Impact of metabolic dysfunction-associated fatty liver disease on the outcomes following laparoscopic hepatectomy for hepatocellular carcinoma.

BACKGROUND: The impact of metabolic dysfunction-associated fatty liver disease (MAFLD) on laparoscopic liver resection (LLR) for hepatocellular carcinoma (HCC) remains unclear. This study aimed to compare the outcomes of LLR for MAFLD-HCC and Non-MAFLD-HCC. METHODS: Patients with HCC who received LLR between October 2017 and July 2021 were enrolled. Inverse probability of treatment weighting (IPTW) was used to generate adjusted comparisons. Both short- and long-term outcomes were evaluated accordingly. RESULTS: A total of 887 patients were enrolled, with 140 in MAFLD group and 747 in Non-MAFLD group. After IPTW adjustment, baseline factors were well matched. The MAFLD group was associated with more blood loss (210 vs 150 ml, p = 0.022), but with similar postoperative hospital stays and complication rates. The 1- and 3-year overall survival rates were 97.4% and 92.5% in MAFLD group, and 97.5% and 88.3% in Non-MAFLD group, respectively (p = 0.14). The 1- and 3-year disease-free survival rates were 84.8% and 62.9% in MAFLD group, and 80.2% and 58.8% in Non-MAFLD group, respectively (p = 0.31). CONCLUSIONS: LLR for MAFLD-HCC was associated with more blood loss but with comparable postoperative recovery and long-term survival compared with Non-MAFLD-HCC patients. LLR is feasible and safe for HCC patients with MAFLD background.

How social media exposure constructs social confidence: An empirical study on impact, mechanisms, and multilateral relationships.

Social confidence functions as a vital spiritual force in fostering the positive and healthy evolution of society. This paper explores how social media exposure contributes to the construction of social confidence within the framework of Media-system Dependency Theory. The research unveils the following key findings: (1) Social media exposure positively facilitates social confidence; (2) Group efficacy and group cohesion, perceived as manifestations of cognitive divergence between "efficacy" and "collective" within collective efficacy, both serve as mediating mechanisms influencing the impact of social media exposure on social confidence. The Channel Testing of Causality confirms that group cohesion plays a significantly more crucial role as a pathway compared to group efficacy; (3) The differentiated impact of social media exposure, encompassing Tencent WeChat and Sina Weibo, materializes in distinct components of social confidence and follows different influence pathways.

Clinical Implications of Left Ventricular Apex Mechanics in Patients with Apical Hypertrophic Cardiomyopathy.

BACKGROUND: Apical hypertrophic cardiomyopathy (ApHCM) is a unique disease with pathological hypertrophy mainly at the left ventricular (LV) apex. Although previous studies have indicated apical dysfunction in ApHCM, how apical mechanics change during disease progression has not been thoroughly examined. We aimed to characterize the mechanics of the LV apex in ApHCM patients at different disease stages and explore the clinical significance of these alterations. METHODS: 104 ApHCM patients were divided into 3 subtypes based on LV apical maximum wall thickness (AMWT) and extent of hypertrophy: relative-type (isolated apical hypertrophy with AMWT <15 mm), pure-type (isolated apical hypertrophy with AMWT ≥15 mm), and mixed-type (both apical and midventricular hypertrophy with AMWT ≥15 mm). Two-dimensional speckle-tracking echocardiography was used to analyze LV segmental strain, global strain, and twist. Comparisons of these parameters were performed among ApHCM subtypes and 30 healthy controls. Logistic regression and Cox proportional hazard regression analyses were employed to explore associations between myocardial mechanics and clinical indicators. A composite outcome of new-onset atrial fibrillation, heart failure hospitalization, myectomy, and all-cause mortality was assessed. RESULTS: Even in relative ApHCM patients, apical longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were significantly impaired compared to controls (LS: -14.6±4.1% vs.-20.0±1.7%, p=0.001; CS: -19.6±2.5% vs.-25.6±3.7%, p=0.002; RS: 26.6±7.4% vs. 35.6±11.1%, p=0.026), while apical rotation and LV twist remained unchanged. In patients with greater apical hypertrophy (mixed and pure patients), apical LS and RS were more abnormal. Moreover, apical rotation showed significant reductions compared to relative-type patients. After adjusting for clinical and myocardial mechanical parameters, apical rotation was independently associated with NYHA class ≥ II (odds ratio =0.81, 95% confidence interval [CI]: 0.66-0.99, p=0.036) and the composite outcome (hazard ratio =0.82, 95% CI: 0.73-0.91, p=0.001). CONCLUSIONS: Relative ApHCM demonstrates apical dysfunction but sparing of apical rotation, which was abnormal in more extensive phenotypes. LV apex mechanics were closely related to clinical patterns, with apical rotation correlated with both NYHA class ≥ II and clinical events.

