Cardiovascular diseases (CVDs) are the leading causes of death and morbidity worldwide. Patients with vascular and cardiac conditions undergo cardiac rehabilitation (CR), a process that may begin before surgery (less frequently), after invasive procedures, or as part of chronic disease management, with durations varying by healthcare facilities or national policies. CR is a valuable non-pharmacological intervention that supports patient health and the resumption of daily activities. These rehabilitation programmes are strongly recommended for cardiac patients and are structured according to guidelines from organisations such as the European Society of Cardiology (ESC) and the American Heart Association/American Association of Cardiovascular and Pulmonary Rehabilitation (AHA/AACPR). This editorial reviews the latest ESC and AHA/AACPR guidelines, emphasising physical activities such as endurance and resistance training, while highlighting the lack of detail on inspiratory muscle training (IMT). The editorial reiterates the Italian Association of Cardiovascular Rehabilitation (AIRC) proposals regarding IMT and calls for further clinical trials.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome marked by inflammation, immune dysregulation, and myocardial fibrosis. Whether pyroptosis intersects with fibrotic remodeling in HFpEF remains uncertain. Two murine cardiac transcriptomic datasets were integrated after batch correction and intersected with curated pyroptosis- and myocardial fibrosis-related gene sets. Functional enrichment, univariate logistic regression, support vector machine-recursive feature elimination (SVM-RFE), and least absolute shrinkage and selection operator (LASSO) regression were used for feature selection. Complete separation in the ordinary three-gene logistic fit prompted refitting with Firth bias-reduced logistic regression. Performance was assessed by apparent area under the curve (AUC), stratified bootstrap optimism correction, and repeated nested cross-validation; the panel was re-estimated in a human left-ventricular dataset for exploratory replication. Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) estimated immune-cell fractions, and expression was examined in a high-fat diet (HFD)/N^ω-nitro-L-arginine methyl ester hydrochloride (L-NAME) murine model and whole blood from patients with HFpEF. Six candidates-Pparg, Ace2, Smad2, Lcn2, Ptpn11, and Sqstm1-were identified. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses linked them to SMAD binding, autolysosome/amphisome activity, cellular senescence, efferocytosis, and renin-angiotensin signaling. In the 45-sample discovery cohort, the fixed Pparg-Ptpn11-Ace2 Firth model had an apparent AUC of 1.0000; bootstrap correction yielded an AUC of 0.9971 (95% percentile interval, 0.9780-1.0000). Repeated nested cross-validation produced a mean out-of-fold AUC of 0.9286 (2.5%-97.5% percentile interval, 0.8726-0.9700), revealing additional feature-selection uncertainty. Re-estimation in the human dataset represented panel-level replication rather than validation of a locked cross-species model. No inferred immune-cell fraction differed between HFpEF and control after false-discovery-rate correction, although exploratory correlations were observed among deconvolved fractions and with Ptpn11 expression. HFD/L-NAME-treated mice developed diastolic dysfunction, reduced exercise capacity, pulmonary congestion, cardiomyocyte hypertrophy, and myocardial fibrosis despite preserved systolic function; myocardial Ptpn11, Pparg, and Ace2 transcripts and their proteins were reduced. In patients with HFpEF, whole-blood PTPN11 mRNA was lower than in controls and inversely associated with N-terminal pro-B-type natriuretic peptide and C-reactive protein; these unadjusted findings remain exploratory. The three-gene panel is hypothesis-generating rather than a stable diagnostic model; its transportability, selection stability, and clinical relevance require prospective validation.

Articaine has been proposed as an alternative to lidocaine for local anesthesia in pediatric dentistry. Several systematic reviews have compared articaine with lidocaine in children; however, their conclusions vary by procedure, injection technique, outcome scale, and safety definition. We conducted an umbrella review of systematic reviews, with or without meta-analyses, comparing articaine and lidocaine in pediatric dental procedures. PubMed, Embase, and the Cochrane Library were searched without a lower date restriction until June 22, 2026. The study protocol was prospectively registered in PROSPERO (CRD420261430185). Eligible reviews included children or adolescents undergoing dental procedures and directly compared the efficacy and safety outcomes of articaine with those of lidocaine. Methodological quality was assessed using the A MeaSurement Tool to Assess Systematic Reviews 2, risk of bias with Risk Of Bias In Systematic reviews, certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation approach, and primary study overlap with the corrected covered area. Twenty records remained after removal of duplicates. Eleven full-text reports were assessed, and eight systematic reviews were included. Six reviews were rated as low and two as critically low confidence using the A MeaSurement Tool to Assess Systematic Reviews 2. Six systematic reviews had a low risk of bias, and two had a high risk of bias. Across eight reviews, 21 unique primary studies generated 55 occurrences, yielding a corrected covered area of 23.1%, indicating very high overlap. Articaine is generally comparable to lidocaine and may provide minor advantages in selected infiltration-based procedures. Safety-focused reviews found no significant difference in overall adverse events between articaine and lidocaine. The outcome-level certainty was low or very low, mainly due to risks of bias, inconsistency, indirectness, imprecision, and concerns about publication bias. Primary study overlap was very high and was considered separately when assessing the independence of the review-level conclusions. Current review-level evidence suggests that articaine is a reasonable alternative to lidocaine for pediatric dental local anesthesia and may offer modest advantages in selected infiltration-based procedures but does not establish universal clinical superiority. The short-term safety appears broadly comparable in available pediatric trials, although rare adverse events and their use in very young children remain insufficiently studied.

