Intensity-Specific Physical Activity Measured by Accelerometer, Genetic Susceptibility, and the Risk of Kidney Stone Disease: Results From the UK Biobank.

RATIONALE & OBJECTIVE: Kidney stone disease (KSD), a significant healthcare problem within both developed and developing countries, has been associated with genetic risk factors. As well, an association between physical activity and KSD risk has been hypothesized but studies have yielded inconsistent findings. This study aimed to investigate the association between the intensity of physical activity and the incidence of KSD accounting for genetic risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A total of 80,473 participants from the UK Biobank Study. EXPOSURES: Physical activity levels, including total physical activity (TPA), moderate-to-vigorous intensity physical activity (MVPA), and light-intensity physical activity (LPA), were measured using accelerometers and quantified using a machine learning model. A polygenic risk score (PRS) for KSD was also constructed. OUTCOMES: Individuals with KSD were identified using the International Classification of Diseases 10th Edition, and procedure codes for KSD surgery. ANALYTICAL APPROACH: A Fine and Gray survival model was used to estimate the associations of incident KSD with TPA, MVPA, LPA, and PRS (as categorical variables). Restricted cubic splines were used to examine potential non-linear associations within the fully adjusted models. RESULTS: During an average follow-up of 6.19 years, 421 participants developed KSD. Participants in the highest quartiles of TPA, MVPA, and LPA had lower adjusted rates of KSD compared to those in the lowest quartiles: HRs (95% confidence interval) of 0.50 (0.44, 0.56), 0.57 (0.51, 0.64), and 0.66 (0.59, 0.74), respectively. TPA, MVPA, and LPA were associated with lower risk of KSD in participants with low and high genetic predisposition for KSD. LIMITATIONS: Selection bias as participants who provided accelerometry data may have been more adherent to health care. CONCLUSION: Physical activity was negatively associated with the risk of KSD, regardless of the genetic risk. Future large studies are warranted to confirm and explain the mechanisms underlying these associations.

Life's Essential 8, genetic susceptibility, and the risk of psoriatic disease: a prospective cohort study.

BACKGROUND: Psoriatic disease (PsD) is closely associated with cardiovascular diseases. The Life's Essential 8 (LE8) score is a new metric for assessing cardiovascular health (CVH), where a higher score indicates better CVH. However, the longitudinal association between LE8 score and the risk of PsD remains uncertain. The main aim of the present study was to explore the association between LE8 scores and the risk of PsD. OBJECTIVE: To investigate the associations between LE8 score, genetic susceptibility, and the risk of PsD within a cohort design. METHODS: This cohort study included 261,642 participants from the UK Biobank without PsD at baseline. LE8 comprises eight indicators: diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Cox proportional hazard models were employed to examine the association between the participants' LE8 scores, PsD genetic risk, and the risk of PsD. Hazard ratios (HRs) and 95% confidential intervals (CIs) were calculated. RESULTS: During an average follow-up of 12.32 years, 1,501 participants developed PsD. Compared to participants with low LE8 scores, the HRs (95% CIs) of developing PsD for those with moderate and high LE8 scores were 0.51 (0.43, 0.59) and 0.34 (0.27, 0.42) after adjustments, respectively. Dose-response analysis revealed a linear negative association between continuous LE8 score and the risk of developing PsD (P < 0.001), with no evidence of non-linear association detected. The genetic susceptibility to PsD did not modify this association (P for interaction = 0.63). Subgroup analyses revealed that women demonstrated a more pronounced beneficial association between LE8 scores and PsD risk (P for interaction = 0.02). CONCLUSIONS: Our study suggests that a higher LE8 score, regardless of genetic risk, was associated with a lower risk of PsD, particularly among women. Consequently, maintaining a high CVH status is recommended to prevent PsD and assess associated risks.

Pulmonary function, genetic predisposition, and the risk of cirrhosis: A prospective cohort study.

