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Background Cardiopulmonary bypass (CPB) is often associated with degrees of complex inflammatory response mediated by various cytokines. This response can, in severe cases, lead to systemic hypotension and organ dysfunction. Cytokine removal might therefore improve outcomes of patients undergoing cardiac surgery. CytoSorb® (Cytosorbents, NJ, USA) is a recent device designed to remove cytokine from the blood using haemoadsorption (HA). This trial aims to evaluate the potential of CytoSorb® to decrease peri-operative cytokine levels in cardiac surgery. Methods We have conducted a single-centre pilot randomized controlled trial in 30 patients undergoing elective cardiac surgery and deemed at risk of complications. Patients were randomly allocated to either standard of care ( n  = 15) or CytoSorb® HA ( n  = 15) during cardiopulmonary bypass (CPB). Our primary outcome was the difference between the two groups in cytokines levels (IL-1a, IL-1b, IL-2, IL-4, IL-5, IL-6, IL-10, TNF-α, IFN-γ, MCP-1) measured at anaesthesia induction, at the end of CPB, as well as 6 and 24 h post-CPB initiation. In a consecutive subgroup of patients (10 in HA group, 11 in control group), we performed cross-adsorber as well as serial measurements of coagulation factors’ activity (antithrombin, von Willebrand factor, factor II, V, VIII, IX, XI, and XII). Results Both groups were similar in terms of baseline and peri-operative characteristics. CytoSorb® HA during CPB was not associated with an increased incidence of adverse event. The procedure did not result in significant coagulation factors’ adsorption but only some signs of coagulation activation. However, the intervention was associated neither with a decrease in pro- or anti-inflammatory cytokine levels nor with any improvement in relevant clinical outcomes. Conclusions CytoSorb® HA during CPB was not associated with a decrease in pro- or anti-inflammatory cytokines nor with an improvement in relevant clinical outcomes. The procedure was feasible and safe. Further studies should evaluate the efficacy of CytoSorb® HA in other clinical contexts. Trial registration ClinicalTrials.gov NCT02775123 . Registered 17 May 2016.

Background and Objectives: Periodontal inflammation, often linked to oral microbiota dysbiosis dominated by pathogenic bacteria, remains a significant challenge in periodontitis management. Traditional periodontal therapies primarily reduce the bacterial load but fail to restore the microbiota balance. Probiotics offer a promising therapeutic adjunct with their ability to enhance beneficial bacteria. This study investigates the effects of probiotics on the oral microbiota, inflammatory markers (IL-1β, TNF-α), and clinical parameters (gingival index, bleeding index, and periodontal pocket depth). Materials and Methods: In this pilot study, 80 patients with moderate-to-severe periodontitis were assigned to two groups. Group A received standard periodontal therapy (non-surgical periodontal therapy (NSPT)) with probiotic supplementation (Lactobacillus reuteri, 2 × 10⁹ CFU daily for 8 weeks), and Group B received standard treatment with a placebo. Microbiological changes were assessed via quantitative PCR, while inflammatory markers (IL-1β, TNF-α) were analyzed using ELISA. Clinical parameters, including the gingival index (GI), bleeding index (BI), and periodontal pocket depth (PPD), were measured at baseline (T0), 4 weeks (T1), and 8 weeks (T2) using standardized methods. Results: Probiotic therapy (Group A) significantly reduced the pathogenic bacteria and increased the beneficial bacteria levels compared to the placebo (p < 0.01). Inflammatory markers decreased by 37% (IL-1β) and 42% (TNF-α), while clinical parameters improved, with reductions in the gingival and bleeding indices (−1.5, −1.3) and a 2 mm decrease in the periodontal pocket depth (p < 0.01). Conclusions: Probiotics, as an adjunct to periodontal therapy, effectively restore the microbiota balance, reduce inflammation, and improve clinical outcomes in periodontitis.

Background Accelerating orthodontic treatment is crucial in reducing complications such as root resorption, caries, and oral hygiene compromise, especially in adults. Piezocision and corticotomy are surgical techniques that accelerate tooth movement by causing bone remodelling. This study compares and evaluates changes in Interleukin-1β (IL-1β) levels in gingival crevicular fluid (GCF) following piezocision and corticotomy-facilitated orthodontics in adults. Aim To assess and compare IL-1β fluctuations in GCF of adult patients undergoing corticotomy and piezocision-assisted orthodontic treatment. Materials & methods This split-mouth study consisted of 16 adult patients (18–25 years) who needed premolar extractions. One half of the maxilla was randomly assigned for piezocision and the other half for corticotomy. GCF samples were taken from maxillary canines at varying time intervals: pre-treatment (T0), before surgery (T1), and 24 h (T2), 7 days (T3), and 21 days (T4) following surgery. IL-1β concentrations were quantified using an ELISA kit, and statistical analysis was done. Results IL-1β concentrations were highest at 24 h after surgery (T2) in both groups and decreased steadily by day 21 (T4), but were still elevated above pre-treatment levels. IL-1β concentrations were significantly greater in the piezocision group at all time points after surgery than in the corticotomy group ( p  < 0.001), reflecting a more intense inflammatory reaction and greater bone cell metabolism. Conclusion This study suggests that piezocision elicits a more intense biological response than corticotomy, as reflected by higher IL-1β levels in gingival crevicular fluid. While this may indicate a potential for enhanced bone remodelling and accelerated tooth movement, further research is needed to directly correlate cytokine expression with the rate of orthodontic tooth movement.

