👤 Mariella Cuomo

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for myocardial infarction and stroke. Elevated Lp(a) >50 mg/dL (>125 nmol/L) is common and present in about 1 in 5 individuals. Although Lp(a) may be a cause of young ischemic stroke (age ≤60), limited data on national testing trends in this population are available, testing in the general population remains low overall, and different organizations have varying guidelines for testing. By determining the degree to which this population is tested, information on national testing trends of Lp(a) in young ischemic stroke patients may influence future guideline recommendations to increase Lp(a) testing. This study aims to use a large, real-world dataset to assess trends of Lp(a) testing in young ischemic stroke patients in the United States from 2015-2024. We performed a retrospective analysis of Lp(a) testing in young ischemic stroke patients across the United States from January 1, 2015 to December 31, 2024 using Epic Cosmos, a nationwide, de-identified electronic health record (EHR) dataset comprising over 300 million patient records from over 1,715 hospitals and 41,000 clinics, including from all 50 states, Washington D.C., Lebanon, and Saudi Arabia. The current count values for patients, hospitals, and clinics are available on the Epic Cosmos website. Although the Epic Cosmos data dictionary includes Lebanon and Saudi Arabia as standardized site locations, no patients from these countries were present in our analytic cohort; thus, all analyses were restricted to individuals within the United States. We evaluated the number of young ischemic stroke patients, defined as age ≤60 with history of an ischemic cerebrovascular accident (CVA), who had ever undergone Lp(a) testing, the testing rate per annual young ischemic stroke patients, geographical variation, and percentages of patients tested stratified by age, sex, ethnicity, race, and diagnosis of coronary artery disease (CAD). Testing rates were calculated as the number of distinct patients tested per year and as the testing rate per annual patient population. For each stratum we calculated the proportion tested with Wilson 95 % confidence intervals and assessed between-group differences using chi square or Fisher exact tests as appropriate. Annual trends in the testing proportion were modeled using a binomial generalized linear model with a logit link, treating the annual number tested as the numerator and the annual young ischemic stroke population as the denominator, and we report the odds ratio per calendar year with robust standard errors. Geographical variation was visualized using a heat map of testing by state. All analyses were descriptive and intended to characterize population-level patterns of ischemic stroke within the Cosmos network rather than infer causal associations. Given the exploratory design, no additional model-based adjustment for confounding was performed. All data are de-identified in compliance with HIPAA standards and governed under Epic's "Rules of the Road" for institutional data use. From 2015 to 2024, out of a total of 188,305 distinct young ischemic stroke patients, 9,226 (4.9 %) underwent Lp(a) testing. Additionally, the annual number of tested patients increased significantly from 179 in 2015 to 1,992 in 2024 (p<0.001), and the annual percentage of patients undergoing Lp(a) testing increased from 4.3 % in 2015 to 9.3 % in 2024. The states with the largest number of tested patients were Ohio (10.4 %), Texas (7.4 %), and Pennsylvania (5.5 %). The rates of testing were significantly different between sexes, with a larger percentage of young women with ischemic strokes tested compared to young men. Analyzing patients with reported racial data, patients who identified as Black or African American underwent testing for Lp(a) at the highest rate, compared with patients who identified as Asian, "None of the above", White, or Other Race. Among patients undergoing testing with reported ethnic identity, a higher percentage of patients who identified as Hispanic or Latino were tested compared to those who identified as non-Hispanic. Stratifying the total tested patients by age, adults between the ages of 50-60 years made up the largest percentage of patients (4,460; 48.3 %); however, the highest rate of testing occurred in patients aged 5-18. In addition, a higher rate of the young ischemic stroke patients who had ever had a diagnosis of CAD underwent testing compared to patients without CAD. Lp(a) testing among young ischemic stroke patients has increased significantly over the past decade, likely reflecting growing clinical recognition of its causal role in atherosclerotic disease. The rise parallels key updates in lipid management and stroke prevention guidelines, including the 2019 European Society of Cardiology and 2024 National Lipid Association recommendations advocating at least once-in-a-lifetime Lp(a) measurement. Increasing assay availability and heightened awareness of the causal relationship of Lp(a) with atherosclerotic disease may also have contributed to the observed upward trend. Despite this, only about one in twenty young ischemic stroke patients had ever been tested, underscoring a substantial implementation gap between evidence and clinical practice. Show less