OBJECTIVE: Pulmonary function is associated with the development of chronic liver disease. However, evidence of the association between pulmonary function and cirrhosis risk is still lacking. This study aimed to investigate the longitudinal associations of pulmonary function with the development of cirrhosis, and to explore whether genetic predisposition to cirrhosis could modify these associations. METHODS: Of 294,835 participants free of cirrhosis and had undergone spirometry at baseline from the UK Biobank were included. Cirrhosis diagnoses were ascertained through linked hospital records and death registries. Cox proportional hazard models were employed to investigate the longitudinal associations between pulmonary function, genetic predisposition, and cirrhosis risk. RESULTS: During a median follow-up of 12.0 years, 2598 incident cirrhosis cases were documented. Compared to individuals with normal spirometry findings, those with preserved ratio impaired spirometry (PRISm) findings (hazard ratio [HR] and 95% confidence interval [CI]: 1.32 [1.18, 1.48]) and airflow obstruction (HR [95%CI]: 1.19 [1.07, 1.31]) had a higher risk of developing cirrhosis after adjustments. These associations were consistent across all categories of genetic predisposition, with no observed modifying effect of genetic predisposition. In joint exposure analyses, the highest risk was observed in individuals with both a high genetic predisposition for cirrhosis and PRISm findings (HR [95% CI]: 1.74 [1.45, 2.08]). CONCLUSIONS: Our findings indicate that worse pulmonary function is a significant risk factor of cirrhosis, irrespective of genetic predisposition. Early identification and appropriate intervention for pulmonary function may lead to more effective healthcare resource utilization and reduce the burden associated with cirrhosis.

Prevalence of Diabetes in Patients with Hyperuricemia and Gout: A Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: To perform a systematic review and meta-analysis of the prevalence of diabetes in patients with hyperuricemia and gout. RECENT FINDINGS: Previous studies have confirmed that hyperuricemia and gout are associated with an increased risk of diabetes. A previous meta-analysis indicated that the prevalence of diabetes in patients with gout is 16%. Thirty-eight studies (458,256 patients) were included in the meta-analysis. The combined prevalence of diabetes among patients with hyperuricemia and gout were 19.10% (95% confidence interval [CI]: 17.60-20.60; I2 = 99.40%) and 16.70% (95% CI: 15.10-18.30; I2 = 99.30%), respectively. Patients from North America showed a higher prevalence of diabetes (hyperuricemia: 20.70% [95% CI: 16.80-24.60], gout: 20.70% [95% CI: 16.80-24.60]) than those from other continents. Older patients with hyperuricemia and those using diuretics showed a higher prevalence of diabetes than younger patients and those who were not using diuretics. Studies with a small sample size, case-control design, and low quality score had a higher prevalence of diabetes than studies with a large sample size, other designs, and a high quality score. The prevalence of diabetes among patients with hyperuricemia and gout is high. Controlling plasma glucose and uric acid levels of patients with hyperuricemia and gout is critical for the prevention of diabetes.

Efficacy of apremilast for psoriasis: a meta-analysis of randomized controlled studies.

Introduction: The efficacy of apremilast for psoriasis remains controversial. Aim: We have conducted a systematic review and meta-analysis to explore the influence of apremilast on treatment efficacy for psoriasis. Material and methods: We have searched PubMed, Embase, Web of science, EBSCO, and Cochrane library databases for randomized controlled trials (RCTs) published until February 2022 and assessing the efficacy and safety of apremilast for psoriasis. This meta-analysis was performed using the random-effects model. Results: Seven RCTs were included in the meta-analysis. Overall, compared with placebo for psoriasis, apremilast was associated with improved PASI-75 (LOCF) (OR = 6.59; 95% CI: 4.55 to 9.53; p < 0.00001), PASI-75 (NRI) (OR = 6.99; 95% CI: 4.43 to 11.04; p < 0.00001), sPGA response (LOCF) (OR = 5.58; 95% CI: 3.82 to 8.16; p < 0.00001), sPGA response (NRI) (OR = 6.06; 95% CI: 4.07 to 9.02; p < 0.00001), PASI-50 (LOCF) (OR = 4.37; 95% CI: 2.72 to 7.01; p < 0.00001), PASI-90 (LOCF) (OR = 7.81; 95% CI: 2.89 to 21.08; p < 0.0001), adverse events (OR = 1.58; 95% CI: 1.19 to 2.10; p = 0.002), but demonstrated no increase in serious adverse events (OR = 1.01; 95% CI: 0.43 to 2.33; p = 0.99). Conclusions: Apremilast is effective and safe to treat psoriasis.

