Assessing the Predictive Accuracy of the aMAP Risk Score for Hepatocellular Carcinoma (HCC): Diagnostic Test Accuracy and Meta-analysis.

Purpose: We aimed to perform a meta-analysis with the intention of evaluating the reliability and test accuracy of the aMAP risk score in the identification of HCC. Methods: A systematic search was performed in PubMed, Scopus, Cochrane, Embase, and Web of Science databases from inception to September 2023, to identify studies measuring the aMAP score in patients for the purpose of predicting the occurrence or recurrence of HCC. The meta-analysis was performed using the meta package in R version 4.1.0. The diagnostic accuracy meta-analysis was conducted using Meta-DiSc software. Results: Thirty-five studies 102,959 participants were included in the review. The aMAP score was significantly higher in the HCC group than in the non-HCC group, with a mean difference of 6.15. When the aMAP score is at 50, the pooled sensitivity, specificity, negative likelihood ratio, and positive likelihood ratio with 95% CI was 0.961 (95% CI 0.936, 0.976), 0.344 (95% CI 0.227, 0.483), 0.114 (95% CI 0.087, 0.15), and 1.464 (95% CI 1.22, 1.756), respectively. At a cutoff value of 60, the pooled sensitivity, specificity, negative likelihood ratio, and positive likelihood ratio with 95% CI was 0.594 (95% CI 0.492, 0.689), 0.816 (95% CI 0.714, 0.888), 0.497 (95% CI 0.418, 0.591), and 3.235 (95% CI 2.284, 4.582), respectively. Conclusion: The aMAP score is a reliable, accurate, and easy-to-use tool for predicting HCC patients of all stages, including early-stage HCC. Therefore, the aMAP score can be a valuable tool for surveillance of HCC patients and can help to improve early detection and reduce mortality.

A novel brown adipocytes-related gene signature predicts and validates prognosis and immune infiltration of clear cell renal cell carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The crosstalk between tumor tissue and adjacent adipose tissue has been appreciated recently. This study examines the predictive usefulness of brown adipocyte-related genes (BARGs) in ccRCC. METHODS: The transcriptome and clinical data of ccRCC patients were obtained from TCGA-KIRC and USA-ccRCC cohorts (848 tumor samples; 72 normal samples). Lasso-Cox methods were used to construct the risk prognostic signature model. We used Kaplan-Meier survival analysis to evaluate the prognostic significance of the risk model with ROC curves ascertaining prediction accuracy. The differences in immune cell infiltrates and signature risk scores between different risk categories were analyzed. Finally, biological experiments were performed to explore the functions of candidate genes. RESULTS: TCGA-KIRC patients were classified into two clusters that differed significantly regarding overall survival (OS) and tumor microenvironment. After screening BARGs candidates, a signature consisting of PPP1R1A, DPYSL3, and PTPRM was created to calculate risk score. Patients were assigned to the high or low-risk group, and the high-risk group had a significantly worse prognosis. Consistent trend was validated in external USA-ccRCC cohort. Meanwhile, the signature risk score affected immune cell infiltrates within the ccRCC microenvironment, positively correlated with the infiltration of CD4+ T cells, CD8+ T cells, CD56dim, CD56bright NK cells, MDSCs, and macrophage cells, while negatively correlated with neutrophil, iDCs, mast cells, and eosinophil. Finally, knockdown of PPP1R1A and DPYSL3 in renal cancer cells showed impairment in tumor proliferation ability of ccRCC in vitro and in vivo. Conversely, knockdown of PTPRM exhibited a promotive effect. CONCLUSION: We developed a predictive BARGs-related risk signature for early diagnosis and classifying ccRCC patients, which offers potential targets for individualized treatment of ccRCC.

Inverse relationship between polygenic risk burden and age of onset of autoimmune vitiligo.

Vitiligo is a common autoimmune disease characterized by patches of depigmented skin and overlying hair due to destruction of melanocytes in the involved regions. We investigated the relationship between vitiligo risk and vitiligo age of onset (AOO) using a vitiligo polygenic risk score that incorporated the most significant SNPs from genome-wide association studies. We find that vitiligo genetic risk and AOO are strongly inversely correlated; subjects with higher common-variant polygenic risk tend to develop vitiligo at an earlier age. Nevertheless, the correlation is not simple. In individuals who carry a single high-risk major histocompatibility complex class II haplotype, the effect of additional polygenic risk on vitiligo AOO is reduced. Particularly among those with early-AOO vitiligo (onset ≤12 years of age), genetic risk can reflect contributions from high common-variant burden but also rare variants of high effect and sometimes both. While the heritability of vitiligo is relatively high, and we here show that genetic risk factors predict vitiligo AOO, vitiligo is never congenital, and thus environmental triggers also play an important role in disease onset.

