Hepatic IL22RA1 deficiency promotes hepatic steatosis by modulating oxysterol in the liver.

BACKGROUND AIMS: Imbalance in lipid metabolism is the main cause of nonalcoholic fatty liver disease (NAFLD). While the pathogenesis of lipid accumulation mediated by extrahepatic regulators has been extensively studied, the intrahepatic regulators modulating lipid homeostasis remain unclear. Previous studies have shown that systemic administration of interleukin-22 (IL-22) protects against NAFLD; however, the role of IL-22/IL22RA1 signaling in modulating hepatic lipid metabolism remains uncertain. APPROACH RESULTS: This study shows hepatic IL22RA1 is vital in hepatic lipid regulation. IL22RA1 is downregulated in palmitic acid-treated mouse primary hepatocytes, as well as in the livers of NAFLD model mice and patients. Hepatocyte-specific Il22ra1 knockout (HKO) mice display diet-induced hepatic steatosis, insulin resistance, impaired glucose tolerance, increased inflammation, and fibrosis compared with flox/flox mice. This is attributed to increased lipogenesis mediated by the accumulation of hepatic oxysterols, particularly, 3 beta-hydroxy-5-cholestenoic acid (3ß HCA). Mechanistically, hepatic IL22RA1 deficiency facilitates 3ß HCA deposition via the activating transcription factor 3 (ATF3)/oxysterol 7 alpha-hydroxylase (CYP7B1) axis. Notably, 3ß HCA facilitates lipogenesis in MPHs and human liver organoids (HLOs) by activating LXR-alpha signaling, but IL-22 treatment attenuates this effect. Additionally, restoring CYP7B1 or silencing hepatic ATF3 reduces both hepatic 3ß HCA and lipid contents in HKO mice. CONCLUSIONS: These findings indicate that IL22RA1 plays a crucial role in maintaining hepatic lipid homeostasis in an ATF3/CYP7B1-dependent manner, and establish a link between 3ß HCA and hepatic lipid homeostasis.

Molecular and Physiological Effects of 17α-methyltestosterone on Sex Differentiation of Black Rockfish, Sebastes schlegelii.

It is widely known that all-female fish production holds economic value for aquaculture. Sebastes schlegelii, a preeminent economic species, exhibits a sex dimorphism, with females surpassing males in growth. In this regard, achieving all-female black rockfish production could significantly enhance breeding profitability. In this study, we utilized the widely used male sex-regulating hormone, 17α-methyltestosterone (MT) at three different concentrations (20, 40, and 60 ppm), to produce pseudomales of S. schlegelii for subsequent all-female offspring breeding. Long-term MT administration severely inhibits the growth of S. schlegelii, while short term had no significant impact. Histological analysis confirmed sex reversal at all MT concentrations; however, both medium and higher MT concentrations impaired testis development. MT also influenced sex steroid hormone levels in pseudomales, suppressing E2 while increasing T and 11-KT levels. In addition, a transcriptome analysis revealed that MT down-regulated ovarian-related genes (cyp19a1a and foxl2) while up-regulating male-related genes (amh) in pseudomales. Furthermore, MT modulated the TGF-ß signaling and steroid hormone biosynthesis pathways, indicating its crucial role in S. schlegelii sex differentiation. Therefore, the current study provides a method for achieving sexual reversal using MT in S. schlegelii and offers an initial insight into the underlying mechanism of sexual reversal in this species.

A machine learning-based model analysis for serum markers of liver fibrosis in chronic hepatitis B patients.

Early assessment and accurate staging of liver fibrosis may be of great help for clinical diagnosis and treatment in patients with chronic hepatitis B (CHB). We aimed to identify serum markers and construct a machine learning (ML) model to reliably predict the stage of fibrosis in CHB patients. The clinical data of 618 CHB patients between February 2017 and September 2021 from Zhejiang Provincial People's Hospital were retrospectively analyzed, and these data as a training cohort to build the model. Six ML models were constructed based on logistic regression, support vector machine, Bayes, K-nearest neighbor, decision tree (DT) and random forest by using the maximum relevance minimum redundancy (mRMR) and gradient boosting decision tree (GBDT) dimensionality reduction selected features on the training cohort. Then, the resampling method was used to select the optimal ML model. In addition, a total of 571 patients from another hospital were used as an external validation cohort to verify the performance of the model. The DT model constructed based on five serological biomarkers included HBV-DNA, platelet, thrombin time, international normalized ratio and albumin, with the area under curve (AUC) values of the DT model for assessment of liver fibrosis stages (F0-1, F2, F3 and F4) in the training cohort were 0.898, 0.891, 0.907 and 0.944, respectively. The AUC values of the DT model for assessment of liver fibrosis stages (F0-1, F2, F3 and F4) in the external validation cohort were 0.906, 0.876, 0.931 and 0.933, respectively. The simulated risk classification based on the cutoff value showed that the classification performance of the DT model in distinguishing hepatic fibrosis stages can be accurately matched with pathological diagnosis results. ML model of five serum markers allows for accurate diagnosis of hepatic fibrosis stages, and beneficial for the clinical monitoring and treatment of CHB patients.