Validity and reproducibility of a FFQ for assessing dietary intake among residents of northeast China: northeast cohort study of China.

The study was to evaluate the reproducibility and validity of the FFQ for residents of northeast China. A total of 131 participants completed two FFQ (FFQ1 and FFQ2) within a 3-month period, 125 participants completed 8-d weighed diet records (WDR) and 112 participants completed blood biomarker testing. Reproducibility was measured by comparing nutrient and food intake between FFQ1 and FFQ2. The validity of the FFQ was assessed by WDR and the triad method. The Spearman correlation coefficients (SCC) and intraclass correlation coefficients (ICC) for reproducibility ranged from 0·41 to 0·69 (median = 0·53) and from 0·18 to 0·68 (median = 0·53) for energy and nutrients and from 0·37 to 0·73 (median = 0·59) and from 0·33 to 0·86 (median = 0·60) for food groups, respectively. The classifications of same or adjacent quartiles ranged from 73·64 to 93·80 % for both FFQ. The crude SCC between the FFQ and WDR ranged from 0·27 to 0·55 (median = 0·46) for the energy and nutrients and from 0·26 to 0·70 (median = 0·52) for food groups, and classifications of the same or adjacent quartiles ranged from 65·32 to 86·29 %. The triad method indicated that validation coefficients for the FFQ were above 0·3 for most nutrients, which indicated a moderate or high level of validity. The FFQ that was developed for residents of northeast China for the Northeast Cohort Study of China is reliable and valid for assessing the intake of most foods and nutrients.

A Protein-Truncating HSD17B13 Variant and Protection from Chronic Liver Disease.

BACKGROUND: Elucidation of the genetic factors underlying chronic liver disease may reveal new therapeutic targets. METHODS: We used exome sequence data and electronic health records from 46,544 participants in the DiscovEHR human genetics study to identify genetic variants associated with serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Variants that were replicated in three additional cohorts (12,527 persons) were evaluated for association with clinical diagnoses of chronic liver disease in DiscovEHR study participants and two independent cohorts (total of 37,173 persons) and with histopathological severity of liver disease in 2391 human liver samples. RESULTS: A splice variant (rs72613567:TA) in HSD17B13, encoding the hepatic lipid droplet protein hydroxysteroid 17-beta dehydrogenase 13, was associated with reduced levels of ALT (P=4.2×10-12) and AST (P=6.2×10-10). Among DiscovEHR study participants, this variant was associated with a reduced risk of alcoholic liver disease (by 42% [95% confidence interval {CI}, 20 to 58] among heterozygotes and by 53% [95% CI, 3 to 77] among homozygotes), nonalcoholic liver disease (by 17% [95% CI, 8 to 25] among heterozygotes and by 30% [95% CI, 13 to 43] among homozygotes), alcoholic cirrhosis (by 42% [95% CI, 14 to 61] among heterozygotes and by 73% [95% CI, 15 to 91] among homozygotes), and nonalcoholic cirrhosis (by 26% [95% CI, 7 to 40] among heterozygotes and by 49% [95% CI, 15 to 69] among homozygotes). Associations were confirmed in two independent cohorts. The rs72613567:TA variant was associated with a reduced risk of nonalcoholic steatohepatitis, but not steatosis, in human liver samples. The rs72613567:TA variant mitigated liver injury associated with the risk-increasing PNPLA3 p.I148M allele and resulted in an unstable and truncated protein with reduced enzymatic activity. CONCLUSIONS: A loss-of-function variant in HSD17B13 was associated with a reduced risk of chronic liver disease and of progression from steatosis to steatohepatitis. (Funded by Regeneron Pharmaceuticals and others.).

Associations between different types and sources of dietary fibre intake and depressive symptoms in a general population of adults: a cross-sectional study.

