Transcatheter closure of atrial septal defect with deficient posterior-inferior or inferior vena cava rim under echocardiography only: a feasibility and safety analysis.

BACKGROUND: The safe closure of atrial septal defect with deficient posterior-inferior or inferior vena cava rim is a controversial issue. Few studies have been conducted on the closure of atrial septal defect with deficient posterior-inferior or inferior vena cava rim without fluoroscopy. This study evaluated the feasibility and safety of echocardiography-guided transcatheter closure of atrial septal defect with deficient posterior-inferior or inferior vena cava rim. METHODS: The data of 136 patients who underwent transcatheter atrial septal defect closure without fluoroscopy from March 2017 to March 2020 were retrospectively analysed. The patients were classified into the deficient (n = 45) and sufficient (n = 91) posterior-inferior or inferior vena cava rim groups. Procedure and the follow-up results were compared between the two groups. RESULTS: Atrial septal defect indexed diameter and the device indexed diameter in the deficient rim group were both larger than that in the sufficient rim group (22.12 versus 17.38 mm/m2, p < 0.001; 24.77 versus 21.21 mm/m2, p = 0.003, respectively). There was no significant difference in the success rate of occlusion between two groups (97.78% in the deficient rim group versus 98.90% in the sufficient rim group, p = 1.000). During follow-up, the incidence of severe adverse cardiac events was not statistically significant (p = 0.551). CONCLUSIONS: Atrial septal defect with deficient posterior-inferior or inferior vena cava rim can safely undergo transcatheter closure under echocardiography alone if precisely evaluated with transesophageal or transthoracic echocardiography and the size of the occluder is appropriate. The mid-term results after closure are similar to that for an atrial septal defect with sufficient rim.

Association of metformin monotherapy or combined therapy with cardiovascular risks in patients with type 2 diabetes mellitus.

BACKGROUND: Metformin is a first-line drug in type 2 diabetes mellitus (T2DM) treatment, yet whether metformin may increase all-cause or cardiovascular mortality of T2DM patients remains inconclusive. METHODS: We searched PubMed and Embase for data extracted from inception to July 14, 2020, with a registration in PROSPERO (CRD42020177283). This study included randomized controlled trials (RCT) assessing the cardiovascular effects of metformin for T2DM. This study is followed by PRISMA and Cochrane guideline. Risk ratio (RR) with 95% CI was pooled across trials by a random-effects model. Primary outcomes include all-cause mortality and cardiovascular mortality. RESULTS: We identified 29 studies that randomly assigned patients with 371 all-cause and 227 cardiovascular death events. Compared with untreated T2DM patients, metformin-treated patients was not associated with lower risk of all-cause mortality (RR: 0.98; 95%CI: 0.69-1.38; P = 0.90), cardiovascular mortality (RR: 1.13; 95% CI: 0.60, 2.15; P = 0.70), macrovascular events (RR: 0.87; 95%CI: 0.70-1.07; P = 0.19), heart failure (RR: 1.02; 95% CI:0.61-1.71; P = 0.95), and microvascular events (RR: 0.78; 95% CI:0.54-1.13; P = 0.19). Combination of metformin with another hypoglycemic drug was associated with higher risk of all-cause mortality (RR: 1.49; 95% CI: 1.02, 2.16) and cardiovascular mortality (RR: 2.21; 95% CI: 1.22, 4.00) compared with hypoglycemic drug regimens with no metformin. CONCLUSION: The combination of metformin treatment may impose higher risk in all-cause and cardiovascular mortality. This finding, at least in part, shows no evidence for benefits of metformin in combination in terms of all-cause/cardiovascular mortality and cardiovascular events for T2DM. However, the conclusion shall be explained cautiously considering the limitations from UK Prospective Diabetes Study (UKPDS).

17ß-Estradiol Promotes Angiogenesis of Rat Cardiac Microvascular Endothelial Cells In Vitro.

