Bisphenol S (BPS) induces glioblastoma progression via regulation of EZH2-mediated PI3K/AKT/mTOR pathway in U87-MG cells.

Bisphenol S (BPS), an alternative to bisphenol A (BPA), exerts proliferative effects similar to those of BPA. BPS is a representative endocrine disruptor associated with cancer progression. However, the mechanisms underlying BPS-induced glioblastoma progression are not fully understood. To investigate the effects of BPS on glioblastoma, U-87 MG cancer cell lines were exposed to BPS. The study focused on analyzing the proliferation and migration of U-87 MG cells. Furthermore, the involvement of the enhancer of the zeste homolog 2 (EZH2)-mediated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of the rapamycin (mTOR) pathway was examined. Pharmacological approaches were employed to inhibit EZH2 activity and observe its effects on BPS-induced changes. The results indicated that BPS promoted the proliferation and migration of U-87 MG cells at a concentration of 0.1µM. These changes appeared to be linked to the activation of the EZH2-mediated PI3K/AKT/mTOR pathway. Moreover, inhibiting EZH2 activity using pharmacological approaches restored the BPS-mediated induction of proliferation and migration. In conclusion, the results of this study indicated that BPS induces glioblastoma progression through EZH2 upregulation. Therefore, targeting the EZH2-mediated PI3K/AKT/mTOR pathway could be considered a potential therapeutic strategy for the treatment of glioblastoma.

Bisphenol A (BPA) and neurological disorders: An overview.

The human body is commonly exposed to bisphenol A (BPA), which is widely used in consumer and industrial products. BPA is an endocrine-disrupting chemical that has adverse effects on human health. In particular, many studies have shown that BPA can cause various neurological disorders by affecting brain development and neural function during prenatal, infancy, childhood, and adulthood exposure. In this review, we discussed the correlation between BPA and neurological disorders based on molecular cell biology, neurophysiology, and behavioral studies of the effects of BPA on brain development and function. Recent studies, both animal and epidemiological, strongly indicate that BPA significantly impacts brain development and function. It hinders neural processes, such as proliferation, migration, and differentiation during development, affecting synaptic formation and activity. As a result, BPA is implicated in neurodevelopmental and neuropsychiatric disorders like autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and schizophrenia.

Enhanced Photocatalytic Activities of Sodium Borohydride-Calcined Magnetic Manganese Ferrite Nanoparticles.

The synthesis, enhancement, and maintenance of magnetite-based catalyst nanoparticles (NPs) are important for photocatalytic activity and recovery rates. We used a sodium borohydride (NaBH4) calcination method to modify MnFe2O4 nanoparticles to optimize their performance in the photocatalytic oxidation of 2,5-hydroxymethylfurfural. The results indicated a 94% increase in photocatalytic efficiency, while magnetic assessments performed using a vibrating sample magnetometer showed an 8.9% improvement in magnetic properties without degradation. These findings show the dual benefits of increased photocatalytic performance with strong magnetic properties, which are important for the application and reusability of photocatalysts. The recycling of these photocatalysts reduces secondary pollution and increases the process cost-effectiveness. These results contribute to the solution of problems with the use of photocatalytic materials.

Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors.

Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. When intratumoral triad formation is disrupted, tumors progress despite equal numbers of tumor-specific CD8+ and CD4+ T cells. In patients with pleural mesothelioma treated with ICB, triads are associated with clinical responses. Thus, CD4+ T cells and triads are required for CD8+ T cell cytotoxicity during the effector phase and tumor elimination.

Triggered saccadic oscillations: case series and review of the literature.

