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BackgroundPrior epidemiological studies have established a correlation between inflammatory cytokines and inflammatory bowel disease (IBD). However, the nature of this relationship remains uncertain. Mendelian randomization (MR) study has the advantages of avoiding confounding and reverse causality compared with traditional observational research.ObjectiveWe aimed to evaluate whether genetically determined circulating levels of cytokines are associated with the risk of IBD by using the MR approach.Materials and methodsWe selected genetic variants associated with circulating levels of 28 cytokines at the genome-wide significance level from a genome-wide association study (GWAS) including 8,293 individuals. Summary-level data for IBD (including Crohn’s disease and ulcerative colitis) were obtained from the International Inflammatory Bowel Disease Genetics Consortium and UK Biobank. We performed the primary analysis using the inverse-variance weighted method, as well as sensitivity analyses to test the stability of our results. We subsequently replicated the results of IBD in the UK Biobank dataset. A reverse MR analysis was also conducted to evaluate the possibility of reverse causation.ResultsGenetically predicted elevated levels of interleukin-17 (IL-17) and monokine induced by interferon-gamma (MIG) were associated with an increased risk of IBD[odds ratio (OR): 1.52, 95% confidence interval (CI):1.10-2.08, P =0.010 for IL-17 and OR: 1.58, 95% CI: 1.24-2.00, P = 1.60×10-4 for MIG]. Moreover, we observed suggestive associations between β-NGF and MIP-1β with the risk of Crohn’s disease (OR: 0.71, 95% CI: 0.52-0.98, P = 0.039) and ulcerative colitis (OR: 1.08, 95% CI: 1.01-1.15, P= 0.019). In the reverse MR study, there was no evidence of causal effects of IBD and these cytokines.ConclusionOur study suggests the potential causal associations of IL-17 and MIG with IBD. Further studies are needed to determine whether IL-17 and MIG or their downstream effectors could be useful in the management of IBD.

Background: Interferon-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) are chemokines recognized as inflammatory biomarkers during HIV-1 infection. We assessed their early and long-term dynamics after initiation of antiretroviral treatment (ART). Methods: Persons with HIV-1 (PWH) aged>18 years starting their first ART in 2015-2021 in a prospective cohort (n=73) were included. IP-10 and MIG plasma levels were quantified using a multiplexed bead-based assay. Results: IP-10 and MIG plasma levels showed a significant and consistent reduction following ART (80% integrase inhibitor [INSTI]-based) initiation, starting at day 20 and maintained throughout the study period (48 months), paralleling the HIV-1 RNA decay and CD4+ count recovery (p<0·001). At baseline, PWH= 50 years, CDC stage C and CD4+ count<350cells/mm3 had higher levels of IP-10 (p=0·022, p=0·001 and p=0·002, respectively) and MIG (p<0·001, p=0·024 and p=0·069, respectively). All of them matched their counterparts several months following ART initiation. MIG levels showed a greater decrease at day 10 in those treated with INSTI (p=0·038). Low-level HIV-1 viremia did not impact MIG or IP-10 levels. Conclusion: Plasma IP-10 and MIG showed an early significant decline following ART initiation, with greater early declines in MIG levels in INSTI-based regimens. These findings suggest a strong impact of HIV-1 viremia on IP-10 and MIG levels. [ABSTRACT FROM AUTHOR]

Background: Autoimmune thyroid disease (AITD) ranks among the most prevalent thyroid diseases, with inflammatory cytokines playing a decisive role in its pathophysiological process. However, the causal relationship between the inflammatory cytokines and AITD remains elusive. Methods: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal connection between AITD and 41 inflammatory cytokines. Genetic variations associated with inflammatory cytokines were sourced from the FinnGen biobank, whereas a comprehensive meta-analysis of genome-wide association studies (GWASs) yielded data on Graves' disease (GD) and Hashimoto thyroiditis. Regarding the MR analysis, the inverse variance-weighted, MR-Egger, and weighted median methods were utilized. Additionally, sensitivity analysis was conducted using MR-Egger regression, MR-pleiotropy residual sum, and outliers. Results: Seven causal associations were identified between inflammatory cytokines and AITD. High levels of tumor necrosis factor-β and low levels of stem cell growth factor-β were indicative of a higher risk of GD. In contrast, high levels of interleukin-12p70 (IL-12p70), IL-13, and interferon-γ and low levels of monocyte chemotactic protein-1 (MCP-1) and TNF-α suggested a higher risk of HD. Moreover, 14 causal associations were detected between AITD and inflammatory cytokines. GD increases the levels of macrophage inflammatory protein-1β, MCP-1, monokine induced by interferon-γ (MIG), interferon γ-induced protein 10 (IP-10), stromal cell-derived factor-1α, platelet-derived growth factor BB, β-nerve growth factor, IL-2ra, IL-4, and IL-17 in blood, whereas HD increases the levels of MIG, IL-2ra, IP-10, and IL-16 levels. Conclusion: Our bidirectional MR analysis revealed a causal relationship between inflammatory cytokines and AITD. These findings offer valuable insights into the pathophysiological mechanisms underlying AITD. [ABSTRACT FROM AUTHOR]

Introduction: Circulating cytokines were considered to play a critical role in the initiation and propagation of sarcopenia and frailty from observational studies. This study aimed to find the casual association between circulating cytokines and sarcopenia and frailty from a genetic perspective by two-sample Mendelian randomization (MR) analysis. Methods: Data for 41 circulating cytokines were extracted from the genome-wide association study dataset of 8,293 European participants. Inverse-variance weighted (IVW) method, MR-Egger, and weighted median method were applied to assess the relationship of circulating cytokines with the risk of aging-related syndromes and frailty. Furthermore, MR-Egger regression was used to indicate the directional pleiotropy, and Cochran's Q test was used to verify the potential heterogeneity. The "leave-one-out" method was applied to visualize whether there was a causal relationship affected by only one anomalous single-nucleotide polymorphisms. Results: Genetic predisposition to increasing levels of interleukin-10 (IL-10), IL-12, and vascular endothelial growth factor (VEGF) was associated with the higher risk of low hand grip strength according to the IVW method [R = 1.05, 95% CI = 1.01-1.10, P = 0.028, false discovery rate (FDR)-adjusted P = 1.000; OR = 1.03, 95% CI = 1.00-1.07, P = 0.042, FDR-adjusted P = 0.784; OR = 1.02, 95% CI = 1.00-1.05, P = 0.038, FDR-adjusted P = 0.567]. Furthermore, genetically determined higher macrophage colony-stimulating factors (M-CSFs) were associated with a lower presence of appendicular lean mass (OR = 1.01, 95% CI = 1.00-1.02, P = 0.003, FDR-adjusted P = 0.103). Monokine induced by interferon-g (MIG) and tumor necrosis factor-beta (TNF-β) were associated with a higher risk of frailty (OR = 1.03, 95% CI = 1.01-1.05, P < 0.0001, FDR-adjusted P = 0.012; OR = 1.01, 95% CI = 1.00-1.03, P = 0.013, FDR-adjusted P = 0.259). In this study, we did not find heterogeneity and horizontal pleiotropy between the circulating cytokines and the risk of frailty and sarcopenia. Conclusion: Genetic predisposition to assess IL-10, IL-12, and VEGF levels was associated with a higher risk of low hand grip strength and M-CSF with the presence of appendicular lean mass. The high levels of TNF-β and MIG were associated with a higher risk of frailty. More studies will be required to explore the molecular biological mechanisms underlying the action of inflammatory factors. [ABSTRACT FROM AUTHOR]

Background: Previous studies have explored the associations between circulating inflammatory cytokines and blinding eye diseases, including glaucoma, cataract and macular degeneration. However, the causality of these associations remains controversial. This study employs a bidirectional Mendelian randomization (MR) study to investigate the causal relationships between 41 circulating inflammatory cytokines and these blinding eye diseases. Methods: Summary data for glaucoma, cataract, macular degeneration and 41 circulating inflammatory cytokines were publicly available. The inverse variance weighted (IVW) method was employed as the main analysis method. Additionally, various sensitivity tests, including MR-Egger regression, weighted median, weight mode, Cochran's Q test, MR pleiotropy Residual Sum and Outlier test, and leave-one-out test, were conducted to evaluate sensitivity and stability of results. Results: The IVW analysis identified six circulating inflammatory cytokines causally associated with the risk of blinding eye diseases: Monokine induced by interferon-gamma (MIG) for glaucoma, interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-10, and platelet derived growth factor BB (PDGFbb) for cataract, and MIG and hepatocyte growth factor (HGF) for macular degeneration. However, it is noteworthy that none of these associations remained significant after Bonferroni correction (p < 0.0004). Reverse MR analyses indicated that cataract may lead to a decrease in vascular endothelial growth factor (VEGF) levels (OR: 3.326 Ã--10-04, 95% CI: 5.198 Ã--10-07 - 2.129 Ã--10-01, p = 0.0151). Conclusion: This study highlights the potential roles of specific inflammatory cytokines in the development of glaucoma, cataract and macular degeneration. Moreover, it suggests that VEGF is likely to be involved in cataract development downstream. These findings offer insights for early prevention and novel therapeutic strategies for these blinding eye diseases. [ABSTRACT FROM AUTHOR]

