Search

John C Alexander, Girish P JoshiDepartment of Anesthesiology & Pain Management, University of Texas Southwestern Medical Center, Dallas, TX, USAChronic pain is a common condition with significant detrimental physical, psychological, social, and economic impact. The Institute of Medicine estimates that >100 million Americans suffer from chronic pain,1 representing approximately one-third of the entire population of the US.2 Conservative estimates suggest that well over US $500 billion per year is spent in the treatment of these pain conditions, not to mention the lost productivity of these individuals or the burden that their suffering engenders for patients and their families. Despite tremendous efforts, chronic pain continues to be a major societal problem.1Smartphones have become one of the most rapidly adopted technologies in the modern history of mankind allowing for previously unimaginable opportunities for communication and access to information.3 Powering this societal revolution is not so much the onboard or attachable hardware for smartphones, but the dizzying array of software programs that use the hardware to add novel functions; we call the unifying software programs “applications” or, more commonly, “apps”. While each phone comes with onboard technologies, such as Wi-Fi, Bluetooth, lights, microphones, cameras, accelerometers, and even barometers, it is the development of the app that combines these functionalities to create new and innovative uses for the same hardware for everything from Skype4 to Pokémon GO.5The use of such applications within the health care industry continues to grow, and it is estimated that the market for mobile health apps will grow to US$26 billion in 2017.6 The immense size of this market is due to the functional flexibility that apps can provide. These emerging technologies also provide new opportunities to engage with patients and improve health care outcomes. Studies have shown that mobile phone messaging helps to improve patient engagement outside the clinic or hospital and facilitates self-management of chronic diseases such as hypertension, diabetes, and asthma,7 and app-based systems may also be of use in this regard. While the overall market for apps in health care is robust, the market segment for pain management is less than impressive.

Post-cardiac surgery atrial fibrillation (AF) places patients at risk for thromboembolism and stroke, while the surgery and cardiopulmonary bypass alter the multiple factors of coagulation and may increase the tendency to bleed. It is in the context of this complex clinical picture that the physician must make decisions regarding the risks and benefits of anticoagulation therapy to lower the risk for thromboembolism and stroke associated with postoperative AF. Physicians must also weigh the usually transient and self-limited duration of new-onset postoperative AF against the potential for postoperative bleeding if anticoagulation therapy is started. No randomized, controlled clinical trials are available that specifically address the problem of anticoagulation therapy for the postoperative AF. In that context, recommendations are based on the established therapy for nonsurgical situations modified by the potential risk of bleeding in the postoperative patient. [ABSTRACT FROM AUTHOR]

A comprehensive evidence review was conducted of the medical literature regarding the relationship between intraoperative interventions and the incidence of postoperative atrial arrhythmias, including, most commonly, atrial fibrillation (AF). Fifteen randomized, controlled studies and one large-scale concurrent cohort study were identified that reported on the following issues: systemic temperature during surgery (one report); "beating heart" surgery vs conventional bypass surgery (three reports); type of myocardial protection (five reports); the use of adjunctive posterior pericardiotomy (one report); the use of thoracic epidural anesthesia (TEA) [two reports]; the use of glucose-insulin-potassium (GIK) solutions (two reports); and the use of heparin-coated circuits for cardiopulmonary bypass (CPB) [two reports]. Based on a systematic review of the reported data and an analysis of the quality of the reported data, we recommend the following: (1) that mild hypothermia, rather than moderate hypothermia, may be effective in reducing the frequency of postoperative AF; (2) the use of posterior pericardiotomy may be a useful adjunct to reduce the frequency of postoperative AF; and (3) the use of heparin-coated CPB circuits is associated with less postoperative AF. Because of conflicting or inadequate data, we cannot conclude that the frequency of postoperative AF is affected by (1) the use of beating-heart techniques, (2) the type of myocardial protection strategy used, (3) the use of TEA, or (4) the use of GIK solutions perioperatively. [ABSTRACT FROM AUTHOR]

