Causal Mediation Research Articles

Associations of cerebrospinal fluid complement proteins with Alzheimer’s pathology, cognition, and brain structure in non-dementia elderly

BackgroundCerebrospinal fluid (CSF) complement activation is a key part of neuroinflammation that occurs in the early stages of Alzheimer’s disease (AD). However, the associations of CSF complement proteins with AD pathology, cognition, and structural neuroimaging biomarkers for AD have been rarely investigated.MethodsA total of 210 participants (125 mild cognitive impairment [MCI] patients and 85 normal controls) were included from Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who measured AD pathology, cognition, and neuroimaging at baseline and every 12 months. The mixed-effect linear models were utilized to investigate longitudinal associations of CSF complement proteins with AD pathology, cognition, and neuroimaging in cognitively normal (CN) and mild cognitive impairment (MCI) subjects. Causal mediation analyses were conducted to explore the potential mediators between CSF complement proteins and cognitive changes.ResultsWe found that the subjects with low CSF complement protein levels at baseline had worse outcomes in AD pathology, indicated by their lowest concentrations observed in A + and A + T + individuals. The reduced CSF complement proteins were associated with faster accumulation of tau among CN subjects and with cognitive decline and greater brain atrophy of specific regions among MCI subjects. Furthermore, mediation analyses showed that the effects of CSF complement proteins on cognitive performance were partially mediated by regional brain structures (mediation proportions range from 19.78 to 94.92%; p < 0.05).ConclusionsThis study demonstrated that CSF complement proteins were involved in the early progression of AD. Our results indicated that regional brain atrophy might be a plausible way to connect CSF complement protein levels and cognition.

Promising Effects of Montelukast for Critically Ill Asthma Patients via a Reduction in Delirium.

Background: Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. Methods: A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Results: Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497-0.999; p = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366-0.840; p = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383-0.896; p = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: -0.053; 95% CI -0.0142 to 0.0002; p = 0.020). Conclusions: In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium.

Investigating the Relationship between Birthweight and Breast Cancer from A Non-Linear and Mediation Perspective.

Epidemiological studies have shown a positive relationship between birthweight and breast cancer; however, inconsistent, sometimes even controversial, observations emerged. We re-explored the association between them in the UK Biobank cohort. Relying on the UK Biobank cohort data of white British volunteers recruited between 2006 and 2010 (5,760 cases and 162,778 controls), we evaluated the causal mediation between birthweight and breast cancer, with age of menarche and age at menopause as two potential mediators under the traditional mediation analysis framework. The non-linear relationship between birthweight and breast cancer was also investigated by including the square of birthweight or discretized birthweight categories (<2.5, 2.5~4.0, or >4.0). Furthermore, we performed a stratification analysis in terms of the menopause status. Birthweight can indirectly influence breast cancer risk in adulthood via the path of age of menarche or age at menopause, and found statistical evidence supporting the existence of suggestive non-linear association between birthweight and breast cancer (β=0.062 and P=0.004 for the square of birthweight) although failing to discover a linear relationship (P=0.230). We also demonstrated such non-linear association seemed more pronounced and robust for premenopausal women compared with postmenopausal ones (27.5% vs. 19.5% increase in breast cancer risk). This study provided an in-depth insight into the observed relationship between birthweight and breast cancer and revealed that non-linear impact and causal mediation commonly drive the connection between the two traits.

The role of breastfeeding support in racial/ethnic disparities in breastfeeding practices

