Citations

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.

Introduction: V-domain Immunoglobulin Suppressor of T-cell Activation (VISTA), a co-inhibitory immune checkpoint protein, is known for regulating adaptive immune responses. Here, we investigated the role of VISTA in atherosclerosis. Hypothesis: VISTA is constitutively expressed on hematopoietic cells, particularly T cells. VISTA functions as both a ligand and receptor to maintain T cell quiescence. We hypothesize that VISTA expression is protective against plaque formation by inhibiting CD4 + T cell activation. Methods: Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) was performed on aortic CD45 + cells of HCD fed ApoE-/- mice. Spatial transcriptomics (VISIUM) was performed on carotid plaques from patients with either asymptomatic or symptomatic cerebrovascular disease. Plaque burden, characterization, and flow cytometry of blood and lymphoid organs were performed on VISTA -/- ApoE -/- (VISTA KO) and VISTA +/+ ApoE -/- (WT) mice that were fed a HCD for 10 weeks. ApoE -/- mice treated with VISTA agonist 8G8 or IgG control (200ug, intra-peritoneal, 3 times per week for the last 6/10 weeks of HCD feeding). In vitro proliferation, migration, and functional T cell assays were performed. Results: We found that VISTA is expressed on plaque T cell populations, particularly regulatory T cells, gamma-delta T cells, and naïve T cells. In humans, individuals with symptomatic CVD have significantly reduced VISTA gene expression in carotid plaques. VISTA KO mice have increased total plaque area and necrotic core area compared to littermate WT controls. VISTA KO mice have increased peripheral CD4 + and CD8 + effector memory T (T EM ) cells with a corresponding decrease in CD4 + and CD8 + naïve T (T N ) cells and CD4 + regulatory T (T reg ) cells. Further, VISTA KO mice have a higher frequency of CD4 + T H 1 (T-bet + IFNy + ) cells and lower frequencies of IL-10 + CD4 + T cells and CD4 + T H 2 (GATA-3 + IL-13 + ) cells. In vitro assays showed that VISTA suppresses CD4 + T cell proliferation, IFNγ production, and migration. Finally, VISTA agonist treatment significantly decreased plaque and necrotic core areas in atherosclerotic mice. Conclusion: Our data reveals a novel role for VISTA in reducing plaque development and in suppressing T cell activation, proliferation, and migration. Further characterization of T-cell specific VISTA-deficient mouse models and mechanistic insights into how VISTA modulates T cells are currently being investigated.

Abstract Inflammation is a key driver of coronary syndromes across the continuum from chronic coronary syndromes to acute coronary syndromes. It contributes to atherogenesis, plaque destabilization, and ischaemic events and influences myocardial injury, repair, and remodelling. Inflammatory activity is further amplified by metabolic and autoimmune comorbidities such as diabetes, obesity, and connective tissue diseases, with obesity representing a major driver of chronic low-grade inflammation through adipose tissue dysfunction and cytokine activation, while psychosocial stress and environmental exposures including air pollution serve as additional triggers. Genetic variations, including human leucocyte antigen genotypes, modulate individual susceptibility to vascular inflammation and myocardial injury. This expert consensus from the European Society of Cardiology’s Association for Acute CardioVascular Care summarizes the current understanding of inflammation across the full spectrum of coronary syndromes, including underlying mechanisms, relevant biomarkers, and imaging approaches that characterize vascular inflammation, and integrates insights from experimental and clinical studies. Importantly, this document provides explicit consensus-based guidance on when, how, and in whom inflammation should be assessed and treated in routine clinical practice. While the causal association between inflammation and atherosclerotic cardiovascular disease is well established, pharmacological modification of inflammation has produced conflicting evidence. Some agents, such as low-dose colchicine, have demonstrated modest reductions in cardiovascular events, although results across trials have been inconsistent. Other anti-inflammatory therapies have not shown clinical benefit, whereas selective cytokine inhibition with canakinumab has reduced cardiovascular risk at the cost of increased infection rates. The present manuscript also focuses on the evaluation of inflammatory activity in cardiovascular patients in routine clinical practice. It further discusses criteria for patient selection and clinical decision-making regarding the introduction of anti-inflammatory therapy in individuals with established atherosclerotic cardiovascular disease.

Solitary plasmacytomas (SPs) are rare localized tumors of clonal plasma cells, either in the bone (solitary bone plasmacytoma) or in soft tissue/extraosseous (extramedullary) with either no or with minimal bone marrow (BM) infiltration (<10% clonal plasma cells by immunohistochemistry) and no evidence of systemic involvement or myeloma defining events. Approximately 50% of SPs will progress to symptomatic myeloma within 5 years after initial definitive local radiotherapy. Increased availability of improved diagnostic and monitoring tools has increased the sensitivity of detection of additional lesions and marrow involvement and has implications for the follow-up strategy after treatment. Thus, the definitions and requirements for the diagnosis and follow-up of SPs are evolving. The diagnosis of SP requires the careful exclusion of multiple myeloma (MM) that would require systemic therapy, by using all the available methods to detect systemic disease (advanced imaging, sensitive BM assessment methods, blood and urine tests). Local radiotherapy remains the mainstay of therapy, and despite the availability of innovative drugs for MM, the clinical benefit of systemic therapy currently remains poorly defined. The International Myeloma Working Group provides here updated recommendations for the diagnosis, evaluation, treatment, and response assessment of patients with SPs, incorporating recent data and advances in diagnostic tools.

