Causal Correlation Research Articles

Hearing loss is not associated with risk of Parkinson's disease: A Mendelian randomization study

PurposeA few observational studies have indicated that Parkinson's disease (PD) risk may be higher in those with hearing loss, but the two's causal relationship is yet unknown. Using Mendelian randomization (MR) methods, this study sought to explore the causal link between hearing loss and the risk of PD. MethodsWe identified single nucleotide polymorphisms (SNPs) linked to hearing loss (P-value<5E-08) in a genome-wide association study (GWAS) included 323,978 people from the UK Biobank. The summary data for PD in the discovery group came from a GWAS meta-analysis of 33,647 cases and 449,056 healthy participants of European descent. Using summary data from the aforementioned GWAS of PD (N = 33,647) and hearing loss (N = 323,978), we carried out a two-sample MR study. As validation groups, two separate PD GWAS studies were used. Inverse variance weighting (IVW) was utilized in the principal MR analysis. For our findings to be reliable, further analyses were carried out with the Cochran's Q test, MR-Egger intercept, and leave-one-out analysis. In addition, we assessed the causal link between various forms of hearing loss and PD using the IVW approach. ResultsTwenty-two SNPs with genome-wide significance linked to hearing loss were used as instrumental factors. In the discovery dataset, we failed to detect a causal relationship between hearing loss and PD (OR = 1.297; 95 % CI = 0.420–4.007; P-value = 0.651). The findings of other methods agreed with the IVW method. The results were robust under sensitivity analyses. Furthermore, the above findings were confirmed in two validation PD datasets. Additionally, no causal correlation was found between genetic prediction of four different types of hearing loss and PD (conductive hearing loss, IVW: OR = 1.058, 95%CI = 0.988–1.133, P-value = 0.108; sudden idiopathic hearing loss, IVW: OR = 0.936, 95%CI = 0.863–1.016, P-value = 0.113; mixed conductive and sensorineural hearing loss, IVW: OR = 0.963, 95%CI = 0.878–1.058, P-value = 0.436; sensorineural hearing loss, IVW: OR = 1.050, 95%CI = 0.948–1.161, P-value = 0.354). ConclusionIn those of European heritage, our investigation revealed no causal link between hearing loss and PD risk.

Genetic Evidence for a Causal Relationship Between Innate Leukocytes and the Risk of Digestive System Cancers in East Asians and Europeans.

Peripheral traditional immune cell disorder plays an important role in cancer onset and development. The causal relationships between leukocytes prior to cancer and the risk of digestive system cancer remain unknown. This study assesses the causal correlations between leukocytes and digestive system cancer risk in East Asians and Europeans. Summary-level data on leukocyte-related genetic variation were extracted from Biobank Japan (107,964 participants) and a recent large-scale meta-analysis (563,946 participants). Summary-level data for the cancers were obtained from Biobank Japan (212,978 individuals) and the FinnGen consortium (178,802 participants). Univariable and multivariable Mendelian randomization (MR) analyses were performed on East Asians and Europeans separately. Univariable MR analysis demonstrated the significant association between circulating eosinophil counts and risk of colorectal cancer (CRC) in East Asians (odds ratio (OR) = 0.80, 95% confidence interval (CI): 0.69 - 0.92, P = 0.002) and a suggestive relationship in the European population (OR = 0.86, 95% CI: 0.77 - 0.97, P = 0.013). An inverse suggestive association was observed between levels of basophils and the risk of gastric cancer (GC) in East Asians (OR = 0.83, 95% CI: 0.72 - 0.97, P = 0.019). The multivariable MR analysis showed the independent causal effect of eosinophil count on CRC risk in East Asians (OR = 0.72, 95% CI: 0.57 - 0.92, P = 0.009) and Europeans (OR = 0.80, 95% CI: 0.70 - 0.92, P = 0.002). Circulating basophils served as the negative causal factor in GC risk in East Asians (OR = 0.80, 95% CI: 0.67 - 0.94, P = 0.007). Our MR analyses revealed a genetic causal relationship between reduced blood eosinophils and an increased CRC risk in both Europeans and East Asians. Furthermore, our results suggested a causal association between decreased basophils and an elevated GC risk specifically in East Asians.

