Prenatal and childhood neonicotinoid exposure and neurodevelopment: A study in a young Taiwanese cohort.

Neonicotinoid insecticides (NEOs) dominate the global pesticide market because of their low cost and effectiveness. However, epidemiological studies regarding the potential adverse health effects of exposure to NEOs before birth and in early childhood are limited. Therefore, this study investigated the associations between NEO exposure before birth and during early childhood and neurodevelopment. A total of 273 mother-child pairs were enrolled in this study. Mothers provided urine samples in the third trimester and breast milk during the first and third months of lactation. Their children provided urine samples and were evaluated for neurodevelopment by using the Bayley Scales of Infant and Toddler Development, Third Edition at 2-3 years (N = 96) and the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV) at 4-6 years (N = 63). The sum of the concentrations of seven NEOs (ΣNEOs) and the relative potency factor of NEOs, based on comparison with imidacloprid (IMIRPF), were used to assess total exposure to NEOs. Multivariate linear regression analyses were conducted to assess the associations between prenatal and childhood exposure to NEOs and neurodevelopment. The results of the analysis revealed that clothianidin (CLO) and thiamethoxam were the most common NEOs to which children in the Taipei metropolitan area were exposed and that exposure concentrations were high in the Taipei metropolitan area. Imidacloprid was the most frequently detected NEO during the postnatal period. Additionally, exposure to NEOs through breast milk was low. Exposure to CLO, ΣNEOs, and IMIRPF in boys aged 4-6 years was negatively correlated with WPPSI-IV Fluid Reasoning Index. The results of this study indicate that exposure during the third trimester to NEOs does not affect neurodevelopment but that childhood exposure to NEOs may, especially for boys. Further studies with larger sample sizes are required to confirm the sex-specific associations between NEO exposure and neurodevelopment.

Ginsenoside Rb1 mitigates acute catecholamine surge-induced myocardial injuries in part by suppressing STING-mediated macrophage activation.

Stress cardiomyopathy (SCM) is associated with cardiovascular mortality rates similar to acute coronary syndrome. Myocardial injuries driven by inflammatory mechanisms may in part account for the dismal prognosis of SCM. Currently, no inflammation-targeted therapies are available to mitigate SCM-associated myocardial injuries. In this study, acute catecholamine surge-induced SCM was modeled by stimulating the ovariectomized (OVX) mice with isoproterenol (ISO). The effects of ginsenoside Rb1 (Rb1) on SCM-associated myocardial injuries were assessed in the OVX-ISO compound mice. RAW 264.7 macrophages stimulated with calf thymus DNA (ctDNA) or STING agonist DMXAA were adopted to further understand the anti-inflammatory mechanisms of Rb1. The results show that estrogen deprivation increases the susceptibility to ISO-induced myocardial injuries. Rb1 mitigates myocardial injuries and attenuates cardiomyocyte necrosis as well as myocardial inflammation in the OVX-ISO mice. Bioinformatics analysis suggests that cytosolic DNA-sensing pathway is closely linked with ISO-triggered inflammatory responses and cell death in the heart. In macrophages, Rb1 lowers ctDNA-stimulated production of TNF-α, IL-6, CCL2 and IFN-ß. RNA-seq analyses uncover that Rb1 offsets DNA-stimulated upregulation in multiple inflammatory response pathways and cytosolic DNA-sensing pathway. Furthermore, Rb1 directly mitigates DMXAA-stimulated STING activation and inflammatory responses in macrophages. In conclusion, the work here demonstrates for the first time that Rb1 protects against SCM-associated myocardial injuries in part by counteracting acute ISO stress-triggered cardiomyocyte necrosis and myocardial inflammation. Moreover, by evidencing that Rb1 downregulates cytosolic DNA-sensing machineries in macrophages, our findings warrant further investigation of therapeutic implications of the anti-inflammatory Rb1 in the treatment of SCM.

Study on the relationship between atrial high-rate episode and left atrial strain in patients with cardiac implantable electronic device.

