Dynamic Perioperative Platelet Activity and Cardiovascular Events in Peripheral Artery Disease.

OBJECTIVE: Patients with peripheral artery disease (PAD) undergo lower extremity revascularization (LER) for symptomatic relief or limb salvage. Despite LER, patients remain at increased risk of platelet-mediated complications, such as major adverse cardiac and limb events (MACLE). Platelet activity is associated with cardiovascular events; yet little is known about the dynamic nature of platelet activity over time. We therefore investigated the change in platelet activity over time and its association with long-term cardiovascular risk. METHODS: Patients with PAD undergoing LER were enrolled into the multicenter, prospective Platelet Activity and Cardiovascular Events (PACE) study. Platelet aggregation was assessed by light transmission aggregometry (LTA) to submaximal epinephrine (0.4µ M) immediately prior to LER, and on post-operative day 1 or 2 (POD1) and 30 (POD30). A hyperreactive platelet phenotype was defined as >60% aggregation. Patients were followed longitudinally for MACLE, defined as the composite of death, myocardial infarction, stroke, major lower extremity amputation, or acute limb ischemia leading to reintervention. RESULTS: Among 287 patients undergoing LER, mean age was 70 ± 11 years, 33% were female, 61% were white, and 89% were on baseline antiplatelet therapy. Platelet aggregation to submaximal epinephrine induced a bimodal response; 15.5%, 16.8%, and 16.4% of patients demonstrated a hyperreactive platelet phenotype at baseline, POD1, and POD30, respectively. Platelet aggregation increased by 18.5% (P=0.001) from baseline to POD1, which subsequently returned to baseline at POD30. After a median follow-up of 19 months, MACLE occurred in 165 (57%) patients. After adjustment for demographics, clinical risk factors, procedure type, and antiplatelet therapy, platelet hyperreactivity at POD1 was associated with a significant hazard of long-term MACLE (aHR 4.61, 95% CI 2.08-10.20, P<0.001). CONCLUSION: Among patients with severe PAD, platelet activity increases following LER. Platelet hyperreactivity to submaximal epinephrine on POD1 is associated with long-term MACLE. Platelet activity following LER may represent a modifiable biomarker associated with excess cardiovascular risk.

Modeling of clinical phenotypes in systemic lupus erythematosus based on the platelet transcriptome and FCGR2a genotype.

BACKGROUND: The clinical heterogeneity of SLE with its complex pathogenesis remains challenging as we strive to provide optimal management. The contribution of platelets to endovascular homeostasis, inflammation and immune regulation highlights their potential importance in SLE. Prior work from our group showed that the Fcγ receptor type IIa (FcγRIIa)-R/H131 biallelic polymorphism is associated with increased platelet activity and cardiovascular risk in SLE. The study was initiated to investigate the platelet transcriptome in patients with SLE and evaluate its association across FcγRIIa genotypes and distinct clinical features. METHODS: Fifty-one patients fulfilling established criteria for SLE (mean age = 41.1 ± 12.3, 100% female, 45% Hispanic, 24% black, 22% Asian, 51% white, mean SLEDAI = 4.4 ± 4.2 at baseline) were enrolled and compared with 18 demographically matched control samples. The FCGR2a receptor was genotyped for each sample, and RNA-seq was performed on isolated, leukocyte-depleted platelets. Transcriptomic data were used to create a modular landscape to explore the differences between SLE patients and controls and various clinical parameters in the context of FCGR2a genotypes. RESULTS: There were 2290 differentially expressed genes enriched for pathways involved in interferon signaling, immune activation, and coagulation when comparing SLE samples vs controls. When analyzing patients with proteinuria, modules associated with oxidative phosphorylation and platelet activity were unexpectedly decreased. Furthermore, genes that were increased in SLE and in patients with proteinuria were enriched for immune effector processes, while genes increased in SLE but decreased in proteinuria were enriched for coagulation and cell adhesion. A low-binding FCG2Ra allele (R131) was associated with decreases in FCR activation, which further correlated with increases in platelet and immune activation pathways. Finally, we were able to create a transcriptomic signature of clinically active disease that performed significantly well in discerning SLE patients with active clinical disease form those with inactive clinical disease. CONCLUSIONS: In aggregate, these data demonstrate the platelet transcriptome provides insight into lupus pathogenesis and disease activity, and shows potential use as means of assessing this complex disease using a liquid biopsy.

Delirium in trauma ICUs: a review of incidence, risk factors, outcomes, and management.

PURPOSE OF REVIEW: This article reviews the impact and importance of delirium on patients admitted to the ICU after trauma, including the latest work on prevention and treatment of this condition. As the population ages, the incidence of geriatric trauma will continue to increase with a concomitant rise in the patient and healthcare costs of delirium in this population. RECENT FINDINGS: Recent studies have further defined the risk factors for delirium in the trauma ICU patient population, as well as better demonstrated the poor outcomes associated with the diagnosis of delirium in these patients. Recent trials and meta-analysis offer some new evidence for the use of dexmedetomidine and quetiapine as preferred agents for prevention and treatment of delirium and add music interventions as a promising part of nonpharmacologic bundles. SUMMARY: Trauma patients requiring admission to the ICU are at significant risk of developing delirium, an acute neuropsychiatric disorder associated with increased healthcare costs and worse outcomes including increased mortality. Ideal methods for prevention and treatment of delirium are not well established, especially in this population, but recent research helps to clarify optimal prevention and treatment strategies.