Incremental Prognostic Value of Carotid Plaque-RADS Over Stenosis Degree in Relation to Stroke Risk.

BACKGROUND: Recently, a standardized classification system for carotid atherosclerotic plaques, known as Carotid Plaque-RADS (Reporting and Data System), has been introduced. However, its capacity to improve stroke risk stratification beyond traditional stenosis degree assessment has not been extensively explored. OBJECTIVES: This study aimed to determine the incremental prognostic value of Carotid Plaque-RADS over stenosis degree for stroke risk. METHODS: A retrospective analysis was performed on data from January 2010 to December 2021, involving subjects who underwent magnetic resonance imaging, computed tomography angiography, and ultrasound evaluations of the carotid artery. Disease-free survival (DFS) and recurrence-free survival (RFS) rates were compared across different stenosis degrees, Carotid Plaque-RADS categories, and their combination, using the Kaplan-Meier and net reclassification improvement formula. RESULTS: The study enrolled 1,378 subjects. During a follow-up period of 57 ± 25 months, 4.6% of 987 asymptomatic individuals and 16.9% of 391 subjects with stroke history experienced initial and recurrent strokes, respectively. Significant differences in DFS and RFS rates were found between subjects with mild/moderate and severe stenosis (P < 0.001). Significant differences in DFS rates were observed across Carotid Plaque-RADS categories (P < 0.001), with a notable decrease in DFS rates as Carotid Plaque-RADS categories increased from 1 to 4. This trend was similar in subjects with a history of stroke (P < 0.001). For patients with mild/moderate stenosis, significant differences in DFS and RFS rates were found between those with Carotid Plaque-RADS of ≥3 vs <3 (P < 0.001). Correct reclassification was achieved for 3.3% (32 of 979) of asymptomatic individuals and 9.7% (37 of 381) of subjects with a stroke history initially identified with mild/moderate stenosis. Incorporating Carotid Plaque-RADS with stenosis grading markedly improved risk assessment, resulting in net reclassification improvement of 63.8% for initial stroke and 47.8% for recurrent stroke prediction. The likelihood ratio test demonstrated that Carotid Plaque-RADS scores significantly enhanced the prognostic accuracy of stenosis degrees for both asymptomatic individuals and patients with a history of stroke (both P < 0.001). CONCLUSIONS: Carotid Plaque-RADS significantly improves stroke risk stratification over traditional stenosis grading, especially in mild/moderate stenosis cases.

Early left atrial reverse remodelling in patients with hypertrophic obstructive cardiomyopathy receiving transapical beating-heart septal myectomy.