Over-expression of Medicago Acyl-CoA-binding 2 genes enhance salt and drought tolerance in Arabidopsis.

Acyl-CoA-binding proteins (ACBPs) are mainly involved in acyl-CoA ester binding and trafficking in eukaryotic cells, and they function in lipid metabolism, membrane biosynthesis, cellular signaling, stress response, disease resistance, and other biological activities in plants. However, the roles of ACBP family members in Medicago remain unclear. In this study, a total of eight ACBP genes were identified in the genome of Medicago truncatula and Medicago sativa, and they were clustered into four sub-families (Class I-IV). Many cis-acting elements related to abiotic response were identified in the promoter region of these ACBP genes, in particular light-responsive elements. These ACBP genes exhibited distinct expression pattern in various tissues, and the expression level of MtACBP1/MsACBP1 and MtACBP2/MsACBP2 gene pairs were significantly increased under NaCl treatment. Subcellular localization analysis showed that MtACBP1/MsACBP1 and MtACBP2/MsACBP2 were localized in the endoplasmic reticulum of tobacco epidermal cells. Arabidopsis seedlings over-expressing MtACBP2/MsACBP2 displayed increased root length than the wild type under short light, Cu2+, ABA, PEG, and NaCl treatments. Over-expression of MtACBP2/MsACBP2 also significantly enhanced Arabidopsis tolerance under NaCl and PEG treatments in mature plants. Collectively, our study identified salt and drought responsive ACBP genes in Medicago and verified their functions in increasing resistance against salt and drought stresses.

Variability in the relationship between light scattering and chlorophyll a concentration in oligotrophic tropical regions of the Western Pacific Ocean.

It is important to determine the relationship between the concentration of chlorophyll a (Chla) and the inherent optical properties (IOPs) of ocean water to develop optical models and algorithms that characterize the biogeochemical properties and estimate biological pumping and carbon flux in this environment. However, previous studies reported relatively large variations in the particulate backscattering coefficient (bbp(λ)) and Chla from more eutrophic high-latitude waters to clear oligotrophic waters, especially in oligotrophic oceanic areas where these two variables have little covariation. In this study, we examined the variability of bbp(λ) and Chla in the euphotic layer in oligotrophic areas of the tropical Western Pacific Ocean and determined the sources of these variations by reassessment of in-situ measurements and the biogeochemical-argo (BGC-Argo) database. Our findings identified covariation of bbp(λ) and Chla in the water column below the deep Chla maximum (DCM) layer, and indicated that there was no significant correlation relationship between bbp(λ) and Chla in the upper layer of the DCM. Particles smaller than 3.2 µm that were in the water column above the DCM layer had a large effect on the bbp(λ) in the vertical profile, but particles larger than 3.2 µm and smaller than 10 µm had the largest effect on the bbp(λ) in the water column below the DCM layer. The contribution of non-algal particles (NAPs) to backscattering is up to 50%, which occurs in the water depth of 50 m and not consistent with the distribution of Chla. Phytoplankton and NAPs were modeled as coated spheres and homogeneous spherical particles to simulate the bbp(λ) of the vertical profile by Aden-Kerker method and Mie theory, and the results also indicated that the backscattering caused by particles less than 20 µm were closer to the measured data when they were below and above the DCM layer, respectively. This relationship also reflects the bbp(λ) of particles in the upper water was significantly affected particle size, but bbp(λ) in the lower water was significantly affected by Chla concentration. This effect may have relationship with phytoplankton photoacclimation and the relationship of a phytoplankton biomass maximum with particle size distribution in the water column according to the previous relevant studies. These characteristics also had spatial and seasonal variations due to changes of Chla concentration at the surface and at different depths. There was mostly a linear relationship between Chla and bbp(700) during winter. During other seasons, the relationship between these two variables was better characterized by a power function (or a logarithmic function) in the lower layer of the DCM. The spatial and vertical relationships between the bbp(λ) and Chla and the corresponding variations in the types of particles described in this study provide parameters that can be used for accurate estimation of regional geochemical processes.