Purpose: Lumbar spine surgery is associated with significant postoperative pain. The benefits of erector spinae plane blocks (ESPBs) combined with multimodal analgesia has not been adequately studied. We evaluated the analgesic effects of bilateral ESPBs as a component of multimodal analgesia after open lumbar laminectomy., Methods: Analgesic effects of preoperative, bilateral, ultrasound-guided ESPBs combined with standardized multimodal analgesia (n = 25) was compared with multimodal analgesia alone (n = 25) in patients undergoing one or two level open lumbar laminectomy. Other aspects of perioperative care were similar. The primary outcome measure was cumulative opioid consumption at 24 h. Secondary outcomes included opioid consumption, pain scores, and nausea and vomiting requiring antiemetics on arrival to the post-anesthesia care unit (PACU), at 24 h, 48 h, and 72 h after surgery, as well as duration of the PACU and hospital stay., Results: Opioid requirements at 24 h were significantly lower with ESPBs (31.9 ± 12.3 mg vs. 61.2 ± 29.9 mg, oral morphine equivalents). Pain scores were significantly lower with ESPBs in the PACU and through postoperative day two. Patients who received ESPBs required fewer postoperative antiemetic therapy (n = 3, 12%) compared to those without ESPBs (n = 12, 48%). Furthermore, PACU duration was significantly shorter with ESPBs (49.7 ± 9.5 vs. 79.9 ± 24.6 min)., Conclusions: Ultrasound-guided, bilateral ESPBs, when added to an optimal multimodal analgesia technique, reduce opioid consumption and pain scores, the need for antiemetic therapy, and the duration of stay in the PACU after one or two level open lumbar laminectomy., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Erector spinae plane blocks (ESPBs) are frequently utilized when treating patients with multiple rib fractures. While previous work has demonstrated the efficacy of ESPB as an adequate method of pain control, there has been no work comparing a continuous ESPB to "best practice" multimodal pain control. We hypothesize that a continuous ESPB catheter combined with a multimodal pain regimen may be associated with a decrease in opioid requirements when compared to a multimodal pain regimen alone., Methods: This was a retrospective observational cohort study at a level 1 trauma center from September 2016 through September 2021. Inclusion criteria included patients 18 y or older with at least three unilateral rib fractures who were not mechanically ventilated during admission. The primary outcome was the total morphine equivalents utilized throughout the index admission., Results: A total of 142 patients were included in this study, 71 in each cohort. Patients included had a mean age of 52.5 y, and 18% were female. Demographic data including injury severity score, total number of rib fractures, and length of stay were similar. While there was a trend toward a decrease in morphine equivalents in the patient cohort undergoing ESPB catheter placement, this was not found to be statistically significant (284.3 ± 244.8 versus 412.6 ± 622.2, P = 0.5)., Conclusions: While ESPB catheters are frequently utilized for analgesia in the setting of multiple rib fractures, there was no decrease in total opioid usage when compared with patients who were managed with a multimodal pain regimen alone. Further assessment comparing ESPB catheters to best practice multimodal pain control regimens through a prospective, multicenter trial is required to further validate these findings., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The discovery that experimental delivery of dsRNA can induce gene silencing at target genes revolutionized genetics research, by both uncovering essential biological processes and creating new tools for developmental geneticists. However, the efficacy of exogenous RNA interference (RNAi) varies dramatically within the Caenorhabditis elegans natural population, raising questions about our understanding of RNAi in the lab relative to its activity and significance in nature. Here, we investigate why some wild strains fail to mount a robust RNAi response to germline targets. We observe diversity in mechanism: in some strains, the response is stochastic, either on or off among individuals, while in others, the response is consistent but delayed. Increased activity of the Argonaute PPW-1, which is required for germline RNAi in the laboratory strain N2, rescues the response in some strains but dampens it further in others. Among wild strains, genes known to mediate RNAi exhibited very high expression variation relative to other genes in the genome as well as allelic divergence and strain-specific instances of pseudogenization at the sequence level. Our results demonstrate functional diversification in the small RNA pathways in C. elegans and suggest that RNAi processes are evolving rapidly and dynamically in nature., Competing Interests: Conflicts of interest statement The authors declare no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Genetics Society of America.)

