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Background: Neoadjuvant chemoradiation therapy (NCRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC); approximately 80% of patients do not achieve complete response. Identifying prognostic factors predictive of survival in these patients to guide further management is needed. The intratumoural lymphocytic response (ILR), peritumoural lymphocytic reaction (PLR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PtLR) are correlated with the tumour microenvironment and cancer-related systemic inflammation. This study aimed to explore the ability of the ILR, PLR, NLR, and PtLR to predict survival in LARC patients without a complete response to NCRT. Methods: Sixty-nine patients who underwent NCRT and surgery were retrospectively reviewed. The ILR and PLR were assessed in surgical specimens, and the NLR and PtLR were calculated using pre- and post-NCRT blood count data. The Kaplan–Meier method and Cox regression analyses were performed for survival analysis. Results: A high PLR and high post-NCRT NLR and PtLR were significantly associated with better prognosis. Lymphovascular invasion (LVI), post-NCRT neutrophil count, and lymphocyte count were significant predictors of overall survival. LVI and the PLR were independent predictors of disease-free survival. Conclusions: NCRT-induced local and systemic immune responses are favourable prognostic predictors in LARC patients without complete response to NCRT.

Variable patterns of disease progression are typically observed in patients with idiopathic pulmonary fibrosis (IPF). We sought to determine the prognostic capacity of blood cell count indexes, derived from routine complete blood cell (CBC) count, in a cohort of IPF patients. The neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) were calculated at baseline in a consecutive series of 82 IPF patients followed for four years. After adjusting for age, gender, body mass index, smoking status, and disease stage, only the AISI was significantly associated with mortality (HR 1.0013, 95% CI 1.0003–1.0023, p = 0.015). Patients with AISI &lt, 434 and ≥434 had a median survival from the diagnosis of 35.3 ± 15.2 and 26.6 ± 16.3 months (p = 0.015), and a four-year survival rate of 54% and 34%, respectively. The AISI, easily derivable from routine laboratory tests, is independently associated with mortality in patients with IPF. Prospective studies in larger cohorts are required to confirm this association.

Bariatric surgery (BS) results in metabolic pathway recalibration. We have identified potential biomarkers in plasma of people achieving type 2 diabetes mellitus (T2DM) remission after BS. Longitudinal analysis was performed on plasma from 10 individuals following Roux-en-Y gastric bypass (n = 7) or sleeve gastrectomy (n = 3). Sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) was done on samples taken at 4 months before (baseline) and 6 and 12 months after BS. Four hundred sixty-seven proteins were quantified by SWATH-MS. Principal component analysis resolved samples from distinct time points after selection of key discriminatory proteins: 25 proteins were differentially expressed between baseline and 6 months post-surgery, 39 proteins between baseline and 12 months. Eight proteins (SHBG, TF, PRG4, APOA4, LRG1, HSPA4, EPHX2 and PGLYRP) were significantly different to baseline at both 6 and 12 months post-surgery. The panel of proteins identified as consistently different included peptides related to insulin sensitivity (SHBG increase), systemic inflammation (TF and HSPA4—both decreased) and lipid metabolism (APOA4 decreased). We found significant changes in the proteome for eight proteins at 6- and 12-months post-BS, and several of these are key components in metabolic and inflammatory pathways. These may represent potential biomarkers of remission of T2DM.

Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation and increased production of reactive oxygen species (ROS), particularly superoxide. Concomitantly released nitric oxide (NO) then reacts with superoxide, leading to the formation of reactive nitrogen species (RNS), predominantly peroxynitrite. Sepsis-induced ROS and RNS can reduce the bioavailability of NO, mediating renal microcirculatory abnormalities, localized tissue hypoxia and mitochondrial dysfunction, thereby initiating a propagating cycle of cellular injury culminating in AKI. In this review, we discuss the various sources of ROS during sepsis and their pathophysiological interactions with the immune system, microcirculation and mitochondria that can lead to the development of AKI. We also discuss the therapeutic utility of N-acetylcysteine and potential reasons for its efficacy in animal models of sepsis, and its inefficacy in ameliorating oxidative stress-induced organ dysfunction in human sepsis. Finally, we review the pre-clinical studies examining the antioxidant and pleiotropic actions of vitamin C that may be of benefit for mitigating septic AKI, including future implications for clinical sepsis.

(1) Background: The prediction of recurrent events after acute myocardial infarction (AMI) does not sufficiently integrate systemic inflammation, coronary morphology or ventricular function in prediction algorithms. We aimed to evaluate the accuracy of inflammatory biomarkers, in association with angiographical and echocardiographic parameters, in predicting 1-year MACE after revascularized AMI. (2) Methods: This is an extension of a biomarker sub-study of the VIP trial (NCT03606330), in which 225 AMI patients underwent analysis of systemic vulnerability and were followed for 1 year. Hs-CRP, MMP-9, IL-6, I-CAM, V-CAM and E-selectin were determined at 1 h after revascularization. The primary end-point was the 1-year MACE rate. (3) Results: The MACE rate was 24.8% (n = 56). There were no significant differences between groups in regard to IL-6, V-CAM and E-selectin. The following inflammatory markers were significantly higher in MACE patients: hs-CRP (11.1 ± 13.8 vs. 5.1 ± 4.4 mg/L, p = 0.03), I-CAM (452 ± 283 vs. 220.5 ± 104.6, p = 0.0003) and MMP-9 (2255 ± 1226 vs. 1099 ± 706.1 ng/mL p = 0.0001). The most powerful predictor for MACE was MMP-9 of &gt, 1155 ng/mL (AUC-0.786, p &lt, 0.001) even after adjustments for diabetes, LVEF, acute phase complications and other inflammatory biomarkers. For STEMI, the most powerful predictors for MACE included I-CAM &gt, 239.7 ng/mL, V-CAM &gt, 877.9 ng/mL and MMP-9 &gt, 1393 ng/mL. (4) Conclusions: High levels of I-CAM and MMP-9 were the most powerful predictors for recurrent events after AMI for the overall study population. For STEMI subjects, the most important predictors included increased levels of I-CAM, V-CAM and MMP-9, while none of the analyzed parameters had proven to be predictive. Inflammatory biomarkers assayed during the acute phase of AMI presented a more powerful predictive capacity for MACE than the LVEF.

