Trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, has been implicated in cardiometabolic inflammation; however, the intracellular signaling mechanisms linking TMAO to macrophage polarization remain incompletely defined. This study aimed to investigate whether TMAO promotes macrophage M1 polarization through a Piezo1-Yes-associated protein (YAP) signaling axis. Gain- and loss-of-function approaches were performed in RAW264.7 cells and primary bone marrow-derived macrophages, including Piezo1 overexpression, small interfering RNA-mediated knockdown of Piezo1 or YAP, and pharmacological inhibition of YAP. Macrophage polarization markers were evaluated by immunofluorescence, flow cytometry, real-time quantitative polymerase chain reaction, and Western blot analysis. Intracellular Ca²⁺ levels were assessed using Fluo-4 acetoxymethyl ester fluorescence imaging. TMAO increased inducible nitric oxide synthase expression and reduced arginase-1 levels (P < .01), accompanied by elevated IL-1β and IL-6 and decreased IL-4 and IL-10 (P < .01). Piezo1 overexpression promoted M1 polarization (P < .01), whereas Piezo1 knockdown under TMAO exposure attenuated inflammatory cytokine induction (P < .001). TMAO enhanced intracellular Ca²⁺ influx (P < .001) and reduced inhibitory phosphorylation of YAP (Ser127) (P < .01). Inhibition or silencing of YAP mitigated TMAO-induced M1 marker expression and downstream kappa B/extracellular signal-regulated kinase activation (P < .05). Similar results were confirmed in primary bone marrow-derived macrophages. These findings suggest that TMAO promotes macrophage M1 polarization in association with Piezo1-dependent Ca²⁺ influx and YAP activation, identifying the Piezo1-YAP axis as a potential mechanistic interface linking microbiota-derived metabolites to inflammatory remodeling. SIGNIFICANCE STATEMENT: This study identifies the Piezo1-Yes-associated protein signaling axis as a potential drug target in trimethylamine N-oxide-induced macrophage polarization toward a proinflammatory phenotype. Inhibition of this pathway attenuates inflammatory responses, suggesting a potential pharmacological strategy for microbiota-associated cardiovascular diseases.

Myocardial infarction (MI) is the most severe clinical complication of coronary atherosclerotic heart disease (CHD), representing a leading cause of global morbidity and mortality. Qi-Blood Harmony Formula (QBHF), a traditional Chinese medicine, has shown clinical promise for managing MI; however, its underlying mechanisms remain to be fully elucidated.

This study aimed to explore the therapeutic mechanism of QBHF against MI in the context of CHD, with a specific focus on its role in angiogenesis.

QBHF chemical components were characterized by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Therapeutic efficacy was evaluated in a high-fat diet-fed ApoE^-/- mouse model with left anterior descending coronary artery ligation and in a hypoxia-induced endothelial cell model. Cardiac function and angiogenesis were assessed through histological, functional, and molecular assays, with the underlying mechanisms further investigated using bioinformatics and experimental validation.

Chemical profiling identified 67 compounds in QBHF, with eight major constituents quantified. In atherosclerosis-myocardial infarction (AS-MI) mice, QBHF dose-dependently improved cardiac function, attenuated myocardial injury, and upregulated angiogenic markers. In vitro, QBHF enhanced hypoxia-induced proliferation, migration, and tube formation in EA.hy926 cells. Mechanistically, a specific circular RNA (hsa_circ_0003296) was found to be significantly upregulated in the peripheral blood of AS and MI patients. It directly bound to eukaryotic initiation factor 4A-III (EIF4A3) to promote its ubiquitin-mediated degradation. QBHF suppressed hsa_circ_0003296 expression, thereby preventing EIF4A3 degradation. The stabilized EIF4A3 subsequently prolonged the mRNA half-lives of vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2), thereby promoting angiogenesis.

These results suggest that QBHF ameliorates MI in CHD by reversing hsa_circ_0003296-mediated inhibition of angiogenesis. This process is executed through the stabilization of EIF4A3, which enhances the mRNA stability of VEGFA and VEGFR2.

Adverse metabolic profile manifested as metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity affect the development and prognosis of heart failure (HF).

