Excessive Polyamine Generation in Keratinocytes Promotes Self-RNA Sensing by Dendritic Cells in Psoriasis.

Psoriasis is a chronic inflammatory disease whose etiology is multifactorial. The contributions of cellular metabolism to psoriasis are unclear. Here, we report that interleukin-17 (IL-17) downregulated Protein Phosphatase 6 (PP6) in psoriatic keratinocytes, causing phosphorylation and activation of the transcription factor C/EBP-ß and subsequent generation of arginase-1. Mice lacking Pp6 in keratinocytes were predisposed to psoriasis-like skin inflammation. Accumulation of arginase-1 in Pp6-deficient keratinocytes drove polyamine production from the urea cycle. Polyamines protected self-RNA released by psoriatic keratinocytes from degradation and facilitated the endocytosis of self-RNA by myeloid dendritic cells to promote toll-like receptor-7 (TLR7)-dependent RNA sensing and IL-6 production. An arginase inhibitor improved skin inflammation in murine and non-human primate models of psoriasis. Our findings suggest that urea cycle hyperreactivity and excessive polyamine generation in psoriatic keratinocytes promote self-RNA sensation and PP6 deregulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis.

A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction.

Micropeptides encoded by short open reading frames (sORFs) within long noncoding RNAs (lncRNAs) are beginning to be discovered and characterized as regulators of biological and pathological processes. Here, we find that lncRNA Dleu2 encodes a 17-amino-acid micropeptide, which we name Dleu2-17aa, that is abundantly expressed in T cells. Dleu2-17aa promotes inducible regulatory T (iTreg) cell generation by interacting with SMAD Family Member 3 (Smad3) and enhancing its binding to the Foxp3 conserved non-coding DNA sequence 1 (CNS1) region. Importantly, the genetic deletion of Dleu2-17aa in mice by start codon mutation impairs iTreg generation and worsens experimental autoimmune encephalomyelitis (EAE). Conversely, the exogenous supplementation of Dleu2-17aa relieves EAE. Our findings demonstrate an indispensable role of Dleu2-17aa in maintaining immune homeostasis and suggest therapeutic applications for this peptide in treating autoimmune diseases.

Single-Cell RNA Sequencing Identifies WARS1+ Mesenchymal Stem Cells with Enhanced Immunomodulatory Capacity and Improved Therapeutic Efficacy.

Psoriasis is a common inflammatory skin disorder with no cure. Mesenchymal stem cells (MSCs) have immunomodulatory properties for psoriasis, but the therapeutic efficacies varied, and the molecular mechanisms were unknown. In this study, we improved the efficacy by enhancing the immunomodulatory effects of umbilical cord-derived MSCs (UC-MSCs). UC-MSCs stimulated by TNF-α and IFN-γ exhibited a better therapeutic effect in a mouse model of psoriasis. Single-cell RNA sequencing revealed that the stimulated UC-MSCs overrepresented a subpopulation expressing high tryptophanyl-tRNA synthetase 1 (WARS1). WARS1-overexpressed UC-MSCs treat psoriasis-like skin inflammation more efficiently than control UC-MSCs by restraining the proinflammatory macrophages. Mechanistically, WARS1 maintained a RhoA-Akt axis and governed the immunomodulatory properties of UC-MSCs. Together, we identify WARS1 as a master regulator of UC-MSCs with enhanced immunomodulatory capacities, which paves the way for the directed modification of UC-MSCs for escalated therapeutic efficacy.

CKBA suppresses mast cell activation via ERK signaling pathway in murine atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)-induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA-seq analysis revealed that CKBA downregulated the extracellular signal-regulated kinase (ERK) signaling in BM-derived mast cells activated by anti-2,4-dinitrophenol/2,4-dinitrophenol-human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t-butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD.

A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting Treg differentiation.