Objective: Investigating the association between inflammatory cytokines and hypothyroidism remains challenging due to limitations in traditional observational studies. In this study, we employed Mendelian randomization (MR) to assess the causal relationship between 41 inflammatory cytokines and hypothyroidism. Method: Inflammatory cytokines in 30,155 individuals of European ancestry with hypothyroidism and in a GWAS summary containing 8,293 healthy participants were included in the study for bidirectional two-sample MR analysis. We utilized inverse variance weighting (IVW), weighted median (WM), and Mendelian randomization-Egger (MR-Egger) methods. Multiple sensitivity analyses, including MR-Egger intercept test, leave-one-out analysis, funnel plot, scatterplot, and MR-PRESSO, were applied to evaluate assumptions. Results: We found evidence of a causal effect of IL-7 and macrophage inflammatory protein-1β (MIP-1β) on the risk of hypothyroidism, and a causal effect of hypothyroidism on several cytokines, including granulocyte colony-stimulating factor (G-CSF), IL-13, IL-16, IL-2rβ, IL-6, IL-7, IL-9, interferon-γ-inducible protein 10 (IP10), monokine induced by interferon (IFN)-γ (MIG), macrophage inflammatory protein-1β (MIP-1β), stem cell growth factors-β (SCGF-β), stromal cell derived factor-1α (SDF-1α), and tumor necrosis factor-α (TNF-α). Conclusion: Our study suggests that IL-7 and MIP-1β may play a role in the pathogenesis of hypothyroidism, and that hypothyroidism may induce a systemic inflammatory response involving multiple cytokines. These findings may have implications for the prevention and treatment of hypothyroidism and its complications. However, further experimental studies are needed to validate the causal relationships and the potential of these cytokines as drug targets. [ABSTRACT FROM AUTHOR]

Objectives: Previous studies have reported that a few inflammatory cytokines have associations with systemic lupus erythematosus (SLE)--for example, IL-6, IL-17, and macrophage inflammatory protein (MIP). This Mendelian randomization was conducted to further assess the causal correlations between 41 inflammatory cytokines and SLE. Methods: The two-sample Mendelian randomization utilized genetic variances of SLE from a large publicly available genome-wide association study (GWAS) (7,219 cases and 15,991 controls of European ancestry) and inflammatory cytokines from a GWAS summary containing 8,293 healthy participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted method. In addition, multiple sensitivity analyses including MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were simultaneously applied to strengthen the final results. Results: The results indicated that cutaneous T cell-attracting chemokine (CTACK) and IL-17 may be suggestively associated with the risk of SLE (odds ratio, OR: 1.21, 95%CI: 1.04-1.41, p = 0.015; OR: 1.37, 95%CI: 1.03-1.82, p = 0.029). In addition, cytokines including beta nerve growth factor, basic fibroblast growth factor, IL-4, IL-6, interferon gamma-induced protein 10, monokine induced by interferongamma, MIP1b, stromal cell-derived factor-1 alpha, and tumor necrosis factoralpha are suggested to be the consequences of SLE disease (Beta: 0.035, p = 0.014; Beta: 0.021, p = 0.032; Beta: 0.024, p = 0.013; Beta: 0.019, p = 0.042; Beta: 0.040, p = 0.005; Beta: 0.046, p = 0.001; Beta: 0.021, p = 0.029; Beta: 0.019, p = 0.045; Beta: 0.029, p = 0.048). Conclusion: This study suggested that CTACK and IL-17 are probably the factors correlated with SLE etiology, while a couple of inflammatory cytokines are more likely to be involved in SLE development downstream. [ABSTRACT FROM AUTHOR]

Objectives: We analyzed the results of the QuantiFERON Glod Plus assay (QFT) and cytokine patterns associated with active tuberculosis (ATB) among patients with positive QFT. Methods: A total of 195 patients are QFT-positive, among which 24 had an ATB and 171 had a latent tuberculosis infection (LTBI). Interferon-gamma (IFN-γ) secretion was analyzed relative to interleukin-2 (IL-2), IFN-γ inducible protein or CXCL-10 (IP-10), and monokine induced by IFN-γ or CXCL-9 (MIG) secretion, and then compared between two sets of peptide antigens [tube 1 - cluster of differentiation 4 (CD4+) T cell stimulation; tube 2 - CD4+/CD8+ T cell response]. Results: Higher IFN-γ responses were measured in the ATB group (p = 0.0089). The results showed that there was a lower ratio of tube 1/tube 2 IFN-γ concentrations in the ATB group (p = 0.0009), and a median [interquartile ranges (IQR)] difference between the two sets at −0.82 IU/ml (−1.67 to 0.18) vs. −0.07 IU/ml (−0.035 to 0.11, p < 0.0001) in the ATB group compared to the LTBI group, respectively. In addition, patients with low ratios of IL-2/IFN-γ, IP-10/IFN-γ, and MIG/IFN-γ were much more likely to have ATB. Conclusion: High levels of IFN-γ secretion, preferential IFN-γ response in tube 2, and lower secretion of IL-2, IP-10, and MIG release relative to IFN-γ secretion were more likely observed in subjects with ATB. These features of T cell response may be helpful in low prevalence settings to suspect ATB in patients tested positive for IFN-γ release assays (IGRA). [ABSTRACT FROM AUTHOR]

The cytokine release syndrome has been proposed as the driver of inflammation in coronavirus disease 2019 (COVID-19). However, studies on longitudinal cytokine profiles in patients across the whole severity spectrum of COVID-19 are lacking. In this prospective observational study on adult COVID-19 patients admitted to two Hong Kong public hospitals, cytokine profiling was performed on blood samples taken during early phase (within 7 days of symptom onset) and late phase (8 to 12 days of symptom onset). The primary objective was to evaluate the difference in early and late cytokine profiles among patient groups with different disease severity. The secondary objective was to assess the associations between cytokines and clinical endpoints in critically ill patients. A total of 40 adult patients (mild = 8, moderate = 15, severe/critical = 17) hospitalized with COVID-19 were included in this study. We found 22 cytokines which were correlated with disease severity, as proinflammatory Th1-related cytokines (interleukin (IL)-18, interferon-induced protein-10 (IP-10), monokine-induced by gamma interferon (MIG), and IL-10) and ARDS-associated cytokines (IL-6, monocyte chemoattractant protein-1 (MCP-1), interleukin-1 receptor antagonist (IL-1RA), and IL-8) were progressively elevated with increasing disease severity. Furthermore, 11 cytokines were consistently different in both early and late phases, including seven (growth-regulated oncogene-alpha (GRO-α), IL-1RA, IL-6, IL-8, IL-10, IP-10, and MIG) that increased and four (FGF-2, IL-5, macrophage-derived chemokine (MDC), and MIP-1α) that decreased from mild to severe/critical patients. IL-8, followed by IP-10 and MDC were the best performing early biomarkers to predict disease severity. Among critically ill patients, MCP-1 predicted the duration of mechanical ventilation, highest norepinephrine dose administered, and length of intensive care stay. [ABSTRACT FROM AUTHOR]

Background: Prediction of the severity of COVID-19 at its onset is important for providing adequate and timely management to reduce mortality. Objective: To study the prognostic value of damage parameters and cytokines as predictors of severity of COVID-19 using an extensive immunologic profiling and unbiased artificial intelligence methods. Methods: Sixty hospitalized COVID-19 patients (30 moderate and 30 severe) and 17 healthy controls were included in the study. The damage indicators high mobility group box 1 (HMGB1), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine aminotransferase (ALT), extensive biochemical analyses, a panel of 47 cytokines and chemokines were analyzed at weeks 1, 2 and 7 along with clinical complaints and CT scans of the lungs. Unbiased artificial intelligence (AI) methods (logistic regression and Support Vector Machine and Random Forest algorithms) were applied to investigate the contribution of each parameter to prediction of the severity of the disease. Results: On admission, the severely ill patients had significantly higher levels of LDH, IL-6, monokine induced by gamma interferon (MIG), D-dimer, fibrinogen, glucose than the patients with moderate disease. The levels of macrophage derived cytokine (MDC) were lower in severely ill patients. Based on artificial intelligence analysis, eight parameters (creatinine, glucose, monocyte number, fibrinogen, MDC, MIG, C-reactive protein (CRP) and IL-6 have been identified that could predict with an accuracy of 83−87% whether the patient will develop severe disease. Conclusion: This study identifies the prognostic factors and provides a methodology for making prediction for COVID-19 patients based on widely accepted biomarkers that can be measured in most conventional clinical laboratories worldwide. [ABSTRACT FROM AUTHOR]

