Miopatías RYR1 en la infancia: correlación fenotipo-genotipo e incidencia / RYR1 myopathies in childhood: phenotype-genotype correlation and incidence

Introducción: Las miopatías relacionadas con el receptor de rianodina de tipo 1 (RYR1-RM) constituyen la categoría más frecuente de miopatías congénitas. La introducción de técnicas genéticas ha cambiado el paradigma diagnóstico y sugiere la prioridad de estudios moleculares sobre biopsias. Este estudio busca explorar las características clinicoepidemiológicas de pacientes con variantes del gen RYR1 en un hospital pediátrico de tercer nivel con el objetivo de ampliar la comprensión de la correlación genotipo-fenotipo en las RYR1-RM. Pacientes y métodos: Estudio observacional, descriptivo y transversal, de pacientes menores de 14 años con síntomas miopáticos y variantes potencialmente patógenas del gen RYR1 entre enero de 2013 y diciembre de 2023, considerando variables como sexo, edad, desarrollo motor, variantes genéticas, patrón de herencia y otras manifestaciones. Todas las variables fueron tabuladas frente a la variante genética. Resultados: De los nueve pacientes incluidos, la incidencia estimada fue de aproximadamente 1/10.000 nacidos vivos. La mediana en el momento del diagnóstico fue de 6 años, con una variabilidad fenotípica significativa. Se observaron síntomas comunes, como debilidad y retraso del desarrollo motor. Las variantes genéticas afectaron al gen RYR1 de manera diversa, y hubo cinco variantes previamente no descritas. La biopsia muscular se realizó en cinco pacientes, en dos de ellos de tipo miopatía central core; en uno, multiminicore; en uno, desproporción congénita de fibras; y en otro, de patrón inespecífico. Conclusiones: Las RYR1-MR de nuestra serie ofrecieron variabilidad fenotípica y de afectación, con una incidencia en nuestra área de en torno a 1/10.000 recién nacidos. La mayoría de los casos fueron varones, de variantes missense dominantes. Aportamos cinco variantes genéticas no descritas con anterioridad.(AU)

Introduction: Ryanodine receptor type 1-related myopathies (RYR1-RM) represent the most prevalent category of congenital myopathies. The introduction of genetic techniques has shifted the diagnostic paradigm, suggesting the prioritization of molecular studies over biopsies. This study aims to explore the clinical and epidemiological characteristics of patients with RYR1 gene variants in a tertiary pediatric hospital, intending to enhance the understanding of the genotype-phenotype correlation in RYR1-RM. Patients and methods: An observational, descriptive, and cross-sectional study was conducted on patients under 14 years old with myopathic symptoms and potentially pathogenic RYR1 gene variants from January 2013 to December 2023. Variables such as gender, age, motor development, genetic variants, inheritance pattern, and other manifestations were considered. All variables were tabulated against the genetic variant. Results: Of the nine included patients, the estimated incidence was approximately 1 in 10,000 live births. The median age at diagnosis was six years, with significant phenotypic variability. Common symptoms such as weakness and delayed motor development were observed. Genetic variants affected the RYR1 gene diversely, including five previously undescribed variants. Muscle biopsy was performed in five patients, revealing central core myopathy in two, multiminicore in one, congenital fiber-type disproportion in one, and a nonspecific pattern in another.(AU)

Genome-wide analysis to uncover how Pocillopora acuta survives the challenging intertidal environment.

Characterisation of genomic variation among corals can help uncover variants underlying trait differences and contribute towards genotype prioritisation in coastal restoration projects. For example, there is growing interest in identifying resilient genotypes for transplantation, and to better understand the genetic processes that allow some individuals to survive in specific conditions better than others. The coral species Pocillopora acuta is known to survive in a wide range of habitats, from reefs artificial coastal defences, suggesting its potential use as a starter species for ecological engineering efforts involving coral transplantation onto intertidal seawalls. However, the intertidal section of coastal armour is a challenging environment for corals, with conditions during periods of emersion being particularly stressful. Here, we scanned the entire genome of P. acuta corals to identify the regions harbouring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) that separate intertidal colonies (n = 18) from those found in subtidal areas (n = 21). Findings revealed 74,391 high quality SNPs distributed across 386 regions of the P. acuta genome. While the majority of the detected SNPs were in non-coding regions, 12% were identified in exons (i.e. coding regions). Functional SNPs that were significantly associated with intertidal colonies were found in overrepresented genomic regions linked to cellular homeostasis, metabolism, and signalling processes, which may represent local environmental adaptation in the intertidal. Interestingly, regions that exhibited CNVs were also associated with metabolic and signalling processes, suggesting P. acuta corals living in the intertidal have a high capacity to perform biological functions critical for survival in extreme environments.