Traumatic brain injury (TBI) is one of the most common neurological disorders worldwide. We aimed to investigate the efficacy of high-dose vitamin D3 on inflammatory biomarkers in patients with moderate to severe TBI. Thirty-five moderate to severe TBI patients were randomly assigned to intervention and control groups. Patients in the intervention group received a single intramuscular (IM) dose of 300,000 IU vitamin D. The primary endpoints were interleukin levels (IL-1β and IL-6), and the secondary endpoints were changes in neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), Glasgow Coma scale (GCS), and Glasgow Outcome Scale-Extended (GOS-E) scores compared between intervention and control arms of the study. The linear Generalized Estimating Equations were used for trend analysis and evaluating the association of independent factors to each outcome. The results revealed a significant decrease in IL-1β levels (-2.71±3.02, in the intervention group: P=0.001 vs. -0.14±3.70, in the control group: P=0.876) and IL-6 (-88.05±148.45, in the intervention group: P=0.0001 vs. -35.54±175.79, in the control groupL P=0.325) 3 days after the intervention. The improvement in the GCS score (P=0.001), reduction in NLR (P=0.001) and PLR (P=0.002), and improvement in the GOS-E score (P=0.039) was found to be greater in the vitamin D3 arm of the study than the control group. Administration of high-dose vitamin D3 in the acute phase of TBI could be effective in lowering the inflammatory markers and improving the level of consciousness and long-term performance outcomes. IRCT20180522039777N2.

Introduction This study aims to compare the efficacy of ropivacaine and lidocaine in the treatment of temporomandibular joint (TMJ) disorders, with the goal of exploring a more effective treatment for TMJ disorders. Methods Patients with Wilkes stage III and IV unilateral TMJ disorders were enrolled in the study. 0.5% ropivacaine was used for local anesthesia in group A, 2% lidocaine was used in group B. Sodium hyaluronate was injected after supra-articular lavage in both groups. The patients’ general conditions, pain scores, and maximum opening before and after treatment were collected, the time of onset and maintenance of anesthesia, and the levels of inflammatory factors IL-1β and IL-6 in the joint lavage fluid were detected. Results Study showed that the onset of anesthesia was faster and longer maintained in group A. The decrease in IL-1β was more pronounced in group A (16.08 ± 3.10) than in group B (18.03 ± 2.84), p  < 0.05. At 2 months after treatment, the joint clicking rate was higher in group A (75%) compared to group B (35%), p  < 0.05. At 3 months after treatment, the joint clicking rate was higher in group A (76.69%) compared to group B (40%) and the maximum mouth opening was greater in group A (45.00 ± 2.38) compared to group B (41.73 ± 4.18), p  < 0.05. There were no statistically significant differences in VAS score and lateral excursion in group A compared with group B at 2 months and 3 months after treatment. Conclusions Compared with lidocaine, the application of ropivacaine combined with sodium hyaluronate supra-articular lavage for the treatment of temporomandibular joint disorder is more clinically effective. Clinical trials Registration Number ChiCTR2300075241 (30/08/2023).

Neuroinflammation is the local reaction of the brain to infection, trauma, toxic molecules or protein aggregates. The brain resident macrophages, microglia, are able to trigger an appropriate response involving secretion of cytokines and chemokines, resulting in the activation of astrocytes and recruitment of peripheral immune cells. IL-1β plays an important role in this response; yet its production and mode of action in the brain are not fully understood and its precise implication in neurodegenerative diseases needs further characterization. Our results indicate that the capacity to form a functional NLRP3 inflammasome and secretion of IL-1β is limited to the microglial compartment in the mouse brain. We were not able to observe IL-1β secretion from astrocytes, nor do they express all NLRP3 inflammasome components. Microglia were able to produce IL-1β in response to different classical inflammasome activators, such as ATP, Nigericin or Alum. Similarly, microglia secreted IL-18 and IL-1α, two other inflammasome-linked pro-inflammatory factors. Cell stimulation with α-synuclein, a neurodegenerative disease-related peptide, did not result in the release of active IL-1β by microglia, despite a weak pro-inflammatory effect. Amyloid-β peptides were able to activate the NLRP3 inflammasome in microglia and IL-1β secretion occurred in a P2X7 receptor-independent manner. Thus microglia-dependent inflammasome activation can play an important role in the brain and especially in neuroinflammatory conditions.