Background: Interest is growing in the dynamic role of gut microbiome disturbances in human health and disease. No direct evidence is yet available to link gut microbiome dysbiosis to endometrial cancer. This review aims to understand any association between microbiome dysbiosis and important risk factors of endometrial cancer, high estrogen levels, postmenopause and obesity. Methods: A systematic search was performed with PubMed as primary database. Three separate searches were performed to identify all relevant studies. Results: Fifteen studies were identified as highly relevant and included in the review. Eight articles focused on the relationship with obesity and eight studies focused on the menopausal change or estrogen levels. Due to the heterogeneity in patient populations and outcome measures, no meta-analysis could be performed. Both the menopausal change and obesity were noted to enhance dysbiosis by reducing microbiome diversity and increasing the Firmicutes to Bacteroidetes ratio. Both also incurred estrobolome changes, leading to increased systemic estrogen levels, especially after menopause. Furthermore, microbiome dysbiosis was reported to be related to systemic inflammation through toll-like receptor signaling deficiencies and overexpression of pro-inflammatory cytokines. Conclusions: This review highlights that the female gut microbiome is intrinsically linked to estrogen levels, menopausal state and systemic inflammation, which indicates gut microbiome dysbiosis as a potential hallmark for risk stratification for endometrial cancer. Studies are needed to further define the role the gut microbiome plays in women at risk for endometrial cancer.

Syndrome of undifferentiated recurrent fever (SURF) is a heterogeneous group of autoinflammatory diseases (AID) characterized by self-limiting episodes of systemic inflammation without a confirmed molecular diagnosis, not fulfilling the criteria for periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. In this review, we focused on the studies enrolling patients suspected of AID and genotyped them with next generation sequencing technologies in order to describe the clinical manifestations and treatment response of published cohorts of patients with SURF. We also propose a preliminary set of indications for the clinical suspicion of SURF that could help in everyday clinical practice.

International audience; Reports on the association of periodontal disease (PD) with systemic lupus erythematosus (SLE) have regularly been published. PD is a set of chronic inflammatory conditions linked to a dysbiotic microbial biofilm, which affects the periodontal tissues, resulting eventually in their destruction and contributing to systemic inflammation. SLE is a multi-system chronic inflammatory autoimmune disease that has a wide range of clinical presentations, touching multiple organ systems. Many epidemiological studies have investigated the two-way relationship between PD and SLE, though their results are heterogeneous. SLE and PD are multifactorial conditions and many biological-based hypotheses suggest common physiopathological pathways between the two diseases, including genetics, microbiology, immunity, and environmental common risk factors. By focusing on recent clinical and translational research, this review aimed to discuss and give an overview of the relationship of SLE with PD, as well as looking at the similarities in the immune-pathological aspects and the possible mechanisms connecting the development and progression of both diseases.

Patients with sepsis-associated encephalopathy (SAE) can develop convulsive or nonconvulsive seizures. The cytokine storm and the overwhelming systemic inflammation trigger the electric circuits that promote seizures. Several neurologic symptoms, associated with this disease, range from mild consciousness impairment to coma. Focal or generalized convulsive seizures are frequent in sepsis, although nonconvulsive seizures (NCS) are often misdiagnosed and prevalent in SAE. In order to map the trigger zone in all patients that present focal or generalized seizures and also to detect NCS, EEG is indicated but continuous EEG (cEEG) is not very widespread; timing, duration, and efficacy of this tool are still unknown. The long-term risk of seizures in survivors is increased. The typical stepwise approach of seizures management begins with benzodiazepines and follows with anticonvulsants up to anesthetic drugs such as propofol or thiopental, which are able to induce burst suppression and interrupt the pathological electrical circuits. This narrative review discusses pathophysiology, clinical presentation, diagnosis and treatment of seizures in sepsis.

Background: Rheumatoid arthritis (RA) occurs more often in elderly individuals. Elderly onset RA (EORA) (onset &gt, 60 years) encompasses a specific subset of patients if compared with young onset RA (YORA) (onset at a younger age). There is a need to define reliable, simple markers to properly assess the inflammatory activity of RA. Hematological markers of systemic inflammation (Platelet-To-Lymphocyte (PLR) and Neutrophil-To-Lymphocyte (NLR) ratios) are novel measures of the inflammatory response. The goal of the study was to analyze the course of EORA vs. YORA patients and to assess associations between systemic and clinical disease activity markers, including PLR and NLR, in different subsets of patients. PLR and NLR have not previously been assessed in EORA and YORA. Methods: The study group consisted of 113 consecutive patients (63 EORA and 50 YORA). The following assessments were performed: joint counts, Disease Activity Score (DAS28), complete blood cell counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Results: EORA was characterized by significantly higher disease activity markers (conventional inflammatory and clinical), a lower rate of remission or low disease activity, and less frequent use of biological drugs and glucocorticoids. The NLR and PLR were positively correlated with disease activity markers. The PLR was significantly lower in EORA compared with in YORA. Conclusion: EORA and YORA patients differed significantly. In EORA, conventional disease activity markers were higher, the PLR was significantly lower.