The effect of obesity on the outcome of thoracic endovascular aortic repair: a systematic review and meta-analysis.

Background: Obesity is a well-known predictor for poor postoperative outcomes of vascular surgery. However, the association between obesity and outcomes of thoracic endovascular aortic repair (TEVAR) is still unclear. This systematic review and meta-analysis was performed to assess the roles of obesity in the outcomes of TEVAR. Methods: We systematically searched the Web of Science and PubMed databases to obtain articles regarding obesity and TEVAR that were published before July 2023. The odds ratio (OR) or hazard ratio (HR) was used to assess the effect of obesity on TEVAR outcomes. Body mass index (BMI) was also compared between patients experiencing adverse events after TEVAR and those not experiencing adverse events. The Newcastle-Ottawa Scale was used to evaluate the quality of the enrolled studies. Results: A total of 7,849 patients from 10 studies were included. All enrolled studies were high-quality. Overall, the risk of overall mortality (OR = 1.49, 95% CI [1.02-2.17], p = 0.04) was increased in obese patients receiving TEVAR. However, the associations between obesity and overall complications (OR = 2.41, 95% CI [0.84-6.93], p = 0.10) and specific complications were all insignificant, including stroke (OR = 1.39, 95% CI [0.56-3.45], p = 0.48), spinal ischemia (OR = 0.97, 95% CI [0.64-1.47], p = 0.89), neurological complications (OR = 0.13, 95% CI [0.01-2.37], p = 0.17), endoleaks (OR = 1.02, 95% CI [0.46-2.29], p = 0.96), wound complications (OR = 0.91, 95% CI [0.28-2.96], p = 0.88), and renal failure (OR = 2.98, 95% CI [0.92-9.69], p = 0.07). In addition, the patients who suffered from postoperative overall complications (p < 0.001) and acute kidney injury (p = 0.006) were found to have a higher BMI. In conclusion, obesity is closely associated with higher risk of mortality after TEVAR. However, TEVAR may still be suitable for obese patients. Physicians should pay more attention to the perioperative management of obese patients.

Overexpression of MsNIP2 improves salinity tolerance in Medicago sativa.

Alfalfa (Medicago sativa) is one of the most widely cultivated forage crops in the world. However, alfalfa yield and quality are adversely affected by salinity stress. Nodulin 26-like intrinsic proteins (NIPs) play essential roles in water and small molecules transport and response to salt stress. Here, we isolated a salt stress responsive MsNIP2 gene and demonstrated its functions by overexpression in alfalfa. The open reading frame of MsNIP2 is 816 bp in length, and it encodes 272 amino acids. It has six transmembrane domains and two NPA motifs. MsNIP2 showed high identity to other known NIP proteins, and its tertiary model was similar to the crystal structure of OsNIP2-1 (7cjs) tetramer. Subcellular localization analysis showed that MsNIP2 protein fused with green fluorescent protein (GFP) was localized to the plasma membrane. Transgenic alfalfa lines overexpressing MsNIP2 showed significantly higher height and branch number compared with the non-transgenic control. The POD and CAT activity of the transgenic alfalfa lines was significantly increased and their MDA content was notably reduced compared with the control group under the treatment of NaCl. The transgenic lines showed higher capability in scavenging oxygen radicals with lighter NBT staining than the control under salt stress. The transgenic lines showed relative lower water loss rate and electrolyte leakage, but relatively higher Na+ content than the control line under salt stress. The relative expression levels of abiotic-stress-related genes (MsHSP23, MsCOR47, MsATPase, and MsRD2) in three transgenic lines were compared with the control, among them, only the expression of MsCOR47 was up-regulated. Consequently, this study offers a novel perspective for exploring the function of MsNIP2 in improving salt tolerance of alfalfa.