BACKGROUND The formation of new blood vessels, known as angiogenesis, is critical for recovery from ischemic heart disease, and estrogen is considered an important factor in this process. Here, we investigated the effects of 17ß-estradiol (17ß-E2) on proliferation and migration of cardiac microvascular endothelial cells (CMECs) in vitro. MATERIAL AND METHODS Rat CMECs were isolated and cultured with 17ß-E2 (0.001-1 µmol/l) in the absence or presence of the estrogen antagonist tamoxifen. Then, the expression level of estrogen receptor alpha was evaluated by using immunofluorescence assay, RT-PCR, and Western blot. Cell proliferation was detected by methyl thiazolyl tetrazolium analysis and the cell migration was verified by a scraping assay and quantified by a Transwell chamber assay. CMEC differentiation was examined using a tube formation assay. Vascular endothelial growth factor (VEGF) secretion was detected by enzyme-linked immunosorbent assay. RESULTS CMECs exhibited homogenous, polygonal, exhibited contact inhibition, and had characteristically ovoid nuclei with 1 or 2 nucleoli, and the cytoplasm exhibited red fluorescence after staining for von Willebrand factor. 17ß-E2 treatment upregulated estrogen receptor alpha expression in CMECs. 17ß-E2 treatment significantly promoted the proliferation, migration, tubular structure formation, and VEGF secretion in CMECs. The maximal proliferation occurred in the presence of 0.01 µmol/l 17ß-E2. Furthermore, estrogen and VEGF were found to synergistically stimulate angiogenesis. CONCLUSIONS Our data show that 17ß-E2 promotes angiogenesis in vitro and suggests that estrogen treatment as a novel therapeutic modality in the management of arterial insufficiency.

Nuclear AMPK regulated CARM1 stabilization impacts autophagy in aged heart.

Senescence-associated autophagy downregulation leads to cardiomyocyte dysfunction. Coactivator-associated arginine methyltransferase 1 (CARM1) participates in many cellular processes, including autophagy in mammals. However, the effect of CARM1 in aging-related cardiac autophagy decline remains undefined. Moreover, AMP-activated protein kinase (AMPK) is a key regulator in metabolism and autophagy, however, the role of nuclear AMPK in autophagy outcome in aged hearts still unclear. Hers we identify the correlation between nuclear AMPK and CARM1 in aging heart. We found that fasting could promote autophagy in young hearts but not in aged hearts. The CARM1 stabilization is markedly decrease in aged hearts, which impaired nucleus TFEB-CARM1 complex and autophagy flux. Further, S-phase kinase-associated protein 2(SKP2), responsible for CARM1 degradation, was increased in aged hearts. We further validated that AMPK dependent FoxO3 phosphorylation was markedly reduced in nucleus, the decreased nuclear AMPK-FoxO3 activity fails to suppress SKP2-E3 ubiquitin ligase. This loss of repression leads to The CARM1 level and autophagy in aged hearts could be restored through AMPK activation. Taken together, AMPK deficiency results in nuclear CARM1 decrease mediated in part by SKP2, contributing to autophagy dysfunction in aged hearts. Our results identified nuclear AMPK controlled CARM1 stabilization as a new actor that regulates cardiac autophagy.

Multivariate Analysis of Pleural Invasion of Peripheral Non-Small Cell Lung Cancer-Based Computed Tomography Features.

OBJECTIVE: The aim of this study was to comprehensively analyze computed tomography features to improve the diagnostic accuracy of visceral pleural invasion of peripheral non-small cell lung cancer. METHODS: The computed tomography features of 205 non-small cell lung cancer patients were retrospectively studied. The lesion's relation to the pleura was classified into 5 grades. A multivariate logistic regression analysis was conducted to identify independent factors predicting pleural invasion. RESULTS: The multivariate logistic regression analysis showed that sex (odds ratio [OR], 1.822; P = 0.080), pleural indentation (OR, 4.111; P < 0.001), tumor density (OR, 2.735; P = 0.008), and distance between the lesion and pleura (OR, 1.981; P = 0.048) were independent predictors of pleural invasion. A patient with a score of 10.6 had an 80% risk of pleural invasion, whereas a score lower than 2 was associated with a lower (20%) risk of pleural invasion. CONCLUSIONS: Comprehensive consideration of these factors of pleural indentation, sex, tumor density, and distance between the lesion and pleura might improve the diagnosis of pleural invasion.

rs2910164 Polymorphism Confers a Decreased Risk for Pulmonary Hypertension by Compromising the Processing of microRNA-146a.

OBJECTIVE: To identify the association between rs2910164 polymorphism and development of pulmonary hypertension, as well as underlying molecular mechanism. METHODS AND RESULTS: 281 patients diagnosed with pulmonary hypertension and 325 normal controls were recruited, and rs2910164 genotype was determined in each participant: As a result, the rs2910164 polymorphism was significantly associated with the development of pulmonary hypertension after adjusting some potential confounding factors. Additionally, lung tissue samples were obtained from 39 patients who received surgical intervention for lung cancer, and mRNA and protein expression levels of miR-146a, COX-2 and PGI2 production were examined. Furthermore, we confirmed COX-2 is a target of miR-146a in pulmonary smooth muscle cells, and identified a differentially expressed miR-146a and COX-2 in each rs2910164 genotype group. We observed a significant association between rs2910164 polymorphism and the levels of either COX-2 or PGI2 using real-time PCR and western blot. In conclusion, the results of this study demonstrate that the rs2910164 CC and GC genotype is associated with a decreased risk of pulmonary hypertension, which could be attributed to defective miRNA processing and compromised ability to inhibit production of COX-2 and PGI2.