To characterize and compare adverse-event reporting patterns for aspirin without statins, statins without aspirin, and aspirin-statin co-exposure in the FDA Adverse Event Reporting System (FAERS), and to explore statistical reporting-interaction signals.

We analyzed FAERS reports from 2004 Q1 through 2025 Q1. Active-comparator disproportionality analyses compared aspirin-statin co-exposure with aspirin-without-statin and statin-without-aspirin reports using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayesian geometric mean (EBGM), followed by Benjamini-Hochberg false discovery rate (BH-FDR) correction. Candidate preferred terms (PTs) common to both active-comparator analyses underwent adjusted statistical interaction analyses using four exposure groups, including a neither-drug reference. Primary models retained missing age, sex, and reporter type as explicit Unknown categories, and a complete-case sensitivity analysis excluded reports with missing adjustment covariates.

After deduplication, 18,932,599 unique FAERS reports were retained. The active-comparator analysis included 134,479 aspirin-without-statin reports, 202,565 statin-without-aspirin reports, and 70,806 aspirin-statin co-exposure reports. Among 9,332 and 9,736 PTs tested in the two active-comparator analyses, 119 and 254 PTs remained after prespecified signal-detection criteria and BH-FDR correction, respectively; 42 PTs were common to both comparisons. Adjusted interaction models were reliably estimable for 40 candidates, and 31 PTs met both additive and multiplicative reporting-interaction criteria. Missingness was substantial for age (42.33%), sex (12.12%), and reporter type (4.35%). The complete-case dataset retained 53.83% of reports, and 21 of the 31 primary both-scale-positive PTs remained jointly positive.

Aspirin-statin co-exposure showed distinct adverse-event reporting patterns in FAERS. The identified signals are exploratory statistical reporting interactions and do not establish increased incidence, clinical risk, causality, or pharmacological drug-drug interactions. Only 21 of the 31 primary both-scale-positive PTs remained jointly positive in the complete-case sensitivity analysis, reinforcing the need for cautious interpretation and validation in denominator-based pharmacoepidemiologic datasets.

The prevalence of pathogenic variants in disease-related genes is population-specific and is of vital importance for the development of national health policies. It is especially important with medically actionable diseases, where early interventions and preventive surveillance are available and can enable effective preventive measures or timely treatment.

We have examined the burden of pathogenic variants in 84 genes associated with medically actionable disease in exome sequencing data of 14.000 Slovenian individuals, representing 0.7% of the whole Slovenian population. The variants were classified according to the ACMG criteria, and the prevalence of pathogenic variants in each gene was compared to the burden of pathogenic variants in the gnomAD database.

The prevalence of pathogenic variants in 84 medically actionable genes in the Slovenian population is 2.73%. Furthermore, we identified an additional 0.48% of novel candidate likely pathogenic variants. Together, these variants accounted for 3.21% of all detected potentially medically actionable variants. Of this variation, 1.73% is cardio-related, 1.21% is cancer-related, and 0.27% is associated with other phenotypes. The prevalence of pathogenic variants in BRCA1, LDLR, and HFE differs significantly between the Slovenian population and the gnomAD database.

Revealing the prevalence of pathogenic variants in medically actionable genes in the Slovenian population highlights the need for careful interpretation of genomic data in our population, as approximately one in 31 individuals carries a potentially medically actionable variant. Our results advocate for population-specific evaluation of genetic disease burden, as tailored measures, particularly for genes enriched in a given population, may be warranted.

