Impact of healthy lifestyle on the incidence and progression trajectory of mental disorders: A prospective study in the UK Biobank.

BACKGROUND: Healthier lifestyle decreased the risk of mental disorders (MDs) such as depression and anxiety. However, research on the effects of a comprehensive healthy lifestyle on their progression is lacking. METHODS: 385,704 individuals without baseline MDs from the UK Biobank cohort were included. A composite healthy lifestyle score was computed by assessing alcohol intake, smoking status, television viewing time, physical activity, sleep duration, fruit and vegetable intake, oily fish intake, red meat intake, and processed meat intake. Follow-up utilized hospital and death register records. Multistate model was used to examine the role of healthy lifestyle on the progression of specific MDs, while a piecewise Cox regression model was utilized to assess the influence of healthy lifestyle across various phases of disease progression. RESULTS: Higher lifestyle score reduced risks of transitions from baseline to anxiety and depression, as well as from anxiety and depression to comorbidity, with corresponding hazard ratios (HR) and 95 % confidence intervals (CI) of 0.94 (0.93, 0.95), 0.90 (0.89, 0.91), 0.94 (0.91, 0.98), and 0.95 (0.92, 0.98), respectively. Healthier lifestyle decreased the risk of transitioning from anxiety to comorbidity within 2 years post-diagnosis, with HR 0.93 (0.88, 0.98). Higher lifestyle scores at 2-4 years and 4-6 years post-depression onset were associated with reduced risk of comorbidity, with HR 0.93 (0.87, 0.99) and 0.92 (0.86, 0.99), respectively. LIMITATION: The generalizability to other ethnic groups is limited. CONCLUSION: This study observed a protective role of holistic healthy lifestyle in the trajectory of MDs and contributed to identifying critical progression windows.

A Mitochondria-Targeted Nitric Oxide Probe for Multimodality Imaging of Macrophage Immune Responses.

Nitric oxide (NO) is a crucial signal molecule closely linked to the biological immune response, especially in macrophage polarization. When activated, macrophages enter a pro-inflammatory state and produce NO, a marker for the M1 phenotype. In contrast, the anti-inflammatory M2 phenotype does not produce NO. We developed a mitochondria-targeted two-photon iridium-based complex (Ir-ImNO) probe that can detect endogenous NO and monitor macrophages' different immune response states using various imaging techniques, such as one- and two-photon phosphorescence imaging and phosphorescence lifetime imaging. Ir-ImNO was used to monitor the immune activation of macrophages in mice. This technology aims to provide a clear and comprehensive visualization of macrophage immune responses.

Microvascular disease, modifiable risk factor profiles and incident arrhythmias in type 2 diabetes.

BACKGROUND: To assess the roles of diabetic microvascular disease and modifiable risk factors and their combination in the development of arrhythmias. METHODS: We included participants with type 2 diabetes (T2D) who were free of arrhythmias during recruitment in the UK Biobank study. The associations of microvascular disease states (defined by the presence of retinopathy, peripheral neuropathy or chronic kidney disease), four modifiable arrhythmic risk factors (body mass index, smoking, systolic blood pressure and glycosylated haemoglobin) and their joint associations with incident arrhythmias were examined. RESULTS: Among the 25 632 participants with T2D, 1705 (20.1%) of the 8482 with microvascular disease and 2017 (11.8%) of the 17 150 without microvascular disease developed arrhythmias during a median follow-up of 12.3 years. Having any of the three microvascular diseases was associated with a 48% increase in the hazard of developing arrhythmias. Incorporating microvascular disease states into a model alongside 11 traditional risk factors significantly enhanced arrhythmia prediction. Furthermore, individuals with microvascular disease who had optimal levels of zero to one, two, three or four arrhythmic risk factors showed an HR of 2.05 (95% CI 1.85, 2.27), 1.67 (95% CI 1.53, 1.83), 1.35 (95% CI 1.22, 1.50) and 0.91 (95% CI 0.73, 1.13), respectively, compared with those without microvascular disease. CONCLUSIONS: Although microvascular disease, a non-traditional risk factor, was associated with incident arrhythmias in individuals with T2D, having optimal levels of risk factors may mitigate this risk.

Microvascular burden and long-term risk of stroke and dementia in type 2 diabetes mellitus.