Saccadic oscillations (SOs) mostly occur spontaneously, but can be occasionally triggered by various stimuli. To determine clinical characteristics and underlying mechanisms of triggered SOs, we analyzed the clinical features and quantitative eye-movement recordings of six new patients and 10 patients in the literature who exhibited with triggered SOs. Eleven of the 16 patients (69%) had a lesion involving cerebellum and/or brainstem such as cerebellar degeneration, cerebellitis, or cerebellar infarction. The other causes were vestibular migraine (n = 2), multiple sclerosis (n = 1), Krabbe disease (n = 1), and idiopathic (n = 1). Vestibular stimulation was the most common trigger (n = 11, 69%), followed by removal of visual fixation (n = 4, 25%), hyperventilation (n = 1), light (n = 1), and blink (n = 1). The types of triggered SOs were varied which included ocular flutter (n = 13), opsoclonus (n = 3), vertical SOs (n = 2), and macrosaccadic oscillations (n = 1). Three patients exhibited downbeat nystagmus either before (n = 1) or after (n = 2) the onset of SOs. The frequency of triggered SOs ranged from 4 to 15 Hz, and oscillations with smaller amplitudes had higher frequencies and smaller peak velocities. SOs can be triggered by the modulation of unstable saccadic neural networks through vestibular and visual inputs in lesions of the brainstem and cerebellum.

Ethanol purification enables high-quality α-phase FAPbI3 perovskite microcrystals for commercial photovoltaic applications.

Reliable quality and sustainable processes must be developed for commodities to enter the commercial stage. For next-generation photovoltaic applications such as perovskite solar cells, it is essential to manufacture high-quality photoactive perovskites via eco-friendly processes. We demonstrate that ethanol, an ideal green solvent, can be applied to yield efficient alpha-phase FAPbI3 perovskite microcrystals.

Feasibility and safety of in-bed cycling/stepping in critically ill patients: A study protocol for a pilot randomized controlled clinical trial.

BACKGROUND: Intensive care unit (ICU)-acquired weakness (ICU-AW) is one of the most common complications of post-ICU syndrome. It is the leading cause of gait disturbance, decreased activities of daily living, and poor health-related quality of life. The early rehabilitation of critically ill patients can reduce the ICU-AW. We designed a protocol to investigate the feasibility and safety of conventional rehabilitation with additional in-bed cycling/stepping in critically ill patients. METHODS: The study is designed as a single-center, single-blind, pilot, randomized, parallel-group study. After the screening, participants are randomly allocated to two groups, stratified by mechanical ventilation status. The intervention group will be provided with exercises of in-bed cycling/stepping according to the level of consciousness, motor power, and function in addition to conventional rehabilitation. In contrast, the control group will be provided with only conventional rehabilitation. The length of intervention is from ICU admission to discharge, and interventions will be conducted for 20 minutes, a maximum of three sessions per day. RESULTS: The outcomes are the number and percentage of completed in-bed cycling/stepping sessions, the duration and percentage of in-bed cycling/stepping sessions, and the number of cessations of in-bed cycling/stepping sessions, the interval from ICU admission to the first session of in-bed cycling/stepping, the number and percentage of completed conventional rehabilitation sessions, the duration and percentage of conventional rehabilitation sessions, the number of cessations of conventional rehabilitation sessions, the number of adverse events, level of consciousness, functional mobility, muscle strength, activities of daily living, and quality of life. DISCUSSION: This study is a pilot clinical trial to investigate the feasibility and safety of conventional rehabilitation with additional in-bed cycling/stepping in critically ill patients. If the expected results are achieved in this study, the methods of ICU rehabilitation will be enriched. TRIAL REGISTRATION: clinicialtrials.gov, Clinical Trials Registration #NCT05868070.

Clinical Value of Single-Projection Angiography-Derived FFR in Noninfarct-Related Artery.