Background: Variation in genes involved in ethanol metabolism has been shown to influence risk for alcohol dependence (AD) including protective loss of function alleles in ethanol metabolizing genes. We therefore hypothesized that people with severe AD would exhibit different patterns of rare functional variation in genes with strong prior evidence for influencing ethanol metabolism and response when compared to genes not meeting these criteria., Objective: Leverage a novel case only design and Whole Exome Sequencing (WES) of severe AD cases from the island of Ireland to quantify differences in functional variation between genes associated with ethanol metabolism and/or response and their matched control genes., Methods: First, three sets of ethanol related genes were identified including those a) involved in alcohol metabolism in humans b) showing altered expression in mouse brain after alcohol exposure, and altering ethanol behavioral responses in invertebrate models. These genes of interest (GOI) sets were matched to control gene sets using multivariate hierarchical clustering of gene-level summary features from gnomAD. Using WES data from 190 individuals with severe AD, GOI were compared to matched control genes using logistic regression to detect aggregate differences in abundance of loss of function, missense, and synonymous variants, respectively., Results: Three non-independent sets of 10, 117, and 359 genes were queried against control gene sets of 139, 1522, and 3360 matched genes, respectively. Significant differences were not detected in the number of functional variants in the primary set of ethanol-metabolizing genes. In both the mouse expression and invertebrate sets, we observed an increased number of synonymous variants in GOI over matched control genes. Post-hoc simulations showed the estimated effects sizes observed are unlikely to be under-estimated., Conclusion: The proposed method demonstrates a computationally viable and statistically appropriate approach for genetic analysis of case-only data for hypothesized gene sets supported by empirical evidence., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gentry et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Multimodal analgesia techniques, including regional analgesia, have been shown to provide effective analgesia and minimize opioid consumption after liver resection surgery. While thoracic epidural analgesia (TEA) is considered the gold standard, its role in the current era of enhanced recovery after surgery (ERAS) has been questioned. Erector spinae plane blocks (ESPBs) have the potential to provide effective postoperative analgesia without the risks associated with epidural analgesia. The primary aim of this quality improvement project was to evaluate the analgesic efficacy of ultrasound-guided ESPB in comparison with TEA in patients undergoing open liver resection., Methods: Fifty patients who underwent open liver resection and received TEA (n=25) or ESPB (n=25) as part of an ERAS pathway were retrospectively identified. The primary outcome measure was cumulative postoperative opioid consumption at 24 hours. Secondary outcomes included opioid consumption, pain scores, the incidence of nausea and vomiting requiring antiemetics, lower extremity muscle weakness, and occurrence of hypotension requiring treatment on arrival to the post-anesthesia care unit and at 2, 6, 12, 24 hours, and daily through postoperative day 7.  Results: Opioid requirements were significantly lower in the TEA group compared to the ESPB group. Postoperative pain scores at rest and with deep inspiration were significantly lower in the TEA group through postoperative day 5. There were no differences in other outcome measures., Conclusions: These findings suggest that compared with ESPB, TEA provides superior pain relief after open liver resection., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Stewart et al.)

Regional anesthesia is frequently employed in efforts to improve postoperative analgesia and reduce opioid requirements following abdominal surgery. The purpose of the current analysis was to determine if there was a difference in postoperative pain and opioid consumption between patients who underwent open total abdominal hysterectomy (TAH) and received ultrasound-guided bilateral transversus abdominis plane (TAP) blocks using either liposomal bupivacaine or ropivacaine. A single-center retrospective analysis was conducted of 215 patients from November 2018 through March 2020 who underwent an open TAH and received bilateral TAP blocks with either liposomal bupivacaine or ropivacaine. The primary outcome measure was opioid consumption at regular intervals until discharge, and the secondary outcome measures included pain scores, incidence of nausea/vomiting, and use of antiemetics at the same time intervals. Intraoperative opioid consumption and postanesthesia recovery unit opioid requirements were similar between the two groups. Opioid requirements at 24 hours ( P  < 0.04) and 48 hours ( P  < 0.01), as well as total morphine equivalent requirements ( P  < 0.05), were significantly lower in the liposomal bupivacaine group compared to the ropivacaine group. Patients undergoing open TAH who received liposomal bupivacaine TAP blocks required fewer postoperative opioids to achieve similar pain scores when compared to patients who received ropivacaine TAP blocks., (Copyright © 2022 Baylor University Medical Center.)