The impact of externalized pancreatic stents in our practice: A comparison of outcomes after pancreaticoduodenectomy in two time periods.

BACKGROUND: Postoperative pancreatic fistula is a severe complication of pancreaticoduodenectomy. Using an externalized pancreatic stent is a potential mitigation strategy not previously studied in Latin America. METHODS: Pancreaticoduodenectomies performed in a single center between 2006 and 2019 were retrospectively analyzed. Clinical variables were collected with a 90-day follow-up according to stent intervention: externalized stent (ES), internal stent (IS), or no stent. Before and after ES implementation (2016) periods were also compared. RESULTS: Out of 237 patients, 77 (32.5 â€‹%) had an ES, 24 (10.1 â€‹%) an IS, and 136 (57.4 â€‹%) none. No difference was found in the overall incidence of POPF. The use of an ES was associated with less type C POPF, despite having an increased risk for fistula development. PD performed after 2016 were also associated with a reduced incidence of type C POPF, surgical reintervention requirement, POPF-associated mortality, and intrahospital stay. CONCLUSIONS: The use of an ES is a low-cost intervention that can mitigate POPF severity in high-risk patients.

Pyrimidine metabolism reshapes immune microenvironment and implies poor prognosis in glioma.

BACKGROUND: The metabolic environment of glioma is extremely complex. Pyrimidine metabolism can significantly influence malignant progression of multiple kinds of cancer cells. In this study, we intend to explore the relationship between pyrimidine metabolism and malignant progression of glioma. METHODS: We analyzed two glioma RNA-sequencing databases to construct a pyrimidine metabolism-related risk signature. An individualized prognosis prediction model based on this risk signature was established. Functional analysis and in vitro experiments were conducted to assess the role of pyrimidine metabolism in the tumor-immune microenvironment and malignant progress of gliomas. RESULTS: The high-risk group, as predicted by the pyrimidine metabolism-related risk score, showed a tendency toward more malignant entities and poorer survival outcomes. Functional analysis revealed that pyrimidine metabolism significantly regulates the tumor-immune microenvironment. In vitro experiments confirmed that targeting pyrimidine metabolism-related genes can inhibit malignancy of glioma cell. CONCLUSION: In short, the pyrimidine metabolism-related signature we established could serve as an independent prognostic biomarker in diffuse gliomas and has a close association with regulation of the tumor-immune microenvironment.

Methods of a cluster-randomized, type II hybrid implementation effectiveness trial to prospectively assess extended-duration thromboprophylaxis for at-risk medical patients being discharged to prevent hospital-associated venous thromboembolism.

Background: Venous thromboembolism (VTE) is the third leading cause of preventable hospital-associated (HA) death. Most HA-VTE, including fatal pulmonary emboli, occur among medically ill patients. The rate of symptomatic VTE more than doubles over the first 21 days after hospital discharge. Trials have demonstrated that the burden of HA-VTE may be reduced with postdischarge thromboprophylaxis; however, few patients receive this therapy. We formerly validated the ability of eVTE (eVTE is the abbreviation for a risk assessment tool constituted by 2 calculations: one predicts 90-day VTE and the other predicts 30-day major bleeding derived from only elements of the complete blood count and basic metabolic panel and age) to identify medical patients being discharged with both an elevated risk of VTE and a low risk of bleeding. Objectives: Implement a cluster-randomized, stepped wedge, type II hybrid implementation/effectiveness trial generating an alert among select at-risk patients upon discharge for implementation of thrombosis chemoprophylaxis in a 23-hospital not-for-profit healthcare system. Methods: We use the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework to guide implementation and outcomes reporting. Results: The primary outcome for aim 1 (implementation) is the prescription of rivaroxaban 10 mg daily for 30 days as postdischarge thromboprophylaxis among at-risk patients. The primary efficacy and safety outcomes (effectiveness) are the 90-day composite of symptomatic VTE, myocardial infartcion, nonhemorrhagic stroke, all-cause mortality, and 30-day major bleeding. Conclusion: The eVTE trial will provide high-quality, real-world evidence on the effectiveness and safety of a pragmatic intervention to implement targeted postdischarge thromboprophylaxis using decision support embedded in the electronic health record.

