Reduced generalization of reward among individuals with subthreshold depression: Behavioral and EEG evidence.

Altered stimulus generalization has been well-documented in anxiety disorders; however, there is a paucity of research investigating this phenomenon in the context of depression. Depression is characterized by impaired reward processing and heightened attention to negative stimuli. It is hypothesized that individuals with depression exhibit reduced generalization of reward stimuli and enhanced generalization of loss stimuli. Nevertheless, no study has examined this process and its underlying neural mechanisms. In the present study, we recruited 25 participants with subthreshold depression (SD group) and 24 age-matched healthy controls (HC group). Participants completed an acquisition task, in which they learned to associate three distinct pure tones (conditioned stimuli, CSs) with a reward, a loss, or no outcome. Subsequently, a generalization session was conducted, during which similar tones (generalization stimuli, GSs) were presented, and participants were required to classify them as a reward tone, a loss tone, or neither. The results revealed that the SD group exhibited reduced generalization errors in the early phase of generalization, suggesting a diminished ability to generalize reward-related stimuli. The event-related potential (ERP) results indicated that the SD group exhibited decreased generalization of positive valence to reward-related GSs and heightened generalization of negative valence to loss-related GSs, as reflected by the N1 and P2 components. However, the late positive potential (LPP) was not modulated by depression in reward generalization or loss generalization. These findings suggested that individuals with subthreshold depression may have a blunted or reduced ability to generalize reward stimuli, shedding light on potential treatment strategies targeting this particular process.

Concurrent spontaneous portosystemic shunt embolization for the prevention of overt hepatic encephalopathy after TIPS: A systematic review and meta-analysis.

BACKGROUND: Overt hepatic encephalopathy remains a serious complication after TIPS. Concomitant SPSS is associated with an increased risk of HE in patients treated with TIPS. PURPOSE: To perform a systematic review and meta-analysis on the effectiveness and safety of the prophylactic embolization of SPSS at the time of TIPS creation. MATERIALS AND METHODS: The PubMed, Embase, Cochrane Library, and Web of Science databases were searched up to April 2023 to identify studies on the association between antegrade embolized SPSS before TIPS placement and the incidence of post-TIPS HE. Odds ratios (ORs) and their corresponding 95% CIs were used to identify significant differences in the outcomes. RESULTS: Four studies enrolling 1243 patients with cirrhosis who received TIPS for variceal bleeding were included. A meta-analysis revealed that TIPS without simultaneous SPSS embolization was associated with an increased risk of overt HE (OR 2.41, 95% CI 1.32-4.38; p = 0.004). The risks of mortality (0.79, 95% CI 0.58-1.07; p = 0.13), variceal rebleeding (0.94, 95% CI 0.66-1.34; p = 0.74) and shunt dysfunction (1.40, 95% CI 0.51-3.83; p = 0.51) did not significantly differ among the groups. CONCLUSION: SPSS prevalence was associated with an increased risk of overt HE after TIPS. Concurrent antegrade SPSS embolization during TIPS creation reduced the risk for overt HE without increasing other complications.

Association of 25-Hydroxyvitamin D with Preterm Birth and Premature Rupture of Membranes: A Mendelian Randomization Study.

Low vitamin D (VitD) level is a risk factor for preterm birth (PTB), but the results of previous studies remained inconsistent, which may be influenced by the confounding factors and different types of PTB. We performed Mendelian randomization (MR) to uncover the association of 25-hydroxyvitamin D (25(OH)D) with PTB, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM). This study was conducted in Zhoushan Maternal and Child Health Hospital, Zhejiang, from August 2011 to March 2022. Plasma 25(OH)D levels in three trimesters of pregnancy were measured. We conducted an MR analysis utilizing a genetic risk score (GRS) approach, which was based on VitD-associated single-nucleotide polymorphisms. The prospective cohort study included 3923 pregnant women. The prevalence of PTB, PROM, and PPROM were 6.09%, 13.18%, and 1.33%, respectively. Compared to those without vitamin D deficiency (VDD), only vaginally delivering pregnant women with VDD had a 2.69 (1.08-6.68) times risk of PTB. However, MR analysis did not support the association. One-unit higher GRS was not associated with an increased risk of PTB, regardless of the trimesters (OR [95% CI]: 1.01 [0.93-1.10], 1.06 [0.96-1.18], and 0.95 [0.82-1.10], respectively). When further taking PROM and PPROM as the outcomes, the MR analysis also showed no consistent evidence of a causal effect of VitD levels on the risk of them. Our MR analyses did not support a causal effect of 25(OH)D concentrations in the three trimesters on PTB, PROM, and PPROM.