BackgroundPersistent racial/ethnic disparities in breastfeeding practices in the United States are well documented but the underlying causes remain unclear. While racial/ethnic disparities are often intertwined with socioeconomic disparities in breastfeeding, studies suggest that lack of breastfeeding support from family, health care organizations and workplaces may contribute to racial/ethnic disparities in breastfeeding rates. No studies have investigated the extent to which racial/ethnic disparities in breastfeeding practices can be explained by breastfeeding support. MethodsWe used survey data from participants of a federal nutrition assistance program in Los Angeles County, the most populous county in the United States, to examine causal mechanisms underlying racial/ethnic disparities in breastfeeding in five groups: Spanish-speaking Latina, English-speaking Latina, Non-Hispanic White (NHW), Non-Hispanic Black (NHB) and Non-Hispanic Asian (NHA). Applying causal mediation analysis, this study estimated the proportion of racial/ethnic differences in breastfeeding (‘any’ breastfeeding, i.e., partial or exclusive) rates at 6 months that could be explained by differential access to breastfeeding support from family, birth hospitals and workplaces. ResultsNHB and English-speaking Latina mothers were less likely, and Spanish-speaking Latina mothers more likely to breastfeed through 6 months than NHW mothers. Lack of breastfeeding support from family, hospitals and workplaces accounted for approximately 68% of the difference in any breastfeeding rates at 6 months between NHW and NHB mothers and 36% of the difference between NHW and English-speaking Latina mothers. ConclusionThese findings highlight the importance of improving support from family, hospitals and workplaces for breastfeeding mothers to reduce racial/ethnic disparities in breastfeeding.

Mediation analysis of chronic kidney disease risk factors using kidney biomarkers in women living with HIV.

Novel urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in persons living with HIV. However, it is unknown whether these biomarkers provide mechanistic insight into the associations between clinical risk factors for CKD and subsequent CKD risk. Among 636 women living with HIV in the Women's Interagency HIV Study with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m 2 , we used a counterfactual approach to causal mediation analysis to evaluate the extent to which systolic blood pressure (SBP), diastolic blood pressure (DBP), hemoglobin a1c (Hba1c) and serum albumin associations with incident CKD were mediated by eight urine proteins. These biomarkers reflect proximal tubular reabsorptive dysfunction (α1-microglobulin [a1m], β2-microglobulin, trefoil factor 3); tubular injury (interleukin 18 [IL-18], kidney injury molecule 1 [KIM-1]); kidney repair (epidermal growth factor); tubular reserve (uromodulin); and glomerular injury (urinary albumin). Incident CKD was defined as eGFR <60 ml/min/1.73 m 2 measured at two consecutive 6-month visits with an average annual eGFR decline ≥3% per year. During a median follow-up of 7 years, 11% developed CKD. Urinary albumin and KIM-1 mediated 32% (95% CI: 13.4%, 76.6%) and 23% (6.9%, 60.7%) of the association between SBP and incident CKD, respectively; and 19% (5.1%, 42.3%) and 22% (8.1%, 45.7%) of the association between DBP and incident CKD, respectively. Urinary albumin, α1m, and IL-18 were significant mediators of the association between Hba1c and incident CKD. None of the eight biomarkers mediated the association between serum albumin and incident CKD. Among women living with HIV, several urinary biomarkers reflecting distinct dimensions of kidney health may partially explain the associations between SBP, DBP, and Hba1c and subsequent CKD risk.

Mediating effect of vascular calcification in galectin-3-related mortality in hemodialysis patients

Galectin-3 levels have been studied as a potential biomarker for predicting cardiovascular (CV) risk and mortality in hemodialysis (HD) patients. Recently, a close relationship between galectin-3 and vascular calcification (VC) has been reported. Here, we investigated the role of VC as a mediating factor in the association between galectin-3 and mortality. Serum galectin-3 and baseline aortic arch calcification (AoAC) score were measured in 477 incident HD patients. Mortality data were obtained at a median follow-up of 40 months. Causal mediation analysis was performed to examine the effect of vascular risk factors on galectin-3-related mortality. The prevalence of AoAC in HD patients was 57% (n = 272), and elevated galectin-3 levels were associated with a significantly increased risk of AoAC. When the galectin-3 level was divided by the median level of 37 ng/mL, a higher galectin group increased the risk of all-cause mortality by 1.71-fold (95% CI 1.02–2.92, p = 0.048), even after adjustment for multiple CV risk factors. Mediation analysis showed that both the direct effect of the galectin-3 on mortality (β = 0.0368, bootstrapped 95% CI [0.0113–0.0622]) and the indirect effects were significant. AoAC score and high-sensitivity CRP levels significantly mediated the association between galectin-3 and mortality (total indirect effects: β = 0.0188, bootstrapped 95% CI [0.0066–0.0352]). This study suggests that the association between high galectin-3 and mortality may be partially mediated by higher VC and inflammatory state in HD patients.