Chronic cerebral hypoperfusion (CCH) is a neurological disorder characterized by persistent insufficiency of cerebral blood flow, yet specific biomarkers and mechanistic insights are lacking.

This study integrated transcriptomic and proteomic multi-omics analyses, along with behavioral assessments and immunofluorescence validation in a bilateral common carotid artery stenosis (BCAS) mouse model, to identify and validate candidate multi-omics biomarkers of CCH and explore their potential druggability. Leveraging public transcriptomic datasets and in-house proteomic data, differential expression analysis, protein-protein interaction network construction, and five topological algorithms identified Tlr2, Anxa5, and Grin2a as candidate biomarkers.

BCAS mice exhibited spatial memory impairments in behavioral tests. Immunofluorescence revealed upregulated TLR2 and ANXA5, downregulated GRIN2A, and increased TLR2-IBA1 co-localization indicating microglial activation. Tlr2 and Anxa5 positively correlated with infiltrating immune cells, whereas Grin2a showed a negative correlation. A putative ceRNA network and in silico molecular docking suggested strong binding of pirinixic acid to both TLR2 and ANXA5.

Tlr2, Anxa5, and Grin2a can serve as candidate multi-omics signature molecules of CCH in the mouse brain, with consistent alterations at the transcriptomic, proteomic, and tissue levels.

Patients diagnosed with primary aldosteronism (PA) are at significantly increased risk of abdominal aortic calcification (AAC) and subsequent cardiovascular complications. Notably, abdominal aortic calcification is independently associated with adverse cardiovascular outcomes. However, to date, no serum proteomic profiling has been specially carried out in PA patients complicated with AAC, leaving an unaddressed research gap. This study was designed to identify serum differentially expressed proteins (DEPs) via DIA-based untargeted proteomics.

In this translational research project, data-independent acquisition (DIA) mass spectrometry was utilized to contrast serum proteomic landscapes from two PA subgroups: patients presenting with AAC and those without the calcification lesion. GO and KEGG functional enrichment analyses were conducted to decode biological functions of screened DEPs. Tenascin-X (TNX), an extracellular matrix molecule encoded by the TNXB gene, was selected as the core candidate and validated via aldosterone-exposed vascular smooth muscle cells (VSMCs) as well as aldosterone-intervened mice.

In total, 38 DEPs were distinguished across the two patient cohorts, comprising 6 upregulated proteins and 32 proteins with lowered expression levels. Gene Ontology results illustrated these molecules predominantly reside within extracellular regions and take part in cellular adhesion and immune regulatory activities. KEGG pathway enrichment further highlighted prominent enrichment within the extracellular matrix receptor interaction cascade. Markedly suppressed TNX expression was detected in aldosterone-treated VSMCs (P < 0.001). In mouse aortic specimens, merely a marginal declining tendency of TNX was observed, which failed to reach statistical significance (P = 0.054).

This proteomic study analyzes serum protein profiles in primary aldosteronism patients with and without abdominal aortic calcification, and identifies reduced serum TNX expression in PA patients complicated by abdominal aortic calcification. Further cellular experiments and aldosterone-intervened mouse studies revealed downregulation or a downward trend of key candidate molecule TNX, providing partial preliminary experimental support for the proteomic-identified candidate TNX. This study offers new research ideas for subsequent mechanistic investigations into abdominal aortic calcification in patients with primary aldosteronism.

Interleukin-6 (IL-6) is frequently measured in heart failure with reduced ejection fraction (HFrEF), but its clinical utility remains unclear.

To assess IL-6 as a biomarker in HFrEF, with emphasis on the effect of treatments (pharmacodynamics) and translation readiness.

MEDLINE and EMBASE were searched through June 2026. Using AI-assisted full-text screening with manual adjudication, eligible studies were classified using BEST classification as prognostic, predictive and/or pharmacodynamic biomarkers.

Eighty studies met inclusion criteria (59 pharmacodynamic, 21 prognostic, 3 predictive; categories overlapping). Across prognostic studies, higher IL-6 consistently tracked disease severity and cardiovascular mortality risk, but associations with hospitalization and composite endpoints weakened after adjustment for natriuretic peptides, limiting incremental clinical value. Pharmacodynamic studies showed that several interventions reduce circulating IL-6-most consistently statins and levosimendan-while findings were heterogeneous for exercise, cardiac device, and sodium-glucose co-transporter-2 inhibitors. However, IL-6 changes did not consistently parallel clinical benefit, arguing against its use as a surrogate measure for outcome improvement. No study supported IL-6 as a predictive biomarker. Assay heterogeneity was substantial, with limited use of in vitro diagnosis-grade assays, representing a major barrier to qualification.

