Genome-wide association study and meta-analysis of phytosterols identifies a novel locus for serum levels of campesterol.

Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of ß-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with ß-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.

Distinct Gene Expression and Immune Features Between Different Neutrophil Extracellular Trap-Related Osteosarcoma Subtypes.

We sought to determine neutrophil extracellular trap (NET)-related genes' potential value in improving the efficacy of diagnosis and identifying novel therapeutic targets for osteosarcoma. Data were obtained from TARGET, GEO, and CCLE database. Differentially expressed genes were identified between the subtypes based on NET-related genes. PPI network was constructed using STRING, following by ClueGO enrichment analysis. Infiltration of immune cells was calculated by ssGSEA. Risk Score model was built by LASSO Cox regression analysis. Western blot and qRT-PCR were applied to validate the expression of genes used in the model. We identified 19 NET-related genes with prognostic potential in osteosarcoma using univariate Cox regression analysis. Patients from TARGET were clustered into two subtypes with distinct prognosis and immune features. 381 DEGs were identified between the two NET subtypes. Risk Score based on BST1, SELPLG, FPR1 and TNFRSF10C was reliable to predict the prognosis of osteosarcoma patients. The four genes expressed significantly lower in osteosarcoma than normal cells. Low Risk Score individuals only existed in C1 subtype with better prognosis. Osteosarcoma were clustered into two subtypes based on NET-related genes. Risk Score model constructed by four NET-related gene was able to independently predict the prognosis of osteosarcoma.

Adoption of the PREVENT (Predicting Risk of Cardiovascular Disease EVENTs) Risk Algorithm: Potential International Implications.

Background: The PREVENT (Predicting Risk of cardiovascular disease EVENTs risk algorithm was developed to better reflect the impact of metabolic factors on cardiovascular risk. Objectives: The purpose of this study was to compare the relative performance of PREVENT with standard comparator algorithms (Framingham risk score, pooled cohort equation, SCORE2 [Systematic COronary Risk Evaluation2]) for risk stratification emphasizing the implications of weighing chronic kidney disease. Methods: A simulated cohort was created of males and females aged 40 to 75 years with and without other traditional risk factors and either normal estimated glomerular filtration rates (eGFR 90 or 60 ml/min/1.73 m2) or abnormal eGFR (45 or 30 ml/min/1.73 m2). The concordance and reclassification rates were calculated for each category of risk with emphasis on subjects characterized as moderate risk by the standard comparator algorithms. Results: PREVENT demonstrated increased risk with progressive decreases in eGFR. When the standard comparator algorithms identified moderate risk, PREVENT was concordant in 6% to 88% of simulations. In simulations with normal eGFR, PREVENT identified a lower risk in 18% to 88% and a higher risk in 0% to 12% of simulations. Conversely, with abnormal eGFR, PREVENT identified lower risk in 0% to 26% and higher risk in 4% to 94% of simulations. Conclusions: PREVENT substantially reclassifies risk and has the potential to alter prevention practice patterns. The tendency to assign a lower risk compared to standard algorithms when eGFR is normal may diminish implementation of preventive therapy. National health care systems need to monitor whether such changes improve overall public health.

Identification of prognostic RNA editing profiles for clear cell renal carcinoma.

Objective: Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer and currently lacks effective biomarkers. This research aims to analyze and identify RNA editing profile associated with ccRCC prognosis through bioinformatics and in vitro experiments. Methods: Transcriptome data and clinical information for ccRCC were retrieved from the TCGA database, and RNA editing files were obtained from the Synapse database. Prognostic models were screened, developed, and assessed using consistency index analysis and independent prognostic analysis, etc. Internal validation models were also constructed for further evaluation. Differential genes were investigated using GO, KEGG, and GSEA enrichment analyses. Furthermore, qPCR was performed to determine gene expression in human renal tubular epithelial cells HK-2 and ccRCC cells A-498, 786-O, and Caki-2. Results: An RNA editing-based risk score, that effectively distinguishes between high and low-risk populations, has been identified. It includes CHD3| chr17:7815229, MYO19| chr17:34853704, OIP5-AS1| chr15:41590962, MRI1| chr19:13883962, GBP4| chr1:89649327, APOL1| chr22:36662830, FCF1| chr14:75203040 edited sites or genes and could serve as an independent prognostic factor for ccRCC patients. qPCR results showed significant up-regulation of CHD3, MYO19, MRI1, APOL1, and FCF1 in A-498, 786-O, and Caki-2 cells, while the expression of OIP5-AS1 and GBP4 was significantly down-regulated. Conclusion: RNA editing site-based prognostic models are valuable in differentiating between high and low-risk populations. The seven identified RNA editing sites may be utilized as potential biomarkers for ccRCC.

