High-grade Inflammation Research Articles

P0433 Pouchitis described by the SES-CD score is more associated with the need for biologics initiation after IPAA than endoscopic subscore of PDAI

Abstract Background The ileal pouch-anal anastomosis (IPAA) is a well-established approach following proctocolectomy for ulcerative colitis (UC) or colorectal dysplasia. Although the functional results are good, many patients develop pouchitis. The pouchitis disease activity index (PDAI) is the most used tool to assess the inflammation of the pouch. However, the PDAI with endoscopic subscore of PDAI (ePDAI) is often not reliable or responsive (1, 2). The simplified endoscopic score for Crohn’s disease (SES-CD) has recently been proposed for this setting (3). In this retrospective study, we aim to describe the correlation between SES-CD score and several important clinical outcomes. Methods We performed a retrospective cohort study of patients who underwent IPAA surgery between March 2015 and February 2024 at out tertiary referral centre. According to internal hospital protocol, endoscopic and clinical examinations were performed at 1, 3, 6, and 12 months after IPAA for each patient. The ePDAI scores, demographics, comorbidities, laboratory tests and medication use were collected from the electronic medical records. Data was collected for the first year following IPAA surgery, and last known follow up. All pouchoscopies (n=497, 86.4% of total) with video- (83.5%) or photodocumentation (16.5 %) were reviewed by the same reviewer (JS) and additionally scored with SES-CD endoscopic score in the pouch body and afferent ileum. Descriptive and univariate analyses was performed. Kaplan-Meier curves were used to assess the impact of the ePDAI and SES CD scores for initiation of biologics. Pouchoscopies were classified as low-grade (ePDAI ≤ 1; SES CD ≤ 3) or high-grade inflammation (ePDAI > 1; SES CD > 3). Results The total cohort included 206 patients (46.1% female), of which 90.3% underwent IPAA surgery due to ulcerative colitis with a median follow up of 25 months after IPAA construction. Of those, 12.6% were receiving biologic therapy at the last follow up. There was linear corelation between ePDAI and SES-CD score (rho 0.69, p<0.001). For both scores, the patients with high-grade inflammation pouchoscopy at months 1 (p 0.0132 for ePDAI, p 0.0008 for SES-CD) and 6 (p 0.0001 for ePDAI, p 0.0007 for SES-CD) had a higher need for biologic therapy than patients with low-grade pouchoscopy. At month 3 and 12, only SES-CD was associated with higher need for biologic therapy (month 3: p 0.467 for ePDAI, p 0.042 for SES-CD; month 12: p 0.0571 for ePDAI and p 0.0387 for SES CD). Conclusion The SES-CD score may be an alternative to ePDAI for scoring of pouch inflammation. The pouch inflammation described by the SES-CD score is more associated with the need for biologics initiation in patients after IPAA than ePDAI. References (1)Jairath V, Feagan BG, Silverberg MS, et al. Mucosal healing with vedolizumab in patients with chronic pouchitis: EARNEST, a randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. Published online 2024. doi: 10.1016/j.cgh.2024.06.037 (2)Sedano R, Nguyen TM, Almradi A, et al. Disease activity indices for pouchitis: A systematic review. Inflamm Bowel Dis. 2022;28(4):622-638. doi:10.1093/ibd/izab124 (3)Barnes EL, Long MD, Raffals L, et al. Development of the endoscopic pouch score for assessment of inflammatory conditions of the pouch. Clin Gastroenterol Hepatol. 2023;21(6):1663-1666.e3. doi: 10.1016/j.cgh.2022.04.026

PKM2-mediated STAT3 phosphorylation promotes acute liver failure via regulating NLRP3-dependent pyroptosis.