This cross-sectional study aimed to examine the associations between dietary fibre (DF) intake and depressive symptoms in a general adult population in Tianjin, China. A total of 24 306 participants (mean age 41 years; range 18-91 years) were enrolled. DF intake was assessed using a validated self-administered FFQ. Depressive symptoms were assessed using the Self-Rating Depression Scale. Associations between DF intake and depressive symptoms were estimated using logistic regression analysis. Socio-demographic, behavioural, health status and dietary factors were adjusted. In men, compared with participants in the lowest quartiles for total, soluble, vegetable and soya DF, OR for depressive symptoms in the highest were 0·83 (95 % CI 0·69, 0·99), 0·74 (95 % CI 0·63, 0·87), 0·79 (95 % CI 0·65, 0·96) and 0·69 (95 % CI 0·60, 0·81), respectively. In women, compared with participants in the lowest quartiles for vegetable and soya DF, the OR for depressive symptoms in the highest were 0·77 (95 % CI 0·64, 0·93) and 0·82 (95 % CI 0·70, 0·95), respectively. No association was found between total or soluble DF intake and depressive symptoms in women. No association was found between insoluble, cereal, fruit or tuber DF intake and depressive symptoms in men and women. Linear associations between DF intake and depressive symptoms were only detected for soya DF (men, ß = -0·148, P < 0·0001; women, ß = -0·069, P = 0·04). Results suggest that intake of soluble, vegetable and soya DF was inversely associated with depressive symptoms. These results should be confirmed through prospective and interventional studies.

Longitudinal associations between household solid fuel use and depression in middle-aged and older Chinese population: A cohort study.

BACKGROUND: Previous studies found that ambient air pollution was associated with a higher prevalence of depressive symptoms. However, the longitudinal associations between household solid fuel use, which is the main source of household air pollution, and depressive symptoms remain unclear. This cohort study aimed to explore the associations between household solid fuel use and incidence of depressive symptoms in China. METHODS: In total, 8637 participants were enrolled in this prospective cohort study. Depressive symptoms were assessed using the 10-item Center for Epidemiological Studies Depression Scale. The associations between baseline household solid fuel use and the incidence of depressive symptoms were examined using Cox proportional hazards regression models. RESULTS: During the 4-year of follow-up, 2074 of 8637 participants developed depressive symptoms. Compared with participants who used clean fuel for both heating and cooking, the multivariate-adjusted hazard ratio (HR) (95% confidence intervals [95% CI]) for depressive symptoms incidence in participants who used solid fuels for two purposes (cooking and heating) was 1.15 (1.01, 1.31). In the solid fuel use subgroup analysis, use of solid fuels for cooking (HR, 1.12; 95% CI, 1.02-1.24) was associated with a higher incidence of depressive symptoms after adjustments while use for heating (HR, 1.05; 95% CI, 0.93-1.18) was not. Moreover, compared with persistent solid fuel users, switching from solid to clean fuels for cooking resulted in a lower risk of depressive symptoms before adjustments (HR, 0.82; 95% CI, 0.71-0.95) and a non-significant association (HR, 0.90; 95% CI, 0.77-1.04) afterwards. CONCLUSIONS: The results suggest that household solid fuel use for cooking was associated with a higher incidence of depressive symptoms. Preventive strategies based on improving household cooking environment for depressive symptoms should be established.

The association between glycemic index, glycemic load, and metabolic syndrome: a systematic review and dose-response meta-analysis of observational studies.

PURPOSE: The association of glycemic index (GI) and glycemic load (GL) with metabolic syndrome (MetS) is controversial. Therefore, we conducted this first systematic review and dose-response meta-analysis of observational studies to quantify these associations. METHODS: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library for relevant studies up to 1 April 2019. Summary odds ratios (OR) and 95% confidence intervals (CI) were calculated by a random-effects model. This study was registered with PROSPERO (CRD42019131788). RESULTS: We included eight high-quality (n = 5) or medium-quality (n = 3) cross-sectional studies in the final meta-analysis, comprising 6058 MetS events and 28,998 participants. The summary ORs of MetS for the highest versus lowest categories were 1.23 (95% CI 1.10-1.38, I2 = 0, tau2 = 0, n = 5) for dietary GI, 1.06 (95% CI 0.89-1.25, I2 = 36.2%, tau2 = 0.0151, n = 6) for dietary GL. The summary OR was 1.12 (95% CI 1.00-1.26, I2 = 0, tau2 = 0, n = 3) per 5 GI units, 0.96 (95% CI 0.83-1.10, I2 = 33.4%, tau2 = 0.0059, n = 2) per 20 GL units. CONCLUSIONS: Dietary GI was positively associated with the prevalence of MetS. However, no significant association was found between dietary GL and the prevalence of MetS. Further studies with prospective design are needed to establish potential causal relationship between dietary GI and the MetS.