OBJECTIVE: To examine the associations between microvascular disease (MVD) and risk of stroke, dementia, and their major subtypes among individuals with type 2 diabetes mellitus (T2DM). METHODS: We included 26,173 participants with T2DM from the UK Biobank who had no known stroke or dementia at baseline. MVD burden was reflected by the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. Cox regression models were used to estimate hazard ratios (HRs) and 95 % confidential intervals (CIs) of stroke and dementia associated with overall MVD burden and individual MVD. RESULTS: During a median follow-up of 11.5 years, 1103 incident stroke (964 ischemic and 269 hemorrhagic stroke) and 813 incident dementia (312 Alzheimer's disease and 304 vascular dementia) cases were identified. The risk of stroke, dementia, and their major subtypes all increased with an increasing number of MVD (all P-trend <0.001). The adjusted HRs (95 % CIs) comparing three with no MVD were 5.03 (3.16, 8.02) for all stroke, 4.57 (2.75, 7.59) for ischemic stroke, and 6.60 (2.65, 16.43) for hemorrhagic stroke. The corresponding estimates were 4.28 (2.33, 7.86) for all-cause dementia, 6.96 (3.02, 16.01) for Alzheimer's disease, and 3.81 (1.40, 10.42) for vascular dementia. Among the three MVD, chronic kidney disease showed the strongest associations with both stroke subtypes, while peripheral neuropathy was most strongly associated with both dementia subtypes. CONCLUSIONS: Risk of stroke, dementia, and their major subtypes increased with an increasing number of MVD. The associations of individual MVD with stroke and dementia varied substantially by types of MVD.

Association of hospital-treated infectious diseases and infection burden with cardiovascular diseases and life expectancy.

BACKGROUND: The association of a broad spectrum of infectious diseases with cardiovascular outcomes remains unclear. OBJECTIVES: We aim to provide the cardiovascular risk profiles associated with a wide range of infectious diseases and explore the extent to which infections reduce life expectancy. METHODS: We ascertained exposure to 900+ infectious diseases before cardiovascular disease (CVD) onset in 453,102 participants from the UK Biobank study. Time-varying Cox proportional hazard models were used. Life table was used to estimate the life expectancy of individuals aged ≥50 with different levels of infection burden (defined as the number of infection episodes over time and the number of co-occurring infections). RESULTS: Infectious diseases were associated with a greater risk of CVD events (adjusted HR [aHR] 1.79 [95% confidence interval {CI} 1.74-1.83]). For type-specific analysis, bacterial infection with sepsis had the strongest risk of CVD events [aHR 4.76 (4.35-5.20)]. For site-specific analysis, heart and circulation infections posed the greatest risk of CVD events [aHR 4.95 (95% CI 3.77-6.50)], whereas noncardiac infections also showed excess risk [1.77 (1.72-1.81)]. Synergistic interactions were observed between infections and genetic risk score. A dose-response relationship was found between infection burden and CVD risks (p-trend <0.001). Infection burden >1 led to a CVD-related life loss at age 50 by 9.3 years [95% CI 8.6-10.3]) for men and 6.6 years [5.5-7.8] for women. CONCLUSIONS: The magnitude of the infection-CVD association showed specificity in sex, pathogen type, infection burden, and infection site. High genetic risk and infection synergistically increased the CVD risk.

Microvascular Disease, Cardiovascular Health, and Risk of Coronary Heart Disease in Type 2 Diabetes: A UK Biobank Study.

CONTEXT: The interplay between cardiovascular health metrics (CVHMs) and microvascular disease (MVD) in relation to the risk of incident coronary heart disease (CHD) among individuals with type 2 diabetes mellitus (T2DM) remains to be evaluated. OBJECTIVE: To investigate the role of MVD and CVHMs in the development of CHD among T2DM. DESIGN: We included 19,664 participants with T2DM from the UK Biobank who had data on CVH metrics (CVHMs) and were free of CHD during recruitment. CVHMs were defined based on five behavioral (body mass index, diet, sleep duration, smoking, and regular exercise) and three biological factors (glycemic control, hyperlipidemia, and hypertension). MVD was defined as the presence of retinopathy, peripheral neuropathy, and chronic kidney disease. HR and 95% CI of CHD were estimated by multivariable Cox regression models. RESULTS: There were 3,252 incident cases of CHD recorded after a median follow-up of 12.3 years. After multivariable adjustment, each MVD was separately associated with risk of CHD, and those who had 1 or ≥2 MVD had a 27% and an 87% increased risk of developing CHD, respectively. Each of the unfavorable CVHMs was associated with a higher risk of CHD. As compared with MVD-free participants who had ideal CVHMs, those who had ≥2 MVD and had poor CVHMs were at particularly high risk of incident CHD (HR=4.58; 95% CI: 3.58, 5.86), similarly when considering behavioral CVH or biological CVH separately. On an additive scale, there was a positive statistically significant interaction between number of MVD and CVHMs. CONCLUSIONS: Coexistence of multiple MVDs was associated with a substantially higher risk of CHD among individuals with T2DM. Such an association may be amplified by unfavorable CVHMs.