Nutritional Status and Physical Exercise Are Associated with Cognitive Function in Chinese Community-Dwelling Older Adults: The Role of Happiness.

We aim to assess the relationship between nutrition status, physical exercise, and cognitive function and particularly examine how happiness modifies and mediates the relationship, among 699 seniors aged 60 and above in Shanghai, China. Linear regression models were used to validate the effects of nutrition and exercise on cognitive function and to test their interaction effects with happiness. When the interactions were significant, stratified analyses in sub-groups were conducted. Mediation effects of happiness were examined using two-step causal mediation models. We confirmed that better nutrition (p < 0.001) and exercise (p = 0.009) were significantly associated with less cognitive decline. Furthermore, the effects of nutrition and exercise on cognitive decline were significant in the unhappy (happiness < 20) (p < 0.001) and younger (age < 74) sub-groups (p = 0.015). Happiness partially mediated 11.5% of the negative association of cognitive decline with nutrition (p = 0.015) and 23.0% of that with exercise (p = 0.017). This study suggests that happiness moderates and partially mediates the effects of exercise and nutrition on cognitive status. The beneficial effects of exercise and nutrition were stronger in less happy or younger seniors. Future intervention studies are required to confirm this path relationship.

Racial and ethnic disparities in preterm birth: a mediation analysis incorporating mixtures of polybrominated diphenyl ethers.

Racial and ethnic disparities persist in preterm birth (PTB) and gestational age (GA) at delivery in the United States. It remains unclear whether exposure to environmental chemicals contributes to these disparities. We applied recent methodologies incorporating environmental mixtures as mediators in causal mediation analysis to examine whether racial and ethnic disparities in GA at delivery and PTB may be partially explained by exposures to polybrominated diphenyl ethers (PBDEs), a class of chemicals used as flame retardants in the United States. Data from a multiracial/ethnic US cohort of 2008 individuals with low-risk singleton pregnancies were utilized, with plasma PBDE concentrations measured during early pregnancy. We performed mediation analyses incorporating three forms of mediators: (1) reducing all PBDEs to a weighted index, (2) selecting a PBDE congener, or (3) including all congeners simultaneously as multiple mediators, to evaluate whether PBDEs may contribute to the racial and ethnic disparities in PTB and GA at delivery, adjusted for potential confounders. Among the 2008 participants, 552 self-identified as non-Hispanic White, 504 self-identified as non-Hispanic Black, 568 self-identified as Hispanic, and 384 self-identified as Asian/Pacific Islander. The non-Hispanic Black individuals had the highest mean ∑PBDEs, the shortest mean GA at delivery, and the highest rate of PTB. Overall, the difference in GA at delivery comparing non-Hispanic Black to non-Hispanic White women was -0.30 (95% CI: -0.54, -0.05) weeks. This disparity reduced to -0.23 (95% CI: -0.49, 0.02) and -0.18 (95% CI: -0.46, 0.10) weeks if fixing everyone's weighted index of PBDEs to the median and the 25th percentile levels, respectively. The proportion of disparity mediated by the weighted index of PBDEs was 11.8%. No statistically significant mediation was found for PTB, other forms of mediator(s), or other racial and ethnic groups. PBDE mixtures may partially mediate the Black vs. White disparity in GA at delivery. While further validations are needed, lowering the PBDEs at the population level might help reduce this disparity.

The Mediating Role of Digital Competence in the Associations Between the Factors Affecting Healthcare Utilization and Access to Care.

