Potential Mediators Research Articles

Socioeconomic traits and the risk of Barrett's esophagus and gastroesophageal reflux disease: A Mendelian randomization study.

Previous observational studies have shown that the prevalence of gastroesophageal reflux disease (GERD) and Barrett's esophagus (BE) is associated with socioeconomic status. However, due to the methodological limitations of traditional observational studies, it is challenging to definitively establish causality. To explore the causal relationship between the prevalence of these conditions and socioeconomic status using Mendelian randomization (MR). We initially screened single nucleotide polymorphisms (SNPs) to serve as proxies for eight socioeconomic status phenotypes for univariate MR analysis. The inverse variance weighted (IVW) method was used as the primary analytical method to estimate the causal relationship between the eight socioeconomic status phenotypes and the risk of GERD and BE. We then collected combinations of SNPs as composite proxies for the eight socioeconomic phenotypes to perform multivariate MR (MVMR) analyses based on the IVW MVMR model. Furthermore, a two-step MR mediation analysis was used to examine the potential mediation of the associations by body mass index, major depressive disorder (MDD), smoking, alcohol consumption, and sleep duration. The study identified three socioeconomic statuses that had a significant impact on GERD. These included household income [odds ratio (OR): 0.46; 95% confidence interval (95%CI): 0.31-0.70], education attainment (OR: 0.23; 95%CI: 0.18-0.29), and the Townsend Deprivation Index at recruitment (OR: 1.57; 95%CI: 1.04-2.37). These factors were found to independently and predominantly influence the genetic causal effect of GERD. Furthermore, the mediating effect of educational attainment on GERD was found to be mediated by MDD (proportion mediated: 10.83%). Similarly, the effect of educational attainment on BE was mediated by MDD (proportion mediated: 10.58%) and the number of cigarettes smoked per day (proportion mediated: 3.50%). Additionally, the mediating effect of household income on GERD was observed to be mediated by sleep duration (proportion mediated: 9.75%). This MR study shed light on the link between socioeconomic status and GERD or BE, providing insights for the prevention of esophageal cancer and precancerous lesions.

Influence of effort expectancy on consumers’ purchase intention within a B2C imported cross-border e-commerce market: The mediating role of consumer trust

This study is primarily aimed at examining the influence of effort expectancy on consumers’ purchase intention within a Business-to-Consumer (B2C) cross-border e-commerce (CBEC) consumption market in China. With the improvement of the living standards for the Chinese consumers, the B2C imported cross-border e-commerce platforms have become the choice of consumers for online shopping. On the basis of the seminal UTAUT Model, consumer trust is proposed as a potential mediator for the relationship between effort expectancy and purchase intention. By using a non-probability sampling technique, an online questionnaire survey distribution was employed with an overall return rate of 108 usable feedback. Data were analysed using the SmartPLS Version 4.0.9.9 statistical software. Results revealed a positive and significant influence of effort expectancy on consumers’ purchasing intentions. Furthermore, we found that consumer trust significantly mediates the relationship between effort expectancy and purchase intention. These findings could assist imported cross-border e-commerce platform enterprises towards enhancing the convenience of online shopping on these platforms and improving consumers' trust in online shopping activities. This study contributes to promoting the platform enterprises to improve the convenience of the whole process of platform operation and purchase, and is conductive to paying attention to the consumer trust to enhance the enterprise’s reputation, which will help develop customer stickiness and cultivate loyal customers.

Mendelian randomization analysis of the brain, cerebrospinal fluid, and plasma proteome identifies potential drug targets for attention deficit hyperactivity disorder