Investigating the Nexus Between GHG Emissions and AFOLU Activities: New Insights from C-Vine Copula Approach

The greenhouse gas (GHG) emissions from agriculture, forestry, and other land use (AFOLU) account for more than 10% of the total GHG emissions in Iran. To reduce the environmental impact, assessments of Iran’s GHG emissions status are critical for identifying the national policies to achieve Sustainable Development Goals (SDGs) in the bio-based industry. However, there is no study exploring the dependency between AFOLU and GHG emissions in Iran by using the Vine Copula approach. Hence, the study aims to examine the causality direction and correlation structure among selected horticulture, farming crops, livestock, and poultry products and carbon dioxide (CO2), nitrogen dioxide (N2O), and methane emissions (CH4) in the Iranian agriculture sector over the period 1961–2019, to determine which crops or products are more responsible to deteriorate the environment. The empirical strategy used a C-Vine Copula model to measure the correlations together with the Granger causality (GC) test to analyze the causality links. According to the empirical findings, several crops and products are the sources of emissions. Rice and vegetable cultivations, as well as meat and milk products (Kendall’s τ values of 0.37, 0.33, 0.31, and 0.31, respectively), are the leading sources of CH4 emissions. Legumes, eggs, maize, rice, and milk enhance N2O emissions, while CO2 emissions are caused by apple, potato, and apricot crops (Kendall’s τ values of 0.22, 0.18, and 0.16, respectively). Finally, based on the findings, policy implications are offered.

Genetic analyses unravel the causal association of cytokine levels on lichen simplex chronicus risk: insights from a mendelian randomization study.

Lichen simplex chronicus (LSC) presents a challenge in dermatology due to its elusive pathogenic mechanisms. While associations between circulating inflammatory cytokines and LSC were observed, the definitive causal dynamics remain to be elucidated. Our study used a two-sample Mendelian randomization (MR) approach to investigate causal relationships. We applied a suite of MR methodologies, including IVW, Weighted Median, MR-Egger, Weighted Mode, Simple Mode, MR-PRESSO, and the Steiger test, to ensure robust causal inference. Our analysis confirmed the causal impact of genetically determined cytokine levels on LSC risk, particularly MMP-10 (OR = 0.493, P = 0.004) and DNER (OR = 0.651, P = 0.043) in risk attenuation. We also found a positive causal correlation between GDNF levels (OR = 1.871, P = 0.007) and LSC prevalence. Notably, bidirectional causality was observed between DNER and LSC. Consistency across various MR analyses and sensitivity analyses confirmed the absence of horizontal pleiotropy, validating the causal estimates. This pioneering MR investigation unveils a novel genetically anchored causal relationship between the circulating levels of MMP-10, DNER, and GDNF and LSC risk. Although further validation is requisite, our findings augment the understanding of cytokine mediation in LSC and underscore prospective avenues for research.

Causal relationship between gut microbiota and intracranial hemorrhage: A two-sample Mendelian randomization study.

Patients with intracranial hemorrhage (ICH) usually have an imbalance in the gut microbiota (GM); however, whether this is a causal correlation remains unclear. This study used summary data from an open genome-wide association study to conduct double-sample Mendelian randomization (MR) to test the causal correlation between GM and ICH. First, we used a cutoff value of P < 10E-5 to select single nucleotide polymorphisms critical for each GM. Inverse variance weighted, weighted median, and MR-PRESSO methods were used to evaluate the strength of this causal association. Finally, functional maps and annotations from genome-wide association studies were used to determine the biological functions of the genes. MR analysis revealed that Rikenellaceae RC9 gut group was significantly positively correlated with ICH risk. For every unit increase in Rikenellaceae RC9 gut group, the relative risk of ICH increased by 34.4%(P = 4.62E-04). Rhodospirillales, Terrisporobacter, Veillonellaceae, Coprococcus 3, unknown genus, Alphaproteobacteria, and Allisonella groups were negatively correlated with the risk of ICH, while Anaerofilum, Eubacteriumbrachy group, Clostridia, Howardella, and Romboutsia were negatively correlated with the risk of ICH. Nonetheless, the specific role of single nucleotide polymorphisms gene enrichment requires further investigation. This study suggests the causal effect on ICH. The discovery of >10 GMs associated with ICH could be used to prevent and treat ICH.

Cholecystitis may decrease the risk of sudden death: A 2-sample Mendelian randomization study.