Objectives: To examine with a population-based longitudinal survey design whether poor health, longstanding activity limitation, impaired cognitive functioning, mental distress, or loneliness predict poor access to healthcare and whether digital competence mediates these associations. Methods: The data were from the longitudinal FinHealth -survey gathered in Finland in 2017 and 2020 including 3,771 respondents (57.1% women). Linear regression analyses were used to examine the associations of factors affecting healthcare utilization with access to care adjusted for age, sex, and education. Counterfactual causal mediation framework was used to examine the mediating role of digital competence in the relationships among these factors and access to healthcare. Results: Factors affecting healthcare utilization were associated with poor access to care and these associations were partly mediated by low digital competence. Low digital competence mediated 12%, 9% and 8%, of the associations of impaired cognitive functioning, longstanding activity limitation, and loneliness with poor access to care, respectively. Conclusion: According to our results, one way to improve the access to healthcare among vulnerable groups could be to improve their digital competence.

The role of psychosocial well-being and emotion-driven impulsiveness in food choices of European adolescents

BackgroundIt is unclear whether a hypothetical intervention targeting either psychosocial well-being or emotion-driven impulsiveness is more effective in reducing unhealthy food choices. Therefore, we aimed to compare the (separate) causal effects of psychosocial well-being and emotion-driven impulsiveness on European adolescents’ sweet and fat propensity.MethodsWe included 2,065 participants of the IDEFICS/I.Family cohort (mean age: 13.4) providing self-reported data on sweet propensity (score range: 0 to 68.4), fat propensity (range: 0 to 72.6), emotion-driven impulsiveness using the UPPS-P negative urgency subscale, and psychosocial well-being using the KINDLR Questionnaire. We estimated, separately, the average causal effects of psychosocial well-being and emotion-driven impulsiveness on sweet and fat propensity applying a semi-parametric doubly robust method (targeted maximum likelihood estimation). Further, we investigated a potential indirect effect of psychosocial well-being on sweet and fat propensity mediated via emotion-driven impulsiveness using a causal mediation analysis.ResultsIf all adolescents, hypothetically, had high levels of psychosocial well-being, compared to low levels, we estimated a decrease in average sweet propensity by 1.43 [95%-confidence interval: 0.25 to 2.61]. A smaller effect was estimated for fat propensity. Similarly, if all adolescents had high levels of emotion-driven impulsiveness, compared to low levels, average sweet propensity would be decreased by 2.07 [0.87 to 3.26] and average fat propensity by 1.85 [0.81 to 2.88]. The indirect effect of psychosocial well-being via emotion-driven impulsiveness was 0.61 [0.24 to 1.09] for average sweet propensity and 0.55 [0.13 to 0.86] for average fat propensity.ConclusionsAn intervention targeting emotion-driven impulsiveness, compared to psychosocial well-being, would be marginally more effective in reducing sweet and fat propensity in adolescents.

Amyloid Pathology Modulates the Associations of Neuropsychiatric Symptoms with Cognitive Impairments and Neurodegeneration in Non-Demented Elderly.

The associations between neuropsychiatric symptoms (NPSs) and Alzheimer's disease (AD) have been well-studied, yet gaps remain. We aimed to examine the associations of four subsyndromes (hyperactivity, psychosis, affective symptoms, and apathy) of NPSs with cognition, neurodegeneration, and AD pathologies. Totally 1,040 non-demented elderly (48.07% males) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included. We assessed the relationships between NPSs and AD neuropathologies, cognition, neurodegeneration, and clinical correlates in cross-sectional and longitudinal via multiple linear regression, linear mixed effects, and Cox proportional hazard models. Causal mediation analyses were conducted to explore the mediation effects of AD pathologies on cognition and neurodegeneration. We found that individuals with hyperactivity, psychosis, affective symptoms, or apathy displayed a poorer cognitive status, a lower CSF amyloid-β (Aβ) level and a higher risk of clinical conversion (p < 0.05). Hyperactivity and affective symptoms were associated with increasing cerebral Aβ deposition (p < 0.05). Except psychosis, the other three subsyndromes accompanied with faster atrophy of hippocampal volume (p < 0.05). Specific NPSs were predominantly associated with different cognitive domains decline through an 8-year follow-up (p < 0.05). Moreover, the relationships between NPSs and cognitive decline, neurodegeneration might be associated with Aβ, the mediation percentage varied from 6.05% to 17.51% (p < 0.05). NPSs could be strongly associated with AD. The influences of NPSs on cognitive impairments, neurodegeneration might be partially associated with Aβ.