The Association of Vitamin D during Pregnancy and mRNA Expression Levels of Inflammatory Factors with Preterm Birth and Prelabor Rupture of Membranes.

The aim of this study was to elucidate the association between vitamin D (VD) and the risk for preterm birth (PTB) and prelabor rupture of membranes (PROM). This study included two parts, with a cohort study and a case-control study. Plasma 25-hydroxyvitamin vitamin D [25(OH)D] levels in three trimesters in the cohort study and maternal 25(OH)D before delivery in the case-control study were measured. Quantitative real-time PCR was used to detect relative mRNA expression levels of the inflammatory factors associated with pyroptosis in peripheral blood mononuclear cell (PBMC), placenta and fetal membranes. Multinomial logistic regression and the Wilcoxon test were applied to analyze the associations. In the cohort study, 6381 pregnant women were included. We found that VD deficiency in T3 (PTB without PROM: OR = 1.90, 95% CI: 1.02-3.55, Term PROM (TPROM): OR = 0.76, 95% CI: 0.59-0.98) and less change of 25(OH)D between T1 and T3 (PTB without PROM: OR = 2.32, 95% CI: 1.07-5.06, TPROM: OR = 0.73, 95% CI: 0.56-0.96) were associated with the increased risk of PTB without PROM, while there was a decreased risk of TPROM. Neither VD, nor the increase of VD during pregnancy was associated with the premature rupture of membranes preterm delivery (PPROM). In the case-control study, there were no associations between VD during delivery and PTB or PROM (TPROM: OR = 1.33, 95% CI: 0.52-3.44); PTB without PROM: OR = 1.66, 95% CI: 0.33-8.19; PPROM: OR = 1.19, 95% CI: 0.42-3.40). The mRNA expression of NLRP1 (NOD-like receptor thermal protein domain associated protein 1) (p = 0.0165) in PBMC in the TPROM group was higher than that in the term group, and IL-18 (p = 0.0064) was lower than that in the term group. Plasma 25(OH)D in T3 and the increase of 25(OH)D between T1 and T3 were associated with a lower risk for PTB without PROM but a higher risk for TPROM. Further studies are warranted to clarify the association between VD and PTB and PROM and its mechanism.

The prevalence of vitamin A deficiency and its public health significance in children in low- and middle-income countries: A systematic review and modelling analysis.

Background: Vitamin A deficiency (VAD) is widely recognised as a major public health concern in low- and middle-income countries (LMICs). Despite various interventions implemented in many countries, a lack of reliable data is hindering progress. We aimed to consolidate available data and quantify estimates of the prevalence of VAD among children ≤18 years in LMICs. Methods: We searched PubMed, Medline and Embase for studies reported the prevalence of VAD or marginal (m)VAD among children. A multilevel mixed-effects meta-regression approach was applied to establish the regression models for VAD and mVAD prevalence. The total numbers of children affected by VAD and mVAD in LMICs in 2019 were separately calculated from the estimated age- and socio-demographic index (SDI)-specific prevalence with their corresponding United Nations Population Division populations projections. We estimated areas of significant public health concern in 165 LMICs using the lower confidence interval (CI) of VAD prevalence. Results: A total of 116 articles from 40 LMICs were retained. In 2019, VAD and mVAD affected 333.95 million (95% CI = 253.00-433.74) and 556.13 million (95% CI = 388.83-767.94) children and adolescents in 165 LMICs, respectively, corresponding to a prevalence of 14.73% (95% CI = 11.16-19.14) and 24.54% (95% CI = 17.15-33.88). The prevalence of both VAD and mVAD was the highest in children aged 0-5 years at 19.53% (95% CI = 15.03-24.91) and 28.22% (95% CI = 20.00-38.24), respectively, with both steadily decreasing to 10.09% (95% CI = 7.44-13.50) and 20.76% (95% CI = 14.16-29.50) in adolescents aged 13-18 years. The prevalence of VAD was significantly higher in the low SDI region at 29.67% (95% CI = 22.67-37.53) compared to 5.17% (95% CI = 3.14-8.43) estimated in the high-middle SDI region. 68 of the 165 LMICs (41.21%) were classified as areas of moderate to severe VAD public health significance. Conclusions: VAD continues to pose a significant public health concern in many low-income settings. Development in LMICs is a crucial factor for VAD, with a disproportionately higher burden in low SDI regions. Registration: This study protocol was registered with PROSPERO, CRD42020220654.