Idiopathic mesenteric phlebosclerosis occurring in a patient with liver cirrhosis: A case report.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare gastrointestinal disease with unclear etiology and pathogenesis. IMP occurring in a patient with liver cirrhosis is more scarcely reported than independent IMP. In this study, we reported a case of IMP occurring in a patient with liver cirrhosis, so as to provide a reference for understanding liver cirrhosis with IMP. METHOD: A 63-year-old man with liver cirrhosis was admitted in the hospital's department of infectious disease because of fatigue and constipation for 1 month. The patient had an irregular medical history of antivirus drug and Chinese herbal medicine intake because of the hepatitis B virus infection. No other abnormalities were found in the functions of the liver, coagulation, renal, or complete blood count. Fecal occult blood tests were all positive in 5 detections. Contrast-enhanced computed tomography revealed liver cirrhosis and showed thickening of the wall of the right hemicolon and multiple calcifications of the mesenteric veins. Mesenteric vein computed tomography venography displayed diffuse colon mural thickening of the right colon and tortuous linear calcification line in the right colic veins. Colonoscopy revealed a purple-blue, swollen, rough, and vanished vascular texture mucosa. He was finically diagnosed as liver cirrhosis with IMP by a series of examinations during hospitalization. RESULTS: His symptoms of fatigue and constipation subsided after conservative treatment and withdraw from Chinese herbal medicine. The patient experienced no obvious discomfort during the follow-up period. CONCLUSION: A comprehensive medical diagnosis is necessary for the discovery of IMP, especially IMP with liver cirrhosis. Liver cirrhosis maybe play a key role in the development of IMP. The regulatory mechanism of liver cirrhosis contributing to IMP needs to be further studied based on more clinical cases.

Detection of Chylous Plasma Based on Machine Learning and Hyperspectral Techniques.

Chylous blood is the main cause of unqualified and scrapped blood among volunteer blood donors. Therefore, a diagnostic method that can quickly and accurately identify chylous blood before donation is needed. In this study, the GaiaSorter "Gaia" hyperspectral sorter was used to extract 254 bands of plasma images, ranging from 900 nm to 1700 nm. Four different machine learning algorithms were used, including decision tree, Gaussian Naive Bayes (GaussianNB), perceptron, and stochastic gradient descent models. First, the preliminary classification accuracies were compared with the original data, which showed that the effects of the decision tree and GaussianNB models were better; their average accuracies could reach over 90%. Then, the feature dimension reduction was performed on the original data. The results showed that the effects of the decision tree were better with a classification accuracy of 93.33%. the classification of chylous plasma using different chylous indices suggested that the accuracies of the decision trees model both before and after the feature dimension reductions were the best with over 80% accuracy. The results of feature dimension reduction showed that the characteristic bands corresponded to all kinds of plasma, thereby showing their classification and identification potential. By applying the spectral characteristics of plasma to medical technology, this study suggested a rapid and effective method for the identification of chylous plasma and provided a reference for the blood detection technology to achieve the goal of reducing wasting blood resources and improving the work efficiency of the medical staff.

Cardiac-specific deletion of BRG1 ameliorates ventricular arrhythmia in mice with myocardial infarction.

Malignant ventricular arrhythmia (VA) after myocardial infarction (MI) is mainly caused by myocardial electrophysiological remodeling. Brahma-related gene 1 (BRG1) is an ATPase catalytic subunit that belongs to a family of chromatin remodeling complexes called Switch/Sucrose Non-Fermentable Chromatin (SWI/SNF). BRG1 has been reported as a molecular chaperone, interacting with various transcription factors or proteins to regulate transcription in cardiac diseases. In this study, we investigated the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. Myocardial infarction (MI) mice were established by ligating the left anterior descending (LAD) coronary artery, and electrocardiogram (ECG) was monitored. Epicardial conduction of MI mouse heart was characterized in Langendorff-perfused hearts using epicardial optical voltage mapping. Patch-clamping analysis was conducted in single ventricular cardiomyocytes isolated from the mice. We showed that BRG1 expression in the border zone was progressively increased in the first week following MI. Cardiac-specific deletion of BRG1 by tail vein injection of AAV9-BRG1-shRNA significantly ameliorated susceptibility to electrical-induced VA and shortened QTc intervals in MI mice. BRG1 knockdown significantly enhanced conduction velocity (CV) and reversed the prolonged action potential duration in MI mouse heart. Moreover, BRG1 knockdown improved the decreased densities of Na+ current (INa) and transient outward potassium current (Ito), as well as the expression of Nav1.5 and Kv4.3 in the border zone of MI mouse hearts and in hypoxia-treated neonatal mouse ventricular cardiomyocytes. We revealed that MI increased the binding among BRG1, T-cell factor 4 (TCF4) and ß-catenin, forming a transcription complex, which suppressed the transcription activity of SCN5A and KCND3, thereby influencing the incidence of VA post-MI.