Some observational studies have highlighted a significant association between cholecystitis and factors leading to sudden death; however, the specific relationship between the 2 has not been fully elucidated. The primary objective of this study was to elucidate the causal interplay between cholecystitis and augmented risk of sudden cardiac death. We used large-scale genetic summary data from genome-wide association study, genetic summary statistics were sourced from 3 eminent repositories: the UK Biobank (N = 463,010), the FinnGen consortium (N = 215,027), and the European Bioinformatics Institute (N = 471,251). By employing 2-sample Mendelian randomization (MR) to decipher the causal interplay between cholecystitis and sudden death etiologies, a meta-analytical approach was employed to amalgamate the findings derived from these disparate data sources. The primary MR methodologies used included inverse variance weighting with random effects, inverse variance weighting with fixed effects, maximum likelihood, MR-Egger, and weighted median. Subsequently, we performed heterogeneity testing, polyvalency examination, and sensitivity analysis to bolster the robustness of causal relationship assessments. Meta-analysis and amalgamating variegated data sources revealed a statistically significant inverse correlation between cholecystitis and ventricular arrhythmias (odds ratio, 0.896; 95% confidence interval: 0.826-0.971; P = .008). Similarly, an inverse association was observed between cholecystitis and aortic aneurysm (odds ratio, 0.899; 95% confidence interval: 0.851-0.951, P < .001). This study substantiates the absence of a direct causal link between cholecystitis and cerebrovascular accidents (P = .771), pulmonary embolism (P = .071), and acute myocardial infarction (P = .388). A direct causal correlation existed between cholecystitis and sudden death associated with ventricular arrhythmias and aortic aneurysms. The onset of cholecystitis may mitigate the risk of sudden death due to ventricular arrhythmias and aortic aneurysms.

Deciphering the brain-gut axis: elucidating the link between cerebral cortex structures and functional gastrointestinal disorders via integrated Mendelian randomization.

Observational studies have suggested associations between functional gastrointestinal disorders (FGIDs) and variations in the cerebral cortex. However, the causality of these relationships remains unclear, confounded by anxiety and depression. To clarify these causal relationships and explore the mediating roles of anxiety and depression, we applied univariate, multivariable, and mediation Mendelian randomization (MR) analyses. We utilized genome-wide association study (GWAS) summary data from the FinnGen database and the ENIGMA consortium, identifying genetic variants associated with irritable bowel syndrome (IBS), functional dyspepsia (FD), and cerebral cortex structures. Data on anxiety and depression came from FinnGen and a large meta-analysis. Utilizing a bidirectional univariate MR approach, we explored correlations between FD, IBS, and cortex variations. Then, independent effects were assessed through multivariable MR. A meta-analysis of these results, incorporating data from two cohorts, aimed to increase precision. We also explored the potential mediating roles of anxiety and depression. Our findings indicate a negative causal correlation between FD and the thickness of the rostral anterior cingulate cortex (rACC) across both global and regional adjustments (β = -0.142, 95% confidence interval (CI): -0.209 to-0.074, P.FDR = 0.004; β = -0.112, 95%CI: -0.163 to-0.006, P.FDR = 0.003) and a positive causal correlation with the globally adjusted thickness of the superior frontal gyrus (SFG) (β = 0.107, 95%CI: 0.062 to 0.153, P.FDR = 0.001). The causal correlation with the rACC persisted after multiple variable adjustments (β = -0.137, 95% CI: -0.187 to-0.087, P.FDR = 1.81 × 10-5; β = -0.109, 95%CI: -0.158 to-0.06, P.FDR = 0.002). A significant causal association was found between globally adjusted surface area of the caudal anterior cingulate cortex (cACC) and IBS (odds ratio = 1.267, 95%CI: 1.128 to 1.424, P.FDR = 0.02). The analysis showed that neither anxiety nor depression mediated the relationship between FGIDs and cerebral cortex structures. Our research provides significant MR evidence of a bidirectional causal relationship between FGIDs and the cerebral cortex structures. This evidence not only confirms the two-way communication along the brain-gut axis but also illuminates the underlying pathophysiology, paving the way for identifying potential therapeutic approaches.

Predictors of histologic remission in patients with biologic-naïve, moderate-to-severe ulcerative colitis treated with first-line biologic agents and small-molecule drugs: a single-center, retrospective cohort study.