Nanocatalysts for modulating antitumor immunity: fabrication, mechanisms and applications.

Immunotherapy harnesses the inherent immune system in the body to generate systemic antitumor immunity, offering a promising modality for defending against cancer. However, tumor immunosuppression and evasion seriously restrict the immune response rates in clinical settings. Catalytic nanomedicines can transform tumoral substances/metabolites into therapeutic products in situ, offering unique advantages in antitumor immunotherapy. Through catalytic reactions, both tumor eradication and immune regulation can be simultaneously achieved, favoring the development of systemic antitumor immunity. In recent years, with advancements in catalytic chemistry and nanotechnology, catalytic nanomedicines based on nanozymes, photocatalysts, sonocatalysts, Fenton catalysts, electrocatalysts, piezocatalysts, thermocatalysts and radiocatalysts have been rapidly developed with vast applications in cancer immunotherapy. This review provides an introduction to the fabrication of catalytic nanomedicines with an emphasis on their structures and engineering strategies. Furthermore, the catalytic substrates and state-of-the-art applications of nanocatalysts in cancer immunotherapy have also been outlined and discussed. The relationships between nanostructures and immune regulating performance of catalytic nanomedicines are highlighted to provide a deep understanding of their working mechanisms in the tumor microenvironment. Finally, the challenges and development trends are revealed, aiming to provide new insights for the future development of nanocatalysts in catalytic immunotherapy.

Association of changes in waist circumference, waist-to-height ratio and weight-adjusted-waist index with multimorbidity among older Chinese adults: results from the Chinese longitudinal healthy longevity survey (CLHLS).

BACKGROUND: The association of changes in waist circumference (WC), waist-to-height ratio (WHtR) and weight-adjusted-waist index (WWI) with subsequent risk of multimorbidity remains unclear among older Chinese adults. Therefore, we aimed to assess this association by utilizing data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). METHODS: Our study was based on the 2011/2012 wave of the CLHLS whose follow-up surveys were conducted in 2014 and 2017/2018. A total of 2900 participants aged 65 and above at baseline were enrolled. WC, WHtR, and WWI were calculated from measured height, weight, and waist circumference. Multimorbidity refers to the coexistence of two or more of 18 chronic diseases. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) to evaluate the effect of three-year changes in WC, WHtR, and WWI on the risk of multimorbidity. RESULTS: During a mean follow-up time of 4.2 (2.0) years, 906 multimorbidity cases were identified. Compared to participants in the persistently low WC group, those in the WC gain group and the persistently high WC group had a higher multimorbidity risk with adjusted HRs (95%CI) of 1.23 (1.01-1.50) and 1.34(1.14-1.58), respectively. Participants in the WHtR gain group and the persistently high WHtR group also had higher risks of multimorbidity with HRs (95%CI) of 1.35 (1.08-1.67) and 1.27 (1.05-1.53), respectively, relative to the persistently low WHtR group. Compared to the persistently low WWI group, those in the WWI loss group had a lower risk of multimorbidity with HRs (95%CI) of 0.80 (0.66-0.98). For every standard deviation increase in WC, WHtR, and WWI over three years, the risk of multimorbidity was higher by 12% (95%CI: 1.05-1.19), 13% (95%CI: 1.06-1.20), and 12% (95%CI: 1.05-1.20), respectively. CONCLUSIONS: Associations of changes in WC, WHtR and WWI with multimorbidity are significant among older Chinese adults. The findings highlight the importance of evaluating changes in WC, WHtR, and WWI in screening and prevention of multimorbidity in older adults.

Effects of intensive glycemic control on microvascular outcomes in type 2 diabetes mellitus are modified by long-term HbA1c variability: A post hoc analysis of the ACCORD trial.