OBJECTIVES: This study aims to investigate the short-term effects of transapical beating-heart septal myectomy (TA-BSM) on left atrial (LA) anatomy and function and its association with clinical indicators in patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: A total of 105 HOCM patients who received TA-BSM were included. Clinical and comprehensive echocardiographic data were obtained before surgery, at discharge, and 3 months after myectomy. LA reverse remodelling was defined as LA maximum volume index (LAVI) ≤34 ml/m2 and a change of ≥10%. RESULTS: At 3 months after TA-BSM, New York Heart Association (NYHA) functional class and 6-min walking test were significantly improved, N-terminal pro-B-type natriuretic peptide (NT-proBNP) decreased, left ventricular outflow tract (LVOT) peak gradient and mitral regurgitation were significantly reduced. LAVI decreased in 76%, with a median change of 20%, and the criteria for LA reverse remodelling were met in 48%. LA strain parameters were improved at 3 months after TA-BSM. Moreover, left ventricular (LV) diastolic function was significantly improved, but LV global longitudinal strain was not significantly changed at 3 months after operation. Improvement in LVOT peak gradient, LAVI, LA reservoir strain (LASr) and conduit strain (LAScd) were associated with reduction in NT-proBNP. CONCLUSIONS: Along with effectively relieving the obstruction of the LVOT and mitral regurgitation, TA-BSM could significantly improve LA size and function during the short-term follow-up for HOCM patients. The indicators of LA reverse remodelling were associated with reduction in a biomarker of myocardial wall stress, indicating the early recovery of LV relaxation and clinical status for patients.

Inhibition of TTX-S Na+ currents by a novel blocker QLS-278 for antinociception.

Genetic loss-of-function mutations of Nav1.7 channel, abundantly expressed in peripheral nociceptive neurons, cause congenital insensitivity to pain (CIP) in humans, indicating that selective inhibition of the channel may lead to potential therapy of pain disorders. In this study, we investigated a novel compound, 5-chloro-N-(cyclopropylsulfonyl)-2-fluoro-4-(2-(8-(furan-2-ylmethyl)-8-azaspiro [4.5] decan-2-yl) ethoxy) benzamide (QLS-278) that inhibits Nav1.7 channel and exhibits anti-nociceptive activity. Compound QLS-278 exhibits inactivation- and concentration-dependent inhibition of macroscopic currents of Nav1.7 channels stably expressed in HEK293 cells with an IC50 of 1.2 {plus minus} 0.2 µM. QLS-278 causes a hyperpolarization shift of the channel inactivation and delays recovery from inactivation, without an obvious effect on voltage-dependent activation. In mouse DRG neurons, QLS-278 suppresses native TTX-sensitive Nav currents and also reduces neuronal firing. Moreover, QLS-278 dose-dependently relieves neuropathic pain induced by spared nerve injury and inflammatory pain induced by formalin without significant alteration of spontaneous locomotor activity in mice. Altogether, our identification of the novel compound QLS-278 may hold developmental potential for the treatment of chronic pain. Significance Statement QLS-278, a novel voltage-gated sodium Nav1.7 channel blocker, inhibits native TTX-S Na+ current and reduces action potential firings in DRG sensory neurons. QLS-278 also exhibits antinociceptive activity in mouse models of pain, thus demonstrating potential for the development of a treatment for chronic pain.

Case Report: Mechanical hemolysis resulting from left ventricular outflow tract obstruction after aortic valve replacement relieved by transapical beating-heart septal myectomy.

Background: Aortic stenosis (AS) in combination with left ventricular outflow tract obstruction (LVOTO) has occasionally been reported. However, making a precise diagnosis and successfully treating this combination is challenging due to the hemodynamic interaction between the two conditions. Case summary: A 56-year-old male patient who had been diagnosed with severe AS and asymmetric left ventricular hypertrophy underwent aortic valve replacement (AVR) and a conventional septal myectomy. Immediately after the procedure, significant systolic anterior motion and mitral regurgitation developed, necessitating a surgical mitral edge-to-edge repair. Ten days after the procedure, the patient developed hematuria and LVOTO, which was confirmed by echocardiography. Because the LVOTO might have been the cause of the hematuria, the patient underwent alcohol septal ablation, but this had little effect. Three months later, a transapical beating-heart septal myectomy (TA-BSM) was performed in our hospital. Postoperatively, the LVOTO had been significantly ameliorated and the hematuria had resolved. Conclusion: For patients with AS and LVOTO due to a hypertrophic interventricular septum, inadequate amelioration of the LVOTO after AVR may lead to severe hemolytic hematuria. TA-BSM is a minimally invasive, safe, and effective surgical procedure for ameliorating LVOTO in patients with aortic valve prostheses.