Acute liver failure (ALF) is a life-threatening clinical syndrome characterized by high-grade inflammation and multi-organ failure. Our previous study shows that targeting the M2 isoform of pyruvate kinase (PKM2) to inhibit macrophage inflammation may be a promising strategy for ALF treatment. however, the mechanism by which PKM2 regulates the inflammatory response is unclear. Here we demonstrate that PKM2 contributes to ALF by modulating NLRP3-mediated pyroptosis activation in liver macrophages. The specific knockout of PKM2 in myeloid cells reduces mortality and alleviates hepatic injury in D-galactosamine/LPS-induced ALF mice. Single-cell transcriptome analysis suggests that NLRP3 inflammasome activation of macrophages involves in ALF, knockout of PKM2 in macrophages reduces the expression of NLRP3, and activation of pyroptosis. Pharmacological inhibition of the PKM2 nuclear translocation, but not glycolytic activity, protects mice from ALF. Pharmacological and genetic inhibition of PKM2 attenuates NLRP3-mediated pyroptosis activation and consequently reduces the release of IL-1β and IL-18 by macrophages. Mechanistically, PKM2 translocates into the nucleus and combines with STAT3, enhancing its phosphorylation and recruitment to the NLRP3 promoter region, thereby increasing NLRP3 expression. This work defines PKM2 acts as an important nonmetabolic regulator of NLRP3 that modulates pyroptosis activation in macrophages and guides future therapeutic strategies development for ALF.

Pulmonary Mycobacterium avium infection in 2 domestic cats

Two domestic cats (Abyssinian and Carthusian) presented with chronic respiratory signs including cough, respiratory sounds, and polypnea. One of the cats also showed intermittent fever. Thoracic radiographs demonstrated severe changes with predominantly micronodular interstitial lung patterns, some with mineralized areas. Bronchoalveolar lavage detected high-grade pyogranulomatous airway inflammation. A cytological examination for acid-fast bacteria and a PCR for Mycobacteria species of the bronchoalveolar lavage fluid (BALF) were negative in both cats. A culture for Mycobacteria of the BALF detected Mycobacterium avium subspecies in both cats. While the clinical signs, but not the radiographic findings, could be controlled in one cat with prolonged double antibiotic therapy, the other cat developed septic peritonitis shortly after diagnosis and was euthanized. In unexplained chronic respiratory disease in cats, mycobacterial infection should be considered as a differential diagnosis. The breed of the first patient is consistent with the known predisposition for Abyssinians.

Metabolic and lifestyle factors accelerate disease onset and alter gut microbiome in inflammatory non-communicable diseases.

Biomedical and lifestyle factors in Western populations have significantly shifted in recent decades, influencing public health and contributing to the increasing prevalence of non-communicable diseases (NCDs) that share inflammation as common pathology. We investigated the relationship between these factors and 11 NCDs in the cross-sectional FoCus cohort (n = 1220), using logistic regression models. Associations with age-at-disease-onset were specifically analyzed for type 2 diabetes (T2D, low-grade chronic inflammation) and inflammatory bowel disease (IBD, high-grade chronic inflammation) in disease-specific cohorts (FoCus-T2D, n = 514; IBD-KC, n = 1110). Important factors for disease risk were identified using Cox-PH-regression models and time-to-event analysis. We further explored the interaction between identified risk factors and gut microbiome composition using linear models. Lifestyle factors were clearly linked to disease phenotypes, particularly in T2D and IBD. Still, some factors affected only the age-at-onset, but not disease prevalence. High-quality nutrition significantly delayed onset for both IBD and T2D (IBD: HR = 0.81 [0.66; 0.98]; T2D: HR = 0.45 [0.28; 0.72]). Smoking accelerated T2D onset (HR = 1.82 [1.25; 2.65]) but delayed onset in ulcerative colitis (UC: HR = 0.47 [0.28; 0.79]). Higher microbiota diversity delayed IBD onset (Shannon: HR = 0.58 [0.49; 0.71]) but had no effect on T2D. The abundance of specific microbial genera was strongly associated with various biomedical and lifestyle factors in T2D and IBD. In unaffected controls, these effects were smaller or reversed, potentially indicating a greater susceptibility of the gut microbiome to negative influences in T2D and IBD. The dual insights into age-at-disease-onset and gut microbiota composition in disease emphasize the role of certain biomedical and lifestyle factors, e.g., nutrition quality, in disease prevention and management. Understanding these relationships provides a foundation for developing targeted strategies to mitigate the impact of metabolic and inflammatory diseases through lifestyle modifications and gut health management.