Background: Although atrial high-rate episode (AHRE) and atrial fibrillation (AF) cannot entirely be identical, recent studies suggest AHRE is linked to AF development and shares some characteristics with AF regarding thromboembolism. At present, there is still lack of predictive indicators for AHRE and diagnostic methods and clinical indicators for AHRE in patients without cardiac implantable electronic device (CIED). The aim of this study was thus to explore the relationship between AHRE and left atrial (LA) strain parameters with the goal of identifying high-risk populations of AHRE by LA strain characteristics. Methods: From February 2022 to May 2023, a total of 105 CIED patients were enrolled and divided into two groups based on whether AHRE had occurred: AHRE (-) group (n=65) and AHRE (+) group (n=40). Real-time three-dimensional echocardiography (RT-3DE) technique was used to obtain the LA time-volume curve. The collected dynamic images were analyzed on the Echopac 204 workstation to obtain the parameters of LA. The four-dimensional automatic LA quantitative analysis (4D Auto LAQ) technology was used to analyze the LA strain parameters: LA reservoir longitudinal strain (LASr), LA conduit longitudinal strain (LAScd), LA contraction longitudinal strain (LASct), LA reservoir circumferential strain (LASr-c), LA conduit circumferential strain (LAScd-c), LA contraction circumferential strain (LASct-c). Correlation analysis was carried out using Binary logistic regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic performance of LASct in AHRE. Results: Body surface area (BSA) [odds ratio (OR) =8.34, 95% confidence interval (CI): 1.32-72.30, P=0.037], LASct (OR =1.20, 95% CI: 1.05-1.39, P=0.013) and LA end-systolic volume (LAESV) (OR =1.02, 95% CI: 1.00-1.04, P=0.023) were the influencing factors of AHRE. Only LASct (OR =1.18, 95% CI: 1.01-1.38, P=0.041) was found to be an independent influencing factor of AHRE. This result remained significant after adjusting for age, sex, hypertension, diabetes, and stroke history. The ROC curve showed that the cut-off for predicting AHRE was LASct =-4.125% with sensitivity of 37.5% and specificity of 87.7%. Conclusions: This cross-sectional study found that decreased LASct (absolute value) is an independent risk factor for the AHRE and has diagnostic efficacy in certain degree for the occurrence of AHRE.

Prenatal to preschool exposure of nonylphenol and bisphenol A exposure and neurodevelopment in young children.

BACKGROUND: Nonylphenol (NP) and bisphenol A (BPA) are produced in large quantities worldwide as multipurpose agents. However, studies on relations between NP and BPA exposure and childhood neurodevelopment are few, and the results are inconsistent. This study aimed to investigate associations between prenatal and early childhood NP and BPA exposure and neurodevelopment in mother-child pairs. METHODS: Pregnant women at 27-38 weeks' gestation were recruited, as were children 2-3 years of age (n = 94) and 4-6 years of age (n = 56) years. Urine was collected to assess NP and BPA exposure. Bayley Scales of Infant and Toddler Development (3rd edition; Bayley-III), Wechsler Preschool and Primary Scale of Intelligence (4th edition), and the Full Scale Intelligence Quotient (WPPSI-IV-FSIQ) were used to assess the neurodevelopment of the children. RESULTS: The detection rate and concentration of NP and BPA in the urine of children 4-6 years old were higher than in those 2-3 years old. Children were divided into a high concentration group (3rd tertile) and a reference group (1st and 2nd tertiles) based on natural log-transformed urine concentration of NP and BPA. Girls' Bayley-III motor scores in the high concentration group were higher than those of the BPA reference group of urine of mothers (ß = 6.85, 95% confidence interval [CI]: 1.58-12.13). Boys' FSIQ in the higher concentration group were significantly lower than those in children 2-3 years old in the NP reference group (ß = -11.29, 95% CI: -18.62 to -3.96) (all, p < 0.05). CONCLUSIONS: Prenatal and childhood exposure to NP and BPA may have different effects on the neurodevelopment of young children, and there are no consistent effects between boys and girls.

Hyperoside protects against oxidative stress-mediated photoreceptor degeneration: therapeutic potentials for photoreceptor degenerative diseases.

