Cardiovascular Metabolic Comorbidities (CMM) share common physiological mechanisms in inflammation and immunity, oxidative stress, and insulin resistance, leading to mutual disease interactions and complex clinical manifestations. To address challenges in describing CMM status based solely on clinical features, this paper proposes a digital marker to characterize the differences from single to multiple diseases, systematically revealing distinct CMM subgroups based on cross-sectional data. This paper constructed a directed acyclic network for CMM using demographic characteristics, clinical laboratory parameters, and disease status as nodes via the DirectLiNGAM algorithm. Network features were described using in degree, out degree, degree centrality, betweenness centrality, and closeness centrality, ranking node importance. The top seven significant clinical laboratory parameters were selected based on this ranking. Subsequently, the performance of ten machine learning algorithms (Random Forest, XGBoost, MLP, KNN, Gradient Boosting, SVC, Linear Regression, Ridge, ElasticNet, Lasso) in generating digital markers by predicting death was evaluated to determine the optimal algorithm. The generated digital markers were then binned to classify CMM into Low, Middle, and High groups. Finally, linear regression validated the rationality of the network filtered clinical laboratory parameters. In the CMM network, the top three disease nodes by in degree are DM, MemD, and DL, while the top five by out degree are TC, HBALC, GLU, HCT, and HGB. Regarding network centrality, the top five nodes by degree centrality are Male, TG, DM, CYC, and DL; by betweenness centrality, Male, Stroke, TG, DL,and DM; and by closeness centrality, Male, DM, Married, Stroke, and CA. Network analysis identified top clinical laboratory parameters as GLU, HBALC, TC, UA, HCT, TG, HGB, WBC, and CYC, consistent with statistically significant parameters (P < 0.05) in linear regression validation. Among machine learning algorithms, Ridge regression performed best in AUC, PR‑AUC, Brier Score, and Log Loss. The digital marker generated by Ridge regression yielded average scores of 0.016(0.008), 0.058(0.019), 0.296(0.197) for Low, Middle, and High groups, respectively. This paper developed a digital marker by integrating network analysis and machine learning to delineate CMM's cross‑sectional subgroups, indicating its potential for early detection and enabling future research on stratified interventions for high risk groups.

Organs-on-a-Chip (OoC) are innovative models designed to reproduce an architecture close to in vivo physiology, by recreating the specific microenvironment of each organ. They represent a promising advance in the process of developing new drugs, aimed at improving the prediction of adverse effects in preclinical studies and reducing the use of laboratory animals. However, a lack of validated standards governing these technologies currently limits their acceptance by regulatory authorities, who rely on guidelines to judge the admissibility of non-clinical studies. This is particularly the case for assessing the risk of cardiac damage using in silico, in vitro and in vivo tests. However, animal models are not always able to accurately detect adverse effects in humans. OoC are additional tools that could improve the assessment of drug cardiac toxicity. According to data in the literature, the results of studies with OoC overlap with those of conventional models. What's more, in some cases, OoC offer better prediction via the detection of biomarkers such as alpha-actin and troponin T. These results could lead to their integration into the regulatory process for preclinical drug evaluation.

Poor neurologic outcomes are common in post-cardiac arrest patients. Reduced cerebral perfusion and inadequate oxygen delivery may persist even following return of spontaneous circulation (ROSC), which may exacerbate hypoxic-ischemic brain injury. Cerebral oximetry is a noninvasive method of assessing brain oxygenation. We performed a systematic review to assess whether post-arrest regional oxygen saturation (rSO2) during the initial 48 hours post-ROSC is associated with death or severe disability.

MEDLINE, Embase, Cochrane Central Register of Controlled Trials, World Health Organization Global Health Library.

We included studies reporting outcomes in adult post-arrest patients who underwent continuous cerebral oximetry immediately following ROSC for at least 6 hours.

rSO2 over the 48 hours post-arrest was compared between patients with favorable vs. unfavorable outcomes, as dichotomized within individual studies.

Random effects models were used to pool studies. 10,876 records were identified, of which 16, with a total of 864 patients, met inclusion criteria. Twelve studies provided neurologic outcomes, and four reported only survival. rSO2 was similar at baseline, but higher at 24 hours (3.3%, 0.9-5.7%, p = 0.009) and 48 hours (2.1%, 0.3-3.9%, p = 0.02) post-arrest among patients with favorable outcomes. There was significant heterogeneity between studies. rSO2 averaged over time was significantly higher between 24 and 48 hours in patients with favorable outcomes (5.2%, 1.6-8.8%; p = 0.005). rSO2 was lower in studies where cardiac arrest duration was relatively longer (modeled difference -7.1%, -3.1% to -11.1%, p = 0.0005). Although very low rSO2 had high specificity for unfavorable outcome in two studies, no consistent threshold could be identified for use in neuroprognostication.

