Sergey Karamnov

Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain

Self‐resolving inflammatory exudates and lipid mediator metabolomics recently uncovered a new family of potent anti‐inflammatory and proresolving mediators biosynthesized by macrophages (MΦs), denoted maresins. Here we determined that maresin 1 (MaR1) produced by human MΦs from endogenous docosahexaenoic acid (DHA) matched synthetic 7R,14S‐dihydroxydocosa‐4Z,8E,10E,12Z,16Z,19Z‐hexaenoic acid. The MaR1 alcohol groups and Z/E geometry of conjugated double bonds were matched using isomers prepared by total organic synthesis. MaR1s potent defining actions were confirmed with synthetic MaR1, i.e., limiting polymorphonuclear neutrophil (PMN) infiltration in murine peritonitis (ng/mouse range) as well as enhancing human macrophage uptake of apoptotic PMNs. At 1 nM, MaR1 was slightly more potent than resolvin D1 in stimulating human MΦ efferocytosis, an action not shared by leukotriene B4. MaR1 also accelerated surgical regeneration in planaria, increasing the rate of head reappearance. On injury of planaria, MaR1 was biosynthesized from deuterium‐labeled (d5)‐DHA that was blocked with lipoxygenase (LOX) inhibitor. MaR1 dose‐dependently inhibited TRPV1 currents in neurons, blocked capsaicin (100 nM)‐ induced inward currents (IC50 0.49±0.02 nM), and reduced both inflammation‐ and chemotherapy‐induced neuropathic pain in mice. These results demonstrate the potent actions of MaR1 in regulating inflammation resolution, tissue regeneration, and pain resolution. These findings suggest that chemical signals are shared in resolution cellular trafficking, a key process in tissue regeneration. Moreover, immunoresolvents of the innate immune response, such as MaR1, offer new opportunities for assessing MΦs and their local DHA metabolome in the return to tissue homeostasis.—Serhan, C. N., Dalli, J., Karamnov, S., Choi, A., Park, C.‐K., Xu, Z.‐Z., Ji, R.‐R., Zhu, M., Petasis, N. A. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. 26, 1755‐1765 (2012). www.fasebj.org

Novel Proresolving Aspirin-Triggered DHA Pathway

Endogenous mechanisms in the resolution of acute inflammation are of interest because excessive inflammation underlies many pathologic abnormalities. We report an aspirin-triggered DHA metabolome that biosynthesizes a potent product in inflammatory exudates and human leukocytes, namely aspirin-triggered Neuroprotectin D1/Protectin D1 [AT-(NPD1/PD1)]. The complete stereochemistry of AT-(NPD1/PD1) proved to be 10R,17R-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. The chirality of hydroxyl groups and geometry of the conjugated triene system essential for bioactivity were established by matching biological materials with stereochemically pure isomers prepared by organic synthesis. AT-(NPD1/PD1) reduced neutrophil (PMN) recruitment in murine peritonitis in a dose-dependent fashion whereby neither a Δ(15)-trans-isomer nor DHA was effective. With human cells, AT-(NPD1/PD1) decreased transendothelial PMN migration as well as enhanced efferocytosis of apoptotic human PMN by macrophages. These results indicate that AT-(NPD1/PD1) is a potent anti-inflammatory proresolving molecule.

Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation

Although specialized pro‐resolving mediators (SPMs) biosynthesized from polyunsaturated fatty acids are critical for the resolution of acute inflammation, the molecules and pathways that induce their production remain elusive. Here, we show that TLR7, a receptor recognizing viral ssRNA and damaged self‐RNA, mobilizes the docosahexaenoic acid (DHA)‐derived biosynthetic pathways that lead to the generation of D‐series SPMs. In mouse macrophages and human monocytes, TLR7 activation triggered production of DHA‐derived monohydroxy metabolome markers and generation of protectin D1 (PD1) and resolvin D1 (RvD1). In mouse allergic airway inflammation, TLR7 activation enhanced production of DHA‐derived SPMs including PD1 and accelerated the catabasis of Th2‐mediated inflammation. D‐series SPMs were critical for TLR7‐mediated resolution of airway inflammation as this effect was lost in Alox15−/− mice, while resolution was enhanced after local administration of PD1 or RvD1. Together, our findings reveal a new previously unsuspected role of TLR7 in the generation of D‐series SPMs and the resolution of allergic airway inflammation. They also identify TLR stimulation as a new approach to drive SPMs and resolution of inflammatory diseases.

Analysis of Adverse Events Associated With Adult Moderate Procedural Sedation Outside the Operating Room