The prevalence and incidence of ulcerative colitis (UC) in Korea is increasing. Each patient has a different disease course and treatment response. Recently, with the development of biologic agents, histological remission has become a treatment goal. In this study, we aimed to identify the predictors of histological remission after first-line biologic agent treatment in patients with biologic agent-naïve UC. We retrospectively analyzed the medical records of 92 patients who had been diagnosed with UC and treated with first-line biologic agent treatment at our center, between 2015 and 2022. The clinical characteristics, laboratory test results, and endoscopic and biopsy findings were analyzed. Histological remission was defined as the absence of cryptitis, crypt abscesses, and inflammatory cells on histology. Univariate and multivariate logistic regression analyses were performed to identify the predictors of histological remission after first-line treatment. Of the total 92 patients, 25 (27.2%) achieved histological remission. Each cohort had a varied body mass index (BMI) distribution, with a statistically significant overweight ratio, as defined by the Asian-Pacific BMI category of 23-25 kg/m2, of 48.0% in the histological remission cohort (P= 0.026). A causal correlation between the overweight category and histological remission was confirmed (odds ratio, 3.883; 95% confidence interval, 1.141-13.212; P= 0.030). We confirmed that the overweight category was a predictor of histological remission after first-line treatment with a biological agent. However, as BMI does not account for skeletal muscle mass, future studies are required to confirm the correlation between skeletal muscle mass and histological remission.

Relationship between immune cells and diabetic nephropathy: a Mendelian randomization study.

Although previous studies have suggested potential correlations between immunocytes and diabetic nephropathy (DN), the causal correlations between them remain unclarified. In this study, we employed Mendelian randomization (MR) to analyze the potential causative correlations between immune 731 cells and DN. We used the Genome-Wide Association Studies (GWAS) database to aggregate signatures of immune cells and DN from European and East Asian populations. Single-nucleotide polymorphisms (SNPs) were used as instrumental variables. MR analysis was conducted using Mendelian randomization-Egger (MR-Egger) regression and the random-effects inverse-variance weighted (IVW) method. A total of 3,571 SNPs were included as instrumental variables. The MR-Egger regression model indicated no genetic pleiotropy (P = 0.6284). The results of the IVW method indicated a statistically significant causal relationship between immune cell HLA-DR on CD14-CD16- (P = 0.029), CD45RA-CD28-CD8 + T cell% T cells (P = 0.0278), CD11c on myeloid dendritic cells (P = 0.0352), HLA-DR on CD14+ monocytes (P < 0.001), CD27 on CD24 + CD27 + B cells (P = 0.0334), CD27 on IgD + CD24 + B cells (P = 0.0137), CD4 on CD39 + CD4 + T cells (P = 0.0347), CD28 on CD39 + CD4 + T cells (P = 0.0414), CD39 on CD39 + CD4 + T cells (P = 0.0426), and DN. Additionally, there was no heterogeneity in SNPs related HLA-DR on CD14-CD16-cells and DN(I2 = 32%, Cochran's Q = 2.9476, P = 0.2291). Moreover, leave-one-out analysis showed a causal correlation between HLA-DR on CD14-CD16- cells and DN. Higher expression of immune cell HLA-DR on CD14-CD16- cells may indicate a lower risk of DN.

Effects of Murâbahah Financing And Mudharabah Towards Customer Welfare Case Study at Bank Syariah Indonesia Kcp Bsd South Tangerang