A Radiomics-Based Nomogram Using Ultrasound Carotid Plaque Evaluation For Predicting Cerebro-Cardiovascular Events In Asymptomatic Patients.

RATIONALE AND OBJECTIVES: This study aims to assess whether a radiomics-based nomogram correlates with a higher risk of future cerebro-cardiovascular events in patients with asymptomatic carotid plaques. Additionally, it investigates the nomogram's contribution to the revised Framingham Stroke Risk Profile (rFSRP) for predicting cerebro-cardiovascular risk. MATERIALS AND METHODS: Predictive models aimed at identifying an increased risk of future cerebro-cardiovascular events were developed and internally validated at one center, then externally validated at two other centers. Survival curves, constructed using the Kaplan-Meier method, were compared through the log-rank test. RESULTS: This study included a total of 2009 patients (3946 images). The final nomogram was generated using multivariate Cox regression variables, including dyslipidemia, lumen diameter, plaque echogenicity, and ultrasonography (US)-based radiomics risk. The Harrell's concordance index (C-index) for predicting events-free survival (EFS) was 0.708 in the training cohort, 0.574 in the external validation cohort 1, 0.632 in the internal validation cohort, and 0.639 in the external validation cohort 2. The final nomogram showed a significant increase in C-index compared to the clinical, conventional US, and US-based radiomics models (all P < 0.05). Furthermore, the final nomogram-assisted method significantly improved the sensitivity and accuracy of radiologists' visual qualitative score of plaque (both P < 0.001). Among 1058 patients with corresponding 1588 plaque US images classified as low-risk by the rFSRP, 75 (7.1%) patients with corresponding 93 (5.9%) carotid plaque images were appropriately reclassified to the high-risk category by the final nomogram. CONCLUSION: The radiomics-based nomogram demonstrated accurate prediction of cerebro-cardiovascular events in patients with asymptomatic carotid plaques. It also improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque and enhanced the risk stratification ability of rFSRP. SUMMARY: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. KEY RESULTS: The radiomics-based nomogram allowed accurate prediction of cerebro-cardiovascular events, especially ipsilateral ischemic stroke in patients with asymptomatic carotid atherosclerotic plaques. The radiomics-based nomogram improved the sensitivity and accuracy of radiologists' visual qualitative score of carotid plaque. The radiomics-based nomogram improved the discrimination of high-risk populations from low-risk populations in asymptomatic patients with carotid atherosclerotic plaques and the risk stratification capability of the rFSRP.

Epitaxial Growth of Monolayer SnP3 with High Mobility and Chiral Boundary Junctions.

Two-dimensional materials with layered structures, appropriate band gaps, and high carrier mobility have attracted tremendous interest for their potential applications. Here we report the growth of monolayer SnP3 on Au(111) surfaces by molecular beam epitaxy. The kinetic processes for the growth and the crystalline properties are studied by scanning tunneling microscopy. The weak interaction between SnP3 and its Au(111) substrate is signified by the random crystal orientation distributions of SnP3 nanosheets. The electronic structures exhibit a band gap of ∼0.25 eV and high charge carrier mobility comparable to that of black phosphorus engineered by compressive strain. Additionally, domain boundary junctions with opposite chirality are observed, resulting from the strained film in the epitaxial growth process. Our work provides a method to fabricate high-quality monolayer SnP3 and suggests that the monolayer SnP3 is a promising candidate for applications in nanoelectronics and optoelectronics.