Early microbial intervention reshapes phenotypes of newborn Bos taurus through metabolic regulations.

The rumen of neonatal calves has limited functionality, and establishing intestinal microbiota may play a crucial role in their health and performance. Thus, we aim to explore the temporal colonization of the gut microbiome and the benefits of early microbial transplantation (MT) in newborn calves. We followed 36 newborn calves for 2 months and found that the composition and ecological interactions of their gut microbiomes likely reached maturity 1 month after birth. Temporal changes in the gut microbiome of newborn calves are widely associated with changes in their physiological statuses, such as growth and fiber digestion. Importantly, we observed that MT reshapes the gut microbiome of newborns by altering the abundance and interaction of Bacteroides species, as well as amino acid pathways, such as arginine biosynthesis. Two-year follow-up of those calves further showed that MT improves their later milk production. Notably, MT improves fiber digestion and antioxidant capacity of newborns while reducing diarrhea. MT also contributes to significant changes in the metabolomic landscape, and with putative causal mediation analysis, we suggest that altered gut microbial composition in newborns may influence physiological status through microbial-derived metabolites. Our study provides a metagenomic and metabolomic atlas of the temporal development of the gut microbiome in newborn calves. MT can alter the gut microbiome of newborns, leading to improved physiological status and later milk production. The data may help develop strategies to manipulate the gut microbiota during early life, which may be relevant to the health and production of newborn calves.

Hypothesis-driven mediation analysis for compositional data: an application to gut microbiome

Sequencing read-count data often exhibit sparsity (zero-count inflation) and overdispersion. As most sequencing techniques provide an arbitrary total count, taxon-specific counts should be treated under the compositional data-analytic framework. There is increasing interest in the role of gut microbiome composition in mediating the effects of exposures on health. Previous compositional mediation approaches have focused on identifying mediating taxa among a number of candidates. We here consider compositional causal mediation when a priori knowledge is available about the hierarchy for a restricted number of taxa, building on a single hypothesis structured as contrasts between appropriate sub-compositions. Based on the assumed causal graph and the theory of multiple contemporaneous mediators, we define non-parametric estimands for overall and coordinate-wise mediation effects and show how they are estimated based on parametric linear models. The mediators have straightforward and coherent interpretations, related to causal questions about interrelationships between the sub-compositions. We perform a simulation study focusing on the impact of sparsity on estimation. While unbiased, the estimators' precision depends on sparsity and the relative magnitudes of exposure-to-mediator and mediator-to-outcome effects in a complex manner. In the empirical application we find an inverse association of fibre intake on insulin level, mainly attributable to the direct effects.

Shared Risk Volatile Organic Compounds Among Chronic Respiratory Diseases: Mediation Effects of System Inflammation