Background: Current guidelines for severe rib fractures recommend neuraxial blockade in addition to multimodal pain therapies. While the guidelines for venous thromboembolism prevention recommend chemoprophylaxis, these medications must be held for neuraxial blockade placement. Erector spinae plane block (ESPB) is a newly described block for thoracic pain control. Advantages include its quick learning curve and potential for less bleeding complications. We describe the use of ESPB for rib fractures in patients on chemoprophylaxis. We hypothesize that ESPB can be performed in this patient population without holding chemoprophylaxis., Materials and Methods: This was a retrospective observational cohort study of a level 1 trauma center from 9/2016 to 12/2018. All patients with trauma with rib fractures undergoing neuraxial blockade or ESPB were included. Demographics, chemoprophylaxis and anticoagulation regimens, outcomes, and complications were collected., Results: Nine hundred sixty-four patients with rib fracture(s) were admitted. Of these, 73 had a pain management consult. Thirteen had epidural catheters and 25 had ESPBs placed. There was no difference in demographics, injury patterns, bleeding complications, or venous thromboembolism rates among the groups. Patients with ESPB were less likely to have a dose of chemoprophylaxis held because of placement of a catheter (25% versus 100%, P < 0.00001). Three patients with ESPB were on oral anticoagulation on admission, and two were able to continue their regimen during placement., Conclusions: ESPB can be safely placed in patients on chemoprophylaxis. It should be considered over traditional blocks in patients with blunt chest wall trauma because of its technical ease and ability to be performed with chemoprophylaxis., (Published by Elsevier Inc.)

This prospectively designed, clinical quality improvement project compared pain scores and opioid consumption between ultrasound-guided, erector spinae plane blocks (ESPB) and thoracic paravertebral blocks (PVB) in patients undergoing total bilateral mastectomies without reconstruction. Twenty-five patients were included in an enhanced recovery pathway and received an ESPB on one side and a PVB on the contralateral side. Numeric rating scores at rest and with movement for each side were recorded in the recovery room at 2, 6, 12, 24, and 48 hours and on days 3 to 7. There were no significant differences in the resting or movement-evoked pain scores between sides receiving ESPB or PVB at any time point up to day 7 after surgery. Both ESPB and PVB confer equal analgesic effects in patients undergoing mastectomies. ESPB provides an alternative to PVB in reducing postoperative pain in patients undergoing mastectomy as part of an enhanced recovery pathway., (Copyright © 2021 Baylor University Medical Center.)

