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We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospective case-control study conducted in nine hospitals from seven European countries. A total of 624 patients were included, of which 415 were deceased (cases) and 209 were still alive 90 days after a CDI diagnosis (controls). The most common antibiotics used previously in both groups were β-lactams; previous exposure to fluoroquinolones was significantly (p = 0.0004) greater in deceased patients. Multivariate logistic regression showed that the factors independently related with death during CDI were older age, inadequate CDI therapy, cachexia, malignancy, Charlson Index, long-term care, elevated white blood cell count (WBC), C-reactive protein (CRP), bacteraemia, complications, and cognitive impairment. In addition, older age, higher levels of WBC, neutrophil, CRP or creatinine, the presence of malignancy, cognitive impairment, and complications were strongly correlated with shortening the time from CDI diagnosis to death. CDI prevention should be primarily focused on hospitalised elderly people receiving antibiotics. WBC, neutrophil count, CRP, creatinine, albumin and lactate levels should be tested in every hospitalised patient treated for CDI to assess the risk of a fatal outcome.

Background: Exposure to airborne particulate matter, especially its organic part, is strongly related to the development of cardiovascular disorders including atherosclerosis. The role of inorganic part of air pollution in the pathogenesis of atherosclerosis is still unclear. The aim of this study was to investigate the mechanism of action of two substantial components of inorganic part of airborne particulate matter (SiO2 and Fe2O3) in atherosclerosis. To do this, we used apolipoprotein E-knockout mice exposed to silica (SiNPs) and ferric oxide (FeNPs) nanoparticles in a whole body inhalation chamber for 16 weeks. To our knowledge, this is the first time when whole body exposure system was applied to examine the effects of silica and ferric oxide nanoparticles on atherosclerosis development in mouse model of atherosclerosis. Results: Inhaled silica nanoparticles augmented the atherosclerotic lesions and increased the percentage of pro-inflammatory M1 macrophages in both the plaque and the peritoneum in apoE-/- mice. Exposure to ferric oxide nanoparticles did not enhance atherogenesis process, however, it caused significant changes in the atherosclerotic plaque composition (elevated content of CD68-positive macrophages and enlarged necrotic core accompanied by the decreased level of M1 macrophages). Both silica and iron oxide NPs altered the phenotype of T lymphocytes in the spleen by promoting polarization towards Th17 cells. Conclusions: Exposure to silica and ferric oxide nanoparticles exerts differential impact on atherosclerosis development. Silica nanoparticles enhance atherosclerosis, which is associated with increased level of M1 macrophages, while ferric oxide nanoparticles alter atherosclerotic plaque composition without influencing the size of the lesions.

Lifestyle modifications focused on diet, physical activity, and behavior have only a modest impact on weight reduction in children, adolescents, and young adults (YA) with overweight and obesity. Several anti-obesity medications (AOMs) have been approved by the Food and Drug Administration (FDA) for use among adult patients with a body mass index (BMI) ≥27 kg/m2 and at least one obesity-related illness. However, only two FDA-approved AOMs are available for use in children and adolescents, which leads to the frequent off-label use of adult AOMs among this population. We sought to investigate current prescribing patterns of on- and off-label AOMs across a spectrum of age ranges from school age through to young adulthood and assess …

We aimed to describe the clinical presentation, treatment, outcome and report on factors associated with mortality over a 90-day period in Clostridioides difficile infection (CDI). Descriptive, univariate, and multivariate regression analyses were performed on data collected in a retrospective case-control study conducted in nine hospitals from seven European countries. A total of 624 patients were included, of which 415 were deceased (cases) and 209 were still alive 90 days after a CDI diagnosis (controls). The most common antibiotics used previously in both groups were β-lactams; previous exposure to fluoroquinolones was significantly (p = 0.0004) greater in deceased patients. Multivariate logistic regression showed that the factors independently related with death during CDI were older age, inadequate CDI therapy, cachexia, malignancy, Charlson Index, long-term care, elevated white blood cell count (WBC), C-reactive protein (CRP), bacteraemia, complications, and cognitive impairment. In addition, older age, higher levels of WBC, neutrophil, CRP or creatinine, the presence of malignancy, cognitive impairment, and complications were strongly correlated with shortening the time from CDI diagnosis to death. CDI prevention should be primarily focused on hospitalised elderly people receiving antibiotics. WBC, neutrophil count, CRP, creatinine, albumin and lactate levels should be tested in every hospitalised patient treated for CDI to assess the risk of a fatal outcome.