At this time there are not a few banks that carry out activities conventionally or based on sharia principles. Currently the development of the Islamic financial market (Financial Market Sharia) is rife in the world, especially in countries with a majority Muslim population. This was marked by the establishment of the Islamic Financial Market in Kuala Lumpur which was pioneered by Islamic countries. The progress of the Sharia Financial Market in Indonesia, especially in Islamic banking and insurance is quite significant, followed by the Islamic capital market and pawnshops. Many financing contracts are carried out in the practice of Islamic financial institutions, for example murabahah, mudharabah, ijarah, musyarakah and so on. In this research the authors focus on murabaha and mudharabah financing. The purpose of writing this thesis is to analyze the effect of murabahah and mudharabah financing on the welfare of customers of Bank Syariah Indonesia KCP BSD South Tangerang. This research includes quantitative descriptive analysis research. The design used in this study is a correlational analysis design (a problem to find a relationship between two phenomena) precisely causal correlation. Data collection uses research instruments, data analysis is quantitative/statistical. The primary data used in this study are 132 customers who received financing according to the criteria and the secondary data in this study is in the form of documents and archives at Bank Syariah Indonesia which contains reports on customer funds that carry out murabaha and mudharabah financing. The sampling technique in this study used purposive sampling, which is a method of determining respondents to be sampled based on certain criteria. Based on the results of data analysis with the help of the SPSS 26.0 program, research that has been conducted at Bank Syariah Indonesia KCP BSD Tangerang using linear regression analysis through SPSS program data processing shows that, (1) There is an effect of Murabahah financing on the welfare of customers of Bank Syariah Indonesia KCP BSD Tangerang. The statistical test results showed that Fcount = 27.898 at db 1 and 94 was 3.94 at the 5% level. Based on the explanation above, 27,898 &gt; 3.94 at the 5% level, so H0 is rejected, meaning that there is an influence of Murabahah financing on customer welfare of Mandiri Syariah Bank KCP Tangerang, (2) There is an influence of Mudharabah financing on the welfare of customers of Bank Syariah Indonesia KCP BSD Tangerang. The statistical test results showed that Fcount = 15.048 at db 1 and 34 was 4.13 at the 5% level.

The Emergence of Consciousness in a Physical Universe

Consciousness appears so mysterious and hard to formulate within physical sciences because the present day scientific thinking excludes an element of reality and a general mechanics of its processing from its consideration. The primary missing element is the reality of information in the physical universe as an intrinsic causal correlate of observable physical states. Moreover, there exists a general formalism of information processing that is universally applicable to the processing resulting from each physical interaction. As shown, the formalism further enables a general mechanism to construct arbitrary structured and abstract semantics or object description in modular hierarchy as well as a powerful mechanism of population coding to represent arbitrary precision and variation in object description resolving the combinatorial problem. Here, a semantic value, or simply semantics, is equivalent (\(\equiv\)) to the content of information of causal correlation, and treated as a value to enable its formal processing. The primary motive here is to lay down a formal account of information (semantic) processing that leads to bridging the conceptual gap between the objectively observable elements in nature and the subjective consciousness. It is shown that the qualities we associate with consciousness are causally correlated semantics of relation that a represented agency holds with other objects within a dynamically evolving semantic structure, where the state of the population of physical systems (neurons) correlating with the structure holds causal powers to effect appropriate behavior. Since the information (semantic value) arises from natural causal dependence, the correlation based consciousness forms an undeniable reality of existence. It is derived here how a semantic value equivalent to ‘a self as an observer of objects and controller of actions’ is constructed. If the semantic components of a conscious experience, such as the self, the objects of experience, and the relation of experience attributing the self as the owner or experiencer, causally correlate with a system’s state having causal influence in action, then it suffices to bridge the gap between the objective reality and the subjective consciousness. That is, the semantic value corresponding to the thoughts and senses is the reality of nature the semantics of self relates to as the owner. Moreover, the semantics of ‘self as an observer and controller of action’ is itself shown to form a part of observed objects giving rise to self awareness.

Genetic Prediction of Osteoporosis by Anti-Müllerian Hormone Levels and Reproductive Factors in Women: A Mendelian Randomization Study

Previous observational studies have suggested that anti-Müllerian hormone (AMH) and reproductive factors are linked to reduced bone mineral density (BMD) and an increased risk of osteoporosis (OP) in women. However, related studies are limited, and these traditional observational studies may be subject to residual confounders and reverse causation, while also lacking a more comprehensive observation of various reproductive factors. Univariate and multivariate two-sample Mendelian randomization analyses were conducted to determine the causal associations of AMH levels and six reproductive factors with BMD and OP, using the random-effects inverse-variance weighted method. Heterogeneity was assessed using Cochran’s Q-statistic, and sensitivity analyses were performed to identify causal correlations. Age at menarche (AAM) was negatively associated with total body BMD (TB-BMD) in females aged 45–60 and over 60 years, as well as with heel bone mineral density (eBMD). Conversely, age at natural menopause (ANM) was positively associated with TB-BMD in the same age ranges and with eBMD. ANM was only causally associated with self-reported OP and showed no significant correlation with definitively diagnosed OP. Neither AMH level nor other reproductive factors were significantly associated with a genetic predisposition to BMD at any age and OP. Later AAM and earlier ANM are significantly genetically causally associated with decreased BMD but not with OP. AMH levels, length of menstrual cycle, age at first birth, age at last birth, and number of live births, in terms of genetic backgrounds, are not causally related to BMD or OP.