Recent evidence has revealed that small polypeptides (containing fewer than 100 amino acids) can be translated from noncoding RNAs (ncRNAs), which are usually defined as RNA molecules that do not encode proteins. However, studies on functional products translated from primary transcripts of microRNA (pri-miRNA) are quite limited. Here, we describe a peptide termed miPEP31 that is encoded by pri-miRNA-31. miPEP31 is highly expressed in Foxp3+ regulatory T cells (Tregs ) and significantly promotes the differentiation of Tregs without affecting their inhibitory ability. Our results show that miPEP31 is a cell-penetrating peptide both in vitro and in vivo. miPEP31 downregulates miR-31 expression, enhances peripheral Treg induction, and dramatically suppresses experimental autoimmune encephalomyelitis. Mechanistically, we show that miPEP31 acts as a transcriptional repressor inhibiting the expression of miRNA-31, a negative regulator of Tregs . Our results reveal an indispensable role of miPEP31 in maintaining immune homeostasis by promoting Treg differentiation and also present a potential therapeutic peptide for modulating miRNA expression and treating autoimmune diseases.

Association of metabolically healthy obesity in young adulthood with myocardial structure and function.

BACKGROUND: Obesity is major cause of cardiovascular diseases. Metabolically healthy obesity (MHO) may increase heart failure risk early in life, and may be reflected in impaired cardiac structure and function. Therefore, we aimed to examine the relationship between MHO in young adulthood and cardiac structure and function. METHODS: A total of 3066 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study were included, who completed echocardiography in young adulthood and middle age. The participants were grouped by obesity status (body mass index ≥30 kg/m2) and poor metabolic health (≥2 criteria for metabolic syndrome) into four metabolic phenotypes as follows: metabolically healthy non-obesity (MHN), MHO, metabolically unhealthy non-obesity (MUN), metabolically unhealthy obesity (MUO). The associations of the metabolic phenotypes (MHN serving as the reference) with left ventricular (LV) structure and function were evaluated using multiple linear regression models. RESULTS: At baseline, mean age was 25 years, 56.4% were women, and 44.7% were black. After a follow-up 25 years, MUN in young adulthood was associated with worse LV diastolic function (E/é ratio, ß [95% CI], 0.73 [0.18, 1.28]), worse systolic function (global longitudinal strain [GLS], 0.60 [0.08, 1.12]) in comparison with MHN. MHO and MUO were associated with LV hypertrophy (LV mass index, 7.49 g/m2 [4.63, 10.35]; 18.23 g/m2 [12.47, 23.99], respectively), worse diastolic function (E/é ratio, 0.67 [0.31, 1.02]; 1.47 [0.79, 2.14], respectively), and worse systolic function (GLS, 0.72 [0.38, 1.06]; 1.35 [0.64, 2.05], respectively) in comparison with MHN. These results were consistent in several sensitivity analyses. CONCLUSIONS: In this community-based cohort using data from the CARDIA study, obesity in young adulthood was significantly associated with LV hypertrophy, worse systolic and diastolic function regardless of metabolic status. Relationship of Baseline Metabolic Phenotypes with Young Adulthood and Midlife Cardiac Structure and Function. Adjusted for year 0 covariates: age, sex, race, educational level, smoking status, drinking status, and physical activity; metabolically healthy non-obesity was used as a reference category for comparison. † Criteria for metabolic syndrome are listed in Supplementary Table S6. MUN metabolically unhealthy non-obesity, MHO metabolically healthy obesity, LVMi left ventricular mass index, LVEF left ventricular ejection fraction, E/A early to late peak diastolic mitral flow velocity ratio, E/é mitral inflow velocity to early diastolic mitral annular velocity, CI confidence interval.

SZB120 Exhibits Immunomodulatory Effects by Targeting eIF2α to Suppress Th17 Cell Differentiation.

IL-17-secreting Th17 cells play an important role in the pathogenesis of various inflammatory and autoimmune diseases. IL-17-targeted biologics and small molecules are becoming promising treatments for these diseases. In this study, we report that SZB120, a derivative of the natural compound 3-acetyl-ß-boswellic acid, inhibits murine Th17 cell differentiation by interacting with the α-subunit of eukaryotic initiation factor 2 (eIF2α). We showed that SZB120 directly interacts with eIF2α and contributes to serine 51 phosphorylation of eIF2α. The suppressive effect of SZB120 on Th17 cell differentiation was reversed by GSK2606414, an inhibitor of eIF2α phosphokinase. Phosphorylation of eIF2α induced by SZB120 decreased the protein expression of IκBζ, which is important for Th17 cell differentiation. Notably, interaction with eIF2α by SZB120 also impaired glucose uptake and glycolysis in T cells. In vivo, SZB120 treatment of C57BL/6 mice significantly attenuated IL-17/Th17-mediated autoimmune disease. Our study indicates that SZB120 is a promising drug candidate for IL-17/Th17-mediated inflammatory diseases.