In HFrEF, IL-6 reflects inflammatory burden and may serve as pharmacodynamic readout in mechanistic studies, but it is not supported for treatment selection and adds limited prognostic information beyond natriuretic peptides. Progress towards translational utility requires standardized measurements and, potentially, biomarkers reflecting the IL-6 axis beyond IL-6 alone.

Ischemic stroke triggers persistent neuroinflammation, microglial activation, and peripheral immune changes that aggravate secondary brain injury. Astragaloside IV (AS-IV), a major bioactive constituent of Astragalus membranaceus, has neuroprotective and immunomodulatory effects, but its influence on Tregs and CD86/CD206-associated microglial phenotypic responses remains unclear.

This study investigated whether AS-IV attenuates post-ischemic neuroinflammation in association with Treg-related immune responses, PI3K/AKT signaling alterations, and CD86/CD206-associated brain myeloid phenotypic responses.

A mouse middle cerebral artery occlusion (MCAO) model was established using the intraluminal filament method. Neurological deficits, infarct volume, and histopathological injury were evaluated after AS-IV treatment. Western blotting and ELISA were used to assess inflammatory cytokines and PI3K/AKT-associated signaling in ischemic brain tissue. Transcriptomic analysis identified AS-IV-related biological processes and pathways. Flow cytometry quantified CD4⁺CD25⁺FOXP3⁺ regulatory populations and additionally analyzed CD4⁺FOXP3⁺ populations in the spleen and cervical lymph nodes, together with CD86⁺/CD206⁺ phenotypic responses within the CD11b⁺CD45^low/int population in brain tissue. Immunofluorescence evaluated brain CD3⁺FOXP3⁺ signals and Iba1/CD86 or Iba1/CD206 double-positive signals. Anti-CD25 intervention was used to evaluate the involvement of Treg-related immune responses in AS-IV-associated effects.

AS-IV reduced infarct volume, showed a trend toward improvement in neurological deficit scores, and alleviated histopathological injury after MCAO. It decreased IL-6 and TNF-α and increased IL-10 and TGF-β in ischemic brain tissue. Transcriptomic analysis identified changes associated with the PI3K/AKT signaling pathway and immune regulatory processes, while western blotting showed increased p-PI3K/PI3K and p-AKT/AKT ratios after AS-IV treatment. AS-IV increased Treg proportions in the spleen and cervical lymph nodes and increased CD3⁺FOXP3⁺ signals in brain tissue. It also reduced CD86⁺-associated and increased CD206⁺-associated brain myeloid phenotypic responses. Anti-CD25 partially attenuated AS-IV-associated improvements in neurological and brain injury outcomes, as well as its effects on inflammatory cytokines and brain myeloid phenotypic responses.

AS-IV attenuated post-ischemic neuroinflammation in association with Treg-related immune responses and PI3K/AKT-associated signaling alterations, accompanied by changes in CD86/CD206-associated brain myeloid phenotypic responses. These findings support AS-IV as a potential neuroimmunomodulatory intervention for ischemic stroke.

It is critical to investigate innovative methods of providing immediate mental health support for youth. Soluna is a digital mental health and wellbeing platform for youth ages 13-25 launched and developed through a partnership between the California Department of Health Care Services and Kooth Digital Health as part of California's Children and Youth Behavioral Health Initiative. Soluna provides users with rapid access to self-help content and tools, pre-moderated peer community, coaching sessions, and care navigation from any internet-connected device.

The purpose of this study is to examine mental health and wellbeing outcomes over time among a self-selected subset of Soluna users aged 14-17.

We conducted a non-randomized, prospective, observational study. Participants completed three surveys (baseline, one-month, and three-months post-baseline) that assessed psychosocial outcomes and self-reported engagement with platform features. The primary outcome was psychological distress as measured by the YP-CORE. We conducted pre-registered analyses to determine whether outcomes changed among participants over the three-month evaluation period.

A total of 232 participants completed baseline measures, with 136 and 98 participants retained at one- and three-month follow-ups, respectively. Participants showed statistically significant within-group reductions in the primary outcome of distress from baseline to three-months (d = 0.63), and statistically significant improvements in secondary outcomes of depression, anxiety, hopelessness, loneliness, suicidal ideation, and quality of life (r = 0.35-0.53).

In this prospective observational study, participants showed statistically-significant within-person reductions in distress. Findings point towards the potential that scalable digital platforms like Soluna may offer accessible mental health and wellbeing support for youth.