BACKGROUND: The Murray law-based quantitative flow ratio (µFR) is an emerging technique that requires only 1 projection of coronary angiography with similar accuracy to quantitative flow ratio (QFR). However, it has not been validated for the evaluation of noninfarct-related artery (non-IRA) in acute myocardial infarction (AMI) settings. Therefore, our study aimed to evaluate the diagnostic accuracy of µFR and the safety of deferring non-IRA lesions with µFR >0.80 in the setting of AMI. METHODS: µFR and QFR were analyzed for non-IRA lesions of patients with AMI enrolled in the FRAME-AMI trial (Fractional Flow Reserve Versus Angiography-Guided Strategy for Management of Non-Infarction Related Artery Stenosis in Patients With Acute Myocardial Infarction), consisting of fractional flow reserve (FFR)-guided percutaneous coronary intervention and angiography-guided percutaneous coronary intervention groups. The diagnostic accuracy of µFR was compared with QFR and FFR. Patients were classified by the non-IRA µFR value of 0.80 as a cutoff value. The primary outcome was a vessel-oriented composite outcome, a composite of cardiac death, non-IRA-related myocardial infarction, and non-IRA-related repeat revascularization. RESULTS: µFR and QFR analyses were feasible in 443 patients (552 lesions). µFR showed acceptable correlation with FFR (R=0.777; P<0.001), comparable C-index with QFR to predict FFR ≤0.80 (µFR versus QFR: 0.926 versus 0.961, P=0.070), and shorter total analysis time (mean, 32.7 versus 186.9 s; P<0.001). Non-IRA with µFR >0.80 and deferred percutaneous coronary intervention had a significantly lower risk of vessel-oriented composite outcome than non-IRA with performed percutaneous coronary intervention (3.4% versus 10.5%; hazard ratio, 0.37 [95% CI, 0.14-0.99]; P=0.048). CONCLUSIONS: In patients with multivessel AMI, µFR of non-IRA showed acceptable diagnostic accuracy comparable to that of QFR to predict FFR ≤0.80. Deferred non-IRA with µFR >0.80 showed a lower risk of vessel-oriented composite outcome than revascularized non-IRA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02715518.

Effect of high-dose intravenous iron injection on hepatic function in a rat model of cirrhosis.

OBJECTIVE: To investigate the hepatic effects of high-dose intravenous (IV) iron, including those on liver function and the degree of fibrosis, in a rat model of cirrhosis. METHODS: We evenly allocated 25 Sprague-Dawley rats into five groups: normal rats (control group), cirrhotic rats receiving IV normal saline (liver cirrhosis [LC] group), and cirrhotic rats receiving 20, 40, or 80 mg/kg IV ferric carboxymaltose (LC-iron20, LC-iron40, and LC-iron80 group, respectively). Biochemical parameters were compared at 0, 7, 14, 21, and 28 days. The degrees of hepatic fibrosis and iron deposition were evaluated. Inflammatory and oxidative stress markers were also compared. RESULTS: There were no significant differences in the 28-day serum alanine aminotransferase levels among the LC-iron20, LC-iron40, and LC-iron80 groups (69 ± 7, 1003 ± 127, 1064 ± 309, 919 ± 346, and 820 ± 195 IU/L in the control, LC, LC-iron20, LC-iron40, and LC-iron80 groups, respectively). Hepatic iron accumulation increased in a dose-dependent manner, but the degree of hepatic fibrosis was comparable among the groups. The inflammatory and oxidative stress marker levels did not differ significantly according to the IV iron dose. CONCLUSIONS: Administration of IV iron at various high doses appears safe in our rat model of cirrhosis.

Cigarette smoke impairs the hematopoietic supportive property of mesenchymal stem cells via the production of reactive oxygen species and NLRP3 activation.

BACKGROUND: Mesenchymal stem cells (MSCs) play important roles in tissue homeostasis by providing a supportive microenvironmental niche for the hematopoietic system. Cigarette smoking induces systemic abnormalities, including an impeded recovery process after hematopoietic stem cell transplantation. However, the role of cigarette smoking-mediated alterations in MSC niche function have not been investigated. METHODS: In the present study, we investigated whether exposure to cigarette smoking extract (CSE) disrupts the hematopoietic niche function of MSCs, and pathways impacted. To investigate the effects on bone marrow (BM)-derived MSCs and support of hematopoietic stem and progenitor cells (HSPCs), mice were repeatedly infused with the CSE named 3R4F, and hematopoietic stem and progenitor cells (HSPCs) supporting function was determined. The impact of 3R4F on MSCs at cellular level were screened by bulk-RNA sequencing and subsequently validated through qRT-PCR. Specific inhibitors were treated to verify the ROS or NLRP3-specific effects, and the cells were then transplanted into the animal model or subjected to coculture with HSPCs. RESULTS: Both direct ex vivo and systemic in vivo MSC exposure to 3R4F resulted in impaired engraftment in a humanized mouse model. Furthermore, transcriptomic profile analysis showed significantly upregulated signaling pathways related to reactive oxygen species (ROS), inflammation, and aging in 3R4F-treated MSCs. Notably, ingenuity pathway analysis revealed the activation of NLRP3 inflammasome signaling pathway in 3R4F-treated MSCs, and pretreatment with the NLRP3 inhibitor MCC950 rescued the HSPC-supporting ability of 3R4F-treated MSCs. CONCLUSION: In conclusion, these findings indicate that exposure to CSE reduces HSPCs supportive function of MSCs by inducing robust ROS production and subsequent NLRP3 activation.