Vitamin D3 receptor polymorphisms regulate T cells and T cell-dependent inflammatory diseases.

It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.

Characteristics of intracardiac electrogram of the interventricular septum in the left bundle branch pacing.

BACKGROUND: Left bundle branch pacing (LBBP) has become a hot topic in the field of physiological pacing. However, only a few studies have described the characteristics of the intrinsic intracardiac electrogram (EGM) while placing the left bundle branch (LBB) lead. CASE PRESENTATION: Herein, we reported a case with atrial premature contractions to the ventricle during the LBBP procedure. Paced and intrinsic (supraventricular) EGMs were recorded and analyzed. CONCLUSIONS: The myocardium of the interventricular septum could be divided into four regions based on electrophysiology: the right septal area, the left septal area, the endocardium of the left ventricular septum, and the LBB area. This might guide the electrophysiological localization of the LBB lead in the septum.

The left bundle branch has been captured but shows the left ventricular septal pacing:What is the mechanism?

It was shown that V6 R-wave peak time (V6 RWPT) prolongs with transition form non-selective left bundle branch pacing (ns-LBBP) to left ventricular septal pacing (LVSP) but remains constant or slightly prolongs with transition to selective left bundle branch pacing (sel-LBBP) [1,2]. Here, we report on a patient who was observed with a LBB potential, isoelectric interval, where the V6 RWPT substantially prolonged with transition from ns-LBBP to sel-LBBP at near threshold output.

PTSD Among Shidu Parents in China: The Roles of Personality Types and Social Support.

Background: The psychological problems of Shidu Parents (SDP) under the China's One-Child Policy have been documented. The purpose of this study was to investigate the relationships among personality types, social support, and post-traumatic stress disorder (PTSD) in SDP. Methods: The PTSD Checklist-Civilian Version (PCL-C), The Big Five Personality Traits (NEO), and Social Support Revalued Scale (SSRS) were administered to the sample of 149 SDP who were over 50 years old and had lost their only child more than one year ago. Results: Among SDP, mothers were more likely to develop PTSD than fathers (χ2 = 11.16, p < 0.01). Parents who were extraverted had a lower risk of developing PTSD-related symptoms (χ2 = 8.58, p < 0.01), and the effect of neuroticism was significant (χ2 = 23.73, p < 0.01). The more social support parents utilized, the lower the incidence of PTSD (t = 4.56, p < 0.01). The result of multilevel linear regression showed that sex, neuroticism, and objective social support remained significantly different after combining all personality types and social support systems in the same model. Social support partially mediated the relationship between neuroticism and PTSD. Meanwhile, it was a complete mediator between extraversion and PTSD. Conclusions: Female sex/gender, neuroticism, and introversion were risk factors of developing PTSD, while receiving social support protected SDP from developing PTSD symptoms. Losing an only child is undoubtedly an enormous disaster for the family, which has become a huge, unavoidable social problem that must be addressed in China.

An Optimized Model of Hypertrophic Preconditioning Confers Cardioprotection in the Mouse.