Whether treatments targeting metabolic derangements such as sodium-glucose cotransporter 2 inhibitors (SGLT2 inhibitors) and glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) are associated with improved outcomes patients with both HF and MASLD or obesity warrants investigation.

This retrospective study included 7 propensity score matched cohort analyses using deidentified electronic health record data from the TriNetX global health research network.

We evaluated the associations between MASLD, obesity, and the use of SGLT2 inhibitors or GLP-1 receptor agonists with adverse outcomes in patients with HF. Cohorts were defined based on combinations of comorbidities (HF subtype, MASLD, obesity, diabetes status) and medication exposure. Time-to-event outcomes with the Kaplain-Meier method and with Cox proportional hazards models for the calculation of hazard ratios (HRs) and 95% confidence intervals.

Among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction, MASLD was consistently linked to increased risk of nonfatal cardiovascular events, including HF (HR = 1.09, P < 0.001 and HR = 1.23, P < 0.001), myocardial infarction (HR = 1.03, P = 0.07 and HR = 1.08, P < 0.001), and stroke (HR = 1.04, P = 0.08 and HR = 1.07, P = 0.07). Use of SGLT2 inhibitors in HFpEF and MASLD patients with or without diabetes was associated with reduced all-cause mortality (HR = 0.76, P < 0.001 and HR = 0.69, P < 0.001) and major cardiovascular events. GLP-1 receptor agonists demonstrated a significant survival benefit (HR = 0.38, P < 0.001) in obese patients with HFpEF and MASLD without diabetes.

In patients with HFpEF, pharmacologic interventions targeting metabolic pathways demonstrate meaningful cardioprotective effects, especially in metabolically vulnerable subgroups.

Post-kidney transplantation hypertension is common and is frequently driven by calcineurin inhibitor (CNI)-mediated sodium retention and vasoconstriction, producing a salt-sensitive phenotype in which sodium-chloride cotransporter (NCC) inhibition remains the mechanistically aligned cornerstone of therapy. This opinion piece examines aldosterone synthase inhibitors (ASIs) as an emerging drug class that may have adjunctive relevance in selected resistant phenotypes after kidney transplantation. We summarize the class rationale, distinguish older less selective compounds from newer CYP11B2-selective agents, and position baxdrostat within the broader ASI landscape alongside lorundrostat, vicadrostat, and earlier-stage dexfadrostat data. In non-transplant populations, baxdrostat and lorundrostat have lowered blood pressure in uncontrolled or resistant hypertension, whereas vicadrostat has shown cardiorenal promise in chronic kidney disease, including combination development with empagliflozin. However, no ASI has been studied in kidney transplant recipients. This gap is especially important because transplant recipients have reduced nephron reserve, frequent CNI exposure, narrow potassium margins, and a hypertensive phenotype often dominated by NCC activation rather than uniform aldosterone excess. Accordingly, ASIs should be viewed in transplantation as hypothesis-generating investigational agents rather than therapeutic recommendations. Any transplant-specific trial should incorporate rigorous hyperkalemia monitoring, comparator arms that reflect optimized NCC-directed therapy, and formal assessment of drug-drug interactions with immunosuppressants.

Houseless trauma patients (HTPs) face triple the complications and nearly double the mortality of nonhouseless trauma patients (nHTPs), which may be related to a higher burden of undiagnosed or untreated chronic conditions. This study aims to explore whether HTPs have a longer length of stay (LOS) and encounter more difficulties in accessing rehabilitation services compared to nHTPs. We hypothesize that HTPs, as compared to nHTPs, have longer LOS and decreased access to rehabilitation services.

The 2021-2023 Trauma Quality Improvement Program database was queried for admitted adult HTPs. HTPs were compared to nHTPs. The LOS for surviving HTPs and nHTPs was compared in a variety of clinical scenarios. Chi-square and Mann-Whitney U tests were performed. A multivariable logistic regression analysis was used to determine risk of prolonged LOS (defined as ≥5 d).