Liver Cirrhosis: The Immunocompromised State.

Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.

Increased interleukin-6 levels are associated with atrioventricular conduction delay in severe COVID-19 patients.

Severely ill patients with coronavirus disease 2019 (COVID-19) show an increased risk of new-onset atrioventricular blocks (AVBs), associated with high rates of short-term mortality. Recent data suggest that the uncontrolled inflammatory activation observed in these patients, specifically interleukin (IL)-6 elevation, may play an important pathogenic role by directly affecting cardiac electrophysiology. The aim of our study was to assess the acute impact of IL-6 changes on electrocardiographic indices of atrioventricular conduction in severe COVID-19. We investigated (1) the behavior of PR-interval and PR-segment in patients with severe COVID-19 during active phase and recovery, and (2) their association with circulating IL-6 levels over time. During active disease, COVID-19 patients showed a significant increase of PR-interval and PR-segment. Such atrioventricular delay was transient as these parameters rapidly normalized during recovery. PR-indices significantly correlated with circulating IL-6 levels over time. All these changes and correlations persisted also in the absence of laboratory signs of cardiac strain/injury or concomitant treatment with PR-prolonging drugs, repurposed or not. Our study provides evidence that in patients with severe COVID-19 and high-grade systemic inflammation, IL-6 elevation is associated with a significant delay of atrioventricular conduction, independent of concomitant confounding factors. While transient, such alterations may enhance the risk of severe AVB and associated short-term mortality. Our data provide further support to current anti-inflammatory strategies for severe COVID-19, including IL-6 antagonists.

Fibroblast expression of neurotransmitter receptor HTR2A associates with inflammation in rheumatoid arthritis joint

The study of neuroimmune crosstalk and the involvement of neurotransmitters in inflammation and bone health has illustrated their significance in joint-related conditions. One important mode of cell-to-cell communication in the synovial fluid (SF) is through extracellular vesicles (EVs) carrying microRNAs (miRNAs). The role of neurotransmitter receptors in the pathogenesis of inflammatory joint diseases, and whether there are specific miRNAs regulating differentially expressed HTR2A, contributing to the inflammatory processes and bone metabolism is unclear. Expression of neurotransmitter receptors and their correlated inflammatory molecules were identified in rheumatoid arthritis (RA) and osteoarthritis (OA) synovium from a scRNA-seq dataset. Immunohistochemistry staining of synovial tissue (ST) from RA and OA patients was performed for validation. Expression of miRNAs targeting HTR2A carried by SF EVs was screened in low- and high-grade inflammation RA from a public dataset and validated by qPCR. HTR2A reduction by target miRNAs was verified by miRNAs mimics transfection into RA fibroblasts. HTR2A was found to be highly expressed in fibroblasts derived from RA synovial tissue. Its expression showed a positive correlation with the degree of inflammation observed. 5 miRNAs targeting HTR2A were decreased in RA SF EVs compared to OA, three of which, miR-214-3p, miR-3120-5p and miR-615-3p, mainly derived from monocytes in the SF, were validated as regulators of HTR2A expression. The findings suggest that fibroblast HTR2A may play a contributory role in inflammation and the pathogenesis of RA. Additionally, targeting miRNAs that act upon HTR2A could present novel therapeutic strategies for alleviating inflammation in RA.

Inflammatory Risk Status Shapes the Association Between Uric Acid and Cognitive Function in Non-Hyperuricemia Middle Aged and Elderly.