BACKGROUND: Photoreceptor degeneration underpinned by oxidative stress-mediated mitochondrial dysfunction and cell death leads to progressive and irreversible vision impairment. Drug treatments that protect against photoreceptor degeneration are currently available in the clinical settings. It has been shown that hyperoside, a flavonol glycoside, protects against neuronal loss in part by suppressing oxidative stress and maintaining the functional integrity of mitochondria. However, whether hyperoside protects against photoreceptor degeneration remains unknown. METHODS: To address the pharmacological potentials of hyperoside against oxidative stress-mediated photoreceptor degeneration on molecular, cellular, structural and functional levels, multiple in vitro and in vivo methodologies were employed in the current study, including live-cell imaging, optical coherence tomography, electroretinography, histological/immunohistochemical examinations, transmission electron microscopy, RNA-sequencing and real-time qPCR. RESULTS: The in vitro results demonstrate that hyperoside suppresses oxidative stress-mediated photoreceptor cell death in part by mitigating mitochondrial dysfunction. The in vivo results reveal that hyperoside protects against photooxidative stress-induced photoreceptor morphological, functional and ultrastructural degeneration. Meanwhile, hyperoside treatment offsets the deleterious impact of photooxidative stress on multiple molecular pathways implicated in the pathogenesis of photoreceptor degeneration. Lastly, hyperoside attenuates photoreceptor degeneration-associated microglial inflammatory activation and reactive Müller cell gliosis. CONCLUSIONS: All things considered, the present study demonstrates for the first time that hyperoside attenuates oxidative stress-induced photoreceptor mitochondrial dysfunction and cell death. The photoreceptor-intrinsic protective effects of hyperoside are corroborated by hyperoside-conferred protection against photooxidative stress-mediated photoreceptor degeneration and perturbation in retinal homeostasis, warranting further evaluation of hyperoside as a photoreceptor protective agent for the treatment of related photoreceptor degenerative diseases.

Cinnamic acid mitigates left ventricular hypertrophy and heart failure in part through modulating FTO-dependent N6-methyladenosine RNA modification in cardiomyocytes.

Left ventricular hypertrophy leads to heart failure, a serious medical condition associated with high rates of hospitalization and mortality. Limited success with the existing pharmacological treatments necessitates the development of mechanisms-based new therapies to better control the progression from left ventricular hypertrophy to heart failure. The current work investigated the pharmacological potentials and mechanisms of naturally occurring cinnamic acid in the treatment of left ventricular hypertrophy and heart failure. The in vitro findings reveal that cinnamic acid attenuates the hypertrophic responses and mitochondrial dysfunction in the phenylephrine (PE)-stimulated cardiomyocytes. Furthermore, cinnamic acid offsets PE-induced increases in N6-methyladenosine (m6A) RNA modification and reductions in the expression of the key m6A demethylase FTO in cardiomyocytes. Most importantly, FTO knockdown abrogates anti-hypertrophic and mitochondrial protective effects of cinnamic acid in the PE-stimulated cardiomyocytes. The in vivo results further demonstrate that cinnamic acid mitigates left ventricular hypertrophy, left ventricular systolic dysfunction and ultrastructural impairment of cardiomyocyte mitochondria and myofibrils in the mice subjected to transverse aortic constriction (TAC)-induced pressure overload. Moreover, FTO knockdown abolishes these beneficial effects of cinnamic acid in the TAC mice. In conclusion, the work here demonstrates for the first time that cinnamic acid is effective at mitigating pressure overload-induced left ventricular hypertrophy and heart failure in part by modulating the expression of FTO and the level of FTO-dependent m6A RNA modification in cardiomyocytes. These novel findings warrant further evaluation of cinnamic acid as a pharmacological agent/component to complement the existing treatment of pressure overload-mediated left ventricular hypertrophy and heart failure.

Application of an angiogenesis-related genes risk model in lung adenocarcinoma prognosis and immunotherapy.

Lung adenocarcinoma (LUAD) is an essential pathological subtype of non-small cell lung cancer and offers a severe problem for worldwide public health. There is mounting proof that angiogenesis is a crucial player in LUAD progression. Consequently, the purpose of this research was to construct a novel LUAD risk assessment model based on genetic markers related to angiogenesis. We accessed The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases for LUAD mRNA sequencing data and clinical information. Based on machine algorithms and bioinformatics, angiogenic gene-related risk scores (RS) were calculated. Patients in the high-risk category had a worse prognosis (p < 0.001) in the discovery TCGA cohort, and the results were confirmed by these three cohorts (validation TCGA cohort, total TCGA cohort, and GSE68465 cohort). Moreover, risk scores for genes involved in angiogenesis were independent risk factors for lung cancer in all four cohorts. The low-risk group was associated with better immune status and lower tumor mutational load. In addition, the somatic mutation study revealed that the low-risk group had a lower mutation frequency than the high-risk group. According to an analysis of tumor stem cell infiltration, HLA expression, and TIDE scores, the low-risk group had higher TIDE scores and HLA expression levels than the high-risk group, and the amount of tumor stem cell infiltration correlated with the risk score. In addition, high-risk groups may benefit from immune checkpoint inhibitors and targeted therapies. In conclusion, we developed an angiogenesis-related gene risk model to predict the prognosis of LUAD patients, which may aid in the classification of patients with LUAD and select medications for LUAD patients.