Increasing human Adenovirus (HAdV) infections complicated with acute respiratory distress syndrome (ARDS) even fatal outcome were reported in immunocompetent adolescent and adult patients. Here, we characterized the cytokine/chemokine expression profiles of immunocompetent patients complicated with ARDS during HAdV infection and identified biomarkers for disease severity/progression. Forty-eight cytokines/chemokines in the plasma samples from 19 HAdV-infected immunocompetent adolescent and adult patients (ten complicated with ARDS) were measured and analyzed in combination with clinical indices. Immunocompetent patients with ARDS caused by severe acute respiratory disease coronavirus (SARS-CoV)-2, 2009 pandemic H1N1 (panH1N1) or bacteria were included for comparative analyses. Similar indices of disease course/progression were found in immunocompetent patients with ARDS caused by HAdV, SARS-CoV-2 or panH1N infections, whereas the HAdV-infected group showed a higher prevalence of viremia, as well as increased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and creatine kinase (CK). Expression levels of 33 cytokines/chemokines were increased significantly in HAdV-infected patients with ARDS compared with that in healthy controls, and many of them were also significantly higher than those in SARS-CoV-2-infected and panH1N1-infected patients. Expression of interferon (IFN)-γ, interleukin (IL)-1β, hepatocyte growth factor (HGF), monokine induced by IFN-γ (MIG), IL-6, macrophage-colony stimulating factor (M-CSF), IL-10, IL-1α and IL-2Ra was significantly higher in HAdV-infected patients with ARDS than that in those without ARDS, and negatively associated with the ratio of the partial pressure of oxygen in arterial blood/fraction of inspired oxygen (PaO2/FiO2). Analyses of the receiver operating characteristic curve (ROC) showed that expression of IL-10, M-CSF, MIG, HGF, IL-1β, IFN-γ and IL-2Ra could predict the progression of HAdV infection, with the highest area under the curve (AUC) of 0.944 obtained for IL-10. Of note, the AUC value for the combination of IL-10, IFN-γ, and M-CSF reached 1. In conclusion, the "cytokine storm" occurred during HAdV infection in immunocompetent patients, and expression of IL-10, M-CSF, MIG, HGF, IL-1β, IFN-γ and IL-2Ra was closely associated with disease severity and could predict disease progression. [ABSTRACT FROM AUTHOR]

Background: Depot Medroxyprogesterone (DMPA) is one of the most widely used contraceptives in Sub-Saharan Africa where HIV incidence is high. We explored the effect of DMPA on the activation of HIV cellular targets and inflammation as a possible mechanism of increased HIV risk with DMPA use. Since sex work is known to affect the immune system, this study aimed to understand the effect of DMPA on the immune system among sex workers and non-sex worker women. Methods: Twenty-seven DMPA-using HIV seronegative female sex workers (FSW) and 30 DMPA-using HIV seronegative non-sex worker (SW) women were enrolled in the study. Twenty-four FSWs and 30 non-sex workers who were not using any hormonal contraception (no HC) were recruited as controls. Blood and cervico-vaginal samples were collected from all participants and assayed for T cell activation and proinflammatory cytokines. Results: Among no HC users, sex workers had lower expression of CD38 and CD69 on blood-derived CD4+ T cells along with lower CD4+CCR5+ cells frequency in the endocervix. Plasma MCP-1, TNFα and IL-17 also had reduced expression in FSW not using HC. Non-sex workers using DMPA had elevated proportions of blood-derived CD4+CD38+, CD4+CD69+ and CD4+HLA-DR+ T cells relative to non-sex workers who were not taking any HC. DMPA-using non-sex workers also had an increased level of plasma interferon gamma (IFN- γ), monokine induced by interferon- γ (MIG) and sCD40L, alongside higher proportion of CD4+CD38+ and CD4+CD69+ T cells at the cervix compared to non-sex workers no-HC controls., Finally, non-sex workers and FSWs using DMPA had similar levels of genital and peripheral CD4+ T cell activation and inflammation. Conclusion: DMPA increased inflammation and expression of activation markers on potential HIV target cells in non-sex workers. These data show that DMPA is a strong immune modulator and its use counteracts the decreased immune activation associated with sex work. These findings suggest that inflammation and increased HIV target cells in blood and at the genital tract may be mechanisms by which DMPA increases susceptibility to HIV. [ABSTRACT FROM AUTHOR]

Adalimumab (ADA), a fully human monoclonal tumor necrosis factor (TNF)-α antibody, is one of the most widely used biologics in the treatment of inflammatory diseases. However, ADA can exacerbate infectious conditions, induce paradoxical reactions such as inflammation, and cause neoplasia. Human T-cell leukemia virus type 1 (HTLV-1) is an infectious agent that induces inflammation and neoplastic infiltration in the eye. To date, numerous HTLV-1 carriers have been treated with adalimumab to suppress inflammation out of necessity, when standard anti-inflammatory drugs such as steroids and immunosuppressive agents have proven inadequate to control the inflammation. Here, we clarify the safety of adalimumab for the eye under HTLV-1 infectious conditions in vitro. We used the adult retinal pigment epithelial cell line (ARPE)-19 cell line as ocular resident cells, and used MT2 and TL-Om1 as HTLV-1-infected cells. ARPE-19 and MT2/TL-Om1 were co-cultured, and then adalimumab was administered. Production of cytokines and chemokines, TNF-α receptor (TNF-R), HTLV-1 proviral load (PVL), and apoptosis were measured to assess the effects of adalimumab. Contact between ARPE-19 and MT2/TL-Om1 produced inflammatory cytokines such as TNF, interleukin (IL)-6, IL-8 and IL-10, and transduced chemokines such as interferon-inducible protein-10 (IP-10), monocyte chemotactic protein-1 (MCP-1), monokine induced by interferon-γ (MIG), and regulated on activation, normal T cell expressed and secreted (RANTES). No inflammatory cytokines and chemokines were exacerbated by adalimumab. Expression of TNF-R on ARPE-19 and MT2/TL-Om1 cells, HTLV-1 PVLs of MT2/TL-Om1 cells, and cell growth rate and apoptotic rate of ARPE-19 were unaffected by adalimumab. In conclusion, adalimumab does not appear to exacerbate HTLV-1-associated inflammatory conditions in the eye or increase PVL in HTLV-1-infected T cells. These data suggest that adalimumab could be used safely for the eye under HTLV-1 infectious conditions from the perspective of in vitro assessment. [ABSTRACT FROM AUTHOR]

Background: Pleural mesothelioma (PM) is a rare cancer with a dismal prognosis. Dual immune checkpoint inhibitors have improved overall survival, but the rate of immune-related adverse events (irAEs) is high. Serum cytokines reflect systemic immune reactions and may serve as biomarkers for irAEs. Patients and methods: Patients with pleural mesothelioma treated with nivolumab and ipilimumab with or without UV1 vaccine in the NIPU study were included. Serum cytokine levels were measured by Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay. Correlations between cytokine levels and irAEs were analyzed by generalized linear mixed models to identify potential diagnostic and predictive biomarkers. Results: Higher levels of MIG, eotaxin, MIP-1α, IP-10, TNF-α, MIP-1β, IL-4, MIF, IL-16, IL-2RA, SCGF.β and PDFG-BB at baseline are associated with increased risk of developing one or more irAEs. In particular, higher baseline levels of MIG are positively associated with thyroiditis and hypophysitis, and elevated levels of IP-10 and MIG to dermatitis. During the course of treatment, higher levels of MIG, eotaxin, MIF, TNF-α, MIP-1β, IL-4 and IL-16 are associated with an ongoing irAE. We found both predictive and diagnostic value of MIF with fatigue and of eotaxin with both colitis and pneumonitis. Higher levels of CTACK is associated with a lower risk of developing hepatitis, both before and after treatment. Conclusions: Elevated levels of certain cytokines, both before and after onset of treatment, correlate with specific irAEs in PM patients receiving ICIs. These cytokines may be used as biomarkers to predict and detect irAES. [ABSTRACT FROM AUTHOR]