Background: Volatile organic compounds (VOCs) are indoor and outdoor air pollution, but the VOCs that were shared across chronic respiratory diseases (CRDs) remained unknown. Meanwhile, the mediating roles of system inflammation need to be further explored.Methods: This study included 9114 adults based on the National Health and Nutrition Examination Survey (NHANES) 2005–2006 and 2011–2018. Internal exposure levels of 14 urinary metabolites of VOC (mVOCs), blood cell count–derived inflammatory biomarkers, and prevalent CRDs, including asthma, chronic bronchitis, and emphysema, were assessed and collected. Associations of single‐ and multiple‐mVOCs with CRDs were assessed by using logistic regression and quantile‐based g‐computation (QGcomp) methods to select the key and shared mVOCs among CRDs. Mediation effects of system inflammation on mVOC‐CRD associations were further evaluated by causal mediation analysis.Results: Increased levels of total 14 mVOCs were associated with increased risk of chronic bronchitis (OR = 1.62, 95% CI: 1.37–1.91), emphysema (OR = 1.73, 95% CI: 1.27–2.35), and both conditions combined (defined as chronic obstructive pulmonary disease, COPD) (OR = 1.61, 95% CI: 1.37–1.88), but not for asthma (OR = 1.07, 95% CI: 0.94–1.21). In both single‐ and multiple‐mVOC exposure models, 8 key mVOCs were COPD associated, including 6 mVOCs (34MHA, AMCC, CEMA, DHBMA, 3HPMA, and MHBMA3) and 5 mVOCs (34MHA, CYMA, 3HPMA, MA, and MHBMA3) that were associated with increased risk of chronic bronchitis and emphysema, respectively. Particularly, 34MHA, 3HPMA, and MHBMA3 were shared risk factors across chronic bronchitis, emphysema, and COPD. Neutrophils mediated the associations of three shared mVOCs with chronic bronchitis (by 5.20%, 7.80%, 6.30%), emphysema (by 6.90%, 9.30%, 9.70%), and COPD (by 5.80%, 8.90%, 7.70%).Conclusions: These findings provide valuable insights into the shared risk mVOCs and mediating roles of neutrophils involved in the pathogenesis of CRDs, which can be useful in developing more effective prevention and intervention strategies for CRDs.

Epigenomic and epigenetic investigations of food allergy.

As a potential link between genetic predisposition, environmental exposures, and food allergy outcomes, epigenetics has been a molecular variable of interest in ongoing efforts to understand food allergy mechanisms and outcomes. Here we review population-based investigations of epigenetic loci associated with food allergy, focusing on established clinical food allergy. We first provide an overview of epigenetic mechanisms that have been studied in cohorts with food allergy, predominantly DNA methylation but also microRNA. We then discuss investigations that have implemented epigenome-wide approaches aimed at genome-wide profiling and discovery. Such epigenome-wide studies have collectively identified differentially methylated and differentially regulated loci associated with T cell development, antigen presentation, reaction severity, and causal mediation in food allergy. We then discuss candidate-gene investigations that have honed in on Th1, Th2, T regulatory, and innate genes of a priori interest in food allergy. These studies have highlighted methylation changes in specific candidate genes as associated with T regulatory cell activity as well as differential methylation of Type 1 and Type 2 cytokine genes associated with various food allergies. Intriguingly, epigenetic loci associated with food allergy have also been explored as potential biomarkers for the clinical management of food allergy. We conclude by highlighting several priority directions for advancing population-based epigenomic and epigenetic understandings of food allergy.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization.

Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (β=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (β=-0.127), showed an indirect effect on infertility mediated by SUA (β=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

Causal effects and metabolites mediators between immune cell and risk of colorectal cancer: a Mendelian randomization study.

The involvement of immune cells in colorectal cancer (CRC) and their interplay with metabolic disorders are yet to be fully elucidated. This study examines how peripheral immune cells, inferred genetically, affect CRC and investigates the intermediary roles of metabolites. We employed a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal influence of immune cells on CRC. Additionally, a two-step MR strategy was utilized to pinpoint potential metabolites that mediate this effect. Our analysis incorporated data from genome-wide association studies (GWAS), involving 731 immune cell types, 1,400 metabolites, and CRC outcomes. The primary method of analysis was randomized inverse variance weighting (IVW), supported by MR-Egger, weighted median, simple mode, and weighted mode analyses. Sensitivity checks were conducted using Cochran's Q test, MR-PRESSO test, MR-Egger regression intercept, and leave-one-out analysis. The study identified 23 immune cell types and 17 metabolites that are causally linked to CRC. Our mediation analysis highlighted that nine metabolites act as intermediaries in the relationship between nine specific immune cells and CRC risk. Notably, The ratios of Adenosine 5'-monophosphate (AMP) to aspartate and Retinol (Vitamin A) to linoleoyl-arachidonoyl-glycerol (18:2 to 20:4) were found to concurrently mediate the promoting effects of Myeloid DC %DC and BAFF-R on B cells in colorectal cancer (CRC). Moreover, iminodiacetate (IDA) was found to mediate the protective effect of CD14+ CD16- monocytes on CRC, contributing 11.8% to this mediation. In contrast, IDA was also seen to decrease the protective effect of IgD+ CD38br %B cells on CRC risk, with a mediation effect proportion of -10.4%. This study delineates a complex network involving immune cells, metabolites, and CRC, suggesting a multifaceted pathophysiological interaction. The identified causal links and mediation pathways underscore potential therapeutic targets, providing a foundation for interventions aimed at modulating immune responses to manage CRC.