Comparison of X-ray Radiant Power Absolute Measurement between a Free-Air Ionization Chamber and a Cryogenic Electrical Substitution Radiometer.

Absolute measurement of radiant power in the X-ray region is essential for many applications in astrophysics, spectroscopy, and X-ray diagnostics. Comparison between different measuring methods is an effective way to check their reliability. In the present work, a comparison of X-ray radiant power absolute measurement between a free-air ionization chamber and a cryogenic electrical substitution radiometer was performed at Beijing Synchrotron Radiation Facility. The absolute radiant power obtained by these two methods were mutually compared via a transfer standard detector's spectral responsivity at a photon energy of 10 keV. The result of the comparison showed that the difference was 0.47%. A conclusion was reached that the free-air ionization chamber and the cryogenic electrical substitution radiometer agreed within the combined relative uncertainty of 3.35%.

Left bundle branch pacing on mechanical synchrony and myocardial work in bradycardia patients.

Left bundle branch pacing (LBBP) has emerged as a novel physiological pacing method to produce narrower QRS duration, but whether it could restore mechanical synchrony and improve myocardial work still lacks sufficient evidence. Therefore, the goal of this study was to evaluate mechanical synchrony and myocardial work in LBBP. We collected 20 patients with LBBP due to symptomatic bradycardia and another 29 age-matched patients with right ventricular pacing (RVP). For LBBP patients, cardiac electro-mechanical synchrony and myocardial work were measured at baseline and 7 days after implantation and compared with the RVP patients. In the LBBP group, paced QRS duration and mechanical synchrony were not significantly different from baseline(all P > 0.05), but significantly smaller than that in the RVP group (all P<0.05). Meanwhile, global longitudinal strain (GLS) in LBBP was greater than that in the RVP group (17.7 ± 3.5% vs. 14.8 ± 3.1%, P < 0.05). Global myocardial work index and global constructive work were also better than that in the RVP group(all P<0.05). Global work efficiency was 91.9 ± 3.1%, which was greater when compared with RVP (P < 0.05). LBBP provides better cardiac electro-mechanical synchrony and more effective myocardial work than that in RVP, thus improving global heart function.

Circulating MicroRNA-505 May Serve as a Prognostic Biomarker for Hypertension-Associated Endothelial Dysfunction and Inflammation.

Our previous study has reported that the plasma microRNA-505 (miR-505) is elevated in hypertensive patients. However, the pathophysiological significance of miR-505 in hypertension remains to be elucidated. Hypertension is not only a vascular disorder, but also an inflammatory condition. The current study therefore aims to further investigate the pathophysiological implications of miR-505 in hypertension-associated vascular and inflammatory changes. In vivo experiments reveal that the plasma level of miR-505 is elevated in spontaneously hypertensive rats and angiotensin II-infused mice. In addition, miR-505 agomir treatment results in elevated blood pressure, endothelial dysfunction, increased vascular expression of inflammatory genes and renal inflammatory injuries as well as pre-activation of PBMCs in mice. In vitro experiments further demonstrate that miR-505 agomir increases the expression of IL1B and TNFA, whereas miR-505 antagomir attenuates TNF-α-induced upregulation of IL1B and TNFA in endothelial cells, HUVECs. In addition, miR-505 modulates the levels of endothelial activation markers VCAM1 and E-selectin in HUVECs as well as the adhesion of THP-1 monocytes to HUVECs. Lastly, the plasma level of miR-505 is positively correlated with systolic blood pressure and the level of C-reactive protein in human subjects. Our work links for the first time miR-505 to endothelial dysfunction and inflammation under hypertensive conditions, supporting the translational value of miR-505 in prognosticating hypertension-associated endothelial impairment and inflammatory injuries in target organs such as the vessels and kidneys.