Peer Social Genetic Effects and the Etiology of Substance Use Disorders, Major Depression, and Anxiety Disorder in a Swedish National Sample.

OBJECTIVE: There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder. METHOD: Cox models were used with data from a population-based Swedish cohort (N=655,327). Outcomes were drug use disorder, AUD, major depression, and anxiety disorder registrations between ages 17 and 30 from medical, criminal, and pharmacy registries. The authors indexed peer social genetic effects with peers' family genetic risk scores (FGRSs) for the same disorders, which are personalized measures of genetic risk inferred from diagnoses in first- to fifth-degree relatives. RESULTS: Across disorders, peer FGRSs predicted increased risks of proband registration (hazard ratio range, 1.01-1.59), with stronger effects for drug use disorder and AUD than for major depression and anxiety disorder. Peer social genetic effects were stronger for school classmates than for geographically proximal peers, and for peers from upper secondary school (ages 16-19) versus peers from lower secondary school (ages 7-16). Peer social genetic effects remained significant following statistical control for sociodemographic confounders, whether peers were affected, and peers' FGRS for educational attainment. Peer social genetic effects were more pronounced for probands at higher genetic risk. CONCLUSIONS: The genetic makeup of adolescents' peers has long-reaching consequences on risks for drug use disorder, AUD, major depression, and anxiety disorder. Individuals at high genetic risk are more sensitive to social genetic effects. Alternative hypotheses such as sociodemographic stratification, exposure to affected peers, and genetic predispositions for educational attainment did not explain the risk associated with peer social genetic effects for substance use and psychiatric disorders.

Associations of polygenic risk scores differentiating attention-deficit hyperactivity disorder from autism spectrum disorder with cognitive and cortical alterations in Schizophrenia patients.

Schizophrenia (SCZ) is a clinically and genetically heterogeneous disorder that shares genetic factors with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). A genome-wide association study (GWAS) differentiating ADHD from ASD was performed recently. In this study, we investigated whether polygenic risk scores (PRSs) differentiating ASD from ADHD are associated with cognitive impairments and alterations in cortical structures in SCZ patients. Based on the GWAS data (9,315 ASD and 11,964 ADHD patients), PRSs differentiating ADHD from ASD (indicating a greater risk of ADHD and a lower risk of ASD) were calculated for SCZ patients (n = 168). Cognitive performance, including verbal comprehension (VC), perceptual organization (PO), working memory (WM), and processing speed (PS), was assessed using the WAIS-III (n = 145). The surface areas and cortical thicknesses of 34 bilateral brain regions were extracted using FreeSurfer (n = 126). We examined the associations of these PRSs with cognitive performance and cortical structures in SCZ patients. Among the four cognitive domains, a higher PRS, indicating a greater risk of ADHD, was associated with impaired WM in SCZ patients (beta=-0.21, p = 0.012). A lower PRS, indicating a greater risk of ASD, was associated with decreased surface areas of the left medial orbitofrontal (beta = 0.21, p = 8.29 × 10- 4), left entorhinal (beta = 0.21, p = 0.025), left postcentral (beta = 0.18, p = 7.52 × 10- 3), right fusiform (beta = 0.17, p = 6.64 × 10- 3), and left fusiform cortices (beta = 0.17, p = 7.77 × 10- 3) in SCZ patients. A higher PRS, indicating a greater risk of ADHD, was associated with decreased cortical thickness in the bilateral transverse temporal regions (left, beta=-0.17, p = 0.039; right, beta=-0.17, p = 0.045). Our study revealed a relationship between genetic factors that differentiate ADHD patients from ASD patients and both cortical structure and cognitive performance in SCZ patients. These findings suggest that the heterogeneity of SCZ might be partly derived from genetic factors related to neurodevelopmental and psychiatric disorders other than SCZ.