Spatiotemporal dynamics of traffic bottlenecks yields an early signal of heavy congestions.

Heavy traffic jams are difficult to predict due to the complexity of traffic dynamics. Understanding the network dynamics of traffic bottlenecks can help avoid critical large traffic jams and improve overall traffic conditions. Here, we develop a method to forecast heavy congestions based on their early propagation stage. Our framework follows the network propagation and dissipation of the traffic jams originated from a bottleneck emergence, growth, and its recovery and disappearance. Based on large-scale urban traffic-speed data, we find that dissipation duration of jams follows approximately power-law distributions, and typically, traffic jams dissolve nearly twice slower than their growth. Importantly, we find that the growth speed, even at the first 15 minutes of a jam, is highly correlated with the maximal size of the jam. Our methodology can be applied in urban traffic control systems to forecast heavy traffic bottlenecks and prevent them before they propagate to large network congestions.

Numerical study on the effect of temperature rise of humeral bone nails in magnetic resonance imaging based on the finite-element method.

BACKGROUND: Humeral fracture is a common long bone fracture in orthopedic clinical diagnosis and treatment. OBJECTIVE: To investigate the local temperature increase owing to changes in the specific absorption ratio (SAR) of the human body caused by humeral bone nails during magnetic resonance imaging (MRI). METHODS: A refined geometric model of the upper body was constructed via data segmentation and post-processing using the digital human image dataset. Finally, the geometric model was imported into COMSOL, a 3-T magnetic resonance coil was built, and the operating frequency (128 MHz) was set to analyze the SAR of the bone-nail pair and temperature changes. RESULTS: The analysis of the changes after bone-nail implantation under different tissue conditions revealed that the SAR and temperature after implantation and fixation were three times higher than those before, and the areas with abrupt changes in SAR and temperature were primarily concentrated in the bone-nail area. CONCLUSION: In MRI, metal implants can cause local elevation of the SAR near the implant in the human body, resulting in a temperature increase around the implant. Consequently, long-term scanning can damage the human body.

Two CYP93A enzymes play a dual role in isoflavonoid biosynthesis in Glycine max L.

Glycine max L. is rich in isoflavonoids with diverse biological activities. However, isoflavonoid biosynthetic pathway is not fully elucidated in soybean. In the present study, we investigated characteristics of all the thirteen CYP93 subfamily members, and found GmCYP93A1, GmCYP93A2, and GmCYP93A3 are closely clustered, preferentially expressed in roots, and highly inducible by elicitor. When expressed in yeast, GmCYP93A1 was active towards liquiritigenin, naringenin, and 3,9-dihydroxyptercarpan, GmCYP93A2 towards 3,9-dihydroxyptercarpan with strict substrate specificity, whereas GmCYP93A3 did not show any activity towards all the tested substrates. Both GmCYP93A1 and GmCYP93A2 could catalyze 3,9-dihydroxyptercarpan into daidzein and glycinol, with both hydroxylation and aryl migration activity. Site-directed mutagenesis assays revealed that mutation in Thr446 to Ser446 in heme-binding domain increased the enzyme activity of GmCYP93A1 towards 3,9-dihydroxyptercarpan, which highlights its key amino acid residues as shown with its molecular docking with 3,9-dihydroxyptercarpan and HEM. Overexpression of GmCYP93A1 and GmCYP93A2 in the soybean hairy roots reduced the content of daidzein, whereas knockdown of these two genes increased genistein content, indicating changes in expression level of GmCYP93A1 and GmCYP93A2 altered isoflavonoid flux in soybean. Our studies on the activity of GmCYP93A1 and GmCYP93A2 enriched diverse functions of CYP93 subfamily in soybean isoflavonoid pathway, which is valuable for further understanding and bioengineering of isoflavonoid pathway in soybean.

The effect of sodium bicarbonate on OHCA patients: A systematic review and meta-analysis of RCT and propensity score studies.