Outcomes of inferior vena cava reconstruction using artificial or autologous materials in ex vivo liver resection and autotransplantation.

BACKGROUND: The use of artificial or autologous materials for inferior vena cava (IVC) reconstruction is controversial. This study retrospectively explored the effects of different materials on perioperative outcomes. METHODS: This study included 91 patients who underwent IVC reconstruction during liver autotransplantation between 2014 and 2020. A univariate analysis was performed to select variables affecting postoperative morbidity. The effect of IVC reconstruction materials on perioperative outcomes was tested with a multivariable generalized linear model. The effects on postoperative morbidity and operation time were further tested with the multivariate regression analysis based on the generalized estimating equation. Adjusted models were used in all analyses. RESULTS: A median operation time of 710 (633-790) min, a median blood loss of 2200 (1550-3000) mL, an incidence of 33% (30/91) for major morbidities and a median comprehensive complication index (CCI) of 0.0 (0.0-26.2) were observed, with no IVC reconstruction-related complications postoperatively or in the long term. The IVC reconstruction material had no significant effect on postoperative outcomes, while artificial materials significantly increased inpatient cost (191 ± 35 vs. 164 ± 36 k Yuan, p < 0.001). The multivariate regression revealed a significant shift in outcomes of operation time (p = 0.0368). DISCUSSION: Artificial grafts are recommended for IVC reconstruction if cost is not a factor.

Associations of metabolic heterogeneity of obesity with frailty progression: Results from two prospective cohorts.

BACKGROUND: Previous studies indicated that obesity would accelerate frailty progression. However, obesity is heterogeneous by different metabolic status. The associations of metabolic heterogeneity of obesity with frailty progression remain unclear. METHODS: A total of 6730 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 4713 from the English Longitudinal Study of Ageing (ELSA) were included at baseline. Metabolic heterogeneity of obesity was evaluated based on four obesity and metabolic phenotypes as metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight/obesity (MHOO), and metabolically unhealthy overweight/obesity (MUOO). Frailty status was assessed by the frailty index (FI) ranging from 0 to 100 and frailty was defined as FI ≥ 25. Linear mixed-effect models were used to analyse the associations of metabolic heterogeneity of obesity with frailty progression. RESULTS: In the CHARLS, MUOO and MUNW presented the accelerated FI progression with additional annual increases of 0.284 (95% CI: 0.155 to 0.413, P < 0.001) and 0.169 (95% CI: 0.035 to 0.303, P = 0.013) as compared with MHNW. MHOO presented no accelerated FI progression (ß: -0.011, 95% CI: -0.196 to 0.173, P = 0.904) as compared with MHNW. In the ELSA, the accelerated FI progression was marginally significant for MUOO (ß: 0.103, 95% CI: -0.005 to 0.210, P = 0.061) and MUNW (ß: 0.157, 95% CI: -0.011 to 0.324, P = 0.066), but not for MHOO (ß: -0.047, 95% CI: -0.157 to 0.062, P = 0.396) in comparison with MHNW. The associations of MUOO and MUNW with the accelerated FI progression were stronger after excluding the baseline frail participants in both cohorts. The metabolic status changed over time. When compared with stable MHNW, participants who changed from MHNW to MUNW presented the accelerated FI progression with additional annual increases of 0.356 (95% CI: 0.113 to 0.599, P = 0.004) and 0.255 (95% CI: 0.033 to 0.477, P = 0.024) in the CHARLS and ELSA, respectively. The accelerated FI progression was also found in MHOO participants who transitioned to MUOO (CHARLS, ß: 0.358, 95% CI: 0.053 to 0.663, P = 0.022; ELSA, ß: 0.210, 95% CI: 0.049 to 0.370, P = 0.011). CONCLUSIONS: Metabolically unhealthy overweight/obesity and normal weight, but not metabolically healthy overweight/obesity, accelerated frailty progression as compared with metabolically healthy normal weight. Regardless of obesity status, transitions from healthy metabolic status to unhealthy metabolic status accelerated frailty progression as compared with stable metabolically healthy normal weight. Our findings highlight the important role of metabolic status in frailty progression and recommend the stratified management of obesity based on metabolic status.

A Macrophage Differentiation-Mediated Gene: DDX20 as a Molecular Biomarker Encompassing the Tumor Microenvironment, Disease Staging, and Prognoses in Hepatocellular Carcinoma.