Exploring the Enigmatic Link: Unraveling the Relationship Between Obesity and Cigarette Smoking Among Diverse College Students at Imam Mohammed Ibn Saud Islamic University in Riyadh, Saudi Arabia.

BACKGROUND: Obesity is defined as an excess of body fat. This medical condition frequently results in a high BMI and an increased risk of a variety of health problems, including diabetes, cardiovascular disease, and certain types of cancer. Cigarette smoking includes inhaling smoke created by the combustion of tobacco. It is linked to a variety of health issues, including lung cancer, heart disease, and respiratory ailments, and is a primary cause of preventable disease and premature death worldwide. The association between obesity and cigarette smoking is complex and incompletely understood. This study aims to investigate the intriguing association between obesity and cigarette smoking among diverse college students at Imam Mohammed Ibn Saud Islamic University in Riyadh, Saudi Arabia. METHODOLOGY: The study was conducted as an observational study, specifically an analytical cross-sectional study, to measure the prevalence of cigarette smoking and obesity and their association. This type of study is chosen because of its advantages including targeting a large sample in a short time and inexpensive way, with no loss to follow-up, unlike some other study designs. RESULTS: In this study, we were able to collect data from 603 participants, of which 57.4% were male and 67.8% of them aged between 20 and 24 years old. Moreover, we found that 39.6% had normal weight; however, the prevalence of obesity, overweight, and underweight were 24%, 28.1%, and 8.3%, respectively. Considering the prevalence of smoking, we found that 22.6% of the participants reported being current smokers, while 5.3% were former smokers. There is a significant difference between participants with different BMIs (P=0.001). The prevalence of smoking was significantly higher in obese and overweighted participants (35.1% and 31.3%, respectively) compared with 28.4% in normal-weighted participants. CONCLUSION: The prevalence of smoking and obesity in this study was significantly higher than reported in different studies. Moreover, we found a significant relationship between smoking and obesity; however, further investigation should be conducted to determine the cause of this relationship.

Illuminating the landscape of high-level clinical trial opportunities in the All of Us Research Program.

OBJECTIVE: With its size and diversity, the All of Us Research Program has the potential to power and improve representation in clinical trials through ancillary studies like Nutrition for Precision Health. We sought to characterize high-level trial opportunities for the diverse participants and sponsors of future trial investment. MATERIALS AND METHODS: We matched All of Us participants with available trials on ClinicalTrials.gov based on medical conditions, age, sex, and geographic location. Based on the number of matched trials, we (1) developed the Trial Opportunities Compass (TOC) to help sponsors assess trial investment portfolios, (2) characterized the landscape of trial opportunities in a phenome-wide association study (PheWAS), and (3) assessed the relationship between trial opportunities and social determinants of health (SDoH) to identify potential barriers to trial participation. RESULTS: Our study included 181 529 All of Us participants and 18 634 trials. The TOC identified opportunities for portfolio investment and gaps in currently available trials across federal, industrial, and academic sponsors. PheWAS results revealed an emphasis on mental disorder-related trials, with anxiety disorder having the highest adjusted increase in the number of matched trials (59% [95% CI, 57-62]; P < 1e-300). Participants from certain communities underrepresented in biomedical research, including self-reported racial and ethnic minorities, had more matched trials after adjusting for other factors. Living in a nonmetropolitan area was associated with up to 13.1 times fewer matched trials. DISCUSSION AND CONCLUSION: All of Us data are a valuable resource for identifying trial opportunities to inform trial portfolio planning. Characterizing these opportunities with consideration for SDoH can provide guidance on prioritizing the most pressing barriers to trial participation.

[Clinical acute and emergency medicine curriculum-focus on internal medicine : Recommendations for advanced training in internal medicine in the emergency department]. / Curriculum Klinische Akut- und Notfallmedizin ­ Schwerpunkt Innere Medizin : Empfehlung zu Weiterbildungsinhalten der Inneren Medizin in der Notaufnahme.