AIMS: To assess the impact of long-term visit-to-visit variability in HbA1c on microvascular outcomes in type 2 diabetes mellitus (T2DM), and its influence on the effects of intensive glycemic control. METHODS: Included were participants with T2DM enrolled in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) who had at least three measurements of HbA1c prior to new-onset microvascular outcomes, namely nephropathy, retinopathy and neuropathy. Variability in HbA1c was defined as the coefficient of variation (CV) across HbA1c measurements obtained from enrollment to the transition from intensive to standard glycemic therapy. RESULTS: During a median of 22,005, 23,121, and 13,080 person-years of follow-up, 2,905 nephropathy, 2,655 retinopathy, and 1,974 neuropathy cases were recorded, respectively. Median CV (IQR) was 7.91 % (5.66 %-10.76 %) in the standard treatment group and 9.79 % (7.32 %-13.35 %) in the intensive treatment group. In the standard treatment group, lower HbA1c-CV (the first versus the second quartile) was associated with a higher risk of all microvascular outcomes, while higher HbA1c-CV (the fourth quartile) was associated with a higher risk of nephropathy only. In the intensive treatment group, only higher HbA1c-CV was associated with a higher risk of developing the microvascular outcomes. Intensive therapy reduced all microvascular outcomes among individuals with lower HbA1c-CV, but increased the risk among those with the highest HbA1c-CV (all P values for interaction < 0.0001). For example, hazard ratios (95 % CI) of retinopathy comparing intensive with standard treatments were 0.65 (0.56-0.75), 0.84 (0.71-0.98), 0.97 (0.82-1.14) and 1.28 (1.08-1.53) across the lowest to the highest quartiles of HbA1c variability. CONCLUSIONS: The effects of intensive glycemic control on microvascular outcomes in T2DM appear to be modified by the variability of HbA1c during the treatment process, suggesting the significance of dynamic monitoring of HbA1c levels and timely adjustments to the therapeutic strategy among individuals with a high HbA1c variability.

Jiawei guomin decoction regulates the degranulation of mast cells in atopic dermatitis mice via the HIS/PAR-2 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Guomin decoction (GMD) is a traditional Chinese medicine commonly used in clinical practice. It has traditionally been used to treat all allergic diseases. Currently, Jiawei Guomin Decoction (JWGMD) is used to treat sensitive skin after initial therapy. Although it has a significant clinical therapeutic effect, the exact role of mast cell degranulation in treating atopic dermatitis (AD) is still unclear. AIM OF THE STUDY: GMD and JWGMD can both treat allergic diseases, while JWGMD focuses on skin allergies. This study aims to explore the potential effect of JWGMD on the degranulation of mast cells in an AD mouse model induced by 2,4-dinitrofluorobenzene (DNFB) and investigate the effectiveness of JWGMD in alleviating disease progression to further provide specific therapeutic targets for treating AD. MATERIALS AND METHODS: The scratching times and skin lesions of model mice induced by DNFB were observed, and skin tissues were collected for subsequent measurement. Histopathological changes in the back skin of mice were observed by haematoxylin eosin (H&E) staining, Toluidine blue staining was used to detect the degranulation of mouse skin mast cells, and the relationship between the expression of histamine (HIS), mast cell tryptase (MCT) and mast cell degranulation was analysed by enzyme-linked immunosorbent assay (ELISA). The expression of protease-activated receptor-2 (PAR-2), histamine 1 receptor (H1R), H2R, H4R and MCT proteins in AD mice was detected by Western blot (WB). Immunofluorescence assay (IFA) further confirmed the localization of PAR-2, H1R, H2R, H4R, and MCT proteins in the skin. Quantitative real-time PCR (qPCR) was used to determine PAR-2, H1R, H2R and H4R mRNA levels in skin lesions to further clarify the mechanism by which JWGMD amplifies mast cell degranulation in AD. In addition, a reliable ultrahigh-performance liquid chromatography-quadrupole electrostatic field orbitrap mass spectrometry (UPLC-QE-MS) nontargeted metabolomics analysis was performed to analyse the differences in metabolite abundance between GMD and JWGMD, and these results were used to identify the active components in JWGMD that may have antipruritic and anti-inflammatory properties and inhibit mast cell degranulation. RESULTS: After intermittent stimulation with DNFB, the skin lesions showed extensive desquamation, dryness, scabbing, skin thickening, and slight bleeding. Both treatments alleviated this phenomenon and reduced the number of scratches, with JWGMD being the most effective. JWGMD can significantly reduce inflammatory cell infiltration, oedema, and some capillary neogenesis in mice and reduce the degranulation of mast cells. The ELISA results showed that JWGMD can increase the levels of MCT and HIS proteins. The WB and IFA results demonstrated that JWGMD reduced the expression levels of PAR-2, H1R, H4R, and MCT proteins in skin lesions, with protein localization mainly in the epidermal layer, while H2R protein levels were increased and mainly localized in the dermis. In addition, JWGMD downregulates the mRNA expression of PAR-2, H1R, H2R, and H4R. Interestingly, through UPLC-QE-MS nontargeted metabolomic analysis, we detected the anti-inflammatory and antiallergy active substances in JWGMD, such as methyl eugenol, dictamnine and sinapine. CONCLUSIONS: JWGMD may alleviate itching through methyl syringol, dictamnine, sinapine and other substances, and its mechanism may be related to inhibiting the HIS/PAR-2 pathway in AD model mice and further regulating the self-amplification of mast cell degranulation. JWGMD is a potential drug for treating AD. Therefore, it deserves continuous attention and research.