Adjuvant Therapy With PD1/PDL1 Inhibitors for Human Cancers: A Systematic Review and Meta-Analysis.

Background: Immune checkpoint inhibitors (ICIs) have made a breakthrough in the systemic treatment of patients with advanced tumors. However, little is known about their efficacy and safety in adjuvant settings after the resection of solid tumors. Methods: We performed a meta-analysis on the efficacy and safety of programmed death 1 (PD1)/PD-1 ligand (PDL1) inhibitors in adjuvant therapy after tumor resection using Review Manager 5.3, based on published clinical studies. The outcomes included recurrence-free survival (RFS), disease-free survival (DFS), overall survival (OS), and adverse events (AEs). Results: Eight randomized controlled trials (RCTs) were included in the analysis. The use of PD1/PDL1 inhibitors in adjuvant therapy significantly improved RFS (hazard ratio [HR] = 0.72; 95% confidence interval [CI] 0.67-0.78, p < 0.00001). However, there was no statistically significant difference in OS between PD1/PDL1 inhibitors and placebo (HR = 0.86; 95% CI 0.74-1.00, p = 0.05). Gender, age, and PDL1 status were independent predictors of RFS with PD1/PDL1 inhibitors. As for the safety analysis results, PD1/PDL1 inhibitors had a higher incidence of fatigue (risk ratio [RR] = 1.22; 95% CI 1.01-1.49, p = 0.04), nausea (RR = 1.47; 95% CI 1.11-1.94, p = 0.007), and pruritus (RR = 1.96; 95% CI 1.57-2.44, p < 0.00001). In addition, the incidence of any grade adverse events increased in the PD1/PDL1 inhibitor group (RR = 1.03; 95% CI 1.02-1.05, p < 0.0001). Conclusions: This is the first meta-analysis on the efficacy and safety of PD1/PDL1 inhibitors in adjuvant therapy. The use of PD1/PDL1 inhibitors in adjuvant therapy could significantly reduce the recurrence rate after solid tumor resection. However, the incidence of fatigue, nausea, pruritus, and any grade AEs also increased, which should be monitored with vigilance.

The sex-specific association of prenatal phthalate exposure with low birth weight and small for gestational age: A nationwide survey by the Taiwan Maternal and Infant Cohort Study (TMICS).

The Taiwan Maternal and Infant Cohort Study (TMICS) was launched with the aim to assess the effects of prenatal exposure to phthalic acid esters (PAEs) on infant health. A total of 1102 pregnant women were enrolled in this study from 2012 to 2015. All participants completed a structured questionnaire, and provided urine specimens. The urinary concentrations of PAE metabolites in the third trimester were measured using liquid chromatography-electrospray ionization tandem mass spectrometry. Generalized additive model-penalized regression splines and logistic regression models were employed to determine the risk for low birth weight (LBW) or small for gestational age (SGA) among pregnant women exposed to PAEs. After adjustments for other covariates, each incremental unit of ln-transformed mono-n-butyl phthalate (MnBP) for pregnant women increased the odds of SGA in male neonates by 1.44 (95% CI: 0.92-2.23). An inverse association between SGA and maternal MnBP exposure level was observed in female neonates. An increase in one ln-transformed MnBP concentration unit decreased the risk of female SGA to 0.50 (95% CI: 0.24-0.97). In the penalized regression splines, increased risks of LBW/SGA in male neonates were presented while pregnant women exposed to increased MnBP levels. However, an association in the opposite direction was observed between maternal MnBP and LBW or SGA for male and female neonates. This study indicated that high maternal MnBP exposure in the third trimester was associated with LBW or SGA for male infants. Adverse effects on susceptible populations exposed to high levels of PAEs should be of concern.

KLF2 regulates neutrophil activation and thrombosis in cardiac hypertrophy and heart failure progression.