Current evidence suggests that rSO2 during the initial 48 hours following ROSC is slightly lower in post-cardiac arrest patients with unfavorable neurologic outcomes (low certainty of evidence). Prospective research is needed to determine whether treatment of reduced rSO2 can improve outcomes.

This study aimed to investigate the therapeutic effects of Jiangzhi Huaban Decoction(JZHB) on atherosclerosis(AS) model mice and to explore its potential molecular mechanisms using proteomic analysis. C57BL/6J mice fed with a standard diet served as the control group. ApoE~(-/-) knockout mice were fed with a high-fat diet for 8 weeks to induce atherosclerosis, after which they were randomly divided into 5 groups(n=8 per group): the model group, low-, medium-, and high-dose JZHB groups(1.32, 2.64, and 5.28 g·kg~(-1)), and the atorvastatin calcium group(3.75 mg·kg~(-1)). All intervention groups lasted for 8 weeks. The body weight and general conditions of the mice were recorded weekly. Prior to sample collection, small animal color Doppler ultrasound was employed to assess carotid artery and aortic wall plague lesions. After sample collection, serum lipid and liver function levels were measured using an automated biochemical analyzer. Serum levels of interleukin(IL)-6, IL-1β, IL-4, and tumor necrosis factor-alpha(TNF-α) were quantified by enzyme-linked immunosorbent assay(ELISA). Hematoxylin-eosin(HE) staining. Masson and oil red O staining were used to comprehensively evaluate pathological changes in AS plaques. Proteomics sequencing technology was used to analyze core molecular mechanisms, and Western blot, qPCR, and immunofluorescence assays were used to verify the expression of core targets. The results showed that JZHB significantly improved serum lipid levels, liver function, and serum inflammatory microenvironment in AS mice(P&lt;0.05, P&lt;0.01). It can also comprehensively improved various pathological markers, including carotid artery and aortic root plaque area, collagen fiber content, lipid deposition, lumen stenosis, and hemorheological parameters(P&lt;0.05, P&lt;0.01). Proteomics analysis revealed that its core mechanism was associated with the mitogen-activated protein kinase(MAPK)/nuclear factor-κB(NF-κB) signaling pathway axis to improve macrophage polarization in AS plaques. Molecular biological assays indicated that JZHB could reduce the mRNA levels and the phosphorylation ratios of MAPK, c-Jun N-terminal kinase(JNK), NF-κB p65, and inhibitor of nuclear factor-κBα(IκBα) in the aortic tissue of mice. It also downregulated the mRNA and protein expressions of inducible nitric oxide synthase(iNOS) and IL-6(P&lt;0.05, P&lt;0.01). Additionally, JZHB improved the expression and localization of M1/M2 macrophage polarization markers, cluster of differentiation 86(CD86) and mannose receptor(CD206), within aortic plaques(P&lt;0.05, P&lt;0.01). In conclusion, JZHB can synergistically ameliorate the pathological changes in arterial plaques of AS mice through multiple pathways. Its core mechanism involves regulating the MAPK/NF-κB signaling pathway axis, ameliorating the macrophage polarization status and the internal inflammatory microenvironment within plaques, thereby exerting a comprehensive pharmacological effect on the prevention and treatment of atherosclerosis.