Over the last decade, increased research into the cognizance of the gut–liver–brain axis in medicine has yielded powerful evidence suggesting a strong association between alcoholic liver diseases (ALD) and the brain, including hepatic encephalopathy or other similar brain disorders. In the gut–brain axis, chronic, alcohol-drinking-induced, low-grade systemic inflammation is suggested to be the main pathophysiology of cognitive dysfunctions in patients with ALD. However, the role of gut microbiota and its metabolites have remained unclear. Eubiosis of the gut microbiome is crucial as dysbiosis between autochthonous bacteria and pathobionts leads to intestinal insult, liver injury, and neuroinflammation. Restoring dysbiosis using modulating factors such as alcohol abstinence, promoting commensal bacterial abundance, maintaining short-chain fatty acids in the gut, or vagus nerve stimulation could be beneficial in alleviating disease progression. In this review, we summarize the pathogenic mechanisms linked with the gut–liver–brain axis in the development and progression of brain disorders associated with ALD in both experimental models and humans. Further, we discuss the therapeutic potential and future research directions as they relate to the gut–liver–brain axis.

Background&mdash, Postoperative serum C-reactive protein (CRP) is an important diagnostic parameter for systemic inflammation and reflects surgical trauma. While trends and normal trajectories after total knee (TKA) or hip arthroplasty (THA) are established, there is no reference standard for shoulder arthroplasty (SA). Therefore, the aim of this study was to research CRP trends and influencing factors following SA. Methods&mdash, This retrospective study analyzed postoperative serum CRP levels and trajectories in 280 patients following SA. Influence of prosthesis design, sex, operating time, BMI, and humeral augmentation with bone cement were analyzed using descriptive statistics and (non-) parametric testing. Results&mdash, There is a CRP trend with a peak on day two or three, with a subsequent decrease until day seven. Reverse and stemmed prostheses show a statistically higher CRP peak than stemless prostheses or hemiarthroplasties (HA). There was no influence of gender, body mass index (BMI), operating time, or bone cement. Conclusion&mdash, The presented findings may contribute to a better understanding of the postoperative CRP course after SA. The results of this retrospective study should be validated by a prospective study design in the future.

Whether the COVID-19 pandemic may have modified the clinical planning and course in bronchiectasis patients remains to be fully elucidated. We hypothesized that the COVID-19 pandemic may have influenced the management and clinical outcomes of bronchiectasis patients who were followed up for 12 months. In bronchiectasis patients (n = 30, 23 females, 66 years), lung function testing, disease severity [FEV1, age, colonization, radiological extension, dyspnea (FACED), exacerbation (EFACED)] and dyspnea scores, exacerbation numbers and hospitalizations, body composition, sputum microbiology, and blood analytical biomarkers were determined at baseline and after a one-year follow-up. Compared to baseline (n = 27, three patients dropped out), in bronchiectasis patients, a significant increase in FACED and EFACED scores, number of exacerbations, and erythrocyte sedimentation rate (ESR) was observed, while FEV1, ceruloplasmin, IgE, IgG, IgG aspergillus, IgM, and IgA significantly decreased. Patients presenting colonization by Pseudomonas aeruginosa (PA) remained unchanged (27%) during follow-up. In bronchiectasis patients, FEV1 declined only after a one-year follow-up along with increased exacerbation numbers and disease severity scores, but not hospitalizations. However, a significant decrease in acute phase-reactants and immunoglobulins was observed at the one-year follow-up compared to baseline. Despite the relatively small cohort, the reported findings suggest that lung function impairment may not rely entirely on the patients’ inflammatory status.

Sj&ouml, gren&rsquo, s syndrome (SS) is a chronic systemic inflammation disease with clinical presentation of dry eye, dry mouth, and polyarthralgia. Active inflammation is associated with an increased risk of associated arterial stiffness or subclinical atherosclerosis-related cardiovascular events. We used the longitudinal health insurance database of Taiwan, which includes one million participants, to evaluate the relationship between the clinical medication of hydroxychloroquine (HCQ) and the development of coronary artery disease (CAD). In total, 1674 patients with SS receiving HCQ medication were included after exclusion for previous CAD. Altogether, 1142 SS patients were included for evaluation after follow-up for more than one year. After adjusting for age, gender, medications, and chronic comorbidities, a significantly decreased hazard ratio (HR) for developing CAD was found among SS patients with higher medication possession ratio (MPR) of HCQ (HR = 0.49, 95% confidence interval, CI: 0.26&ndash, 0.94) when compared with low MPR of HCQ. A low HR for CAD was observed in SS patients with a high cumulative dose of at least 100,267 mg of HCQ (HR = 0.25, 95% CI: 0.09&ndash, 0.66). Long-term HCQ therapy may decrease the HR of CAD in SS patients. The significant cardiovascular protective effect of HCQ therapy was observed in our study.

Amyloid-&beta, peptide (A&beta, 1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer&rsquo, s disease. A&beta, 1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1&beta, (IL-1&beta, ) in immune cells within and out of the nervous system. Known interaction partners of A&beta, 1-42 are &alpha, 7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of A&beta, 1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1&beta, by canonical and non-canonical agonists of nAChRs containing subunits &alpha, 7, &alpha, 9, and/or &alpha, 10. Here, we tested the hypothesis that A&beta, 1-42 modulates this inhibitory cholinergic mechanism. Lipopolysaccharide-primed monocytic U937 cells and human mononuclear leukocytes were stimulated with the P2X7 receptor agonist 2&prime, (3&prime, )-O-(4-benzoylbenzoyl)adenosine-5&prime, triphosphate triethylammonium salt (BzATP) in the presence or absence of nAChR agonists and A&beta, 1-42. IL-1&beta, concentrations were measured in the supernatant. A&beta, 1-42 dose-dependently (IC50 = 2.54 &micro, M) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1&beta, release by monocytic cells, whereas reverse A&beta, 42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory A&beta, 1-42 function that enables monocytic IL-1&beta, release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of A&beta, 1-42 in the context of sterile systemic inflammation.