Relationship between legume consumption and metabolic syndrome: A systematic review and meta-analysis of observational studies.

AIMS: The prevalence of metabolic syndrome (MetS) has been increasing in recent years. Investigation of whether consumption of legumes as a part of healthy diet could reduce the odds of MetS has led to inconsistent conclusions. Here, we performed the first meta-analysis of observational studies to analyze the association between legume consumption and prevalence of MetS. DATA SYNTHESIS: PubMed, EMBASE, and Web of Science databases were searched to identify observational studies up to June 1, 2019. We extracted data from the studies included and performed quality assessments. Summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random-effects model. Publication bias and subgroup and sensitivity analyses were also performed. We finally included four cross-sectional studies, two cohort studies, and one case-control study involving 56,028 participants. The summary OR revealed no statistically significant association between legume consumption and odds of MetS (OR = 0.93, 95% CI = 0.76-1.12, I2 = 73.5%). Subgroup analysis of study characteristics and adjustment for confounding along with sensitivity analyses revealed no statistically significant differences. No evidence of publication bias was detected. CONCLUSION: Legume consumption is not associated with the odds of MetS. These findings require validation in well-designed cohort studies and randomized clinical trials with accurate measurement of legume intake and strict control of confounders. REGISTRATION: This study was registered with the International Prospective Register of Systematic Reviews (registration number: CRD42019131777).

Carbohydrate intake and risk of metabolic syndrome: A dose-response meta-analysis of observational studies.

BACKGROUND AND AIMS: Epidemiological association studies have reported inconsistent findings on the relationship between carbohydrate intake and risk of metabolic syndrome (MetS). Therefore, we aimed to conduct the first dose-response meta-analysis to investigate this effect. METHODS AND RESULTS: A systematic search in PubMed and Web of Science databases from their inception to June 01, 2019, together with relevant literature scrutiny, was performed to identify related studies for inclusion into the meta-analysis. We calculated the odds ratios (ORs) with 95% confidence intervals (CIs) using a random effects model. Furthermore, subgroup, sensitivity, heterogeneity, and publication bias analyses were performed. This meta-analysis included 14 cross-sectional and four cohort studies, totaling 284,638 participants and 69,554 MetS cases. The highest versus the lowest carbohydrate intake values were associated with an increased risk of MetS (OR: 1.253, 95% CI: 1.147-1.368), with moderate heterogeneity (I2 = 54.5%). Using dose-response analysis, we found a linear association between carbohydrate consumption and MetS risk with a corresponding OR of 1.026 (95% CI, 1.004-1.048) and with significant heterogeneity (I2 = 82.0%) at 5% energy intake from carbohydrates. We have found similar results using subgroup analyses for major study characteristics and adjustment for confounders. Sensitivity analysis further enhanced the robustness of the results, and no publication bias was detected. CONCLUSION: Carbohydrate intake is associated with an increased risk of developing MetS. Therefore, additional large prospective cohort studies are warranted to confirm our findings.

Multiplex Immuno-Liquid Chromatography-Mass Spectrometry-Parallel Reaction Monitoring (LC-MS-PRM) Quantitation of CD8A, CD4, LAG3, PD1, PD-L1, and PD-L2 in Frozen Human Tissues.

