Trained Immunity Enhances Host Resistance to Infection in Aged Mice.

Aging significantly increases the incidence and severity of infections, with individuals aged 65 and above accounting for 65% of sepsis cases. Innate immune training, known as "trained immunity" or "innate immune memory", has emerged as a potential strategy to enhance infection resistance by modulating the aging immune system. We investigated the impact of β-glucan-induced trained immunity on aged mice (18-20 months old) compared to young adult mice (10-12 weeks old).

Immunoresponsive Gene 1 Facilitates TLR4-agonist-Induced Augmentation of Innate Antimicrobial Immunity.

Treatment with the toll-like receptor (TLR) 4 agonist monophosphoryl lipid A (MPLA) conditions innate immunocytes to respond robustly to subsequent infection, a phenotype termed innate immune memory. Our published studies show that metabolic reprogramming of macrophages is a prominent feature of the memory phenotype. We undertook studies to define the functional contributions of tricarboxylic acid (TCA) cycle reprogramming to innate immune memory.

Breaking the photoswitch speed limit.

The forthcoming generation of materials, including artificial muscles, recyclable and healable systems, photochromic heterogeneous catalysts, or tailorable supercapacitors, relies on the fundamental concept of rapid switching between two or more discrete forms in the solid state. Herein, we report a breakthrough in the "speed limit" of photochromic molecules on the example of sterically-demanding spiropyran derivatives through their integration within solvent-free confined space, allowing for engineering of the photoresponsive moiety environment and tailoring their photoisomerization rates. The presented conceptual approach realized through construction of the spiropyran environment results in ~1000 times switching enhancement even in the solid state compared to its behavior in solution, setting a record in the field of photochromic compounds.

Bacteria- and fungus-derived PAMPs induce innate immune memory via similar functional, metabolic, and transcriptional adaptations.

Exposure to pathogen-associated molecular patterns (PAMPs) induces an augmented, broad-spectrum antimicrobial response to subsequent infection, a phenomenon termed innate immune memory. This study examined the effects of treatment with β-glucan, a fungus-derived dectin-1 ligand, or monophosphoryl lipid A (MPLA), a bacteria-derived Toll-like receptor 4 ligand, on innate immune memory with a focus on identifying common cellular and molecular pathways activated by these diverse PAMPs. Treatment with either PAMP prepared the innate immune system to respond more robustly to Pseudomonas aeruginosa infection in vivo by facilitating mobilization of innate leukocytes into blood, recruitment of leukocytes to the site of infection, augmentation of microbial clearance, and attenuation of cytokine production.

MyD88-dependent signaling drives toll-like receptor-induced trained immunity in macrophages.

Immunocompromised populations are highly vulnerable to developing life-threatening infections. Strategies to protect patients with weak immune responses are urgently needed. Employing trained immunity, whereby innate leukocytes undergo reprogramming upon exposure to a microbial product and respond more robustly to subsequent infection, is a promising approach.

Confinement-Driven Photophysics in Hydrazone-Based Hierarchical Materials.

Confinement-imposed photophysics was probed for novel stimuli-responsive hydrazone-based compounds demonstrating a conceptual difference in their behavior within 2D versus 3D porous matrices for the first time. The challenges associated with photoswitch isomerization arising from host interactions with photochromic compounds in 2D scaffolds could be overcome in 3D materials. Solution-like photoisomerization rate constants were realized for sterically demanding hydrazone derivatives in the solid state through their coordinative immobilization in 3D scaffolds.

INTRAPULMONARY TREATMENT WITH A NOVEL TLR4 AGONIST CONFERS PROTECTION AGAINST KLEBSIELLA PNEUMONIA.

Objectives: Nosocomial pneumonia is a common complication in critically ill patients. The goal of this study was to examine the efficacy of the Toll-like receptor 4 agonist 3-deacyl phosphorylated hexacyl disaccharide (3D PHAD), in a clinically relevant murine model of pneumonia, and assess the cellular mechanisms that mediate the protective response. Design: Mice received intrapulmonary 3D PHAD (20 μg) or vehicle for 2 consecutive days before challenge with intrapulmonary Klebsiella pneumoniae (2.

Innate Immune Memory and the Host Response to Infection.

Unlike the adaptive immune system, the innate immune system has classically been characterized as being devoid of memory functions. However, recent research shows that innate myeloid and lymphoid cells have the ability to retain memory of prior pathogen exposure and become primed to elicit a robust, broad-spectrum response to subsequent infection. This phenomenon has been termed innate immune memory or trained immunity.

β-Glucan Induces Distinct and Protective Innate Immune Memory in Differentiated Macrophages.

Bacterial infections are a common and deadly threat to vulnerable patients. Alternative strategies to fight infection are needed. β-Glucan, an immunomodulator derived from the fungal cell wall, provokes resistance to infection by inducing trained immunity, a phenomenon that persists for weeks to months.

Immune Checkpoints: Novel Therapeutic Targets to Attenuate Sepsis-Induced Immunosuppression.

Sepsis is a leading cause of death in intensive care units and survivors develop prolonged immunosuppression and a high incidence of recurrent infections. No definitive therapy exists to treat sepsis and physicians rely on supportive care including antibiotics, intravenous fluids, and vasopressors. With the rising incidence of antibiotic resistant microbes, it is becoming increasingly critical to discover novel therapeutics.

