Autoimmune diseases, including Type 1 diabetes (T1D), are often characterized by overactive inflammatory signaling pathways. The proinflammatory cytokine interleukin-1β (IL-1β) elicits global gene expression changes in islet β-cells which overlap with islets obtained from human donors with T1D. The direct transcriptional link between NF-κB subunit p65 and target genes involved with autoimmune events was investigated. We used a multiomics approach including bulk RNA-sequencing (RNA-Seq), single-cell RNA-sequencing (scRNA-Seq), and chromatin immunoprecipitation coupled to deep sequencing (ChIP-Seq), alongside molecular docking simulations, and transcriptional assays. Through the various experimental modalities, we identified early response genes driven by IL-1β that were differentially expressed in pancreatic islets from human T1D donors and also conserved across mouse, rat, and human tissues. ChIP-Seq revealed genes that are direct genomic targets of the NF-κB p65 transcription factor. Moreover, regions that gained RNA polymerase II binding following cellular exposure to IL-1β were identified, complementing the early response gene profile induced by β-cell exposure to IL-1β. Molecular docking simulations predicted that mutations reducing p65 transcriptional capacity do not alter DNA binding ability. These findings clearly show that IL-1β signaling in pancreatic β-cells directs p65 to specific genomic regions congruent with increased gene expression relevant to T1D in β-cell lines as well as mouse and human islets exposed to cytokines. Islets from human donors with T1D express genes identified as direct p65 targets using unbiased approaches, implicating heightened NF-κB activity as a critical component of autoimmune disease etiology. NEW & NOTEWORTHY Using multiple Seq-based approaches, this study identified genes expressed in human pancreatic tissue from donors with Type 1 diabetes that are regulated acutely by exposure to the cytokine interleukin-1beta. The NF-kB transcription factor p65 (RelA) was determined via ChIP-Seq to be a major control node regulating this immediate early response. These collective datasets are consistent with a paradigm of overactive NF-kB signaling as a critical component of autoimmunity in both rodents and humans.

To the Editor The retrospective cohort study by Dr Savage and colleagues1 compared outcomes of narrow- vs broader-spectrum antibiotics for acute sinusitis. Although the authors’ findings support use o...

Background: Unfractionated heparin (UFH) is widely used for treatment of acute venous thromboembolism (VTE); however, its anticoagulant response is highly varia...

Advertisement

Objective: To review the pharmacology, efficacy, and safety of subcutaneous depemokimab-ulaa as add-on therapy in the treatment of severe eosinophilic asthma. ...

<P>Title: Let Me Teach</P> <P>Summary: Medication counseling in clinical practice is variable, inadequate, and frequently nonexistent. Let Me Teach is a pocket-sized reference that condenses a memorab...

Subscription and open access journals from Sage, the world's leading independent academic publisher.

Background Artificial intelligence (AI), particularly large language models (LLMs) such as ChatGPT, is increasingly being used for statistical interpretation and research support. While traditional s...

Sleep disorders are associated with a variety of health outcomes, including cardiovascular disease, diabetes, and Alzheimer’s disease. Previous studies hav

Subscription and open access journals from Sage, the world's leading independent academic publisher.

The argatroban to warfarin transition in heparin-induced thrombocytopenia (HIT) is complicated as argatroban falsely elevates the international normalized ratio. The evaluation aims were to assess compliance with institutional guidelines for this transition and transition success. This was a retrospective, single-system, observational cohort study of confirmed HIT patients receiving argatroban with the goal of warfarin transition between January-2019 and June-2024. Data collection included demographics, anticoagulant dosing, venous and arterial thromboses, major and clinically relevant non-major bleeding (CRNMB), and laboratory data. The primary endpoint was compliance with all eight steps of institutional guidelines. Secondary endpoints included individual compliance steps and transition success (defined as completion within seven days and absence of bleeding, thrombosis, non-therapeutic international normalized ratios (INRs) and argatroban restarts). A Fisher’s Exact test assessed the relationship between compliance and outcomes, significance at p < 0.05. Thirty-two argatroban to warfarin courses were evaluated in 29 patients. Compliance occurred in 10/32 (31.3%) of courses. Non-compliance was often due to failure to perform a two-step argatroban discontinuation process with doses > 2 mcg/kg/min (6/14, 42.9%). Transition success occurred in 50% (16/32) of courses. An extended bridge (argatroban and warfarin co-therapy) beyond seven days was the most common reason for failure in 29% (9/31). Bleeding (major and CRNMB) and thrombosis occurred in 18.8% and 6.3% of courses, respectively. There was no relationship between compliance and outcomes. The process for transitioning HIT patients from argatroban to warfarin is complex. The low rate of compliance and transition success highlights the challenging nature of this transition. Graphical Abstract A single center retrospective study assessed outcomes in 32 argatroban to warfarin transition courses in heparin-induced thrombocytopenia. Compliance with institution guidelines for the transition and transition success were low. Bleeding was a greater concern than thrombosis. Future areas of research were identified.