Amyloid-β peptide (Aβ1-42), the cleavage product of the evolutionary highly conserved amyloid precursor protein, presumably plays a pathogenic role in Alzheimer’s disease. Aβ1-42 can induce the secretion of the pro-inflammatory cytokine intereukin-1β (IL-1β) in immune cells within and out of the nervous system. Known interaction partners of Aβ1-42 are α7 nicotinic acetylcholine receptors (nAChRs). The physiological functions of Aβ1-42 are, however, not fully understood. Recently, we identified a cholinergic mechanism that controls monocytic release of IL-1β by canonical and non-canonical agonists of nAChRs containing subunits α7, α9, and/or α10. Here, we tested the hypothesis that Aβ1-42 modulates this inhibitory cholinergic mechanism. Lipopolysaccharide-primed monocytic U937 cells and human mononuclear leukocytes were stimulated with the P2X7 receptor agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine-5′-triphosphate triethylammonium salt (BzATP) in the presence or absence of nAChR agonists and Aβ1-42. IL-1β concentrations were measured in the supernatant. Aβ1-42 dose-dependently (IC50 = 2.54 µM) reversed the inhibitory effect of canonical and non-canonical nicotinic agonists on BzATP-mediated IL-1β-release by monocytic cells, whereas reverse Aβ42-1 was ineffective. In conclusion, we discovered a novel pro-inflammatory Aβ1-42 function that enables monocytic IL-1β release in the presence of nAChR agonists. These findings provide evidence for a novel physiological function of Aβ1-42 in the context of sterile systemic inflammation.

Infections with SARS-CoV-2 can result in severe clinical manifestations. As such patients present with systemic inflammation, we studied the prevalence and predictive value of anemia of inflammation (AI) or functional iron deficiency (FID), originating from immune-mediated alterations of iron homeostasis. Within this retrospective analysis of 259 hospitalized patients with COVID-19, we found that, upon admission, 24.7% were anemic, with the majority suffering from AI (68.8%). Anemia was associated with a significantly higher in-hospital mortality (OR 3.729 (95%CI 1.739&ndash, 7.995), p = 0.001) but not an increased frequency of intensive care unit (ICU) admission or need for mechanical ventilation. FID was present in 80.0% of patients upon admission, linked to more advanced inflammation and associated with significantly longer hospital stay. Notably, a ferritin/transferrin ratio &gt, 10 predicted a five-fold higher risk of ICU admission and an eight-fold higher risk of the need for mechanical ventilation. Anemia and alterations of iron homeostasis are highly prevalent in hospitalized COVID-19 patients. Iron metabolism biomarkers and hemoglobin can contribute to risk stratification of patients, as initial anemia is associated with increased mortality, whereas alterations of iron homeostasis with a higher ferritin/transferrin ratio reflect more advanced inflammation and predicts subsequent insufficient pulmonary oxygenation with the need for ICU admission and mechanical ventilation.

Background: While systemic inflammation is recognized as playing a central role in the pathogenesis of organ failures in patients with liver cirrhosis, less is known about its relevance in the development of classical hepatic decompensation. Aim: To characterize the relationship between systemic inflammation, hemodynamics, and anemia with decompensation of liver cirrhosis. Methods: This is a post-hoc analysis of a cohort study of outpatients with advanced liver fibrosis or cirrhosis. Results: Analysis included 338 patients of whom 51 patients (15%) were hospitalized due to decompensation of liver cirrhosis during a median follow-up time of six months. In univariate analysis, active alcoholism (p = 0.002), model of end-stage liver disease (MELD) score (p = 0.00002), serum IL-6 concentration (p = 0.006), heart rate (p = 0.03), low arterial blood pressure (p &lt, 0.05), maximal portal venous flow (p = 0.008), and low hemoglobin concentration (p &lt, 0.00001) were associated with hospitalization during follow-up. Multivariate analysis revealed an independent association of low hemoglobin (OR = 0.62, 95% CI = 0.51&ndash, 0.78, p = 0.001) and serum IL-6 concentration (OR = 1.02, 95% CI = 1.01&ndash, 1.04, p = 0.03)&mdash, but not of hemodynamic parameters&mdash, with hepatic decompensation. An inverse correlation between hemoglobin concentration and portal venous flow (R = &minus, 0.362, p &lt, 0.0001) was detected for the non-hospitalized patients. Accuracy of baseline hemoglobin levels for predicting hospitalization (AUC = 0.84, p &lt, 0.000001) was high. Conclusion: Anemia and systemic inflammation, rather than arterial circulatory dysfunction, are strong and independent predictors of hepatic decompensation in outpatients with liver cirrhosis.

Background: Ocular involvement in Psoriatic Arthritis (PsA) patients is mainly associated with uveitis but there remains a paucity of data on dry eye and retinal abnormalities. We aimed to analyze dry eye and subclinical retinal abnormalities in a cohort of PsA patients sine-psoriasis (PsO). Methods: PsA patients sine-PsO were enrolled. Best-corrected-visual-acuity, ocular-surface-disease-index (OSDI), Schirmer test, tear film breakup-time, standard-automated-perimetry (SAP, mean deviation&mdash, MD, pattern standard deviation&mdash, PSD), fundus-perimetry (FP), and spectral-domain-optical-coherence-tomography (SD-OCT) were performed. Results: A total of 80 eyes from 40 PsA patients with moderate-severe disease activity, and 70 eyes from 35 healthy control (HC) were evaluated. Higher dry eye prevalence occurred in PsA than HC (p &lt, 0.0001). ESR was positively related with OSDI (p &lt, 0.001) and negatively related with Schirmer (p = 0.007). In PsA, SAP registered higher MD (p &lt, 0.0001) and higher PSD (p = 0.005) in comparison with HC. PSD resulted positively correlated with ESR (p = 0.04) and CRP (p = 0.01), while MD showed a negative correlation with CRP (p = 0.01). Both FP mean differential sensitivity and mean defect were lower in PsA then HC (p &lt, 0.0001). In PsA, FP differential sensitivity was directly related with cumulative steroids (p = 0.02). Conclusions: In PsA patients sine-PsO, dry eye and subclinical abnormalities in visual functions occurred being potentially related to systemic inflammation.