The need for new therapeutics for attention deficit hyperactivity disorder (ADHD) is evident. Brain, cerebrospinal fluid (CSF), and plasma protein biomarkers with causal genetic evidence could represent potential drug targets. However, a comprehensive screen of the proteome has not yet been conducted. We employed a three-pronged approach using Mendelian Randomization (MR) and Bayesian colocalization analysis. Firstly, we studied 608 brains, 214 CSF, and 612 plasma proteins as potential causal mediators of ADHD using MR analysis. Secondly, we analysed the consistency of the discovered biomarkers across three distinct subtypes of ADHD: childhood, persistent, and late-diagnosed ADHD. Finally, we extended our analysis to examine the correlation between identified biomarkers and Tourette syndrome and pervasive autism spectrum disorder (ASD), conditions often linked with ADHD. To validate the MR findings, we conducted sensitivity analysis. Additionally, we performed cell type analysis on the human brain to identify risk genes that are notably enriched in various brain cell types. After applying Bonferroni correction, we found that the risk of ADHD was increased by brain proteins GMPPB, NAA80, HYI, CISD2, and HYI, TIE1 in CSF and plasma. Proteins GMPPB, NAA80, ICA1L, CISD2, TIE1, and RMDN1 showed overlapped loci with ADHD risk through Bayesian colocalization. Overexpression of GMPPB protein was linked to an increase in the risk for all three ADHD subtypes. While ICA1L provided protection against both ASD and ADHD, CISD2 increased the probability of both disorders. Cell-specific studies revealed that GMPPB, NAA80, ICA1L, and CISD2 were predominantly present on the surface of excitatory-inhibitory neurons. Our comprehensive MR investigation of the brain, CSF, and plasma proteomes revealed seven proteins with causal connections to ADHD. Particularly, GMPPB and TIE1 emerged as intriguing targets for potential ADHD therapy. This work was partly funded by the Key R & D Program of Zhejiang (T.L. 2022C03096); the National Natural Science Foundation of China Project (C.Z. 82001413); Postdoctoral Foundation of West China Hospital (C.Z. 2020HXBH163).

Emotional Invalidation and Relationship Quality: A Mediational Model Through a Social Learning Lens.

While we know childhood experiences are influential on a child's later socioemotional awareness and behavior, we are still searching for specific mechanisms that influence the transferability of childhood experiences and adult relationship functioning. In this study, we seek to further this area of investigation by examining the interpretation of ambiguous social interactions and perceptions of emotional invalidation as potential mediators of the relationship between perceptions of childhood emotional invalidation and current relationship quality. Participants completed online measures of hostile intent attributions, perceptions of childhood emotional invalidation, and current relationship quality with a significant other. They read emotionally provocative interpersonal scenarios and then reported likely emotionally invalidating reactions from their significant other to measure current perceptions of emotional invalidation. Results supported our hypotheses that perceptions of current emotional invalidation in a close, personal relationship would mediate the relationship between perceptions of childhood maternal emotional invalidation and both current relationship support and relationship conflict. Furthermore, the strength of this mediational pathway outweighed the influence of a more general hostile attribution bias. These findings have implications for prevention and intervention strategies designed to enhance interpersonal functioning.

Platelet proteomic profiling reveals potential mediators of immunothrombosis and proteostasis in myeloproliferative neoplasms

Platelet proteomic profiling reveals potential mediators of immunothrombosis and proteostasis in myeloproliferative neoplasms

Prostate Cancer Diagnosis Rates among Insured Men with and without HIV in South Africa: A Cohort Study.

Several studies have found lower prostate cancer diagnosis rates among men with human immunodeficiency virus (HIV; MWH) than men without HIV but reasons for this finding remain unclear. We used claims data from a South African private medical insurance scheme (July 2017- July 2020) to assess prostate cancer diagnosis rates among men aged ≥ 18 years with and without HIV. Using flexible parametric survival models, we estimated hazard ratios (HR) for the association between HIV and incident prostate cancer diagnoses. We accounted for potential confounding by age, population group, and sexually transmitted infections (confounder-adjusted model) and additionally for potential mediation by prostatitis diagnoses, prostate-specific antigen testing, and prostate biopsies (fully adjusted model). We included 288,194 men, of whom 20,074 (7%) were living with HIV. Prostate cancer was diagnosed in 1,614 men without HIV (median age at diagnosis: 67 years) and in 82 MWH (median age at diagnosis: 60 years). In the unadjusted analysis, prostate cancer diagnosis rates were 35% lower among MWH than men without HIV [HR, 0.65; 95% confidence interval (CI), 0.52-0.82]. However, this association was no longer evident in the confounder-adjusted model (HR, 1.03; 95% CI, 0.82-1.30) or in the fully adjusted model (HR, 1.14; 95% CI, 0.91-1.44). When accounting for potential confounders and mediators, our analysis found no evidence of lower prostate cancer diagnosis rates among MWH than men without HIV in South Africa. Our results do not support the hypothesis that HIV decreases the risk of prostate cancer.