Impact of Esterification with Octenyl Succinic Anhydride on the Structural Characteristics and Glucose Response in Mice of Wheat Starch.

In this study, we investigated the structural properties and digestibility of wheat starch treated with octenyl succinic anhydride (OSA). For the experiment, the samples were reacted with 2, 4, 6, 8, and 10% OSA (pH 8.5-9.0) for 2 h. A light micrograph showed that there was no difference in the morphology and Maltese cross between native and OSA-treated starch. The X-ray diffraction (XRD) patterns of the native and OSA-treated starches showed typical A-type diffraction. In addition, the Fourier transform infrared (FT-IR) spectrum showed a distinct carbonyl peak at approximately 1730 cm-1, indicating the stretching vibration of the C=O bond of the ester group. The degree of substitution (DS) and content of resistant starch (RS) increased with increasing concentrations of treated OSA because of the increase in ester bonds. In particular, RS was thermostable compared to the RS content in uncooked and cooked starch. Blood glucose levels and response in vivo decreased as the OSA concentration increased. Treatment of wheat starch with 8% OSA concentration produced 35.6% heat-stable resistant starch. These results suggest that starch modified with OSA can be used to produce functional foods for diabetes.

Preoperative C-reactive protein/albumin ratio and mortality of off-pump coronary artery bypass graft.

Background: We sought to investigate the prognostic value of preoperative C-reactive protein (CRP)-to-albumin ratio (CAR) for the prediction of mortality in patients undergoing off-pump coronary artery bypass grafting (OPCAB). Methods: From January 2010 to August 2016, adult patients undergoing OPCAB were analyzed retrospectively. In a total of 2,082 patients, preoperative inflammatory markers including CAR, CRP, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were recorded. Receiver operating characteristic (ROC) curves were used to determine the optimal threshold and compare the predictive values of the markers. The patients were divided into two groups according to the cut-off value of CAR, and then the outcomes were compared. The primary end point was 1-year mortality. Results: During the 1-year follow-up period, 25 patients (1.2%) died after OPCAB. The area under the curve of CAR for 1-year mortality was 0.767, which was significantly higher than other inflammatory markers. According to the calculated cut-off value of 1.326, the patients were divided into two groups: 1,580 (75.9%) patients were placed in the low CAR group vs. 502 (24.1%) patients in the high CAR group. After adjustment with inverse probability weighting, high CAR was significantly associated with increased risk of 1-year mortality after OPCAB (Hazard ratio, 5.01; 95% Confidence interval, 2.01-12.50; p < 0.001). Conclusions: In this study, we demonstrated that preoperative CAR was associated with 1-year mortality following OPCAB. Compared to previous inflammatory markers, CAR may offer superior predictive power for mortality in patients undergoing OPCAB. For validation of our findings, further prospective studies are needed.

Ticagrelor, but Not Clopidogrel, Attenuates Hepatic Steatosis in a Model of Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND: Previous studies have suggested that platelets are associated with inflammation and steatosis and may play an important role in liver health. Therefore, we evaluated whether antiplatelet agents can improve metabolic disorder-related fatty liver disease (MASLD). METHODS: The mice used in the study were fed a high-fat-diet (HFD) and were stratified through liver biopsy at 18 weeks. A total of 22 mice with NAFLD activity scores (NAS) ≥ 4 were randomly divided into three groups (HFD-only, clopidogrel (CLO; 35 mg/kg/day), ticagrelor (TIC; 40 mg/kg/day) group). And then, they were fed a feed mixed with the respective drug for 15 weeks. Blood and tissue samples were collected and used in the study. RESULTS: The TIC group showed a significantly lower degree of NAS and steatosis than the HFD group (p = 0.0047), but no effect on the CLO group was observed. Hepatic lipogenesis markers' (SREBP1c, FAS, SCD1, and DGAT2) expression and endoplasmic reticulum (ER) stress markers (CHOP, Xbp1, and GRP78) only reduced significantly in the TIC treatment group. Inflammation genes (MCP1 and TNF-α) also decreased significantly in the TIC group, but not in the CLO group. Nile red staining intensity and hepatic lipogenesis markers were reduced significantly in HepG2 cells following TIC treatment. CONCLUSION: Ticagrelor attenuated NAS and hepatic steatosis in a MASLD mice model by attenuating lipogenesis and inflammation, but not in the CLO group.