The predictive, preventive, and personalized medicine of insomnia: gut microbiota and inflammation.

Background: The human gut microbiota (GM) has been recognized as a significant factor in the development of insomnia, primarily through inflammatory pathways, making it a promising target for therapeutic interventions. Considering the principles of primary prediction, targeted prevention, and personalized treatment medicine (PPPM), identifying specific gut microbiota associated with insomnia and exploring the underlying mechanisms comprehensively are crucial steps towards achieving primary prediction, targeted prevention, and personalized treatment of insomnia. Working hypothesis and methodology: We hypothesized that alterations in the composition of specific GM could induce insomnia through an inflammatory response, which postulates the existence of a GM-inflammation-insomnia pathway. Mendelian randomization (MR) analyses were employed to examine this pathway and explore the mediative effects of inflammation. We utilized genetic proxies representing GM, insomnia, and inflammatory indicators (including 41 circulating cytokines and C-reactive protein (CRP)), specifically identified from European ancestry. The primary method used to identify insomnia-related GM and examine the medicative effect of inflammation was the inverse variance weighted method, supplemented by the MR-Egger and weighted median methods. Our findings have the potential to identify individuals at risk of insomnia through screening for GM imbalances, leading to the development of targeted prevention and personalized treatment strategies for the condition. Results: Nine genera and three circulating cytokines were identified to be associated with insomnia; only the associations of Clostridium (innocuum group) and ß-NGF on insomnia remained significant after the FDR test, OR = 1.08 (95% CI = 1.04-1.12, P = 1.45 × 10-4, q = 0.02) and OR = 1.06 (95% CI = 1.02-1.10, P = 1.06 × 10-3, q = 0.04), respectively. CRP was associated with an increased risk of insomnia, OR = 1.05 (95% CI = 1.01-1.10, P = 6.42 × 10-3). CRP mediated the association of Coprococcus 1, Holdemania, and Rikenellaceae (RC9gut group) with insomnia. No heterogeneity or pleiotropy were detected. Conclusions: Our study highlights the role of specific GM alterations in the development of insomnia and provides insights into the mediating effects of inflammation. Targeting these specific GM alterations presents a promising avenue for advancing the transition from reactive medicine to PPPM in managing insomnia, potentially leading to significant clinical benefits. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-023-00345-1.

Shift work and risk of incident gastroesophageal reflux disease: the association and mediation.

Introduction: Shift work has become an increasingly common work mode globally. This study aimed to investigate the association between shift work and the risk of incident gastroesophageal reflux disease (GORD), an upward gastrointestinal disorder disease worldwide, and to explore the mediating factors. Method: A total of 262,722 participants from the UK Biobank free of GORD and related gastrointestinal diseases were included to investigate the association and potential mediators between shift work and incident GORD. Multivariate-adjusted Cox models were used to evaluate the association between shift work status and GORD incidence. Results: Compared to non-shift workers, shift workers had a 1.10-fold greater risk of incident GORD [95% confidence intervals (CIs): 1.03, 1.18], after adjusting for a range of potential confounders. However, the excess risk of GORD attenuated to the null after further adjusting for selected mediators. Specifically, the association was mediated by sleep patterns (25.7%), healthy behaviors (16.8%), depressive symptoms (20.2%), chronic conditions (13.3%), and biological factors (17.6%). After adjustment for all the mediators together, the association was attenuated by 71.5%. Discussion: Our findings indicated that long-term shift workers may have a higher risk of incident GORD, yet the excess risk may be explained by poor sleep quality, unhealthy behaviors, depressive symptoms, etc. This has positive implications for protecting the health of shift workers.