Both obstructive sleep apnea (OSA) and obesity are major health issues that contribute to increased systemic inflammation in children. To date, adenotonsillectomy (AT) is still the first-line treatment for childhood OSA. However, the relationships among and predictive values of obesity, inflammation, and OSA severity have not been comprehensively investigated. This prospective study investigated body mass index (BMI), serum inflammatory markers, and OSA severity before and after AT in 60 pediatric patients with OSA. At baseline, differences in levels of interleukin-6, interleukin-9, basic fibroblast growth factor, platelet-derived growth factor-BB, as well as regulated on activation, normal T cell expressed and secreted (RANTES) were significant among the various weight status and OSA severity subgroups. After 3 months postoperatively, the differences in these inflammatory markers diminished along with a decrease in OSA severity while obesity persisted. The rate of surgical cure (defined as postoperative obstructive apnea-hypopnea index &lt, 2.0 and obstructive apnea index &lt, 1.0) was 62%. Multivariate analysis revealed that age, BMI z-score, granulocyte-macrophage colony-stimulating factor, monocyte chemotactic protein-1, and RANTES independently predicted surgical cure. Despite the significant reductions in inflammatory markers and OSA severity after AT, an inter-dependent relationship between obesity and OSA persisted. In addition to age and BMI, several inflammatory markers helped to precisely predict surgical cure.

Several studies suggest that variations in the concentration of plasma glycoproteins can influence cellular changes in a large number of diseases. In recent years, proton nuclear magnetic resonance (1H-NMR) has played a major role as an analytical tool for serum and plasma samples. In recent years, there is an increasing interest in the characterization of glycoproteins through 1H-NMR in order to search for reliable and robust biomarkers of disease. The objective of this review was to examine the existing studies in the literature related to the study of glycoproteins from an analytical and clinical point of view. There are currently several techniques to characterize circulating glycoproteins in serum or plasma, but in this review, we focus on 1H-NMR due to its great robustness and recent interest in its translation to the clinical setting. In fact, there is already a marker in H-NMR representing the acetyl groups of the glycoproteins, GlycA, which has been increasingly studied in clinical studies. A broad search of the literature was performed showing a general consensus that GlycA is a robust marker of systemic inflammation. The results also suggested that GlycA better captures systemic inflammation even more than C-reactive protein (CRP), a widely used classical inflammatory marker. The applications reviewed here demonstrated that GlycA was potentially a key biomarker in a wide range of diseases such as cancer, metabolic diseases, cardiovascular risk, and chronic inflammatory diseases among others. The profiling of glycoproteins through 1H-NMR launches an encouraging new paradigm for its future incorporation in clinical diagnosis.

This proof-of-concept study aimed to evaluate a novel method of flow cytometry-based quantification of neutrophil extracellular traps (NETs) in septic shock patients and to identify possible interactions between the number of free-circulating NETs and alterations of the coagulatory system. Patients suffering from septic shock, a matched control group (CTRL), and patients suffering from systemic inflammation after cardiac (CABG) or major abdominal surgery (MAS) were enrolled in this prospective proof-of-concept study. Compared to the matched controls, free-circulating NETs were significantly elevated in septic shock and postsurgical patients (data are presented in median (IQR)), septic shock: (2.7 (1.9&ndash, 3.9), CABG: 2.7 (2.1&ndash, 3.7), MAS: 2.7 (2.1&ndash, CTRL: 1.6 (1&ndash, 2), CTRL vs. septic shock: p = 0.001, CTRL vs. CABG: p &lt, 0.001, CTRL vs. MAS: p &lt, 0.001). NETs correlated positively with FIBTEM mean clot firmness (MCF) in septic shock patients (r = 0.37, p &lt, 0.01) while they correlated negatively in surgical patients (CABG: r = &minus, 0.28, p &lt, 0.01, MAS: r = &minus, 0.25, p = 0.03). Flow-cytometric quantification of NETs showed a significant increase in free-circulating NETs under inflammatory conditions. Furthermore, this study hints to an association of the number of NETs with hypercoagulation in septic shock patients and hypocoagulation in surgery-induced inflammation.

Sodium&ndash, glucose co-transporter 2 inhibitors (iSGLT2) have been linked to a considerable reduction in cardiovascular risk in patients with type 2 diabetes (T2D), but the precise molecular mechanisms are still elusive. We aimed to evaluate the effects of the iSGLT2 empagliflozin on systemic inflammation and its potential antioxidant properties. This is an observational, prospective follow-up study of a cohort of fifteen patients with T2D who received 10 mg/day of empagliflozin according to standard clinical care. Measures at baseline, 12 and 24 weeks were taken. Metabolic and anthropometric parameters were evaluated. Production of mitochondrial superoxide, glutathione content, and glutathione s-reductase and catalase mRNA levels were measured in leukocytes. Serum levels of myeloperoxidase, hs-CRP and IL-10 were determined. In addition to decreased body weight and reduced glucose and HbA1c levels, we observed a reduction in superoxide production in leukocytes of diabetic patients and increased glutathione content, prominently after 24 weeks of empagliflozin treatment. Leukocyte expression of glutathione s-reductase and catalase, and serum levels of IL-10 were enhanced at 24 weeks of empagliflozin treatment. Concomitantly, reduced hs-CRP and myeloperoxidase levels were seen. This study provides evidence of the antioxidant and anti-inflammatory properties of empagliflozin treatment in humans, which may contribute to its beneficial cardiovascular effects.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated chronic liver disease. It is characterised by high 28-day mortality, the presence of one or more organ failures (OFs) and a variable but severe grade of systemic inflammation. Despite the peculiarity of each one, every definition proposed for ACLF recognizes it as a proper clinical entity. In this paper, we provide an overview of the diagnostic criteria proposed by the different scientific societies and the clinical characteristics of the syndrome. Established and experimental treatments are also described. Among the former, the most relevant are directed to support organ failures, treat precipitating factors and carry out early assessment for liver transplantation (LT). Further studies are needed to better clarify pathophysiology of the syndrome and discover new therapies.

