With the ever increased security throughout the world’s countries, terrorists have begun to find new ways to inflict fear upon the masses. One such...

The 2001 anthrax bioterrorism attacks demonstrated vulnerability for future similar attacks. This article describes mechanisms that can be used to prepare the medical community and healthcare facilities for the diagnosis and management of a subsequent bioterrorism attack should such an event occur …

Objective Multimodal analgesia pathways have been shown to reduce opioid use and side effects in surgical patients. A quality improvement initiative was implemented to increase the use of multimodal analgesia in adult patients presenting for general anaesthesia at an academic tertiary care centre. The aim of this study was to increase adoption of a perioperative multimodal analgesia protocol across a broad population of surgical patients. The use of multimodal analgesia was tracked as a process metric. Our primary outcome was opioid use normalised to oral morphine equivalents (OME) intraoperatively, in the postanaesthesia care unit (PACU), and 48 hours postoperatively. Pain scores and use of antiemetics were measured as balancing metrics. Methods We conducted a quality improvement study of a multimodal analgesia protocol implemented for adult (≥18 and≤70) non-transplant patients undergoing general anaesthesia (≥180 min). Components of multimodal analgesia were defined as (1) preoperative analgesic medication (acetaminophen, celecoxib, diclofenac, gabapentin), (2) regional anaesthesia (peripheral nerve block or catheter, epidural catheter or spinal) or (3) intraoperative analgesic medication (ketamine, ketorolac, lidocaine infusion, magnesium, acetaminophen, dexamethasone ≥8 mg, dexmedetomidine). We compared opioid use, pain scores and antiemetic use for patients 1 year before (baseline group—1 July 2018 to 30 June 2019) and 1 year after (implementation group—1 July 2019 to 30 June 2020) project implementation. Results Use of multimodal analgesia improved from 53.9% in the baseline group to 67.5% in the implementation group (p

Opioid misuse concerns have led trauma practitioners to recommend multimodal pain control. A trauma surgeon talks about pain management revision and success requisites, the opioid epidemic, and current and future pain management.

Driven by illicit fentanyl, opioid related deaths have reached the highest level in 2020. Currently, an opioid overdose is resuscitated by the use of naloxone, which competitively binds and antagonizes the μ-opioid receptor (mOR). Thus, knowledge of the residence times of opioids at mOR and the unbinding mechanisms is valuable for assessing the effectiveness of naloxone. In the present study, we calculate the fentanyl-mOR dissociation time and elucidate the mechanism by applying an enhanced sampling molecular dynamics (MD) technique. Two sets of metadynamics simulations with different initial structures were performed while accounting for the protonation state of the conserved H2976.52, which has been suggested to modulate the ligand-mOR affinity and binding mode. Surprisingly, with the Nδ-protonated H2976.52, fentanyl can descend as much as 10 Å below the level of the conserved D1473.32 before escaping the receptor and has a calculated residence time τ of 38 s. In contrast, with the Nϵ- and doubly protonated H2976.52, the calculated τ are 2.6 and 0.9 s, respectively. Analysis suggests that formation of the piperidine–Hid297 hydrogen bond strengthens the hydrophobic contacts with the transmembrane helix (TM) 6, allowing fentanyl to explore a deep pocket. Considering the experimental τ of ∼4 min for fentanyl and the role of TM6 in mOR activation, the deep insertion mechanism may be biologically relevant. The work paves the way for large-scale computational predictions of opioid dissociation rates to inform evaluation of strategies for opioid overdose reversal. The profound role of the histidine protonation state found here may shift the paradigm in computational studies of ligand–receptor kinetics.

Definition and History of Social Injustice in America

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Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal pattern recognition receptors that detect a variety of single-stranded RNA species. While TL…

Toll-like receptor (TLR) 2 is a key regulator of innate immune responses and has been shown to play an important role in inflammation-associated cance…

The ability of the ocular surface to respond to pathogens is in part attributed to toll-like receptors (TLRs) that recognize conserved motifs on vario…

Toll-like receptors (TLRs) are a family of transmembrane receptors that recognize various pathogen- and damage-associated molecular pattern molecules …

To determine if hypofractionated post-operative prostate bed radiotherapy (HYPORT) does not increase patient-reported genitourinary (GU) or gastrointestinal (GI) toxicity over conventionally fractionated post-operative radiotherapy (COPORT).

Alzheimer’s disease (AD) is the most common cause of dementia worldwide. The pathogenesis of this neurodegenerative disease, currently without curative treatment, is associated with the accumulation of amyloid β (Aβ) in brain parenchyma and cerebral vasculature. AD patients are unable to clear this toxic peptide, leading to Aβ accumulation in their brains and, presumably, the pathology associated with this devastating disease. Compounds that stimulate the immune system to clear Aβ may therefore have great therapeutic potential in AD patients. Monophosphoryl lipid A (MPL) is an LPS-derived Toll-like receptor 4 agonist that exhibits unique immunomodulatory properties at doses that are nonpyrogenic. We show here that repeated systemic injections of MPL, but not LPS, significantly improved AD-related pathology in APPswe/PS1 mice. MPL treatment led to a significant reduction in Aβ load in the brain of these mice, as well as enhanced cognitive function. MPL induced a potent phagocytic response by microglia while triggering a moderate inflammatory reaction. Our data suggest that the Toll-like receptor 4 agonist MPL may be a treatment for AD.

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Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the ...

Bruton's tyrosine kinase (Btk), a member of the Tec family of tyrosine kinases, plays an important role in the differentiation and activation of B cells. Mutations affecting Btk cause immunodeficiency in both humans and mice. In this study we set out ...

Neonates rely on their innate immune system, and neutrophils in particular, to recognize and combat life-threatening bacterial infections. Pretreatment with lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 agonist, improves survival to polymicrobial ...

Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited ...

Scientific Reports - Toll-like receptor dual-acting agonists are...