Background: DDX20 involves the mechanism of cell proliferate, mitogenic Ets transcriptional suppressor (METS), which can arrest the cell cycle of macrophages. However, little is known about DDX20 expression, clinical values, and the relationship with tumor microenvironment in HCC. Methods: We mined the transcriptional, protein expression and survival data of DDX20 in HCC from online databases. The immunological effects of DDX20 were estimated by bioinformatic algorithms. The RNAi and CRISPR screening were used to assess the gene effect of DDX20 for the EGFR gene in liver tumor cell. Results: We found that the DDX20 was highly expressed in HCC. The qRT-PCR result shows a significantly upregulated DDX20 expression in HCC samples from the West China Hospital. The high mRNA expression of DDX20 is associated with a poor survival. DDX20 expression is positively correlated with MDSCs in HCC tissues. Moreover, DDX20 has a high predicted ability for the response to immunotherapy. Furthermore, hsa-mir-324-5p could regulate the macrophage differentiation by interacting with DDX20. Meanwhile, the EGFR gene gets a high dependency score for DDX20. Conclusion: In sum, DDX20 may serve as a prognostic marker for worse clinical outcomes with HCC and potentially enable more precise and personalized immunotherapeutic strategies in the future.

Efficacy of Postoperative Adjuvant Transcatheter Arterial Chemoembolization in Hepatocellular Carcinoma Patients With Microscopic Portal Vein Invasion.

Background: Microscopic portal vein invasion (MPVI) strongly predicts poor prognosis in patients with hepatocellular carcinoma (HCC). This study aims to investigate the impact of MPVI on the efficacy of postoperative adjuvant transcatheter arterial chemoembolization (PA-TACE). Methods: From April 2014 to July 2019, a total of 512 HCC patients who underwent curative liver resection (LR) with microscopic vascular invasion (MVI) confirmed by histopathological examination were enrolled and divided into LR alone and PA-TACE groups. They were subsequently stratified into subgroups according to the presence of MPVI. Recurrence-free survival (RFS) and overall survival (OS) were compared using Kaplan-Meier curves and the log-rank test. The efficacy of PA-TACE was tested using univariate and multivariate Cox regression analyses. Sensitivity analysis was conducted after propensity score matching (PSM). Results: Among all patients, 165 (32.3%) patients underwent PA-TACE, and 196 (38.2%) patients presented MPVI. In the entire cohort, PA-TACE and the presence of MPVI were identified as independent predictors for RFS and OS (all p<0.05). In the subgroup analysis, patients without MPVI who received PA-TACE had significantly better outcomes than those who underwent LR alone before and after PSM (all p<0.05). For patients with MPVI, PA-TACE displayed no significant benefit in terms of improving either RFS or OS, which was consistent with the results from the PSM cohort. Conclusion: Among the HCC patients without MPVI who underwent curative liver resection, those who received PA-TACE had better RFS and OS outcomes than those who underwent LR alone. For patients with MPVI, PA-TACE had no significant effect on either RFS or OS outcomes.

Comprehensive Molecular Analyses of a Macrophage-Related Gene Signature With Regard to Prognosis, Immune Features, and Biomarkers for Immunotherapy in Hepatocellular Carcinoma Based on WGCNA and the LASSO Algorithm.

Macrophages have been reported to exert a crucial role in hepatocellular carcinoma (HCC). This study aimed to explore the macrophage-related genes and establish a macrophage-related signature (MRS) model to predict the overall survival (OS) of patients with HCC based on these genes' expression. We screened the macrophage-related gene module by weighted gene coexpression network analysis (WGCNA), the least absolute shrinkage and selection operator (LASSO) Cox regression analysis was utilized for further selection, and the selected genes were entered into stepwise regression to develop the MRS model, which was further validated in the Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) datasets. We analyzed the biological phenotypes associated with macrophages in terms of functional enrichment, tumor immune signature, and tumor mutational signature. The patient's response to immunotherapy was inferred by the tumor immune dysfunction and exclusion (TIDE) score, the immunophenotype score (IPS), and the IMvigor210 dataset. A novel MRS model was established based on the LASSO regression coefficients of the genes PON1, IL15RA, NEIL3, HILPDA, PFN2, HAVCR1, ANXA10, CDCA8, EPO, S100A9, TTK, KLRB1, SPP1, STC2, CYP26B1, GPC1, G6PD, and CBX2. In either dataset, MRS was identified as an independent risk factor for OS in HCC patients. Additionally, our research indicated that a high-risk score in the MRS model was significantly correlated with tumor staging, pathological grade, tumor-node-metastasis (TNM) stage, and survival. Several genes of the human leukocyte antigen (HLA) family and immune checkpoints were highly expressed in the high-risk group. In addition, the frequency of tumor mutations was also higher in the high-risk group. According to our analyses, a higher risk score in the MRS model may predict a better response to immunotherapy.