Abstract Seizure forecasting has progressed from theoretical aspiration to a rapidly advancing research domain, yet clinical translation remains limited. Over the past decades, advances in algorithm development, chronic electroencephalography (EEG), wearable sensors, and the characterization of seizure cycles have demonstrated that seizure risk is not random but fluctuates according to identifiable biological rhythms and patient‐specific patterns. Forecasting algorithms have shown promising performance across diverse retrospective datasets, including intracranial EEG, subscalp recordings, wearable physiological signals, and even self‐reported diaries. However, the clinical value of forecasting is contentious. Prospective real‐world validation and regulatory approval of patient‐facing forecasting systems remain rare. This review incorporates perspectives presented at the 5th International Congress on Mobile Health and Digital Technology in Epilepsy (2025). We examine barriers impeding clinical translation and current attempts to address them. Crucially, forecasting performance cannot be evaluated in isolation from intended use. Applications range from low‐risk uses, like scheduling diagnostic monitoring or visualization of historical trends, to higher risk interventions, including medication titration and adaptive neuromodulation. Each application entails distinct performance thresholds, ethical considerations, and regulatory requirements. Translational challenges include reliable seizure annotation, nonstationarity dynamics of biological cycles, and practical constraints for real‐time deployment. Ethical concerns center on miscalibrated reliance on low‐risk states, potential anxiety associated with high‐risk advisories, and the heterogeneity of patient preferences and risk tolerance. Regulatory pathways are likely to depend on clearly defined use cases and clinically meaningful endpoints, which may extend beyond seizure counts to include quality of life, anxiety, locus of control, and other patient‐reported outcomes. Ultimately, translation will require rigorous prospective evaluation against transparent benchmarks, sustainable scientific–commercial partnerships, and integration of probabilistic risk information into clinical workflows. With careful implementation, seizure forecasting may evolve from proof‐of‐concept research into a clinically meaningful component of epilepsy management, and we remain cautiously optimistic.

Abstract Context Biochemical test results are central to clinical decision-making for the diagnosis and management of Cushing syndrome (CS). With emerging research and increasing availability of different tests, updated consensus on the utility of these biomarkers is warranted. Objective To establish an updated consensus on the role of biomarkers in the diagnosis and monitoring of adrenocorticotropic hormone-dependent CS, address novel therapeutic approaches, and identify areas for future research. Design A modified 2-round Delphi panel was conducted. Consensus was defined as ≥70% agreement/disagreement for Likert-scale statements or ≥70% selection of the same option for single-choice questions. Setting Participants represented a range of international expertise. Participants Forty-one participants took part in the Delphi panel, with no attrition between rounds (one nonclinician was not required to complete the second round). An 8-member Steering Committee guided statement development. Results Of statements designed to reach consensus, 45% (14/31) and 44% (11/25) statements reached consensus in Rounds 1 and 2, respectively. Notably, most panelists reported the use of late-night salivary cortisol for diagnosis of mild CS and for monitoring following pituitary surgery or medical or radiation therapy. Most panelists responded that block-and-replace therapies can be considered in patients with cyclical or severe CS, and consensus was reached that restoration of circadian rhythm is a treatment goal for patients with CS. Conclusion Areas of alignment among experts on the diagnosis and monitoring of CS are presented. The findings from this study are intended to support clinicians in their clinical decision-making and highlight priority areas for future research.

Abstract Gangliosides are structurally complex glycosphingolipids that regulate cellular signaling via interactions with extracellular binding partners and by influencing protein function within the membrane. Their comprehensive analysis remains analytically challenging, in part due to low endogenous abundance, extensive structural diversity, and the frequent occurrence of isomeric species arising from both glycan and ceramide moieties. Here, we present a hydrophilic interaction liquid chromatography (HILIC) nanoelectrospray ionization tandem mass spectrometry (nanoESI-MS/MS) method specifically designed to achieve isomer-resolved analysis and molecular species-level quantification of gangliosides. To improve characterization of low-abundance fatty acyl fragments, the workflow was extended by combining nanoESI with online fraction collection and subsequent direct infusion. The method demonstrated stable chromatographic performance, high sensitivity, and reproducible quantitative results across ten mouse tissues. Application of the workflow enabled quantification of 80 ganglioside molecular species belonging to 18 subclasses and revealed pronounced tissue-specific differences in subclass distribution and ceramide composition. Overall, this study establishes a robust and sensitive platform for comprehensive ganglioside analysis, providing new opportunities to investigate ganglioside diversity, regulation, and function in complex biological systems.

The integration of artificial intelligence (AI) into healthcare systems is central to the realization of 6P Medicine that emphasizes Predictive, Preventive, Personalized, Participatory, Precision-oriented, and Public-centered care. While several conceptual AI adoption models have been proposed, few provide prescriptive guidance for real-world validation across technical, sociotechnical, and ethical dimensions. This paper introduces a comprehensive validation framework for the Scalable Multi-Layer AI Adoption Model for 6P Medicine. The framework aligns architectural prerequisites, regulatory governance, and continuous lifecycle monitoring with the six interdependent layers of the model. Validation is addressed across data integrity, model robustness, clinical efficacy, human-AI collaboration, scalability, and ethical governance, drawing on FDA Good Machine Learning Practice (GMLP) principles and WHO regulatory considerations. The resulting framework intends to support continuous, real-world validation, positioning AI as a trustworthy, scalable, and ethically governed enabler of 6P Medicine.

Pharmacological plasminogen reduction enhanced liver regeneration experimentally and clinically. siRNA-induced plasminogen deficiency promoted hepatocyte proliferation after partial hepatectomy in mice, contrasting genetic deficiency models. In the HeLiX trial, tranexamic acid reduced post-hepatectomy liver failure odds, suggesting a novel therapeutic strategy.