Systemic inflammation and hypercoagulopathy are known pathophysiological processes of coronavirus disease 2019 (COVID-19), particularly in patients with known cardiovascular disease or its risk factors (CVD). However, whether a cumulative assessment of these biomarkers at admission could contribute to the prediction of in-hospital outcomes remains unknown. The CLAVIS-COVID registry was a Japanese nationwide retrospective multicenter observational study, supported by the Japanese Circulation Society. Consecutive hospitalized patients with pre-existing CVD and COVID-19 were enrolled. Patients were stratified by the tertiles of CRP and D-dimer values at the time of admission. Multivariable Cox proportional hazard models were constructed. In 461 patients (65.5% male, median age, 70.0), the median baseline CRP and D-dimer was 58.3 (interquartile range, 18.2–116.0) mg/L and 1.5 (interquartile range, 0.8–3.0) mg/L, respectively. Overall, the in-hospital mortality rate was 16.5%, and the rates steadily increased in concordance with both CRP (5.0%, 15.0%, and 28.2%, respectively p &lt, 0.001) and D-dimer values (6.8%, 19.6%, and 22.5%, respectively p = 0.001). Patients with the lowest tertiles of both biomarkers (CRP, 29.0 mg/L, D-dimer, 1.00 mg/L) were at extremely low risk of in-hospital mortality (0% until day 50, and 1.4% overall). Conversely, the elevation of both CRP and D-dimer levels was a significant predictor of in-hospital mortality (Hazard ratio, 2.97, 95% confidence interval, 1.57–5.60). A similar trend was observed when the biomarker threshold was set at a clinically relevant threshold. In conclusion, the combination of these abnormalities may provide a framework for rapid risk estimation for in-hospital COVID-19 patients with CVD.

Alterations of intestinal microbiota play a significant role in the pathogenesis of psoriasis. Dysbiosis may cause disruption of the intestinal barrier, which contributes to immune activation by translocation of microbial antigens and metabolites. Intestinal fatty acid binding protein (I-FABP) serves as a biomarker of enterocyte damage. The aim of this study was to investigate clinical and metabolic factors affecting plasma concentration of I-FABP in patients with psoriasis. Eighty patients with psoriasis and 40 control subjects were enrolled in the study. Serum I-FABP (243.00 (108.88&ndash, 787.10) vs. 114.38 (51.60&ndash, 241.60) pg/ml, p &lt, 0.001) and neutrophil to lymphocyte ratio (NLR, 2.59 (1.96&ndash, 3.09) vs. 1.72 (1.36&ndash, 47 2.11), p &lt, 0.01) were significantly increased in patients with psoriasis compared to controls. A significant positive correlation was found between I-FABP and body mass index (BMI) (r = 0.82, p &lt, 0.001), Psoriasis Area Severity Index (PASI) (r = 0.78, p &lt, 0.001) and neutrophil to lymphocyte ratio (NLR) (r = 0.24, p &lt, 0.001). Rising quartiles of I-FABP were associated with increasing values of BMI, PASI and NLR. The results of the logistic regression model confirmed an increased risk of higher disease severity with I-FABP concentration &ndash, odds ratio 3.34 per 100 pg/mL I-FABP increase. In conclusion, intestinal integrity in patients with psoriasis is affected by obesity, severity of the disease and systemic inflammation. The modulation of gut barrier may represent a new therapeutic approach for psoriasis.

Background: Metabolic syndrome is associated with low-grade systemic inflammation, which is a key driver of premature atherosclerosis. We characterized immune cell behavior in metabolic syndrome, its consequences, and the potential involvement of the CX3CL1/CX3CR1 and CCL2/CCR2 chemokine axes. Methods: Whole blood from 18 patients with metabolic syndrome and 21 age-matched controls was analyzed by flow cytometry to determine the leukocyte immunophenotypes, activation, platelet-leukocyte aggregates, and CX3CR1 expression. ELISA determined the plasma marker levels. Platelet-leukocyte aggregates adhesion to tumor necrosis factor-&alpha, (TNF&alpha, )-stimulated arterial endothelium and the role of CX3CL1/CX3CR1 and CCL2/CCR2 axes was investigated with the parallel-plate flow chamber. Results: When compared with the controls, the metabolic syndrome patients presented greater percentages of eosinophils, CD3+ T lymphocytes, Mon2/Mon3 monocytes, platelet-eosinophil and -lymphocyte aggregates, activated platelets, neutrophils, eosinophils, monocytes, and CD8+ T cells, but lower percentages of Mon1 monocytes. Patients had increased circulating interleukin-8 (IL-8) and TNF&alpha, levels and decreased IL-4. CX3CR1 up-regulation in platelet-Mon1 monocyte aggregates in metabolic syndrome patients led to increased CX3CR1/CCR2-dependent platelet-Mon1 monocyte adhesion to dysfunctional arterial endothelium. Conclusion: We provide evidence of generalized immune activation in metabolic syndrome. Additionally, CX3CL1/CX3CR1 or CCL2/CCR2 axes are potential candidates for therapeutic intervention in cardiovascular disorders in metabolic syndrome patients, as their blockade impairs the augmented arterial platelet-Mon1 monocyte aggregate adhesiveness, which is a key event in atherogenesis.