Prodeath signaling of G protein-coupled receptor kinase 2 in cardiac myocytes after ischemic stress occurs via extracellular signal-regulated kinase-dependent heat shock protein 90-mediated mitochondrial targeting.

RATIONALE: G protein-coupled receptor kinase 2 (GRK2) is abundantly expressed in the heart, and its expression and activity are increased in injured or stressed myocardium. This upregulation has been shown to be pathological. GRK2 can promote cell death in ischemic myocytes, and its inhibition by a peptide comprising the last 194 amino acids of GRK2 (known as carboxyl-terminus of ß-adrenergic receptor kinase [bARKct]) is cardioprotective. OBJECTIVE: The aim of this study was to elucidate the signaling mechanism that accounts for the prodeath signaling seen in the presence of elevated GRK2 and the cardioprotection afforded by the carboxyl-terminus of ß-adrenergic receptor kinase. METHODS AND RESULTS: Using in vivo mouse models of ischemic injury and also cultured myocytes, we found that GRK2 localizes to mitochondria, providing novel insight into GRK2-dependent pathophysiological signaling mechanisms. Mitochondrial localization of GRK2 in cardiomyocytes was enhanced after ischemic and oxidative stress, events that induced prodeath signaling. Localization of GRK2 to mitochondria was dependent on phosphorylation at residue Ser670 within its extreme carboxyl-terminus by extracellular signal-regulated kinases, resulting in enhanced GRK2 binding to heat shock protein 90, which chaperoned GRK2 to mitochondria. Mechanistic studies in vivo and in vitro showed that extracellular signal-regulated kinase regulation of the C-tail of GRK2 was an absolute requirement for stress-induced, mitochondrial-dependent prodeath signaling, and blocking this led to cardioprotection. Elevated mitochondrial GRK2 also caused increased Ca(2+)-induced opening of the mitochondrial permeability transition pore, a key step in cellular injury. CONCLUSIONS: We identify GRK2 as a prodeath kinase in the heart, acting in a novel manner through mitochondrial localization via extracellular signal-regulated kinase regulation.

Diffusion-weighted images (DWI) without ADC values in assessment of small focal nodules in cirrhotic liver.

OBJECTIVE: To assess if diffusion-weighted magnetic resonance (MR) imaging without apparent diffusion coefficient (ADC) values provides added diagnostic value in combination with conventional MR imaging in the detection and characterization of small nodules in cirrhotic liver. METHODS: Two observers retrospectively and independently analyzed 86 nodules (≤3 cm) certified pathologically in 33 patients with liver cirrhosis, including 48 hepatocellular carcinoma (HCC) nodules, 13 high-grade dysplastic nodules (HDN), 10 low-grade dysplastic nodules (LDNs) and 15 other benign nodules. All these focal nodules were evaluated with conventional MR images (T1-weighted, T2-weighted and dynamic gadolinium-enhanced images) and breath-hold diffusion-weighted images (DWI) (b=500 s/mm(2)). The nodules were classified by using a scale of 1-3 (1, not seen; 3, well seen) on DWI for qualitative assessment. These small nodules were characterized by two radiologists. ADC values weren't measured. The diagnostic performance of the combined DWI-conventional images and the conventional images alone was evaluated using receiver operating characteristic (ROC) curves. The area under the curves (Az), sensitivity and specificity values for characterizing different small nodules were also calculated. RESULTS: Among 48 HCC nodules, 33 (68.8%) were graded as 3 (well seen), 6 (12.5%) were graded as 2 (partially obscured), and 9 weren't seen on DWI. Among 13 HDNs, there were 3 (23.1%) and 4 (30.8%) graded as 3 and 2 respectively. Five (50%) of 10 benign nodules were partially obscured and slightly hyperintense. For 86 nodules, the average diagnostic accuracy of combined DWI-conventional images was 82.56%, which was increased significantly compared with conventional MR images with 76.17%. For HCC and HDN, the diagnostic accuracy of combined DWI-conventional images increased from 78.69% to 86.07%. CONCLUSIONS: Diffusion-weighted MR imaging does provide added diagnostic value in the detection and characterization of HDN and HCC, and it may not be helpful for LDN and regenerative nodule (RN) in cirrhotic liver.