The immune status of tumors critically influences their responsiveness to PD1 blockades and other immune-based therapies. Programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) is a clinically validated predictive biomarker of response to checkpoint-inhibitor therapy in a limited number of clinical settings but is poorly predictive in most. With emerging evidence that multiple pathways and immune-checkpoint proteins may coordinately contribute to the adaptive immune resistance, the identification and quantitation of multiple immune markers in tumor tissue could help identify the controlling pathways in a given patient, guide the selection of optimal therapy, and monitor response to treatment. We developed and validated a sensitive and robust immuno-liquid chromatography-parallel reaction monitoring assay to simultaneously quantify the expression levels of six immune markers (CD8A, CD4, LAG3, PD1, PD-L1, and PD-L2) using as little as 1-2 mg of fresh frozen tissue. The lower limit of quantitation ranged from 0.07 ng/mg protein for PD1 to 1.0 ng/mg protein for CD4. The intrabatch accuracy was within -16.6% to 15.0% for all proteins at all concentrations, and the variation ranged from 0.8% to 14.7%, while interbatch accuracy was within -6.3% to 8.6%, and the variation ranged from 1.3% to 12.8%. The validated assay was then applied to quantify all six biomarkers in different tissues and was confirmed to have sufficient sensitivity (0.07-1.00 ng/mg protein) and reproducibility (variation ranged from 4.3 to 12.0%). In an analysis of 26 cervical tumors, CD8A and CD4 were detected in all tumors, followed by PD-L1 in 85%, LAG-3 in 65%, PD1 in 50%, and PD-L2 in 35%. The strongest correlations were observed between CD8A and CD4 ( r = 0.88) and CD8A and LAG-3 ( r = 0.86). PD1 was not significantly correlated with any of the other proteins tested. This method can be applied to survey the immune signatures across tumor types and tailored to incorporate additional markers as needed.

Epitope Mapping by HDX-MS Elucidates the Surface Coverage of Antigens Associated with High Blocking Efficiency of Antibodies to Birch Pollen Allergen.

Epitopes of a native pollen allergen protein, birch Bet v1, against four of the noncompeting anti-Bet v1 antibodies individually or in combination, were identified by solution-phase amide backbone H/D exchange (HDX) coupled with high-resolution Q-TOF or Orbitrap mass spectrometry. The HDX results indicates that the four anti-Bet v1 antibodies protected specific regions of Bet v1, explaining the difference in their blocking efficiency of each antibody against Bet v1 binding to polyclonal IgEs in Bet v1 allergic patients. An in-house HDX-MS system was further developed to explore the surface protection of Bet v1 in the presence of all four antibodies with 100% sequence coverage and high redundancy. The data demonstrated that four anti-Bet v1 antibodies were able to simultaneously bind to Bet v1 in solution to provide the most effective blocking for 9 of 10 tested IgE donors in an in vitro antibody-blocking assay. For the first time, we have applied HDX to elucidate the therapeutic advantage of combination antibodies compared with individual antibodies in treating Bet v1 induced allergy.

Metabolomic biosignature differentiates melancholic depressive patients from healthy controls.

BACKGROUND: Major depressive disorder (MDD) is a heterogeneous disease at the level of clinical symptoms, and this heterogeneity is likely reflected at the level of biology. Two clinical subtypes within MDD that have garnered interest are "melancholic depression" and "anxious depression". Metabolomics enables us to characterize hundreds of small molecules that comprise the metabolome, and recent work suggests the blood metabolome may be able to inform treatment decisions for MDD, however work is at an early stage. Here we examine a metabolomics data set to (1) test whether clinically homogenous MDD subtypes are also more biologically homogeneous, and hence more predictiable, (2) devise a robust machine learning framework that preserves biological meaning, and (3) describe the metabolomic biosignature for melancholic depression. RESULTS: With the proposed computational system we achieves around 80 % classification accuracy, sensitivity and specificity for melancholic depression, but only ~72 % for anxious depression or MDD, suggesting the blood metabolome contains more information about melancholic depression.. We develop an ensemble feature selection framework (EFSF) in which features are first clustered, and learning then takes place on the cluster centroids, retaining information about correlated features during the feature selection process rather than discarding them as most machine learning methods will do. Analysis of the most discriminative feature clusters revealed differences in metabolic classes such as amino acids and lipids as well as pathways studied extensively in MDD such as the activation of cortisol in chronic stress. CONCLUSIONS: We find the greater clinical homogeneity does indeed lead to better prediction based on biological measurements in the case of melancholic depression. Melancholic depression is shown to be associated with changes in amino acids, catecholamines, lipids, stress hormones, and immune-related metabolites. The proposed computational framework can be adapted to analyze data from many other biomedical applications where the data has similar characteristics.

Quantitative proteomics for cardiac biomarker discovery using isoproterenol-treated nonhuman primates.

