Citations

Abstract Background GLP-1 receptor agonists reduce major adverse cardiovascular events among patients with diabetes, overweight, and obesity. Whether these benefits extend to patients undergoing aortic valve replacement (AVR) for severe aortic stenosis (AS) remains unknown. Thus, we investigated the association between GLP-1 receptor agonist treatment and cardiovascular outcomes after AVR. Methods Nationwide population-based cohort study including consecutive patients with severe AS undergoing TAVI or SAVR in Western Denmark between January, 2016 and April, 2022. Patients were followed until death, emigration, crossover, or end of follow up on May 12, 2026. Propensity score-matching was performed to balance confounding. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, or aortic valve reoperation. Secondary outcomes included all-cause mortality, heart failure hospitalization, aortic valve reoperation, with analyses accounting for the competing risk of death. Results Among 5259 eligible patients undergoing AVR, 292 propensity score-matched patients were included in the final analyses. During a mean follow up of 4.8±2.4 years, GLP-1 receptor agonist treatment was associated with a lower risk of the primary composite outcome compared with controls (HR 0.69, 95%CI 0.50-0.96, p=0.029). GLP-1 receptor agonist treatment was also associated with lower risk of all-cause mortality (HR 0.66, 95%CI 0.46-0.95, p=0.025). In competing risk analyses accounting for death, lower risks were observed for heart failure hospitalization (HR 0.67, 95%CI 0.48-0.93, p=0.018), and aortic valve reoperation (HR 0.69, 95%CI 0.49-0.98, p=0.037). Conclusion Treatment with GLP-1 receptor agonists was associated with lower risk of cardiovascular outcomes including mortality following AVR among patients with severe AS.

BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCAs) and angina with nonobstructive coronary arteries (ANOCAs) present diagnostic and therapeutic challenges. We assessed the frequency of coronary microvascular disease (CMD) and its subtypes in MINOCA compared with ANOCA and evaluated long-term cardiovascular outcomes. METHODS: Patients with nonobstructive coronary arteries undergoing invasive coronary function testing from 2012 to 2022 were prospectively enrolled and retrospectively classified as MINOCA or ANOCA (reference group). Myocardial infarction due to atherothrombosis, myocarditis, and Takotsubo syndrome were excluded. Invasive provocation testing was performed. CMD was classified as endothelium-independent (coronary flow reserve <2.5 with adenosine) and endothelium-dependent (<50% increase in coronary blood flow with acetylcholine). Major adverse cardiovascular events (cardiac death, nonfatal myocardial infarction, heart failure hospitalization, urgent revascularization, stroke) were recorded over 8 years. RESULTS: Of 622 patients, 73 (12%) had MINOCA (69% female, median age 56 years) and 549 (88%) ANOCA (72% female, median age 53 years). CMD was common in both groups (71% versus 64%; P =0.271), while endothelium-independent CMD was more frequent in MINOCA (41% versus 21%; P <0.001). Over a median follow-up of 4.5 years, major adverse cardiovascular events occurred more often in MINOCA (40% versus 11%; adjusted hazard ratio, 2.4; P =0.001). CMD predicted higher major adverse cardiovascular events in both MINOCA (hazard ratio, 3.6 [95% CI, 1.1–12.0]; P =0.038) and ANOCA (hazard ratio, 7.9 [95% CI, 2.9–21.8]; P <0.001). CONCLUSIONS: CMD is common in both MINOCA and ANOCA. The higher prevalence of endothelium-independent CMD in MINOCA suggests a potential mechanistic role in infarction. Patients with MINOCA have a worse prognosis than ANOCA, particularly when CMD is present.

Abstract Immune cell function is tightly coupled to cellular metabolism, with glycolysis, oxidative phosphorylation, and amino acid and lipid metabolism governing activation, differentiation, survival, and effector responses. In rheumatoid arthritis (RA), an autoimmune disease characterized by destructive joint inflammation, metabolic checkpoints have emerged as critical regulators of immune-cell behavior and drivers of tissue pathology. RA CD4+ T cells undergo profound metabolic reprogramming: glycolysis is suppressed, and glucose is redirected into the pentose phosphate pathway, resulting in NADPH accumulation, reduced ROS levels, and a highly reductive intracellular environment. Concurrent defects in mitochondrial DNA repair and electron transport chain function compromise mitochondrial fitness, leading to NAD+ depletion, altered tricarboxylic acid cycle activity, and metabolic exhaustion. The resulting accumulation of citrate and acetyl-CoA promotes lipogenesis and protein acetylation, driving membrane remodeling, tissue invasiveness, and proinflammatory effector functions. Depletion of oxaloacetate and aspartate limits NAD+ regeneration, inducing endoplasmic reticulum expansion and enhanced tumor necrosis factor production. Defective lysosomal coordination of AMPK and mTORC1 signaling uncouples energy sensing from anabolic programs, enabling cellular activation and proliferation despite metabolic insufficiency. Macrophage fate and function are similarly shaped by metabolic state. In synovial macrophages, GLUD1-dependent glutamine oxidation sustains mitochondrial respiration and ATP production, enabling survival under nutrient-deprived conditions while promoting antigen presentation. Conversely, metabolic stress in MerTK+ macrophages activates the NAD+ hydrolase SARM1, triggering NAD+ depletion, mitochondrial collapse, and PANoptotic cell death. Together, these findings identify NAD+ availability, mitochondrial fitness, and organelle-based signaling as central metabolic gatekeepers linking bioenergetic stress to immune-cell dysfunction and chronic inflammation in RA.