It is widely recognized that inflammation plays a critical role in cardiac hypertrophy and heart failure. However, clinical trials targeting cytokines have shown equivocal effects, indicating the need for a deeper understanding of the precise role of inflammation and inflammatory cells in heart failure. Leukocytes from human subjects and a rodent model of heart failure were characterized by a marked reduction in expression of Klf2 mRNA. Using a mouse model of angiotensin II-induced nonischemic cardiac dysfunction, we showed that neutrophils played an essential role in the pathogenesis and progression of heart failure. Mechanistically, chronic angiotensin II infusion activated a neutrophil KLF2/NETosis pathway that triggered sporadic thrombosis in small myocardial vessels, leading to myocardial hypoxia, cell death, and hypertrophy. Conversely, targeting neutrophils, neutrophil extracellular traps (NETs), or thrombosis ameliorated these pathological changes and preserved cardiac dysfunction. KLF2 regulated neutrophil activation in response to angiotensin II at the molecular level, partly through crosstalk with HIF1 signaling. Taken together, our data implicate neutrophil-mediated immunothrombotic dysregulation as a critical pathogenic mechanism leading to cardiac hypertrophy and heart failure. This neutrophil KLF2-NETosis-thrombosis mechanism underlying chronic heart failure can be exploited for therapeutic gain by therapies targeting neutrophils, NETosis, or thrombosis.

The Prognostic Value of ctDNA and bTMB on Immune Checkpoint Inhibitors in Human Cancer.

BACKGROUND: Circulating tumor DNA (ctDNA) levels and blood tumor mutation burden (bTMB) have a significant impact on the prognosis of tumor patients. However, their prognostic role in immune checkpoint inhibitors (ICIs) in cancer patients is still unclear. METHODS: We used the Review Manager software (version 5.3) to perform a meta-analysis based on the published literature to explore the prognostic value of ctDNA and bTMB in patients receiving immunotherapy. We extracted the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) for each included study and their respective 95% confidence intervals (CIs) and p-values for analysis. RESULTS: Thirteen studies were included in the meta-analysis. Higher ctDNA levels were significantly associated with shorter OS (HR = 3.35, 95%CI = 2.49-4.51, p < 0.00001) and PFS (HR = 3.28, 95%CI = 2.47-4.35, p < 0.00001). The results of ctDNA subgroup analysis showed that high posttreatment ctDNA levels significantly correlated with shorter OS in cancer patients receiving ICIs (HR = 5.09, 95%CI = 1.43-18.07, p = 0.01). Moreover, patients with ctDNA clearance had better OS (HR = 4.94, 95%CI = 2.96-8.26, p < 0.00001). Patients with high posttreatment ctDNA levels had shorter PFS (HR = 3.00, 95%CI = 2.02-4.46, p < 0.00001) and those with ctDNA clearance had longer PFS (HR = 4.61, 95%CI = 2.78-7.65, p < 0.00001). However, there was no statistically significant difference in the OS benefits between a high and a low bTMB after ICI therapy (HR = 0.68, 95%CI = 0.33-1.37, p = 0.28). CONCLUSIONS: The host immune system and tumor burden together determine whether cancer patients can benefit from ICI therapy. Our systematic review and meta-analysis revealed for the first time that the levels of pretreatment and posttreatment ctDNA and the clearance of ctDNA can independently be used as prognostic factors for antitumor immunotherapy, while bTMB cannot. In conclusion, ctDNA levels have great potential as an assistant tool for radiological assessments to make clinical therapeutic decisions. The prognostic utility of bTMB still requires further exploration.

Assessment of atrial septal defect using 2D or real-time 3D transesophageal echocardiography and outcomes following transcatheter closure.

BACKGROUND: The assessment of interatrial septum (IAS) requires a standardized, systematic approach, including two-dimensional transthoracic echocardiography (2D TTE), 2D transesophageal echocardiography (2D TEE), and three-dimensional (3D) TEE. Although 2D TEE has been widely used for the preoperative assessment of atrial septal defect (ASD), its ability to provide reliable information is often limited due to the structural characteristics of IAS. The introduction of 3D TEE provides a unique "en face" view of IAS, which allows the visualization and accurate measurements of diameters, area, and rims of ASD. Hence, appropriate ASD imaging information is particularly important in successful transcatheter closure. METHODS: In this retrospective study, 2D TTE/TEE, and 3D TEE were performed before ASD closure, with 2D minimal and maximal diameters, areas, and residual rims being recorded. Adequate 3D TEE imaging data sets were collected and then analyzed. ASD related parameters were compared using different echocardiography. Patients who underwent ASD closure completed a clinical follow-up. RESULTS: The mean defect maximal diameter and aperture area by 3D TEE was significantly larger than that of the corresponding 2D TEE (P<0.05). There was no statistical difference in the minimal and maximal diameter or area by TEE for circular-shaped ASDs. For oval ASDs, mean minimal diameter on 2D TEE was larger than that on 3D TEE. The mean maximal diameter measured using 2D TEE was smaller than the 3D TEE measurement (16.0±7.1 vs. 19.8±8.6; P<0.05). For complex-shaped defects, there were statistical differences in minimal and maximal diameter between TEEs. Furthermore, 2D and 3D TEE had a longer superior vena cava (SVC) residual rim than did 2D TTE (P<0.05). The 3D TEE residual rims of the inferior vena cava (IVC) was significantly larger than the corresponding 2D TEE. There was a very strong correlation between the residual rim measurements using 3D and 2D TEE. However, the limits of agreement between 2D and real-time 3D TEE measurements were more apparent in the IVC rim group than in the other groups. CONCLUSIONS: Our study confirms the value of 3D TEE in assessing ASD shape and size reported by previous studies, and is also the first to accurately and systematically characterize ASD residual rim in complex ASDs.