The interaction between polyphenol intake and genes (MC4R, Cav-1, and Cry1) related to body homeostasis and cardiometabolic risk factors in overweight and obese women: a cross-sectional study.

Background: Cardiovascular disease (CVD), which is an important global health challenge, is expanding. One of the main factors in the occurrence of CVD is a high genetic risk. The interaction between genetic risk in CVD and nutrition is debatable. Polyphenols are one of the important dietary components that may have a protective role in people who have a high genetic risk score (GRS) for cardiometabolic risk factors. This study, conducted in overweight and obese women, examines the interaction between polyphenol intake and specific genes (MC4r, Cav-1, and Cry1) related to maintaining body balance and their interaction with cardiometabolic risk factors. Methods: This cross-sectional study included 391 women who were overweight or obese, aged 18 to 48 years, with a body mass index (BMI) between 25 and 40 kg/m2. Body composition was measured using the InBody 770 scanner. Total dietary polyphenol intake (TDPI) was assessed with a validated 147-item food frequency questionnaire (FFQ), and polyphenol intakes were determined using the Phenol-Explorer database. Serum samples underwent biochemical tests. The Genetic Risk Score (GRS) was calculated based on the risk alleles of three genes: MC4r, Cav-1, and Cry1. Results: The mean ± standard deviation (SD) age and BMI of women were 36.67 (9.1) years and 30.98 (3.9) kg/m2, respectively. The high GRS and high TDPI group had a significant negative interaction with fasting blood glucose (FBS) (p = 0.01). Individuals who had a high GRS and a high phenolic acid intake were found to have a significant negative interaction with Triglyceride (p = 0.04). Similarly, individuals with high GRS and a high intake of flavonoids had a significant negative interaction with TG (p < 0.01) and a significant positive interaction with High-density lipoprotein (HDL) (p = 0.01) in the adjusted model. Conclusion: According to our findings, those with a high GRS may have a protective effect on cardiometabolic risk factors by consuming high amounts of polyphenols. Further studies will be necessary in the future to validate this association.

Genetic Polymorphisms and Genetic Risk Scores Contribute to the Risk of Coronary Artery Disease (CAD) in a North Indian Population.

Coronary artery disease (CAD) is the leading cause of death in India. Many genetic polymorphisms play a role in regulating oxidative stress, blood pressure and lipid metabolism, contributing to the pathophysiology of CAD. This study examined the association between ten polymorphisms and CAD in the Jat Sikh population from Northern India, also considering polygenic risk scores. This study included 177 CAD cases and 175 healthy controls. The genetic information of GSTM1 (rs366631), GSTT1 (rs17856199), ACE (rs4646994), AGT M235T (rs699), AGT T174M (rs4762), AGTR1 A1166C (rs5186), APOA5 (rs3135506), APOC3 (rs5128), APOE (rs7412) and APOE (rs429358) and clinical information was collated. Statistical analyses were performed using SPSS version 27.0 and SNPstats. Significant independent associations were found for GST*M1, GST*T1, ACE, AGT M235T, AGT T174M, AGTR1 A1166C and APOA5 polymorphisms and CAD risk (all p < 0.05). The AGT CT haplotype was significantly associated with a higher CAD risk, even after controlling for covariates (adjusted OR = 3.93, 95% CI [2.39-6.48], p < 0.0001). The APOA5/C3 CC haplotype was also significantly associated with CAD (adjusted OR = 1.86, 95% CI [1.14-3.03], p < 0.05). A higher polygenic risk score was associated with increased CAD risk (adjusted OR = 1.98, 95% CI [1.68-2.34], p < 0.001). Seven polymorphisms were independently associated with an increase in the risk of CAD in this North Indian population. A considerable risk association of AGT, APOA5/C3 haplotypes and higher genetic risk scores is documented, which may have implications for clinical and public health applications.