The association between uric acid (UA) and cognitive function still remains controversial. Moreover, the role of inflammation in the above association is also unclear. We aimed to determine the association between UA and cognitive function among non-hyperuricemia adults, and in particular, whether the association was shaped by different inflammation levels. From the China Health and Retirement Longitudinal Study (CHARLS), 7,272 participants aged 45 and above were enrolled in 2011. Cognitive function measurement included orientation and attention, episodic memory, and visuospatial ability. Fasting blood samples were collected to measure levels of UA and high-sensitivity C-reactive protein (hs-CRP). Generalized estimating equation models were used to evaluate the effect of UA on cognitive function in all participants and those at different levels of hs-CRP (hs-CRP <3 mg/L or ≥3 mg/L). Among non-hyperuricemia adults (mean age: 58.08, 49.59% males) for a median of 7 years follow-up, participants with higher levels of UA had better cognitive function score compared to those with lower UA levels (β: 0.09, 95% confidence interval [CI]: 0.01-0.17, p = 0.023). And this association was significant under low-grade inflammation levels condition (β:0.10, 95% CI: 0.10-0.19, p = 0.024), but not in high-grade inflammation levels condition. Further, the cognitive function benefit of elevated UA existed only in people with persistent low-grade inflammation levels at a longitudinal perspective (β: 0.14, 95% CI: 0.01-0.27, p = 0.039). Elevated UA levels were associated with better cognitive function in non-hyperuricemia population, especially for those at low inflammation levels.

Shear wave elastography and shear wave dispersion correlated to biopsy at the scheduled follow-up of pediatric liver grafts.

It is unknown how shear wave dispersion (SWD) is displayed in pediatric liver transplant recipients and not fully elucidated how ultrasound shear wave elastography (2D-SWE) display within this cohort, which is important to determine to improve noninvasive surveillance of these patients. The study aimed to compare SWE and SWD values with histopathology in pediatric liver recipients. Forty-eight pediatric liver recipients were examined with SWE in conjunction with an elective liver biopsy (clinically without complication). Additionally, SWD values were measured in 21 children. SWE and SWD values were compared to histologically determined fibrosis graded as none-to-mild (F0-1) and moderate-to-severe (F2-4), and inflammation graded as low (grade 0-1) and high (grade 2-4). Two children were excluded due to SWE IQR/median > 30% kPa. The mean age across 46 included patients was 10.9 years (range 1.4-18). The number of patients and median (range) SWE value (kPa) for each stage of fibrosis were: F0-1 [n = 23; 5.8 (3.2-16.1)], F2 [n = 22; 6.0 (4.5-25.9)], F3 [n = 1; 33.3], and F4 [n = 0]. Significantly higher SWE values and greater variability were registered in F2-4 vs. F0-1 (p = .05). Grade of fibrosis correlated weakly to SWE values (r = .3; p = .05), but not to SWD values (r = .2; p = .27). In patients with low-grade inflammation, median SWD was 13.7 m/s KHz (10.7-17.6). Only one patient had high-grade inflammation. Uncomplicated transplanted liver grafts in a small pediatric cohort revealed slightly increased SWE and SWD values compared to previously reported values in healthy children. This likely reflect both the fibrotic and inflammatory elements in the grafts; however, other confounders impacting the liver's viscoelastic properties are also probable factors.

The Relationship Between Dietary Inflammatory Index and All-Cause, Cardiovascular Disease-Related, and Cancer-Related Mortality.