Prognostic Impact of Memory CD8(+) T Cells on Immunotherapy in Human Cancers: A Systematic Review and Meta-Analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to determine the prognostic value of memory CD8(+) T cells in cancer patients with immunotherapy. METHODS: EMBASE, MEDLINE (PubMed), and Web of Science databases were searched to identify suitabile articles published before March 2021. Risk of bias on the study level was assessed using the Cochrane Bias Risk Assessment Tool. The hazard ratios (HRs) and 95% confidence intervals (CIs) of pooled progression-free survival (PFS) and overall survival (OS) were calculated using RevMan 5.4 to evaluate the prognostic impact of memory CD8(+) T cells. RESULTS: In total, nine studies were included in the final analysis. High levels of memory CD8(+) T cells were significantly closely correlated with better progression-free survival (PFS) and overall survival (OS) of cancer patients with immunotherapy (PFS, HR 0.64, 95% CI 0.53-0.78; OS, HR 0.37, 95% CI 0.21-0.65). Memory CD8(+) T cells still have significant prognostic value in cancer patients given immunotherapy alone after excluding of other interfering factors such as chemotherapy, radiotherapy, and targeted therapy (PFS, HR 0.65, 95% CI 0.48-0.89; OS, HR 0.23, 95% CI 0.13-0.42). However, high memory CD8(+) T cells levels did not correspond to a longer PFS or OS in cancer patients with non-immunotherapy (PFS, HR 1.05, 95% CI 0.63-1.73; OS, HR 1.29, 95% CI 0.48-3.48). Thus, memory CD8(+) T cells might be a promising predictor in cancer patients with immunotherapy. CONCLUSIONS: The host's overall immune status, and not only the tumor itself, should be considered to predict the efficacy of immunotherapy in cancer patients. This study is the first to show the significant prognostic value of memory CD8(+) T cells in immunotherapy of cancer patients through systematic review and meta-analysis. Thus, the detection of memory CD8(+) T cells has a considerable value in clinical practice in cancer patients with immunotherapy. Memory CD8(+) T cells may be promising immunotherapy targets.

Dual Activity of Ginsenoside Rb1 in Hypertrophic Cardiomyocytes and Activated Macrophages: Implications for the Therapeutic Intervention of Cardiac Hypertrophy.