In Germany, physicians qualify for emergency medicine by combining a specialty medical training-e.g. internal medicine-with advanced training in emergency medicine according to the statutes of the State Chambers of Physicians largely based upon the Guideline Regulations on Specialty Training of the German Medical Association. Internal medicine and their associated subspecialities represent an important column of emergency medicine. For the internal medicine aspects of emergency medicine, this curriculum presents an overview of knowledge, skills (competence levels I-III) as well as behaviours and attitudes allowing for the best treatment of patients. These include general aspects (structure and process quality, primary diagnostics and therapy as well as indication for subsequent treatment; resuscitation room management; diagnostics and monitoring; general therapeutic measures; hygiene measures; and pharmacotherapy) and also specific aspects concerning angiology, endocrinology, diabetology and metabolism, gastroenterology, geriatric medicine, hematology and oncology, infectiology, cardiology, nephrology, palliative care, pneumology, rheumatology and toxicology. Publications focussing on contents of advanced training are quoted in order to support this concept. The curriculum has primarily been written for internists for their advanced emergency training, but it may generally show practising emergency physicians the broad spectrum of internal medicine diseases or comorbidities presented by patients attending the emergency department.

MGCNSS: miRNA-disease association prediction with multi-layer graph convolution and distance-based negative sample selection strategy.

Identifying disease-associated microRNAs (miRNAs) could help understand the deep mechanism of diseases, which promotes the development of new medicine. Recently, network-based approaches have been widely proposed for inferring the potential associations between miRNAs and diseases. However, these approaches ignore the importance of different relations in meta-paths when learning the embeddings of miRNAs and diseases. Besides, they pay little attention to screening out reliable negative samples which is crucial for improving the prediction accuracy. In this study, we propose a novel approach named MGCNSS with the multi-layer graph convolution and high-quality negative sample selection strategy. Specifically, MGCNSS first constructs a comprehensive heterogeneous network by integrating miRNA and disease similarity networks coupled with their known association relationships. Then, we employ the multi-layer graph convolution to automatically capture the meta-path relations with different lengths in the heterogeneous network and learn the discriminative representations of miRNAs and diseases. After that, MGCNSS establishes a highly reliable negative sample set from the unlabeled sample set with the negative distance-based sample selection strategy. Finally, we train MGCNSS under an unsupervised learning manner and predict the potential associations between miRNAs and diseases. The experimental results fully demonstrate that MGCNSS outperforms all baseline methods on both balanced and imbalanced datasets. More importantly, we conduct case studies on colon neoplasms and esophageal neoplasms, further confirming the ability of MGCNSS to detect potential candidate miRNAs. The source code is publicly available on GitHub https://github.com/15136943622/MGCNSS/tree/master.

Causal relationship between gut microbiota and gastric cancer: A two­sample Mendelian randomization analysis.

The gut microbiota is associated with GC; however, the causal association between the gut microbiota and GC remains to be determined. The aim of the present study was to investigate the causal association between gut microbiota and gastric cancer (GC) from the perspective of Mendelian randomization (MR). The present study performed MR analysis using summary statistics from a genome-wide association study of the gut microbiome and GC. Inverse-variance weighted, MR-Egger and weighted median methods were used to investigate the causal relationship between gut microbiota and GC. Heterogeneity tests were performed using Cochrane's Q statistic. Horizontal polytropy was detected using Mendelian Randomization Pleiotropy RESidual Sum and Outlier were eliminated. Estimates from MR indicated that nine gut microorganism remained stable with regard to acceptance of heterogeneity and sensitivity methods. Among them, the genera Prevotella 7, Roseburia and Ruminococcaceae UCG014 were associated with an increased risk of GC; by contrast, the family Enterobacteriaceae, the genera Allisonella, Lachnospiraceae FCS020, Ruminococcaceae UCG004 and Ruminococcaceae UCG009, and the order Enterobacteriales decreased the risk of GC development. The present study demonstrated the potential importance of modulating the abundance of gut microbiota for the prevention and treatment of GC.

Integrated analysis of transcriptional changes in major depressive disorder: Insights from blood and anterior cingulate cortex.

