaluronic acid needle tips with a supporting patch (PLLA MP-MN). This device was designed to deliver PLLA MPs precisely and uniformly to the dermis and to provide dual stimulation through MN puncture and MP implantation, thereby enabling the rapid and long-lasting regeneration of dermal collagen. When applied to rat skin, the MN array evenly distributed the PLLA MPs throughout the penetrated regions, which prevented local PLLA overdosing and elicited a milder inflammatory response compared with that induced by intradermal PLLA MP injections. An in vivo efficacy study revealed that MN-mediated delivery of PLLA MPs not only promptly initiated collagen production through microwound-triggered wound-healing cascades in the early treatment stage but also enabled the long-term stimulation of collagen deposition through MP-induced foreign body reactions, thereby significantly enhancing neocollagenesis. This innovative PLLA MP-MN system can augment the benefits and minimize the adverse effects associated with traditional PLLA fillers, providing a safe and reliable anti-aging therapeutic option.

Characteristics of Nocturnal Boundary Layer over a Subtropical Forest: Implications for the Dispersion and Fate of Atmospheric Species.

The nocturnal boundary layer (NBL) significantly influences the dispersion and fate of atmospheric species at night. Subtropical forests are crucial in carbon and water exchange between the biosphere and the atmosphere. However, the NBL characteristics and their impact on atmospheric species over these forests remain unknown. This study conducted vertical measurements of atmospheric species such as O3 and volatile organic compounds (VOCs), along with meteorological variables, over a national forest reserve in Southern China. Results reveal that the NBL height ranged from 180 to 300 m in the summer and from 80 to 160 m in the winter. The vertical distribution of chemical species varied by time and season, with greater concentration gradients observed in the summer. Over 90% of VOCs above the NBL were anthropogenic, while biogenic VOCs were mainly found within the NBL. Higher O3 concentration and VOC product-to-reactant ratios were observed in the residual layer, suggesting enhanced oxidation levels. This unique vertical distribution of atmospheric species at night is driven by factors, such as emission, deposition, turbulence, and atmospheric chemistry, potentially affecting ecosystem functions. Results from this study highlight the importance of incorporating NBL dynamics into atmospheric models to better understand the evolution of chemical species and their ecological effects over forests.

Integrated anti-fatigue effects of polysaccharides and small molecules coexisting in water extracts of ginseng: Gut microbiota-mediated mechanisms.

ETHNOPHARMACOLOGICAL RELEVANCE: Both clinical and animal studies have demonstrated that ginseng has curative effects on fatigue. Our previous study found that water extracts of ginseng (WEG) could significantly mitigate exercise-induced fatigue (EF). Notably, polysaccharides (GP) and small molecules (GS, mainly ginsenosides) coexist in WEG. Whether and how GP and GS contribute to the anti-EF effects of WEG remains unknown. AIM OF THE STUDY: To evaluate the contribution of GP and GS to the anti-EF effects of WEG and clarify the potential gut microbiota-mediated mechanisms. MATERIALS AND METHODS: Firstly, the anti-EF effects of WEG, GP and GS were comparatively investigated by determining fatigue phenotypes (energy metabolism and oxidative stress parameters), gut microbiota composition as well as exogenous and endogenous metabolites in EF modeling rats. Then, the gut microbiota mediated mechanisms were verified by antibiotics (ABX) intervention and fecal microbial transplantation (FMT). RESULTS: GP, GS and WEG each exhibited distinct anti-EF effects in differentially improving EF-induced energy metabolism abnormality and oxidative stress, reshaping gut microbiota composition, and elevating systemic metabolites. Notably, WEG showed stronger anti-EF effects than both GP and GS, characterized by better alleviation of disturbances in energy metabolism (e.g. Glc) and oxidative stress parameters (e.g. SOD), regulation of gut microbiota homeostasis (e.g. enriching the genus Coprococcus and species Collinsella provencensis etc.), as well as increases in exogenous secondary ginsenosides (e.g. 20(S)-Rg3, 20(R)-Rg3, CK), endogenous bile acids (BAs) (e.g. CA, DCA, LCA), and short chain fatty acids (SCFAs) (e.g. butyric acid). The stronger anti-EF effects of WEG compared to GP and GS could be abolished by ABX intervention, and transferred by FMT. CONCLUSION: GP and GS could collectively contribute to the anti-EF effects of WEG through integrated actions. Gut microbiota mediate the integrated anti-EF effects of GP and GS in WEG, potentially by regulating the levels of exogenous bioactive secondary ginsenosides, as well as endogenous BAs and SCFAs, thereby alleviating fatigue-related energy metabolic abnormalities and oxidative stress.

