Anti-HIV-1 B cell antigen receptor signaling and structure.

Unlabelled: The B cell antigen receptor (BCR) complex, comprised of antigen recognition and signaling components, functions in initiating B cell activation. While structural studies have described BCR domain organization, gaps remain in our understanding of its antigen binding domain (Fab, fragment antigen-binding) disposition, and how antigen binding is sensed to initiate signaling. Here, we report antigen affinity and signaling of the immunoglobulin (Ig) class IgM and IgG BCRs and define conformational states of full-length BCRs of two human broadly neutralizing antibodies, the glycan-specific, heavy chain domain-swapped, I-shaped 2G12, and a canonical Y-shaped antibody, CH31, that recognizes the CD4-binding site on the HIV-1 Envelope protein (Env).

The road less traveled: Developing pharmacist clinician-scientists through divergent training pathways.

Purpose: Professional organizations have emphasized the growing need for pharmacists to possess advanced research skills; however, there is a scarcity of training programs aimed at nurturing clinician-scientists. This report outlines 3 critical care-focused research programs, each offering a unique approach to training clinician-scientists.

Summary: Limited resources and formalized programs are available to bridge the gap between the demand for and availability of skilled clinician-scientists.

Publication of pharmacy resident research projects: A systematic review and meta-analysis.

Purpose: Pharmacy residents often aspire to develop research skills through conducting a research project. Project publication rates among pharmacy residents are variable and at times low; however, previous studies have been limited to specific geographic regions and timeframes. This study sought to conduct a systematic review and meta-analysis to determine the proportion of pharmacy resident research projects published in the peer-reviewed literature.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

Background: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance.

Methods: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury.

Multicenter comparison of antiplatelet treatment strategies for urgent/emergent neuroendovascular stenting.

Background: Emergent neuroendovascular stenting presents challenges for the utilization of antiplatelet agents.

Methods: This was a multicenter, retrospective cohort of patients who underwent emergent neuroendovascular stenting. The primary endpoints were thrombotic and bleeding events in relation to the timing of antiplatelet administration, route of administration, and choice of intravenous (IV) agent and the study investigated practice variability in antiplatelet utilization.

Multicenter Comparison of the Safety and Efficacy of Clopidogrel Versus Ticagrelor for Neuroendovascular Stents.

Background: Dual antiplatelet therapy (DAPT) is commonly employed for neuroendovascular stenting due to the significant risk of thromboembolism. Clopidogrel and aspirin are most often selected as initial DAPTs; however, there is limited literature available to support guidance of DAPT in this setting. The objective of this study was to evaluate safety and efficacy in patients whose final regimen included either DAPT with aspirin and clopidogrel (DAPT-C) or DAPT with aspirin and ticagrelor (DAPT-T).

Personalized antiseizure medication therapy in critically ill adult patients.

Precision medicine has the potential to have a significant impact on both drug development and patient care. It is crucial to not only provide prompt effective antiseizure treatment for critically ill patients after seizures start but also have a proactive mindset and concentrate on epileptogenesis and the underlying cause of the seizures or seizure disorders. Critical illness presents different treatment issues compared with the ambulatory population, which makes it challenging to choose the best antiseizure medications and to administer them at the right time and at the right dose.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

Background: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent.

Hypertonic saline use in neurocritical care for treating cerebral edema: A review of optimal formulation, dosing, safety, administration and storage.

Purpose: Current Neurocritical Care Society guidelines on the management of cerebral edema recommend hypertonic saline (HTS) over mannitol in some scenarios, but practical questions remain regarding the appropriate administration method, concentration/dose, monitoring to ensure safe use, and storage. The aim of this article is to address these practical concerns based on the evidence currently available.

Summary: Many different hypertonic solutions have been studied to define the optimal hyperosmolar substance to relieve acute cerebral edema in patients with conditions such as acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury.

Feeding state-dependent modulation of feeding-related motor patterns.

Studies elucidating modulation of microcircuit activity in isolated nervous systems have revealed numerous insights regarding neural circuit flexibility, but this approach limits the link between experimental results and behavioral context. To bridge this gap, we studied feeding behavior-linked modulation of microcircuit activity in the isolated stomatogastric nervous system (STNS) of male crabs. Specifically, we removed hemolymph from a crab that was unfed for ≥24 h ("unfed" hemolymph) or fed 15 min to 2 h before hemolymph removal ("fed" hemolymph).