The clinical utility of a glaucoma polygenic risk score in four population-based European-ancestry cohorts.

OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

Mapping associations of polygenic scores with autistic and ADHD traits in a single city region.

BACKGROUND: The genetic and environmental aetiology of autistic and Attention Deficit Hyperactivity Disorder (ADHD) traits is known to vary spatially, but does this translate into variation in the association of specific common genetic variants? METHODS: We mapped associations between polygenic scores for autism and ADHD and their respective traits in the Avon Longitudinal Study of Parents and Children (N = 4,255-6,165) across the area surrounding Bristol, UK, and compared them to maps of environments associated with the prevalence of autism and ADHD. RESULTS: Our results suggest genetic associations vary spatially, with consistent patterns for autistic traits across polygenic scores constructed at different p-value thresholds. Patterns for ADHD traits were more variable across thresholds. We found that the spatial distributions often correlated with known environmental influences. CONCLUSIONS: These findings shed light on the factors that contribute to the complex interplay between the environment and genetic influences in autistic and ADHD traits.

Risk prediction of multiple-station N2 metastasis in patients with upfront surgery for clinical single-station N2 non-small cell lung cancer.

To investigate long-term outcomes and develop a risk model for pathological multi-station N2 (pN2b) in patients who underwent upfront surgery for clinical single-station N2 (cN2a) non-small cell lung cancer (NSCLC). From 2006 to 2018, 547 patients who had upfront surgery for suspected cN2a NSCLC underwent analysis. A risk model for predicting pN2b metastasis was developed using preoperative clinical variables via multivariable logistic analysis. Among 547 clinical cN2a NSCLC patients, 118 (21.6%), 58 (10.6%), and 371 (67.8%) had pN0, pN1, and pN2. Among 371 pN2 NSCLC patients, 77 (20.8%), 165 (44.5%), and 129 (34.7%) had pN2a1, pN2a2, and pN2b. The 5-year overall survival rates for pN2a1 and pN2a2 were significantly higher than for pN2b (p = 0.041). Histologic type (p < 0.001), age ≤ 50 years (p < 0.001), preoperatively confirmed N2 metastasis (p < 0.001), and clinical stage IIIB (vs. IIIA) (p = 0.003) were independent risk factors for pN2b metastasis. The risk scoring system based on this model demonstrated good discriminant ability for pN2b disease (area under receiver operating characteristic: 0.779). In cN2a NSCLC patients, those with multiple N2 metastases indicate worse prognosis than those with a single N2 metastasis. Our risk scoring system effectively predicts pN2b in these patients.

An Association of Framingham Risk Score with Patient Determined Disease Steps in a Cohort of Relapsing-Remitting Multiple Sclerosis Patients: An Italian Real-World Monocentric Experience.

BACKGROUND: The associations between Multiple Sclerosis (MS) and cardiovascular diseases, drawn from epidemiological studies, have attracted much attention in recent years. MATERIALS AND METHODS: The present study employed a monocentric, observational, retrospective cohort design. The primary objective of the study was to describe the Framingham Risk Score (FRS) rate in a cross-sectional analysis of our cohort of relapsing-remitting MS patients who are regularly followed up and, if applicable, to identify any association with the patient's Patient Determined Disease Steps (PDDS). Cardiovascular risk was classified as follows: low if the FRS is less than 10%, moderate if it is 10% to 19%, and high if it is 20% or higher. RESULTS: A total cohort of 229 patients was enrolled. The sample consists of 163 women (71.2%). FRS categories were distributed as follows: 97 (42.3%) patients had low FRS, 84 (36.7%) patients had moderate FRS, and 48 (21%) patients had high FRS. In the univariable ordinal regression analysis, one one-point increase in the PDDS scale was associated with a 24% risk of high FRS (vs. low) (proportional odds ratio [OR] =2.426, 95% confidence interval [CI] 1.660-3.545; p <.0001). The results were also confirmed by the EDSS score, with a point increase in the EDSS score associated with a 19% risk of high FRS (vs. low) (proportional OR =1.953, 95% CI 1.429-2.669-1.04; p <.0001). CONCLUSION: The FRS demonstrated an association with the patient's "perception of the disease" as indicated by the PDDS. Further studies with larger cohorts are needed to adequately address cardiovascular risk in life-threatening conditions, such as MS.