Investigation of the differential susceptibility of extraocular muscles in patients diagnosed with ocular myasthenia gravis based on the computerized diplopia test and the Ocular Motor Nerve Palsy Scale.

Introduction: The pattern of extraocular muscle involvement in ocular myasthenia gravis varies across different reports, diverging from our own observations. Thus, we employed two novel tools to discern this pattern. Methods: A retrospective analysis was conducted to collect and organize clinical data from 43 patients diagnosed with ocular myasthenia gravis. Each patient underwent both the computerized diplopia test and the Ocular Motor Nerve Palsy Scale assessment to evaluate the involvement of extraocular muscles. Results: Among the patients, there were 30 male and 13 female individuals, with a total of 113 affected extraocular muscles identified. Among all the affected extraocular muscles, the involvement of the levator palpebrae superioris muscle accounted for 35.40%, medial rectus muscle 7.7%, lateral rectus muscle 16.81%, superior rectus muscle 13.27%, inferior rectus muscle 12.39%, superior oblique muscle 1.77%, and inferior oblique muscle 2.65% of the total affected extraocular muscles. The positivity rates of the Neostigmine test were 89.19%, AChR antibody detection was 59.38%, and repetitive nerve stimulation was 34.38%. The AChR antibody positive rate among patients with only diplopia was 100%; among those with only ptosis, it was 80%; and among those with both diplopia and ptosis, it was 86.67%. Conclusion: The involvement of the extraocular muscles is not uniform. The levator palpebrae superioris exhibits the highest incidence rate, followed by the four rectus muscles and two oblique muscles. The inferior oblique involvement typically occurs when four or more EOMs are affected. Moreover, the levator palpebrae superioris and medial rectus show a higher tendency for bilateral involvement compared with other extraocular muscles.

An antagonist-based two-photon fluorogenic probe for imaging metabotropic glutamate receptor 5 in neuronal cells.

The expression of metabotropic glutamate receptor 5 (mGluR5) is subject to developmental regulation and undergoes significant changes in neuropsychiatric disorders and diseases. Visualizing mGluR5 by fluorescence imaging is a highly desired innovative technology for biomedical applications. Nevertheless, there are substantial problems with the chemical probes that are presently accessible. In this study, we have successfully developed a two-photon fluorogenic probe, mGlu-5-TP, based on the structure of mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP). Due to this antagonist-based probe selectively recognizes mGluR5, high expression of mGluR5 on living SH-SY5Y human neuroblastoma cells has been detected during intracellular inflammation triggered by lipopolysaccharides (LPS). Of particular significance, the probe can be employed along with two-photon fluorescence microscopy to enable real-time visualization of the mGluR5 in Aß fiber-treated neuronal cells, thereby establishing a connection to the progression of Alzheimer's disease (AD). These results revealed that the probe can be a valuable imaging tool for studying mGluR5-related diseases in the nervous system.

Cascading Detection of Hydrogen Sulfide and N-Acetyltransferase 2 in Hepatocellular Carcinoma Cells Using a Two-Photon Fluorescent Probe.

Hydrogen sulfide (H2S), a critical gas signaling molecule, and N-acetyltransferase 2 (NAT2), a key enzyme in drug metabolism, are both known active biomarkers for liver function. However, the interactions and effects of H2S and NAT2 in living cells or lesion sites remain unknown due to the lack of imaging tools to achieve simultaneous detection of these two substances, making it challenging to implement real-time imaging and precise tracking. Herein, we report an activity-based two-photon fluorescent probe, TPSP-1, for the cascade detection of H2S and NAT2 in living liver cells. Continuous conversion from TPSP-1 to TPSP-3 was achieved in liver cells and tissues. Significantly, leveraging the outstanding optical properties of this two-photon fluorescent probe, TPSP-1, has been effectively used to identify pathological tissue samples directly from clinical liver cancer patients. This work provides us with this novel sensing and two-photon imaging probe, which can be used as a powerful tool to study the physiological functions of H2S and NAT2 and will help facilitate rapid and accurate diagnosis and therapeutic evaluation of hepatocellular carcinoma.