To identify new cardiac biomarkers, a quantitative proteomic analysis has been performed on serum and heart tissue proteins from three species of nonhuman primates following isoproterenol (ISO) treatment. Three serum proteins--serum amyloid A (SAA), α-1-acid glycoprotein (A1AG), and apolipoprotein A-1 (Apo A1)--were consistently identified as changed and remained altered 72 h post dose in all three species post ISO treatment, indicating the potential of including these proteins in preclinical or clinical evaluation of drug-induced cardiac injury. Furthermore, proteomic analysis of heart tissue proteins following ISO treatment demonstrated detrimental effects on calcium signaling and energy generation in cardiac myocytes. It is worth noting that cardiac troponins were not identified in serum but were identified as altered in heart tissue lysate along with other cardiac-specific proteins. This strategy for cardiac biomarker discovery by proteomic screening of heart tissue proteins, followed by verification in serum samples using immunoassays or targeted mass spectrometry, could be applied in future biomarker studies.

CD90 is identified as a candidate marker for cancer stem cells in primary high-grade gliomas using tissue microarrays.

Although CD90 has been identified as a marker for various kinds of stem cells including liver cancer stem cells (CSCs) that are responsible for tumorigenesis, the potential role of CD90 as a marker for CSCs in gliomas has not been characterized. To address the issue, we investigated the expression of CD90 in tissue microarrays containing 15 glioblastoma multiformes (GBMs), 19 WHO grade III astrocytomas, 13 WHO grade II astrocytomas, 3 WHO grade I astrocytomas and 8 normal brain tissues. Immunohistochemical analysis showed that CD90 was expressed at a medium to high level in all tested high-grade gliomas (grade III and GBM) whereas it was barely detectable in low-grade gliomas (grade I and grade II) and normal brains. Double immunofluorescence staining for CD90 and CD133 in GBM tissues revealed that CD133(+) CSCs are a subpopulation of CD90(+) cells in GBMs in vivo. Flow cytometry analysis of the expression of CD90 and CD133 in GBM-derived stem-like neurospheres further confirmed the conclusion in vitro. The expression levels of both CD90 and CD133 were reduced along with the loss of stem cells after differentiation. Furthermore, the limiting dilution assay demonstrated that the sphere formation ability was comparable between the CD90(+)/CD133(+) and the CD90(+)/CD133(-) populations of GBM neurospheres, which is much higher than that of the CD90(-)/CD133(-) population. We also performed double staining for CD90 and a vascular endothelial cell marker CD31 in tissue microarrays which revealed that the CD90(+) cells were clustered around the tumor vasculatures in high-grade glioma tissues. These findings suggest that CD90 is not only a potential prognostic marker for high-grade gliomas but also a marker for CSCs within gliomas, and it resides within endothelial niche and may also play a critical role in the generation of tumor vasculatures via differentiation into endothelial cells.

Associations between frailty, genetic predisposition, and chronic kidney disease risk in middle-aged and older adults: A prospective cohort study.

OBJECTIVES: Cross-sectional evidence has shown that frailty is highly prevalent in patients with chronic kidney disease (CKD). However, there is limited evidence of the longitudinal associations between frailty, genetic predisposition to CKD, and the risk of CKD in the general population. Therefore, this study aimed to examine such associations among participants in the UK Biobank. STUDY DESIGN: This is a prospective cohort study included 370,965 middle-aged and older adults from the UK Biobank. Physical frailty was assessed using a modified version of the Fried phenotype classification. A weighted genetic risk score was built using 263 variants associated with estimated glomerular filtration rate. MAIN OUTCOME MEASURES: Incident CKD was identified from hospital inpatient records. RESULTS: Over a median follow-up of 12.3 years, we documented a total of 11,121 incident CKD cases. Time-dependent Cox proportional hazards regression models indicated that individuals with frailty (hazard ratio [HR]: 1.94, 95 % confidence interval [CI]: 1.81-2.08) and pre-frailty (HR: 1.27, 95 % CI: 1.22-1.33) had an increased risk of developing CKD, compared with non-frail individuals. No significant interaction between frailty and genetic risk score was observed (P for interaction = 0.41). The highest risk was observed among the individuals with high genetic risk and frailty (HR: 2.31, 95 % CI: 2.00-2.68). CONCLUSION: Our results demonstrated that frailty and pre-frailty were associated with increased risk of incident CKD in middle-age and older adults, regardless of genetic risk of CKD. Our study underscores the importance of frailty screening and intervention as a potential strategy to prevent CKD. Future clinical trials are needed to validate our findings.