NSAID medication mediates the causal effect of genetically predicted major depressive disorder on falls: Evidence from a Mendelian randomization study

BackgroundIncreasing evidence supports that depression including major depressive disorder (MDD) is associated with an increased risk of falls. However, some studies suggest no association between MDD and falls. Therefore, the specific causal relationship whereby MDD affects the risk of falls remains elusive, and the potential mediators are unclear. MethodsSummary-level data for MDD and falls were collected from the Genome-wide association studies (GWAS) in this study. Mendelian randomization (MR) and multivariable MR (MVMR) analyses were performed to evaluate the causal associations between MDD and falls. A Two-step MR analysis was employed to analyze the mediating effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the causal association between MDD and the risk of falls. ResultsUsing the inverse-variance weighted (IVW) method, genetically predicted MDD was associated with an increased risk of falls (β = 0.15, SE = 0.034; P = 1.61E-5). MVMR and two-step MR analyses demonstrated that MDD was a causal determinant of increased falls independent of body mass index (BMI), smoking initiation, and alcohol consumption and that this causal relationship was mediated by NSAID medication. LimitationsExtracted GWAS summary statistics are from European ancestry. Stratified analyses by sex and age were not included in our study. Therefore, it is unclear whether the results are the same for other ethnic groups, genders, and ages. ConclusionsOur results demonstrate that MDD is independently associated with an increased risk of falls, in which NSAIDs mediate the association. This study suggests that avoiding the use of NSAIDs may reduce the risk of falls in patients diagnosed with MDD.

Childhood trauma associated with psychotic-like experiences among people living with HIV: The chain mediation effect of stigma and resilience

BackgroundPrevious research established the associations between childhood trauma and psychosis, but the effects of childhood trauma on psychotic-like experiences (PLEs) among people living with HIV (PLWH) and the potential mediation mechanisms in these associations remain unclear. ObjectiveThis study aimed to investigate the effects of childhood trauma on PLEs, as well as the chain mediation roles of stigma and resilience in this relationship. Furthermore, we explored whether the aforementioned associations differed when hallucinatory experiences (HEs) and delusional experiences (DEs) were separately modeled. Participants and settingThe sample included 333 outpatients participants (95.2 % males, Mage = 28.24 ± 7.12) living with HIV recruited from Hunan Province, China; and data were collected with a cross-sectional survey. MethodThe hypothesized chain mediation models were examined using SPSS PROCESS macro 3.3 software. ResultsVarious influencing mechanisms of childhood trauma on HEs and DEs were examined in this study. Our results showed that, (a) childhood trauma directly exerted negative effect on HEs, while the chain mediation effect of stigma and resilience were not statistically significant. Conversely, (b) childhood trauma exerted no direct influence on DEs but rather through the chain mediation effect of stigma and resilience. ConclusionsThe identification of two different routes between that childhood trauma can have on HEs and DEs highlighted the importance of tailored prevention and intervention among PLWH with a history of childhood trauma.