BACKGROUND: Evidence on the efficacy of sodium bicarbonate (SB) in out-of-hospital cardiac arrest (OHCA) is controversial and generally of low quality. A systematic review and meta-analysis was performed to evaluate the effect of SB in OHCA patients based on randomized controlled trial (RCT) and propensity score matching (PSM) cohort studies. METHODS: We searched the PubMed, Cochrane, and Embase databases for RCTs and PSM cohort studies from inception to July 15, 2023. We included studies involving adult (>16 years) no-trauma OHCA patients with clear comparisons between the Bicarbonate group and Control group. All studies reported our primary outcome of short-term survival rate included ROSC and survival to emergency department or hospital admission or secondary outcome of long-term survival rate included survival at hospital discharge and good neurologic survival at 1 month. Results were expressed as odds ratio (OR) with accompanying 95% confidence interval (CI). To reduce bias, we performed a subgroup analysis of RCTs and PSM cohort studies. Also, we performed sensitivity analysis to resolve the heterogeneity. RESULTS: Six studies (3 RCTs and 3 PSMs) comprising 21,402 patients were included. The primary outcome of this meta-analysis showed that short-term survival rate between the two groups was no difference (OR = 1.04; 95% CI, 0.98 to 1.12; P = 0.21; χ2 = 6.68; I2 = 25%). Secondary outcome demonstrated that long -term survival rate between the two groups was no difference (OR = 0.82; 95% CI, 0.50 to 1.34; P = 0.43; χ2 = 14.96; I2 = 80%). A sensitive analysis was performed by removing one study showed long-term survival rate of the Bicarbonate group was lower than that of the Control group. CONCLUSIONS: In patients with OHCA, sodium bicarbonate administration was associated neither with short-term survival rate nor with long-term survival rate, it may even worsen the long-term survival.

Clinical Distribution Characteristics and Identification for Significant Liver Inflammation of Patients in Chronic Hepatitis B with Indeterminate Phase.

Aim: In clinical practice, a considerable proportion of patients with chronic hepatitis B (CHB) who do not conform to any immune status are considered to be in the "indeterminate phase". In this study, we aim to study the clinical distribution characteristics and identification of significant liver inflammation in patients in indeterminate phase. Methods: This study retrospectively analyze clinical data of 1226 patients with CHB at two medical centers in Zhejiang province. According to American Association for the Study of Liver Diseases (AASLD) 2018 hepatitis B guidance, CHB can be divided into four phases: immune-tolerant phase, HBeAg-positive immune active phase, inactive phase, and HBeAg-negative immune active phase. Liver inflammation grade was evaluated using the Scheuer scoring system, and significant liver inflammation was defined as G ≥ 2. Results: The distribution of different immune status was as follows: 259 (21.1%) patients in immune-tolerant phase, 365 (29.8%) patients in HBeAg-positive immune active phase, 128 (10.4%) patients in inactive phase, and 33 (2.7%) patients in HBeAg-negative immune active phase. However, 441 (36.0%) patients did not meet any of the above immune phases, which were defined as indeterminate phase. Significant liver inflammation (54.1%) was common in CHB patients with indeterminate phase. Prothrombin time (PT), platelet count (PLT), alanine aminotransferase (ALT), and hepatitis B virus (HBV)-DNA were associated with significant inflammation. Conclusions: The results of this study showed that about 36.0% of patients were divided into indeterminate phase. The proportion of patients with significant inflammation in indeterminate phase and liver inflammation becomes more severe with aggravation of fibrosis stage. PT, PLT, ALT, and HBV-DNA may have a significant correlation with severe inflammation and prognosis of CHB.

Predictive value of extubation failure by decrease in central venous oxygen saturation: A systematic review and meta-analysis.

Background: The predictive power of extubation failure diagnosed by decrease in central venous oxygen saturation (ΔScvO2) varies by studies. Here we summarized the diagnostic value of extubation failure tested by ΔScvO2. Methods: A comprehensive online search was performed to select potentially eligible studies that evaluated the predictive power of extubation failure tested by ΔScvO2. A manual search was also performed to identify additional studies. Data were extracted to calculate the pooled sensitivity, specificity, positive likelihood ratio (LR), negative LR, diagnostic odds ratio (DOR), and area under the receiver operating characteristic curve (AUC) to evaluate the predictive power of extubation failure. Results: Overall, five studies including 353 patients were included in this review, of whom 105 (30%) were extubation failure. The cutoff values of ΔScvO2 varied across studies, ranging from 3.8% to 5.4%. Heterogeneity between studies was assessed with an overall Q = 0.007, I2 = 0%, and P = 0.498. The pooled sensitivity and specificity for the overall population were 0.83 (95% CI: 0.74-0.90) and 0.88 (95% CI: 0.83-0.92), respectively. The pooled positive LR and negative LR were 7.2 (95%CI: 4.6-11.2) and 0.19 (95%CI: 0.12-0.31), respectively. The DOR was 38 (95% CI: 17-86). Overall, the pooled AUROC was 0.92 (95% CI: 0.90-0.94). Conclusions: The ΔScvO2 performed well in predicting extubation failure in adult mechanical ventilation patients. Further studies with a larger data set and well-designed models are required to confirm the diagnostic accuracy and utility of ScvO2 in predicting extubation outcomes in mechanical ventilation patients.