This study investigated the therapeutic effects of the Qixue Bingzhi Formula(QXBZ) on coronary heart disease, focusing on its bidirectional regulation of angiogenesis in myocardial ischemia and atherosclerosis, using in vivo and in vitro models. Male ApoE~(-/-)mice were fed a high-fat diet for 9 weeks and then randomized into the following groups, with high-fat feeding continuing until 12 weeks: a control group, a model group, QXBZ groups(at high, medium, and low doses of 11.7, 5.85, and 2.92 g·kg~(-1)·d~(-1), respectively), and a positive group(receiving 26 mg·kg~(-1)·d~(-1) metoprolol plus 5.2 mg·kg~(-1)·d~(-1) simvastatin), with 12 mice per group. A myocardial infarction and atherosclerosis(MI-AS) composite model was established by ligating the left anterior descending coronary artery at week 11, and drug administration continued for 2 weeks post-surgery. C57BL/6J mice served as a blank control, receiving standard diet and intragastric administration of normal saline throughout the study and being subjected to threading but not ligating the coronary artery. After the final administration, cardiac function and carotid artery intima-media thickness were assessed by ultrasound. Histopathological examinations of the heart and plaques were performed using hematoxylin and eosin(HE), Masson, and Movat staining, along with immunofluorescence. Blood lipid levels were measured using biochemical assays, and the expression level of vascular endothelial growth factor A(VEGFA) was determined by RT-qPCR and Western blot. In vitro, endothelial cells were used to establish a hypoxic-induced(1% O_2) MI model and an oxidized low-density lipoprotein(ox-LDL)-induced AS model and divided into control, model, QXBZ(2.5%, 5%, 10%, and 15%), and positive groups. Cell proliferation was assessed using the cell counting kit-8(CCK-8) assay, cell migration was evaluated by the scratch assay, and tube formation ability was examined by the tube formation assay. The expression level of VEGFA was detected by RT-qPCR and Western blot. RESULTS:: showed that QXBZ significantly reduced triglyceride and low-density lipoprotein cholesterol levels, increased left ventricular ejection fraction and left ventricular fractional shortening, and attenuated both myocardial fibrosis area and atherosclerotic plaque area in MI-AS composite model mice. It enhanced the fluorescence intensities of cluster of differentiation 31(CD31) and α-smooth muscle actin(α-SMA) in the ischemic myocardium but decreased them in plaques. QXBZ also promoted cell viability, migration, and tube formation in the MI model, while inhibiting these processes in the AS model. Furthermore, QXBZ upregulated VEGFA expression in the ischemic myocardium and the MI cell model, but downregulated it in the aortic tissue and the AS cell model, demonstrating a microenvironment-dependent bidirectional regulation. These findings suggested that QXBZ ameliorates coronary heart disease by promoting angiogenesis in the ischemic myocardium while inhibiting angiogenesis in plaques, potentially through bidirectional regulation of the VEGFA signaling pathway in different pathological microenvironments of ischemic myocardium and plaques.

This study aims to explore the pathogenesis of the comorbidity of atherosclerosis(AS) accompanied by seborrhea and the intervention effect of Zhuyu Pills. A mouse model of AS with seborrhea was constructed by feeding ApoE~(-/-)mice with a high-fat diet for 12 weeks. The 50 successfully modeled ApoE~(-/-)mice were randomly assigned into 5 groups: model, low-dose, medium-dose, and high-dose(130. 54, 261. 08, and 522. 16 mg·kg~(-1), respectively) Zhuyu Pills, and atorvastatin calcium(10. 40 mg·kg~(-1)), with 10 mice in each group. Ten normal C57BL/6J mice were used as the blank control group. The blank control group and the model group were administrated with an equal volume of normal saline by gavage, while the other groups were administrated with corresponding drugs by gavage once a day for 12 weeks. After the administration was completed, hematoxylin-eosin(HE) staining was performed to observe the pathological changes of the aorta and auricle, and the percentage of aortic plaque area and the inflammation score of the auricle were calculated. The levels of total cholesterol(TC), triacylglycerol(TG), low-density lipoprotein cholesterol(LDL-C), and fasting blood glucose( FBG) in the serum were quantified by biochemical methods. The levels of free non-esterified fatty acids(NEFA) and TG in the auricular sebaceous glands were measured by colorimetric methods. The levels of helper T cell 1(Th1)-type pro-inflammatory cytokines [tumor necrosis factor-α(TNF-α) and interleukin(IL)-6], Th2-type anti-inflammatory cytokines(IL-4 and IL-10), and fasting insulin( FINS) in the serum were assessed by enzyme-linked immunosorbent assay( ELISA). The homeostatic model assessment of insulin resistance(HOMA-IR) was calculated. The changes of invariant natural killer T(iNKT) cells in the thymus, spleen, and liver were detected by flow cytometry. The expression of differentiation cluster 1d(CD1d) in the thymus, spleen, and liver was detected by immunohistochemistry. The protein levels of TNF-α, IL-6, IL-4 and IL-10 in the liver were quantified by Western blot. The results showed that compared with the blank control group, the model group exhibited extensive thickening of the aortic intima, an increase in the percentage of aortic plaque area(P&lt;0. 01), extensive infiltration of inflammatory cells in the auricle, an increase in the inflammation score(P&lt;0. 01), elevated levels of TC, TG, LDL-C, and FBG in the serum(P&lt;0. 01) and NEFA, TG in the auricle(P&lt; 0. 01), raised serum levels of TNF-α, IL-6 and an increase in HOMA-IR(P&lt; 0. 01), lowered serum levels of IL-4, IL-10, and FINS(P&lt;0. 01), an increase in CD1d expression in the thymus, spleen, and liver(P&lt;0. 01), an increase in the proportion of iNKT cells(P&lt;0. 01), up-regulation in the protein levels of TNF-α and IL-6(P&lt;0. 01), and down-regulation in the protein levels of IL-4 and IL-10 in the liver(P&lt;0. 01). Compared with the model group, low, medium, and high doses of Zhuyu Pills as well as atorvastatin calcium decreased the enriched area of aortic plaques and the percentage of plaque area(P&lt;0. 01), attenuated the infiltration of inflammatory cells in the auricle, and reduced the inflammation score(P&lt;0. 01), lowered the levels of TC, TG, LDL-C, and FBG in the serum(P&lt;0. 05, P&lt;0. 01) and NEFA, TG in auricular sebaceous glands(P&lt;0. 05, P&lt;0. 01), lowered the serum levels of TNF-α, IL-6 and decreased the HOMA-IR(P&lt;0. 05, P&lt;0. 01), raised the serum levels of IL-4, IL-10, and FINS(P&lt;0. 05, P&lt;0. 01), inhibited the expression of CD1d in the thymus, spleen, and liver(P&lt;0. 01), decreased the proportion of iNKT cells(P&lt;0. 01), down-regulated the protein levels of TNF-α and IL-6(P&lt;0. 01), and up-regulated the protein levels of IL-4 and IL-10 in the liver(P&lt;0. 01). In conclusion, Zhuyu Pills demonstrate definite therapeutic effects on aortic plaques and seborrhea in mice and can alleviate inflammatory responses by regulating the CD1d/iNKT cell axis-mediated Th1/Th2 balance.