Abstract Emotional experiences during focal seizures are often misinterpreted as psychiatric disorders. We aimed to evaluate symptoms involving affective symptoms at seizure onset. We aimed to identify the most prevalent affective symptoms at seizure onset and characterize their localizing and lateralizing value. We performed a scoping review based on Preferred Reporting Items for Systematic reviews and Meta‐Analyses–extension for Scoping Reviews guidelines. A systematic search identified records from 4 databases: PubMed, Embase, CINAHL (via EBSCOhost), and Web of Science. Two reviewers independently screened titles/abstracts and full texts; discrepancies were resolved by consensus. This review focused on patients with focal seizures, as affective symptoms may occur in generalized epilepsies. The affective symptoms: fear, anxiety, panic, sadness, mystic, ecstatic, sexual, and mirth were identified, and semiology was evaluated in accordance with ILAE guidelines. Symptom onset, frequency, brain localization, and video‐EEG monitoring technique were evaluated to assess localization and lateralization of regional networks. Scalp EEG, invasive EEG recordings, and electrical stimulation were analyzed. A total of 1276 documents were identified, with 98 studies included for review. Fear was the most frequently reported ictal emotion, identified in 274 patients (66%), predominantly in temporal lobe epilepsy. Sadness and sexual, ecstatic symptoms were also consistently associated with temporal networks. Mirth was more frequently reported with frontal onset seizures. Evidence, primarily from Class IV studies, reported right hemispheric predominance for ecstasy, mystic, and sexual symptoms at seizure onset. Ictal affective symptoms at seizure onset yield localizing information. The limbic system, especially the temporal lobe, followed by the frontal lobe, was the most common site of origin. Fear was the most common spontaneous and electrically elicited symptom, followed by anxiety. While bi‐hemispheric lateralization occurred, right lateralization predominated. Recognizing paroxysmal affective symptoms as ictal phenomena may reduce misdiagnosis and aid presurgical evaluation in drug‐resistant focal epilepsy.

ABSTRACT Measles virus (MeV) is the most contagious human respiratory pathogen. To understand how it spreads in the airways, we infected well-differentiated primary cultures of human airway epithelial cells (HAE). We discovered that the MeV attachment protein (hemagglutinin, H), the fusion (F) protein, and the assembly organizer protein (matrix, M) reach newly infected cells ahead of, and independently from, the replicative complex proteins. To characterize the mechanisms of MeV spread, we generated a replication-deficient adenoviral vector expressing the MeV M, F, and H proteins in a doxycycline-inducible manner. This viral vector formed infectious centers that preserved epithelial function like those from MeV infection. To further dissect this process, we generated Ad vectors expressing individual MeV proteins, termed Ad-M, Ad-F, and Ad-H. Transduction of HAE with single, double, and triple Ad vector combinations revealed that Ad-F and Ad-H are necessary and sufficient to form MeV-like infectious centers. MeV enters and spreads within airway epithelia via H protein binding to adherens junction protein, nectin-4. To disrupt spread, we introduced the point mutation H Y543A , a mutation previously described to inhibit nectin-4 binding, in the Ad-H vector. Co-transduction of Ad-F and Ad-H Y543A did not result in MeV-like infectious center formation. Finally, we assessed whether the MeV-related paramyxovirus Nipah (NiV) attachment and fusion proteins (G and F, respectively) support cell-to-cell spread. Co-transduction of HAE with Ad-NiV-G and Ad-NiV-F did not result in infectious center formation, suggesting that decoupling of the membrane fusion apparatus function from replication is a unique feature of the MeV envelope glycoproteins. IMPORTANCE Measles virus is a highly contagious pathogen. We characterized a mechanism by which measles virus spreads rapidly through the cells that line the human airway in an ex vivo model. We show that the proteins of the viral membrane fusion apparatus, hemagglutinin (H) and fusion (F), move independently from and reach newly infected cells before the proteins of the replicative complex. Thus, viral protein spread is assembled and arranged in order (i.e., marshaled ). Using adenovirus-based vectors, we show that co-expression of H and F proteins promotes rapid sequential spread to multiple cells and the formation of infectious centers. Further elucidation of the mechanism of measles virus amplification and cell-to-cell spread within the lung may help explain its highly contagious nature.

Abstract Positron emission tomography (PET)-based molecular imaging is a clinically important tool for the evaluation of dementia and other neurodegenerative disorders, using radiotracers that target specific molecular and pathophysiological processes. Fluorodeoxyglucose brain PET has historically supported neurodegenerative disorder evaluation through detection of characteristic patterns of regional glucose hypometabolism. In recent years, the molecular imaging of protein aggregates has taken on an increasingly important role. This is evident with the widespread clinical adoption of amyloid PET and early use of tau PET to provide diagnostic and prognostic information for patients with suspected Alzheimer’s disease. Additional classes of radiotracers relevant to neurodegenerative diseases are under active investigation, including those targeting neuroinflammation, synaptic density, and α-synuclein aggregates. We review the major classes of PET radiotracers for neurodegenerative diseases, describing their molecular mechanisms, diagnostic performance, and their current and emerging clinical roles in dementia evaluation. Case examples for clinically used tracers illustrate imaging features relevant to diagnosis and characterization of prognosis and treatment effect. Finally, we discuss early developments and current challenges in the development of theranostic approaches and novel radiotracers for neurodegenerative diseases.