Growth dynamics of Rathke's Cleft cyst: a risk score system for surgical decision making.

OBJECTIVE: Rathke's cleft cysts (RCCs) exhibit variable growth patterns, thus posing a challenge in predicting progression. While some RCCs may not cause symptoms, others can insidiously cause pituitary dysfunction, which is often irreversible, even following surgery. Hence, it is crucial to identify asymptomatic RCCs that grow rapidly and pose a higher risk of causing endocrinologic dysfunction. This enables timely surgical intervention to prevent permanent damage. Our study examines the growth rate of RCCs, identifies factors that accelerate growth, and discusses the clinical implications of these findings. METHODS: A retrospective analysis of a prospectively maintained electronic database revealed 45 patients aged 18-80 years who underwent endoscopic endonasal surgery (EEA) for RCCs between 2010 and 2022 at our center. Of these, 20 required early operative intervention. The remaining 25 patients were followed closely clinically and radiologically before requiring surgery (initial conservative management group). We conducted an analysis of the factors predicting growth over time in this group. Using a regression model, we constructed a risk score system to predict RCC growth over time. RESULTS: Patients in the initial conservative group had smaller cysts and were generally older than those in the early surgery group. Patients with preoperative pituitary dysfunction showed a higher median growth of 1.0 mm in the longest diameter compared to those with normal pituitary function, with an increase of 0.5 mm. A sum of annual cyst growth of all (z, y, x) diameters, at a rate of 3 mm or greater, was associated with a clinically significant increase in the risk of pituitary dysfunction, exceeding 50%.The most significant factors predicting rapid growth in RCCs were smoking status, age, and T1-weighted magnetic resonance imaging (MRI) intensity of cysts. Smoking was the most critical risk factor for rapid cyst growth (p = < .001). Our risk score system accurately predicted RCC growth with a 74% accuracy rate, 73% sensitivity, and 75% specificity. CONCLUSION: Our analysis showed a strong link between active smoking and the rapid growth of RCC. This novel finding has significant preventive implications but needs validation by a large population database. Surgical intervention for RCC currently is often reserved for symptomatic cases. However, utilizing our risk-based scoring system to predict rapidly growing cysts may indicate early surgery in minimally symptomatic patients, thereby potentially preserving pituitary function.

Simplified rapid hydration and contrast-associated acute kidney injury among CKD patients stratified by Mehran score: sub-analysis from the TIME Trial.

Simplified rapid hydration has been proven to be non-inferior to standard hydration in preventing contrast-associated acute kidney injury among chronic kidney disease patients undergoing coronary angiography. The current investigation aimed to further confirm the feasibility and safety of the newly proposed hydration method-simplified rapid hydration (SH) in each risk stratification by Mehran risk score (MRS). Eligible patients (n = 954) randomized to the SH group and standard hydration group were allocated into 2 groups based on MRS: low to moderate-risk and high to very high-risk groups. Primary endpoints were the incidence of contrast-associated acute kidney injury (CA-AKI) and acute heart failure (AHF) (SH vs standard hydration). Secondary endpoints included serum creatinine (Scr), blood urea nitrogen (BUN), cystatin-C (Cys-C), and C-reactive protein (CRP) at 24 h, 48 h, and 72 h after PCI procedure, and the incidence of major adverse cardiac events (MACE). MRS was associated with a higher incidence of CA-AKI (OR = 1.101, 95%CI 1.049-1.156, P < 0.001). In the low to moderate-risk and high to very-high-risk groups, the incidence of CA-AKI in the SH and standard hydration group was 3.3% versus 4.9% (P = 0.5342), 10% versus 12% (P = 0.6392), respectively. Meanwhile, there might be subtle differences in renal function indexes and inflammatory indicators between SH and the control group at different time points. The preventive effect of SH in CA-AKI was similar to standard hydration regardless of MRS-guided risk stratification.

Clinical Utility of Genetic Variants in PNPLA3 and TM6SF2 to Predict Liver-Related Events in Metabolic Dysfunction-Associated Steatotic Liver Disease.