Association between serum neurofilament light chain and periodontitis

ObjectivesThe association between serum neurofilament light chain (sNfL) and periodontitis remains unclear, and there is a need to examine the contribution of serum albumin (SA) in this association. The objective of the study is to investigate the correlation between sNfLand periodontitis, while examining the potential mediator role of SA in this association.MethodsThe study, which included 1218 participants from the 2013–2014 National Health and Nutrition Examination Survey (NHANES), aimed to evaluate the association between sNfL and periodontitis through weighted multivariable logistic regression analysis, restricted cubic spline (RCS) models, and stratified models. In addition, mediation analysis was used to investigate the role of SA in mediating this association.ResultsThe multivariable logistic regression models revealed that sNfL was significantly linked to periodontitis (model 1: odds ratio [OR], 3.08, 95% confidence interval [CI], 1.48 to 6.39, model 2: OR, 3.69; 95% CI, 1.73 to 7.90, model 3: OR, 3.58, 95% CI, 1.52 to 8.43). The RCS models suggested a linear relationship between sNfL and periodontitis. The stratified analysis revealed no significant moderating effects (p-value > 0.05). The mediation analysis demonstrated that SA mediated the correlation between sNfL and periodontitis, with a mediation proportion of 10.62%.ConclusionsThe results point to sNfL being a factor in the heightened risk of periodontitis. Additionally, SA may mediate the changes in periodontitis that are associated with sNfL.Clinical relevancesNfL may contribute to the development of periodontitis by mediating changes in SA in humans.

Effects of dispositional greed and need for cognition on consumer judgments of cryptocurrency and stocks

AbstractThe volatile cryptocurrency market offers investors the chance for substantial capital gains. In this research, we examine the role of dispositional greed and need for cognition (NFC) on judgments about crypto and stocks. Drawing on the dualistic model of passion, we examine two potential mediators of the effects: harmonious passion (HP) and obsessive passion (OP). Journal of Personality and Social Psychology, 85(4), 756–767. https://doi.org/10.1037/pspp0000031, we examine two potential mediators of the effects: harmonious passion (HP) and obsessive passion (OP). Following a preregistered survey (N = 258), we found that the effect of greed on crypto judgments was mediated by HP rather than OP. This result was replicated for stocks. The effect of NFC on attitudes was mediated by HP. The findings show that (1) dispositional greed and NFC offer insights into consumer judgments of crypto and stocks, (2) HP rather than OP mediates the effects of greed and NFC on crypto and share judgments, and (3) that the effects of dispositional greed and NFC on judgments is similar for crypto and stocks.

Osteopontin/SPP1: a potential mediator between immune cells and vascular calcification.

Vascular calcification (VC) is considered a common pathological process in various vascular diseases. Accumulating studies have confirmed that VC is involved in the inflammatory response in heart disease, and SPP1+ macrophages play an important role in this process. In VC, studies have focused on the physiological and pathological functions of macrophages, such as pro-inflammatory or anti-inflammatory cytokines and pro-fibrotic vesicles. Additionally, macrophages and activated lymphocytes highly express SPP1 in atherosclerotic plaques, which promote the formation of fatty streaks and plaque development, and SPP1 is also involved in the calcification process of atherosclerotic plaques that results in heart failure, but the crosstalk between SPP1-mediated immune cells and VC has not been adequately addressed. In this review, we summarize the regulatory effect of SPP1 on VC in T cells, macrophages, and dendritic cells in different organs' VC, which could be a potential therapeutic target for VC.

Vascular dysfunction occurs prior to the onset of amyloid pathology and Aβ plaque deposits colocalize with endothelial cells in the hippocampus of female APPswe/PSEN1dE9 mice

Increasing evidence shows that cardiovascular diseases (CVDs) are associated with an increased risk of cognitive impairment and Alzheimer’s diseases (AD). It is unknown whether systemic vascular dysfunction occurs prior to the development of AD, if this occurs in a sex-dependent manner, and whether endothelial cells play a role in the deposition of amyloid beta (Aβ) peptides. We hypothesized that vascular dysfunction occurs prior to the onset of amyloid pathology, thus escalating its progression. Furthermore, endothelial cells from female mice will present with an exacerbated formation of Aβ peptides due to an exacerbated pressure pulsatility. To test this hypothesis, we used a double transgenic mouse model of early-onset AD (APPswe/PSEN1dE9). We evaluated hippocampus-dependent recognition memory and the cardiovascular function by echocardiography and direct measurements of blood pressure through carotid artery catheterization. Vascular function was evaluated in resistance arteries, morphometric parameters in the aortas, and immunofluorescence in the hippocampus and aortas. We observed that endothelial dysfunction occurred prior to the onset of amyloid pathology irrespective of sex. However, during the onset of amyloid pathology, only female APP/PS1 mice had vascular stiffness in the aorta. There was elevated Aβ deposition which colocalized with endothelial cells in the hippocampus from female APP/PS1 mice. Overall, these data showed that vascular abnormalities may be an early marker, and potential mediator of AD, but exacerbated aortic stiffness and pressure pulsatility after the onset of amyloid pathology may be associated with a greater burden of Aβ formation in hippocampal endothelial cells from female but not male APP/PS1 mice.Graphical