Causal inference between pernicious anemia and cancers: a bidirectional two-sample mendelian randomization analysis

BackgroundObservational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly contradictory. The purpose of this study was to investigate the potential causal relationship between PA and cancers through bidirectional two-sample Mendelian randomized (MR) analysis.MethodsThe European sample FinnGen project provided the genetic summary data for PA and 20 site-specific cancers. This bidirectional two-sample MR design mainly used the inverse variance weighting (IVW) method to evaluate the causal relationship between PA and cancer risk. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests.ResultsOur study shows that there was a causal relationship between PA and gastric cancer, prostate cancer, testicular cancer and malignant melanoma of skin, and there was a reverse causal relationship between prostate cancer or gastric cancer and PA (P < 0.05). After Benjamini-Hochberg correction test, there was still a causal correlation between PA and gastric or prostate cancer (P’ < 0.05), while there was only an implied causal association between PA and testicular cancer and malignant melanoma of skin (P’> 0.05). There was still a reverse causal relationship between gastric cancer and PA (P‘< 0.05), while prostate cancer shows an implied reverse causal relationship(P’> 0.05). In addition, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy.ConclusionsPA may be genetically associated with testicular cancer, prostate cancer, gastric cancer, and malignant melanoma of skin.

Exploiting relation of video segments for temporal action detection

With the development of urban intelligence, intelligent identification of human activities has become imminent. Temporal Action Detection (TAD) is designed to identify real human social activities, which is a challenging task in video understanding. The current methods mainly use global features for boundary matching or predefine all possible proposals, while ignoring the interference of background and the causal relevance of the temporal action, resulting in the generation of more redundant proposals and the decline of detection accuracy. To fill this gap, we propose a novel Dilated Convolution Locate and Action Relevant Score model called DCAR. Specifically, DCAR includes a Dilated Location Network (DL-Net) and Action Relevance Calculation (ARC) block. For the DL-Net, we design a Boundary Feature Enhancement (BFE) block, which enhances the boundary feature of actions and fuses the similar features of different channels by pooling and channel squeeze to reduce the interference of the background. Meanwhile, we also design multiple dilated convolutional structures to aggregate long contextual information in time point/interval after boundary enhancement. For the ARC block, we use the hyperbolic space distance and cross attention to calculate the causal correlation of action proposals classification, which removes the misclassification of action proposals. We conduct extensive experiments on Thumos14 and ActivityNet-1.3, which shows our method significantly improves the performance and achieves state-of-the-art results. On Thumos14, at tIoU 0.3, 0.4 and 0.5, it achieves mAP of 63.2%, 57.0% and 48.5%, respectively; On ActivityNet-1.3 it reaches 9.42% at tIoU 0.95.

Overexpressed Trophoblast Glycoprotein Contributes to Preeclampsia Development by Inducing Abnormal Trophoblast Migration and Invasion Toward the Uterine Spiral Artery.

Preeclampsia is a significant pregnancy disorder with an unknown cause, mainly attributed to impaired spiral arterial remodeling. Using RNA sequencing, we identified key genes in placental tissues from healthy individuals and preeclampsia patients. Placenta and plasma samples from pregnant women were collected to detect the expression of TPBG (trophoblast glycoprotein). Pregnant rats were injected with TPBG-carrying adenovirus to detect preeclamptic features. HTR-8/SVneo cells transfected with a TPBG overexpression lentiviral vector were used in cell function experiments. The downstream molecular mechanisms of TPBG were explored using RNA sequencing and single-cell RNA sequencing data. TPBG expression was knocked down in the lipopolysaccharide-induced preeclampsia-like rat model to rescue the preeclampsia features. We also assessed TPBG's potential as an early preeclampsia predictor using clinical plasma samples. TPBG emerged as a crucial differentially expressed gene, expressed specifically in syncytiotrophoblasts and extravillous trophoblasts. Subsequently, we established a rat model with preeclampsia-like phenotypes by intravenously injecting TPBG-expressing adenoviruses, observing impaired spiral arterial remodeling, thus indicating a causal correlation between TPBG overexpression and preeclampsia. Studies with HTR-8/SVneo cells, chorionic villous explants, and transwell assays showed TPBG overexpression disrupts trophoblast/extravillous trophoblast migration/invasion and chemotaxis. Notably, TPBG knockdown alleviated the lipopolysaccharide-induced preeclampsia-like rat model. We enhanced preeclampsia risk prediction in early gestation by combining TPBG expression with established clinical predictors. These findings are the first to show that TPBG overexpression contributes to preeclampsia development by affecting uterine spiral artery remodeling. We propose TPBG levels in maternal blood as a predictor of preeclampsia risk. The proposed mechanism by which TPBG overexpression contributes to the occurrence of preeclampsia via its disruptive effect on trophoblast and extravillous trophoblast migration/invasion on uterine spiral artery remodeling, thereby increasing the risk of preeclampsia.