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

Activation of lymphocytes during contact with the Epstein–Barr virus (EBV) was studied. The lymphocytes were obtained from patients treated due to the acute phase of infectious mononucleosis in the Jagiellonian University Hospital in Krakow. The changes in the averaged Raman spectra of the lymphocytes during their treatment, on the 1st, 3rd, 5th, 9th and 12th day of hospitalization, were analyzed using the 2D-COS method. The most interesting activation marker was the Raman band at 520 cm−1 attributed to the formation of immunoglobulins. This band does not occur in the control group samples. The 2D-COS analysis revealed some additional details of lymphocyte activation. In the 2D synchronous maps, the greatest changes occur for auto-peaks at 2929 cm−1, due to the CH vibrations in the methyl groups of lipids and proteins, at 1638 cm−1, corresponding to the changes in α -helix amide I, 1585 cm−1 corresponding to nucleic acids and some amino acids, Trp, Phe and Gln, indicating cell remodeling. 2D synchronous maps monitor the formation of a receptor complex, as a subsequent functional lymphocyte maturation. 2D asynchronous maps point to the B-cell development towards immune response, i.e., the formation of immunoglobulins.

N-type (CaV2.2) calcium channels are key for action potential-evoked transmitter release in the peripheral and central nervous system. Previous studies have highlighted the functional relevance of N-type calcium channels at both the peripheral and central level. In the periphery, N-type calcium channels regulate nociceptive and sympathetic responses. At the central level, N-type calcium channels have been linked to aggression, hyperlocomotion, and anxiety. Among the areas of the brain that are involved in anxiety are the basolateral amygdala, medial prefrontal cortex, and ventral hippocampus. These three areas share similar characteristics in their neuronal circuitry, where pyramidal projection neurons are under the inhibitory control of a wide array of interneurons including those that express the peptide cholecystokinin. This type of interneuron is well-known to rely on N-type calcium channels to release GABA in the hippocampus, however, whether these channels control GABA release from cholecystokinin-expressing interneurons in the basolateral amygdala and medial prefrontal cortex is not known. Here, using mouse models to genetically label cholecystokinin-expressing interneurons and electrophysiology, we found that in the basolateral amygdala, N-type calcium channels control ~50% of GABA release from these neurons onto pyramidal cells. By contrast, in the medial prefrontal cortex N-type calcium channels are functionally absent in synapses of cholecystokinin-expressing interneurons, but control ~40% of GABA release from other types of interneurons. Our findings provide insights into the precise localization of N-type calcium channels in interneurons of brain areas related to anxiety.

The main restraint obstructing the wider adoption of lupins as protein crops is the presence of bitter and toxic quinolizidine alkaloids (QAs), whose contents might increase under exposure to stressful environmental conditions. A poor understanding of how QAs accumulate hinders the breeding of sweet varieties. Here, we characterize the expression profiles of QA-related genes, along with the alkaloid content, in various organs of sweet and bitter narrow-leafed lupin (NLL, Lupinus angustifolius L.). Special attention is paid to the RAP2-7 transcription factor, a candidate regulator of the QA pathway. We demonstrate the upregulation of RAP2-7 and other QA-related genes, across the aerial organs of a bitter cultivar and the significant correlations between their expression levels, thus supporting the role of RAP2-7 as an important regulatory gene in NLL. Moreover, we showed that the initial steps of QA synthesis might occur independently in all aerial plant organs sharing common regulatory mechanisms. Nonetheless, other regulatory steps might be involved in RAP2-7-triggered QA accumulation, given its expression pattern in leaves. Finally, the examination of QA-related gene expression in plants infected with Colletotrichum lupini evidenced no connection between QA synthesis and anthracnose resistance, in contrast to the important role of polyamines during plant–pathogen interactions.