Understanding the mediation effects of cigarettes per day on time to first cigarette and carcinogen biomarkers: National Health and Nutrition Examination Survey 2015-2016.

Previous research indicates that cigarette smokers with a time to first cigarette (TTFC) of less than 30 minutes after waking up had significantly higher levels of carcinogen biomarkers compared to those with a TTFC of more than 30 minutes. The mediation (potential mediator: cigarettes smoked per day) between TTFC and carcinogen biomarkers, remains unclear and has yet to be established. Multivariable linear regression models were used to estimate adjusted geometric means (GMs) and ratios of GMs for urine biomarkers of VOCs by smokers' TTFC status (≤30 vs >30 min). Further, data from the NHANES 2015-2016 special sample were analyzed to assess the mediation between TTFC (exposure) and carcinogen biomarkers, including urine metabolites of polycyclic aromatic hydrocarbons (PAHs), volatile organic compounds (VOCs), and cadmium. Cigarette smokers with a short TTFC (≤30 min) presented significantly higher concentrations in 8 out of 17 urine metabolites of VOCs examined compared to smokers with TTFC >30 min. The association between exposure and carcinogen biomarkers was not mediated by CPD. Cigarette smokers with a short TTFC (≤30 min) had significantly higher levels in VOCs, PAHs, and cadmium, but the association was not mediated by cigarettes smoked per day.

Osteoarthritis in Older Adults: Is More Emphasis on Managing and Mitigating its Stressful Ramifications, and Enhancing Coping, and Self Efficacy Cognitions Indicated?

Efforts to mitigate or prevent painful disabling osteoarthritis have been pursued for more than a century with limited success. This current overview briefly summarizes how selected beliefs and behaviors, including coping and stress management approaches are potential mediators or moderators of osteoarthritis pain and its overall common adverse prognosis and outcome. Published data housed predominantly in PUBMED, PUBMED CENTRAL, SCIENCE DIRECT, and GOOGLE SCHOLAR sites and pertaining to selected aspects of the literature of current interest, cumulative results reported as of May 30, 2024, show a modest to strong rationale exists for considering the abovementioned factors in efforts to reduce pain and enable daily functions. Accordingly this line of research should be continued, and translated clinically without undue delay, especially in the face of increases in the aging population and osteoarthritis prevalence and undue suffering.

Alterations of the peptidomic composition of peripheral plasma after portal hypertension correction by transjugular intrahepatic portosystemic shunt

Portal hypertension develops in patients with advanced chronic liver diseases (CLD), especially cirrhosis and is associated with complications, such as gastrointestinal bleeding and ascites resulting in high mortality. The transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for portal hypertension, aiming to decrease portal venous pressure by establishing an artificial passage for blood from the gastrointestinal tract to the liver vein. This study focuses on the differences in the molecular composition of plasma samples from patients with portal hypertension before and after TIPS intervention to identify and characterise potential mediators influencing gut-liver cross-talk. The plasma of 23 patients displaying advanced CLD with portal hypertension was collected from peripheral veins before and after TIPS treatment and analysed using a well-established non-targeted chromatography-mass spectrometric (LC-MS) approach. Sialomucin core protein 24(CD164)(160–180), meckelin(99-118), Histone-lysine N-methyltransferase(MLL3)(3019-3045) and transient receptor potential cation channel subfamily V member 5(TRPV5)(614-630) were identified to be downregulated after the TIPS treatment. In addition, the metabolites 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), uric acid, dopamine, homoarginine, leucylproline and 5-methyluridine were significantly decreased after TIPS, whereas one yet unidentified low molecular-weight metabolite showed an increase after the medical procedure. In conclusion, these substances are novel potential biomarkers for portal hypertension in patients with CLD, with mechanistic clues of involvement in regulating pathological gut-liver cross-talk.

