Iguratimod, an allosteric inhibitor of macrophage migration inhibitory factor (MIF), prevents mortality and oxidative stress in a murine model of acetaminophen overdose.

Background: Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that has been implicated in multiple inflammatory and non-inflammatory diseases, including liver injury induced by acetaminophen (APAP) overdose. Multiple small molecule inhibitors of MIF have been described, including the clinically available anti-rheumatic drug T-614 (iguratimod); however, this drug's mode of inhibition has not been fully investigated.

Methods: We conducted in vitro testing including kinetic analysis and protein crystallography to elucidate the interactions between MIF and T-614.

Duration of Untreated Psychosis and Outcomes in First-Episode Psychosis: Systematic Review and Meta-analysis of Early Detection and Intervention Strategies.

Background: The role of duration of untreated psychosis (DUP) as an early detection and intervention target to improve outcomes for individuals with first-episode psychosis is unknown.

Study Design: PRISMA/MOOSE-compliant systematic review to identify studies until February 1, 2023, with an intervention and a control group, reporting DUP in both groups. Random effects meta-analysis to evaluate (1) differences in DUP in early detection/intervention services vs the control group, (2) the efficacy of early detection strategies regarding eight real-world outcomes at baseline (service entry), and (3) the efficacy of early intervention strategies on ten real-world outcomes at follow-up.

Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study.

Background: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes persistent synovitis, bone damage, and progressive joint destruction. Neuroimmune modulation through electrical stimulation of the vagus nerve activates the inflammatory reflex and has been shown to inhibit the production and release of inflammatory cytokines and decrease clinical signs and symptoms in RA. The RESET-RA study was designed to determine the safety and efficacy of an active implantable device for treating RA.

Patient interest in and clinician reservations on polygenic embryo screening: a qualitative study of stakeholder perspectives.

Purpose: We explored and compared perspectives of reproductive endocrinology and infertility specialists (REIs) and in vitro fertilization (IVF) patients regarding polygenic embryo screening (PES), a new type of preimplantation screening that estimates the genetic chances of developing polygenic conditions and traits in the future.

Methods: Qualitative thematic analysis of semi-structured interviews with US-based REIs and IVF patients.

Results: Clinicians and patients often held favorable views of screening embryos for physical or psychiatric conditions, though clinicians tended to temper their positive attitudes with specific caveats.

Lupus autoantibodies initiate neuroinflammation sustained by continuous HMGB1:RAGE signaling and reversed by increased LAIR-1 expression.

Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus, present in up to 80% of patients and leading to a diminished quality of life. In the present study, we used a model of lupus-like cognitive impairment that is initiated when antibodies that crossreact with excitatory neuronal receptors penetrate the hippocampus, causing immediate, self-limited, excitotoxic death of hippocampal neurons, which is then followed by a significant loss of dendritic complexity in surviving neurons. This injury creates a maladaptive equilibrium that is sustained in mice for at least 1 year.

Eutectic mixture of local anesthetics and amethocaine as topical anesthetics in pediatrics: a meta-analysis.

Background: Pediatric patients often receive topical anesthesia before skin procedures in the Emergency Department, with EMLA cream and amethocaine gel being common choices. The most effective option remains a subject of debate.

Objective: Our goal was to compare EMLA cream with amethocaine gel in pediatric patients undergoing topical anesthesia, focusing on outcomes: first-attempt cannulation success, child-reported visual analogue scale (VAS) score, parent-reported VAS score, observed pain score, child-reported absence of pain, and child-reported acceptable anesthesia.

An iron rheostat controls hematopoietic stem cell fate.

Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis.

Optimizing Surgical Planning for Epilepsy Patients With Multimodal Neuroimaging and Neurophysiology Integration: A Case Study.

Current preoperative evaluation of epilepsy can be challenging because of the lack of a comprehensive view of the network's dysfunctions. To demonstrate the utility of our multimodal neurophysiology and neuroimaging integration approach in the presurgical evaluation, we present a proof-of-concept for using this approach in a patient with nonlesional frontal lobe epilepsy who underwent two resective surgeries to achieve seizure control. We conducted a post-hoc investigation using four neuroimaging and neurophysiology modalities: diffusion tensor imaging, resting-state functional MRI, and stereoelectroencephalography at rest and during seizures.

Intracranial electroencephalography reveals effector-independent evidence accumulation dynamics in multiple human brain regions.

Neural representations of perceptual decision formation that are abstracted from specific motor requirements have previously been identified in humans using non-invasive electrophysiology; however, it is currently unclear where these originate in the brain. Here we capitalized on the high spatiotemporal precision of intracranial EEG to localize such abstract decision signals. Participants undergoing invasive electrophysiological monitoring for epilepsy were asked to judge the direction of random-dot stimuli and respond either with a speeded button press (N = 24), or vocally, after a randomized delay (N = 12).

An engineered poly(A) tail attenuates gut ischemia/reperfusion-induced acute lung injury.