Relative apical sparing obtained with speckle tracking echocardiography is not a sensitive parameter for diagnosing light-chain cardiac amyloidosis.

Background: Distinguishing light-chain cardiac amyloidosis (AL CA) from left ventricular wall thickening (LVWT) resulted from other etiologies has proven to be challenging. This study aimed to determine the sensitivity and specificity of relative apical sparing in diagnosing AL CA and investigate the differences in clinical and echocardiographic characteristics between AL CA patients with apical sparing and those with non-apical sparing. Methods: A total of 63 consecutive patients with AL CA, 102 consecutive patients with LVWT (including 51 hypertrophic cardiomyopathy (HCM) and 51 hypertension) and 33 healthy individuals were recruited retrospectively at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Conventional and speckle tracking echocardiography were performed on all subjects. Results: Although wall thickening was observed in all patients, almost all functional parameters were worse in AL CA, except for relative apical longitudinal strain (LS) (P=0.906). Of 63 patients with AL CA, only 17.5% (n=11) showed an apical sparing pattern. Patients with apical sparing had poorer cardiac performance than those with non-apical sparing. Relative apical sparing showed the lowest diagnostic accuracy with an area under the curve (AUC) of 0.58 [95% confidence interval (CI): 0.49-0.67, sensitivity: 17.5%, specificity: 98.0%, P=0.095] to detect AL CA, but right ventricular strain (RVS) (AUC: 0.86, P<0.001) showed the highest among all echocardiographic parameters. When diagnosing AL CA patients with non-apical sparing, RVS continued to maintain excellent diagnostic accuracy (AUC: 0.84, P<0.001), followed by left atrial reservoir strain (LASr) (AUC: 0.77, P<0.001). Conclusions: The diagnostic value of relative apical sparing for AL CA was limited with low sensitivity. In clinical practice, the diagnosis of early AL CA patients should not solely rely on relative apical sparing.

Improvements of myocardial strain and work in diabetes patients with normal ejection fraction after empagliflozin treatment.

AIMS/INTRODUCTION: To assess the effect of empagliflozin treatment on left ventricular (LV), right ventricular (RV) and left atrial (LA) functions in diabetes patients with normal ejection fraction. MATERIALS AND METHODS: The study included a total of 128 diabetes patients with multiple cardiovascular risk factors who were subjected to a 6-month follow up from the initiation of empagliflozin treatment. Before and after treatment with empagliflozin, LV, RV and LA strain, and noninvasive myocardial work parameters were evaluated by speckle tracking echocardiography. RESULTS: In 128 diabetes patients (mean age 56 ± 8 years, 85 men) with multiple cardiovascular risk factors, myocardial strain and work parameters were impaired, despite the absence of significant clinical symptoms of heart failure. After 6-month treatment with empagliflozin, the absolute value of LV strain in all directions increased, represented by LV global longitudinal strain (-18.0 ± 1.7% to -19.2 ± 1.7% [mean ± SD]). The same trend in LV global work efficiency (93 [91-94] % to 94 [93-95] % [median (IQR)]), RV free-wall longitudinal strain (-24.0 ± 2.7% to -25.0 ± 2.8%), LA reservoir (31 ± 5% to 34 ± 5%) and conduit strain (-14 ± 4% to -16 ± 4%) was also observed. LV mass index (106.9 ± 16.8-103.6 ± 16.4 g/m2) and LV global wasted work (143 [111-185] mmHg% to 108 [88-141] mmHg%) decreased after treatment (P < 0.05 for all). LV volume and LA volume index remained unchanged after treatment. In the multivariable analysis, the change in LA reservoir strain (ß = 0.050, P = 0.035) and baseline global longitudinal strain (ß = -0.488, P < 0.001) were independent predictors of improvement in LV global longitudinal strain. CONCLUSIONS: This study suggests that 6-month treatment with empagliflozin improved LV, RV and LA functions in diabetes patients with normal ejection fraction.

