Diminished capacity to make treatment decision for COVID-19 vaccination in schizophrenia

Recent evidence suggests that people with schizophrenia are at high risk for severe COVID-19 and should be prioritized for vaccination. However, impaired decision-making capacities could negatively affect the uptake of COVID-19 vaccination in this population. Capacity to consent to COVID-19 vaccination was assessed in 80 outpatients with schizophrenia. Using the MacArthur Competence Assessment Tool for Treatment, 56.3% of the sample were classified as having diminished capacity to consent to the vaccination. Diminished capacity to consent to COVID-19 vaccination was associated with lower vaccination rates, poorer cognition and higher level of psychotic symptoms. Developing interventions for enhancing informed consent for vaccination is urgent within this population.

     

Gut intraepithelial lymphocyte development

CD8alphabeta(+) and CD4(+) intraepithelial lymphocytes, the progeny of double-positive thymocytes, are oligoclonal T-cell populations that have accumulated in the gut wall as the result of repeated antigenic stimulations, which lead to rounds of traffic through the lymph/blood circuit ending in an alpha4beta7-integrin-driven homing all along the gut mucosa. In contrast, CD8alphaalpha(+) intraepithelial lymphocytes, which may be TCRgammadelta(+) or alphabeta(+), result in part from local differentiation in the gut, but studies comparing euthymic and athymic mice suggest a thymic double-negative origin for many of them.     

Matrix metalloprotease 8-dependent extracellular matrix cleavage at the blood-CSF barrier contributes to lethality during systemic inflammatory diseases

Systemic inflammatory response syndrome (SIRS) is a highly mortal inflammatory disease, associated with systemic inflammation and organ dysfunction. SIRS can have a sterile cause or can be initiated by an infection, called sepsis. The prevalence is high, and available treatments are ineffective and mainly supportive. Consequently, there is an urgent need for new treatments. The brain is one of the first organs affected during SIRS, and sepsis and the consequent neurological complications, such as encephalopathy, are correlated with decreased survival. The choroid plexus (CP) that forms the blood-CSF barrier (BCSFB) is thought to act as a brain "immune sensor" involved in the communication between the peripheral immune system and the CNS. Nevertheless, the involvement of BCSFB integrity in systemic inflammatory diseases is seldom investigated. We report that matrix metalloprotease-8 (MMP8) depletion or inhibition protects mice from death and hypothermia in sepsis and renal ischemia/reperfusion. This effect could be attributed to MMP8-dependent leakage of the BCSFB, caused by collagen cleavage in the extracellular matrix of CP cells, which leads to a dramatic change in cellular morphology. Disruption of the BCSFB results in increased CSF cytokine levels, brain inflammation, and downregulation of the brain glucocorticoid receptor. This receptor is necessary for dampening the inflammatory response. Consequently, MMP8(+/+) mice, in contrast to MMP8(-/-) mice, show no anti-inflammatory response and this results in high mortality. In conclusion, we identify MMP8 as an essential mediator in SIRS and, hence, a potential drug target. We also propose that the mechanism of action of MMP8 involves disruption of the BCSFB integrity.     

Genetic pathways linking hemostasis and cancer

Oncogenic events impact interactions of cancer cells with their surroundings. Amongst the most consequential, in this regard, is the influence on angiogenesis, inflammation and hemostasis. Indeed, mutant oncogenes (EGFR, HER2, RAS, MET, PML-RARα) are known to alter the expression of angiogenic and pro-inflammatory factors, as well as change the cancer cell coagulome, including the levels of tissue factor (TF) and other mediators (PAI-1, COX2). Accompanying losses of tumour suppressor genes (PTEN, p53), and changes in microRNA (miR-19b, miR-520) facilitate these effects. Transforming genes may also trigger ectopic production of coagulation factors (e.g. FVII) by cancer cells and their release and properties of procoagulant microparticles (MPs). By deregulating protease activated receptors (PAR1/2) oncogenes may also change tumour cell responses to coagulation factor signalling. These changes act in concert with microenvironmental factors (hypoxia), stress responses (therapy) and differentiation programs, including epithelial-to-mesechymal transitions (EMT) and through tumour initiating cell (TIC) compartment. In so doing, the coagulation system influences early (initiation, angiogenesis), intermediate (growth, invasion) and late stages (metastasis, relapse) of cancer progression. In fact, TF may act as a molecular switch that controls the transition between dormant, latent and progressive/metastatic disease. TIC-like cells may play a role in these effects, as they express TF and PAR-1/2, and respond to stimulation with their agonists. As major human malignancies (e.g. glioblastoma) are increasingly recognized to consist of a spectrum of molecularly distinct disease subtypes driven by specific genetic pathways, so too may their patterns of interaction differ with the coagulation system. A better understanding of these linkages may be a source of new diagnostic, prognostic and therapeutic opportunities.     