Introduction: Evidence on the association of biomarkers of host response to infection with COVID-19 clinical outcomes has focused mainly on hospitalized patients. We investigated the prognostic performance of 39 immune and endothelial activation markers measured early in the course of disease to predict the development of severe COVID-19 and hospitalization. Methods: We conducted a nested case-control study from a randomized clinical trial evaluating the efficacy of COVID-19 convalescent plasma in outpatients aged 50 years or older presenting with mild-to-moderate COVID-19. We selected participants who were hospitalized within 28 days (cases) and who were not (controls) to compare their biomarker levels in plasma samples collected at enrolment. Results: A total of 42 cases and 42 controls were included in this study. The levels of CRP, IL6, IP10, ferritin, IFNα, IL8, IL1RA, MCP1, and RANTES, determined within 7 days of symptoms onset, showed good individual prognostic performance for COVID-19 associated hospitalization by day 28. The biomarkers CRP, IL6, IP10, IL8, IL1RA, and suPAR showed good individual prognostic performance for severe COVID-19. CRP, IL6 and IP10 had the most robust association with both hospitalization and severe COVID-19, with CRP having the highest discriminatory capacity with hospitalization, and IL6 for severe COVID-19. Discussion: Our study shows good prognostic performance of CRP and IL6 for 28-day hospitalization in patients with mild-to-moderate COVID-19, in the absence of clinical criteria for admission upon enrolment. These findings confirm the value of these biomarkers at early stages of COVID-19 disease in the outpatient setting to support management decisions. [ABSTRACT FROM AUTHOR]

Introduction: Dysregulated host cytokine responses to SARS-CoV-2 infection are a primary cause of progression to severe disease, whereas early neutralizing antibody responses are considered protective. However, there are gaps in understanding the early temporal dynamics of these immune responses, and the profile of productive immune responses generated by non-hospitalized people with mild infections in the community. Methods: Here we conducted a prospective cohort study of people with suspected infections/exposures in the US state of North Carolina, before vaccine availability. We recruited participants not only in hospitals/clinics, but also in their homes. With serial sampling, we compared virologic and immunologic factors in 258 community cases versus 114 hospital cases of COVID-19 to define factors associated with severity. Results: We found that high early neutralizing antibodies were associated with lower nasal viral load, but not protection from hospitalization. Cytokine responses were evaluated in 125 cases, with subsets at first versus second week of illness to assess for time-dependent trajectories. The hospital group demonstrated a higher magnitude of serum IL-6, IL-1R antagonist, IP-10, and MIG; prolonged upregulation of IL-17; and lesser downregulation of GROα, IL-1R antagonist, and MCP1, in comparison to the community group suggesting that these factors may contribute to immunopathology. In the second week of illness, 2-fold increases in IL-6, IL-1R antagonist, and IP-10 were associated with 2.2, 1.8, and 10-fold higher odds of hospitalization respectively, whereas a 2-fold increase in IL-10 was associated with 63% reduction in odds of hospitalization (p<0.05). Moreover, antibody responses at 3-6 months post mild SARS-CoV-2 infections in the community revealed long-lasting antiviral IgM and IgA antibodies as well as a stable set point of neutralizing antibodies that were not waning. Discussion: Our data provide valuable temporal cytokine benchmarks to track the progression of immunopathology in COVID-19 patients and guide improvements in immunotherapies. [ABSTRACT FROM AUTHOR]

Introduction: Tuberculosis remains the leading cause of death from infectious diseases among adults worldwide. To date, an overarching review of the immune response to Mtb in humans has not been fully elucidated, with innate immunity remaining poorly understood due to historic focus on adaptive immunity. Specifically, there is a major gap concerning the contribution of the immune system to overall bacterial clearance, particularly residual bacteria. This review aims to describe the time course of interactions between the host immune system and Mtb , from the start of the infection to the development of the adaptive response. Concordantly, we aim to crystallize the pathogenic effects and immunoevasive mechanisms of Mtb. The translational value of animal data is also discussed. Methods: The literature search was conducted in the PubMed, ScienceDirect, and Google Scholar databases, which included reported research from 1990 until 2024. A total of 190 publications were selected and screened, of which 108 were used for abstraction and 86 were used for data extraction. Graphical summaries were created using the narrative information (i.e., recruitment, recognition, and response) to generate clear visual representations of the immune response at the cellular and molecular levels. Results: The key cellular players included airway epithelial cells, alveolar epithelial cells, neutrophils, natural killer cells, macrophages, dendritic cells, T cells, and granulomatous lesions; the prominent molecular players included IFN-γ, TNF-α, and IL-10. The paper also sheds light on the immune response to residual bacteria and applications of the data. Discussion: We provide a comprehensive characterization of the key immune players that are implicated in pulmonary tuberculosis, in line with the organs or compartments in which mycobacteria reside, offering a broad vignette of the immune response to Mtb and how it responds to residual bacteria. Ultimately, the data presented could provide immunological insights to help establish optimized criteria for identifying efficacious treatment regimens and durations for relapse prevention in the modeling and simulation space and wider fields. [ABSTRACT FROM AUTHOR]

Introduction: Patients with Primary Sjögren's syndrome (pSS) are at a higher risk of thyroid disorders than the general population. This retrospective analysis of 202 patients with pSS was conducted to uncover risk factors associated with thyroid involvement and to create a predictive model for this condition. Methods: We analyzed 202 patients with pSS from Guang'anmen Hospital, China Academy of Chinese Medical Sciences, with 105 cases of thyroid involvement and 97 without. The Least Absolute Shrinkage and Selection Operator method was used to identify key variables for our risk model. These variables were then subjected to multivariate logistic regression to develop the model. The accuracy of the model was assessed through the C-index, receiver operating characteristic curves, calibration plots, and decision curve analysis, with internal validation via bootstrapping. Results: High-sensitivity C-reactive protein (HCRP), pulmonary disease, pharyngeal dryness, forgetfulness, night sweats, hyperuricemia, nasal dryness, anxiety, Ro52, and aspartate aminotransferase (AST) were incorporated into the nomogram. The model showed robust discrimination and calibration abilities. Decision curve analysis indicated the clinical utility of our nomogram in intervening on the probability thresholds of thyroid disease. Conclusion: By integrating HCRP, pulmonary disease, pharyngeal dryness, forgetfulness, night sweats, hyperuricemia, nasal dryness, anxiety, Ro52, and AST, our thyroid risk nomogram can predict the risk of thyroid involvement in patients with pSS, aiding in more informed treatment strategies. [ABSTRACT FROM AUTHOR]

Cytokine of interferon-gamma (IFNγ) plays a vital role in the immune response against Mycobacteria tuberculosis (Mtb) infection, yet the specific function of T cells producing IFNγ in this process remains unclear. In this study, we first isolated IFNγ+CD3+ T cells induced by Mtb antigens using surface staining assays. which showed a strong ability to inhibit the growth of intracellular mycobacteria in macrophages. Peripheral blood mononuclear cells (PBMCs) from healthy individuals were then challenged with Bacillus Calmette–Guérin (BCG) or Mtb, respectively, to sort IFNγ-secreting T cells for mRNA sequencing to analyze the gene expression patterns. The results of the integrated data analysis revealed distinct patterns of gene expression between IFNγ+CD3+ T cells induced by the BCG vaccine and those induced by Mtb pathogens. Further, unlike Mtb-induced cells, BCG-induced IFNγ+CD3+ T cells expressed high levels of interleukin-2 (IL-2), which increased the frequencies of these cells and the production of effector cytokines IFNγ and IL-2. Our findings suggested that IFNγ+CD3+ T cells with high IL-2 expression presented potent effector functions to inhibit intracellular Mtb growth, while Mtb infection impaired IL-2 expression in IFNγ+CD3+ T cells. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have suggested an association between blood inflammation-related factors and postherpetic neuralgia. However, the causal relationship between blood inflammation-related factors and postherpetic neuralgia remains unclear. Methods: We employed a bidirectional Two-sample Mendelian randomization (MR) analysis to explore the causal relationship between blood inflammation-related factors and postherpetic neuralgia. The instrumental variables were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. The instrumental variables of the blood inflammation-related factors come from the database numbers GCST004420 to GCST004460 and GCST90029070. Postherpetic neuralgia has 195,191 samples with a total of 16,380,406 single nucleotide polymorphisms (SNPs). MR analyses were performed using inverse-variance weighted, MR-Egger, and weighted median methods. Results: The MR results revealed a significant causal effect of Macrophage Inflammatory Protein 1 Beta (MIP1β) on reducing the risk of postherpetic neuralgia (95%CI = 0.492–0.991, p = 0.044). Additionally, higher levels of interleukin (IL)-10 (95%CI = 0.973–0.998, p = 0.019) and IL-12p70 (95%CI = 0.973–0.997, p = 0.013) were associated with a lower risk of postherpetic neuralgia. Other inflammatory markers showed no significant causal relationship with this condition. Conclusion: This study identifies MIP1β, IL-10, and IL-12p70 as potential therapeutic targets for preventing or treating postherpetic neuralgia, underscoring the need for further research in this area. [ABSTRACT FROM AUTHOR]