Intensive care nurse practitioners in Australia: A description of a service model in an adult tertiary intensive care unit.

BACKGROUND: Although well-established internationally, nurse practitioners (NPs) in Australian adult intensive care units (ICUs) are rare. Australian literature clearly highlights the importance of creating ICU NP roles to meet emerging demands. An ICU NP model of care at a metropolitan hospital in Sydney provides care in four core practice areas: complex case management, vascular access, tracheostomy management, and intrahospital transport of critically ill patients. The ICU NPs also provide training and assessment for ICU nurses and medical officers in these same core practice areas and can efficiently meet service gaps in crisis such as the most recent COVID-19 pandemic. RESULTS: The ICU NP program described is an innovative model of care that has demonstrated potential benefits to patients and their families. Potential benefits to the healthcare system including supporting advanced practice nursing development in regional and rural Australia and in addressing future ICU workforce issues are also identified. This model of care provides a clear role and structure for the integration of NPs in the adult ICU. Research to evaluate the impact of the role is required and is underway. CONCLUSIONS: This model is being used to develop a national adult ICU NP fellowship training program for ICU transitional NPs preparing for endorsement or endorsed NPs who require additional ICU-specific training. This immersive clinical training program combined with didactic learning modules offers a framework to support the implementation of the adult ICU NP role as well as a framework for NP fellowship programs in other specialties.

A supramolecular host for phosphatidylglycerol (PG) lipids with antibacterial activity.

Lipids fulfill a variety of important physiological functions, such as energy storage, providing a hydrophobic barrier, and signal transduction. Despite this plethora of biological roles, lipids are rarely considered a potential target for medical applications. Here, we report a set of neutral small molecules that contain boronic acid and urea functionalities to selectively recognize the bacterial lipid phosphatidylglycerol (PG). The affinity and selectivity was determined using 1H NMR titrations and a liposome-based Alizarin Red S assay. Minimum inhibitory concentrations (MIC) were determined to assess antibacterial activity. The most potent compounds display an association constant with PG in liposomes of at least 5 × 103 M-1, function as antibacterial agents against Gram-positive bacteria (MIC = 12.5-25 µM), and show little hemolytic activity. Mode of action studies suggest that the boronic acids bind to the headgroup of the PG lipids, which leads to a change in membrane fluidity and ultimately causes membrane depolarization and cell death.

Uniquely human CHRFAM7A gene increases the hematopoietic stem cell reservoir in mice and amplifies their inflammatory response.

A subset of genes in the human genome are uniquely human and not found in other species. One example is CHRFAM7A, a dominant-negative inhibitor of the antiinflammatory α7 nicotinic acetylcholine receptor (α7nAChR/CHRNA7) that is also a neurotransmitter receptor linked to cognitive function, mental health, and neurodegenerative disease. Here we show that CHRFAM7A blocks ligand binding to both mouse and human α7nAChR, and hypothesized that CHRFAM7A-transgenic mice would allow us to study its biological significance in a tractable animal model of human inflammatory disease, namely SIRS, the systemic inflammatory response syndrome that accompanies severe injury and sepsis. We found that CHRFAM7A increased the hematopoietic stem cell (HSC) reservoir in bone marrow and biased HSC differentiation to the monocyte lineage in vitro. We also observed that while the HSC reservoir was depleted in SIRS, HSCs were spared in CHRFAM7A-transgenic mice and that these mice also had increased immune cell mobilization, myeloid cell differentiation, and a shift to inflammatory monocytes from granulocytes in their inflamed lungs. Together, the findings point to a pathophysiological inflammatory consequence to the emergence of CHRFAM7A in the human genome. To this end, it is interesting to speculate that human genes like CHRFAM7A can account for discrepancies between the effectiveness of drugs like α7nAChR agonists in animal models and human clinical trials for inflammatory and neurodegenerative disease. The findings also support the hypothesis that uniquely human genes may be contributing to underrecognized human-specific differences in resiliency/susceptibility to complications of injury, infection, and inflammation, not to mention the onset of neurodegenerative disease.

More frequent olive oil intake is associated with reduced platelet activation in obesity.

BACKGROUND AND AIMS: Obesity is an independent risk factor for atherosclerotic cardiovascular disease (CVD), and platelet hyperactivation in obesity may contribute to this association. Olive oil consumption is associated with lower cardiovascular disease (CVD) risk in the general population. However, little is known for individuals with obesity. We investigated whether olive oil intake is associated with platelet activation in obesity. METHODS AND RESULTS: We assessed platelet activation (surface P-selectin expression) with and without thrombin exposure and diet composition in 63 patients with severe obesity. Among 63 subjects with obesity, the mean age was 32.2 ± 8.0 years and BMI 44.1 ± 8.5 kg/m2. Olive oil intake was stratified into <1 time/week (n = 21), 1-3 times/week (n = 18), ≥4 times/week (n = 24). Strata did not differ by age, BMI or platelet count. Unstimulated P-selectin expression did not differ by olive oil consumption. Subjects with more frequent olive oil intake exhibited lower P-selectin expression on submaximal thrombin exposure. CONCLUSIONS: More frequent olive oil intake is associated with reduced thrombin-induced platelet activation in obesity.