The differential diagnosis of lung precursor glandular lesions, micro-invasive adenocarcinoma, and invasive adenocarcinoma using low dose spectral computed tomography perfusion imaging.

Background: Few studies about the association between computed tomography (CT) perfusion imaging parameters and invasiveness in lung adenocarcinoma (LUAD) have been conducted using low dose spectral CT perfusion imaging. The purpose of this study was to investigate application of spectral revolution CT low-dose perfusion imaging in the differential diagnosis of different pathological subtypes of LUAD. Methods: This was a cross-sectional study based on historical data from January 2018 to May 2019 in Peking University Cancer Hospital & Institute. A total of 62 cases were enrolled, including 2 cases of atypical adenomatous hyperplasia (AAH), 3 cases of adenocarcinoma in situ (AIS), 4 cases of minimally invasive adenocarcinoma (MIA), and 53 cases of invasive adenocarcinoma (IAC), all confirmed with pathology. The inclusion and exclusion criteria were regulated. Using Revolution low-dose CT perfusion imaging (GE, USA), the CT perfusion parameters of hemodynamics were obtained: blood flow (BF), blood volume (BV), impulse residue function time of arrival (IRF TO), maximum slope of increase (MSI), mean transit time (MTT), permeability surface area product (PS), positive enhancement integral (PEI), and maximum enhancement time (Tmax). Univariate analysis of variance (ANOVA) or Kruskal-Wallis test was used to compare the differences of CT perfusion quantitative parameters among AAH, AIS, MIA, and IAC. Mann-Whitney test was used to compare the difference of CT perfusion imaging parameters between preinvasive lesions (AAH and AIS) and invasive lung cancer (MIA and IAC). Results: Statistically significant differences in IRF TO were observed in LUAD with different invasiveness, namely, among AIS, MIA, and IAC groups (0.56±0.74 vs. 0.54±1.08 vs. 4.39±2.19, P=0.004). Statistically significant differences in IRF TO were also observed between pre-invasive lesions group (AAH and AIS) and invasive lung cancer group (MIA and IAC) (1.12±1.27 vs. 3.75±2.79, P=0.031), and between AAH + AIS + MIA groups and IAC group (0.83±1.13 vs. 4.12±2.69, P<0.001). There were no statistically significant differences in other CT perfusion parameters of hemodynamics among different pathological subtypes of LUAD (P>0.05). Conclusions: The low-dose perfusion parameter IRF TO of revolution CT has the potential to be employed in the differential diagnosis of different pathological subtypes of LUAD.

Comparison of perventricular and percutaneous ultrasound-guided device closure of perimembranous ventricular septal defects.

Background: Ultrasound-guided percutaneous device closure of perimembranous ventricular septal defects (PmVSD) is a minimally invasive recent treatment approach. Perventricular PmVSD device closure is an emerging radiation-free intervention, yet it comes with certain limitations. No studies compared both of these treatment approaches. Methods: We performed a retrospective institutional data comparison of percutaneous (PCP Group, n = 138) and perventricular (PVP Group, n = 67) ultrasound-guided device closure procedures in 205 patients with PmVSD between March 2017 and December 2022. Results: Patients of the PCP and PVP groups had a median age of 4.9 years (IQR, 3.1-14.0) and 5.3 years (IQR, 3.4-13.1) respectively. The median PmVSD diameter in the PCP Group was 4.0 mm (IQR, 3.3-5.3) and 5.2 mm (IQR, 4.0-7.0) in the PVP Group (p = 0.001). There was no significant difference in success rates between the PCP and PVP Groups (intention-to-treat population, 88.4% vs. 92.5%, p = 0.36; as-treated population, 88.4% vs. 89.3%, p = 0.84). 5/8 failed percutaneous cases that were shifted to the perventricular approach were successful. Compared to the PVP Group, patients of the PCP group experienced a significant decrease in ventilation time, drainage volume, and postoperative hospital stay (p < 0.001). The median follow-up period was 24 months (IQR, 6-42) for the PCP group and 61 months (IQR, 53-65) for the PVP group. The overall severe adverse event rate was 0% in the PCP group and 3.0% in the PVP group. Conclusions: Perventricular and percutaneous ultrasound-guided device closure of PmVSD are both effective and safe treatment options. The percutaneous approach offers less trauma and faster recovery and may be the preferred approach in selected patients.

Prediction of the lymphatic, microvascular, and perineural invasion of pancreatic neuroendocrine tumors using preoperative magnetic resonance imaging.