Intravascular imaging-guided percutaneous coronary intervention in patients with acute myocardial infarction and cardiogenic shock.

INTRODUCTION AND OBJECTIVES: There are no clinical data on the efficacy of intravascular imaging-guided percutaneous coronary intervention (PCI) compared with angiography-guided PCI in patients with acute myocardial infarction (AMI) and cardiogenic shock. The current study sought to evaluate the impact of intravascular imaging-guided PCI in patients with AMI and cardiogenic shock. METHODS: Among a total of 28 732 patients from the nationwide pooled registry of KAMIR-NIH (November, 2011 to December, 2015) and KAMIR-V (January, 2016 to June, 2020), we selected a total of 1833 patients (6.4%) with AMI and cardiogenic shock who underwent PCI of the culprit vessel. The primary endpoint was major adverse cardiovascular events (MACE) at 1 year, a composite of cardiac death, myocardial infarction, repeat revascularization, and definite or probable stent thrombosis. RESULTS: Among the study population, 375 patients (20.5%) underwent intravascular imaging-guided PCI and 1458 patients (79.5%) underwent angiography-guided PCI. Intravascular imaging-guided PCI was associated with a significantly lower risk of 1-year MACE than angiography-guided PCI (19.5% vs 28.2%; HR, 0.59; 95%CI, 0.45-0.77; P<.001), mainly driven by a lower risk of cardiac death (13.7% vs 24.0%; adjusted HR, 0.53; 95%CI, 0.39-0.72; P<.001). These results were consistent in propensity score matching (HR, 0.68; 95%CI, 0.46-0.99), inverse probability weighting (HR, 0.61; 95%CI, 0.45-0.83), and Bayesian analysis (Odds ratio, 0.66, 95% credible interval, 0.49-0.88). CONCLUSIONS: In AMI patients with cardiogenic shock, intravascular imaging-guided PCI was associated with a lower risk of MACE at 1-year than angiography-guided PCI, mainly driven by the lower risk of cardiac death.

Optimization and modelling of magnesium oxide (MgO) photocatalytic degradation of binary dyes using response surface methodology.

Textile industry dye effluent contains a mixture of different kinds of dyes. Many times, photocatalysis is targeted as a solution for the treatment of dye effluent from the textile industry. Many researches have been published related to the photocatalysis of single textile dyes but in the real-world scenario, effluent is a mixture of dyes. Magnesium oxide (MgO) is used as a photocatalyst to treat a mixture (binary solution) of Methylene blue (MB) and Methylene violet (MV) along with individual MB and MV dyes in this article. MgO shows remarkable photocatalytic activity at about 93 and 88% for MB and MV dye in binary solution within 135 min. Furthermore, to study the influence of process parameters, experiments are designed with the help of the central composite design (CCD), and Response surface methodology (RSM) is used to study the interactions between parameters. For this study, five parameters are selected i.e., Photocatalyst dosage, initial concentration of both dyes, time of exposure to the light source, and pH of the binary solution. The photocatalytic process is also optimized and finally optimization of process parameters is validated with an experiment. The result of the validation experiment is very close to the predicted photocatalytic activity.

Performance of the galactomannan test for the diagnosis of invasive pulmonary aspergillosis using non-invasive proximal airway samples.