In the general population of the United States (U.S.), the relationship between dietary inflammatory index (DII) and mortality (all-cause, cardiovascular disease (CVD)-related, and cancer-related) is still unclear. Therefore, in this research, we examined the association of DII with mortality caused by all-cause, CVD-related, and cancer-related causes. Data from the National Health and Nutrition Examination Survey (NHANES) from 1999-2018 was used for exploring the link between DII and all-cause, CVD-related, and cancer-related mortality through the use of Cox proportional hazard models and restricted cubic spline model. In addition, subgroup analyses were further performed. The study included 29,013 individuals from the NHANES from 1999 to 2018. The DII scores were nominated as low (T1: -5.281-0.724), medium (T2: 0.725-2.513), and high-grade inflammation (T3: 2.514-5.795), with T1 serving as the reference group. The linear positive correlation between DII and all-cause and CVD-related mortality was studied using Cox regression analysis. In the full-adjusted model, as compared with the individuals with T1 DII scores, adjusted odds ratios with 95% confidence intervals for all-cause and CVD-related mortality were 1.149 (1.059, 1.247), and 1.186 (1.084, 1.297), as well as 1.197 (1.032, 1.387), and 1.198 (1.019, 1.409), respectively. However, there was no statistical significance between DII and cancer-related mortality. The RCS plot also showed a significant increase in all-cause and CVD-related mortality with increased DII. Nevertheless, as DII scores increased, cancer-related mortality first increased and then decreased. All-cause and CVD-related mortality are linked independently to high DII scores, independently. Further study of the association of DII scores with mortality caused by all-cause, CVD-related, and cancer-related causes is necessary to explore.

The interleukin-1 receptor type-1 in disturbed flow-induced endothelial mesenchymal activation.

Atherosclerosis is a progressive disease that develops in areas of disturbed flow (d-flow). Progressive atherosclerosis is characterized by bulky plaques rich in mesenchymal cells and high-grade inflammation that can rupture leading to sudden cardiac death or acute myocardial infarction. In response to d-flow, endothelial cells acquire a mesenchymal phenotype through endothelial-to-mesenchymal transition (EndMT). However, the signaling intermediaries that link d-flow to EndMT are incompletely understood. In this study we found that in human atherosclerosis, cells expressing SNAI1 (Snail 1, EndMT transcription factor) were highly expressed within the endothelial cell (EC) layer and in the pre-necrotic areas in unstable lesions, whereas stable lesions did not show any SNAI1 positive cells, suggesting a role for EndMT in lesion instability. The interleukin-1 (IL-1), which signals through the type-I IL-1 receptor (IL-1R1), has been implicated in plaque instability and linked to EndMT formation in vitro. Interestingly, we observed an association between SNAI1 and IL-1R1 within ECs in the unstable lesions. To establish the causal relationship between EndMT and IL-1R1 expression, we next examined IL-1R1 levels in our Cre-lox endothelial-specific lineage tracing mice. IL-1R1 and Snail1 were highly expressed in ECs under atheroprone compared to athero-protective areas, and oscillatory shear stress (OSS) increased IL-1R1 protein and mRNA levels in vitro. Exposure of ECs to OSS resulted in loss of their EC markers and higher induction of EndMT markers. By contrast, genetic silencing of IL-1R1 significantly reduced the expression of EndMT markers and Snail1 nuclear translocation, suggesting a direct role for IL-1R1 in d-flow-induced EndMT. In vivo, re-analysis of scRNA-seq datasets in carotid artery exposed to d-flow confirmed the IL-1R1 upregulation among EndMT population, and in our partial carotid ligation model of d-flow, endothelial cell specific IL-1R1 KO significantly reduced SNAI1 expression. Global inhibition of IL-1 signaling in atherosclerosis as a therapeutic target has recently been tested in the completed CANTOS trial, with promising results. However, the data on IL-1R1 signaling in different vascular cell-types are inconsistent. Herein, we show endothelial IL-1R1 as a novel mechanosensitive receptor that couples d-flow to IL-1 signaling in EndMT.

Pyroptosis: the potential eye of the storm in adult-onset Still's disease.

Pyroptosis, a form of programmed cell death with a high pro-inflammatory effect, causes cell lysis and leads to the secretion of countless interleukin-1β (IL-1β) and IL-18 cytokines, resulting in a subsequent extreme inflammatory response through the caspase-1-dependent pathway or caspase-1-independent pathway. Adult-onset Still's disease (AOSD) is a systemic inflammatory disease with extensive disease manifestations and severe complications such as macrophage activation syndrome, which is characterized by high-grade inflammation and cytokine storms regulated by IL-1β and IL-18. To date, the pathogenesis of AOSD is unclear, and the available therapy is unsatisfactory. As such, AOSD is still a challenging disease. In addition, the high inflammatory states and the increased expression of multiple pyroptosis markers in AOSD indicate that pyroptosis plays an important role in the pathogenesis of AOSD. Accordingly, this review summarizes the molecular mechanisms of pyroptosis and describes the potential role of pyroptosis in AOSD, the therapeutic practicalities of pyroptosis target drugs in AOSD, and the therapeutic blueprint of other pyroptosis target drugs.