Introduction Moderate sedation outside the operating room is performed for a variety of medical and surgical procedures. It involves the administration of different drug combinations by nonanesthesia professionals. Few data exist on risk stratification and patient outcomes in the adult population. Current literature suggests that sedation can be associated with significant adverse outcomes. Objectives The aims of this study were to evaluate the nature of adverse events associated with moderate sedation and to examine their relation to patient characteristics and outcomes. Methods In this retrospective review, 52 cases with moderate sedation safety incidents were identified out of approximately 143,000 cases during an 8-year period at a tertiary care medical center. We describe types of adverse events and the severity of associated harm. We used bivariate and multivariate analyses to examine the links between event types and both patient and procedure characteristics. Results The most common adverse event and unplanned intervention were oversedation leading to apnea (57.7% of cases) and the use of reversal agents (55.8%), respectively. Oversedation, hypoxemia, reversal agent use, and prolonged bag-mask ventilation were most common in cardiology (84.6%, 53.9%, 84.6%, and 38.5% of cases, respectively) and gastroenterology (87.5%, 75%, 87.5%, and 50%) suites. Miscommunication was reported most frequently in the emergency department (83.3%) and on the inpatient floor (69.2%). Higher body mass index was associated with increased rates of hypoxemia and intubation but lower rates of hypotension. Advanced age boosted the rates of oversedation, hypoxemia, and reversal agent use. Women were more likely than men to experience oversedation, hypotension, prolonged bag-mask ventilation, and reversal agent use. Patient harm was associated with age, body mass index, comorbidities, female sex, and procedures in the gastroenterology suite. Conclusions Providers should take into account patient characteristics and procedure types when assessing the risks of harmful sedation-related complications.

Affective Interactions in Medical Visits Ethnic Differences Among American Indian Older Adults

Objective: Investigate influence of ethnicity on older American Indian patients’ interpretations of providers’ affective behaviors. Method: Using data from 115 older American Indian patients, random effects ordered logit models related patient ratings of providers’ respect, empathy, and rapport first to separate measures of American Indian and White American ethnicity, then to “ethnic discordance,” or difference between providers’ and patients’ cultural characteristics. Results: In models accounting for patients’ ethnicity only, high scores for American Indian ethnicity were linked to reduced evaluations for providers’ respect; high scores on White ethnicity were associated with elevated ratings for empathy and rapport. In models accounting for provider–patient ethnic discordance, high discordance on either ethnicity scale was associated with reduced ratings for the same behaviors. Discussion: Findings support “orthogonal ethnic identity” theory and extend “cultural health capital” theory, suggesting a pathway by which ethnicity becomes relevant to experience of health care among older adults.

Characteristics of Reported Adverse Events During Moderate Procedural Sedation: An Update

BACKGROUND Many interventional procedures are performed under moderate procedural sedation (MPS). It is important to understand the nature of and factors contributing to adverse events (AEs). Little data exist examining reportable AEs during MPS across specialties. A study was conducted to investigate adverse events during MPS and to compare associated patient and provider characteristics. METHODS In a retrospective review, 83 MPS cases in which safety incidents were reported (out of approximately 20,000 annual cases during a 12-year period at a tertiary medical center) were analyzed. The type of AE and severity of harm were examined using bivariate and multivariate analyses to uncover associations between events with provider, procedure, and patient characteristics. RESULTS The most common AEs were oversedation/apnea (60.2%), hypoxemia (42.2%), and aspiration (24.1%). The most common unplanned interventions were the use of reversal agents (55.4%) and prolonged bag-mask ventilation (25.3%). Cardiology, gastroenterology, and radiology were the specialties most frequently associated with AEs. Reversal agents, oversedation, and hypoxemia occurred most frequently in the gastroenterology and cardiology suites. Women were more likely to experience AEs than men, incurring higher rates of hypotension, prolonged bag-mask ventilation, and reversal agents. Increased body mass index was associated with lower rates of hypoxemia, while advanced age correlated with high rates of oversedation, harm done, and use of reversal agents. Malignancy and cardiovascular comorbidities were associated with increased AEs. Patients with respiratory comorbidities were less likely to be subject to AEs. CONCLUSION Certain patient characteristics and types of procedures may be associated with increased risk of AEs during MPS.

Risk Factors and Outcomes Associated With Sepsis After Coronary Artery Bypass and Open Heart Valve Surgeries

Purpose. Sepsis causes significant morbidity and mortality after cardiac surgery and carries a significant burden on health care costs. There is a general association of increased risk of post–cardiac surgery sepsis in patients with postoperative complications. We sought to investigate significant patient and procedural risk factors and outcomes associated with sepsis after cardiac surgery. Materials and Methods. In this retrospective study, we analyzed 531 coronary artery bypass grafting and open heart valve surgery cases that developed postoperative sepsis in the National Surgical Quality Improvement Program database between 2007 and 2014. Patient-based and surgery-based parameters were analyzed for risk factors and outcomes reported in the 30 days postoperatively. The association between sepsis and patient outcomes was assessed in a propensity-matched cohort using univariable logistic regression. Results. Modifiable and nonmodifiable patient characteristics, including age >80, poor preoperative functional status, chronic diseases such as diabetes mellitus, congestive heart failure, chronic kidney disease with serum creatinine ⩾1.5, as well as serum albumin <3.5 and emergent nature of the case were associated with post–cardiac surgery sepsis. Surgical outcomes associated with sepsis included mortality (15.4% vs 4.5%), unplanned intubation (29.8% vs 8.2%), transfusion (53.4% vs 48.4%), acute kidney injury (7.1% vs 1.4%), postoperative dialysis (18.8% vs 3.5%), and return to the operating room (29.8% vs 8.2%). Conclusions. We identified multiple patient and surgical characteristics as well as postoperative outcomes associated with postoperative sepsis development in the high-risk population of patients undergoing cardiac surgery. Early identification of patients who are at high risk for postoperative sepsis can facilitate early treatment interventions.