Enterprise violation risk deduction combining generative AI and event evolution graph

AbstractIn the current realms of scientific research and commercial applications, the risk inference of regulatory violations by publicly listed enterprises has attracted considerable attention. However, there are some problems in the existing research on the deduction and prediction of violation risk of listed enterprises, such as the lack of analysis of the causal logic association between violation events, the low interpretability and effectiveness of the deduction and the lack of training data. To solve these problems, we propose a framework for enterprise violation risk deduction based on generative AI and event evolution graphs. First, the generative AI technology was used to generate a new text summary of the lengthy and complex enterprise violation announcement to realize a concise overview of the violation matters. Second, by fine‐tuning the generative AI model, an event entity and causality extraction framework based on automated data augmentation are proposed, and the UIE (Unified Structure Generation for Universal Information Extraction) event entity extraction model is used to create the event entity extraction for listed enterprises ‘violations. Then, a causality extraction model CDDP‐GAT (Event Causality Extraction Based on Chinese Dictionary and Dependency Parsing of GAT) is proposed. This model aims to identify and analyse the causal links between corporate breaches, thereby deepening the understanding of the event logic. Then, the merger of similar events was realized, and the causal correlation weights between enterprise violation‐related events were evaluated. Finally, the listed enterprise's violation risk event evolution graph was constructed, and the enterprise violation risk deduction was carried out to form an expert system of financial violations. The deduction results show that the method can effectively reveal signs of enterprise violations and adverse consequences.

The possible causal relationship between COVID-19 and imaging markers of cerebral small vessel disease: a Mendelian randomization study

ABSTRACT Objectives Observational studies have suggested that SARS-CoV-2 infection may increase the burden of cerebral small vessel disease (CSVD). This study aims to explore the causal correlation between COVID-19 and the imaging markers of CSVD using Mendelian randomization (MR) methods. Methods Summary-level genome-wide association study (GWAS) statistics for COVID-19 susceptibility, hospitalization, and severity were utilized as proxies for exposure. Large-scale meta-analysis GWAS data on three neuroimaging markers of white matter hyperintensity, lacunar stroke, and brain microbleeds, were employed as outcomes. Our primary MR analysis employed the inverse variance weighted (IVW) approach, supplemented by MR-Egger, weighted median, and MR-PRESSO methods. We also conducted multivariable MR analysis to address confounding bias and validate the robustness of the established causal estimates. Comprehensive sensitivity analyses included Cochran’s Q test, Egger-intercept analysis, MR-PRESSO, and leave-one-out analysis. Results The MR analysis revealed a significant causal correlation between the severity of COVID-19 and an increased risk of lacunar stroke, as demonstrated by the IVW method (ORivw = 1.08, 95% CI: 1.03–1.16, pivw = 0.005, FDR = 0.047). Nevertheless, no causal correlations were observed between COVID-19 susceptibility or hospitalization and any CSVD imaging markers. The robustness and stability of these findings were further confirmed by multivariable MR analysis and comprehensive sensitivity analyses. Discussion This study provides compelling evidence of a potential causal effect of severe COVID-19 on the incidence of lacunar stroke, which may bring fresh insights into the understanding of the comorbidity between COVID-19 and CSVD.

Exploring causal correlations between inflammatory cytokines and Ménière's disease: a Mendelian randomization.