BACKGROUND AND AIMS: Fibrosis-4 (FIB-4) index and genetic polymorphisms have been used in assessing the risk of liver-related events (LRE) in metabolic dysfunction-associated steatotic liver disease (MASLD). To establish a more efficient prediction strategy for LRE, we investigated a combined approach that uses the FIB-4 index and genetic polymorphisms. METHODS: We enrolled 1304 Japanese patients with biopsy-proven MASLD in this longitudinal multicenter cohort study. PNPLA3, TM6SF2, GCKR and MBOAT7 genotypes were genotyped, and polygenic risk score high fat content (PRS-HFC) were calculated. RESULTS: During the follow-up period of 8.1 year, 96 LRE occurred and 53 patients died. PNPLA3, TM6SF2 and GCKR genotypes were associated with LRE development. We divided patients into three groups based on the FIB-4 index and PNPLA3 and TM6SF2 genotype. The cumulative LRE development rate in each group was 2.1%/28.9%/53.5%, respectively, at 10 years. Multivariate analysis revealed hazard ratios (HRs) for LRE of 10.72 in the high-risk group and 4.80 in the intermediate-risk group. Overall survival in each group was 98.8%/85.2%/72.4%, respectively, at 10 years. HRs for prognosis were 8.74 in the high-risk group and 5.62 in the intermediate-risk group. Patients with FIB-4 index > 2.67 and high PRS-HFC had HR of 6.70 for LRE development and HR of 6.07 for prognosis compared to patients with FIB-4 ≤ 2.67. CONCLUSIONS: The approach of measuring the FIB-4 index first followed by assessment of genetic polymorphisms efficiently detected patients at high risk of developing LRE. Therefore, this two-step strategy could be used as a screening method in large populations of patients with MASLD.

GWASBrewer: An R Package for Simulating Realistic GWAS Summary Statistics.

Many statistical genetics analysis methods make use of GWAS summary statistics. Best statistical practice requires evaluating these methods in realistic simulation experiments. However, simulating summary statistics by first simulating individual genotype and phenotype data is extremely computationally demanding. This high cost may force researchers to conduct overly simplistic simulations that fail to accurately measure method performance. Alternatively, summary statistics can be simulated directly from their theoretical distribution. Although this is a common need among statistical genetics researchers, no software packages exist for comprehensive GWAS summary statistic simulation. We present GWASBrewer, an open source R package for direct simulation of GWAS summary statistics. We show that statistics simulated by GWASBrewer have the same distribution as statistics generated from individual level data, and can be produced at a fraction of the computational expense. Additionally, GWASBrewer can simulate standard error estimates, something that is typically not done when sampling summary statistics directly. GWASBrewer is highly flexible, allowing the user to simulate data for multiple traits connected by causal effects and with complex distributions of effect sizes. We demonstrate example uses of GWASBrewer for evaluating Mendelian randomization, polygenic risk score, and heritability estimation methods.

GWAS and polygenic risk score of severe COVID-19 in Eastern Europe.

Background: COVID-19 disease has infected more than 772 million people, leading to 7 million deaths. Although the severe course of COVID-19 can be prevented using appropriate treatments, effective interventions require a thorough research of the genetic factors involved in its pathogenesis. Methods: We conducted a genome-wide association study (GWAS) on 7,124 individuals (comprising 6,400 controls who had mild to moderate COVID-19 and 724 cases with severe COVID-19). The inclusion criteria were acute respiratory distress syndrome (ARDS), acute respiratory failure (ARF) requiring respiratory support, or CT scans indicative of severe COVID-19 infection without any competing diseases. We also developed a polygenic risk score (PRS) model to identify individuals at high risk. Results: We identified two genome-wide significant loci (P-value <5 × 10-8) and one locus with approximately genome-wide significance (P-value = 5.92 × 10-8-6.15 × 10-8). The most genome-wide significant variants were located in the leucine zipper transcription factor like 1 (LZTFL1) gene, which has been highlighted in several previous GWAS studies. Our PRS model results indicated that individuals in the top 10% group of the PRS had twice the risk of severe course of the disease compared to those at median risk [odds ratio = 2.18 (1.66, 2.86), P-value = 8.9 × 10-9]. Conclusion: We conducted one of the largest studies to date on the genetics of severe COVID-19 in an Eastern European cohort. Our results are consistent with previous research and will guide further epidemiologic studies on host genetics, as well as for the development of targeted treatments.