BACKGROUND: Significant correlation between lymphatic, microvascular, and perineural invasion (LMPI) and the prognosis of pancreatic neuroendocrine tumors (PENTs) was confirmed by previous studies. There was no previous study reported the relationship between magnetic resonance imaging (MRI) parameters and LMPI. AIM: To determine the feasibility of using preoperative MRI of the pancreas to predict LMPI in patients with non-functioning PENTs (NFPNETs). METHODS: A total of 61 patients with NFPNETs who underwent MRI scans and lymphadenectomy from May 2011 to June 2018 were included in this retrospective study. The patients were divided into group 1 (n = 34, LMPI negative) and group 2 (n = 27, LMPI positive). The clinical characteristics and qualitative MRI features were collected. In order to predict LMPI status in NF-PNETs, a multivariate logistic regression model was constructed. Diagnostic performance was evaluated by calculating the receiver operator characteristic (ROC) curve with area under ROC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. RESULTS: There were significant differences in the lymph node metastasis stage, tumor grade, neuron-specific enolase levels, tumor margin, main pancreatic ductal dilatation, common bile duct dilatation, enhancement pattern, vascular and adjacent tissue involvement, synchronous liver metastases, the long axis of the largest lymph node, the short axis of the largest lymph node, number of the lymph nodes with short axis > 5 or 10 mm, and tumor volume between two groups (P < 0.05). Multivariate analysis showed that tumor margin (odds ratio = 11.523, P < 0.001) was a predictive factor for LMPI of NF-PNETs. The area under the receiver value for the predictive performance of combined predictive factors was 0.855. The sensitivity, specificity, PPV, NPV and accuracy of the model were 48.1% (14/27), 97.1% (33/34), 97.1% (13/14), 70.2% (33/47) and 0.754, respectively. CONCLUSION: Using preoperative MRI, ill-defined tumor margins can effectively predict LMPI in patients with NF-PNETs.

Procedure-related pain during CT-guided percutaneous transthoracic needle biopsies of lung lesions: a prospective study.

BACKGROUND: The existing data on the degree of pain in patients during CT-guided percutaneous transthoracic needle biopsy (PTNB) of lung lesions are limited and the factors related to pain are unclear. In this study, we aimed to evaluate the prevalence and severity of pain reported during PTNB and to identify factors associated with increased reported pain. METHODS: Patients who underwent PTNB from April 2022 to November 2022 were prospectively evaluated using the numeric rating scale, which assesses subjective pain based on a 0-10 scoring system (0 = no pain; 10 = the worst pain imaginable). The scale divides the scores into three categories: mild pain (1-3 points), moderate pain (4-6 points), and severe pain (7-10 points). Pain scores from 4 to 10 were considered significant pain. Demographic data of patients, lesion characteristics, biopsy variables, complications, the patient's subjective feelings, and pathological result data were analyzed by multivariable logistic regression analysis to identify variables associated with significant pain. RESULTS: We enrolled 215 participants who underwent 215 biopsy procedures (mean age: 64.5 ± 9.3 years, 123 were men). The mean procedure-related pain score was 2 ± 2. Overall, 20% (43/215) of participants reported no pain (score of 0), 67.9% (146/215) reported pain scores of 1-3, 11.2% (24/215) reported scores of 4-6, and 0.9% (2/215) reported scores of 7 or higher. Furthermore, non-significant pain (scores of 0-3) was reported during 87.9% (189/215) of the procedures. In the adjusted model, significant pain was positively associated with lesions ≥ 34 mm (p = 0.001, odds ratio [OR] = 6.90; 95% confidence interval [CI]: 2.18, 21.85), a needle-pleural angle ≥ 77° (p = 0.047, OR = 2.44; 95% CI: 1.01, 5.89), and a procedure time ≥ 26.5 min (p = 0.031, OR = 3.11; 95% CI: 1.11, 8.73). CONCLUSIONS: Most participants reported no pain or mild pain from CT-guided percutaneous transthoracic needle biopsies of lung lesions. However, those with a larger lesion, a greater needle-pleural angle, and a longer procedure time reported greater pain.

G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia.

