Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflammatory cytokines. Macrophages from mice lacking MR in myeloid cells (referred to herein as MyMRKO mice) exhibited a transcription profile of alternative activation. In vitro, MR deficiency synergized with inducers of alternatively activated macrophages (for example, IL-4 and agonists of PPARγ and the glucocorticoid receptor) to enhance alternative activation. In vivo, MR deficiency in macrophages mimicked the effects of MR antagonists and protected against cardiac hypertrophy, fibrosis, and vascular damage caused by L-NAME/Ang II. Increased blood pressure and heart rates and decreased circadian variation were observed during treatment of MyMRKO mice with L-NAME/Ang II. We conclude that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloid cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPARγ and glucocorticoid receptor. Furthermore, myeloid MR is critical for blood pressure control and for hypertrophic and fibrotic responses in the mouse heart and aorta.
Abstract-Peroxisome proliferator-activated receptor (PPAR)-␥ is a nuclear receptor and transcription factor in the steroidsuperfamily. PPAR-␥ agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-␥ also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-␥ activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-␥ activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-␥ activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor B. This system is likely to be even more prominent in modulating disease in vascular cells V ascular complications such as atherosclerosis and hypertension are primary causes to mortality associated with diabetes and obesity. With the increasing prevalence of diabetes and obesity, 1,2 vascular protection is critical to decreasing this mortality and improving public health as a whole. To accomplish this protection, one member in the nuclear receptor superfamily, peroxisome proliferator-activated receptor (PPAR)-␥, has emerged as an important player. PPAR-␥ ligands, thiazolidinediones (TZDs), are clinically used for type 2 diabetes. It is clear that improving glucose and lipid homeostasis by treating diabetes or insulin resistance has beneficial effects on cardiovascular diseases.
A major unifying role for PPARs in hypertension and its complications through modification of the innate immune system and inflammation is increasingly likely. PPAR agonists may be beneficial, alone or in combination with other drugs that modify the inflammatory response, in treating hypertension, atherosclerosis and metabolic derangements associated with obesity.
Background: Covid-19 disease causes significant morbidity and mortality through increase inflammation and thrombosis. Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are states of chronic inflammation and indicate advanced metabolic disease. We sought to understand the risk of hospitalization for Covid-19 associated with NAFLD/NASH. Methods: Retrospective analysis of electronic medical record data of 6,700 adults with a positive SARS-CoV-2 PCR from March 1, 2020 to Aug 25, 2020. Logistic regression and competing risk were used to assess odds of being hospitalized. Additional adjustment was added to assess risk of hospitalization among patients with a prescription for metformin use within the 3 months prior to the SARS-CoV-2 PCR result, history of home glucagon-like-peptide 1 receptor agonist (GLP-1 RA) use, and history of metabolic and bariatric surgery (MBS). Interactions were assessed by gender and race. Results: A history of NAFLD/NASH was associated with increased odds of admission for Covid-19: logistic regression OR 2.04 (1.55, 2.96, p<0.01), competing risks OR 1.43 (1.09-1.88, p<0.01); and each additional year of having NAFLD/NASH was associated with a significant increased risk of being hospitalized for Covid-19, OR 1.86 (1.43-2.42, p<0.01). After controlling for NAFLD/NASH, persons with obesity had decreased odds of hospitalization for Covid-19, OR 0.41 (0.34-0.49, p<0.01). NAFLD/NASH increased risk of hospitalization in men and women, and in all racial/ethnic subgroups. Mediation treatments for metabolic syndrome were associated with non-significant reduced risk of admission: OR 0.42 (0.18-1.01, p=0.05) for home metformin use and OR 0.40 (0.14-1.17, p=0.10) for home GLP-1RA use. MBS was associated with a significant decreased risk of admission: OR 0.22 (0.05-0.98, p<0.05). Conclusions: NAFLD/NASH is a significant risk factor for hospitalization for Covid-19, and appears to account for risk attributed to obesity. Treatments for metabolic disease mitigated risks from NAFLD/NASH. More research is needed to confirm risk associated with visceral adiposity, and patients should be screened for and informed of treatments for metabolic syndrome.
BACKGROUND Interhospital transfer is an understudied area within transitions of care. The process by which hospitals accept and transfer patients is not well described. National trends and best practices are unclear. OBJECTIVE To describe the demographics of large transfer centers, to identify common handoff practices, and to describe challenges and notable innovations involving the interhospital transfer handoff process. DESIGN AND PARTICIPANTS A convenience sample of 32 tertiary care centers in the United States was studied. Respondents were typically transfer center directors surveyed by phone. MAIN MEASURES Data regarding transfer center demographics, handoff communication practices, electronic infrastructure, and data sharing were obtained. RESULTS The median number of patients transferred each month per receiving institution was 700 (range, 250–2500); on average, 28% of these patients were transferred to an intensive care unit. Transfer protocols and practices varied by institution. Transfer center coordinators typically had a medical background (78%), and critical care–trained registered nurse was the most prevalent (38%). Common practices included: mandatory recorded 3-way physician-to-physician conversation (84%) and mandatory clinical status updates prior to patient arrival (81%). However, the timeline of clinical status updates was variable. Less frequent transfer practices included: electronic medical record (EMR) cross-talk availability and utilization (23%), real-time transfer center documentation accessibility in the EMR (32%), and referring center clinical documentation available prior to transport (29%). A number of innovative strategies to address challenges involving interhospital handoffs are reported. CONCLUSIONS Interhospital transfer practices vary widely amongst tertiary care centers. Practices that lead to improved patient handoffs and reduced medical errors need additional prospective evaluation.
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