Modified FOLFOX6 with Cetuximab versus with Radiotherapy in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: A Single-Center, Prospective, Randomized Controlled Trial.

In this trial, the feasibility and efficacy of neoadjuvant chemotherapy with targeted agents in the treatment of patients with locally advanced rectal cancer were evaluated. In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. We performed a random assignment by a computer-generated random number sequence. The primary end point was the R0 resection rate. The secondary end points were rates of pathologic complete response, downstaging, adverse events, postoperative complications, preventive enterostomy and low anterior resection syndrome. From January 6, 2020 to October 28, 2022, 80 patients were assigned and evaluated. In the mFOLFOX6-RT and mFOLFOX6-Cet groups, the rate of R0 resection was 96.7 and 96.9% (p = 1.000); the rate of pathological complete response (pCR) was 23.3 and 21.9% (p = 0.891); and the rate of downstaging (ypStage 0 to 1) was 53.3 and 53.1% (p = 1.000), respectively. No statistical differences between the two groups were observed in the incidence of adverse events and postoperative complications. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.

Deconstruction the feedforward inhibition changes in the layer III of anterior cingulate cortex after peripheral nerve injury.

The anterior cingulate cortex (ACC) is one of the critical brain areas for processing noxious information. Previous studies showed that peripheral nerve injury induced broad changes in the ACC, contributing to pain hypersensitivity. The neurons in layer 3 (L3) of the ACC receive the inputs from the mediodorsal thalamus (MD) and form the feedforward inhibition (FFI) microcircuits. The effects of peripheral nerve injury on the MD-driven FFI in L3 of ACC are unknown. In our study, we record the enhanced excitatory synaptic transmissions from the MD to L3 of the ACC in mice with common peroneal nerve ligation, affecting FFI. Chemogenetically activating the MD-to-ACC projections induces pain sensitivity and place aversion in naive mice. Furthermore, chemogenetically inactivating MD-to-ACC projections decreases pain sensitivity and promotes place preference in nerve-injured mice. Our results indicate that the peripheral nerve injury changes the MD-to-ACC projections, contributing to pain hypersensitivity and aversion.

Drug-Free Mesoporous Silica Nanoparticles Enable Suppression of Cancer Metastasis and Confer Survival Advantages to Mice with Tumor Xenografts.

Despite advancements in nanomedicine for drug delivery, many drug-loaded nanoparticles reduce tumor sizes but often fail to prevent metastasis. Mesoporous silica nanoparticles (MSNs) have attracted attention as promising nanocarriers. Here, we demonstrated that MSN-PEG/TA 25, with proper surface modifications, exhibited unique antimetastatic properties. In vivo studies showed that overall tumor metastasis decreased in 4T1 xenografts mice treated with MSN-PEG/TA 25 with a notable reduction in lung tumor metastasis. In vitro assays, including wound-healing, Boyden chamber, tube-formation, and real-time cell analyses, showed that MSN-PEG/TA 25 could modulate cell migration of 4T1 breast cancer cells and interrupt tube formation by human umbilical vein endothelial cells (HUVECs), key factors in suppressing cancer metastasis. The synergistic effect of MSN-PEG/TA 25 combined with liposomal-encapsulated doxorubicin (Lipo-Dox) significantly boosted mouse survival rates, outperforming Lipo-Dox monotherapy. We attributed the improved survival to the antimetastatic capabilities of MSN-PEG/TA 25. Moreover, Dox-loaded MSN-PEG/TA 25 suppressed primary tumors while retaining the antimetastatic effect, thereby enhancing therapeutic outcomes and overall survival. Western blot and qPCR analyses revealed that MSN-PEG/TA 25 interfered with the phosphorylation of ERK, FAK, and paxillin, thus impacting focal adhesion turnover and inhibiting cell motility. Our findings suggest that drug-free MSN-PEG/TA 25 is highly efficient for cancer treatment via suppressing metastatic activity and angiogenesis.