In the acute care setting, consensus is lacking on whether patients initially treated with parenteral anticoagulation for venous thromboembolism (VTE) should complete the full high-intensity period (HIP) of apixaban or rivaroxaban. This study examines HIP prescribing patterns following parenteral anticoagulation and assesses the influence of patient, provider, and facility characteristics. Patients initiating rivaroxaban or apixaban for VTE after parenteral anticoagulation were identified from the Michigan Anticoagulation Quality Improvement Initiative (MAQI2) database between November 2015 and March 2024. Those with an indeterminate duration of parenteral treatment were excluded. Patients were categorized into full HIP and shortened HIP cohorts based on DOAC dose and duration. Demographics and comorbidities were compared using Student’s t-test and Chi-squared or Fisher’s exact tests. Variables with p < 0.3 were included in a logistic regression model, with stepwise selection at a 0.1 significance threshold. Among 816 patients, 687 (84.2%) received the full HIP, while 129 (15.8%) had a shortened HIP. Patients with private insurance (OR 0.3 [0.11–0.82], p = 0.02) or Medicare (OR 0.31 [0.11–0.92], p = 0.04) were less likely to receive a shortened HIP than Medicaid patients. Higher HAS-BLED scores were associated with increased odds of receiving a shortened HIP (OR 1.32 [1.1–1.59], p = 0.003). Provider type did not significantly impact HIP prescribing patterns. Despite prior parenteral anticoagulation, most patients completed the full DOAC HIP. Further research is needed to assess how patient, provider, and facility factors influence decision-making and to evaluate the impact of these decisions on clinical outcomes. Graphical abstract

AbstractPurpose. Hospitalized patients taking direct factor Xa inhibitors (DFXaIs), such as apixaban and rivaroxaban, often need to be transitioned to unfr

Altered joint stiffness is common after stroke, yet clinically feasible tools to objectively quantify joint stiffness during walking are lacking. Quasi-stiffnes...

In this real-world study of patients with type 2 diabetes, treatment with semaglutide resulted in greater reductions in body weight and hemoglobin A1c than dulaglutide.

The aging of the global population has profound implications for multiple sclerosis (MS), a disease increasingly affecting older adults. Motor and cognitive impairments are common in both aging and...

The tumor microenvironment (TME), composed of cancer, immune, and stromal cells together with the extracellular matrix, plays critical roles in tumor initiation, progression, metastasis, and therap...

Background As the health care landscape evolves rapidly, the demand for an expanded role of pharmacists is also growing. There is ample literature documenting the positive health outcomes of pharmac...

BackgroundHigh blood pressure (BP) is a known risk factor for dementia, but the relationships between BP and gross brain volumes are mixed and are understudi...

Background: Community pharmacies offer a unique and accessible opportunity to close the existing mental health care gap. Many pharmacists and student pharmacists, however, lack the confidence to effec...

INTRODUCTION Better cardiovascular health (CVH) is associated with better cognitive function, but limited data exist on its association with cerebrovascular disease (CVD) burden using the Life's Ess.....

Aim: This study investigated the effects of Muno-IgY®, a multi-pathogen-specific immunoglobulin Y (IgY), on microbial growth, adhesion, fermentation activity, and immune signaling using a multi-tiered...

<p style="caret-color: #000000; color: #000000; font-style: normal; font-variant-caps: normal; font-weight: 400; letter-spacing: normal; orphans: auto; text-align: start; text-indent: 0px; text-transf...