Changing the approach to rehabilitation exercise during the COVID-19 pandemic: A brief review

Background: It is necessary to design a comprehensive rehabilitation program after high-grade systemic inflammation caused by the coronavirus, followed by a long rest and quarantine. In addition, pandemic quarantine has led to a lack of access to rehabilitation clinics and sports clubs. However, integrated information on how to implement a rehabilitation program in pandemic conditions is not yet available. Objectives: We aimed to investigate clinical trials regarding exercise rehabilitation related to Covid-19 in PubMed. Methods: The keywords (Covid-19 and exercise rehabilitation) were examined in PubMed electronic database until 11 August 2021, and 707 articles were found. Results: Twenty-nine clinical trial articles were found, and one unrelated article was deleted. Particular attention should be paid to maintaining the physiological and psychological health of health care workers. Most of the programs implemented include home-based rehabilitation (HBR) through web-based rehabilitation [WBR]. The multiplicity and variety of existing programs are not enough to cover all groups in society, including the healthy and sick ones. No problems have been reported for healthy people during strenuous exercise when wearing a surgical or cloth mask Conclusions: In addition to conventional therapies and modern rehabilitation techniques, virtual rehabilitation learning through WBR is expanding [due to the quarantine conditions of patients and the closure of sports and clinical centers] with positive physiological and psychological effects.

Cardiovascular issues in rheumatic diseases.

Cardiovascular disease is a major cause of morbidity and mortality in rheumatic diseases, particularly rheumatoid arthritis and systemic lupus erythematosus. Timely detection and monitoring of cardiovascular affections by advanced visualization techniques may improve outcomes across most rheumatic diseases. Although high-grade inflammation and (auto)immune pathways are well known for their negative effects on the heart and vasculature, cardiovascular risk estimation remains one of the unresolved critical issues in rheumatic diseases. The issue is complicated further in view of the latest reports on enhanced atherogenesis in the setting of fibromyalgia and osteoarthritis, where inflammation is seemingly not a major pathogenic factor. The intensity of systemic inflammation has been associated with major vascular events in some large cohort studies of inflammatory rheumatic diseases. Experts advocate for tight control of systemic inflammation and modifiable cardiovascular risk factors for reducing the overall risk of vascular events. Increasing patients' and specialists' knowledge and skills in cardiovascular monitoring and prevention is warranted to solve some of the cardiovascular issues in rheumatic diseases. Key Points • Cardiovascular issues are prevalent across all age groups of patients with rheumatic diseases. • Large cohort studies suggest that the intensity of systemic inflammation is a powerful predictor of vascular events in rheumatic diseases. • Reliable and widely tested tools for predicting vascular events in inflammatory rheumatic diseases are currently unavailable. • Empowering patients with rheumatic diseases and first-contact specialists with knowledge and skills to monitor and reduce cardiovascular risk factors' effects is a promising strategy.

Synergistic Interactions of Insufficient Physical Activity and a High Systemic Immune-Inflammation Index on Psychological Problems in Indonesians With Type 2 Diabetes Mellitus.