From 2,474,565 patients, 26,349 (1.1%) were HTPs. HTPs exhibited higher rates of alcohol use (22.6% versus 7.4%, P< 0.001) and mental health disorders (25.1% versus 12.3%, P< 0.001). After adjusting for age, injury severity, and comorbidities, HTPs continued to have a higher risk for prolonged LOS (odds ratio 1.49, 95% confidence interval 1.44-1.54, P< 0.001). HTPs had a longer median LOS in all scenarios, most notably with severe lower extremity fractures (19 versus 10 d, P< 0.001) and severe trauma (injury severity score >15) (12 versus 8 d, P< 0.001). HTPs also had decreased discharges to short-term/intermediate/long-term care rehabilitation (6% versus 13.2%, P< 0.001) but increased rates of leaving against medical advice (10.7% vs. 1.8%, P< 0.001).

This prognostic and epidemiological analyses highlight significant disparities faced by HTPs, including longer LOS and lower rates of discharge to rehabilitation services. By focusing on integrated care models and advocating for policies that address houselessness and health disparities, hopefully we can move closer to a health-care system that serves all individuals with equity and compassion.

Older adults are disproportionately affected by suicide, yet suicidal ideation in this population remains underexplored. This study examines gender-specific risk factors and regional differences in late-life suicidal ideation across Nordic and Visegrad countries, with loneliness as a key social determinant. This study analysed data from 11,712 participants aged 50 years and older from seven European countries (Nordic and Visegrad regions), drawing on Wave 8 of the Survey of Health, Ageing and Retirement in Europe (SHARE). Logistic regression was used to examine gender- and region-specific associations with late-life suicidal ideation. Increased loneliness was strongly associated with higher odds of suicidal thoughts in both men and women. Higher education acts as a protective factor, with middle and high education reducing risk in men, and high education reducing risk in women. Living with a partner lowers suicidal thoughts for women but not for men. Age showed no consistent association, and Nordic men show a lower risk compared to their Visegrad counterparts, whereas no regional differences observed for women. Social and contextual factors, especially loneliness, education, and partnership, shape late-life suicidal ideation in gender- and region-specific ways, highlighting the need for targeted preventive interventions.

Migraine is a primary headache disorder wherein vascular changes are well known. We aimed to evaluate the retinal and choroidal parameters in migraine patients longitudinally, with a particular focus on treatment-related changes.

We conducted a prospective longitudinal study of 45 patients with migraine (ICHD-3 criteria) who were indicated for prophylactic treatment. The patients were evaluated clinically using the visual analogue scale (VAS), monthly migraine days (MMD), migraine disability assessment score (MIDAS), and Optical Coherence Tomography (OCT) at baseline and after 3 months of follow-up. The peripapillary retinal nerve fibre layer (PPRNFL), peripapillary choroid thickness (PPCHT), subfoveal choroid thickness (SFC), ganglion cell layer (GCL), and central macular thickness (CMT) were the parameters assessed using OCT. 45 age- and gender-matched healthy controls were recruited for comparison of baseline parameters.

The majority of patients (38/45) were females, and the mean age was 37.3 ± 10.0 years. The PPRNFL, PPCHT, SFC LE, GCL, and CMT were thinner in patients than in controls. All parameters, except the GCL and CMT, increased significantly during follow-up after 3 months of prophylactic treatment.

This longitudinal study demonstrated partial structural recovery, suggesting that some retinal and choroidal changes in migraine may be reversible. Our findings support the role of these OCT parameters as surrogate markers of disease burden and treatment response in migraine. Large-scale, multicentre prospective studies with longer follow-up are warranted to evaluate the prognostic utility of OCT parameters in migraine.

The Internet holds potential for alleviating cognitive decline through cognitive stimulation and social engagement. However, existing studies often overlook the crucial role of Internet access as the foundational layer of the digital divide. This study investigated the association between Internet access and cognitive function among middle-aged and older adults and examined age-specific differences in this relationship. Data were drawn from the 2015 and 2018 waves of the China Health and Retirement Longitudinal Study (CHARLS). Participants aged ≥ 50 years with complete follow-up cognitive assessments were included (n = 7721; mean age = 60.48, SD = 9.37; male, 56.1%). Lagged dependent variable models were used to evaluate associations between Internet access and cognitive function. Chain mediation analyses were used to test whether family connection mediated this association. Internet access was significantly associated with better cognitive outcomes over time. Participants with Internet access demonstrated greater significant improvements in episodic memory (β = 0.29,95%CI = 0.14-0.44) and mental status (β = 0.28,95%CI = 0.12-0.44) compared to those without access. Age-stratified models indicated stronger effects in adults aged 50-59 for episodic memory (β = 0.36,95%CI = 0.17-0.55) and aged 60-69 for mental status (β = 0.42,95%CI = 0.15-0.69). Chain mediation analyses revealed that Internet access enhanced family connection, thereby contributing to better cognitive function. Internet access is positively associated with cognitive function in mid- to later life, partly through strengthened family ties. These findings underscore the importance of digital inclusion policies to support cognitive health and promote healthy aging.