Identifying ureteral stent encrustation using machine learning based on CT radiomics features: a bicentric study.

Obstructive: To develop and validate radiomics and machine learning models for identifying encrusted stents and compare their recognition performance with multiple metrics. Methods: A total of 354 patients with ureteral stent placement were enrolled from two medical institutions and divided into the training cohort (n = 189), internal validation cohort (n = 81) and external validation cohort (n = 84). Based on features selected by Wilcoxon test, Spearman Correlation Analysis and least absolute shrinkage and selection operator (LASSO) regression algorithm, six machine learning models based on radiomics features were established with six classifiers (LR, DT, SVM, RF, XGBoost, KNN). After comparison with those models, the most robust model was selected. Considering its feature importance as radscore, the combined model and a nomogram were constructed by incorporating indwelling time. Accuracy, sensitivity, specificity, area under the curve (AUC), decision curve analysis (DCA) and calibration curve were used to evaluate the recognition performance of models. Results: 1,409 radiomics features were extracted from 641 volumes of interest (VOIs) and 20 significant radiomics features were selected. Considering the superior performance (AUC 0.810, 95%CI, 0.722-0.888) in the external validation cohort, feature importance of XGBoost was used as a radscore, constructing a combined model and a nomogram with indwelling time. The accuracy, sensitivity, specificity and AUC of the combined model were 98, 100, 97.3% and 0.999 for the training cohort, 83.3, 80, 84.5% and 0.867 for the internal cohort and 78.2, 76.3, 78.8% and 0.820 for the external cohort, respectively. DCA indicates the favorable clinical utility of models. Conclusion: Machine learning model based on radiomics features enables to identify ureteral stent encrustation with high accuracy.

Total and Regional Fat/Muscle Mass Ratio and Risks of Incident Cardiovascular Disease and Mortality.

Background To evaluate the sex-specific associations of total and regional fat/muscle mass ratio (FMR) with cardiovascular disease (CVD) incidence and mortality, and to explore the underlying mechanisms driven by cardiometabolites and inflammatory cells. We compared the predictive value of FMRs to body mass index. Methods and Results This population-based, prospective cohort study included 468 885 UK Biobank participants free of CVD at baseline. Fat mass and muscle mass were estimated using a bioelectrical impedance assessment device. FMR was calculated as fat mass divided by muscle mass in corresponding body parts (total body, trunk, arm, and leg). Multivariable Cox proportional hazards models and mediation analyses were used. During 12.5 years of follow-up, we documented 49 936 CVD cases and 4158 CVD deaths. Higher total FMR was associated with an increased risk of incident CVD (hazard ratios [HRs] were 1.63 and 1.83 for men and women, respectively), ischemic heart disease (men: HR, 1.61; women: HR, 1.81), myocardial infarction (men: HR, 1.72; women: HR, 1.49), and congestive heart failure (men: HR, 2.25; women: HR, 2.57). The positive associations of FMRs with mortality from total CVD or its subtypes were significant mainly in trunk and arm for male patients (P for trend <0.05). We also identified 8 cardiometabolites and 5 inflammatory cells that partially mediated FMR-CVD associations. FMRs were modestly better at discriminating cardiovascular mortality risk. Conclusions Higher total and regional FMRs were associated with an increased risk of CVD and mortality, partly mediated through cardiometabolites and inflammatory cells. Early monitoring of FMR should be considered to alleviate CVD risk. FMRs were superior to body mass index in predicting CVD mortality.

Recent progress on tyrosine kinase 2 JH2 inhibitors.

Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, which can regulate the signaling of multiple pro-inflammatory cytokines, including IL12, IL23 and type I interferon (IFNα/ß), and its inhibitors can treat autoimmune diseases caused by the abnormal expression of IL12 and IL23. Interest in TYK2 JH2 inhibitors has increased as a result of safety concerns with JAK inhibitors. This overview introduces TYK2 JH2 inhibitors that are already on the market, including Deucravactinib (BMS-986165), as well as those currently in clinical trials, such as BMS-986202, NDI-034858, and ESK-001.

Associations of blood biomarkers with arterial stiffness in patients with diabetes mellitus: A population-based study.