PURPOSE: Owing to the important mechanistic implications in the pathogenesis of cardiac hypertrophy and heart failure, inflammation has been proposed as a druggable target for the treatment of cardiac hypertrophy and heart failure. Ginseng is a widely used medicinal herb for the treatment of cardiovascular disorders. As one of the major chemical components of ginseng, ginsenoside Rb1 (Rb1) contributes to the cardiovascular effects of ginseng. Meanwhile, anti-inflammatory activity of Rb1 has also been documented. The current work aims to further delineate the pharmacological implications of Rb1 in the treatment of cardiac hypertrophy. METHODS: Angiotensin II (Ang II) infusion mouse model was adopted to investigate the effects of Rb1 on cardiac hypertrophic remodeling and associated inflammation in vivo. Furthermore, the mechanisms of actions of Rb1 in modulating the hypertrophic and inflammatory responses were investigated in cardiomyocytes and macrophages, respectively. RESULTS: Rb1 mitigates Ang II-induced cardiac hypertrophy, cardiac inflammation and systemic inflammation in vivo. In cardiomyocytes, Rb1 directly counteracts the pro-hypertrophic effects of Ang II and phenylephrine and maintains the mitochondrial function. In lipopolysaccharide (LPS)-stimulated macrophages, Rb1 decreases the phosphorylation of mitogen-activated protein kinases (MAPKs) and mitogen-activated protein kinase kinase 1/2 (MEK1/2) and reduces the production of inflammation mediators such as interleukin (IL)-1 beta, IL-6 and tumor necrosis factor (TNF). Rb1 also suppresses the expression of pro-hypertrophic microRNA-155 (miR-155) in LPS- or Ang II-stimulated macrophages. Furthermore, in activated macrophages, miR-155 is in part accountable for the suppressive effect of Rb1 on the production of IL-6, an inflammation mediator with pro-hypertrophic functions in the heart. CONCLUSION: The work here provides novel experimental evidence supporting the notion that Rb1 protects against cardiac hypertrophy in part through suppressing the inflammatory mechanisms that promotes the pathological remodeling of the heart.

Successful same day discharge after immediate post-mastectomy alloplastic breast reconstruction: A single tertiary centre retrospective audit.

BACKGROUND: Immediate Post-Mastectomy Alloplastic Breast Reconstruction (IPMABR) traditionally requires a post-operative overnight stay. Recent initiatives have identified same day discharge as a safe option. METHODS: A retrospective audit of all cases at a tertiary breast cancer centre was performed. Patients received surgery at a day care facility or regional hospital (RH). Unplanned admission was defined as any patient unable to be discharged or any patient returning to the emergency room within the first 24 h. Planned admission cases had a history of BMI >40, obstructive sleep apnoea or previous anaesthetic complications. Data were collected on planned same day discharge, unplanned admission and planned admission cases. Factors differentiating the groups were identified and variables predicting unplanned admission were determined. RESULTS: A total of 785 patients received IPMABR over a 5-year period of which 743 had satisfactory data sets for review. Greater than 96% of patients receiving care at the day care facility were successfully discharged. The success rate for same day discharge at the RH was 65%. We determined that the greatest variables determining successful planned discharge were shorter surgical time (67 min; SD 6 min; p<.01), shorter PACU time (130 min; SD 21 min; p<.01) and surgical institution (p<.01). This difference between institutions was significant when all other variables (age, co-morbidities, unilateral/bilateral and BMI) were controlled, indicating a strong institutional bias. There was no difference between groups in complication rates (infection, dehiscence, seroma and haematoma). CONCLUSION: Same day discharge following IPMABR is safe and greatly reduces resource use. It is imperative that members of the perioperative team understand the validity and benefits of the programme to ensure success and reduce unplanned admissions.

Candesartan attenuates hypertension-associated pathophysiological alterations in the gut.

Intestinal pathophysiological alterations have recently been revealed to be implicated in the pathogenesis of hypertension, necessitating further investigations to better understand the intestinal effects of anti-hypertensive drugs. The current study thus investigated the pharmacological implications of a commonly used first-line angiotensin II type 1 receptor blocker, candesartan cilexetil, on the intestinal barrier impairment and gut dysbiosis in spontaneously hypertensive rats (SHRs). The results revealed that candesartan treatment protected against ileal and colonic pathologies and increased the intestinal expression of genes encoding tight junction proteins such as cingulin, occludin and tight junction protein 1 in SHRs. Serum level of lipopolysaccharides-binding protein was increased in candesartan-treated SHRs, supporting the notion that candesartan treatment provided protection against hypertension-associated impairment of intestinal barrier. Candesartan treatment also increased the amount of fecal short-chain fatty acids (SCFAs) including acetic acid, propionic acid, and butyric acid in SHRs. Fecal 16S rDNA sequencing further revealed that candesartan treatment normalized hypertension-altered ratio of Firmicutes to Bacteroidetes in SHRs. Most notably, candesartan treatment counteracted hypertension-associated diminishment of lactic acid-producing genus Lactobacillus. Taken together, the current study demonstrates for the first time that candesartan treatment alleviates hypertension-associated pathophysiological alterations in the gut, increases microbial production of SCFAs and preserves gut Lactobacillus under hypertensive conditions, which sheds novel light on the pharmacological implications of candesartan in the treatment of hypertension.