Background: Major depressive disorder (MDD) was involved in widely transcriptional changes in central and peripheral tissues. While, previous studies focused on single tissues, making it difficult to represent systemic molecular changes throughout the body. Thus, there is an urgent need to explore the central and peripheral biomarkers with intrinsic correlation. Methods: We systematically retrieved gene expression profiles of blood and anterior cingulate cortex (ACC). 3 blood datatsets (84 MDD and 88 controls) and 6 ACC datasets (100 MDD and 100 controls) were obtained. Differential expression analysis, RobustRankAggreg (RRA) analysis, functional enrichment analysis, immune associated analysis and protein-protein interaction networks (PPI) were integrated. Furthermore, the key genes were validated in an independent ACC dataset (12 MDD and 15 controls) and a cohort with 120 MDD and 117 controls. Results: Differential expression analysis identified 2211 and 2021 differential expressed genes (DEGs) in blood and ACC, respectively. RRA identified 45 and 25 robust DEGs in blood and ACC based on DEGs, and all of them were closely associated with immune cells. Functional enrichment results showed both the robust DEGs in blood and ACC were enriched in humoral immune response. Furthermore, PPI identified 8 hub DEGs (CD79A, CD79B, CD19, MS4A1, PLP1, CLDN11, MOG, MAG) in blood and ACC. Independent ACC dataset showed the area under the curve (AUC) based on these hub DEGs was 0.77. Meanwhile, these hub DEGs were validated in the serum of MDD patients, and also showed a promising diagnostic power. Conclusions: The biomarker panel based on hub DEGs yield a promising diagnostic efficacy, and all of these hub DEGs were strongly correlated with immunity. Humoral immune response may be the key link between the brain and blood in MDD, and our results may provide further understanding for MDD.

Association between gut microbiota and gastric cancers: a two-sample Mendelian randomization study.

Background: Gastric cancer (GC) is the fifth most commonly diagnosed cancer worldwide, with its etiology attributed to a complex interplay of genetic, dietary, environmental factors, and infections such as Helicobacter pylori. Despite the known risk factors, the role of gut microbiota in the development of gastric cancer remains insufficiently explored. This study aims to elucidate the causal relationship between gut microbiota and gastric cancer using a two-sample Mendelian Randomization (MR) approach. Methods: Utilizing genome-wide association study (GWAS) summary data from the MiBioGen consortium and gastric cancer datasets, we selected instrumental variables for MR analysis based on their association with specific microbiota. We employed several MR methods, including inverse variance weighted (IVW), MR-Egger, weighted median, and others, to estimate the causal effects of gut microbiota diversity on the risk of developing gastric cancer. Results: Our analysis identified significant associations between certain gut microbiota and gastric cancer risk. Specifically, taxa such as Clostridium sensustricto1 (OR = 0.540, 95%CI: 0.354-0.823, p = 0.004), Actinomycetales (OR = 0.756, 95%CI: 0.613-0.932, p = 0.009), Selenomonadales (OR = 0.816, 95%CI: 0.666-1.000, p < 0.05), Negativicutes (OR = 0.816, 95%CI: 0.666-1.000, p < 0.05), Rikenellaceae (OR = 0.863, 95%CI: 0.746-0.999, p = 0.048) were found to have a protective effect against gastric cancer. Conversely, an increased risk of gastric cancer was associated with the abundance of Roseburia (OR = 1.342, 95%CI: 1.071-1.681, p = 0.011), Family XI (OR = 1.132, 95%CI: 1.012-1.267, p = 0.030), and Eubacterium brachy group (OR = 1.207, 95%CI: 1.074-1.355, p = 0.002). The findings were robust across various MR methods and were not driven by any single SNP, indicating a genuine causal relationship. Conclusion: Our studies have shown that there is a causal relationship between intestinal flora and gastric cancer at the genetic level. Clostridium sensustricto1, Actinomycetales, Rikenellaceae, Selenomonadales, Negativicutes, and Actinomycetaceae as having a protective role against GC, while Roseburia, Family XI, and Eubacterium brachy group were associated with an increased risk.

Causal relationship between chronic obstructive pulmonary disease and heart failure: A Mendelian randomization study.