Sleep quality during an overnight on-call program.

Purpose: Many institutions deploy pharmacy residents to expand clinical pharmacy services, often in the form of overnight, in-house on-call programs. There is little published evidence regarding pharmacy resident sleep and sleepiness after a night of overnight, in-house on-call activity. A prospective observational cohort study was conducted to determine the relationship between overnight, in-house on-call programs and pharmacy resident sleep and sleep quality.

Efficacy and safety of vancomycin loading doses in critically ill patients with methicillin-resistant infection.

Background: While vancomycin loading doses may facilitate earlier pharmacokinetic-pharmacodynamic target attainment, the impact of loading doses on clinical outcomes remains understudied. Critically ill patients are at highest risk of morbidity and mortality from methicillin resistant (MRSA) infection and hypothesized to most likely benefit from a loading dose. We sought to determine the association between receipt of a vancomycin loading dose and clinical outcomes in a cohort of critically ill adults.

Identifying errors and safety considerations in patients undergoing thrombolysis for acute ischemic stroke.

Background & Purpose: Alteplase is the standard of care for early pharmacologic thrombolysis after acute ischemic stroke (AIS). Alteplase is also considered a high-alert medication and is fraught with potential for error. We sought to describe the difference in medication error rates in in patients receiving alteplase for acute ischemic stroke from regional hospitals compared to patients receiving alteplase at the Comprehensive Stroke Center.

Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response.

Objectives: Neonatal seizures are common complications. Phenobarbital is the agent of choice but leads to adverse neurologic outcomes. There has been increased use of newer agents like levetiracetam.

Inactivated Four-Factor Prothrombin Complex Concentrate Dosing Practices for Reversal of Warfarin-Related Intracranial Hemorrhage.

Background/objective: Inactivated four-factor prothrombin complex concentrate (I4F-PCC, Kcentra) has become an important agent for the urgent or emergent reversal of bleeding associated with vitamin K antagonists such as warfarin. There is recognized inter-institutional variability with the use of I4F-PCC, especially as it relates to dosing practices. We sought to characterize variations in I4F-PCC dosing practices and their impact on patient outcomes and describe overall real-world clinical practice surrounding I4F-PCC utilization in the context of the management of warfarin-related intracranial hemorrhage (ICH).

First-Dose Vancomycin Pharmacokinetics Versus Empiric Dosing on Area-Under-the-Curve Target Attainment in Critically Ill Patients.

Background: Early attainment of target area under the curve (AUC) to minimum inhibitory concentration (MIC) ratios have been associated with clinical success, as well as lower incidence of acute kidney injury (AKI), in patients receiving vancomycin for methicillin-resistant Staphylococcus aureus (MRSA). Critically ill patients are particularly vulnerable to poor outcomes from infection and face multiple risk factors for AKI, thus early precision dosing of vancomycin is vital in this population. We hypothesized that a personalized dosing approach, using vancomycin levels obtained after the first dose to guide further dosing, would be superior to empiric dosing in terms of AUC target attainment assessed at steady state (SS).

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

Background/objective: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH.

Evaluation of Two Fosphenytoin Loading Dose Regimens and Monitoring in Infants and Neonates Less Than Six Months of Age.

Objectives: The objectives of the study were to compare the free serum concentrations after different fosphenytoin loading dose strategies in patients younger than 6 months old and to investigate the frequency of seizure cessation following a loading dose of fosphenytoin.

Methods: This retrospective cohort study included neonates and infants admitted to a 150-bed children's hospital between August 1, 2014, and February 1, 2018. Patients were included if they were younger than 6 months old and had a postload free phenytoin serum concentration collected during the specified time frame.

Different microcircuit responses to comparable input from one versus both copies of an identified projection neuron.

Neuronal inputs to microcircuits are often present as multiple copies of apparently equivalent neurons. Thus far, however, little is known regarding the relative influence on microcircuit output of activating all or only some copies of such an input. We examine this issue in the crab () stomatogastric ganglion, where the gastric mill (chewing) microcircuit is activated by modulatory commissural neuron 1 (MCN1), a bilaterally paired modulatory projection neuron.