OBJECTIVE: To diagnose invasive pulmonary aspergillosis (IPA), galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (BALF) is widely used. However, the utility of proximal airway GM test (from induced sputum or tracheal aspirate) has not been well elucidated. METHODS: In this retrospective cohort study, we evaluated the diagnostic performance of proximal airway GM in diagnosis of IPA including COVID-19 associated pulmonary aspergillosis (CAPA). Between January 2022 and January 2023, patients who had been tested for GM with clinical suspicion or for surveillance from any specimen (serum, induced sputum, tracheal aspirate, and BALF) were screened. IPA was diagnosed using EORTC/MSGERC criteria, and CAPA was diagnosed following the 2020 ECMM/ISHAM consensus criteria. RESULTS: Of 624 patients with GM results, 70 met the criteria for proven/probable IPA and 427 had no IPA. The others included possible IPA and chronic form of aspergillosis. The sensitivities and specificities of serum, proximal airway, and BALF GM for proven/probable IPA versus no IPA were 78.9% and 70.6%, 93.1% and 78.7%, and 78.6% and 91.0%, respectively. Areas under the receiver operating characteristic curve (AUCs) were 0.742 for serum GM, 0.935 for proximal airway GM, and 0.849 for BALF GM (serum GM vs proximal airway GM, p = 0.014; proximal airway GM vs BALF GM, p = 0.334; serum GM vs BALF GM, p = 0.286). CONCLUSION: This study demonstrates that the performance of GM test from non-invasive proximal airway samples is comparable or even better than those from serum and distal airway sample (BALF).

Prognostic Implications of Microvascular Resistance Reserve in Symptomatic Patients With Intermediate Coronary Stenosis.

BACKGROUND: Microvascular resistance reserve (MRR) is a novel index reflecting coronary microcirculatory function, irrespective of epicardial coronary artery stenosis. There is limited evidence regarding whether MRR can be an independent prognostic tool in patients with stable ischemic heart disease (IHD). OBJECTIVES: The aim of this study was to evaluate clinical outcomes according to MRR in patients with stable IHD accompanied with or without significant epicardial coronary artery stenosis. METHODS: The present study included 547 consecutive patients undergoing systematic echocardiographic and invasive physiological assessment for suspected stable IHD. Significant epicardial coronary artery stenosis was defined as fractional flow reserve (FFR) ≤0.80. Coronary microvascular dysfunction (CMD) was defined as MRR ≤3.0. The primary outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure. RESULTS: Among the study group, 172 patients (31.4%) had FFR ≤0.80, and 200 patients (36.6%) had CMD defined by MRR ≤3.0. MRR showed no significant correlation with FFR (R = -0.031; P = 0.469), but it was significantly correlated with the index of microcirculatory resistance (R = -0.353; P < 0.001), N-terminal pro-B-type natriuretic peptide (R = -0.296; P < 0.001), left ventricular filling pressure (E/e' ratio) (R = -0.224; P < 0.001), and diastolic dysfunction grade (P < 0.001). During a median follow-up period of 3.3 years (Q1-Q3: 2.0-4.5 years), MRR was significantly associated with MACE risk (HR: 1.23 per 1-U decrease; 95% CI: 1.12-1.36; P < 0.001). CMD defined by MRR ≤3.0 was associated with an increased MACE risk for both FFR >0.80 (41.0% vs 26.0%; adjusted HR: 1.59; 95% CI: 1.07-2.35; P = 0.021) and FFR ≤0.80 (34.7% vs 14.8%; adjusted HR: 2.32; 95% CI: 1.12-4.82; P = 0.024). CONCLUSIONS: Decreased MRR was associated with the presence of cardiac diastolic dysfunction as well as increased left ventricular filling pressure. The presence of CMD defined by MRR was independently associated with the risk for a composite of cardiovascular death, myocardial infarction, repeat revascularization, and admission for heart failure in patients with stable IHD, irrespective of significant epicardial coronary artery stenosis. (Prognostic Impact of Cardiac Diastolic Function and Coronary Microvascular Function [DIAST-CMD]; NCT05058833).

Deletion of Mixed Lineage Kinase Domain Like Pseudokinase Aggravates Chronic Alcohol-Induced Liver Injury via Increasing Apoptosis.