BACKGROUND: Causal association between chronic obstructive pulmonary disease (COPD) and heart failure (HF) has been controversial. This study used Mendelian Randomization (MR) analysis to clarify the potential causal connection between these two conditions. OBJECTIVES: The purpose of the study was to investigate the causal relationship between COPD and HF based on the hypothesis that the genetic predisposition to COPD could lead to an increased risk of developing HF METHODS: A two-sample MR analysis of genetic data was performed for COPD and HF. This study was based on genome-wide association study (GWAS) data, including 6,915 patients with confirmed COPD and 186,723 controls. The odds ratios (ORs) and their 95 % confidence intervals (95 %CIs) were estimated using a fixed effects inverse variance weighting (IVW) method. Several supplementary statistical methods, including MR-Egger, weighted median, maximum likelihood, penalized weighted median, and random effects IVW, were applied to enhance the robustness of findings. Moreover, MR-PRESSO was employed as an alternative method for statistical detection. RESULTS: Pooled data for HF were obtained from different GWASs, including 4,7309 confirmed HF patients and 930,014 controls. The MR analysis, based on the IVW model, revealed that COPD was significantly associated with an increased risk of HF. Specifically, the obtained findings showed that COPD patients had a higher risk of developing HF (Model 1: OR = 1.068, 95 %CI: 1.006-1.134, p = 0.031; Model 2: OR = 1.038, 95 %CI: 1.006-1.071, p = 0.020), indicating a causal relationship between COPD and HF. No evidence was found to suggest a reverse causal effect of HF on COPD incidence. CONCLUSION: The MR analysis substantiates a causal link between COPD and HF, with no evidence supporting a reverse causation from HF to COPD. These findings underscore the importance of proactive COPD management as a potential strategy to prevent the development of HF, highlighting the need for targeted interventions in patients with COPD to mitigate their risk of HF.

A cross-disease, pleiotropy-driven approach for therapeutic target prioritization and evaluation.

Cross-disease genome-wide association studies (GWASs) unveil pleiotropic loci, mostly situated within the non-coding genome, each of which exerts pleiotropic effects across multiple diseases. However, the challenge "W-H-W" (namely, whether, how, and in which specific diseases pleiotropy can inform clinical therapeutics) calls for effective and integrative approaches and tools. We here introduce a pleiotropy-driven approach specifically designed for therapeutic target prioritization and evaluation from cross-disease GWAS summary data, with its validity demonstrated through applications to two systems of disorders (neuropsychiatric and inflammatory). We illustrate its improved performance in recovering clinical proof-of-concept therapeutic targets. Importantly, it identifies specific diseases where pleiotropy informs clinical therapeutics. Furthermore, we illustrate its versatility in accomplishing advanced tasks, including pathway crosstalk identification and downstream crosstalk-based analyses. To conclude, our integrated solution helps bridge the gap between pleiotropy studies and therapeutics discovery.

Genetic Association of Toll-Like Receptor 4 (TLR4) Gene Polymorphism (rs4986790) With Oral Squamous Cell Carcinoma (OSCC): A Pilot Case-Control Study.

Introduction Oral squamous cell carcinoma (OSCC) is a highly prevalent and most common form of oral malignancy in the Indian population. Toll-like receptors belong to an important family of receptors that are involved in the process of pathogen recognition and mounting immune response. The expression of this receptor is dysregulated on the tumor cells as reported across several cancer types. The genetic variants in this gene could have a profound impact on the expression of the Toll-like receptor 4 (TLR4) gene.  Objective This study aimed to understand the association of TLR4 gene polymorphism (rs4986790) with OSCC. The objective of this study was to compare the allele and genotype frequencies between the two groups, viz., OSCC and normal healthy subjects, recruited in the study. Materials and methods The blood samples were collected from normal healthy subjects (N = 25) and OSCC patients (N = 25). Genomic DNA was isolated from all samples, and genotyping was performed for the TLR4 gene polymorphism (rs4986790) employing the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. The frequency distribution of genotypes and alleles across the study groups was determined by the Chi-square test.  Results The allele frequency for TLR4 gene polymorphism (rs4986790) in the case group was found to be 60% (A allele) and 40% (G allele), respectively. The study population in both groups were found to agree with the Hardy-Weinberg equilibrium (HWE). The genotype frequency did not differ significantly among the two study groups which was evident from the p-value = 0.8285.  Conclusion The present study did not report any significant association of the TLR4 polymorphic marker rs4986790 with OSCC. Further investigations into the association of other polymorphic markers in the TLR4 gene, among the larger population of OSCC patients, could provide evidence of their association with OSCC.