Sleep-related eating disorder (SRED) is a parasomnia characterized by involuntary nocturnal eating with amnesia, which can result in serious injuries, weight gain, and metabolic complications. Reports implicate the use of ultra-short-acting benzodiazepine receptor agonists (USBZRAs)-especially zolpidem-in SRED, but the magnitude of this risk in psychiatric patients remains unclear.

We performed a cross-sectional observational survey at two Japanese hospitals of 157 psychiatric outpatients receiving one of four USBZRAs (triazolam, zopiclone, zolpidem, or eszopiclone) for ≥7 days. High-dose USBZRA therapy was defined as the maximum recommended dose per package insert. SRED was assessed using an International Classification of Sleep Disorders-based checklist. A Firth bias-reduced logistic regression model with four prespecified clinically relevant variables was employed due to the limited number of events.

Fourteen patients met SRED criteria (8.9%; 95% CI, 4.9-14.4). Zolpidem use (adjusted odds ratio [aOR] 5.98; 95% CI, 1.57-33.58) and high-dose USBZRA therapy (aOR 4.87; 95% CI, 1.56-17.51) were independently associated with SRED. Age (aOR 0.98; 95% CI, 0.94-1.02) and female sex (aOR 0.75; 95% CI, 0.22-2.87) were not significant.

The observed prevalence aligns with earlier reports, confirming that nearly one in eleven psychiatric outpatients receiving USBZRAs experiences SRED. Our study extends prior work by showing that SRED risk is highest at the maximum recommended dose, and especially with zolpidem. The wide confidence intervals reflect the small number of events and should be interpreted as hypothesis generating rather than definitive. These findings support limiting USBZRA dosage, favoring lower-risk hypnotics, and actively screening for nocturnal eating. This pilot study warrants validation in larger cohorts.

Cognitive impairments are common in depression and often persist beyond mood resolution. However, the relationship between cognitive performance, its neurological underpinnings, and future depression risk is unclear, limiting strategies for primary and secondary prevention.

Our objective was to determine whether cognition associates with subsequent depression, both relapse and first-episode occurrences.

1862 UK Biobank participants with a history of International Classification of Diseases (ICD)-10-defined depression in remission (RD) (mean (SD) age: 52.7 (7.13) years) were age-matched and sex-matched to 1862 participants without depression history or current antidepressant use. Cognitive scores were compared between groups at the composite (z-score), domain and task levels. MRI-derived phenotypes assessed brain network structure and functional connectivity. Longitudinal associations with future depression were assessed using logistic regression models and a Cox proportional hazards model controlling for key confounders.

Participants with RD had a higher risk of future depression (33%) than controls (13%), including when we accounted for temporal differences in longitudinal assessment (HR=3.16 (95% CI 2.71 to 3.67), global proportional hazard assumption p=0.07). Composite cognitive performance in controls was inversely associated with future depression risk (risk estimated marginal means: 0.25% at -1SD, 0.20% at mean, 0.15% at +1 SD). In RD, this relationship was reversed (0.74% at -1SD, 0.90% at mean, 1.10% at +1 SD). Executive functioning, processing speed and reasoning task scores all contributed. Higher grey matter in default mode network regions was associated with better concurrent cognitive performance across all participants, but not with future depression risk. Other MRI findings were limited.

RD carried a threefold higher risk of future depression than controls. Cognitive performance was a risk marker for future depression in both groups but in opposing directions. Neuroimaging metrics provided little predictive value.

Personalised risk factor assessment for depression is likely to be dependent on depression history. Those without previous history of diagnosed depression are at higher risk of future depression when cognitive performance is lower at baseline. RD is a high-risk group for future depression, and those with relatively higher cognitive performance may be more likely to report future depressive symptoms.