Regional nerve blocks are an effective method of managing acute pain associated with surgery. The relative benefit of preoperative versus postoperative peripheral nerve blocks is not entirely clear. The primary aim of this study was to determine differences in pain scores in patients undergoing preoperative block versus postoperative block versus no block. We hypothesized that patients receiving preoperative blocks would have reduced pain scores and decreased opioid use in the immediate postoperative period. We conducted a retrospective cohort analysis of 302 consecutive patients undergoing unilateral open reduction and internal fixation of ankle fracture under general anesthesia. We identified 3 groups: preoperative block, postoperative block, or no block. Data obtained from our electronic medical records included demographic information, postanesthesia care unit length of stay, pain scores obtained preoperatively, upon arrival to the postanesthesia care unit, and upon discharge from the postanesthesia care unit as well as intraoperative and postanesthesia care unit opioid utilization. Patients receiving preoperative block had significantly lower pain scores, less intraoperative or postanesthesia care unit opioid use, and shorter postanesthesia care unit dwell time compared with patients receiving postoperative block or no block. Preoperative popliteal sciatic and adductor canal blocks in patients undergoing ankle fracture surgery appears to be more effective than either postoperative block or no block., (Copyright © 2020 the American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The current opioid epidemic is perhaps the greatest public health crisis in the United States. Although multiple factors led to the rise of this epidemic, it is without question associated with the rise in opioid prescribing., Objectives: Better understanding of the opioid prescribing may provide insights into population-level trends contributing to this epidemic, and opportunities to decrease the magnitude of opioid overdose-related death. Therefore we assessed trends in opioid prescribing habits based on analysis of the Texas Prescription Drug Monitoring Program (PDMP) and geographic, ethnic, and income-related data from the US Census Bureau., Study Design: Multiple linear regression analysis of Texas PDMP and US Census Bureau data were performed to assess for correlations to opioid prescribing based on geographic, ethnic, income, and time-related variables., Setting: All controlled substances prescribed in the state of Texas from April 2015 to May 2018 were analyzed., Methods: We obtained data from the Texas PDMP for all controlled substances from April 2015 to May 2018. We performed multiple linear regression analysis of these data along with US Census Bureau data to assess for correlations based on geographic, ethnic, income, and time-related variables. We hypothesized that there would be substantial variability in opioid prescribing habits based on geographic, ethnic, and economic variables., Results: Approximately 200 million pills of controlled substances were prescribed per month over the studied time frame. Overall, high geographic variability was noted, and this strongly correlated to race and ethnicity. Opioid prescribing increased along with the proportion of white residents within a county, but a similar negative correlation was noted with increasing Hispanic population proportion. This correlation was noted throughout the study period, but up until 2017, lower income levels among higher white population had even higher correlation with increased opioid prescribing. Cumulative opioid prescriptions throughout the state fell beginning in 2017., Limitations: This analysis does not include opioids obtained illicitly or from prescriptions outside the state of Texas. The specificity of geographic data are limited to the county level due to irregular entry of zip code data by prescribing pharmacies., Conclusions: In the state of Texas over the studied time period, there was strong correlation for higher rates of opioid prescribing as white population increased despite overall decreased opioid prescribing starting in 2017. Until 2017, this correlation grew stronger as low-income white population increased., Key Words: Opioid, opioid epidemic, opioid utilization.

In the midst of an epidemic of opioid abuse and overdose-related morbidity and mortality, the use of opioids remains the most common means of providing analgesia in the perioperative period. In this article, we review the risks and benefits of opioid use in preoperative, intraoperative and post-operative phases of care. Furthermore, we describe the role that surgeons and anaesthesiologists can play in reducing perioperative opioid use and mitigate their adverse effects, from both an individual and a population health perspective., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Marijuana, derived from plants of the genus Cannabis , is the most commonly used illicit drug in the United States. Marijuana is illegal at the federal level and remains a Drug Enforcement Agency Schedule 1 substance. Nevertheless, most states have passed less stringent legislation related to its use, ranging from decriminalization of possession to allowing medical or even recreational use, and some county and municipal law enforcement agencies have refrained from prosecuting personal possession and/or use even when statute would require such action. Therefore, as use of marijuana becomes more common in the larger population, more patients who are chronic and/or heavy users of marijuana present for surgical procedures, raising the question of best practices to care for these patients in the perioperative period. This review summarizes the known physiologic effects of marijuana in humans, discusses potential implications of marijuana use that the anesthesiologist should consider at each phase of the perioperative period, and outlines recommendations for future study.

Competing Interests: Competing interests: None declared.

Background and Objectives: Fascia iliaca compartment block (FICB) has been shown to provide excellent pain relief in patients undergoing total hip arthroplasty (THA). However, the analgesic efficacy of FICB, in comparison with periarticular infiltration (PAI) for THA, has not been evaluated. This randomized, controlled, observer-blinded study was designed to compare suprainguinal FICB (SFICB) with PAI in patients undergoing THA via posterior approach., Methods: After institutional review board approval, 60 consenting patients scheduled for elective THA were randomized to one of two groups: ultrasound-guided SFICB block or PAI. The local anesthetic solution for both the groups included 60 mL ropivacaine 300 mg and epinephrine 150 µg. The remaining aspects of perioperative care, including general anesthetic and non-opioid multimodal analgesic techniques, were standardized. An investigator blinded to group allocation documented pain scores at rest and with movement and supplemental opioid requirements at various time points. Patients were evaluated for sensory changes and quadriceps weakness in the operated extremity., Results: There were no differences between the groups with respect to demographics, intraoperative opioid use, duration of surgery, recovery room stay, nausea scores, need for rescue antiemetics, time to ambulation and time to discharge readiness as well as 48 hours postoperative opioid requirements. The pain scores at rest and with movement also were similar at all time points. Significantly more patients in the SFICB group experienced muscle weakness at 6 hours after surgery., Conclusions: Under the circumstances of our study, in patients undergoing THA, SFICB provided the similar pain relief compared with PAI, but was associated with muscle weakness at 6 hours postoperatively., Trial Registration Number: NCT02658240., Competing Interests: Competing interests: GPJ has received honoraria from Pacira Pharmaceuticals (Exparel), Baxter Pharmaceuticals, Mallinckrodt Pharmaceuticals, and Merck Pharmaceuticals., (© American Society of Regional Anesthesia & Pain Medicine 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