BACKGROUND: Alterations in cardiac energy metabolism downstream of neurohormonal stimulation play a crucial role in the pathogenesis of heart failure. The chronic adrenergic stimulation that accompanies heart failure is a signaling abnormality that leads to the upregulation of G protein-coupled receptor kinase 2 (GRK2), which is pathological in the myocyte during disease progression in part owing to uncoupling of the ß-adrenergic receptor system. In this study, we explored the possibility that enhanced GRK2 expression and activity, as seen during heart failure, can negatively affect cardiac metabolism as part of its pathogenic profile. METHODS AND RESULTS: Positron emission tomography studies revealed in transgenic mice that cardiac-specific overexpression of GRK2 negatively affected cardiac metabolism by inhibiting glucose uptake and desensitization of insulin signaling, which increases after ischemic injury and precedes heart failure development. Mechanistically, GRK2 interacts with and directly phosphorylates insulin receptor substrate-1 in cardiomyocytes, causing insulin-dependent negative signaling feedback, including inhibition of membrane translocation of the glucose transporter GLUT4. This identifies insulin receptor substrate-1 as a novel nonreceptor target for GRK2 and represents a new pathological mechanism for this kinase in the failing heart. Importantly, inhibition of GRK2 activity prevents postischemic defects in myocardial insulin signaling and improves cardiac metabolism via normalized glucose uptake, which appears to participate in GRK2-targeted prevention of heart failure. CONCLUSIONS: Our data provide novel insights into how GRK2 is pathological in the injured heart. Moreover, it appears to be a critical mechanistic link within neurohormonal crosstalk governing cardiac contractile signaling/function through ß-adrenergic receptors and metabolism through the insulin receptor.

Pharmacokinetics, bioavailability and tissue distribution of chitobiose and chitotriose in rats.

Chitooligosaccharides (COSs) have various physiological activities and broad application prospects; however, their pharmacokinetics and tissue distribution remain unclear. In this study, a sensitive and selective ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) method for determining chitobiose (COS 2) and chitotriose (COS 3) in rat serum and tissues was developed. This method was successfully validated based on FDA guidelines in terms of selectivity, calibration curves (lower limit of quantification was 0.002 µg/mL for COS 2 and 0.02 µg/mL for COS 3), precision (intra-day relative standard deviation of 0.04%-3.55% and inter-day relative standard deviation of 1.94%-11.63%), accuracy (intra-day relative error of - 1.81%-11.06% and inter-day relative error of - 9.41%-8.63%), matrix effects, recovery (97.10%-101.29%), stability, dilution integrity, and carry-over effects. Then, the method was successfully applied to the pharmacokinetics and tissue distribution study of COS 2 and COS 3 after intragastric and intravenous administration. After intragastric administration, COS 2 and COS 3 were rapidly absorbed, reached peak concentrations in the serum after approximately 0.45 h, and showed rapid elimination with clearances greater than 18.82 L/h/kg and half-lives lower than 6 h. The absolute oral bioavailability of COS 2 and COS 3 was 0.32%-0.52%. COS 2 and COS 3 were widely distributed in Wistar rat tissues and could penetrated the blood-brain barrier without tissue accumulation.

Low-dose spectral CT perfusion imaging of lung cancer quantitative analysis in different pathological subtypes.

BACKGROUND: To explore the value of the quantitative parameters of low-dose computed tomography (CT) perfusion in the diagnosis of lung cancers of different pathological types. METHODS: Eighty-five patients with lung cancer confirmed by pathology underwent enhanced spectral CT imaging with a General Electric (GE) Revolution Xtream CT scanner, including 7 patients with lung squamous cell carcinoma, 8 patients with small cell carcinoma, 67 patients with lung adenocarcinoma, and 3 patients with other pathologies. The low-dose CT perfusion parameters [blood flow (BF), blood volume (BV), time of arrival (IRF TO), maximum slope of increase (MSI), mean transit time (MTT), positive enhancement integral (PEI), time to peak (TTP) and time to maximum (Tmax)] were calculated and compared among the first three groups. One-way analysis of variance (ANOVA) or the Kruskal-Wallis test was used to compare the quantitative parameters among the three groups, and the Bonferroni method was used to correct for multiple comparisons. RESULTS: Among the quantitative parameters, MSI was significantly different among the three lung cancers (adenocarcinoma vs. squamous cell carcinoma vs. small cell carcinoma: 11.37±8.74 vs. 2.35±0.88 vs. 1.40±0.26, respectively; P=0.016). The MSI of lung adenocarcinoma was lower than that of non-adenocarcinoma (P=0.001), and the MSI of small cell carcinoma was lower than that of non-small cell carcinoma (P=0.014). There were no significant differences in the other parameters among these three groups (P>0.05). CONCLUSIONS: Low-dose CT perfusion parameters may have a certain value in classifying the pathological type of lung cancer.

Deficient auditory emotion processing but intact emotional multisensory integration in alexithymia.