The potential up-regulation risk of 3' UTR SNP (rs10787760 G > A) for the VAX1 gene is associated with NSCLP in the northwest Chinese population.

AIMS: To investigate the association between single nucleotide polymorphisms (SNPs) in 3'UTR region of VAX1, SYT14 and PAX7 genes and the risk of non-syndromic cleft palate (NSCLP) in a northwest Chinese population. MAIN METHODS: A case-control study was conducted in 406 normal controls and 399 NSCLP patients. Using iMLDRTM genotyping technology, eight SNPs of three genes ((rs10787760, rs7086344 at VAX1), (rs1010113, rs851114, and rs485874 at PAX7), and (rs61820397, rs4609425, rs12133399 at SYT14)) were genotyped to investigate the differences in alleles and genotype distribution frequencies between NSCLP patients and healthy controls. RNA Folding Form software was used to predict RNA secondary structure and expression vectors were constructed to explore the function of the relevant SNP. The effect of SNP polymorphism of gene transcription and translation was assessed using qPCR and Western blot analysis. KEY FINDINGS: Among the eight SNPs of three genes, rs10787760 of VAX1 gene was found to be associated with an increased risk of NSCLP (OR = 1.341,CI = 1.004-1.790) and the GA genotype of rs10787760 increased the risk of cleft lip and/or palate (CL/P) about 1.42 times (p < 0.05), and carrying the A allele might increase the risk of NSCL/P in male (OR = 1.356, 95 % CI = 1.010-1.823). But there was no association observed with cleft palate only (CPO). Cell function experiments revealed that the G to A mutation in rs10787760 up-regulated GFP-VAX1 transcriptional level by 2.39 and 3.13 times in two cell lines respectively, and enhance the protein expression of the VAX1 gene further. RNA secondary structure study showed that the rs10787760 (G > A) had two different secondary structures in 3'UTR region. SIGNIFICANCE: The rs10787760 variant in the 3'UTR region of VAX1 gene is associated with CL/P in northwest Chinese population. We hypothesize that the machanism of it might be caused by the RNA differenct fold in the 3'UTR region caused by the polymorphism of the gene. LEVEL OF EVIDENCE: Original Reports.

The Exercise Intensity-Music-Tempo Preference Relationship: A Decennial Revisit.

Tempo is a key determinant of the motivational effects of music during exercise and has been the focus of numerous empirical studies (e.g., Karageorghis & Jones, 2014). The present study sought to address the limitations of previous related work and revisit the relationship between exercise intensity and music-tempo preference using unfamiliar, non-lyrical music (to isolate the tempo manipulation). A within-within experimental design was employed to test hypotheses pertaining to the non-linear relationship and associated psychological outcomes (e.g., core affect and state attention). Twenty-four participants (Mage = 20.6 years, SD = .92 years) exercised at five intensities (10% of peak VO2 below ventilatory threshold [VT]; 5% of peak VO2 below VT, at VT, midway between VT and the respiratory compensation point [RCP], and at RCP) during which they were administered music tracks at four tempi (90 bpm, 110 bpm, 130 bpm and 150 bpm) and a no-music control. A music liking item, measures of core affect (valence and arousal), attentional focus and perceived exertion were recorded during the exercise bouts. Results indicated that unlike previous findings with familiar, lyrical music, there was no discernible relationship between exercise intensity and preference for music tempo. The most positive psychological outcomes were associated with fast-tempo music. In accord with previous findings, slow-tempo music attracted low liking scores and the least desirable psychological outcomes at every exercise intensity. The present findings have implications for the use of unfamiliar, non-lyrical music during exercise. Specifically, that such music should be ∼10 bpm faster than familiar, lyrical music.

Genome-wide association study identifies DRAM1 associated with Tourette syndrome in Taiwan.