A novel dual serotonin transporter and M-channel inhibitor D01 for antidepression and cognitive improvement.

Cognitive dysfunction is a core symptom common in psychiatric disorders including depression that is primarily managed by antidepressants lacking efficacy in improving cognition. In this study, we report a novel dual serotonin transporter and voltage-gated potassium Kv7/KCNQ/M-channel inhibitor D01 (a 2-methyl-3-aryloxy-3-heteroarylpropylamines derivative) that exhibits both anti-depression effects and improvements in cognition. D01 inhibits serotonin transporters (Ki = 30.1 ± 6.9 nmol/L) and M channels (IC50 = 10.1 ± 2.4 µmol/L). D01 also reduces the immobility duration in the mouse FST and TST assays in a dose-dependent manner without a stimulatory effect on locomotion. Intragastric administrations of D01 (20 and 40 mg/kg) can significantly shorten the immobility time in a mouse model of chronic restraint stress (CRS)-induced depression-like behavior. Additionally, D01 dose-dependently improves the cognitive deficit induced by CRS in Morris water maze test and increases the exploration time with novel objects in normal or scopolamine-induced cognitive deficits in mice, but not fluoxetine. Furthermore, D01 reverses the long-term potentiation (LTP) inhibition induced by scopolamine. Taken together, our findings demonstrate that D01, a dual-target serotonin reuptake and M channel inhibitor, is highly effective in the treatment-resistant depression and cognitive deficits, thus holding potential for development as therapy of depression with cognitive deficits.

Vancomycin relieves tacrolimus-induced hyperglycemia by eliminating gut bacterial beta-glucuronidase enzyme activity.

Up to 40% of transplant recipients treated long-term with tacrolimus (TAC) develop post-transplant diabetes mellitus (PTDM). TAC is an important risk factor for PTDM, but is also essential for immunosuppression after transplantation. Long-term TAC treatment alters the gut microbiome, but the mechanisms of TAC-induced gut microbiota in the pathogenesis of PTDM are poorly characterized. Here, we showed that vancomycin, an inhibitor of bacterial beta-glucuronidase (GUS), prevents TAC-induced glucose disorder and insulin resistance in mice. Metagenomics shows that GUS-producing bacteria are predominant and flourish in the TAC-induced hyperglycemia mouse model, with upregulation of intestinal GUS activity. Targeted metabolomics analysis revealed that in the presence of high GUS activity, the hydrolysis of bile acid (BAs)-glucuronic conjugates is increased and most BAs are overproduced in the serum and liver, which, in turn, activates the ileal farnesoid X receptor (FXR) and suppresses GLP-1 secretion by L-cells. The GUS inhibitor vancomycin significantly eliminated GUS-producing bacteria and inhibited bacterial GUS activity and BAs levels, thereby enhancing L-cell GLP-1 secretion and preventing hyperglycemia. Our results propose a novel clinical strategy for inhibiting the bacterial GUS enzyme to prevent hyperglycemia without requiring withdrawal of TAC treatment. This strategy exerted its effect through the ileal bile acid-FXR-GLP-1 pathway.

Allosteric Activation of α7 Nicotinic Acetylcholine Receptors by Novel 2-Arylamino-thiazole-5-carboxylic Acid Amide Derivatives for the Improvement of Cognitive Deficits in Mice.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6-9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 µM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 µM). The structure-activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 µM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

Incremental prognostic utility of left ventricular and left atrial strains in coronary artery disease patients with reduced systolic function.