Alexithymia has been associated with emotion recognition deficits in both auditory and visual domains. Although emotions are inherently multimodal in daily life, little is known regarding abnormalities of emotional multisensory integration (eMSI) in relation to alexithymia. Here, we employed an emotional Stroop-like audiovisual task while recording event-related potentials (ERPs) in individuals with high alexithymia levels (HA) and low alexithymia levels (LA). During the task, participants had to indicate whether a voice was spoken in a sad or angry prosody while ignoring the simultaneously presented static face which could be either emotionally congruent or incongruent to the human voice. We found that HA performed worse and showed higher P2 amplitudes than LA independent of emotion congruency. Furthermore, difficulties in identifying and describing feelings were positively correlated with the P2 component, and P2 correlated negatively with behavioral performance. Bayesian statistics showed no group differences in eMSI and classical integration-related ERP components (N1 and N2). Although individuals with alexithymia indeed showed deficits in auditory emotion recognition as indexed by decreased performance and higher P2 amplitudes, the present findings suggest an intact capacity to integrate emotional information from multiple channels in alexithymia. Our work provides valuable insights into the relationship between alexithymia and neuropsychological mechanisms of emotional multisensory integration.

Metformin-Enhanced Cardiac AMP-Activated Protein Kinase/Atrogin-1 Pathways Inhibit Charged Multivesicular Body Protein 2B Accumulation in Ischemia-Reperfusion Injury.

Background: Cardiac autophagic flux is impaired during myocardial ischemia/reperfusion (MI/R). Impaired autophagic flux may exacerbate MI/R injury. Charged multivesicular body protein 2B (CHMP2B) is a subunit of the endosomal sorting complex required for transport (ESCRT-III) complex that is required for autophagy. However, the reverse role of CHMP2B accumulation in autophagy and MI/R injury has not been established. The objective of this article is to elucidate the roles of AMP-activated protein kinase (AMPK)/atrogin-1 pathways in inhibiting CHMP2B accumulation in ischemia-reperfusion injury. Methods: Male C57BL/6 mice (3-4 months) and H9c2 cardiomyocytes were used to evaluate MI/R and hypoxia/reoxygenation (H/R) injury in vivo and in vitro, respectively. MI/R was built by a left lateral thoracotomy and occluded the left anterior descending artery. H9c2 cells were firstly treated in 95% N2 and 5% CO2 for 15 h and reoxygenation for 1 h. Metformin (100 mg/kg/d) and CHMP2B (Ad-CHMP2B) transfected adenoviruses were administered to the mice. The H9c2 cells were treated with metformin (2.5 mM), MG-132 (10 µM), bafilomycin A1 (10 nM), and compound C (20 µM). Results: Autophagic flux was found to be inhibited in H/R-treated cardiomyocytes and MI/R mice, with elevated cardiac CHMP2B accumulation. Upregulated CHMP2B levels in the in vivo and in vitro experiments were shown to inhibit autophagic flux leading to the deterioration of H/R-cardiomyocytes and MI/R injury. This finding implies that CHMP2B accumulation increases the risk of myocardial ischemia. Metformin suppressed CHMP2B accumulation and ameliorated H/R-induced autophagic dysfunction by activating AMPK. Activated AMPK upregulated the messenger RNA expression and protein levels of atrogin-1, a muscle-specific ubiquitin ligase, in the myocardium. Atrogin-1 significantly enhanced the interaction between atrogin-1 and CHMP2B, therefore, promoting CHMP2B degradation in the MI/R myocardium. Finally, this study revealed that metformin-inhibited CHMP2B accumulation induced autophagic impairment and ischemic susceptibility in vivo through the AMPK-regulated CHMP2B degradation by atrogin-1. Conclusion: Impaired CHMP2B clearance in vitro and in vivo inhibits autophagic flux and weakens the myocardial ischemic tolerance. Metformin treatment degrades CHMP2B through the AMPK-atrogin-1-dependent pathway to maintain the homeostasis of autophagic flux. This is a novel mechanism that enriches the understanding of cardioprotection.

Is there any correlation between spectral CT imaging parameters and PD-L1 expression of lung adenocarcinoma?

