Premature Acute Myocardial Infarction Treated with Invasive Revascularization: Comparing STEMI to NSTEMI in a Population-Based Study of Young Patients.

BACKGROUND: Acute myocardial infarction (AMI) usually presents in older populations, where there are established demographic and outcome differences between ST-elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). No similar comparisons for young AMI exist. METHODS: We compared all index NSTEMI and STEMI hospitalizations in the young (18-45 years) requiring revascularization in Alberta, Canada. Outcomes were survival to discharge, and a composite of heart failure hospitalization, cardiac arrest hospitalization, and all-cause mortality at 1- and 5-years. RESULTS: There were 1679 patients included with an index AMI requiring revascularization (655 (39.0%) NSTEMI and 1024 (61.0%) STEMI). The population was disproportionately male (86%), particularly in STEMI (87.3%). Marked dyslipidemia (35%) and active smoking (42%) were common, with similar rates between groups. Percutaneous coronary intervention was used in 98.7% of STEMI and 91.5% of NSTEMI patients (P<0.001), with the remainder undergoing surgical revascularization. In-hospital mortality during index AMI was higher STEMI compared to NSTEMI patients (1.7% vs 0%, P<0.001). The rates of the composite outcome were similar between groups at 1- and 5-years of follow-up in patients who survived to index hospital discharge. After adjusting for sex, age, heart failure and/or cardiac arrest at index AMI, outcomes remained similar between groups at 1- and 5-years. CONCLUSIONS: In young patients with AMI, STEMI was a disproportionately male phenomenon and associated with higher mortality at index hospitalization. One-year and 5-year outcomes were similar between STEMI and NSTEMI in those discharged alive at index AMI. Smoking and dyslipidemia appear to be major risk factors in the young.

Alzheimer's disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice.

Microglia play diverse pathophysiological roles in Alzheimer's disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-ß (Aß) deposition. Mice expressing CD33M have increased Aß levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function.

Low Nirmatrelvir/Ritonavir Use Among Patients With Rheumatoid Arthritis: A Signal of Concern.

Individuals with rheumatoid arthritis (RA) may be at increased risk of severe coronavirus disease 2019 (COVID-19) outcomes.1 Nirmatrelvir/ritonavir has been shown to reduce the risk for hospitalization and death among patients with COVID-19 at risk for progression to severe disease.2.

Use of Guideline-Directed Medical Therapy in Patients Aged ≥ 65 Years After the Diagnosis of Heart Failure: A Canadian Population-Based Study.

Background: Guideline-directed medical therapy (GDMT) improves clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). Despite its proven efficacy, GDMT is underutilized in clinical practice. The current study examines GDMT utilization after incident hospitalization for HF to promote medication initiation, and titration to target dosing within a reasonable time period. Methods: This observational study identified 66,372 patients with HFrEF who were aged ≥ 65 years and had an incident HF hospitalization, using administrative health data (2013-2018). GDMT (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor-neprilysin inhibitors, ß-blockers (BB), and mineralocorticoid receptor antagonists ) received within the 6 months after hospitalization was evaluated by monitoring therapy combinations, optimal dosing (proportion receiving ≥ 50% of the target dose for these inhibitors and blockers, and any dose of MRA), and maximal and last dose assessed, and by use of a GDMT intensity score. Results: Among patients with HFrEF, 4768 (7.2%) were on no therapy, 17,184 (25.9%), were on monotherapy, 30,912 (46.6%) were on dual therapy, and 13,508 (20.4%) were on triple therapy. Only 8747 (13.2%) and 5484 (8.3%) achieved optimal GDMT based on the maximum dose and the last dispensed dose, respectively, within 6 months postdischarge. Finally, 38,869 (58.6%) achieved < 50% of the maximum intensity score, 23,006 (34.7%) achieved between 50% and 74% of the maximum intensity score, and 4497 (6.8%) achieved a score that was ≥ 75% of the maximum intensity score. Conclusions: Current pharmacologic management for patients with HFrEF does not align with the Canadian guidelines. Given this gap in care, innovative strategies to optimize care in patients with HFrEF are needed.

Introduction: Les traitements médicamenteux préconisés dans les lignes directrices (TMPLD) permettent d'améliorer les résultats cliniques des patients atteints d'insuffisance cardiaque à fraction d'éjection réduite (ICFER). En dépit des preuves de leur efficacité, les TMPLD sont sous-utilisés dans la pratique clinique. La présente étude porte sur l'utilisation des TMPLD après une hospitalisation incidente en raison d'une IC afin de favoriser l'amorce de la médication, et l'ajustement de la posologie en vue d'atteindre la dose cible dans un délai raisonnable. Méthodes: Cette étude observationnelle portait sur 66 372 patients atteints d'ICFER qui avaient ≥ 65 ans et une hospitalisation incidente en raison d'une IC, et reposait sur les données administratives sur la santé (2013-2018). Nous avons évalué les TMPLD (inhibiteurs de l'enzyme de conversion de l'angiotensine, bloqueurs des récepteurs de l'angiotensine, ß-bloquants [BB] et antagonistes des récepteurs des minéralocorticoïdes [ARM]) reçus dans les six mois après l'hospitalisation par la surveillance des combinaisons de traitement, la posologie optimale (proportion recevant ≥ 50 % de la dose cible pour ces inhibiteurs et ces bloquants, et toute dose d'ARM), la dose maximale et la dernière dose évaluées, et par l'utilisation d'un score d'intensité des TMPLD. Résultats: Parmi les patients atteints d'ICFER, 4 768 (7,2 %) n'avaient reçu aucun traitement, 17 184 (25,9 %), avaient reçu une monothérapie, 30 912 (46,6 %) avaient reçu une bithérapie et 13 508 (20,4 %) avaient reçu une trithérapie. Seuls 8 747 (13,2 %) et 5 484 (8,3 %) avaient obtenu les TMPLD optimaux en fonction de la dose maximale et de la dernière dose administrée, et ce, respectivement, dans les six mois après la sortie de l'hôpital. Enfin, 38 869 (58,6 %) avaient obtenu < 50 % du score d'intensité maximale, 23 006 (34,7 %) avaient obtenu entre 50 % et 74 % du score d'intensité maximale, et 4 497 (6,8 %) avaient obtenu un score qui était ≥ 75 % du score d'intensité maximale. Conclusions: La prise en charge pharmacologique actuelle des patients atteints d'ICFER va à l'encontre des lignes directrices canadiennes. Compte tenu de cette lacune dans les soins, des stratégies novatrices pour optimiser les soins aux patients atteints d'ICFER sont nécessaires.

A versatile soluble siglec scaffold for sensitive and quantitative detection of glycan ligands.

Sialic acid-binding immunoglobulin-type lectins (Siglecs) are immunomodulatory receptors that are regulated by their glycan ligands. The connections between Siglecs and human disease motivate improved methods to detect Siglec ligands. Here, we describe a new versatile set of Siglec-Fc proteins for glycan ligand detection. Enhanced sensitivity and selectivity are enabled through multimerization and avoiding Fc receptors, respectively. Using these Siglec-Fc proteins, Siglec ligands are systematically profiled on healthy and cancerous cells and tissues, revealing many unique patterns. Additional features enable the production of small, homogenous Siglec fragments and development of a quantitative ligand-binding mass spectrometry assay. Using this assay, the ligand specificities of several Siglecs are clarified. For CD33 (Siglec-3), we demonstrate that it recognizes both α2-3 and α2-6 sialosides in solution and on cells, which has implications for its link to Alzheimer's disease susceptibility. These soluble Siglecs reveal the abundance of their glycan ligands on host cells as self-associated molecular patterns.