Transition of cardiometabolic status and the risk of type 2 diabetes mellitus among middle-aged and older Chinese: A national cohort study.

AIMS/INTRODUCTION: The cardiometabolic index (CMI) has been proposed as a novel indicator of cardiometabolic status. This study aimed to investigate the effects of CMI and its longitudinal transitions on the development of type 2 diabetes mellitus in middle-aged and older Chinese. MATERIALS AND METHODS: We used data from the China Health and Retirement Longitudinal Study (2011-2018). CMI was calculated as the product of the waist circumference to height ratio and the triglyceride to high-density lipoprotein cholesterol ratio. At baseline in 2011, the subjects were classified into low- and high-CMI groups, and then divided into four transition patterns during follow-up, i.e. maintained-low, low-to-high, high-to-low, and maintained-high CMI. The hazard ratios (HRs) of different transition patterns for type 2 diabetes mellitus were calculated using multivariable Cox frailty models. RESULTS: During 2011-2018, 7,347 participants were included. Participants with a high-CMI at baseline had a significantly higher risk of new-onset type 2 diabetes mellitus than those with a low-CMI (HR = 1.78, 95% CI:1.55-2.05). For subjects with a low-CMI at baseline, the risk of developing type 2 diabetes mellitus increased by 75% if their CMI status changed to high during follow-up (HRlow-to-high = 1.75, 95% CI:1.35-2.28). Meanwhile, for subjects with a maintained-high CMI, no significant risk reduction for type 2 diabetes mellitus was found when their CMI changed to low status (HRhigh-to-low = 0.77, 95% CI: 0.58-1.01). CONCLUSIONS: Baseline CMI levels and longitudinal CMI transition patterns were associated with a higher risk of type 2 diabetes mellitus. Early anti-lipid measures should be taken to prevent type 2 diabetes mellitus in middle-aged and older Chinese.

Impact of cirrhosis on long-term survival outcomes of patients with intrahepatic cholangiocarcinoma.

BACKGROUND: The correlation between cirrhosis and the long-term oncological outcome in intrahepatic cholangiocarcinoma (ICC) is debatable, and this study aimed to explore the impact of cirrhosis on the long-term prognosis of patients with ICC. METHODS: A total of 398 ICC patients were identified in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2018. The diagnosis of cirrhosis was based on the Ishak fibrosis score provided by the SEER database. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) analysis were performed to minimize the potential confounders. Overall survival (OS) and cancer-specific survival (CSS) were observed, and the Cox regression model was used to select potential factors that affect the prognosis of the patients with ICC. RESULTS: Of the included patients, there were 142 patients and 256 patients in the cirrhotic and noncirrhotic groups, respectively. Additionally, 299 of 398 patients (75.1%) died following a median follow-up of 19 months (interquartile range [IQR], 7, 43). The OS and CSS indicated advantage trend in the noncirrhotic group than the cirrhotic group in either the original cohort (OS: 17 vs 12 months, p = 0.023; CSS: 26 vs 15 months, p = 0.004) or the PSM (OS: 17 vs 12 months, p = 0.52; CSS: 22 vs 14 months, p = 0.15) or IPTW (OS: 20 vs 13 months, p = 0.163; CSS: 22 vs 15 months, p = 0.059) cohorts. Subgroup analyses displayed that the prognosis of patients who experienced surgery for ICC in the noncirrhotic group was better than that of the cirrhotic group with regard to OS and CSS. CONCLUSIONS: Collectively, it seems that the noncirrhotic patients have similar relative OS but better CSS compared with that of the cirrhotic patients.

Evaluating the Benefits and Risks of Ex Vivo Liver Resection and Autotransplantation in Treating Hepatic End-stage Alveolar Echinococcosis.