Impact of hyperuricemia on CKD risk beyond genetic predisposition in a population-based cohort study.

The bidirectional effect of hyperuricemia on chronic kidney disease (CKD) underscores the importance of hyperuricemia as a risk factor for CKD. We evaluated the effect of hyperuricemia on the presence and development of CKD after considering genetic background by calculating polygenic risk scores (PRSs). We employed genome-wide association study summary statistics-excluding the United Kingdom Biobank (UKB) datasets among published CKD Gen Consortium papers-to calculate the PRSs for CKD in white background subjects. To validate PRS performance, we divided the UKB into two datasets to validate and test the data. We used logistic regression analysis to evaluate the association between hyperuricemia and CKD, and performed Kaplan-Meier survival analysis exclusively for subjects with available follow-up data. In total, 438,253 clinical data and 4,307,940 single nucleotide polymorphisms from 459,155 samples were included. We observed a significant positive association between PRS and CKD and the presence and development of CKD. Hyperuricemia significantly increased CKD risk (adjusted odds ratio 1.55, 95% confidence interval 1.48-1.61). The impact of hyperuricemia on CKD was maintained irrespective of PRS range. In addition, negative interaction between hyperuricemia and PRS for CKD was found. Survival analysis indicates that the presence of hyperuricemia significantly increased the risk of CKD development. The PRS for CKD thoroughly reflects the risk of CKD development. Hyperuricemia is a significant indicator of CKD risk, even after incorporating the genetic risk score for CKD. Irrespective of genetic risk, patients with a prospective risk of developing CKD require uric acid monitoring and management.

Colorectal Cancer Polygenic Risk Score Is Associated With Screening Colonoscopy Findings but Not Follow-Up Outcomes.

Background and Aims: Colorectal cancer (CRC) polygenic risk scores (PRS) may help personalize CRC prevention strategies. We investigated whether an existing PRS was associated with advanced neoplasia (AN) in a population undergoing screening and follow-up colonoscopy. Methods: We evaluated 10-year outcomes in the Cooperative Studies Program #380 screening colonoscopy cohort, which includes a biorepository of selected individuals with baseline AN (defined as CRC or adenoma ≥10 mm or villous histology, or high-grade dysplasia) and matched individuals without AN. A PRS was constructed from 136 prespecified CRC-risk single nucleotide polymorphisms. Multivariate logistic regression was used to evaluate the PRS for associations with AN prevalence at baseline screening colonoscopy or incident AN in participants with at least one follow-up colonoscopy. Results: The PRS was associated with AN risk at baseline screening colonoscopy (P = .004). Participants in the lowest PRS quintile had more than a 70% decreased risk of AN at baseline (odds ratio 0.29, 95% confidence interval 0.14-0.58; P < .001) compared to participants with a PRS in the middle quintile. Using a PRS cut-off of more than the first quintile to indicate need for colonoscopy as primary screening, the sensitivity for detecting AN at baseline is 91.8%. We did not observe a relationship between the PRS and incident AN during follow-up (P = .28). Conclusion: A PRS could identify individuals at low risk for prevalent AN. Ongoing work will determine whether this PRS can identify a subset of individuals at sufficiently low risk who could safely delay or be reassured about noninvasive screening. Otherwise, more research is needed to augment these genetic tools to predict incident AN during long-term follow-up.

Urinary Epinephrine Sulfate Can Predict Cardiovascular Risk in Moderate-to-Severe OSA: A Metabolomics-Based Study.