Development and validation of a lung cancer polygenic risk score incorporating susceptibility variants for risk factors.

Incorporating susceptibility genetic variants of risk factors has been reported to enhance the risk prediction of polygenic risk score (PRS). However, it remains unclear whether this approach is effective for lung cancer. Hence, we aimed to construct a meta polygenic risk score (metaPRS) of lung cancer and assess its prediction of lung cancer risk and implication for risk stratification. Here, a total of 2180 genetic variants were used to develop nine PRSs for lung cancer, three PRSs for different histopathologic subtypes, and 17 PRSs for lung cancer-related risk factors, respectively. These PRSs were then integrated into a metaPRS for lung cancer using the elastic-net Cox regression model in the UK Biobank (N = 442,508). Furthermore, the predictive effects of the metaPRS were assessed in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial (N = 108,665). The metaPRS was associated with lung cancer risk with a hazard ratio of 1.33 (95% confidence interval: 1.27-1.39) per standard deviation increased. The metaPRS showed the highest C-index (0.580) compared with the previous nine PRSs (C-index: 0.513-0.564) in PLCO. Besides, smokers in the intermediate risk group predicted by the clinical risk model (1.34%-1.51%) with the intermediate-high genetic risk had a 6-year average absolute lung cancer risk that exceeded the clinical risk model threshold (≥1.51%). The addition of metaPRS to the clinical risk model showed continuous net reclassification improvement (continuous NRI = 6.50%) in PLCO. These findings suggest the metaPRS can improve the predictive efficiency of lung cancer compared with the previous PRSs and refine risk stratification for lung cancer.

Impact of the Hospital Frailty Risk Score on Outcomes After Transcatheter Aortic Valve Replacement in Late Elderly Patients.

OBJECTIVES: Prognostic prediction using objective indices is needed to optimize the indications for transcatheter aortic valve replacement (TAVR). We evaluated the impact of the Hospital Frailty Risk Score (HFRS), an International Classification of Diseases (ICD)-based frailty index, on the prognosis after TAVR in the late elderly. METHODS: We identified patients aged ≥75 years undergoing TAVR from April 2014 to September 2020 from the Shizuoka Kokuho Database (SKDB). Cox logistic regression analysis was performed to examine predictors of long-term mortality. We also evaluated the relationship between HFRS categories (low risk: <5, intermediate risk: 5-15, high risk: >15) and functional decline. RESULTS: This study involved 607 patients (189 (31.1%) men) with a mean age of 85.0 years. During the median follow-up period of 20 months, survival significantly differed among HFRS categories (survival at two years; low (HFRS <5): 88.9%, intermediate (HFRS 5-15): 82.6%, high (HFRS >15): 67.7%; log-rank p = 0.002). In the multivariate regression model, male sex (hazard ratio (HR): 2.15, 95% confidence interval (CI): 1.42-3.24), preoperative care needs level of ≥3 (HR: 2.43, 95% CI: 1.17-5.06), and HFRS (HR: 1.07, 95% CI: 1.03-1.12) were significant predictors of mortality. Functional decline-free survival significantly differed among HFRS categories (event-free survival at two years; low: 79.4%, intermediate: 75.2%, high: 50.8%; log-rank p = 0.001). CONCLUSIONS: The HFRS is a predictor of long-term mortality after TAVR in the late elderly and is associated with postoperative functional decline. The HFRS can provide additional information for decision-making regarding treatment strategies for the late elderly.

Impact of the Hospital Frailty Risk Score on Outcomes following Primary Total Elbow Arthroplasty.