Background: Gut ischemia/reperfusion causes the release of damage-associated molecular patterns, leading to acute lung injury and high mortality. Cold-inducible ribonucleic acid-binding protein is a ribonucleic acid chaperon that binds the polyadenylation tail of messenger ribonucleic acid intracellularly. Upon cell stress, cold-inducible ribonucleic acid-binding protein is released, and extracellular cold-inducible ribonucleic acid-binding protein acts as a damage-associated molecular pattern, worsening inflammation.

Mechanistically based blood proteomic markers in the TGF-β pathway stratify risk of hepatocellular cancer in patients with cirrhosis.

Hepatocellular carcinoma (HCC) is the third leading cause of death from cancer worldwide but is often diagnosed at an advanced incurable stage. Yet, despite the urgent need for blood-based biomarkers for early detection, few studies capture ongoing biology to identify risk-stratifying biomarkers. We address this gap using the TGF-β pathway because of its biological role in liver disease and cancer, established through rigorous animal models and human studies.

Association between pre-dementia psychiatric diagnoses and all-cause dementia is independent from polygenic dementia risks in the UK Biobank.

Background: Psychiatric disorders have been associated with higher risk for future dementia. Understanding how pre-dementia psychiatric disorders (PDPD) relate to established dementia genetic risks has implications for dementia prevention.

Methods: In this retrospective cohort study, we investigated the relationships between polygenic risk scores for Alzheimer's disease (AD PRS), PDPD, alcohol use disorder (AUD), and subsequent dementia in the UK Biobank (UKB) and tested whether the relationships are consistent with different causal models.

Perioperative Management of Anticoagulant and Antiplatelet Therapy.

Anticoagulant and Antiplatelet Drug ManagementManagement of patients on an anticoagulant or antiplatelet drug who require surgery or an invasive procedure is a common clinical problem. Douketis and Spyropoulos provide an evidence-based but practical approach to managing anticoagulants and antiplatelet drugs in the perioperative setting.

Extracellular CIRP induces CD4CD8αα intraepithelial lymphocyte cytotoxicity in sepsis.

Background: In sepsis, intestinal barrier dysfunction is often caused by the uncontrolled death of intestinal epithelial cells (IECs). CD4CD8αα intraepithelial lymphocytes (IELs), a subtype of CD4 T cells residing within the intestinal epithelium, exert cytotoxicity by producing granzyme B (GrB) and perforin (Prf). Extracellular cold-inducible RNA-binding protein (eCIRP) is a recently identified alarmin which stimulates TLR4 on immune cells to induce proinflammatory responses.

Low respiratory quotient correlates with high mortality in patients undergoing mechanical ventilation.

Objective: Oxygen consumption (VO), carbon dioxide generation (VCO), and respiratory quotient (RQ), which is the ratio of VO to VCO, are critical indicators of human metabolism. To seek a link between the patient's metabolism and pathophysiology of critical illness, we investigated the correlation of these values with mortality in critical care patients.

Methods: This was a prospective, observational study conducted at a suburban, quaternary care teaching hospital.

A NOVEL OLIGONUCLEOTIDE MRNA MIMIC ATTENUATES HEMORRHAGE-INDUCED ACUTE LUNG INJURY.

Hemorrhagic shock (HS) is accompanied by a pronounced activation of the inflammatory response in which acute lung injury (ALI) is one of the most frequent consequences. Among the pivotal orchestrators of this inflammatory cascade, extracellular cold-inducible RNA-binding protein (eCIRP) emerges as a noteworthy focal point, rendering it as a promising target for the management of inflammation and tissue injury. Recently, we have reported that oligonucleotide poly(A) mRNA mimic termed A 12 selectively binds to the RNA binding region of eCIRP and inhibits eCIRP binding to its receptor TLR4.

Umbrella Review: Atlas of the Meta-Analytical Evidence of Early-Onset Psychosis.

Objective: Early-onset psychosis (EOP) refers to the development of psychosis before the age of 18 years. We aimed to summarize, for the first time, the meta-analytical evidence in the field of this vulnerable population and to provide evidence-based recommendations.

Method: We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant, pre-registered (PROSPERO: CRD42022350868) systematic review of several databases and registers to identify meta-analyses of studies conducted in EOP individuals to conduct an umbrella review.

The Female Emergency Medical Services Experience: A Mixed Methods Study.

Background: Emergency Medical Services (EMS) is a challenging profession. Little is known if there are gender differences in the experiences among EMS clinicians. Therefore, our aim was to understand and characterize the occupational experiences of female EMS clinicians.

Surviving Sepsis Campaign Research Priorities 2023.

Objectives: To identify research priorities in the management, epidemiology, outcome, and pathophysiology of sepsis and septic shock.

Design: Shortly after publication of the most recent Surviving Sepsis Campaign Guidelines, the Surviving Sepsis Research Committee, a multiprofessional group of 16 international experts representing the European Society of Intensive Care Medicine and the Society of Critical Care Medicine, convened virtually and iteratively developed the article and recommendations, which represents an update from the 2018 Surviving Sepsis Campaign Research Priorities.

Methods: Each task force member submitted five research questions on any sepsis-related subject.