Neoadjuvant therapy with Disitamab vedotin in treating muscle-invasive bladder cancer: A case report.

Purpose: Platinum-based regimens are regarded as the preferred alternative for neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) patients. However, some patients cannot tolerate platinum-based regimens. We report an MIBC case with severe renal insufficiency treated by neoadjuvant therapy with gemcitabine and Disitamab Vedotin. Materials and Methods: A 68-year-old man with severe renal insufficiency was admitted to our department and diagnosed with cT3N0M0 MIBC. Immunohistochemical staining of the biopsy tissues showed human epidermal growth factor receptor 2 expression (1+). This patient received neoadjuvant therapy with gemcitabine 1600 mg and DV 120 mg intravenously every three weeks 3 times. We compared the imaging results of the patient before and after neoadjuvant therapy. In addition, the white blood cell count, alanine aminotransferase, aspartate aminotransferase, and serum creatinine were followed up during neoadjuvant therapy. Abnormal symptoms such as hair loss, fatigue, and hypoesthesia were also recorded. Results: According to the imaging examinations, the lesions were significantly reduced after receiving neoadjuvant therapy. Significant adverse side effects did not occur during neoadjuvant therapy. Conclusions: In this T3N0M0 cisplatin-ineligible patient, gemcitabine combined with DV as neoadjuvant therapy achieved radiological partial response, and no significant adverse events were observed during neoadjuvant therapy.

PFI-3 induces vasorelaxation with potency to reduce extracellular calcium influx in rat mesenteric artery.

Background: PFI-3 is a small-molecule inhibitor that targets the bromodomains (BRDs) of Brahma-related gene 1 (BRG1). This monomeric compound, which has high selectivity and potent cellular effects, has recently been developed. Although PFI-3 has been reported as a potential therapeutic agent targeting thrombomodulin, its role in the regulation of vascular function remains unknown. Therefore, we aimed to investigate the impact of PFI-3 on arterial vessel tone. Methods: A microvascular tension measurement device (DMT) was utilized to identify alterations in vascular tension within the mesenteric artery. To detect variations in cytosolic [Ca2+]i, a Fluo-3/AM fluorescent probe and fluorescence microscope were employed. Additionally, whole-cell patch clamp techniques were utilized to evaluate the activity of L-type voltage-dependent calcium channels (VDCCs) in cultured arterial smooth muscle cells (A10 cells). Results: PFI-3 exerted a dose-dependent relaxation effect on rat mesenteric arteries with both intact and denuded endothelium after phenylephrine (PE)- and high-K+-induced constriction. PFI-3-induced vasorelaxation was not affected by the presence of L-NAME/ODQ or K+ channel blockers (Gli/TEA). PFI-3 abolished Ca2+-induced contraction on endothelium-denuded mesenteric arteries preincubated by PE in Ca2+-free solution. Incubation with TG had no impact on PFI-3-induced vasorelaxation pre-contracted by PE. PFI-3 reduced Ca2+-induced contraction on endothelium-denuded mesenteric arteries pre-incubated by KCl (60 mM) in Ca2+-free solution. PFI-3 declined extracellular calcium influx in A10 cells detected by Fluo-3/AM fluorescent probe and fluorescence microscope. Furthermore, we observed that PFI-3 decreased the current densities of L-type VDCC by whole-cell patch clamp techniques. Conclusions: PFI-3 blunted PE and high K+-induced vasoconstriction independent of endothelium on rat mesenteric artery. The vasodilatory effect of PFI-3 may be attributed to its inhibition of VDCCs and receptor-operated calcium channels (ROCCs) on vascular smooth muscle cells (VSMCs).