BACKGROUND: The Hospital Frailty Risk Score (HFRS) has demonstrated strong correlation with adverse outcomes in various joint replacement surgeries, yet its applicability in total elbow arthroplasty (TEA) remains unexplored. The purpose of this study is to assess the association between HFRS and postoperative complications following elective primary TEA. METHODS: The Nationwide Readmissions Database was queried to identify patients undergoing primary TEA from 2016 to 2020. The HFRS was used to compare medical, surgical, and clinical outcomes of frail vs. non-frail patients. Mean and relative costs, total hospital length of stay (LOS), and discharge disposition for frail and non-frail patients were also compared. RESULTS: We identified 2,049 primary TEA in frail patients and 3,693 in non-frail patients. Frail patients had increased complication rates including acute respiratory failure (13.6% vs. 1.1%; p < 0.001), urinary tract infections (12.3% vs. 0.0%; p < 0.001), transfusions (3.9% vs. 1.1%; p < 0.001), pneumonia (1.1% vs. 0.2%; p < 0.001), acute respiratory distress syndrome (3.2% vs 0.6%; p < 0.001), sepsis (0.7% vs. 0.1%; p < 0.001), and hardware failure (1.2% vs 0.1%; p < 0.001). Frail patients also experienced higher rates of readmission (37% vs. 25%; p < 0.001) and death (1.7% vs. 0.2%; p < 0.001), while being less likely to undergo revision (6.5% vs. 17%; p < 0.001). Frail patients incurred higher healthcare costs ($28,497 vs. $23,377; p < 0.001) and longer LOS (5.3 days vs. 2.6 days; p < 0.001), with reduced likelihood of routine hospital stays (36% vs. 71%; p < 0.001) and increased utilization of short-term hospitalization (p < 0.001), care facilities (p < 0.001), and home health care services (p < 0.001). CONCLUSION: HFRS is a validated indicator of frailty and is strongly associated with increased rates of complications in patients undergoing elective primary TEA. These findings should be considered by orthopedic surgeons when assessing surgical candidacy and discussing treatment options in this at-risk patient population.

From Calculation to Communication: Using Risk Score Calculators to Inform Clinical Decision Making and Facilitate Patient Engagement.

BACKGROUND: Risk score calculators are a widely developed tool to support clinicians in identifying and managing risk for certain diseases. However, little is known about physicians' applied experiences with risk score calculators and the role of risk score estimates in clinical decision making and patient communication. METHODS: Physicians providing care in outpatient community-based clinical settings (N = 20) were recruited to participate in semi-structured individual interviews to assess their use of risk score calculators in practice. Two study team members conducted an inductive thematic analysis using a consensus-based coding approach. RESULTS: Participants referenced at least 20 risk score calculators, the most common being the Atherosclerotic Cardiovascular Disease Risk Calculator. Ecological factors related to the clinical system (e.g., time), patient (e.g., receptivity), and physician (e.g., experience) influenced conditions and patterns of risk score calculator use. For example, compared with attending physicians, residents tended to use a greater variety of risk score calculators and with higher frequency. Risk score estimates were generally used in clinical decision making to improve or validate clinical judgment and in patient communication to serve as a motivational tool. CONCLUSIONS: The degree to which risk score estimates influenced physician decision making and whether and how these scores were communicated to patients varied, reflecting a nuanced role of risk score calculator use in clinical practice. The theory of planned behavior can help explain how attitudes, beliefs, and norms shape the use of risk score estimates in clinical decision making and patient communication. Additional research is needed to evaluate best practices in the use of risk score calculators and risk score estimates. HIGHLIGHTS: The risk score calculators and estimates that participants referenced in this study represented a range of conditions (e.g., heart disease, anxiety), levels of model complexity (e.g., probability calculations, scales of severity), and output formats (e.g., point estimates, risk intervals).Risk score calculators that are easily accessed, have simple inputs, and are trusted by physicians appear more likely to be used.Risk score estimates were generally used in clinical decision making to improve or validate clinical judgment and in patient communication to serve as a motivational tool.Risk score estimates helped participants manage the uncertainty and complexity of various clinical situations, yet consideration of the limitations of these estimates was relatively minimal.Developers of risk score calculators should consider the patient- (e.g., response to risk score estimates) and physician- (e.g., training status) related characteristics that influence risk score calculator use in addition that of the clinical system.

Comprehensive evaluation of immunological attributes and immunotherapy responses of positive T cell function regulators in colorectal cancer.

BACKGROUND: Positive regulators of T-cell function (PTFRs), integral to T-cell proliferation and activation, have been identified as potential prognostic markers in colorectal cancer (CRC). Despite this, their role within the tumor microenvironment (TME) and their response to immunotherapy are not yet fully understood. METHODS: This study delved into PTFR-related CRC subtypes by analyzing four independent transcriptome datasets, emphasizing the most significant prognostic PTFRs. We identified differentially expressed genes (DEGs) between two subtypes and developed a PTFR risk model using LASSO and Cox regression methods. The model's associations with survival time, clinical features, TME characteristics, tumor mutation profiles, microsatellite instability (MSI), cancer stem cell (CSC) index, and responses to chemotherapy, targeted therapy, and immunotherapy were subsequently explored. RESULTS: The PTFR risk model demonstrated a strong predictive capacity for CRC. It facilitated the estimation of immune cell composition, HLA expression levels, immune checkpoint expression, mutation burden, CSC index features, and the effectiveness of immunotherapy. CONCLUSIONS: This study enhances our understanding of the role of PTFRs in CRC progression and introduces an innovative assessment framework for CRC immunotherapy. This framework improves the prediction of treatment outcomes and aids in the customization of therapeutic strategies.