Mediating role of obstructive sleep apnea in altering slow-wave activity and elevating Alzheimer's disease risk: Pilot study from a northern Taiwan cohort.

OBJECTIVES: Obstructive sleep apnea is associated with alterations in slow-wave activity during sleep, potentially increasing the risk of Alzheimer's disease. This study investigated the associations between obstructive sleep apnea manifestations such as respiratory events, hypoxia, arousal, slow-wave patterns, and neurochemical biomarker levels. METHODS: Individuals with suspected obstructive sleep apnea underwent polysomnography. Sleep disorder indices, oxygen metrics, and slow-wave activity data were obtained from the polysomnography, and blood samples were taken the following morning to determine the plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aß42) by using an ultrasensitive immunomagnetic reduction assay. Subsequently, the participants were categorized into groups with low and high Alzheimer's disease risk on the basis of their computed product Aß42 × T-Tau. Intergroup differences and the associations and mediation effects between sleep-related parameters and neurochemical biomarkers were analyzed. RESULTS: Forty-two participants were enrolled, with 21 assigned to each of the low- and high-risk groups. High-risk individuals had a higher apnea-hypopnea index, oxygen desaturation index (≥3%, ODI-3%), fraction of total sleep time with oxygen desaturation (SpO2-90% TST), and arousal index and greater peak-to-peak amplitude and slope in slow-wave activity, with a correspondingly shorter duration, than did low-risk individuals. Furthermore, indices such as the apnea-hypopnea index, ODI-3% and SpO2-90% TST were found to indirectly affect slow-wave activity, thereby raising the Aß42 × T-Tau level. CONCLUSIONS: Obstructive sleep apnea manifestations, such as respiratory events and hypoxia, may influence slow-wave sleep activity (functioning as intermediaries) and may be linked to elevated neurochemical biomarker levels. However, a longitudinal study is necessary to determine causal relationships among these factors. STATEMENT OF SIGNIFICANCE: This research aims to bridge gaps in understanding how obstructive sleep apnea is associated with an elevated risk of Alzheimer's disease, providing valuable knowledge for sleep and cognitive health.

Alternations of the gut microbiota and the Firmicutes/Bacteroidetes ratio after biologic treatment in inflammatory bowel disease.

BACKGROUND: The inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC) is a complex disease with multifactorial etiology. The intestinal dysbiosis have been investigated to play an important role in IBD pathogenesis and disease activity. The aim of our study was to analyze the intestinal microbiota composition in IBD across different severity levels and the impact of biologic therapy on microbiota modulation. METHODS: In this study, 27 IBD patients were recruited, including 14 patients undergoing biologic therapy for moderate to severe disease activity and 13 controls with inactive disease. The gut microbial composition was determined by 16 S ribosomal RNA gene sequencing of stool samples. RESULTS: Biologic therapy led to significant clinical improvement in IBD disease activity after 48 weeks. About species richness, community alpha diversity was significant lower in active CD patients and enriched gradually after biologic therapy. The beta-diversity regard to the difference of bacterial community composition showed significant difference between patients in biologic and control group. A decrease in Firmicutes and increase in Bacteroidetes abundance were observed in patients with active disease, both in CD and UC. Biologic treatment induced shifts in gut microbiota, with increased Firmicutes and decreased Bacteroidetes, as well as improved F/B ratio gradually after treatment, correlating with disease activity. CONCLUSIONS: Our study suggested that gut microbiota differences changed after biologic therapies among IBD with different disease activity, and a rising Firmicutes/Bacteroidetes ratio could be a potential predictor for disease activity and treatment response monitoring.

Assessment of Endoscopic Ultrasound for Predicting Preoperative T Staging in Patients With Gastric Adenocarcinoma.