Introduction: Pediatric Acute Liver Failure (PALF) presents as a rapidly evolving, multifaceted, and devastating clinical syndrome whose precise etiology remains incompletely understood. Consequently, predicting outcomes--whether survival or mortality--and informing liver transplantation decisions in PALF remain challenging. We have previously implicated High-Mobility Group Box 1 (HMGB1) as a central mediator in PALF-associated dynamic inflammation networks that could be recapitulated in acetaminophen (APAP)-treated mouse hepatocytes (HC) in vitro. Here, we hypothesized that Growth/Differentiation Factor-15 (GDF-15) is involved along with HMGB1 in PALF. Methods: 28 and 23 inflammatory mediators including HMGB1 and GDF15 were measured in serum samples from PALF patients and cell supernatants from wildtype (C57BL/6)mouse hepatocytes (HC) and from cells fromHC-specificHMGB1- null mice (HC-HMGB1-/-) exposed to APAP, respectively. Results were analyzed computationally to define statistically significant and potential causal relationships. Results: Circulating GDF-15 was elevated significantly (P < 0.05) in PALF nonsurvivors as compared to survivors, and together with HMGB1 was identified as a central node in dynamic inflammatory networks in both PALF patients and mouse HC. This analysis also pointed to MIG/CXCL9 as a differential node linking HMGB1 and GDF-15 in survivors but not in non-survivors, and, when combined with in vitro studies, suggested that MIG suppresses GDF-15-induced inflammation. Discussion: This study suggests GDF-15 as a novel PALF outcome biomarker, posits GDF-15 alongside HMGB1 as a central node within the intricate web of systemic inflammation dynamics in PALF, and infers a novel, negative regulatory role for MIG. [ABSTRACT FROM AUTHOR]

The article provides an in-depth analysis of the immune and non-immune mediators involved in the fibrosis pathogenesis of salivary glands in Sjögren's syndrome. It explores the impact of chronic inflammation, immune cell interactions, viral infections, and molecular mechanisms on the development of fibrosis. The document also discusses therapeutic strategies targeting immune cells and fibroblasts to alleviate fibrosis in Sjögren's syndrome, emphasizing the need for further research to understand the complex pathogenesis and develop effective treatments. Additionally, it delves into the correlation of T follicular helper cells with immunopathology, therapeutic options for systemic sclerosis, and the unique expansion of IL-21+ Tfh and Tph cells in Sjögren's syndrome with ectopic germinal centers and malt lymphoma. [Extracted from the article]

Introduction: Previous studies have suggested an association between blood inflammation-related factors and postherpetic neuralgia. However, the causal relationship between blood inflammation-related factors and postherpetic neuralgia remains unclear. Methods: We employed a bidirectional Two-sample Mendelian randomization (MR) analysis to explore the causal relationship between blood inflammationrelated factors and postherpetic neuralgia. The instrumental variables were obtained from a large Genome-wide association study (GWAS) metaanalysis dataset of European descent. The instrumental variables of the blood inflammation-related factors come from the database numbers GCST004420 to GCST004460 and GCST90029070. Postherpetic neuralgia has 195,191 samples with a total of 16,380,406 single nucleotide polymorphisms (SNPs). MR analyses were performed using inverse-variance weighted, MR-Egger, and weighted median methods. Results: The MR results revealed a significant causal effect of Macrophage Inflammatory Protein 1 Beta (MIP1β) on reducing the risk of postherpetic neuralgia (95%CI = 0.492-0.991, p = 0.044). Additionally, higher levels of interleukin (IL)-10 (95%CI = 0.973-0.998, p = 0.019) and IL-12p70 (95%CI = 0.973-0.997, p = 0.013) were associated with a lower risk of postherpetic neuralgia. Other inflammatory markers showed no significant causal relationship with this condition. Conclusion: This study identifies MIP1β, IL-10, and IL-12p70 as potential therapeutic targets for preventing or treating postherpetic neuralgia, underscoring the need for further research in this area. [ABSTRACT FROM AUTHOR]

Background: Integrated traditional Chinese medicine and biomedicine is an effective method to treat tuberculosis (TB). In our previous research, traditional Chinese medicine preparation NiuBeiXiaoHe (NBXH) achieved obvious anti-TB effects in animal experiments and clinical practice. However, the action mechanism of NBXH has not been elucidated. Method: Peripheral blood mononuclear cells (PBMCs) were collected to extract mRNA and differentially expressed (DE) genes were obtained using gene microarray technology. Finally, GEO databases and RT-qPCR were used to verify the results of expression profile. Result: After MTB infection, most upregulated DE genes in mice were immunerelated genes, including cxcl9, camp, cfb, c4b, serpina3g, and ngp. Downregulated DE genes included lrrc74b, sult1d1, cxxc4, and grip2. After treatment with NBXH, especially high-dose NBXH, the abnormal gene expression was significantly corrected. Some DE genes have been confirmed in multiple GEO datasets or in pulmonary TB patients through RT-qPCR. Conclusion: MTB infection led to extensive changes in host gene expression and mainly caused the host's anti-TB immune responses. The treatment using highdose NBXH partially repaired the abnormal gene expression, further enhanced the anti-TB immunity included autophagy and NK cell-mediated cytotoxicity, and had a certain inhibitory effect on overactivated immune responses. [ABSTRACT FROM AUTHOR]

In the pathogenesis and progression of Sjögren's syndrome (SS), hematopoietic cells in the peripheral circulation, tissue-resident immune cells, and parenchymal cells of salivary gland tissues (such as epithelial cells, endothelial cells, fibroblasts, etc.) all play crucial roles. These diverse cells form intricate networks and interact with each other, leading to tissue destruction and persistent chronic inflammation, ultimately causing irreversible damage in glandular function. Among these, salivary gland epithelial cells (SGECs) consistently hold a key position, characterized by their functions in expressing co-stimulatory and antigen-presenting molecules and secreting pro-inflammatory cytokines and chemokines. Moreover, SGECs actively engage in and facilitate the development of specific pathological structures within the salivary gland, such as lymphoepithelial lesions (LELs) and tertiary lymphoid structures (TLSs), thereby substantially elevating the risk of mucosa-associated lymphoid tissue (MALT) lymphoma. Overall, SGECs are recognized for their essential and irreplaceable contributions to the pathogenesis of SS. This review article initially delves into the anatomical composition of salivary gland epithelial cells, subsequently focusing on elucidating the different cytokines derived from SGECs, encompassing chemokines, pro-inflammatory cytokines, anti-inflammatory cytokines, prosurvival cytokines, and damage-associated molecular patterns (DAMPs), to explore their key roles in the pathogenesis of SS. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is one of the most prevalent malignancies affecting males; however, the role of inflammatory activity in the pathogenesis of this disease is not yet fully elucidated. Although inflammation is recognized as being closely associated with the onset and progression of PCa, the specific causal relationships between individual inflammatory factors and the disease require further clarification. Methods: Mendelian randomization (MR) methodologies can mitigate bias by utilizing whole-genome sequencing data, leveraging specific genetic variants to assess causal relationships between a given exposure and an outcome of interest. This research employed an MR approach to investigate the association between inflammatory cytokines and PCa. Results: In total, 44 inflammatory cytokines were evaluated in a large GWAS dataset to enable the drawing of robust conclusions. Elevated circulating Creactive protein (CRP) and prostaglandin E2 (PGE-2) levels were related to greater PCa risk. The reverse Mendelian randomization (MR) study indicates a causal relationship between prostate cancer and stem cell factor (SCF) (P=0.025). Conclusion: CRP and PGE-2 play crucial roles in the regulation of PCa development. Moreover, PCa may have an impact on SCF levels. Further research is imperative to elucidate whether these biomarkers can be effectively utilized to prevent or treat PCa. [ABSTRACT FROM AUTHOR]