OBJECTIVE: This study aimed to investigate the predictive value of left ventricular global longitudinal strain (GLS) and left atrial reservoir strain (LARS) on adverse events in chronic coronary artery disease (CAD) patients with reduced systolic function. METHODS: A total of 192 consecutive patients clinically diagnosed with chronic CAD and left ventricular ejection fraction (LVEF) ≤ 50% were finally included. Multiple strain parameters were analyzed with speckle tracking echocardiography. The composite endpoint included all-cause mortality, rehospitalization due to heart failure, myocardial infarction, and stroke. RESULTS: Patients experiencing the endpoint showed lower LVEF, lower absolute GLS and LARS than those without events. Both GLS (AUC = 0.82 [GLS] vs. 0.58 [LVEF], p < 0.001) and LARS (AUC = 0.71 [LARS] vs. 0.58 [LVEF], p = 0.033) were superior to LVEF in predicting adverse events. Multivariate cox regression analysis showed that both GLS (hazard ratio, 0.71; 95% CI, 0.63-0.79; p < 0.001) and LARS (hazard ratio, 0.96; 95% CI, 0.93-0.98; p < 0.001) were independent predictors for the endpoint. The addition of LARS (global chi-squared, 35.7 vs. 17.4; p < 0.05), GLS (global chi-squared, 58.6 vs. 17.4; p < 0.05) or both LARS and GLS (global chi-squared, 79.6 vs. 17.4; p < 0.05) to LVEF in the prediction model significantly improved its performance. The same significant improvement was also shown in the subgroups of mild (30% < LVEF ≤ 50%) and severe (LVEF ≤ 30%) reduced systolic function. CONCLUSIONS: Regarding CAD patients with reduced LVEF, both GLS and LARS are superior to LVEF in predicting adverse events, providing significant incremental value to LVEF.

Inhibition of Cardiac Kv4.3/KChIP2 Channels by Sulfonylurea Drug Gliquidone.

The Kv4.3 channel features fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome (BrS), characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac transient outward K+ currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 µM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A and L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. SIGNIFICANCE STATEMENT: We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Association between gout and the risk of osteoporosis and fractures: a meta-analysis.

OBJECTIVE: The relationship between gout and osteoporosis is poorly clarified, and the association between gout and fractures incidence remains controversial. Hence, in the present study, we aimed to comprehensively evaluate the available literature to elucidate whether gout is associated with an increased risk of both osteoporosis and fractures. MATERIALS AND METHODS: We conducted an exhaustive search of pertinent literature published until 20 March 2023, in well-recognized databases, namely Medline, Embase and Cochrane Library, focusing on examining the association between gout and the risk of osteoporosis or fracture. Meta-analysis was performed to aggregate the relative risks (RR) using random- or fixed-effects models. Sensitivity analyses were conducted iteratively, whereby each study was removed sequentially to gauge its impact on the overall outcome. Publication bias was assessed using Egger's and Begg's tests. This study was registered with PROSPERO (registry number: CRD42022376822). RESULTS: Herein, we included 10 observational studies comprising a total of 1,606,095 participants. An independent population sample of four studies validated the significant association between gout and osteoporosis (RR = 1.25, 95% confidence interval [CI] 1.05-1.48), with the results demonstrating robustness. However, our analysis did not detect any association between gout and fracture risk when compared with the control group (RR = 1.09, 95%CI 0.99-1.19), along with high heterogeneity (p for heterogeneity = 0.000; I2 = 79.7%). Further subgroup analysis revealed that gout is positively associated with fracture risk in the Chinese population (RR = 1.17, 95%CI 1.14-1.21), with no evidence of heterogeneity (p for heterogeneity = 0.420; I2 = 0.00%). CONCLUSION: Our meticulous evaluation of the available literature indicates that gout has no discernible impact on fracture incidence, although it is positively associated with an enhanced risk of osteoporosis. Therefore, it is imperative to prioritize preventive measures to prevent osteoporotic complications in individuals diagnosed with gout.