BACKGROUND AND OBJECTIVES: Endoscopic ultrasound (EUS) is an imaging modality that can be applied to predict preoperative T staging. It is important for the patient to decide whether to receive endoscopic therapy, surgical intervention, or neoadjuvant therapy. The objectives of our study were to (1) identify if EUS could precisely predict T1-stage tumor, which is suitable for endoscopic treatment and (2) identify if EUS could precisely predict tumors more advanced than T3, which would mandate neoadjuvant therapy. METHODS: A retrospective study of patients who received gastrectomy was conducted from March 2017 to December 2021 at Taichung Veterans General Hospital. Those who received preoperative EUS, with final pathology showing gastric adenocarcinoma were included. Consistency of EUS prediction and pathology, accuracy, and parameters impacting accuracy were analyzed. RESULTS: The κ value was 0.6 if the T stage was not grouped, indicating moderate agreement. Overall accuracy was 52.8%. Overestimation and underestimation rates were 17.6% and 29.5%, respectively. The accuracy of T stages is highest in T1 (85.23%). The κ value of T1-stage was 0.67, and those of T2, T3, and T4 were below 0.5. Regarding parameters affecting accuracy, we found longitudinal portion, Borrmann type, ulcer presentation, early gastric cancer, and size of tumor could influence the accuracy. CONCLUSIONS: Our study showed that EUS was a good tool for precisely predicting T1-stage of gastric adenocarcinoma preoperatively. For this situation, endoscopic treatment would be enough. However, for predicting more advanced gastric adenocarcinoma, EUS should be combined with other modalities to achieve better accuracy.

Pre-treatment pan-immune-inflammation value as a prognostic marker of pazopanib in soft tissue sarcoma.

Background: Increasingly, more evidence has shown that inflammation stress and the tumor microenvironment pose a negative effect on targeted therapy. The neutrophil-to-lymphocyte ratio is considered to be a surrogate biomarker of inflammation and can predict pazopanib treatment effect in non-adipocytic soft-tissue sarcoma (STS). The role of the pan-immune-inflammation value (PIV) in STS is still yet to be determined. Objectives: We sought whether the pre-treatment PIV could be applied to predict the response of pazopanib in STS. Design: We conducted a retrospective analysis of 75 patients who had been treated with pazopanib for recurrent or metastatic non-adipocytic STS. Methods: Our cohort was stratified into either a pre-treatment high PIV group with PIV ⩾310 (n = 45) or a low PIV group with PIV <310 (n = 30). We compared their clinical features and outcomes. Cox regression analysis was employed to determine the risk factors of disease progression and mortality. Kaplan-Meier survival curves were utilized to assess both the progression-free survival (PFS) and overall survival (OS). Results: The results revealed that a pre-treatment high PIV (⩾310) is a risk factor for progression under pazopanib (hazard ratio: 1.91; 95% confidence interval: 1.08-3.36; p = 0.025). The median PFS and OS of the pre-treatment high PIV group were found to be significantly lower than the low PIV group (0.33 vs 0.75 years; p = 0.023, 0.46 vs 1.63 years; p = 0.025). Conclusion: High pre-treatment PIV in STS patients may indicate an elevated risk of disease progression and mortality. Pre-treatment PIV reflects inflammation stress and acts as a practical biomarker for STS patients treated with pazopanib.

Identifying resistance molecules in TiO2 nanoparticle-tolerant strains to facilitate the development of strategies for combating TiO2 nanoparticle pollution.

The severity of environmental pollution caused by TiO2 nanoparticles (nTiO2) is increasing, highlighting the urgent need for the development of strategies to combat nTiO2 pollution. Insights into resistance molecules from nTiO2-tolerant strains may facilitate such development. In this study, we utilized multi-omics, genetic manipulation, physiological and biochemical experiments to identify relevant resistance molecules in two strains (Physarum polycephalum Z259 and T83) tolerated to mixed-phase nTiO2 (MPnTiO2). We discovered that a competing endogenous RNA (ceRNA) network, comprising one long non-coding RNA (lncRNA), four microRNAs, and nine mRNAs, influenced metabolic rearrangement and was associated with significant resistance in these strains. Additionally, we found that the lncRNA in the ceRNAs network and certain small-weight metabolites associated with the ceRNA exhibited notable mitigation effects not only against MPnTiO2 but also against other types of nTiO2 with broad species applicability (they significantly improved the resistance of several non-nTiO2-tolerant cells/organisms in the laboratory and reduced cell damage of non-nTiO2-tolerant cells/organisms in highly suspected nTiO2-polluted areas of the real world). In summary, this study deepens our understanding of nTiO2-tolerant strains, provides valuable insights into resistance molecules in these strains, and facilitates the development of strategies to combat nTiO2 pollution.