Introduction: Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged as a deadly pathogen with a mortality rate of up to 36.2%. MERS-CoV can cause severe respiratory tract disease and multiorgan failure. Therefore, therapeutic vaccines are urgently needed. This intensive review explores the human immune responses and their immunological mechanisms during MERSCoV infection in the mucosa of the upper and lower respiratory tracts (URT and LRT, respectively). Objective: The aim of this study is to provide a valuable, informative, and critical summary of the protective immune mechanisms against MERS-CoV infection in the URT/LRT for the purpose of preventing and controlling MERS-CoV disease and designing effective therapeutic vaccines. Methods: In this review, we focus on the immune potential of the respiratory tract following MERS-CoV infection. We searched PubMed, Embase, Web of Science, Cochrane, Scopus, and Google Scholar using the following terms: "MERS-CoV", "B cells", "T cells", "cytokines", "chemokines", "cytotoxic", and "upper and lower respiratory tracts". Results: We found and included 152 studies in this review. We report that the cellular innate immune response, including macrophages, dendritic cells, and natural killer cells, produces antiviral substances such as interferons and interleukins to prevent the virus from spreading. In the adaptive and humoral immune responses, CD4+ helper T cells, CD8+ cytotoxic T cells, B cells, and plasma cells protect against MERS-CoV infection in URT and LRT. Conclusion: The human nasopharynx-associated lymphoid tissue (NALT) and bronchus-associated lymphoid tissue (BALT) could successfully limit the spread of several respiratory pathogens. However, in the case of MERS-CoV infection, limited research has been conducted in humans with regard to immunopathogenesis and mucosal immune responses due to the lack of relevant tissues. A better understanding of the immune mechanisms of the URT and LRT is vital for the design and development of effective MERSCoV vaccines. [ABSTRACT FROM AUTHOR]

Plasma cytokine levels were quantified among 30 persons with HIV (PWH) identified as elite controllers (15 transient controllers [studied a median of 1.38 years before losing viral control] and 15 persistent controllers). Thirty antiretroviral therapy (ART)-naive PWH, 30 ART-treated PWH with undetectable viremia, and 30 HIV-uninfected controls also were studied. Higher levels of cytokines were recognized among PWH than among controls, with EC displaying the highest levels. Elevated levels of IP-10 and MIG were identified among transient controllers as predictors of the loss of viral control. These findings offer feasible biomarkers for predicting virologic outcome and loss of control in EC. [ABSTRACT FROM AUTHOR]

Background: Kawasaki disease (KD) is a self-limiting and acute systemic vasculitis of unknown etiology, mainly affecting children. Ferulic acid (FA), a natural phenolic substance, has multiple pharmacological properties, including antiinflammatory, anti-apoptosis, and anti-fibrosis, and so on. So far, the protective effects of FA on KD have not been explored. Methods: In this study, we established Candida albicans water soluble fraction (CAWS)-induced mouse coronary artery vasculitis of KD model and the tumor necrosis factor α (TNF-α)-induced human umbilical vein endothelial cells (HUVECs) injury model to investigate the anti-inflammatory and anti-apoptosis effects of FA on KD, and try to elucidate the underlying mechanism. Results: Our in vivo results demonstrated that FA exerted anti-inflammatory effects on KD by inhibiting the infiltration of CD45-positive leukocytes and fibrosis around the coronary artery. Additionally, FA downregulated the levels of inflammatory and chemotactic cytokines, alleviated splenomegaly, and exhibited anti-apoptotic effects on KD by reducing TUNEL-positive cells, downregulating BAX expression, and upregulating BCL-2 expression. In addition, Our in vitro findings showed that FA could effectively inhibit TNF-α-induced HUVEC inflammation like NF-κB inhibitor QNZ by downregulating the expression of pro-inflammatory cytokines as well as attenuated TNF-α-induced HUVEC apoptosis by reducing apoptotic cell numbers and the BAX/BCL-2 ratio, which could be reversed by the AMPK inhibitor compound c (CC). The further mechanistic study demonstrated that FA could restrain vascular endothelial cell inflammation and apoptosis in KD through activating the AMPK/mTOR/NF-κB pathway. However, FA alone is hard to completely restore KD into normal condition. Conclusion: In conclusion, FA has potential protective effects on KD, suggesting its promising role as an adjuvant for KD therapy in the future. [ABSTRACT FROM AUTHOR]

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by progressive fibrosis, leading to impaired gas exchange and high mortality. The etiology of IPF is complex, with potential links to autoimmune disorders such as hypothyroidism. This study explores the relationship between hypothyroidism and IPF, focusing on the mediating role of plasma proteins. Methods: A two-sample Mendelian randomization (MR) approach was employed to determine the impact of hypothyroidism on IPF and the mediating role of 4,907 plasma proteins, all in individuals of European ancestry. Sensitivity analyses, external validation, and reverse causality tests were conducted to ensure the robustness of the findings. Additionally, the function of causal SNPs was evaluated through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Conclusion: The findings suggest that hypothyroidism, through altered plasma protein expression, particularly CXCL10, may contribute to the pathogenesis of IPF. This novel insight highlights the potential of CXCL10 as a therapeutic target in IPF, especially in patients with hypothyroidism. The study emphasizes the need for further research into the complex interplay between autoimmune disorders and IPF, with a view towards developing targeted interventions for IPF management. [ABSTRACT FROM AUTHOR]

Introduction: Inflammation-induced remodelling of gestational tissues that underpins spontaneous preterm birth (sPTB, delivery < 37 weeks' gestation) may vary by race and context. To explore relationships between markers of these pathological processes, we (a) characterised the cervicovaginal fluid (CVF) cytokine profiles of pregnant South African women at risk of PTB; (b) determined CVF matrix-metalloproteinase-9 (MMP-9) and its regulator tissue inhibitor of metalloproteinase-1 (TIMP-1); and (c) explored the predictive potential of these markers for sPTB. Method of study: The concentrations of 10 inflammatory cytokines and MMP-9 and TIMP-1 were determined by ELISA in CVF samples from 47 non-labouring women at high risk of PTB. We studied CVF sampled at three gestational time points (GTPs): GTP1 (20-22 weeks, n = 37), GTP2 (26-28 weeks, n = 40), and GTP3 (34-36 weeks, n = 29) and analysed for changes in protein concentrations and predictive capacities (area under the ROC curve (AUC) and 95% confidence interval (CI)) for sPTB. Results: There were 11 (GTP1), 13 (GTP2), and 6 (GTP3) women who delivered preterm within 85.3 ± 25.9, 51.3 ± 15.3, and 11.8 ± 7.5 (mean ± SD) days after assessment, respectively. At GTP1, IL-8 was higher (4-fold, p = 0.02), whereas GM-CSF was lower (~1.4-fold, p = 0.03) in the preterm compared with term women with an average AUC = 0.73. At GTP2, IL-1β (18-fold, p < 0.0001), IL-8 (4-fold, p = 0.03), MMP-9 (17-fold, p = 0.0007), MMP-9/TIMP-1 ratio (9-fold, p = 0.004), and MMP-9/GM-CSF ratio (87-fold, p = 0.005) were higher in preterm compared with term women with an average AUC = 0.80. By contrast, IL-10 was associated with term delivery with an AUC (95% CI) = 0.75 (0.55-0.90). At GTP3, IL-1β (58-fold, p = 0.0003), IL-8 (12-fold, p = 0.002), MMP-9 (296-fold, p = 0.03), and TIMP-1 (35-fold, p = 0.01) were higher in preterm compared with term women with an average AUC = 0.85. Elevated IL-1β was associated with delivery within 14 days of assessment with AUC = 0.85 (0.67-0.96). Overall, elevated MMP-9 at GTP3 had the highest (13.3) positive likelihood ratio for distinguishing women at risk of sPTB. Lastly, a positive correlation between MMP-9 and TIMP-1 at all GTPs (r = 0.61, p < 0.01) for women delivering at term was only observed at GTP1 for those who delivered preterm (r = 0.70, p < 0.03). Conclusions: In this cohort, sPTB is associated with gestation-dependent increase in pro-inflammatory cytokines, decreased IL-10 and GM-CSF, and dysregulated MMP-9-TIMP-1 interaction. Levels of cytokine (especially IL-1β) and ECM remodelling proteins rise significantly in the final 2 weeks before the onset of labour when sPTB is imminent. The signalling mechanisms for these ECM remodelling observations remain to be elucidated. [ABSTRACT FROM AUTHOR]