Type-1 cannabinoid receptor signaling in neuronal development

The type-1 cannabinoid receptor (CB1R) was initially identified as the neuronal target of Δ(9)-tetrahydrocannabinol (THC), the major psychoactive substance of marijuana. This receptor is one of the most abundant G-protein-coupled receptors in the adult brain, the target of endocannabinoid ligands and a well-characterized retrograde synaptic regulator. However, CB1Rs are also highly and often transiently expressed in neuronal populations in the embryonic and early postnatal brain, even before the formation of synapses. This suggests important physiological roles for CB1Rs during neuronal development. Several recent reviews have summarized our knowledge about the role of the endocannabinoid (eCB) system in neurodevelopment and neurotransmission by focusing on the metabolism of endocannabinoid molecules. Here, we review current knowledge about the effects of the modulation of CB1R signaling during the different phases of brain development. More precisely, we focus on reports that directly implicate CB1Rs during progenitor cell migration and differentiation, neurite outgrowth, axonal pathfinding and synaptogenesis. Based on theoretical considerations and on the reviewed experimental data, we propose a new model to explain the diversity of experimental findings on eCB signaling on neurite growth and axonal pathfinding. In our model, cell-autonomus and paracrine eCBs acting on CB1Rs are part of a global inhibitory network of cytoskeletal effectors, which act in concert with positive-feedback local-excitation loops, to ultimately yield highly polarized neurons.     

Dual Inhibitor of MurD and MurE Ligases from Escherichia coli and Staphylococcus aureus

d-glutamic acid-containing dual inhibitor of MurD and MurE ligases from Escherichia coli and Staphylococcus aureus (IC₅₀ values between 6.4 and 180 μM) possessing antibacterial activity against Gram-positive S. aureus and its methicillin-resistant strain (MRSA) with minimal inhibitory concentration (MIC) values of 8 μg/mL. The inhibitor was also found to be noncytotoxic for human HepG2 cells at concentrations below 200 μM.     

Impact of whole-body computed tomography on mortality and surgical management of severe blunt trauma

ABSTRACT: INTRODUCTION: The mortality benefit of whole-body computed tomography (CT) in early trauma management remains controversial and poorly understood. The objective of this study was to assess the impact of whole-body CT compared with selective CT on mortality and management of patients with severe blunt trauma. METHODS: The FIRST (French Intensive care Recorded in Severe Trauma) study is a multicenter cohort study on consecutive patients with severe blunt trauma requiring admission to intensive care units from university hospital trauma centers within the first 72 hours. Initial data were combined to construct a propensity score to receive whole-body CT and selective CT used in multivariable logistic regression models, and to calculate the probability of survival according to the Trauma and Injury Severity Score (TRISS) for 1,950 patients. The main endpoint was 30-day mortality. RESULTS: In total, 1,696 patients out of 1,950 (87%) were given whole-body CT. The crude 30-day mortality rates were 16% among whole-body CT patients and 22% among selective CT patients (p = 0.02). A significant reduction in the mortality risk was observed among whole-body CT patients whatever the adjustment method (OR = 0.58, 95% CI: 0.34-0.99 after adjustment for baseline characteristics and post-CT treatment). Compared to the TRISS predicted survival, survival significantly improved for whole-body CT patients but not for selective CT patients. The pattern of early surgical and medical procedures significantly differed between the two groups. CONCLUSIONS: Diagnostic whole-body CT was associated with a significant reduction in 30-day mortality among patients with severe blunt trauma. Its use may be a global indicator of better management.     

3D resolved mapping of optical aberrations in thick tissues

We demonstrate a simple method for mapping optical aberrations with 3D resolution within thick samples. The method relies on the local measurement of the variation in image quality with externally applied aberrations. We discuss the accuracy of the method as a function of the signal strength and of the aberration amplitude and we derive the achievable resolution for the resulting measurements. We then report on measured 3D aberration maps in human skin biopsies and mouse brain slices. From these data, we analyse the consequences of tissue structure and refractive index distribution on aberrations and imaging depth in normal and cleared tissue samples. The aberration maps allow the estimation of the typical aplanetism region size over which aberrations can be uniformly corrected. This method and data pave the way towards efficient correction strategies for tissue imaging applications.