Major depressive disorder (MDD) is increasingly recognized as a disorder of impaired neuroplasticity and large-scale network dysfunction rather than a simple monoaminergic deficit. Converging evidence indicates that chronic stress and depression erode synaptic connectivity, reduce glial support, and destabilize functional interactions among the default mode, salience, and executive networks. Conventional antidepressants indirectly restore circuit function over weeks, but the advent of rapid-acting glutamatergic agents has opened a new path for targeting these abnormalities directly. In this narrative review, we synthesize molecular, cellular, and connectomic findings to outline a conceptual Connectomic Glutamate Framework of Depression. We first examine how NMDAR blockade and subsequent AMPAR facilitation activate mTORC1 and BDNF signaling, driving synaptogenesis and dendritic spine formation. We then highlight the role of astrocytes and microglia in shaping the "quad-partite synapse" and sustaining network integrity. Neuroimaging studies demonstrate that glutamatergic modulators remodel dysfunctional networks: dampening DMN hyperconnectivity, enhancing fronto-limbic coupling, and normalizing salience-driven switching. Integrating these domains, we propose a hypothesis-generating, two-phase model in which glutamatergic agents destabilize maladaptive attractor states and then reintegrate circuits through structural remodeling. This framework bridges molecules, cells, and networks, offering mechanistic insight into the rapid efficacy of glutamatergic antidepressants and highlighting priorities for clinical translation. Show less

With no currently available targeted therapies for lipoprotein(a) [Lp(a)] lowering, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may be an option for management of increased cardiovascular risk in individuals with elevated Lp(a). However, Lp(a) lowering with PCSK9i is variable. We aimed to evaluate the real-world change in Lp(a) and predictors of response. Using data from the University of California Health Data Warehouse, we conducted a multi-center retrospective study among adults prescribed PCSK9i therapy with available Lp(a) measurement before and after prescription. We evaluated change in Lp(a) compared to baseline and evaluated potential predictors of Lp(a) reduction using multivariable linear regression, including among patients with multiple serial Lp(a) measurements. Among 453 included individuals, PCSK9i use was associated with a median 17.3 [IQR 35.3, 0.0]% and 11.3 [31.7, 0.0] mg/dL reduction in Lp(a) overall. Among those with Lp(a) >50 mg/dL, a 17.7 [33.6, 0.0]% and 19.2 [42.0, 0.0] mg/dL reduction was observed. Higher baseline Lp(a) level (β -0.31, p<0.001) was a significant predictor of greater Lp(a) reduction, while female sex was associated with less reduction (β 9.28, p=0.02). Results were consistent across Lp(a) assay types and by PCSK9i type and sustained in those with serial Lp(a) measurements (n=274). In contrast, in a control group of 6750 individuals, a median change of 0.00 [-2.00, 3.00] mg/dL in Lp(a) was noted in serial measurements. PCSK9i are associated with modest Lp(a) lowering of approximately 17% in real-world clinical practice, with a consistent percent reduction by baseline Lp(a) level, PCSK9i type and Lp(a) assay type. Predictors of Lp(a) reduction include baseline Lp(a) level and sex without significant variation by age, race/ethnicity or other evaluated comorbidities. Show less

Females with hypertrophic cardiomyopathy present at a more advanced stage of the disease and have a higher risk of heart failure and death. The factors behind these differences are unclear. We aimed to investigate sex-related differences in clinical and genetic factors affecting adverse outcomes in the Sarcomeric Human Cardiomyopathy Registry. Cox proportional hazard models were fit with a sex interaction term to determine if significant sex differences existed in the association between risk factors and outcomes. Models were fit separately for females and males to find the sex-specific hazard ratio (HR). After a mean follow-up of 6.4 years, females had a higher risk of heart failure (HR, 1.51 [95% CI, 1.21-1.88]; We found that clinical and genetic factors contributing to adverse outcomes in hypertrophic cardiomyopathy affect females and males differently. Thus, research to inform sex-specific management of hypertrophic cardiomyopathy could improve outcomes for both sexes. Show less

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases. Show less

Allergies are on the rise globally, with an enormous impact on affected individuals' quality of life as well as health care resources. They cause a wide range of symptoms, from slightly inconvenient to potentially fatal immune reactions. While allergies have been described and classified phenomenologically, there is an unmet need for easily accessible biomarkers to stratify the severity of clinical symptoms. Furthermore, biomarkers marking the success of specific immunotherapy are urgently needed. Plasma extracellular vesicles (pEV) play a role in coordinating the immune response and may be useful future biomarkers. A pilot study on differences in pEV content was carried out between patients with type I allergy, suffering from rhinoconjunctivitis with or without asthma, and voluntary non-allergic donors. We examined pEV from 38 individuals (22 patients with allergies and 16 controls) for 38 chemokines, cytokines, and soluble factors using high-throughput data mining approaches. Patients with allergies had a distinct biomarker pattern, with 7 upregulated (TNF-alpha, IL-4, IL-5, IL-6, IL-17F, CCL2, and CCL17) and 3 downregulated immune mediators (IL-11, IL-27, and CCL20) in pEV compared to controls. This reduced set of 10 factors was able to discriminate controls and allergic patients better than the total array. The content of pEV showed potential as a target for biomarker research in allergies. Plasma EV, which are readily measurable via blood test, may come to play an important role in allergy diagnosis. In this proof-of-principle study, it could be shown that pEV's discriminate patients with allergies from controls. Further studies investigating whether the content of pEVs may predict the severity of allergic symptoms or even the induction of tolerance to allergens are needed. Show less