Background: Inflammatory heart diseases represent an important clinical problem, nonetheless data regarding activation of cardiac microvascular endothelial cells (MVECs) are limited. Aim: To examine influence of TNF-α and exosomes produced by heart-reactive CD4+ T lymphocytes on activation of cardiac MVECs. Methods: Experimental autoimmune myocarditis (EAM) was induced in wild-type (WT) and TNF-α-deficient (TNF-KO) mice. CD4+ T lymphocytes were isolated from EAM mice at day 21 and activated in vitro to produce conditioned medium and exosomes. Activation of MVECs was assessed by specific assays and leukocyte-to-endothelial adhesion was analysed under shear flow condition using the BioFlux microfluidic system. Results: TNF-KO mice showed lower prevalence of myocarditis when compared to WT mice (50% vs. 90%). Stimulation of MVECs with secretome of antigen-activated autoreactive T cells resulted in upregulation of adhesion molecules (ICAM-1, VCAM-1 and P-selectin), increased ROS and decreased NO production. Addition of anti-TNF-α neutralizing antibodies effectively blocked adhesion of leukocytes to MVECs activated with the conditioned medium. Endothelial activation and dysfunction induced by the conditioned medium were independent of TNF-α produced by T cells. Stimulation of MVECs with T cell-derived exosomes increased ROS and decreased levels of NO and eNOS activation, but exosomes neither increased expression of adhesion molecules in MVECs nor induced their ability to bind leukocytes. Conclusions: TNF-α promotes MVEC activation and EAM development. In this model, autoreactive T cells activate MVECs, and TNF-a produced by MVECs rather than T cells is essential in this process. On the other hand, endothelial dysfunction caused by T cells seems to be mediated mainly by exosomes.

Background/Introduction Myocarditis, a heart-specific inflammation, is a common cause of pathological tissue remodeling and cardiac fibrosis resulting in stiffening of ventricles, functional impairment and heart failure. Immunization of susceptible mice with alpha myosin heavy chain (αMyHC) and complete Freund's adjuvant (CFA) induces CD4+ T cell-mediated experimental autoimmune myocarditis (EAM). In EAM model, resolution of acute cardiac inflammation is followed by a progressive dilated cardiomyopathy and systolic dysfunction. Purpose The aim of our study was to identify the role of resident cardiac fibroblasts, cardiac endothelial as well as inflammatory myeloid cells during the course of EAM. Methods EAM was induced by immunization with αMyHC/CFA in reporter BALB/c mice expressing EGFP under collagen type I promoter (Coll-EGFP) and RFP under a control of α-smooth muscle actin (αSMA) promoter (αSMA-RFP). Using flow cytometry analysis, cardiac cells were phenotyped and quantified at inflammatory (d19–21) and fibrotic (d40) stage of EAM. Sorted EGFP-positive cardiac fibroblasts obtained from healthy and myocarditis-positive mice (day 21 of EAM) were comparatively analyzed for the whole genome transcriptomics using the Next Generation Sequencing with read length 2x150bp and 20–30 million reads per sample. Results A massive infiltration of inflammatory CD45+CD11b+ myeloid cells (mainly CD11b+CD36+ macrophages, CD11b+CD36–Ly6GhiLy6chi neutrophils, CD11b+CD36–Ly6G–Ly6c– monocytes, CD11b+CD36–Ly6G–Ly6chi inflammatory monocytes) was observed at day 21 of EAM. Myeloid cells as well as endothelial cells showed increased production of type I collagen at day 21, which was further reduced at day 40 of EAM. At day 21, collagen-producing endothelial cells showed particularly elevated levels of adhesion molecules ICAM and VCAM. On the other hand, the total number of EGFP-positive cardiac fibroblasts remained unchanged during the course of EAM, as well as the percentage of cardiac fibroblasts positive for αSMA (myofibroblasts). Gene ontology analysis of transcripts differentially regulated in cardiac fibroblasts during acute myocarditis pointed mainly to activation of immune processes, response to stress, cytoskeletal and extracellular matrix organization. Specifically, in EAM at day 21 cardiac fibroblasts increased transcription of chemokines (Ccl6, Ccl9, Cxcl2, Cxcl3, Cxcl5, Cxcl9, Cxcl13), collagens (Col6a4, Col6a5, Col9a1, Col9a3, Col11a2, Col12a1, Col24a1, Col28a1), and genes involved in ECM biology (Bmp7, Kng2, Lgals3, Cthrc1, Cela1, Spn). Conclusions In EAM model, inflammatory myeloid and cardiac endothelial cells seem to contribute to excessive collagen type I production, whereas cardiac fibroblasts actively participate in inflammatory and profibrotic responses. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): The National Science Centre (Poland)