Background Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. Methods/Design This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at > 10 4 colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a ‘biomarker-guided recommendation on antibiotics’ in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to ‘routine use of antibiotics’ in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. Discussion This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP. Trial registration ISRCTN65937227 . Registered on 22 August 2013. ClinicalTrials.gov, NCT01972425 . Registered on 24 October 2013.

To explore severity and progression biomarkers, we examined the clinical relevance of multiple cytokines and mediators involved in the inflammatory response in periodontitis. A cohort of 68 patients was enrolled in the study and periodontal status assessed by the current classification of periodontal diseases. Immune mediators present in saliva, of both patients and healthy controls, were quantified using a Legendplex-13 panel. Clinic parameters were significantly higher in PD patients compared with HC, with a strong significant association with the disease severity (stage) (p < 0.001), but not with progression (grade). The panel of immune mediators evidenced elevated levels of pro-inflammatory cytokines IL-6 and IL-1β as disease established (p < 0.01). IL-1β/IL-1RA ratio was increased in PD patients, being associated with disease stage. An anti-inflammatory response was spotted by higher IL-10. Lower levels of IL-23 and IP-10 were associated with disease severity. No significant statistical differences were found by grade classification. Moreover, salivary IL-1β and IL-6 exhibited significant positive correlations with several clinical measurements (PI, BOP, PPD, CAL), while IP-10 showed a statistical negative correlation with BOP, PPD, and CAL. These insights highlight the complexity of the periodontitis inflammatory network and the potential of cytokines as biomarkers for refined diagnostic and therapeutic strategies.

Background There is a compelling unmet medical need for biomarker-based models to risk-stratify patients with acute respiratory distress syndrome. Effective stratification would optimize participant selection for clinical trial enrollment by focusing on those most likely to benefit from new interventions. Our objective was to develop a prognostic, biomarker-based model for predicting mortality in adult patients with acute respiratory distress syndrome. Methods This is a secondary analysis using a cohort of 252 mechanically ventilated subjects with the diagnosis of acute respiratory distress syndrome. Survival to day 7 with both day 0 (first day of presentation) and day 7 sample availability was required. Blood was collected for biomarker measurements at first presentation to the intensive care unit and on the seventh day. Biomarkers included cytokine-chemokines, dual-functioning cytozymes, and vascular injury markers. Logistic regression, latent class analysis, and classification and regression tree analysis were used to identify the plasma biomarkers most predictive of 28-day ARDS mortality. Results From eight biologically relevant biomarker candidates, six demonstrated an enhanced capacity to predict mortality at day 0. Latent-class analysis identified two biomarker-based phenotypes. Phenotype A exhibited significantly higher plasma levels of angiopoietin-2, macrophage migration inhibitory factor, interleukin-8, interleukin-1 receptor antagonist, interleukin-6, and extracellular nicotinamide phosphoribosyltransferase (eNAMPT) compared to phenotype B. Mortality at 28 days was significantly higher for phenotype A compared to phenotype B (32% vs 19%, p  = 0.04). Conclusions An adult biomarker-based risk model reliably identifies ARDS subjects at risk of death within 28 days of hospitalization.

Background/Aims: Increased production of multiple pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, plays an essential pathogenic role in the progression of systemic lupus erythematosus (SLE). Recent studies have characterized itaconate as a novel and potent nuclear-factor-E2-related factor 2 (Nrf2) activator that activates Nrf2 signaling by alkylating cysteine residues on Keap1 (Kelch-like ECH-associated protein 1). Methods: THP-1 human macrophages and peripheral blood mononuclear cells (PBMCs) of SLE patients were treated with 4-octyl itaconate (OI). Nrf2 signaling activation was tested by qPCR assay and western blotting. mRNA expression and the production of multiple pro-inflammatory cytokines were tested by qPCR and enzyme-linked immunosorbent assays, respectively. Nuclear factor (NF)-κB activation was tested by the p65 DNA-binding assay. Results: We demonstrated that OI, the cell-permeable derivative of itaconate, induced Keap1-Nrf2 dissociation, Nrf2 protein accumulation, and nuclear translocation, which enabled the transcription and expression of multiple Nrf2-dependentantioxidant enzymes (heme oxygenase-1, NAD(P)H:quinone oxidoreductase 1, and glutamate-cysteine ligase modifier subunit) in THP-1 human macrophages. OI also induced significant Nrf2 activation in SLE patient-derived PBMCs. OI pretreatment inhibited mRNA expression and the production of multiple pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in SLE patient-derived PBMCs and lipopolysaccharide (LPS)-activated THP-1 cells. OI potently inhibited NF-κB activation in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Importantly, Nrf2 silencing (by targeted short hairpin RNA) or knockout (by CRISPR/Cas9 gene-editing method) almost abolished OI-induced anti-oxidant and anti-inflammatory actions in SLE patient-derived PBMCs and LPS-activated THP-1 cells. Conclusion: OI activates Nrf2 signaling to inhibit the production of pro-inflammatory cytokines in human macrophages and SLE patient-derived PBMCs. OI and itaconate could have important therapeutic value for the treatment of SLE.