Associations of combined accelerated biological aging and genetic susceptibility with incident dementia: a prospective study in the UK Biobank.

BACKGROUND: Accelerated biological aging has been verified to be a critical risk factor for a number of age-related diseases, but its role in dementia remained unclear. Whether it modified the effects of genetic factors was also unknown. This study evaluated the associations between accelerated biological aging and dementia and the moderating role of accelerated biological aging in the genetic susceptibility to the disease. METHODS: We included 200,731 participants in the UK biobank. Nine clinical blood biomarkers and chronological age were used to calculate Phenotypic age acceleration (PhenoAgeAccel), which is a novel indicator for accelerated biological aging. The associations of PhenoAgeAccel with dementia, both young-onset and late-onset dementia, were assessed by Cox proportional hazard models. Apolipoprotein E (APOE) alleles and polygenic risk scores (PRS) were used to evaluate the genetic risk of dementia. The interactions between genetic susceptibility and biological aging were tested on both multiplicative and additive scales. RESULTS: These findings showed individuals who were in the highest quartile of PhenoAgeAccel had a higher risk with incidence of dementia compared to individuals in the lowest quartile of PhenoAgeAccel (HR: 1.145 (95% CI: 1.050, 1.249)). Individuals with biologically older had a higher risk of dementia than individuals with biologically younger (HR: 1.069 (95% CI: 1.004, 1.138)). Furthermore, compared to individuals with biologically younger and low APOE ε4-related genetic risk, individuals with biologically younger and high APOE ε4-related genetic risk (HR:3.048 (95% CI: 2.811, 3.305)) had a higher risk of dementia than individuals with biologically older and high APOE ε4-related genetic risk (HR: 2.765 (95% CI: 2.523, 3.029)). Meanwhile, referring to low dementia PRS and biologically younger, the risk of dementia increased by 72.7% (HR: 1.727 (95% CI: 1.538, 1.939) in the biologically younger and high PRS group and 58.7% (HR: 1.587 (95% CI: 1.404, 1.793) in the biologically older and high PRS group, respectively. The negative interactions between PhenoAgeAccel with APOE ε4 and PRS were also tested on the additive scale. CONCLUSIONS: Accelerated biological aging could bring the extra risk of dementia but attenuate the effects of genetic risk on dementia. These findings provide insights for precise prevention and intervention of dementia.

Sex-specific associations between 10-year cardiovascular risk, clinical symptoms and cognitive impairments in schizophrenia.

BACKGROUND: Schizophrenia (SCZ) shortens life expectancy, with cardiovascular disease (CVD) as the leading cause of death. The links between psychiatric symptoms, cognitive function and CVD are unclear, and sex differences in this relationship are understudied. This study examined the relationship between clinical characteristics and 10-year cardiovascular risk in males and females with SCZ. METHODS: This study included 802 patients with chronic SCZ. Fasting venous blood samples were collected from all patients to measure relevant glycolipid metabolic indices. The Positive and Negative Syndrome Scale (PANSS) was used to assess psychiatric symptoms. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The Framingham risk score (FRS) was used to estimate the 10-year CVD risk. RESULTS: The mean 10-year cardiovascular risk for all patients was 11.76 ± 8.99%. Among patients with SCZ, 52.8% exhibited an intermediate-high 10-year cardiovascular risk. Multivariate linear regression analysis showed that FRS increased with higher body mass index, blood pressure, glucose, total cholesterol and triglyceride levels, while it was inversely related to high density lipoprotein levels. The general psychopathological scores were negatively associated with FRS (male: B = - 0.086, P = 0.013; female: B = - 0.056, P = 0.039). Negative symptom (B = - 0.088, P = 0.024) and total PANSS scores (B = - 0.042, P = 0.013) showed a negative association with FRS only in males. Additionally, in patients over 60 years old, general psychopathology (B = - 0.168, P = 0.001) and PANSS total scores (B = - 0.057, P = 0.041) were associated with reduced FRS, while immediate memory (B = 0.073, P = 0.025) was associated with higher FRS. CONCLUSION: Patients with SCZ have an elevated risk of developing CVD, with males showing a higher 10-year cardiovascular risk than females. Significant sex differences exist in the relationship between the FRS and psychiatric symptoms, with negative symptoms being negatively related to FRS only in males.