BACKGROUND: Conventional models of hypertrophic preconditioning (C-HP) can be established surgically through transverse aortic constriction (TAC) → deconstriction (De-TAC) → reconstriction (Re-TAC) characterized by dynamic afterload while it exerts technical difficulty on operators and poses high mortality during perioperative period in mice. We aimed to introduce an optimized method for obtaining a hypertrophic preconditioning (O-HP) model for further study on cardiac hypertrophy. METHODS: Ninety mice were divided into four groups: sham, TAC, C-HP, and O-HP. The sham group was exerted on three-time thoracotomies. The TAC group experienced twice thoracotomies and one TAC operation. C-HP and O-HP groups were given TAC, De-TAC, and Re-TAC operation at day 0, day 3, and day 7 in conventional and optimized method, respectively. We optimized the operating procedure in O-HP mice compared with the C-HP group by (1) leaving a ∼3-cm suture fixed in the subcutaneous layer after aortic constriction in TAC surgery (2) using two small forceps to untie the constriction knot instead of cutting it in the De-TAC operation. Ultrasound biomicroscopy was used for hemodynamics and cardiac function detection. Four weeks after the third surgery, all mice were sacrificed and pathology was analyzed among four groups. RESULTS: Four weeks after Re-TAC, the survival of O-HP mice was 63.3% while that of C-HP was 26.7%. Ultrasound biomicroscopy showed a successful establishment of HP models. C-HP and O-HP mice had improved cardiac structure and function indicated by left ventricular end-systolic diameter, left ventricular end-systolic posterior wall thickness, left ventricular ejection fraction, and left ventricular fractional shortening than the TAC group. Pathological analysis showed O-HP as well as C-HP had less hypertrophy than the TAC mice. CONCLUSIONS: Our results provide a rapid, safe, efficient, and reproducible method for optimized establishment of the HP model, which will facilitate studies for early intervention and prevention of left ventricular hypertrophy and heart failure.

Molecular mechanism of wedelolactone inhibits high glucose-induced human retinal vascular endothelial cells injury through regulating miR-190 expression.

To investigate the effects and molecular mechanisms of wedelolactone (WEL) on high glucose-induced injury of human retinal vascular endothelial cells (HRECs). The cell injury model was established by incubating HRECs with 30 mmol/L glucose for 24 hour. HRECs were divided into control (Con) group, high glucose (HG) group, HG + WEL-low dose (L) group, HG + WEL-medium dose (M), HG + WEL-high dose (H) group, HG + miR-NC group, HG + miR-190 group, HG + WEL + antimiR-NC group, HG + WEL + antimiR-190 group. The kit detects cellular reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) content; cell apoptosis was analyzed by flow cytometry; miR-190 expression was detected by real-time quantitative PCR (RT-qPCR). Compared with Con group, the levels of ROS and MDA in the HG group were significantly increased (P < .01), the SOD activity and the expression of miR-190 expression were significantly decreased (P < .05), and the apoptosis rate was significantly increased (P < .01). Compared with HG group, the levels of ROS and MDA in HG + WEL-L group, HG + WEL-M group and HG + WEL-H group were significantly decreased (P < .05), SOD activity and miR-190 expression were significantly increased (P < .05), and apoptosis rate was significantly reduced (P < .05). Compared with the HG + miR-NC group, the levels of ROS and MDA in HG + miR-190 group were significantly reduced (P < .01), SOD activity was significantly increased (P < .01), and apoptosis rate was significantly reduced (P < .05). Compared with the HG + WEL + antimiR-NC group, the ROS level and MDA content in the HG + WEL + antimiR-190 group were significantly increased (P < .05), SOD activity was significantly decreased (P < .05), and apoptosis rate was significantly increased (P < .05). Wedelolactone can attenuate high glucose-induced HRECs apoptosis and oxidative stress by up-regulating miR-190 expression.

Sex-based differences in brain morphometry under chronic stress: A pilot MRI study.

Background: Sex-based differences are known to be a significant feature of chronic stress; however, the morphological mechanisms of the brain underlying these differences remain unclear. The present study aimed to use magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to investigate the effects of sex on gray matter volume (GMV) changes under conditions of chronic stress. Methods: A total of 32 subjects were included for analysis in the present study: 16 participants experiencing chronic stress and 16 healthy controls. T1-weighted (T1WI) images from a 3 T MRI scanner were extracted from the OpenfMRI database. Images were segmented into gray matter using VBM analysis. A two-way analysis of variance (ANOVA) with a 2 × 2 full factorial design was used to evaluate the main and interaction effects of chronic stress and sex on GMV changes, and then post hoc testing was used to verify each simple effect. Results: Two-way ANOVA showed a chronic stress × sex interaction effect on GMV. Simple effects analysis indicated that the GMV of the bilateral pre- and post-central gyri, the right cuneus and superior occipital gyrus was decreased in males, whereas that of the bilateral pre- and post-central gyri, the right superior occipital gyrus and the left middle frontal gyrus and orbital middle frontal gyrus was increased in females, under chronic stress. Additionally, in the control group, the GMV of the bilateral pre- and post-central gyri, the right cuneus and superior occipital gyrus was greater in males than females. While in the chronic stress group, the above sex-based differences were no longer significant. Conclusions: This study preliminarily shows that there are significant differences in gray matter volume changes between males and females under chronic stress. These findings provide a basis for future studies investigating the volumetric mechanisms of sex differences under chronic stress.