PUF ( PU milio/ F BF) RNA-binding proteins recognize distinct elements. In C. elegans , PUF-8 binds to an 8-nt motif and restricts proliferation in the germline. Conversely, FBF-2 recognizes a 9-nt element and promotes mitosis. To understand how motif divergence relates to biological function, we first determined a crystal structure of PUF-8. Comparison of this structure to that of FBF-2 revealed a major difference in a central repeat. We devised a modified yeast 3-hybrid screen to identify mutations that confer recognition of an 8-nt element to FBF-2. We identified several such mutants and validated structurally and biochemically their binding to 8-nt RNA elements. Using genome engineering, we generated a mutant animal with a substitution in FBF-2 that confers preferential binding to the PUF-8 element. The mutant largely rescued overproliferation in animals that spontaneously generate tumors in the absence of puf-8 . This work highlights the critical role of motif length in the specification of biological function., Competing Interests: VB, KM, YW, DF, TS, JA, CQ, MW, TL, TT, ZC No competing interests declared

Patients with type 2 diabetes mellitus receiving oral hypoglycemic drugs (OHDs) are usually instructed to stop them before surgery. We hypothesize that continuing OHD preoperatively should result in lower perioperative blood glucose (BG) levels. Ambulatory surgery patients with type 2 diabetes mellitus on OHDs were randomized to continue (n = 69) or withhold (n = 73) OHDs preoperatively. Log-transformed BG levels at pre-, intra-, and postoperative periods were analyzed. Perioperative BG levels were significantly lower (mean, 138 mg/dL; 95% confidence interval, 130-146 mg/dL) in the group that continued versus the group that discontinued OHDs (mean, 156 mg/dL; 95% confidence interval, 146-167 mg/dL; P < .001).

There have been many attempts to incorporate automation into the practice of anesthesiology, though none have been successful. Fundamentally, these failures are due to the underlying complexity of anesthesia practice and the inability of rule-based feedback loops to fully master it. Recent innovations in artificial intelligence, especially machine learning, may usher in a new era of automation across many industries, including anesthesiology. It would be wise to consider the implications of such potential changes before they have been fully realized.

Use of healthcare-related smartphone applications is common. However, there is concern that inaccurate information from these applications may lead patients to make erroneous healthcare decisions. The objective of this study is to study smartphone applications purporting to measure vital sign data using only onboard technology compared with monitors used routinely in clinical practice. This is a prospective trial comparing correlation between a clinically utilized vital sign monitor (Propaq CS, WelchAllyn, Skaneateles Falls, NY, USA) and four smartphone application-based monitors Instant Blood Pressure, Instant Blood Pressure Pro, Pulse Oximeter, and Pulse Oximeter Pro. We performed measurements of heart rate (HR), systolic blood pressures (SBP), diastolic blood pressure (DBP), and oxygen saturation (SpO 2 ) using standard monitor and four smartphone applications. Analysis of variance was used to compare measurements from the applications to the routine monitor. The study was completed on 100 healthy volunteers. Comparison of routine monitor with the smartphone applications shows significant differences in terms of HR, SpO 2 and DBP. The SBP values from the applications were not significantly different from those from the routine monitor, but had wide limits of agreement signifying a large degree of variation in the compared values. The degree of correlation between monitors routinely used in clinical practice and the smartphone-based applications studied is insufficient to recommend clinical utilization. This lack of correlation suggests that the applications evaluated do not provide clinically meaningful data. The inaccurate data provided by these applications can potentially contribute to patient harm.