BACKGROUND: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Several susceptibility loci associated with TS have been identified previously in populations of European descent using genome-wide association studies (GWAS). However, the exact pathogenic mechanism underlying TS is unknown; additionally, the results of previous GWAS for TS were based on Western populations, which may not translate to other populations. Therefore, we conducted a GWAS in Taiwanese patients with TS and chronic tic disorders (CTDs), with an aim to elucidate the genetic basis and potential risk factors for TS in this population. METHODS: GWAS was performed on a Taiwanese TS/CTDs cohort with a sample size of 1,007 patients with TS and 25,522 ancestry-matched controls. Additionally, polygenic risk score was calculated and assessed. RESULTS: Genome-wide significant locus, rs12313062 (p=1.43 × 10-8) and other 9 single nucleotide polymorphisms, were identified in chromosomes 12q23.2, associated with DRAM1 and was a novel susceptibility locus identified in TS/CTDs group. DRAM1, a lysosomal transmembrane protein regulated by p53, modulates autophagy and apoptosis, with potential implications for neuropsychiatric conditions associated with autophagy disruption. CONCLUSIONS: This study conducted the first GWAS for TS in a Taiwanese population, identifying a significant locus on chromosome 12q23.2 associated with DRAM1. These findings provide novel insights into the neurobiology of TS and potential directions for future research in this area.

Matrix metalloproteinase and aortic aneurysm: a two-sample Mendelian randomization study.

BACKGROUND: Studies have linked matrix metalloproteinases (MMPs) to both abdominal and thoracic aortic aneurysms (TAA and AAA). The precise MMPs entailed in this procedure, however, were still unknown. This study used a two-sample Mendelian randomization (MR) analysis to look into the causal relationship between MMPs and the risk of AA. MMP and aortic aneurysm METHODS: Eight MMPs, including MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, MMP-12, and MMP-13, were found among people of European ancestry with accessible genome-wide association studies (GWAS). We employed the findings from genome-wide association studies (GWAS) for eight MMPs, and TAA and AAA from the FinnGen consortiums (3,201 cases and 317,899 controls, respectively) were used in a two-sample MR analysis. The primary method of analysis for MR was the inverse variance weighted method (IVW), along with analyses of heterogeneity and horizontal pleiotropy. 31 SNPs connected to MMP were retrieved. RESULTS: IVW demonstrated a negative causal association between TAA and AAA and serum MMP-12 levels. The incidence of TAA decreased by 1.031% for every 1ng/mL increase in serum MMP-12 [odds ratio OR=0.897, 95% confidence interval (CI): 0.831-0.968, P=0.005]. The incidence of AAA fell by 1.653% (OR=0.835, 95% CI: 0.752-0.926, P =0.001) for every 1ng/mL increase in serum MMP-12. There was no horizontal pleiotropy or heterogeneity in the MR data (P > 0.05). CONCLUSION: The levels of TAA and AAA and serum MMP-12 are causally related. MMP-12 is a factor that reduces the risk of AAA and TTA. Our study suggested that MMP-12 level is causally associated with a decreased risk of TAA and AAA.

Examination of the shared genetic architecture between multiple sclerosis and systemic lupus erythematosus facilitates discovery of novel lupus risk loci.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease with heterogeneous manifestations, including neurological and psychiatric symptoms. Genetic association studies in SLE have been hampered by insufficient sample size and limited power compared to many other diseases. Multiple Sclerosis (MS) is a chronic relapsing autoimmune disease of the central nervous system (CNS) that also manifests neurological and immunological features. Here, we identify a method of leveraging large-scale genome wide association studies (GWAS) in MS to identify novel genetic risk loci in SLE. Statistical genetic comparison methods including linkage disequilibrium score regression (LDSC) and cross-phenotype association analysis (CPASSOC) to identify genetic overlap in disease pathophysiology, traditional 2-sample and novel PPI-based mendelian randomization to identify causal associations and Bayesian colocalization were applied to association studies conducted in MS to facilitate discovery in the smaller, more limited datasets available for SLE. Pathway analysis using SNP-to-gene mapping identified biological networks composed of molecular pathways with causal implications for CNS disease in SLE specifically, as well as pathways likely causal of both pathologies, providing key insights for therapeutic selection.

Association Between the Improvement of Knowledge, Attitude and Practice of Hypertension Prevention and Blood Pressure Control-A Cluster Randomized Controlled Study.