BACKGROUND: Ex vivo liver resection and autotransplantation (ELRA) has shown promising outcomes in treating end-stage hepatic alveolar echinococcosis (AE). However, the actual benefits and risks remain unclear. This study aims to analyze the benefits and risks of ELRA. METHODS: This retrospective cohort analysis included 228 patients with end-stage hepatic AE who underwent ELRA or nonsurgical treatment between 2014 and 2020. Propensity score matching was used. Long-term survival was compared in the matched cohorts using Kaplan-Meier curves generated with the log-rank test. Short-term mortality in entire cohort was predicted based on the nonsurgical group, and the interaction between the predicted mortality risk and observed mortality was tested. Risk factors for postoperative major morbidity in the ELRA group were evaluated using logistic regression analyses. RESULTS: The long-term overall survival of the ELRA group was superior to that of the nonsurgical group (82.1% vs 19.1%, 5-year survival). Regarding short-term outcomes, the basic risk of 12-month mortality exerted a significant effect on the benefit of ELRA in entire cohort (per 1%, odds ratio, 1.043; 95% confidence interval [CI]: 1.007-1.082; P = .021). Patients with a predicted 12-month mortality risk >75% would significantly benefit from ELRA. Combined resection (hazard ratio [HR], 3.32; 95% CI: 1.01-10.99; P = .049) and overall surgery time (per hour, HR, 1.41; 95% CI: 1.09-1.82; P = .009) were identified as independent risk factors for postoperative major morbidity. CONCLUSIONS: ELRA was significantly beneficial in selected patients with end-stage AE compared with nonsurgical treatment. The timing of conducting ELRA remarkably affected the short-term risk of mortality and should be carefully determined.

An Excretory Protein of Echinococcus multilocularis Inhibits Complement Classical Pathway Activation.

INTRODUCTION: Alveolar echinococcosis is a lethal zoonosis caused by Echinococcus multilocularis (E.m) larvae. The mechanism by which E.m evades host immune attacks and ensures long-term survival remains unexplained. The complement system is a cascade of sequentially activated complement proteins that results in opsonization-related phagocytosis or membrane lysis of invading organisms. Excretory/secretory proteins (ESPs) of parasites are the main antigens that induce the immune response and play important roles in the long-term survival. METHODS: We investigated the possibility that E.m inhibits complement activation through ESPs and examined the potential related mechanism. A haemolysis assay was used to determine if and how in vitro culture medium of E.m containing ESPs can inhibit complement activation. Potential ESPs were annotated using bioinformatics methods, and one ESP was subsequently expressed as a recombinant protein with a eukaryotic expression system. The ability of this protein to inhibit complement activation was also tested by haemolysis assay. RESULTS: These assays showed that in vitro culture medium of E.m inhibited activation of the complement classical pathway. EmuJ_000439500 encodes a protein containing seven Sushi domains, which was the only potential E.m-derived complement inhibitor (Em-CI, UniProt: A0A068Y4F2) annotated among the 653 ESPs. Recombinant Em-CI also displayed the ability to inhibit activation of the complement classical pathway. DISCUSSION: The discovery of Em-CI sheds light on the mechanism by which E.m escapes killing by the complement system and provides potential targets for immunotherapy for parasitic diseases.

An Integrated Analysis of the Identified PRPF19 as an Onco-immunological Biomarker Encompassing the Tumor Microenvironment, Disease Progression, and Prognoses in Hepatocellular Carcinoma.

Background: Targeting the mRNA splicing process has been identified as a therapeutic strategy for human cancer. PRPF19 is an RNA binding protein that is involved in pre-mRNA processing and repairing DNA damage; the aberrant expression of PRPF19 is potentially associated with carcinogenesis. However, the biological role of PRPF19 in hepatocellular carcinoma (HCC) is still elusive. Methods: Data obtained from TCGA, Oncomine, and GEO were used to investigate the PRPF19 expression level and its role in tumor immune infiltration, prognosis, and the tumor progression of cohorts from HCC. Using various databases and tools (UALCAN, TIMER, TISMO, and PathCards), we presented the potential mechanisms of PFPF19 upregulation, PRPF19-related pathways, and its biological functions in liver cancer. Results: For HCC, PRPF19 expression was found upregulated both in single tumor cells and tissues. Furthermore, the increased expression of PRPF19 was significantly correlated to clinical characteristics: advanced stage, vascular invasion, high AFP, and poor prognosis of HCC. According to the tumor-immunological analysis, we found that PRPF19 is positively correlated with infiltrating myeloid-derived suppressor cells (MDSCs). Moreover, the microenvironment of HCC tissues with high expression of PRPF19 is highly immunosuppressive (lower T-lymphocytes, multiple immune checkpoints upregulated). Patients with high expression of PRPF19 and high MDSCs had a worse survival prognosis as well. TP53 mutation may have a positive effect on PRPF19 expression via decreased promoter methylation of PRPF19. By TF-mRNA network analysis, key transcription factors (TFs) in TC-NER and PCS pathways (PRPF19 involved) were identified. Conclusion: This work implied that PRPF19 is associated with tumor immune evasion and progression, and serves as a prognostic marker for worse clinical outcomes with HCC. Thus, this critical regulator could serve as a potential therapeutic target of HCC.