Serum Klotho Modifies the Associations of 25-Hydroxy Vitamin D With All-Cause and Cardiovascular Mortality.

BACKGROUND: The association between 25-hydroxyvitamin D and mortality remains controversial. Klotho, a biomarker of vitamin D activation and metabolism, may play a key role in this association. However, it is unclear whether the association between vitamin D deficiency and mortality risk is modified by klotho levels. Therefore, this study investigated the joint association of serum 25-hydroxyvitamin D [25(OH)D] and klotho with mortality risk in American community-dwelling adults. METHODS: A total of 9870 adults from the National Health and Nutrition Examination Survey (2007-2016) were included in our study. Mortality data were ascertained by linking participants to National Death Index records. Cox proportional hazards models were used to assess the association among serum 25(OH)D, serum klotho, and all-cause and cardiovascular disease (CVD) mortality. RESULTS: We found a significant interaction between klotho and serum 25(OH)D in all-cause mortality (P = .028). With klotho > 848.4 pg/mL (risk threshold on mortality), no significant all-cause and CVD mortality risk was observed at any level of serum 25(OH)D. However, with klotho < 848.4 pg/mL, a significant all-cause and CVD mortality risk was observed with serum 25(OH)D < 50 nmol/L [hazards ratio (HR), 1.36; 95% confidence interval (CI), 1.10-1.69; HR, 1.78; 95% CI, 1.16-3.45) and serum 25(OH)D of continuous variable (HR, 0.98; 95% CI, .97-.99; HR, 0.98; 95% CI, .98-.99). In addition, vitamin D metabolism disruption accessed by the combination of decreasing serum 25(OH)D (<50 nmol/L) and klotho (<848.4 pg/mL) was associated with significant all-cause mortality (HR, 1.48; 95% CI, 1.11-1.96) and CVD mortality (HR, 2.36; 95% CI, 1.48-3.75). CONCLUSIONS: Vitamin D-associated mortality risk is observed only with concurrently decreasing klotho, indicating that vitamin D metabolism dysfunction increases the risk of mortality. Klotho levels could help predict long-term mortality outcomes and thus may be useful concurrently for guiding vitamin D supplementation therapy decision-making in populations with vitamin D deficiency.

Cardiovascular effects of weight loss in old adults with overweight/obesity according to change in skeletal muscle mass.

BACKGROUND: Patients with overweight/obesity and type 2 diabetes are encouraged to lose weight, but not all losing weight gain better cardiovascular health, especially old adults. The change in skeletal muscle mass (SMM) could be the key that explains the heterogenous cardiovascular effects of weight loss. This study aims to assess whether the cardiovascular effects of weight loss vary for those gaining skeletal muscle along with weight loss. METHODS: The old adults with overweight/obesity and type 2 diabetes in the Look AHEAD study having muscle measurement from dual-energy X-ray absorptiometry were included. Based on the weight change (WC) and SMM change (SMMC) between baseline and the 4-year follow-up, participants were allocated into three groups-weight gain (WG) group, weight loss with muscle loss (WL-ML) group and weight loss with muscle gain (WL-MG) group. Cox proportional hazards regression was performed to evaluate the cardiovascular risk of those gaining or losing SMM with weight loss compared with those gaining weight. Among the participants with weight loss, the ratio of SMMC/WC was calculated, and the association of SMMC/WC with primary cardiovascular outcome was assessed. RESULTS: A total of 491 participants were included in the study with an average age of 64.56 ± 3.81 years old. A total of 47.0% were male and 49.9% were from the intensive lifestyle intervention arm. Based on their WC and SMMC, 43 were assigned to the WG group, 373 to the WL-ML group and 75 to the WL-MG group. Over a follow-up of almost 10 years, 97 participants encountered the primary endpoint. The WG group had the highest incidence of 25.59%, the WL-MG group had the lowest incidence of 9.33% and the WL-ML group had 21.18% (P = 0.040). In the fourth adjusted Cox model, the WL-MG group achieved significantly decreased odds of the primary endpoint compared with the WG group (hazard ratio [HR] 0.33, 95% confidence interval [CI] [0.12, 0.87], P = 0.026), whilst the WL-ML group did not (HR 0.91, 95% CI [0.47, 1.78], P = 0.670). Among the participants with weight loss, when SMMC/WC reached around 50%, this HR soared to approximately two-fold. CONCLUSIONS: The participants gaining SMM along with weight loss achieved the lowest odds of adverse cardiovascular events, whilst those who lost SMM along with weight loss had comparable cardiovascular risk with those gaining weight. The more muscle lost during weight loss, the greater the harm. The cardiovascular effects of weight loss were modulated by whether the participants gained SMM meanwhile losing weight.