BACKGROUND: Hypertension-related knowledge, attitude and practice (KAP) of hypertensive patients can affect the awareness, treatment and control of hypertension. However, little attention has been paid to the association between the change of hypertension preventive KAP and blood pressure (BP) control in occupational population using longitudinal data. We assess the effectiveness of a workplace-based multicomponent hypertension intervention program on improving the level of KAP of hypertension prevention, and the association between improvement in KAP and BP control during intervention. METHODS: From January 2013 to December 2014, workplaces across 20 urban regions in China were randomized to either the intervention group (n = 40) or control group (n = 20) using a cluster randomized control method. All employees in each workplace were asked to complete a cross-sectional survey to screen for hypertension patients. Hypertension patients in the intervention group were given a 2-year workplace-based multicomponent hypertension intervention for BP control. The level of hypertension prevention KAP and BP were assessed before and after intervention in the two groups. RESULTS: Overall, 3331 participants (2658 in the intervention group and 673 in the control group) were included (mean [standard deviation] age, 46.2 [7.7] years; 2723 men [81.7%]). After 2-year intervention, the KAP qualified rate was 63.2% in the intervention groups and 50.1% in the control groups (odds ratio = 1.65, 95% CI, 1.36∼2.00, P < .001). Compared with the control group decreased in the qualified rate of each item of hypertension preventive KAP questionnaire, all the items in the intervention group increased to different degrees. The increase of KAP score was associated with the decrease of BP level after intervention. For 1 point increase in KAP score, systolic blood pressure (SBP) decreased by .28 mmHg and diastolic blood pressure (DBP) decreased by .14 mmHg [SBP: ß = -.28, 95%CI: -.48∼-.09, P = .004; DBP: ß = -.14, 95%CI: -.26∼-.02, P = .024]. SBP and DBP was significantly in manual labor workers (SBP: ß = -.34, 95%CI: -.59∼-.09, P = .008; DBP: ß = -.23, 95%CI: -.38∼-.08, P = .003), workers from private enterprise, state-owned enterprise (SOE) (SBP: ß = -.40, 95%CI: -.64∼-.16, P = .001; DBP: ß = -.21, 95%CI: -.36∼-.06, P = .005) and a workplace with an affiliated hospital (SBP: ß = -.31, 95%CI: -.52∼-.11, P = .003; DBP: ß = -.16, 95%CI: -.28∼-.03, P = .016). The improvement of knowledge (SBP: ß = -.29, 95%CI: -.56∼-.02, P = .038; DBP: ß = -.12, 95%CI: -.29∼.05, P = .160), as well as attitude (SBP: ß = -.71, 95%CI: -1.25∼-.18, P = .009; DBP: ß = .18, 95%CI: -.23∼.59, P = .385) and behavior (SBP: ß = -.73, 95%CI: -1.22∼-.23, P = .004; DBP: ß = -.65, 95%CI: -.97∼-.33, P < .001) was gradually strengthened in relation to BP control. CONCLUSION: This study found that workplace-based multicomponent hypertension intervention can effectively improve the level of hypertension preventive KAP among employees, and the improvement of KAP levels were significantly associated with BP control. TRIAL REGISTRATION: Chinese Clinical Trial Registry No. ChiCTR-ECS-14004641.

Influence of emotions on the aggressive driving behavior of online -car-hailing drivers based on association rule mining.

Emotion is an important factor that can lead to the occurrence of aggressive driving. This paper proposes an association rule mining-based method for analysing contributing factors associated with aggressive driving behaviour among online car-hailing drivers. We collected drivers' emotion data in real time in a natural driving setting. The findings show that 29 of the top 50 association rules for aggressive driving are related to emotions, revealing a strong relationship between driver emotions and aggressive driving behaviour. The emotions of anger, surprised, happy and disgusted are frequently associated with aggressive driving behaviour. Negative emotions combined with other factors (for example, driving at high speeds and high acceleration rates and with no passengers in the vehicle) are more likely to lead to aggressive driving behaviour than negative emotions alone. The results of this study provide practical implications for the supervision and training of car-hailing drivers.

Based on the association rule mining method, we found a close connection between drivers' emotional states and the manifestation of aggressive driving behaviours. The findings indicate that the combination of negative emotions and various contributing factors significantly amplifies the likelihood of aggressive driving.