Purpose: There are currently no ideal indicators for predicting the cardiovascular risk of obstructive sleep apnea (OSA). This study aimed to employ urinary metabolomics to detect early cardiovascular risk in patients with moderate-to-severe OSA. Patients and Methods: Male participants who underwent polysomnography from November 2020 to May 2021 were screened. Clinical data, polysomnography data and urine samples were collected. Untargeted metabolomics analyses of urine were performed. Multivariate analyses and receiver operating characteristic (ROC) curve analyses were subsequently performed to identify potential biomarkers. Associations between metabolites and clinical indicators and cardiovascular risk were examined through linear regression analyses with interaction and mediation analyses. Results: Thirty-six male participants were included in the study, comprising 22 males with moderate-to-severe OSA and 14 age-matched controls, with an average age of 39.6 ± 9.2 years. We identified 65 metabolites in the study, involving pathways including pyrimidine, androgen, estrogen, vitamin B6 and sulfate/sulfite metabolism. Among them, epinephrine sulfate was the most significantly altered metabolite. ROC analyses highlighted that epinephrine sulfate had the highest area under the curve (AUC=0.883) for detecting moderate-to-severe OSA. Epinephrine sulfate was statistically correlated with OSA severity, hypoxia-related indicators (apnea-hypopnea index: r=0.685; oxygen desaturation index: r=0.743, p<0.0001), arterial stiffness (arterial augmentation index: r=0.361, p=0.031) and long-term cardiovascular risk (Framingham cardiovascular risk: r=0.375, p=0.024). Linear regression analysis revealed that epinephrine sulfate was significantly associated with an increased in the Framingham risk (ß = 0.004, 95% CI = 0.000-0.009, p = 0.049), with the effect partly mediated by systolic blood pressure (27.6%) and not moderated by other factors. Additionally, it also significantly associated with the increased in the arterial augmentation index (ß = 0.019, 95% CI = 0.000-0.037, p = 0.046), with the effect fully mediated by blood pressure and not moderated by other indices statistically. Conclusion: There are significant metabolic pathway alterations in moderate-to-severe OSA patients. Urinary epinephrine sulfate markedly predicts early cardiovascular risk in OSA patients.

Prognostic and immunotherapeutic significances of M2 macrophage-related genes signature in lung cancer.

Objective: We aimed to investigate the immunological significance of M2 macrophage-related genes in lung cancer (LC) patients, specifically focusing on constructing a risk score to predict patient prognosis and response to immunotherapy. Methods: We developed a novel risk score by identifying and incorporating 12 M2 macrophage-related genes. The risk score was calculated by multiplying the expression levels of risk genes by their respective coefficients. Through comprehensive enrichment analysis, we explored the potential functions distinguishing high- and low-risk groups. Moreover, we examined the relationship between patients in different risk groups and immune infiltration as well as their response to immunotherapy. The single-cell RNA sequencing data were acquired to ascertain the spatial pattern of RNF130 expression. The expression of RNF130 was examined using TCGA datasets and verified by HPA. The qRT-PCR was employed to examine RNF130 expression in LC cells. Finally, in vitro experiments were carried out to validate the expression and function of RNF130. Results: Our results indicated that the risk score constructed from 12 M2 macrophage-related genes was an independent prognostic factor. Patients in the high-risk group had a significantly worse prognosis compared to those in the low-risk group. Functional enrichment analysis showed a significant relationship between the risk score and immunity. Furthermore, we explored immune infiltration in different risk groups using seven immune algorithms. The results demonstrated a negative correlation between high-risk group patients and immune infiltration of B cells, CD4+ cells, and CD8+ cells. We further validated these findings using an immunotherapy response database, which revealed that high-risk patients were more likely to exhibit immune evasion and might have poorer immunotherapy outcomes. Additionally, drug sensitivity analysis indicated that patients in the high-risk group were more sensitive to certain chemotherapeutic and targeted drugs than those in the low-risk group. Single-cell analysis indicated that macrophages were the primary site of RNF130 distribution. The results from the TCGA and HPA database demonstrated a trend toward a low expression of RNF130 in LC. Finally, in vitro experiments further validated the expression and function of RNF130 in LC cells. Conclusions: The high-risk group constructed with M2 macrophage-related genes in LC was closely associated with poor prognosis, low immune cell infiltration, and poorer response to immunotherapy. This risk score can help differentiate and predict the prognosis and immune status of LC patients, thereby aiding in the development of precise and personalized immunotherapy strategies.