Early discontinuation of attention-deficit/hyperactivity disorder (ADHD) medication is common and linked to worse outcomes. Identifying clinical predictors could aid personalised treatment yet evidence is inconsistent across ages and countries/regions.

Investigate psychiatric and neurological comorbidity as predictors of early ADHD medication discontinuation in new ADHD medication users across age groups, sex and countries/regions.

Using health records from eight countries/regions, we identified 1 000 411 (44% female) new ADHD medication users (2011-2020). Discontinuation was defined as a ≥180 day gap between dispensations. We examined 23 indicators of psychiatric or neurological comorbidity, severity and psychotropic medication use. Associations were estimated using Cox regression, pooled with random-effects meta-analyses and stratified by age-at-initiation and sex.

Discontinuation rates varied widely (children 19%-61%, adolescents 37%-68%, young adults 52-67%, adults 38%-68%). In pooled analyses, earlier discontinuation in children was predicted by intellectual disability, autism and use of psychotropic medications (HR range 1.32-1.51), while conduct/oppositional defiant disorder (CD/ODD) was protective (HR 0.83, 95% CI 0.73 to 0.94). In adolescents, no indicators remained statistically significant after multiple-testing control. In young adults, CD/ODD (HR 1.42, 95% CI 1.30 to 1.55), and in adults, schizophrenia (HR 1.25, 95% CI 1.09 to 1.44) and tic disorders (HR 1.27, 95% CI 1.11 to 1.46) predicted earlier discontinuation. Statistical heterogeneity was substantial, largely driven by US estimates. In meta-analyses excluding the USA, additional associations emerged. For example, in children, OCD and anxiety disorders predicted earlier discontinuation, while eating disorders and antidepressants/anxiolytics were protective in adults. Associations with schizophrenia, tic disorders and CD/ODD were no longer significant. Country-specific analyses showed similar association patterns, except in the USA, Hong Kong and the UK. Sex differences were limited.

Children with neuropsychiatric comorbidity and related comedication are more likely to discontinue ADHD medication early, whereas few consistent predictors were seen from adolescence onwards. Marked cross-country variation, particularly in the USA, points to system-level influences on treatment patterns.

Improving ADHD medication persistence will require consideration of healthcare context and age-specific strategies, including close monitoring for children with complex neuropsychiatric profiles, and consideration of broader factors in adolescents and adults, where clinical predictors were limited.