Attachment voices promote safety learning in humans: A critical role for P2.

Humans have evolved to seek the proximity of attachment figures during times of threat in order to obtain a sense of safety. In this context, we examined whether or not the voice of an intimate partner (termed "attachment voice") could reduce fear-learning of conditioned stimuli (CS+) and enhance learning of safety signals (CS-). Although the ability to learn safety signals is vital for human survival, few studies have explored how attachment voices affect safety learning. To test our hypothesis, we recruited thirty-five young couples and performed a classic Pavlovian conditioning experiment, recording behavioral and electroencephalographic (EEG) data. The results showed that compared with a stranger's voice, the voices of the partners reduced expectancy of the unconditioned stimulus (a shock) during fear-conditioning, as well as the magnitude of P2 event-related potentials within the EEG responses, provided the voices were safety signals. Additionally, behavioral and EEG responses to the CS+ and CS- differed more when the participants heard their partner's voice than when they heard the stranger's voice. Thus, attachment voices, even as pure vowel sounds without any semantic information, enhanced acquisition of conditioned safety (CS-). These findings may provide implications for investigating other new techniques to improve clinical treatments for fear- and anxiety-related disorders and for psychological interventions against the mental health effects of the public health emergency.

Competing-risk nomogram for predicting survival in patients with advanced (stage III/IV) gallbladder cancer: A SEER population-based study.

OBJECTIVE: The primary aim of this study was to assess the cumulative incidence of cause-specific mortality (CSM) and other cause-specific mortality (OCSM) for patients with advanced gallbladder cancer (GBC), and then to develop a nomogram based on competing-risk analysis to forecast CSM. METHODS: We identified the patients with GBC with specific screening criteria and from the Surveillance Epidemiology and End Results (SEER) database. We calculated the cumulative incidence function for CSM and OCSM, and constructed a competing-risk nomogram based on the Fine and Gray's proportional subdistribution hazard regression model to forecast the probability of CSM of these patients. In addition, the concordance index and calibration plot were performed to validate the novel established model. RESULTS: A total of 1411 patients were included in this study. The 1-, 2-, and 3-year overall cumulative mortalities were 46.2, 62.2, and 69.6% for CSM, respectively, while they were 6.2, 8.7, and 10.4% for OCSM. Additionally, the 1-, 2-, and 3-year estimates of overall survival were 47.6, 29.1, and 19.9% for above these patients, respectively. We also developed a competing-risk nomogram to estimate the CSM. The concordance index was 0.775 (95% confidence interval (CI): 0.750-0.800) in the training set and that was 0.765 (95% CI: 0.730-0.800) in the internal validation set, which suggests the robustness of the novel established model. Furthermore, the calibration curves and concordance index demonstrated that the nomogram was well-calibrated and demonstrated good discriminative ability. CONCLUSIONS: The ample sample allowed us to develop a reliable model which demonstrated better calibration and discrimination for predicting the probability of CSM of patients with advanced GBC.

Lactation Duration and the Risk of Subtypes of Stroke Among Parous Postmenopausal Women From the China Kadoorie Biobank.

Importance: Previous studies have reported favorable associations between lactation and cardiovascular diseases. Various stroke subtypes are caused by different pathological processes; however, to date, the associations of lactation duration with different stroke subtypes are less well established. Objective: To examine the associations of lactation duration with stroke and its subtypes in parous postmenopausal women. Design, Setting, and Participants: This population-based prospective cohort study included parous postmenopausal women aged 45 to 79 years in the China Kadoorie Biobank (CKB) study at baseline (2004-2008). Lactation duration was counted as lifetime, mean per child, and for the first child. New-onset stroke and its subtypes (ischemic stroke, intracerebral hemorrhage [ICH], and subarachnoid hemorrhage [SAH]) were assessed via disease registries and national health insurance claim databases during follow-up (2008-2015). Data were analyzed from June to December 2021. Exposures: Lactation duration (lifetime, mean per child, and for the first child). Main Outcomes and Measures: The main outcomes were total stroke, ischemic stroke, ICH, and SAH. Multivariable Cox regression was applied to calculate the adjusted hazard ratios (aHRs) with 95% CIs for stroke and subtypes. Results: Of 129 511 parous postmenopausal women (median [IQR] age, 58.3 [54.0-64.6] years) without prior stroke at baseline, 15 721 developed stroke, with median (IQR) lifetime lactation duration of 42.0 (24.0-70.0) months among 13 427 women who had ischemic stroke, 54.0 (36.0-84.0) months among 2567 women who had ICH, and 36.0 (24.0-64.5) months among 284 women with SAH. Compared with parous postmenopausal women who had never lactated, those with lifetime lactation duration of at least 7 months had lower risks of ischemic stroke (aHRs varying from 0.52 [95% CI, 0.50-0.55] to 0.64 [95% CI, 0.59-0.69]) and ICH (aHRs, 0.56 [95% CI, 0.49-0.63] to 0.78 [95% CI, 0.64-0.96]). However, for SAH, such associations were found only in participants with lifetime lactation duration longer than 24 months (aHR, 0.61 [95% CI, 0.47-0.79]). Additionally, women with mean lactation duration per child or lactation duration for the first child of 7 months or longer were less likely to develop stroke (aHRs varying from 0.53 [95% CI, 0.52-0.54] to 0.65 [95% CI, 0.63-0.67]) and its subtypes (aHRs varying from 0.51 [95% CI, 0.30-0.87] to 0.75 [95% CI, 0.69-0.81]). Conclusions and Relevance: In this cohort study, lactation was significantly associated with a lower risk of stroke, especially ischemic stroke, emphasizing the importance of promoting breastfeeding as a targeted prevention strategy of stroke.