BACKGROUND: Arterial stiffness contributes to additional cardiovascular risks in diabetic patients by triggering the loss of vascular and myocardial compliance and promoting endothelial dysfunction. Thus, prevention of arterial stiffness is a public health priority, and the identification of potential biomarkers may provide benefits for early prevention. This study investigates the relationships between serum laboratory tests and pulse wave velocity (PWV) tests. We also investigated the associations between PWV and all-cause mortality. METHODS: We examined a panel of 33 blood biomarkers among diabetic populations in the Atherosclerosis Risk in Communities Study. The carotid-femoral (cfPWV) and femoral-ankle PWV (faPWV) were measured using an automated cardiovascular screening device. The aortic-femoral arterial stiffness gradient (afSG) was calculated as faPWV divided by cfPWV. Biomarker levels were log-transformed and correlated with PWV. Cox proportional hazard models were employed for survival analysis. RESULTS: Among 1079 diabetic patients, biomarkers including high-density lipoprotein cholesterol, glycated hemoglobin, high-sensitivity troponin T, cystatin C, creatinine, and albuminuria were significantly correlated with afSG (R = 0.078, -0.193, -0.155, -0.153, -0.116, and -0.137, respectively) and cfPWV (R = -0.068, 0.175, 0.128, 0.066, 0.202, and 0.062, respectively). Compared with the lowest tertile of afSG, the risk of all-cause mortality was lower in the highest tertile (hazard ratio 0.543; 95% confidence interval 0.328-0.900). CONCLUSION: Certain biomarkers related to blood glucose monitoring, myocardial injury, and renal function significantly correlated with PWV, suggesting that these putative risk factors are likely to be important atherosclerosis mechanisms in diabetic patients. AfSG may be an independent predictor of mortality among diabetic populations.

"Life's Essential 8" Cardiovascular Health and Dementia Risk, Cognition, and Neuroimaging Markers of Brain Health.

OBJECTIVE: To evaluate associations of Life's Essential 8 (LE8) score, the recently updated metric for promoting cardiovascular health (CVH), with the risk of incident dementia and its subtypes, cognition, and neuroimaging outcomes and to determine whether these associations differ among apolipoprotein E (APOE)-ε4 genotypes. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 316,669 participants [mean (SD) age, 56.3 (8.1) years] without prior cardiovascular disease or dementia from the UK Biobank study at baseline survey (2006-2010) were enrolled. METHODS: A modified version of the LE8 score was created (range: 0-100) and categorized into poor (0-49), intermediate (50-79), and optimal (80-100) CVH. Cox proportional hazard and multivariable linear regression models were used. RESULTS: During a median 12.6 years of follow-up, 4238 all-cause dementia cases including 1797 Alzheimer's disease and 939 vascular dementia (VaD) occurred. Individuals with optimal CVH had 44% (95% CI, 0.48-0.64) lower incident all-cause dementia risk and 71% (95% CI, 0.22-0.38) lower VaD risk compared with those who had poor CVH. A 10-point increment in LE8 was associated with higher fluid intelligence scores (ß, 0.088; 95% CI, 0.073-0.102) and numeric memory scores (ß, 0.054; 95% CI, 0.043-0.065), and was also associated with lower white matter hyperintensity volume (ß, -0.673; 95% CI, -0.751 to -0.596), larger total brain volume (ß, 77.93; 95% CI, 62.03-93.84), and hippocampal volume (ß, 0.197; 95% CI, 0.106-0.288). In addition, the association between LE8 profiles and dementia diagnosis differed by APOE genotype (all P for interaction ≤ .001), and was more evident among APOE-ε4 noncarriers. CONCLUSIONS AND IMPLICATIONS: Individuals with a higher LE8 score experienced fewer dementia events (driven especially by incident VaD) and were associated with better neurocognitive brain health profiles. CVH optimization may be beneficial to the maintenance of brain health.

The independent and joint association of accelerometer-measured physical activity and sedentary time with dementia: a cohort study in the UK Biobank.