BACKGROUND: The aim of this study was to explore whether spectral computed tomography (CT) imaging parameters are associated with PD-L1 expression of lung adenocarcinoma. METHODS: Spectral CT imaging parameters (iodine concentrations [IC] of lesion in arterial phase [ICLa] and venous phase [ICLv], normalized IC [NICa/NICv]-normalized to the IC in the aorta, slope of the spectral HU curve [λHUa/λHUv] and enhanced monochromatic CT number [CT40keVa/v, CT70keVa/v] on 40 and 70 keV images) were analyzed in 34 prospectively enrolled lung adenocarcinoma patients with common molecular pathological markers including PD-L1 expression detected with immunohistochemistry. Patients were divided into two groups: positive PD-L1 expression and negative PD-L1 expression groups. Two-sample Mann-Whitney U test was used to test the difference of spectral CT imaging parameters between the two groups. RESULTS: The CT40keVa (127.03 ± 37.92 vs. -54.69 ± 262.04), CT40keVv (124.39 ± 34.71 vs. -45.73 ± 238.97), CT70keVa (49.56 ± 11.76 vs. -136.51 ± 237.08) and CT70keVv (46.13 ± 15.81 vs. -133.10 ± 230.72) parameters in the positive PD-L1 expression group of lung adenocarcinoma were significantly higher than the negative PD-L1 expression group (all P < 0.05). There was no difference detected in IC, NIC and λHU of the arterial and venous phases between both groups (all P > 0.05). CONCLUSION: CT40keVa, CT40keVv, CT70keVa and CT70keVv were increased in positive PD-L1 expression. These parameters may be used to distinguish the PD-L1 expression state of lung adenocarcinoma.

Metformin mediates cardioprotection against aging-induced ischemic necroptosis.

Necroptosis is crucially involved in severe cardiac pathological conditions. However, whether necroptosis contributes to age-related intolerance to ischemia/reperfusion (I/R) injury remains elusive. In addition, metformin as a potential anti-aging related injury drug, how it interacts with myocardial necroptosis is not yet clear. Male C57BL/6 mice at 3-4- (young) and 22-24 months of age (aged) and RIPK3-deficient (Ripk3-/- ) mice were used to investigate aging-related I/R injury in vivo. Metformin (125 µg/kg, i.p.), necrostatin-1 (3.5 mg/kg), and adenovirus vector encoding p62-shRNAs (Ad-sh-p62) were used to treat aging mice. I/R-induced myocardial necroptosis was exaggerated in aged mice, which correlated with autophagy defects characterized by p62 accumulation in aged hearts or aged human myocardium. Functionally, blocking autophagic flux promoted H/R-evoked cardiomyocyte necroptosis in vitro. We further revealed that p62 forms a complex with RIP1-RIP3 (necrosome) and promotes the binding of RIP1 and RIP3. In mice, necrostatin-1 treatment (a RIP1 inhibitor), RIP3 deficiency, and cardiac p62 knockdown in vivo demonstrated that p62-RIP1-RIP3-dependent myocardial necroptosis contributes to aging-related myocardial vulnerability to I/R injury. Notably, metformin treatment disrupted p62-RIP1-RIP3 complexes and effectively repressed I/R-induced necroptosis in aged hearts, ultimately reducing mortality in this model. These findings highlight previously unknown mechanisms of aging-related myocardial ischemic vulnerability: p62-necrosome-dependent necroptosis. Metformin acts as a cardioprotective agent that inhibits this unfavorable chain mechanism of aging-related I/R susceptibility.

Towards a national perioperative clinical quality registry: The diagnostic accuracy of administrative data in identifying major postoperative complications.

Accurately measuring the incidence of major postoperative complications is essential for funding and reimbursement of healthcare providers, for internal and external benchmarking of hospital performance and for valid and reliable public reporting of outcomes. Actual or surrogate outcomes data are typically obtained by one of three methods: clinical quality registries, clinical audit, or administrative data. In 2017 a perioperative registry was developed at the Alfred Hospital and mapped to administrative and clinical data. This study investigated the statistical agreement between administrative data (International Statistical Classification of Diseases and Related Health Problems (10th edition) Australian Modification codes) and clinical audit by anaesthetists in identifying major postoperative complications. The study population included 482 high-risk surgical patients referred to the Alfred Hospital anaesthesia postoperative service over two years. Clinical audit was conducted to determine the presence of major complications and these data were compared to administrative data. The main outcome was statistical agreement between the two methods, as defined by Cohen's kappa statistic. Substantial agreement was observed for five major complications, moderate agreement for three, fair agreement for six and poor agreement for two. Sensitivity and positive predictive value ranged from 0 to 100%. Specificity was above 90% for all complications. There was important variation in inter-rater agreement. For four of the five complications with substantial agreement between administrative data and clinical audit, sensitivity was only moderate (61.5%-75%). Using International Statistical Classification of Diseases and Related Health Problems (10th edition) Australian Modification codes to identify postoperative complications at our hospital has high specificity but is likely to underestimate the incidence compared to clinical audit. Further, retrospective clinical audit itself is not a highly reliable method of identifying complications. We believe a perioperative clinical quality registry is necessary to validly and reliably measure major postoperative complications in Australia for benchmarking of hospital performance and before public reporting of outcomes should be considered.