Activation of the angiotensin II type 2 receptor (AT2R) by administration of Compound 21 (C21), a selective AT2R agonist, induces neuroprotection in models of ischemic stroke in young adult animals. The mechanisms of this neuroprotective action are varied, and may include direct and indirect effects of AT2R activation. Our objectives were to assess the long-term protective effects of post-stroke C21 treatments in a clinically-relevant model of stroke in aged rats and to characterize the cellular localization of AT2Rs in the mouse brain of transgenic reporter mice following stroke. Intraperitoneal injections of C21 (0.03mg/kg) after ischemic stroke induced by transient monofilament middle cerebral artery occlusion resulted in protective effects that were sustained for up to at least 3-weeks post-stroke. These included improved neurological function across multiple assessments and a significant reduction in infarct volume as assessed by magnetic resonance imaging. We also found AT2R expression to be on neurons, not astrocytes or microglia, in normal female and male mouse brains. Stroke did not induce altered cellular localization of AT2R when assessed at 7 and 14 days post-stroke. These findings demonstrate that the neuroprotection previously characterized only during earlier time points using stroke models in young animals is sustained long-term in aged rats, implying even greater clinical relevance for the study of AT2R agonists for the acute treatment of ischemic stroke in human disease. Further, it appears that this sustained neuroprotection is likely due to a mix of both direct and indirect effects stemming from selective activation of AT2Rs on neurons or other cells besides astrocytes and microglia.

Background and Purpose: Targeting the prostaglandin I 2 prostanoid (IP) receptor to reduce stroke injury has been hindered by the lack of selective drugs. MRE-269 is the active metabolite of selexipag showing a high selectivity toward the IP receptor. Selexipag has been recently approved for clinical use in pulmonary hypertension. We hypothesized that postischemic treatment with MRE-269 provides long-lasting neuroprotection with improved neurological outcomes in a clinically relevant rat stroke model., Methods: Aged male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly selected to receive either vehicle or MRE-269 (0.25 mg/kg) intravenously starting at 4.5 hours post ischemia. Accelerating rotarod and adhesive removal tests were conducted before and at 3, 7, 14, and 21 days after stroke. Infarct volume was quantified by magnetic resonance imaging at 48 hours and 21 days post middle cerebral artery occlusion. In parallel experiments, cerebral cortex samples from stroke and nonstroke sides from vehicle- and MRE-269-treated groups were collected at 18 hours post middle cerebral artery occlusion for molecular biology analyses., Results: Quantitative magnetic resonance imaging data showed that postischemic MRE-269 treatment significantly reduced infarct volume compared with vehicle-treated rats at both 48 hours and 3 weeks after stroke. MRE-269 treatment resulted in a significant long-term recovery in both locomotor and somatosensory functions after middle cerebral artery occlusion, which was associated with a reduced weight loss in animals receiving the IP receptor agonist. Postischemic MRE-269 treatment reduced proinflammatory cytokines/chemokines and oxidative stress. Damage to the blood-brain barrier, as assessed by extravasation of immunoglobulin G to the ischemic brain, was significantly reduced by MRE-269, which was associated with a reduction in matrix metalloproteinase-9 activity in the brain of stroked aged rats given the IP agonist at 4.5 hours after ischemia onset., Conclusions: Our data suggest that targeting the IP receptor with MRE-269 is a novel strategy to reduce cerebral ischemia injury and promote long-term neurological recovery in ischemic stroke., (© 2017 American Heart Association, Inc.)