The expression and prognostic value of co-stimulatory molecules in clear cell renal cell carcinoma (ccRCC).

BACKGROUND: Renal cell carcinoma (RCC) was one of the most common malignant cancers in the urinary system. Clear cell carcinoma (ccRCC) is the most common pathological type, accounting for approximately 80% of RCC. The lack of accurate and effective prognosis prediction methods has been a weak link in ccRCC treatment. Co-stimulatory molecules played the main role in increasing anti-tumor immune response, which determined the prognosis of patients. Therefore, the main objective of the present study was to explore the prognostic value of Co-stimulatory molecules genes in ccRCC patients. METHOD: The TCGA database was used to get gene expression and clinical characteristics of patients with ccRCC. A total of 60 Co-stimulatory molecule genes were also obtained from TCGA-ccRCC, including 13 genes of the B7/ CD28 Co-stimulatory molecules family and 47 genes of the TNF family. In the TCGA cohort, the least absolute shrinkage and selection operator (LASSO) Cox regression model was used to generate a multigene signature. R and Perl programming languages were used for data processing and drawing. Real-time PCR was used to verify the expression of differentially expressed genes. RESULTS: The study's initial dataset included 539 ccRCC samples and 72 normal samples. The 13 samples have been eliminated. According to FDR<0.05, there were differences in the expression of 55 Co-stimulatory molecule genes in ccRCC and normal tissues. LASSO Cox regression analysis results indicated that 13 risk genes were optimally used to construct a prognostic model of ccRCC. The patients were divided into a high-risk group and a low-risk group. Those in the high-risk group had significantly lower OS (Overall Survival rate) than patients in the low-risk group. Receiver operating characteristic (ROC) curve analysis confirmed the predictive value of the prognosis model of ccRCC (AUC>0.7). There are substantial differences in immune cell infiltration between high and low-risk groups. Functional analysis revealed that immune-related pathways were enriched, and immune status was different between the two risk groups. Real-time PCR results for genes were consistent with TCGA DEGs. CONCLUSION: By stratifying patients with all independent risk factors, the prognostic score model developed in this study may improve the accuracy of prognosis prediction for patients with ccRCC.