Cross-Validation of Risk Scores for Patients Undergoing Transcatheter Edge-to-Edge Repair for Mitral Regurgitation.

Background: Risk scores may identify patients with mitral regurgitation (MR) who are at risk for adverse events, but who may still benefit from transcatheter edge-to-edge repair (TEER). We sought to cross-validate the MitraScore and COAPT risk score to predict adverse events in patients undergoing TEER. Methods: MitraScore validation was carried out in the COAPT population which included 614 patients with FMR who were randomized 1:1 to guideline-directed medical therapy (GDMT) with or without TEER and were followed for 2 years. Validation of the COAPT risk score was carried out in 1007 patients from the MIVNUT registry of TEER-treated patients with both FMR and degenerative MR who were followed for a mean of 2.1 years. The predictive value was assessed using the area under the receiver operating characteristic curve (AUC) plots. The primary outcome was all-cause mortality. Results: The MitraScore had fair to good predictive accuracy for mortality in the overall COAPT trial population (AUC, 0.67); its accuracy was higher in patients treated with TEER (AUC, 0.74) than GDMT alone (AUC, 0.65). The COAPT risk score had fair predictive accuracy for death in the overall MitraScore cohort (AUC, 0.64), which was similar in patients with FMR and degenerative MR (AUC, 0.64 and 0.66, respectively). There was a consistent benefit of treatment with TEER plus GDMT compared with GDMT alone in the COAPT trial population across all MitraScore risk strata. Conclusions: The COAPT risk score and MitraScore are simple tools that are useful for the prediction of 2-year mortality in patients eligible for or undergoing treatment with TEER.

Hospital frailty risk score predicts high-value care outcomes following brain metastasis resection.

OBJECTIVE: Brain metastases (BM) are the most common adult intracranial tumors, representing a significant source of morbidity in patients with systemic malignancy. Frailty indices, including 11- and 5-factor modified frailty indices (mFI-11 and mFI-5), American Society of Anesthesiologists (ASA) physical status classification, and Charlson Comorbidity Index (CCI), have recently demonstrated an important role in predicting high-value care outcomes in neurosurgery. This study aims to investigate the efficacy of the newly developed Hospital Frailty Risk Score (HFRS) on postoperative outcomes in BM patients. METHODS: Adult patients with BM treated surgically at a single institution were identified (2017-2019). HFRS was calculated using ICD-10 codes, and patients were subsequently separated into low (<5), intermediate (5-15), and high (>15) HFRS cohorts. Multivariate logistic regressions were utilized to identify associations between HFRS and complications, length of stay (LOS), hospital charges, and discharge disposition. Model discrimination was assessed using receiver operating characteristic (ROC) curves. RESULTS: A total of 356 patients (mean age: 61.81±11.63 years; 50.6 % female) were included. The mean±SD for HFRS, mFI-11, mFI-5, ASA, and CCI were 6.46±5.73, 1.31±1.24, 0.95±0.86, 2.94±0.48, and 8.69±2.07, respectively. On multivariate analysis, higher HFRS was significantly associated with greater complication rate (OR=1.10, p<0.001), extended LOS (OR=1.13, p<0.001), high hospital charges (OR=1.14, p<0.001), and nonroutine discharge disposition (OR=1.12, p<0.001), and comparing the ROC curves of mFI-11, mFI-5, ASA,and CCI, the predictive accuracy of HFRS was the most superior for all four outcomes assessed. CONCLUSION: The predictive ability of HFRS on BM resection outcomes may be superior than other frailty indices, offering a new avenue for routine preoperative frailty assessment and for managing postoperative expectations.