Objectives To present three patients with severe coronavirus disease 2019 infection who developed life-threatening hyperpyrexia while being treated with dexmedetomidine for sedation. Data sources Clinical records. Study selection Case report. Data extraction Relevant clinical information. Data synthesis We describe three patients, a 60-year-old female, 43-year-old female, and 46-year-old male, who were hospitalized in surge ICUs during the coronavirus disease 2019 pandemic in the early spring of 2020. All developed hyperpyrexia, defined as a temperature above 41.1°C, following an increase in dexmedetomidine dosing to above 1.5 µg/kg/hr. Fevers resolved following discontinuation of dexmedetomidine. Conclusions While the exact mechanism of hyperpyrexia remains unclear, findings in this study suggest that high doses of dexmedetomidine infusion are associated with hyperpyrexia in a seemingly dose-dependent fashion in critically ill patients with coronavirus disease 2019. Coronavirus disease 2019 infection causes a hyperinflammatory state characterized by pro-inflammatory cytokine dysregulation. Dexmedetomidine, a centrally acting alpha-2 agonist, may alter hypothalamic temperature regulation through disturbances in neurotransmitter expression and metabolism. We postulate that the use of high-dose dexmedetomidine in a hyperinflammatory state may increase the risk of developing hyperpyrexia in this severe disease state.

Spondyloarthritis (SpA) is characterized by chronic inflammation and structural damage involving spine and peripheral joints. Monocytes, as part of innate immune system, following migration into affected tissue, may play a role in the pathogenesis of SpA. Here, potential associations between osteogenesis-linked gene expression profile in particular monocyte subpopulations and clinical signs of SpA were investigated. The 20 patients with axial and 16 with peripheral SpA were enrolled in the study. Monocyte subpopulations (classical—CD14++CD16−, intermediate—CD14++CD16+ and non-classical—CD14+CD16++) were isolated from blood using flow cytometry and gene expression analysis was performed using real-time PCR method and TaqMan Array, Human Osteogenesis, Fast 96-well plates. Next, the characteristic clinical features shared by axial and peripheral SpA were analyzed in the context of the expression of selected genes in the three subpopulations of monocytes. We demonstrated that expression of VEGFA in classical and MSX2 in non-classical monocytes were associated with the number of swollen and painful peripheral joints of SpA patients. We conclude that monocytes may contribute to the development of peripheral arthritis in SpA patients. This might be possible through subpopulation specific effects, linking number of inflamed joints with expression of VEGFA in classical monocytes and MSX2 in non-classical monocytes.

Music listening can lead to strong aesthetic experiences. However, to gain deeper insights into such experiences, more empirical research outside of laboratory settings is required. The current exploratory study measured aesthetic experience (music-induced emotions and absorption) in combination with psychophysiology (facial electromyography and arousal measures) from 98 participants during three live concerts with a program of classical, romantic, and contemporary chamber music. One musical movement from the contemporary work was presented from a recording. Results firstly highlight two key components of the concert frame as influencing the aesthetic experience: a) the programming order led to a rise-and-fall trajectory of emotions with the less familiar contemporary work leading to higher negatively valenced emotions. Nonetheless, this experience was embedded in an overall highly appreciated concert, with b) the factor of liveness becoming apparent in lower engagement with the recorded than the live music. Secondly, the participants’ reactions gave insights into how the multi-movement works were perceived; opening and closing movements elicited higher positively valenced arousal, contrasting the characteristics of an inner section, which evoked lower arousal and mixed emotions. This scheme differed between the classical and the romantic works in the third movements, reflecting a different trajectory of tension and relaxation in the respective styles. Finally, we show relations between physiological responses and self-reports reflecting both positive and negative aesthetic experiences. Overall, we demonstrate that the ecological validity of the current study is particularly informative for theoretical approaches on the aesthetic experience, with the frame as a crucial component.

PURPOSE OF REVIEW: We review the current options to manage adolescent obesity which include nutrition, physical activity, behavior modification, sleep management, pharmacotherapy and surgery. Since lifestyle interventions alone are often not effective in adolescents, a multi-disciplinary treatment approach is necessary in management. RECENT FINDINGS: Medications (often used off-label) and metabolic/bariatric surgery are effective treatment strategies to treat adolescents with severe obesity. SUMMARY: The use of pharmacotherapy and surgery is limited due to lack of pediatric obesity tertiary care centers. With more centers, the treatment of adolescent obesity will improve and aid to decrease the prevalence of adult obesity.