Streptococcus suis causes diseases in pigs and has emerged as a zoonotic agent. When infected, the host develops an exacerbated inflammation that can lead to septic shock and meningitis. Although neutrophils greatly infiltrate the lesions, their dynamics during S. suis infection remain poorly described. Moreover, very few studies reported on the production and role of a key factor in the regulation of neutrophils: the colony-stimulating granulocyte factor (G-CSF). In this study, we characterized the G-CSF-neutrophil axis in the pathogenesis of S. suis induced disease. Using a mouse model of S. suis infection, we first evaluated the recruitment of neutrophils and their activation profile by flow cytometry. We found that infection provokes a massive neutrophil recruitment from the bone marrow to the blood and spleen. In both compartments, neutrophils displayed multiple activation markers. In parallel, we observed high systemic levels of G-CSF, with a peak of production coinciding with that of neutrophil recruitment. We then neutralized the effects of G-CSF and highlighted its role in the release of neutrophils from the bone marrow to the blood. However, it did not affect bacteremia nor the cytokine storm induced by S. suis. In conclusion, systemic GCSF induces the release of neutrophils from the bone marrow to the blood, but its role in inflammation or bacterial clearance seems to be compensated by unknown factors. A better understanding of the role of neutrophils and inflammatory mediators could lead to better strategies for controlling the infection caused by S. suis. [ABSTRACT FROM AUTHOR]

Background: Carotid endarterectomy (CEA) for the prevention of upcoming vascular and cerebral events is necessary in patients with high-grade stenosis (=70%). In the framework of the Italian National project Age.It, a pilot study was proposed aiming at the discovery of amolecular signature with predictive potential of carotid stenosis comparing 65+ asymptomatic and symptomatic inpatients. Methods: A total of 42 inpatients have been enrolled, including 26 men and 16 women, with a mean age of 74 ± 6 years. Sixteen symptomatic and 26 asymptomatic inpatients with =70% carotid stenosis underwent CEA, according to the recommendations of the European Society for Vascular Surgery and the Society for Vascular Surgeons. Plaque biopsies and peripheral blood samples from the same individuals were obtained. Hematobiochemical analyses were conducted on all inpatients, and plasma cytokines/molecules, such as microRNAs (miRs), IL-6, sIL-6Ralpha, sgp130, myostatin (GDF8), follistatin, activin A, CXCL9, FGF21, and fibronectin, were measured using the ELISA standard technique. MiR profiles were obtained in the discovery phase including four symptomatic and four asymptomatic inpatients (both plasma and plaque samples), testing 734 miRs. MiRs emerging from the profiling comparison were validated through RT-qPCR analysis in the total cohort. Results and conclusion: The two groups of inpatients differ in the expression levels of blood c-miRs-126-5p and -1271-5p (but not in their plaques), which are more expressed in symptomatic subjects. Three cytokines were significant between the two groups: IL-6, GDF8, and CXCL9. Using receiver operating characteristic (ROC) analysis with a machine learning-based approach, the most significant blood molecular signature encompasses albumin, C-reactive protein (CRP), the percentage of monocytes, and CXCL9, allowing for the distinction of the two groups (AUC = 0.83, 95% c.i. [0.85, 0.81], p = 0.0028). The potential of the molecular signature will be tested in a second cohort of monitored patients, allowing the application of a predictive model and the final evaluation of cost/benefit for an assessable screening test. [ABSTRACT FROM AUTHOR]

The capacity of lymphocytes continuously home to lymphoid structures is remarkable for cancer immunosurveillance and immunotherapy. Lymphocyte homing and recirculation within the tumor microenvironment (TME) are now understood to be adaptive processes that are regulated by specialized cytokines and adhesion molecule signaling cascades. Restricted lymphocyte infiltration and recirculation have emerged as key mechanisms contributing to poor responses in cancer immunotherapies like chimeric antigen receptor (CAR)-T cell therapy and immune checkpoint blockades (ICBs). Uncovering the kinetics of lymphocytes in tumor infiltration and circulation is crucial for improving immunotherapies. In this review, we discuss the current insights into the adhesive and migrative molecules involved in lymphocyte homing and transmigration. The potential mechanisms within the TME that restrain lymphocyte infiltration are also summarized. Advanced on these, we outline the determinates for tertiary lymphoid structures (TLSs) formation within tumors, placing high expectations on the prognostic values of TLSs as therapeutic targets in malignancies. [ABSTRACT FROM AUTHOR]

Background: Postpartum hemorrhage (PPH) is the primary cause of maternal mortality globally, with uterine atony being the predominant contributing factor. However, accurate prediction of PPH in the general population remains challenging due to a lack of reliable biomarkers. Methods: Using retrospective cohort data, we quantified 48 cytokines in plasma samples from 40 women diagnosed with PPH caused by uterine atony. We also analyzed previously reported hemogram and coagulation parameters related to inflammatory response. The least absolute shrinkage and selection operator (LASSO) and logistic regression were applied to develop predictive models. Established models were further evaluated and temporally validated in a prospective cohort. Results: Fourteen factors showed significant differences between the two groups, among which IL2Ra, IL9, MIP1b, TNFb, CTACK, prenatal Hb, Lymph%, PLR, and LnSII were selected by LASSO to construct predictive model A. Further, by logistic regression, model B was constructed using prenatal Hb, PLR, IL2Ra, and IL9. The area under the curve (AUC) values of model A in the training set, internal validation set, and temporal validation set were 0.846 (0.757–0.934), 0.846 (0.749–0.930), and 0.875 (0.789–0.961), respectively. And the corresponding AUC values for model B were 0.805 (0.709–0.901), 0.805 (0.701–0.894), and 0.901 (0.824–0.979). Decision curve analysis results showed that both nomograms had a high net benefit for predicting atonic PPH. Conclusion: We identified novel biomarkers and developed predictive models for atonic PPH in women undergoing “low-risk” vaginal delivery, providing immunological insights for further exploration of the mechanism underlying atonic PPH. [ABSTRACT FROM AUTHOR]

Background and objective: Neuroinflammatory processes have been identified as playing a crucial role in the pathophysiology of various neurodegenerative diseases, including idiopathic normal-pressure hydrocephalus (iNPH). iNPH, defined as a common disease of cognitive impairment in older adults, poses major challenges for therapeutic interventions owing to the stringent methodological requirements of relevant studies, clinical heterogeneity, unclear etiology, and uncertain diagnostic criteria. This study aims to assess the relationship between circulating inflammatory biomarkers and iNPH risk using bidirectional twosample Mendelian randomization (MR) combined with meta-analysis. Methods: In our bidirectional MR study, genetic data from a genome-wide association study (GWAS) involving 1,456 iNPH cases and 409,726 controls of European ancestry were employed. Single-nucleotide polymorphisms (SNPs) associated with exposures served as instrumental variables for estimating the causal relationships between iNPH and 132 types of circulating inflammatory biomarkers from corresponding GWAS data. Causal associations were primarily examined using the inverse variance-weighted method, supplemented by MR-Egger, weighted median, simple mode, and weighted mode analyses. In the results, heterogeneity was assessed using the Cochran Q test. Horizontal pleiotropy was evaluated through the MR-Egger intercept test and the MR pleiotropy residual sum and outliers test. Sensitivity analysis was conducted through leave-one-out analysis. Reverse MR analyses were performed to mitigate bias from reverse causality. Meta-analyses of identical inflammatory biomarkers from both data sources strengthened the findings. Results: Results indicated a genetically predicted association between Interleukin-16 (IL-16) [OR: 1.228, 95% CI: 1.049-1.439, p = 0.011], TNF-related apoptosis ligand (TRAIL) [OR: 1.111, 95% CI: 1.019-1.210, p = 0.017] and Urokinase-type plasminogen activator (uPA) [OR: 1.303, 95% CI: 1.025-1.658, p = 0.031] and the risk of iNPH. Additionally, changes in human Glial cell line-derived neurotrophic factor (hGDNF) [OR: 1.044, 95% CI: 1.006-1.084, p = 0.023], Matrix metalloproteinase-1 (MMP-1) [OR: 1.058, 95% CI: 1.020, 1.098, p = 0.003] and Interleukin-12p70 (IL-12p70) [OR: 0.897, 95% CI: 0.946-0.997, p = 0.037] levels were identified as possible consequences of iNPH. Conclusion: Our MR study of inflammatory biomarkers and iNPH, indicated that IL-16, TRAIL, and uPA contribute to iNPH pathogenesis. Furthermore, iNPH may influence the expression of hGDNF, MMP-1, and IL-12p70. Therefore, targeting specific inflammatory biomarkers could be promising strategy for future iNPH treatment and prevention. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the deadliest and most prevalent malignancy worldwide. While smoking is an established cause, evidence to identify other causal factors remains lacking. Current research indicates chronic inflammation is involved in tumorigenesis and cancer development, though the specific mechanisms underlying the role of inflammatory cytokines in lung cancer pathogenesis remain unclear. This study implemented Mendelian randomization (MR) analysis to investigate the causal effects of circulating cytokines on lung cancer development. Methods: We performed a two-sample MR analysis in Europeans utilizing publicly available genome-wide association study summary statistics. Single nucleotide polymorphisms significantly associated with cytokine were selected as genetic instrumental variables. Results: Genetically predicted levels of the chemokine interleukin-18 (IL-18) (OR = 0.942, 95% CI: 0.897-0.990, P = 0.018) exerted significant negative causal effects on overall lung cancer risk in this analysis. Examining specific histologic subtypes revealed further evidence of genetic associations. Stem cell factor (SCF) (OR = 1.150, 95% CI: 1.021-1.296, P = 0.021) and interleukin-1beta (IL-1β) (OR = 1.152, 95% CI: 1.003-1.325, P = 0.046) were positively associated with lung adenocarcinoma risk, though no inflammatory factors showed causal links to squamous cell lung cancer risk. Stratified by smoking status, interferon gammainduced protein 10 (IP-10) (OR = 0.861, 95% CI: 0.781-0.950, P = 0.003) was inversely associated while IL-1β (OR = 1.190, 95% CI: 1.023-1.384, P = 0.024) was positively associated with lung cancer risk in ever smokers. Among never smokers, a positive association was observed between lung cancer risk and SCF (OR = 1.474, 95% CI: 1.105-1.964, P = 0.008). Importantly, these causal inferences remained robust across multiple complementary MR approaches, including MR-Egger, weighted median, weighted mode and simple mode regressions. Sensitivity analyses also excluded potential bias stemming from pleiotropy. Conclusion: This MR study found preliminary evidence that genetically predicted levels of four inflammatory cytokines--SCF, IL-1β, IL-18, and IP-10--may causally influence lung cancer risk in an overall and subtype-specific manner, as well as stratified by smoking status. Identifying these cytokine pathways that may promote lung carcinogenesis represents potential new targets for the prevention, early detection, and treatment of this deadly malignancy. [ABSTRACT FROM AUTHOR]