Predicting cardiometabolic disease in medical students using FibroScan and 30-year Framingham risk scores.

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) has become a major cause of end-stage hepatic disease worldwide requiring liver transplantation, whereas cardiovascular disease (CVD) remains the leading cause of morbidity and mortality globally. Development of MASLD and CVD among young adults is understudied. This study aimed to assess CVD risk in healthy young medical university students using lipid-based and body mass index (BMI)-based 30-year Framingham risk scores (FS30) and to evaluate disease burden for asymptomatic patients with MASLD by performing FibroScan. Methods: We included medical university students aged 18-30 years without any known medical conditions. All participants underwent physical and anthropometric measurements, and completed a questionnaire. Blood samples were collected for the analysis of glycosylated haemoglobin levels, renal and liver function, biomarker analysis to calculate liver fibrosis risk, and subclinical atherosclerosis biomarkers. Liver stiffness measurements (LSM) and controlled attenuation parameter (CAP) values were measured using FibroScan 430 mini to calculate liver fibrosis and steatosis, respectively. FS30 based on body mass index (FS30-BMI) and lipid levels (FS30-Lipid) were also calculated. Results: Overall, 138 medical students participated in this study after providing informed consent. Using FS30-Lipid and FS30-BMI, CVD risk was identified in two (1.5%; n = 138) and 23 (17.6%; n = 132) individuals, respectively. MASLD fibrosis was identified based on FibroScan LSMs >7.0 kPa in 12 medical students (9.4%, n = 128; 95% CI, 4.7-14.8%). Consumption of coffee and sugary soft drinks were predictive of liver fibrosis. In total, 36 students (28.6%; n = 128) were found to have hepatic steatosis based on FibroScan CAP values >236 dB, and the predictive factors included increased body fat percentage, male sex, and lack of physical activity. Levels of inflammatory biomarkers, such as C-reactive protein and lipids were not elevated in participants with MASLD. Discussion: CVD risk was identified in >17% of young medical students. The frequency of liver fibrosis and steatosis was also high among the participants, indicating that liver damage starts at a relatively early age. Early intervention is needed among young adults via health promotion and lifestyle changes.

Prediabetes in a French overseas territory: Clinical Characteristics, Risk Factors, and Implications for type 2 diabetes prevention.

Background: People with prediabetes are at high risk of developing type 2 diabetes (T2D). This study evaluates clinical, sociodemographic characteristics, and Finnish Diabetes Risk Score (FINDRISC) of individuals with prediabetes recruited in primary care by their general practitioner (GP) for PREDIABRUN study. Methods: PREDIABRUN, a prospective cohort study in primary care on Reunion Island, aimed to identify risk factors for developing T2D in 500 adults with prediabetes (18-70 years) between July 2019 and December 2022. Sociodemographic, anthropometric, health, and lifestyle data were collected. Participants were categorized as having known prediabetes if their GP was aware of glucose abnormalities before the study, otherwise as newly diagnosed. Results: A total of 469 subjects were included, with a median age of 55 years; 58.4 % were women. Employment was more common among men (53.3 %) than women (36.1 %). Precariousness affected 35.4 % overall, with higher rates in women (41.6 %) than men (26.7 %, p < 0.001). The major associated health issues were obesity (40.1 %), musculoskeletal disorders (50.5 %), hypertension (46.3 %) and cardiovascular diseases (11.5 %). The median FINDRISC score was 16 [IQR: 12-19], higher in women (17 [14-20]) than men (15 [11-17], p < 0.001). For more than half the population (55.0 %), prediabetes status was already known. However, lifestyle habits were similar for those with newly diagnosed prediabetes and those with prediabetes already known. Conclusion: Screened population in primary care on Reunion Island is relatively young, with a high FINDRISC score and numerous medical conditions. Tailored intervention to improve dietary habits and increase physical activity could help prevent diabetes in this high-risk group.