BACKGROUND AND AIM: he mixed lineage kinase domain like pseudokinase (MLKL) is known to play a protective role in non-alcoholic fatty liver disease (NAFLD) via inhibition of necroptosis pathway. However, the role of MLKL in alcoholic liver disease (ALD) is not yet clear. METHOD: C57BL/6N wild-type (WT) and MLKL-knockout (KO) mice (8-10 weeks old) were randomly divided into eight groups. To establish ALD model of different durations, ethanol (EtOH) was fed to WT and MLKL KO for 10 days, 4 weeks, and 8 weeks. The control group was fed with Lieber-DeCarli control diet for 8 weeks. Mortality, degree of hepatic inflammation, and steatosis were compared among the groups. Bulk mRNA transcriptome analysis was performed. Abundance of transcript and gene expressions were calculated based on read count or Transcript by Million (TPM) value. RESULTS: Survival rate of MLKL KO mice compared to WT was similar until 4 weeks, but the survival of MLKL KO mice significantly decreased after 8 weeks in ALD model. There was no difference in degree of inflammation, steatosis, and NAS scores between EtOH-fed MLKL KO and EtOH-fed WT mice at 10 days. However, at 4 weeks and 8 weeks, the degree of hepatic steatosis, NAS, and inflammation were increased in MLKL KO mice. RNA transcriptome data showed that fatty acid synthesis, and lipogenesis, mitochondria, and apoptosis-related pathways were upregulated in EtOH-fed MLKL KO mice compared to EtOH-fed WT mice. Although hepatocyte apoptosis (BAX/BCL2 ratio, caspase-3, and TUNEL staining) increased after EtOH intake; however, apoptosis was more significantly increased in EtOH-fed MLKL KO mice compared to the WT group. At the same time, hepatic cFLIP was decreased in EtOH-fed MLKL KO mice compared to the WT group. CONCLUSION: MLKL deletion did not prevent chronic alcohol-induced liver damage independently of necroptosis and exacerbated hepatic steatosis by increasing hepatocyte apoptosis.

Synergistic Effect of Manually Assisted Cough During Mechanical Insufflation-Exsufflation in Patients With Spinal Cord Injury.

BACKGROUND: Mechanical insufflation-exsufflation (MI-E) and manually assisted cough are frequently employed cough augmentation methods for enhancing cough efficiency in individuals with cervical spinal cord injury (CSCI). This study aimed to evaluate the synergistic impact of combining manually assisted cough and MI-E on cough peak flow in subjects with CSCI and identify their related factors. METHODS: Fifteen subjects with CSCI with cough peak flow > -270 L/min underwent 5 consecutive days of 5 cough augmentation sessions; cough peak flow during exsufflation and the total insufflation volume (TIV) during insufflation were measured. Only MI-E was administered on days 1 and 5, whereas on days 2-4 one MI-E-only session followed by 3 MI-E and manually assisted cough sessions was implemented followed by a fifth MI-E-only session. The cumulative and carry-over effects of increasing treatment sessions and any associated factor on cough peak flow during MI-E-assisted coughing were assessed using a linear mixed model (LMM) with repetitive air-flow measurements within the same participants. RESULTS: No cumulative or carry-over effects of manually assisted cough and MI-E were shown with the accumulation of treatment days or sessions. The LMM confirmed that using manually assisted cough (-0.283 L/s, P < .001), TIV (-0.045 L/s, P = .002), and the individual manually assisted cough variance (-0.022 L/s, P = .01) significantly influenced cough peak flow. Estimated mean cough peak flows for MI-E with manually assisted cough and MI-E alone were -4.006 L/s (95% CI -4.237 to -3.775) and -3.723 L/s (95% CI -3.953 to -3.492), respectively, surpassing the initial voluntary cough peak flow without MI-E assistance (-1.65 ± 0.53 L/s). CONCLUSIONS: The use of manually assisted cough and amount of TIV correlated with improved cough peak flow, emphasizing the importance of adequate in-expiratory support. No carry-over effect was associated with using manually assisted cough, highlighting the need to combine MI-E with manually assisted cough for each MI-E treatment to achieve optimal cough effectiveness.