Moving From Organ Donation to Knowledge Donation: A Novel Opportunity for Surgical Education Following Organ Donation.

The objective of this article is to share how our institution implemented the use of organ donors for surgical education following organ recovery. Despite technological advances, realistic surgical simulation models are lacking, leaving little opportunity to practice a procedure prior to performance on a living patient. Utilization of organ donors following organ donation offers an opportunity for life-like surgical simulation.

The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma.

Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens.

Immunobiology and application of toll-like receptor 4 agonists to augment host resistance to infection.

Infectious diseases remain a threat to critically ill patients, particularly with the rise of antibiotic-resistant bacteria. Septic shock carries a mortality of up to ∼40% with no compelling evidence of promising therapy to reduce morbidity or mortality. Septic shock survivors are also prone to nosocomial infections.

A cost-effectiveness analysis of sensor-augmented insulin pump therapy and automated insulin suspension versus standard pump therapy for hypoglycemic unaware patients with type 1 diabetes.

Objective: To assess the cost-effectiveness of sensor-augmented insulin pump therapy with "Low Glucose Suspend" (LGS) functionality versus standard pump therapy with self-monitoring of blood glucose in patients with type 1 diabetes who have impaired awareness of hypoglycemia.

Methods: A clinical trial-based economic evaluation was performed in which the net costs and effectiveness of the two treatment modalities were calculated and expressed as an incremental cost-effectiveness ratio (ICER). The clinical outcome of interest for the evaluation was the rate of severe hypoglycemia in each arm of the LGS study.

Early hyperglycemia is associated with poor gross motor outcome in asphyxiated term newborns.

Background: Hyperglycemia after ischemic stroke in adults and after near-drowning in children is associated with a poor neurological outcome. Anaerobic metabolism of glucose leads to buildup of lactic acid, free radical production, mitochondrial failure, and ultimately an increase in neurological injury. In asphyxiated infants, high lactate peaks are seen in the basal ganglia with magnetic resonance spectroscopy.

Long-term, naturalistic treatment with olanzapine, risperidone, quetiapine, or haloperidol monotherapy: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

Objective. To compare the effectiveness of olanzapine, risperidone, quetiapine, or haloperidol monotherapy in patients with schizophrenia who were treated in routine clinical practice settings for a period of 2 years. The incidence and persistence of adverse events encountered during long-term therapy are also reported.

Antipsychotic prescription patterns in outpatient settings: 24-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

This report describes antipsychotic prescription patterns for outpatients with schizophrenia prescribed olanzapine (n=3,222), clozapine (n=236), risperidone (n=1,117), quetiapine (n=189) or haloperidol (n=256) monotherapy at study entry and treated in a naturalistic, clinical practice setting over 24 months. Predictive factors associated with remaining on monotherapy were also identified. Olanzapine patients had significantly greater odds of remaining on their initial monotherapy compared to other treatment groups, while clozapine or risperidone recipients were more likely to remain on monotherapy, compared to haloperidol patients.

Effectiveness of antidepressants in the treatment of major depressive disorder in Latin America.

Objective. Painful physical symptoms occur frequently in patients with major depressive disorder (MDD), and although numerous studies report the effect of antidepressants on emotional aspects of depression, few focus on their effect on physical symptoms. This observational study was conducted, in a clinical practice setting, to determine antidepressant treatment decisions and their outcome on the physical and emotional symptoms of MDD.

Effects of atypical and typical antipsychotic treatments on sexual function in patients with schizophrenia: 12-month results from the Intercontinental Schizophrenia Outpatient Health Outcomes (IC-SOHO) study.

Purpose: Sexual dysfunction in patients with schizophrenia can reduce quality of life and treatment compliance. This report will compare the effects of selected atypical and typical antipsychotics on sexual function in a large, international population of outpatients with schizophrenia who were treated over 1 year.

Subjects And Methods: Outpatients with schizophrenia, who initiated or changed antipsychotic treatment, and entered this 3-year, prospective, observational study were classified according to the monotherapy prescribed at baseline: olanzapine (N=2638), risperidone (N=860), quetiapine (N=142) or haloperidol (N=188).

Major depressive disorder in Latin America: the relationship between depression severity, painful somatic symptoms, and quality of life.

Background: We report on two multi-center, prospective, observational studies (H6U-BC-LRAG and H6U-BL-LRAH) to determine the clinical profile of Latin American outpatients with major depressive disorder (MDD) and the relationship between depression severity, painful somatic symptoms, and quality of life.

Method: Patients (n = 989) with MDD were classified according to the presence (SS+) or absence (SS-) of painful somatic symptoms using the Somatic Symptom Inventory (SSI). Visual Analogue Scale (VAS) quantified pain severity, HAMD17 and CGI-S determined depression severity, while the Quality of Life in Depression Scale (QLDS) quantified subjective well-being.

Prevalence of sexual dysfunction in patients with schizophrenia: international variation and underestimation.

The prevalence of sexual dysfunction in schizophrenia patients was investigated as part of this large (n = 7655), prospective, international (27 countries) study. Based on patient reports, sexual dysfunction affected approx. 50% of patients and the prevalence of complaints varied significantly between regions (p < 0.