Previous studies have highlighted associations between certain inflammatory cytokines and Ménière's Disease (MD), such as interleukin (IL) -13 and IL-1β. This Mendelian randomization aims to comprehensively evaluate the causal relationships between 91 inflammatory cytokines and MD. A comprehensive two-sample Mendelian randomization (MR) analysis was conducted to determine the causal association between inflammatory cytokines and MD. Utilizing publicly accessible genetic datasets, we explored causal links between 91 inflammatory cytokines and MD risk. Comprehensive sensitivity analyses were employed to assess the robustness, heterogeneity, and presence of horizontal pleiotropy in our findings. Our findings indicate that MD causally influences the levels of two cytokine types: IL-10 (P=0.048, OR=0.945, 95%CI =0.894~1.000) and Neurotrophin-3 (P=0.045, OR=0954, 95%CI =0.910~0.999). Furthermore, three cytokines exhibited significant causal effects on MD: CD40L receptor (P=0.008, OR=0.865, 95%CI =0.777-0.963), Delta and Notch-like epidermal growth factor-related receptor (DNER) (P=0.010, OR=1.216, 95%CI =1.048-1.412), and STAM binding protein (P=0.044, OR=0.776, 95%CI =0.606-0.993). This study suggests that the CD40L receptor, DNER, and STAM binding protein could potentially serve as upstream determinants of MD. Furthermore, our results imply that when MD is regarded as the exposure variable in MR analysis, it may causally correlate with elevated levels of IL-10 and Neurotrophin-3. Using these cytokines for MD diagnosis or as potential therapeutic targets holds great clinical significance.

Unraveling the genetic basis of the causal association between inflammatory cytokines and osteonecrosis.

Previous studies have reported that the occurrence and development of osteonecrosis is closely associated with immune-inflammatory responses. Mendelian randomization was performed to further assess the causal correlation between 41 inflammatory cytokines and osteonecrosis. Two-sample Mendelian randomization utilized genetic variants for osteonecrosis from a large genome-wide association study (GWAS) with 606 cases and 209,575 controls of European ancestry. Another analysis included drug-induced osteonecrosis with 101 cases and 218,691 controls of European ancestry. Inflammatory cytokines were sourced from a GWAS abstract involving 8,293 healthy participants. The causal relationship between exposure and outcome was primarily explored using an inverse variance weighting approach. Multiple sensitivity analyses, including MR-Egger, weighted median, simple model, weighted model, and MR-PRESSO, were concurrently applied to bolster the final results. The results showed that bFGF, IL-2 and IL2-RA were clinically causally associated with the risk of osteonecrosis (OR=1.942, 95% CI=1.13-3.35, p=0.017; OR=0.688, 95% CI=0.50-0.94, p=0.021; OR=1.386, 95% CI=1.04-1.85, p = 0.026). there was a causal relationship between SCF and drug-related osteonecrosis (OR=3.356, 95% CI=1.09-10.30, p=0.034). This pioneering Mendelian randomization study is the first to explore the causal link between osteonecrosis and 41 inflammatory cytokines. It conclusively establishes a causal association between osteonecrosis and bFGF, IL-2, and IL-2RA. These findings offer valuable insights into osteonecrosis pathogenesis, paving the way for effective clinical management. The study suggests bFGF, IL-2, and IL-2RA as potential therapeutic targets for osteonecrosis treatment.

Causal relationship between gut microbiota and diabetic nephropathy: A bidirectional mendelian randomization study.

In this study, we summarized the key findings and potential implications of association studies investigating the relationship between gut microbiota composition and risks for Diabetic nephropathy (DN). We used Mendelian randomization (MR) analysis to explore the relationship between gut microbiota and DN using two different publicly available DN databases. The results were also summarized using five mainstream MR analysis methods. We controlled for various possible biases in the results. The results showed that specific bacterial genera were associated with increased or decreased risk of DN. These associations can be attributed to a variety of factors, including metabolites produced by certain bacteria. Most of our findings are consistent with the existing research findings, but there are still some differences with the existing results. In addition, we also pointed out that some microbiota that may be associated with DN but remain unnoticed can bring new research directions. Our work made use of MR, a reliable technique for examining causal correlations using genetic data investigating potential processes, carrying out longitudinal studies, looking into intervention options, and using a multi-omics approach may be future research avenues. Further, our findings also point to a few unexplored possible study paths for DN in the future. These initiatives may improve our reconciliation of the internal relationships between the gut microbiota and DN and pave the way for more precise prevention and treatment methods. However, it is also critical to recognize any potential restrictions, such as those caused by sample size, population variety, and analytical techniques.