Background: Patients with chronic obstructive pulmonary disease (COPD) often suffer from multiple morbidities, which occur in clusters and are sometimes related to accelerated aging. This study aimed to assess the disease specificity of comorbidity clusters in COPD and their association with a biomarker of accelerated aging as a potential mechanistic factor. Methods: Body composition, metabolic, cardiovascular, musculoskeletal, and psychological morbidities were objectively evaluated in 208 COPD patients (age 62 &plusmn, 7 years, 58% males, FEV1 50 &plusmn, 16% predicted) and 200 non-COPD controls (age 61 &plusmn, 7 years, 45% males). Based on their presence and severity, the morbidities were clustered to generate distinct clusters in COPD and controls. Telomere length in circulating leukocytes was compared across the clusters. Results: (co)morbidities were more prevalent in COPD patients compared to controls (3.9 &plusmn, 1.7 vs. 2.4 &plusmn, 1.5, p &lt, 0.05). A &ldquo, Psychologic&rdquo, and &ldquo, Cachectic&rdquo, cluster were only present in the COPD population. &ldquo, Less (co)morbidity&rdquo, &ldquo, Cardiovascular&rdquo, Metabolic&rdquo, clusters were also observed in controls, although with less complexity. Telomere length was reduced in COPD patients, but did not differ between the (co)morbidity clusters in both populations. Conclusions: Two COPD-specific comorbidity clusters, a &ldquo, cluster, were identified and warrant further studies regarding their development. Accelerated aging was present across various multimorbidity clusters in COPD.

Primary hypercholesterolemia (PH) is associated with a low grade systemic inflammation that is likely the main driver of premature atherosclerosis. Accordingly, we characterized the immune cell behaviour in PH and its potential consequences. Whole blood from 22 PH patients and 21 age-matched controls was analysed by flow cytometry to determine the percentage of leukocyte immunophenotypes, activation, and platelet-leukocyte aggregates. Plasma markers were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The adhesion of platelet-leukocyte aggregates to tumor necrosis factor-&alpha, (TNF&alpha, )-stimulated arterial endothelium was investigated using the dynamic model of the parallel-plate flow chamber. PH patients presented greater percentage of Mon 3 monocytes, Th2 and Th17 lymphocytes, activated platelets, and leukocytes than controls. The higher percentages of circulating platelet-neutrophil, monocyte and lymphocyte aggregates in patients caused increased platelet-leukocyte adhesion to dysfunctional arterial endothelium. Circulating CXCL8, CCL2, CX3CL1, and IL-6 levels positively correlated with key lipid features of PH, whereas negative correlations were found for IL-4 and IL-10. We provide the first evidence that increased platelet and leukocyte activation leads to elevated platelet-leukocyte aggregates in PH and augmented arterial leukocyte adhesiveness, a key event in atherogenesis. Accordingly, modulation of immune system behavior might be a powerful target in the control of further cardiovascular disease in PH.

COVID-19 is currently considered an inflammatory disease affecting the entire organism. In severe forms, an augmented inflammatory response leads to the fulminant “cytokine storm”, which may result in severe multisystemic end-organ damage. Apart from the acute inflammatory response, it seems that chronic inflammation also plays a major role in the clinical evolution of COVID-19 patients. Pre-existing inflammatory conditions, such as those associated with chronic coronary diseases, type 2 diabetes mellitus or obesity, may be associated with worse clinical outcomes in the context of COVID-19 disease. These comorbidities are reported as powerful predictors of poor outcomes and death following COVID-19 disease. Moreover, in the context of chronic coronary syndrome, the cytokine storm triggered by SARS-CoV-2 infection may favor vulnerabilization and rupture of a silent atheromatous plaque, with consequent acute coronary syndrome, leading to a sudden deterioration of the clinical condition of the patient. This review aims to present the current status of knowledge regarding the link between COVID-19 mortality, systemic inflammation and several major diseases associated with poor outcomes, such as cardiovascular diseases, diabetes and obesity.

Background: Chronic obstructive pulmonary disease (COPD) is a progressive condition characterized by chronic airway inflammation and lung parenchyma damage. Systemic inflammation and oxidative stress also play a role in the pathogenesis of COPD. Serum albumin is a negative acute-phase protein with antioxidant effects and an important marker of malnutrition. The aim of this meta-analysis was to investigate differences in serum albumin concentrations between patients with stable COPD and non-COPD subjects. Methods: A systematic search was conducted, using the terms “albumin” and “chronic obstructive pulmonary disease” or “COPD”, in the electronic databases PubMed and Web of Science, from inception to May 2020. Results: Twenty-six studies were identified on a total of 2554 COPD patients and 2055 non-COPD controls. Pooled results showed that serum albumin concentrations were significantly lower in COPD patients (standard mean difference, SMD = −0.50, 95% CI −0.67 to −0.32; p < 0.001). No significant differences were observed in SMD of serum albumin concentrations between COPD patients with forced expiratory volume in the 1st second (FEV1) < 50% and those with FEV1 > 50%. Conclusions: Our systematic review and meta-analysis showed that serum albumin concentrations are significantly lower in patients with stable COPD compared to non-COPD controls. This supports the presence of a deficit in systemic anti-inflammatory and antioxidant defense mechanisms in COPD.

The cryopyrin-associated periodic syndromes (CAPS) are usually caused by heterozygous NLRP3 gene variants, resulting in excessive inflammasome activation with subsequent overproduction of interleukin (IL)-1β. The CAPS spectrum includes mild, moderate, and severe phenotypes. The mild phenotype is called familial cold autoinflammatory syndrome (FCAS), the moderate phenotype is also known as Muckle–Wells syndrome (MWS), and the neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous articular syndrome (CINCA) describes the severe phenotype. The CAPS phenotypes display unspecific and unique clinical signs. Dermatologic, musculoskeletal, ocular, otologic, and neurologic disease symptoms combined with chronic systemic inflammation are characteristic. Nevertheless, making the CAPS diagnosis is challenging as several patients show a heterogeneous multi-system clinical presentation and the spectrum of genetic variants is growing. Somatic mosaicisms and low-penetrance variants lead to atypical clinical symptoms and disease courses. To avoid morbidity and to reduce mortality, early diagnosis is crucial, and a targeted anti-IL-1 therapy should be started as soon as possible. Furthermore, continuous and precise monitoring of disease activity, organ damage, and health-related quality of life is important. This review summarizes the current evidence in diagnosis and management of patients with CAPS.