Trust in the Leader, Organizational Commitment, and Nurses' Intention to Leave-Insights from a Nationwide Study Using Structural Equation Modeling.

Nursing retention is a major challenge globally. Ongoing workforce instability across countries underscores the need to understand the factors influencing turnover and nursing retention. Trust is a crucial element in managing workplace relationships between nurse managers and nurses. Existing studies have shown the direct impact of trust on employees' intention to leave their job but have not explored the effects of potential mediators such as organizational commitment. The aim of this study was to examine the impact of trust in the leader on nurses' intention to leave their job through the mediation of organizational commitment. A cross-sectional study was conducted in Italy. A convenience sample of 1853 nurses completed a self-report survey. The study tested a hypothesis-based mediation model using structural equation modeling, which showed good fit indices. The results indicated that trust in the leader had a significant impact on nurses' intention to leave, and this relationship was partially mediated by organizational commitment. Nurses who trust their leader are more likely to demonstrate higher levels of organizational commitment, resulting in a lower intention to leave their job. Furthermore, organizational commitment and trust emerge as critical factors in reducing nurses' intention to leave their current positions. Therefore, managers can reduce nurses' intention to leave by building trustful relationships that enhance organizational commitment.This study was not registered.

Remnant cholesterol, preinflammatory state and chronic kidney disease: association and mediation analyses

Blood lipid management is a key approach in the prevention of chronic kidney disease (CKD). Remnant cholesterol (RC) plays an important role in the development of multiple diseases via chronic inflammation. The aim of our study was to determine the relationship between RC and CKD and explore the role of inflammation in this relationship. The 7696 subjects from the Chinese Health and Nutrition Survey were divided into four subgroups according to the quartile of RC. The estimated glomerular filtration rate was calculated using the CKD Epidemiology Collaboration equation. Fasting RC was calculated as total cholesterol minus low-density lipoprotein cholesterol and high-density lipoprotein cholesterol. Logistic regression analysis was employed to evaluate the relationships between RC and CKD. Mediation analysis was undertaken to identify potential mediators of high-sensitivity C-reactive protein (hs-CRP) and white blood cells (WBCs). Of all participants, the mean age was 51 years, and the male accounted for 47.8%. The multivariable-adjusted odds ratios (95% CIs) for the highest versus lowest quartile of remnant cholesterol were 1.40 (1.10–1.78, p for trend = 0.006) for CKD. RC and preinflammatory markers have combined effect on CKD. The preinflammatory state, presented by increased hs-CRP or WBCs, partially mediated the association between RC and CKD with proportion of 10.14% (p = 0.002) and 11.65% (p = 0.012), respectively. In conclusion, this study suggested a positive relationship between RC and CKD, which was partially mediated by preinflammatory state. These findings highlight the importance of RC and inflammation in renal dysfunction. IMPACT STATEMENT What is already known on this subject?: Dyslipidemia plays an important role in the development of chronic kidney disease (CKD). Remnant cholesterol (RC), as a triglyceride-rich particle, can contribute to target organ damage, primarily through inflammatory pathways. However, the relationship between RC and CKD in the community-dwelling population, particularly the role of inflammation, is not yet fully understood. What do the results of this study add?: This study shows that RC was significantly associated with CKD. RC and preinflammatory status exhibit a combined effect on CKD. Preinflammatory state, presented by increased high-sensitivity C-reactive protein or white blood cells, partially mediated the association between RC and CKD. What are the implications of these findings for clinical practice and/or further research?: The study provides us with a better understanding of the role of RC and inflammation in kidney dysfunction and raises the awareness of RC in the management of CKD.

Phenotypes of Polish primary care patients using hierarchical clustering: Exploring the risk of mortality in the LIPIDOGEN2015 study cohort.