Home noninvasive ventilation in severe COPD: in whom does it work and how?

Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide (PaCO2), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved PaCO2. We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on PaCO2, HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in PaCO2. Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14 versus ≥14 cmH2O) and with lower adherence (<5 versus ≥5 h·day-1) had less improvement in PaCO2 (mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival. PaCO2 improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in PaCO2. With greater pressure support and better daily NIV usage, a larger improvement in PaCO2 and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal PaCO2.

The Interaction between Dramatic Writing and the Construction of National Identity in the Southern National Society Period

Abstract Starting from the background of the development of Chinese and Western cultures, this paper analyzes the textual themes and interprets the ideas of the dramas created during the period of the Nanguosha. Taking into account the specificity of the era and the national perception of Nanguosha’s theatrical works, the concept of theatrical cultural interaction is put forward to analyze the basis of cultural interaction in the cultural acceptance behavior of drama. Audience interaction behavior and audience emotional intelligence are chosen as intermediary and moderating variables respectively, and a four-variable research model is constructed for the creation of Nanguosha’s dramas, the construction of national identity, audience interaction behavior and audience emotional intelligence. Introduce the causal mediation effect model based on Nanguosha theater culture, explain the symbolic variables, and discuss the estimation method for the causal mediation effect. Combine the empirical data with the descriptive analysis and correlation analysis of the variables, and carry out the main effect test, mediation effect test, moderating effect test, and moderated mediation effect test of the research hypotheses in order to verify the interaction of the variables. After introducing the mediator variable of audience interaction behavior, the regression coefficient of Nanguosha’s drama creation on national identity construction is β =0.198, P&lt;0.01, which confirms that there is a relationship of positive influence of Nanguosha’s drama creation on national identity construction, and that the audience interaction behavior plays a partly mediating role in the process of Nanguosha’s drama creation’s role in national identity construction.

Common Social and Health Disparities Contribute to Racial Differences in Ambulatory Impairment in Multiple Sclerosis.

We previously reported more rapid accrual of ambulatory impairments in Black compared to White individuals with relapsing remitting multiple sclerosis (RRMS) and higher body mass index (BMI). Hypertension and lower neighborhood socioeconomic status (SES) were associated with greater impairment, irrespective of race. We hypothesize that these common social and health inequities may explain a substantial portion of the racial differences in ambulation in American individuals with RRMS. Causal mediation analyses investigated baseline and change-over-time mediators of ambulatory impairment differences between 1795 Black and White individuals with RRMS using a retrospective cohort study comprised of electronic health record data from 8491 clinical encounters between 2008 and 2015 where Timed 25-Foot Walk (T25FW) speeds without assistive devices were recorded. The hypothesis was that BMI, neighborhood SES, and hypertension were possible mediators. At baseline, Black individuals with RRMS (n = 175) had significantly slower T25FW speeds (5.78 vs 5.27 ft/s), higher BMI, a higher prevalence of hypertension, and they were more likely to live in lower-income neighborhoods than White individuals (n = 1,620). At baseline, a significant proportion (33.7%; 95% CI, 18.9%-59.4%) of the T25FW difference between Black and White individuals was indirectly due to a higher BMI (12.5%), hypertension burden (9.5%), and living in lower-income neighborhoods (11.2%). Once baseline mediation relationships were accounted for, there were no significant longitudinal mediation relationships. The findings implicate social and health disparities as prominent drivers of ambulatory differences between Black and White individuals with RRMS, suggesting that wellness and health promotion are essential components of MS care, particularly for Black individuals.