BACKGROUND: Research on the association of physical activity and sedentary time with dementia is accumulating, though elusive, and the interaction effects of the two remain unclear. We analysed the joint associations of accelerometer-measured physical activity and sedentary time with risk of incident dementia (all-cause dementia, Alzheimer's disease and vascular dementia). METHODS: A total of 90,320 individuals from the UK Biobank were included. Accelerometer-measured total volume of physical activity (TPA) and sedentary time were measured at baseline and dichotomised by median (low TPA [< 27 milli-gravity (milli-g)], high TPA [≥ 27 milli-g]; low sedentary time [< 10.7 h/day], high sedentary time [≥ 10.7 h/day]). Cox proportional hazards models were used to evaluate the joint associations with incident dementia on both additive and multiplicative scales. RESULTS: During a median follow-up of 6.9 years, 501 cases of all-cause dementia were identified. Higher TPA was associated with a lower risk of all-cause dementia, Alzheimer's disease and vascular dementia; the multivariate adjusted hazard ratios (HRs) (95% CI) per 10 milli-g increase were 0.63 (0.55-0.71), 0.74 (0.60-0.90) and 0.69 (0.51-0.93), respectively. Sedentary time was only found to be linked to all-cause dementia, and the HR for high sedentary time was 1.03 (1.01-1.06) compared with that for low sedentary time. No additive and multiplicative relationship of TPA and sedentary time to incident dementia was found (all P values > 0.05). CONCLUSION: Higher TPA level was related to a lower risk of incident dementia irrespective of sedentary time, which highlighted the implication of promoting physical activity participation to counteract the potential detrimental effect of sedentary time on dementia.

Association of serum uric acid and fasting plasma glucose with cognitive function: a cross-sectional study.

BACKGROUND: The combined effect of serum uric acid (SUA) and blood glucose on cognition has not been explored. This study aimed to examine the separate and combined association of SUA and fasting plasma glucose (FPG) or diabetes mellitus (DM) with cognition in a sample of Chinese middle-aged and elderly population. METHODS: A total of 6,509 participants aged 45 years or older who participated in the China Health and Retirement Longitudinal Study (CHARLS, 2011) were included. The three cognitive domains assessed were episodic memory, mental status, and global cognition (the sum of the first two terms). Higher scores indicated better cognition. SUA and FPG were measured. The participants were grouped based on SUA and FPG quartiles to evaluate their combined associations of cognition with SUA Q1-Q3 only (Low SUA), with FPG Q4 only (High FPG), without low SUA and high FPG levels (Non), and with low SUA and high FPG levels (Both), multivariate linear regression models were used to analyze their association. RESULTS: Lower SUA quartiles were associated with poorer performance in global cognition and episodic memory compared with the highest quartile. Although no association was found between FPG or DM and cognition, high FPG or DM combined with low SUA levels in women (ßFPG = -0.983, 95% CI: -1.563--0.402; ßDM = -0.800, 95% CI: -1.369--0.232) had poorer cognition than those with low SUA level only (ßFPG = -0.469, 95% CI: -0.926--0.013; ßDM = -0.667, 95% CI: -1.060--0.275). CONCLUSION: Maintaining an appropriate level of SUA may be important to prevent cognitive impairment in women with high FPG.

Role of uric acid as a biomarker of cognitive function in schizophrenia during maintenance period.

Background: Previous studies involving uric acid (UA) in some specialized disease populations have found that high UA is associated with enhanced patient function. The mechanism to explain this association may be that UA, an important antioxidant, exerts neuroprotective effects. Patients with schizophrenia (SCZ) have severe oxidative stress abnormalities, and cognitive impairment is a major obstacle to their rehabilitation. Only few studies have been conducted on UA and cognitive impairment in SCZ. This study aims to clarify the relationship between UA and cognitive impairment and explore whether UA could be used as a potential biological marker of cognition in SCZ during maintenance period. Methods: A total of 752 cases of SCZ during maintenance period from Baiyun Jingkang Hospital were included. Cognition was measured using the Mini-Mental State Examination scale. UA was measured using the Plus method. The participants were grouped on the basis of UA to evaluate the association of cognition with low-normal (3.50-5.07 mg/dL for men, 2.50-4.19 mg/dL for women), middle-normal (5.07-6.39 mg/dL for men, 4.19-5.18 mg/dL for women), high-normal (6.39-7.00 mg/dL for men, 5.18-6.00 mg/dL for women), and high (>7.00 mg/dL for men, >6.00 mg/dL for women) levels of UA. Multiple logistic regression and linear regression models and restricted cubic spline (RCS) were utilized to evaluate the relationship. Results: Uric acid was positively associated with cognitive function. Subgroup analyses showed that high UA was associated with enhanced cognition in participants with low anticholinergic cognitive burden (ACB). Conclusion: Uric acid may be used as a simple objective biological indicator to assess cognition in SCZ during maintenance period.