Background: Resolution of inflammation is an emerging new strategy to reduce damage following ischemic stroke. Lipoxin A 4 (LXA 4 ) is an anti-inflammatory, pro-resolution lipid mediator that reduces neuroinflammation in stroke. Since LXA 4 is rapidly inactivated, potent analogs have been synthesized, including BML-111. We hypothesized that post-ischemic, intravenous treatment with BML-111 for 1 week would provide neuroprotection and reduce neurobehavioral deficits at 4 weeks after ischemic stroke in rats. Additionally, we investigated the potential protective mechanisms of BML-111 on the post-stroke molecular and cellular profile., Methods: A total of 133 male Sprague-Dawley rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) and BML-111 administration was started at the time of reperfusion. Two methods of week-long BML-111 intravenous administration were tested: continuous infusion via ALZET ® osmotic pumps (1.25 and 3.75 μg μl -1  hr -1 ), or freshly prepared daily single injections (0.3, 1, and 3 mg/kg). We report for the first time on the stability of BML-111 and characterized an optimal dose and a dosing schedule for the administration of BML-111., Results: One week of BML-111 intravenous injections did not reduce infarct size or improve behavioral deficits 4 weeks after ischemic stroke. However, post-ischemic treatment with BML-111 did elicit early protective effects as demonstrated by a significant reduction in infarct volume and improved sensorimotor function at 1 week after stroke. This protection was associated with reduced pro-inflammatory cytokine and chemokine levels, decreased M1 CD40+ macrophages, and increased alternatively activated, anti-inflammatory M2 microglia/macrophage cell populations in the post-ischemic brain., Conclusion: These data suggest that targeting the endogenous LXA 4 pathway could be a promising therapeutic strategy for the treatment of ischemic stroke. More work is necessary to determine whether a different dosing regimen or more stable LXA 4 analogs could confer long-term protection.

Background: Hydrocodone-containing products were recently rescheduled from Drug Enforcement Agency (DEA) schedule III to schedule II due to concerns of abuse and misuse. These changes went into effect on October 6, 2014., Objective: This quality improvement project involved a retrospective analysis to determine the effect of the DEA schedule change on prescribing habits of hydrocodone-containing products as well as the remaining schedule III and IV opioids, codeine (schedule III) and tramadol (schedule IV)., Methods: The authors performed a medication use evaluation at our academic level 1 trauma hospital system on outpatient use of hydrocodone-containing products, tramadol, and codeine-containing products for 6 months before and 6 months after the change to schedule II using our electronic record and pharmacy system., Results: A total of 88,428 prescription orders were analyzed. Comparison of prescriptions before and after the DEA schedule changes showed hydrocodone prescriptions reduced from an average of 225.97 per day to 1.20 per day. In addition, tramadol increased from 60.04 per day to 91.85 per day and codeine from 6.81 per day to 98.94 per day., Conclusions: Our data show a very substantial decrease in utilization of hydrocodone-containing products and concomitant increase in the utilization of tramadol and codeine products at our hospital after the DEA schedule change.

Tobacco addiction is characterized by a lack of control over smoking and relapse after periods of abstinence. Smoking cessation leads to a dysphoric state that contributes to relapse to smoking. After the acute withdrawal phase, exposure to stressors increases the risk for relapse. Blockade of melanocortin 4 (MC4 ) receptors has anxiolytic and antidepressant-like effects in animal models. The aim of these studies was to investigate the role of MC4 receptors in the dysphoria associated with nicotine withdrawal and stress-induced reinstatement of nicotine seeking. To study stress-induced reinstatement, rats self-administered nicotine for 16 days and then nicotine seeking was extinguished by substituting saline for nicotine. Nicotine seeking was reinstated by intermittent footshock stress. The intracranial self-stimulation (ICSS) procedure was used to assess the negative mood state associated with nicotine withdrawal. Elevations in the ICSS thresholds are indicative of a dysphoric state. The selective MC4 receptor antagonists HS014 and HS024 prevented stress-induced reinstatement of extinguished nicotine seeking. Drug doses that prevented stress-induced relapse did not affect responding for food pellets, which indicates that the drugs did not induce sedation or motor impairments. In the ICSS experiments, the nicotinic acetylcholine receptor antagonist mecamylamine elevated the ICSS thresholds of the nicotine-dependent rats. Pre-treatment with HS014 or HS024 did not prevent the elevations in ICSS thresholds. These studies indicate that MC4 receptors play a critical role in stress-induced reinstatement of nicotine seeking, but these receptors may not play a role in the dysphoria associated with acute nicotine withdrawal., (© 2014 Society for the Study of Addiction.)