The visceral adiposity index and risk of type 2 diabetes mellitus in China: A national cohort analysis.

AIMS: Visceral Adiposity Index (VAI) is a sex-specific index of visceral adiposity based on body mass index, waist circumference, triglycerides and high-density lipoprotein cholesterol. This study aims to demonstrate the association of VAI and its longitudinal transition patterns with type 2 diabetes mellitus (T2DM) in middle-aged and older Chinese. MATERIALS AND METHODS: Data from the China Health and Retirement Longitudinal Study (2011, 2013, 2015, and 2018) were analysed. Participants were classified into high- and low-VAI groups at baseline, and subsequently into four transition patterns during follow-up (2011-2015): maintained-high, maintained-low, high-to-low, and low-to-high VAI. Multivariable Cox frailty models with random effects were used to assess the associations of VAI and its transitions with T2DM. RESULTS: A total of 7245 participants were analysed, among which 818 developed T2DM by 2018. A positive association between baseline high-VAI levels and T2DM was observed (HR = 1.49, 95% CI: 1.27-1.75). Compared with people with maintained low-VAI pattern during follow-up, those with transition patterns of maintained-high VAI, high-to-low VAI, and low-to-high VAI were at higher risk of T2DM (HR = 1.97, 1.52, and 1.56, respectively, all p < 0.05). The risk of T2DM decreased significantly in the high-to-low VAI group as compared to the maintained-high VAI group (HR = 0.77, 95% CI: 0.60-0.99). CONCLUSIONS: This study demonstrated the significant associations of baseline VAI and its transitions with the risk of new-onset T2DM. Early prevention efforts are needed to control the development of T2DM in Chinese with high-VAI levels.

Learning Curve of Ex Vivo Liver Resection and Autotransplantation in Treating End-Stage Hepatic Alveolar Echinococcosis: A RA-CUSUM Analysis.

Background: This retrospective study aimed to evaluate the safety and learning curve of ex vivo liver resection and autotransplantation (ELRA). Methods: A total of 102 consecutive end-stage HAE patients who underwent ELRA between 2014 and 2020 in West China Hospital were enrolled. The primary endpoint was major postoperative complications (comprehensive complication index, CCI > 26). The ELRA learning curve was evaluated using risk-adjusted cumulative sum (RA-CUSUM) methods. The learning phases were determined based on RA-CUSUM analysis and tested for their association with intra- and post-operative endpoints. Results: The median surgery time was 738 (659-818) min, with a median blood loss of 2,250 (1,600-3,000) ml. The overall incidence of major morbidity was 38.24% (39/102). Risk-adjusted cumulative sum analysis demonstrated a learning curve of 53 ELRAs for major postoperative complications. The learning phase showed a significant association with the hemodynamic unstable time (HR -30.29, 95% CI -43.32, -17.25, P < 0.0001), reimplantation time (HR -13.92, 95% CI -23.17, -4.67, P = 0.004), total postoperative stay (HR -6.87, 95% CI -11.33, -2.41, P = 0.0033), and postoperative major morbidity (HR 0.25, 95% CI 0.09, 0.68, p = 0.007) when adjusted for age, disease course, liver function, and remote metastasis. Discussion: Ex vivo liver resection and autotransplantation is feasible and safe with a learning curve of 53 cases for major postoperative complications.