Comorbidities in primary care do not occur in isolation but tend to cluster together causing various clinically complex phenotypes. This study aimed to distinguish phenotype clusters and identify the risks of all-cause mortality in primary care. The baseline cohort of the LIPIDOGEN2015 sub-study involved 1779 patients recruited by 438 primary care physicians. To identify different phenotype clusters, we used hierarchical clustering and investigated differences between clinical characteristics and mortality between clusters. We then performed causal analyses using causal mediation analysis to explore potential mediators between different clusters and all-cause mortality. A total of 1756 patients were included (mean age 51.2, SD 13.0; 60.3% female), with a median follow-up of 5.7 years. Three clusters were identified: Cluster 1 (n = 543) was characterised by overweight/obesity (body mass index ≥ 25 kg/m2), older (age ≥ 65 years), more comorbidities; Cluster 2 (n = 459) was characterised by non-overweight/obesity, younger, fewer comorbidities; Cluster 3 (n = 754) was characterised by overweight/obesity, younger, fewer comorbidities. Adjusted Cox regression showed that compared with Cluster 2, Cluster 1 had a significantly higher risk of all-cause mortality (HR 3.87, 95% CI: 1.24-15.91), whereas this was insignificantly different for Cluster 3. Causal mediation analyses showed that decreased protein thiol groups mediated the hazard effect of all-cause mortality in Cluster 1 compared with Cluster 2, but not between Clusters 1 and 3. Overweight/obesity older patients with more comorbidities had the highest risk of long-term all-cause mortality, and in the young group population overweight/obesity insignificantly increased the risk in the long-term follow-up, providing a basis for stratified phenotypic risk management.

Dynamin-1 is a potential mediator in Cancer-Related Cognitive Impairment.

Dynamin-1 (DNM1) consolidates memory through synaptic transmission and modulation and has been explored as a therapeutic target in Alzheimer's disease. Through a two-prong approach, this study examined its role in cancer-related cognitive impairment (CRCI) pathogenesis using human and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Concurrently, a syngeneic young-adult WT (C57BL/6 female) mouse model of breast cancer was developed to study DNM1 expression in the brain. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were significantly lower among cancer participants compared to non-cancer prior to treatment. While receiving cancer treatment, cognitively impaired patients were found with a significant downregulation of DNM1, but not among those without impairment. In murine breast cancer-bearing mice receiving chemotherapy, we consistently found a significant decline in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions. Observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. Future research should explore the potential of DNM1 in CRCI pathogenesis and therapeutics development.

Causal link between hypothyroidism and gastric cancer risk: insights gained through multivariable Mendelian randomization and mediation analysis.

Gastric cancer (GC) is the third leading cause of cancer death worldwide, and hypothyroidism has been identified as a potential influencing factor. Despite known associations between hypothyroidism and various cancers, the causal link between hypothyroidism and GC and potential mediators of this relationship remains unclear. This study aimed to clarify these relationships using Mendelian randomization (MR). Utilizing genetic variant information from the FinnGen and MRC Integrative Epidemiology Unit open genome-wide association studies (GWAS) databases, we conducted univariable and multivariable MR analyses to explore the causal relationship between hypothyroidism and GC risk. The analysis was adjusted for confounders such as BMI, smoking status, and alcohol intake, and included mediator MR analysis to examine the role of high cholesterol. We identified a significant inverse association between hypothyroidism and GC risk (OR = 0.93, 95% CI= 0.89-0.98, P = 0.003), with no evidence of reverse causation or pleiotropy. Adjustments for Helicobacter pylori infection weakened this association. Mediator analysis highlighted high cholesterol levels, chronic hepatitis B infection, and diabetes/endocrine disease status as significant mediators of the protective effect of hypothyroidism on GC risk. Our findings suggest that hypothyroidism may confer a protective effect against GC, mediated in part by high cholesterol and other factors. These results underscore the importance of thyroid function and metabolic health in GC risk, offering new insights for preventive strategies and highlighting the need for further research into these complex associations.