Background: We previously identified increased tissue localization of monomeric C-reactive protein (mCRP) in the infarcted cortical brain tissue of patients following ischaemic stroke. Here, we investigated the relationship of mCRP expression in haemorrhagic stroke, and additionally examined the capacity of mCRP to travel to or appear at other locations within the brain that might account for later chronic neuroinflammatory or neurodegenerative effects. Methods: Immunohistochemistry was performed on Formalin-fixed, paraffin-embedded archived brain tissue blocks obtained at autopsy from stroke patients and age-matched controls. We modelled mCRP migration into the brain after haemorrhagic stroke by infusing mCRP (3.5 µg) into the hippocampus of mice and localized mCRP with histological and immunohistochemistry methods. Results: On human tissue in the early stages of haemorrhage, there was no staining of mCRP. However, with increasing post-stroke survival time, mCRP immunostaining was associated with some parenchymal brain cells, some stroke-affected neurons in the surrounding areas and the lumen of large blood vessels as well as brain capillaries. Further from the peri-haematoma region, however, mCRP was detected in the lumen of micro-vessels expressing aquaporin 4 (AQP4). In the hypothalamus, we detected clusters of neurons loaded with mCRP along with scattered lipofuscin-like deposits. In the peri-haematoma region of patients, mCRP was abundantly seen adjacent to AQP4 immunoreactivity. When we stereotactically injected mCRP into the hippocampus of mice, we also observed strong expression in distant neurones of the hypothalamus as well as cortical capillaries. Conclusions: mCRP is abundantly expressed in the brain after haemorrhagic stroke, directly impacting the pathophysiological development of the haematoma. In addition, it may have indirect effects, where the microcirculatory system appears to be able to carry it throughout the cortex as far as the hypothalamus, allowing for long-distance effects and damage through its capacity to induce inflammation and degenerate neuronal perivascular compartments., This work was supported by a grant of the Romanian National Authority for Science Research and Innovation, CNCS—UEFISCDI, project number TE-41/2020 and from a grant from the Competitiveness Operational Programme 2014-2020: C-reactive protein therapy for stroke-associated dementia: ID_P_37_674, My SMIS code: 103432 contract 51/05.09.2016, and also and a grant from the Spanish Ministry of Science and Innovation SAF2016-77703 to CS. This research was also supported by the Stroke Chair-(project number R-1441-164).

White blood cell counts (WBC), lymphocyte-to-monocyte ratio (LMR), and monocyte-to-high-density lipoprotein cholesterol ratio (MHR) are used as chronic inflammation markers. Polycystic ovary syndrome (PCOS) is a constellation of systemic inflammation linked to central obesity (CO), hyperandrogenism, insulin resistance, and metabolic syndrome. The waist-to-height ratio (WHtR) constitutes a highest-concordance anthropometric CO measure. This study aims to access WBC, LMR, and MHR in PCOS and healthy subjects, with or without CO. Establishing relationships between complete blood count parameters, high-sensitivity C-reactive protein (hsCRP), and hormonal, lipid and glucose metabolism in PCOS. To do this, WBC, LMR, MHR, hsCRP, anthropometric, metabolic, and hormonal data were analyzed from 395 women of reproductive age, with and without, PCOS. Correlations between MHR, and dysmetabolism, hyperandrogenism, and inflammation variables were examined. No differences were found in WBC, LMR, MHR, and hsCRP between PCOS and controls (p &gt, 0.05). PCOS subjects with CO had higher hsCRP, MHR, and WBC, and lower LMR vs. those without CO (p &lt, 0.05). WBC and MHR were also higher in controls with CO vs. without CO (p &lt, 0.001). MHR correlated with anthropometric, metabolic, and endocrine parameters in PCOS. WHtR appeared to strongly predict MHR in PCOS. We conclude that PCOS does not independently influence WBC or MHR when matched for CO. CO and dysmetabolism may modify MHR in PCOS and control groups.

Background: An accurate measurement of disease activity is essential for the appropriate management of a patient with rheumatoid arthritis (RA). Hematological markers of systemic inflammation (Neutrophil-to-Lymphocyte (NLR), Platelet-to-Lymphocyte (PLR) and Lymphocyte-to-Monocyte (LMR) ratios) are reported to be novel, sensitive measures of inflammatory response, in addition to conventional markers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Disease Activity Score (DAS28)). The goal of the study was to assess the relationship of NLR, PLR, and LMR with ultrasonography (US) parameters of disease activity in RA patients. Methods: The study group consisted of 126 consecutive RA patients (100 women, 26 men). The following assessments were performed: joint counts, DAS28, complete blood cell counts, ESR, CRP, and US of 24 small joints. Results: NLR and PLR were significantly positively correlated with all US parameters of disease activity (Grey Scale US, Power Doppler US, and Global scores). The mean values of NLR and PLR were significantly higher in patients with poor prognostic factors: moderate/high vs. low disease activity (NLR: p &lt, 0.001, PLR: p = 0.007), anti-CCP positive vs. anti-CCP negative (NLR: p = 0.01, PLR: p = 0.006). In multiple regression tests, significant correlations were confirmed for: NLR and DAS28 (p = 0.04), and CRP (p = 0.001), PLR and Power Doppler US (p = 0.04), and ESR (p = 0.02). No correlation was found for LMR. Conclusion: NLR and PLR are associated with US disease activity parameters and may serve as reliable, inexpensive markers, with prognostic significance in RA.