Association between Coronary Heart Disease, Heart Failure, and Risk of Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Background: Cardiovascular diseases such as coronary heart disease (CHD), heart failure (HF), and stroke have been linked to the development of Alzheimer's disease (AD). However, previous studies have reported inconsistent results. The study aimed to investigate the association between CHD, HF, and the risk of AD using a meta-analysis. Methods: STATA 12.0 software is used to compute odds ratios (ORs)/relative risks (RRs) and 95% confidence intervals (CIs) for the association between CHD, HF, and the risk of AD. Results: A total of 12 studies (including N = 36,913 individuals with AD and N = 1,701,718 participants) investigated the association between CHD and the risk of AD. Meta-analysis indicated that CHD was associated with an increased risk of AD with a random effects model (OR/RR: 1.22, 95% CI: 1.00-1.48, I2 = 97.2%, P < 0.001). Additionally, seven studies (including N = 5,119 individuals with AD and N = 1,231,399 participants) investigated the association between myocardial infarction (MI) and the risk of AD. Our meta-analysis demonstrated no significant association between MI and the risk of AD with a fixed effects model (RR: 1.09, 95% CI: 0.91-1.30, I2 = 42.8%, P = 0.105). Finally, six studies (including N = 83,065 individuals with AD and N = 2,414,963 participants) examined the association between HF and the risk of AD. Our meta-analysis revealed that HF was associated with an increased risk of AD using a random effects model (RR: 1.53, 95% CI: 1.05-2.24, I2 = 96.8%, P < 0.001). Conclusion: In conclusion, our meta-analysis suggests that CHD and HF are associated with an increased risk of developing AD. Nonetheless, more large-scale prospective studies are necessary to further investigate the associations between CHD, HF, and the risk of AD.

A Continuous Pacing and Recording Technique for Differentiating Left Bundle Branch Pacing From Left Ventricular Septal Pacing: Electrophysiologic Evidence From an Intrapatient-Controlled Study.

BACKGROUND: Left bundle branch pacing (LBBP) is a promising approach for achieving near-physiologic pacing. However, differentiating LBBP from left ventricular septal endocardial pacing (LVS(e)P) remains a challenge. This study aimed to establish a simple and effective method for differentiating LBBP from LVS(e)P and to evaluate their electrophysiologic characteristics. METHODS: LBBP, using continuous uninterrupted pacing and real-time monitoring of electrocardiograms along with intracardiac electrograms, was performed in 97 consecutive patients. We evaluated the electrophysiologic characteristics observed during LBBP using 6 modalities: right ventricular septal pacing (RVSP), intraventricular septal pacing (IVSP 1 and 2), LVS(e)P, nonselective LBBP (NSLBBP), and selective LBBP (SLBBP). RESULTS: Of the 97 patients, 87 (89.7%) met the criteria (abrupt change in paced QRS morphology with a transition from Qr to QR/qR in lead V1 and shortening of stimulus to V6 R-wave peak time [Stim-V6RWPT] of ≥ 10 ms with constant output while rather than after lead screwing) for nonselective left bundle branch (LBB) capture. Selective LBB capture was observed in 82 patients (84.5%). The Stim-V6RWPT of NSLBBP and SLBBP were significantly shorter than LVS(e)P (respectively, 67.1 ± 8.7 ms, 67.0 ± 9.3 ms, and 82.1 ± 10.9 ms). Stim-QRSend was the narrowest in IVSP2 (136.6 ± 15.2 ms) instead of NSLBBP (140.0 ± 17.1 ms). CONCLUSIONS: The uninterrupted pacing technique for differentiating LBBP from LVS(e)P in the same group of patients is feasible. Electrophysiologic evidence from our intrapatient-controlled study shows that LBBP and LVS(e)P differ in ventricular electrical synchronization.

Premature beat of selective left bundle branch: a novel marker for reaching and capturing the left bundle branch.

BACKGROUND: It was recently shown that template beats and fixation beats of the premature ventricular contractions (PVCs) were generated during lead deployment. These could be exploited to guide the left bundle branch (LBB) pacing (LBBP) procedure. However, lack of a revolving connector that can continuously record and pace during lead rotations has been a limitation when using the traditional implant technique. Here, we report ten cases in which a revolving connector was used and showed that the premature beats of selective left bundle branch (SLBB-PBs) were generated as the lead was reached and the electrical stimulus selectively captured the LBB. METHODS AND RESULTS: Ten patients who underwent the transseptal placement of the pacing lead using a revolving connector were included in the study. We aimed to examine whether the SLBB-PB was a marker of LBB capture during LBBP and the clinical significance of SLBB-PB. LBBP was performed and data of these cases were analyzed to show the characteristics of the electrocardiogram and the intracardiac electrogram of SLBB-PBs. CONCLUSIONS: This is the first case series on SLBB-PBs in LBBP. The presence of SLBB-PBs suggested that the LBB was reached and selectively captured and possibly increased the safety of lead implantation.