High-grade inflammation represents a critical contribution to the onset of depression and might be manageable by physical activity (PA). Nevertheless, no study has examined synergistic interactions of insufficient PA and high values of the systemic immune-inflammation index (SII) on psychological problems. We investigated independent and synergistic interactions of insufficient PA and high SII levels on stress, anxiety, and depression in T2DM patients. A cross-sectional research design with 294 T2DM patients was conducted. An XP-100 automated hematology analyzer was used to evaluate inflammatory biomarkers. Depression, Anxiety, and Stress Scale-21 items and a standardized questionnaire about PA were respectively used to measure psychological problems and metabolic equivalent of task (MET)-h/week. A multiple linear regression demonstrated that patients with insufficient PA were significantly more likely to have higher stress (β = 1.84, 95% confidence interval (CI) = 1.03-2.65), anxiety (β = 1.88, 95% CI = 1.81-2.96), and depression (β = 2.53, 95% CI = 0.82-4.24) than those with active PA. A high SII level was a key predictor and was most strongly associated with stress (β = 2.61, 95% CI = 2.02-3.20), anxiety (β = 3.16, 95% CI = 2.37-3.94), and depression (β = 3.72, 95% CI = 2.49-4.96) compared to those who had low SII levels. Notably, additive interaction results showed that combining insufficient PA and a high SII level had a significantly escalated 1.71-fold risk of stress, 1.82-fold risk of anxiety, and 2.69-fold risk of depression. Active PA and a low SII had a positive synergistic effect of decreasing psychological problems.

Eating Disorders in the Time of the COVID-19 Pandemic: A Perspective.

Due to the COVID-19 pandemic, current epidemiological conditions may exacerbate the risk of new-onset, recurrence and relapse of eating disorders. This perspective aims to better analyse the phenomenon. Some data suggest that new-onset and recurrence/relapse of eating disorders are increasing due to the pandemic. Government restrictions, self-confinement, social isolation, restriction to healthcare facilities access, delayed access to diagnosis and cure, fear of contagion, distress and difficulties related to the telemedicine approach contribute to this burden. The Immune system dysfunction usually observed in undernourishment (e.g., anorexia nervosa) could delay the diagnosis of respiratory infections, including COVID-19, and predispose to possible bacterial superinfections. Conversely, patients with binge eating, obesity or metabolic syndrome are susceptible to high-grade systemic inflammation and poor prognosis once the infection has occurred. More detailed data combining research on eating disorders and COVID-19 are required despite some evidence. Many data show that telemedicine has beneficial aspects, but its impact on long-term mental health is still poorly understood. Short- and long-term consequences of COVID-19 in patients with eating disorders are unknown, but they will likely become more apparent over time. Working on emotion regulating strategies in a post-pandemic world, when people have inadequate control over the background of negative emotions, could be a future treatment strategy. Long-term studies with a larger sample size are essential to assess the long-term consequences of the blockade on patients and their healthcare providers and identify useful strategies to improve clinical management.

Relapsing pericarditis: Peripheral blood neutrophilia, lymphopenia and high neutrophil-to-lymphocyte ratio herald acute attacks, high-grade inflammation, multiserosal involvement, and predict multiple recurrences.

To identify peripheral blood cellular correlates of active pericarditis and to verify whether peripheral blood neutrophils, lymphocytes and the neutrophil to-lymphocyte ratio (NLR) are associated with disease phenotype or prognosis. Observational prospective study on a cohort of 63 patients with idiopathic pericarditis followed for 12 months after each pericarditis recurrence. Two distinct analyses were performed: the "index attack" analysis focused on the first pericarditis episode in each patient, while the "all attacks" analysis included all episodes occurring during the study. Absolute and relative neutrophilia and lymphopenia, together with high NLR, were observed during active pericarditis, as compared with disease remission, at both analyses. Neutrophils showed a positive correlation with plasma C-reactive protein levels, while lymphocyte count showed a negative correlation. Relative neutrophil count was higher, and lymphocyte count lower in patients with pleural effusion; a higher NLR and lower absolute lymphocyte count were observed in those with peritoneal involvement. No correlations were found between peripheral blood neutrophil or lymphocyte counts and size of pericardial effusion, or with the presence of myocardial involvement. Peripheral neutrophilia, lymphopenia and NLR during acute attacks predicted the number of recurrences in the following 12 months. Peripheral blood neutrophilia and lymphopenia are typical of acute idiopathic pericarditis. Acute attacks of pericarditis are associated with neutrophilia and lymphopenia, as compared with disease remission. During acute attacks, neutrophilia and lymphopenia reflect the extent of serosal inflammation and could help to customize therapeutic management after remission has been achieved.