Ultra-processed food consumption, genetic susceptibility, and the risk of hip/knee osteoarthritis.

BACKGROUND: The associations between ultra-processed food (UPF) consumption, genetic susceptibility, and the risk of osteoarthritis (OA) remain unknown. This study was to examine the effect of UPF consumption, genetic susceptibility, and their interactions on hip/knee OA. METHODS: Cohort analyses included 163,987 participants from the UK Biobank. Participants' UPF consumption was derived from their 24-h dietary recall using a questionnaire. Genetic risk scores (GRSs) of 70 and 83 single nucleotide polymorphisms (SNPs) for hip and knee OA were constructed. FINDINGS: After 1,461,447 person-years of follow-up, 11,540 patients developed OA. After adjustments, compared to participants in the low quartile of UPF consumption, those in the high quartile had a 10 % (hazard ratio [HR], 1.10; 95% confidence interval [CI], 1.03-1.18) increased risk of knee OA. No significant association was found between UPF consumption and hip OA. Replacing 20% of UPF diet weight with an equivalent proportion of unprocessed or minimally processed food caused a 6% (HR, 0.94; 95% CI, 0.89-0.98) decreased risk of knee OA, respectively. A significant interaction was found between UPF consumption, genetic predisposition, and the risk of knee OA (P = 0.01). Participants with lower OA-GRS scores experienced higher knee OA risks due to UPF consumption. INTERPRETATION: UPF consumption was associated with a higher risk of knee OA but not hip OA, particularly in those with lower genetic susceptibility. These results highlight the importance of reducing UPF consumption to prevent knee OA.

Physical frailty, genetic predisposition, and the risks of severe non-alcoholic fatty liver disease and cirrhosis: a cohort study.

BACKGROUND: Frailty, defined as a phenotype of decreased physiological reserves and diminished ability to respond to stressors, has been linked to the development of chronic diseases. Epidemiological evidence connecting frailty to non-alcoholic fatty liver disease (NAFLD) and cirrhosis risks remain sparse. We aimed to assess the longitudinal associations of frailty with the risks of severe NAFLD and cirrhosis in middle-aged to older adults and further explore the modification role of genetic risk on these associations. METHODS: This study included a total of 398 386 participants from the UK Biobank. Incident cases of severe NAFLD and cirrhosis were ascertained through linked hospital records and death registries. Frailty status was assessed by a modified version of the frailty phenotype, encompassing five key components: weight loss, tiredness, physical activity, gait speed, and grip strength. Participants were classified as pre-frailty if they met one or two of these criteria, and as frailty if they met three or more. Genetic predisposition to NAFLD and cirrhosis was estimated by genetic risk score (GRS) and further categorized into high, intermediate, and low genetic risk levels according to tertiles of GRSs. Cox proportional hazards regression model was employed to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for their associations. RESULTS: The mean (standard deviation) age of the study population was 56.6 (8.03) years. 214 408 (53.8%) of the participants was female; 14 924 (3.75%) of participants met the criteria for frailty, 170 498 (42.8%) for pre-frailty, and 212 964 (53.5%) for non-frailty. Over a median follow-up of 12.0 years, we documented 4439 incident severe NAFLD and 3323 incident cirrhosis cases, respectively. Compared with non-frailty, both pre-frailty (HR: 1.50; 95% CI: 1.40-1.60) and frailty (HR: 1.98; 95% CI: 1.77-2.21) were associated with increased risk of NAFLD. Similar associations were observed for cirrhosis, the corresponding HRs (95% CIs) for non-frailty, pre-frailty, and frailty were 1.00 (reference), 1.29 (1.20, 1.38), and 1.90 (1.66, 2.18). Such associations were consistent across all genetic risk levels, with no observed interactions between frailty and GRSs (all P for interactions ≥0.10). Compared with participants with frailty and a low level of genetic risk, the greatest risk increasement in developing severe NAFLD (HR: 3.36; 95% CI: 2.83-3.99) and cirrhosis (HR: 2.81; 95% CI: 2.29-3.44) was both observed in those with frailty and a high level of genetic risk. CONCLUSIONS: Our findings indicate that frailty is a significant predictor of severe NAFLD and cirrhosis, irrespective of genetic predisposition.