Summary In the development of PD-L1-blocking therapeutics, it is essential to transfer initial in vitro findings into proper in vivo animal models. Classical immunocompetent mice are attractive due to high accessibility and low experimental costs. However, it is unknown whether inter-species differences in PD-L1 sequence and structure would allow for human-mouse cross applications. Here, we disclose the first structure of the mouse (m) PD-L1 and analyze its similarity to the human (h) PD-L1. We show that mPD-L1 interacts with hPD-1 and provides a negative signal toward activated Jurkat T cells. We also show major differences in druggability between the hPD-L1 and mPD-L1 using therapeutic antibodies, a macrocyclic peptide, and small molecules. Our study indicates that while the amino acid sequence is well conserved between the hPD-L1 and mPD-L1 and overall structures are almost identical, crucial differences determine the interaction with anti-PD-L1 agents, that cannot be easily predicted in silico., Graphical abstract, Highlights • Mouse (m) PD-L1 interacts with human (h) PD-1 and inhibits human Jurkat T cells • Small molecule and macrocyclic peptide inhibitors of hPD-L1 do not bind to mPD-L1 • Atezolizumab but not durvalumab binds and blocks mouse PD-L1, Therapeutics; Immunology

OBJECTIVE Significant variability exists in the amount of formal obesity training obtained by physicians caring for pediatric patients. The study objective was to assess the relationship between formal obesity training and pediatrics physicians' perceptions, practice patterns, overall knowledge, and confidence during management of pediatric obesity. METHODS An anonymous survey was distributed via email from February 2020 through March 2020 at a large academic system. Internal medicine/pediatrics (46 total) and pediatrics (104 total) primary care providers were selected. Data were collected on the total number of obesity-related training hours by quartiles, demographics, physicians' clinical practice patterns, and physicians' knowledge of pediatric obesity management, along with their perceptions, attitudes, and beliefs. RESULTS A total of 73 survey participants completed the survey: 69% were female, 77% were older than 40 years, and 74% were White. Physicians with the highest training were most likely to feel confident when managing pediatric obesity. However, only 20% of all physicians felt confident providing pre- and post-bariatric surgery care, and just 6% of physicians self-reported achieving management success. CONCLUSIONS Increased obesity training improves physicians' confidence and leads to familiarity with management guidelines. Formal obesity training should be prioritized during residency and beyond so that physicians who care for pediatric patients are better equipped to offer unbiased and effective care.

Artykul powstal przy wspolpracy Pracowni Optymalizacji Transferu Wiedzy Laboratorium Zagadnien Spoleczenstwa Informacyjnego w Centrum Innowacji i Transferu Wiedzy Techniczno-Przyrodniczej Uniwersytetu Rzeszowskiego.

To ensure successful outcomes in pediatric patients with severe obesity who undergo metabolic and bariatric surgery (MBS), a number of pre-operative patient management options should be considered. This manuscript will review the indications and contraindications of MBS and special considerations for youth who might benefit from MBS. The treatment team conducts a thorough pre-operative evaluation, assessing risks and benefits of surgical intervention, and prepares patients and families to be successful with MBS by providing education about the surgical intervention and lifestyle changes that will be necessary. This article reviews the pre-operative considerations for adolescents with severe obesity who are being considered for MBS, based upon recent clinical practice guidelines.

Neuroinfections are a significant medical problem and can have serious health consequences for patients. Their outcome, if not fatal, can be associated with permanent residual deficits. Cerebrospinal fluid (CSF) examination is commonly used for meningitis confirmation. Fatty acids (FA) are precursors of lipid mediators with pharmacological activity. They actively modulate inflammation as well as contribute to its resolution. Therefore the aim of this study was to determine the FA and selected endocannabinoids (ECB) content in the CSF obtained from patients with bacterial (BM) and viral meningitis (VM) using chromatographic techniques. A significantly lower level of saturated FA was found in patients with BM and VM as compared to controls. There was a significantly higher concentration of long-chain monounsaturated FA and polyunsaturated n-6 FA in the CSF obtained from patients with neuroinfection. Moreover, a significant reduction of n-3 FA in CSF obtained from patients with BM and VM was demonstrated. The highest amount of ECB was detected in the CSF of patients with VM: eicosapentaenoyl ethanolamide (1.65 pg/mL), docosahexaenoyl ethanolamide (655.5 pg/mL) and nervonoyl ethanolamide (3.09 ng/mL). Results indicate the participation of long-chain monounsaturated and polyunsaturated FA and their derivatives in the inflammatory process and likely in the process of resolution of inflammation during neuroinfection. It seems that the determination of the FA and ECB profile in CSF may be a valuable biomarker of health and may allow the development of new pharmacological strategies, therapeutic goals and fatty acids supplementation necessary in the fight against inflammation of the central nervous system.