Lysophosphatidylcholines modulate immunoregulatory checkpoints in peripheral monocytes and are associated with mortality in people with acute liver failure

Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway. Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined invitro. LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls. Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors. We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes invitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach.

Immunosenescence in Aging-Related Vascular Dysfunction.

The immunosenescence-related disproportion in T lymphocytes may have important consequences for endothelial dysfunction, which is a key event in vascular aging. The study was designed to assess the prognostic values of the inflammatory-immune profile to better predict and prevent vascular diseases associated with old age. Eighty individuals aged 70.9 ± 5.3 years were allocated to a low- (LGI) or high-grade inflammation (HGI) group based on CRP (&lt;3 or ≥3 mg/L) as a conventional risk marker of cardiovascular diseases. Significant changes in inflammatory and endothelium-specific variables IL-1β, IL-6, TNFα, oxLDL, H2O2, NO, 3-nitrotyrosine, and endothelial progenitor cells (OR 7.61, 95% CI 2.56-29.05, p &lt; 0.0001), confirmed their interplay in vascular inflammation. The flow-cytometry analysis demonstrated a high disproportion in T lymphocytes CD4+ and CD8+ between LGI and HGI groups. CRP was &lt;3 mg/mL for the CD4/CD8 ratio within the reference values ≥ 1 or ≤2.5, unlike for the CD4/CD8 ratio &lt; 1 and &gt;2.5. The odds ratios for the distribution of CD4+ (OR 5.98, 95% CI 0.001-0.008, p &lt; 0.001), CD8+ (OR 0.23, 95% CI 0.08-0.59, p &lt; 0.01), and CD8CD45RO+ T naïve cells (OR 0.27, 95% CI 0.097-0.695, p &lt; 0.01) and CD4/CD8 (OR 5.69, 95% CI 2.07-17.32, p &lt; 0.001) indicated a potential diagnostic value of T lymphocytes for clinical prognosis in aging-related vascular dysfunction.

Isoprenaline and salbutamol inhibit pyroptosis and promote mitochondrial biogenesis in arthritic chondrocytes by downregulating β-arrestin and GRK2.

Rheumatoid arthritis and osteoarthritis overlap many molecular mechanisms of cartilage destruction. Wear and tear in cartilage is chondrocyte-mediated, where chondrocytes act both as effector and target cells. In current study, role of β2-AR was studied in chondrocytes both in vitro and in vivo. High grade inflammation in vitro and in vivo disease models led to decline in anti-inflammatory β2-AR signaling and use of β2-AR agonist attenuated arthritis symptoms. Detailed analysis in chondrocytes revealed that Isoprenaline (ISO) and Salbutamol (SBT) increased cell viability and relative Bcl-2 expression, meanwhile, decreased proteins levels of TNF-α, IL-6 and IL-8 in arthritic chondrocytes when compared with control, respectively. SBT preserved physiological concentration of antioxidant enzymes (CAT, POD, SOD and GSH) in cartilage homogenates and ISO inhibited IL-1β-mediated genotoxicity in arthritic chondrocytes. Moreover, β2-AR agonist increased mitochondrial biogenesis and proteoglycan biosynthesis by upregulating the gene expression of PGC1-α, NRF2 and COL2A1, Acan, respectively. ISO and SBT inhibited extracellular matrix (ECM) degradation by downregulating the gene expression of MMP1, MMP3, MMP9 and ADAMTS5 in vitro and in vivo study. In mechanism, β2-AR agonists decreased β-arrestin and GRK2 pathway, and as a result mice receiving SBT did not exhibit severe disease. Hence our data suggest β2-AR agonist administered at disease onset can inhibit receptor internalization by downregulating the expression of β-arrestin and GRK2 in chondrocytes.