In recent years, the field of digital health has grown exponentially, leading to notable benefits, such as easier access to health-related information, but also to content saturation and misinformation. Thus, it is crucial to identify digital health tools that provide meaningful value and assess them in real-world settings.

This preregistered study aims to quantitatively assess the Lernstörungen Online-Diagnostik und Intervention (LONDI) platform, a German platform designed for different user groups supporting children with learning disorders. This assessment focused on user groups of mental health professionals (ie, learning therapists and school psychologists) and was grounded in 4 of the 5 reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework dimensions: reach, adoption, implementation, and maintenance.

Data were collected over a 10-month period between May 1, 2024, and March 1, 2025. The reach dimension was measured via a pop-up questionnaire (n=1324) collecting demographic and professional experience data. The adoption dimension was measured via a second pop-up questionnaire (n=160) measuring user experience (UX) and reuse intention for the platform's help system. The implementation dimension was measured via web analytics (N=37,133) measuring reading time for pages intended for mental health professionals. Moreover, this dimension was also assessed by comparing chatbot engagement rates with industry benchmarks, in the absence of established benchmarks for digital health chatbots. The maintenance dimension was measured via web analytics as well, comparing the use in the previous (n=20,496) and current platform versions (N=37,133) in terms of number and location of users, time spent on the platform, number of actions per visit, and used devices and software.

A total of 21.90% (291/1324) and 10.64% (141/1324) of the users who filled out the first pop-up questionnaire stated that they were learning therapists or school psychologists, respectively, exceeding their percentage in the German population (<0.01%). The second pop-up questionnaire revealed an overall mean UX score of 1.54 (SD 1.14), surpassing the benchmark average, and UX ratings predicted intention to reuse. Time spent on the pages intended for mental health professionals was below the time needed to read them. The 0.18% rate of chatbot engagement was very low compared with industry benchmarks of 35% to 40%. Use changed in the 2 time periods compared, and most strikingly, there was an 81.2% (n=16,637) increase in the number of users.

The study provides evidence of the LONDI platform's positive contribution to public health in terms of the reach, adoption, and maintenance dimensions of the RE-AIM framework. Further research and endeavors are needed to better understand and improve the platform's contribution in terms of the implementation dimension.

Although urban green space (UGS) has been widely examined in relation to mental health, its association with suicide mortality remains insufficiently understood, particularly when moving beyond single indicators of green space. This cross-sectional ecological study examined the UGS pattern and its relationships to socioeconomic deprivation (SED) and suicide mortality (2019-2022) in Hong Kong using the large street block as the unit of spatial analysis. Latent profile analysis identified UGS patterns based on three complementary dimensions: availability, accessibility, and visibility. Multinomial logistic regression examined socioeconomic correlates of these patterns, and negative binomial regression assessed their associations with suicide mortality alongside SED, including interaction terms to examine variation in the SED-suicide mortality association across UGS patterns. Four UGS patterns were identified that reflected environmental inequalities. More socioeconomically advantaged areas were more likely to exhibit suburban neighborhoods with high availability and visibility. In contrast, more deprived areas were concentrated in dense urban cores with lower availability but relatively higher accessibility. Moreover, SED was positively associated with suicide mortality, and a weaker positive association was observed in neighborhoods characterized by relatively higher UGS accessibility, even where green space availability was relatively low. These findings highlight green space accessibility as a potentially important dimension for understanding spatial inequalities in suicide mortality in compact, high-density cities.

To determine self-reported psychosocial factors which may be associated with loneliness in persons with Spinal Cord Injury DESIGN AND SETTING: Convergent Parallel virtual structured interviews and quantitative questionnaires PARTICIPANTS: People with traumatic Spinal Cord Injury (tSCI) greater than 1 year prior (questionnaire data from n=20) MAIN OUTCOME MEASURES: Three-Item Loneliness Scale, Craig Hospital Inventory of Environmental Factors (CHIEF), Patient Health Questionnaire (PHQ-9), Short Form 12 SF-12) RESULTS: Higher levels of loneliness correlated with increased environmental barriers (CHIEF r=0.7, p=0.001) and more depressive symptoms (PHQ-9 r=0.67, p=0.001), while environmental barriers also contributed to worse mental health outcomes (SF-12, MCS r=-0.7, p=0.004).

Loneliness in people with tSCI is likely related to both internal and external factors.