Objective: Smoking is the cause of numerous oral pathologies. The aim of the study was to evaluate the effect of smoking traditional cigarettes, e-cigarettes, and heat-not-burn products on the content of salivary cytokines, chemokines, and growth factors in healthy young adults. Design: Three groups of twenty-five smokers each as well as a control group matched in terms of age, gender, and oral status were enrolled in the study. In unstimulated saliva collected from study groups and participants from the control group, the concentrations of cytokines, chemokines, and growth factors were assessed by Bio-Plex® Multiplex System. Results: We demonstrated that smoking traditional cigarettes is responsible for increasing the level of IFN-γ compared to non-smokers and new smoking devices users in unstimulated saliva in the initial period of addiction. Furthermore, e-cigarettes and heat-not-burn products appear to have a similar mechanism of affecting the immune response system of unstimulated saliva, leading to inhibition of the local inflammatory response in the oral cavity. Conclusion: Smoking traditional cigarettes as well as e-cigarettes and heat-notburn products is responsible for changes of the local immune response in saliva. Further research is necessary to fill the gap in knowledge on the effect of new smoking devices on the oral cavity immune system. [ABSTRACT FROM AUTHOR]

Background: Mounting evidence suggests a connection between inflammatory cytokines and adhesive capsulitis (AC). However, the specific systemic inflammatory cytokines contributing to AC have not been clearly identified. This study employed Mendelian randomization (MR) to explore the causal relationships between 41 inflammatory cytokines and AC. Methods: In this bidirectional, two-sample MR analysis, genetic variations associated with AC were derived from a comprehensive genome-wide association study (GWAS). The inflammatory cytokines data were sourced from a GWAS summary involving 8,293 healthy participants. The primary MR method employed was inverse variance weighting, supplemented by MR-Egger, weighted median, and MR-pleiotropy residual sum and outlier for sensitivity analysis. Heterogeneity was assessed using Cochran’s Q test, and the MR results were validated using the leave-one-out method. Results: Elevated levels of interferon gamma-induced protein 10 (IP-10) (odds ratio (OR) = 1.086, 95% confidence interval (CI) = 1.002–1.178) and regulated on activation, normal T cell expressed and secreted (RANTES) (OR = 1.107, 95% CI = 1.026–1.195) were linked to an increased risk of AC. Increased levels of stromal cell-derived factor-1 alpha (SDF-1α) (OR = 0.879, 95% CI = 0.793–0.974) and tumor necrosis factor-alpha (TNF-α) (OR = 0.911, 95% CI = 0.831–0.999) were associated with a reduced AC risk. Moreover, genetically predicted AC exhibited associations with elevated cutaneous T cell attracting (CTACK) levels (OR = 1.202, 95% CI = 1.007–1.435) and diminished levels of interleukin-17 (IL-17) (OR = 0.678, 95% CI = 0.518–0.888) and interleukin-5 (IL-5) (OR = 0.786, 95% CI = 0.654– 0.944), as confirmed through inverse-variance weighted (IVW) methods. Conclusion: The present study successfully establishes a causal association between genetically proxied circulating levels of IP-10, RANTES, SDF-1α, and TNF-α and the risk of AC. Additionally, AC contributes to an increase in CTACK and a decrease in IL-17 and IL-5. This significant finding not only enhances the understanding of the pathogenesis of AC but also holds promise for the development of effective clinical management strategies. [ABSTRACT FROM AUTHOR]

Introduction: Macrophage dysfunction is a common feature of inflammatory disorders such as asthma, which is characterized by a strong circadian rhythm. Methods and results: We monitored the protein expression pattern of the molecular circadian clock in human peripheral blood monocytes from healthy, allergic, and asthmatic donors during a whole day. Monocytes cultured of these donors allowed us to examine circadian protein expression in human monocytederived macrophages, M1- and M2-polarized macrophages. In monocytes, particularly from allergic asthmatics, the oscillating expression of circadian proteins CLOCK, BMAL, REV ERBs, and RORs was significantly altered. Similar changes in BMAL1 were observed in polarized macrophages from allergic donors and in tissue-resident macrophages from activated precision cut lung slices. We confirmed clock modulating, anti-inflammatory, and lung-protective properties of the inverse ROR agonist SR1001 by reduced secretion of macrophage inflammatory protein and increase in phagocytosis. Using a house dust mite model, we verified the therapeutic effect of SR1001 in vivo. Discussion: Overall, our data suggest an interaction between the molecular circadian clock and monocytes/macrophages effector function in inflammatory lung diseases. The use of SR1001 leads to inflammatory resolution in vitro and in vivo and represents a promising clock-based therapeutic approach for chronic pulmonary diseases such as asthma. [ABSTRACT FROM AUTHOR]

BackgroundThe CIAO trial recently demonstrated a probable clinical benefit of omalizumab in the treatment of severe COVID-19; however, the mechanism underlying this benefit remains unclear. Therefore, we sought to longitudinally assess the impact of omalizumab on serum cytokines in CIAO trial patients to determine its mechanism of action.MethodsBlood samples were collected on days 0, 2, 7, and 14 from patients recruited into the CIAO trial and who consented to this substudy. Blood samples were tested by a panel of 25 inflammatory cytokines, as well as for markers of mast cell activation. Levels of inflammatory biomarkers were compared over time between omalizumab- and placebo-treated patients by generalized linear mixed-effects model. Associations between biomarkers and clinical outcomes were investigated by mixed-effects logistic regression.ResultsNineteen patients were recruited into this substudy; 10 were assigned to placebo and 9 to omalizumab. Monokine induced by gamma interferon was significantly positively associated with severe COVID-19 (Odds Ratio [OR] = 1.06, 95%CI = 1.00–1.11, p = 0.043). Further, omalizumab significantly reduced interleukin-15 (Coefficient = −0.95, p = 0.048) and macrophage inflammatory protein-1 (Coefficient = −1.31, p = 0.010) levels. However, neither was significant in analyses adjusting for multiple hypothesis testing.ConclusionAlthough limited by a small sample size, these results suggest that omalizumab’s potential benefit in COVID-19 may be mediated independently of modulation of the measured serum biomarkers. Further studies are needed to investigate omalizumab’s mechanism of action in COVID-19.

Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD, and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity, patterns of expression indicated involvement of certain T-cell cytokines, vascular changes, and loss of certain growth factors, with disease progression. The results demonstrate the feasibility of profiling inflammatory molecules using diseased human brain samples, and have provided additional targets to validate in relation to PD pathology. [ABSTRACT FROM AUTHOR]

Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity, patterns of expression indicated involvement of certain T-cell cytokines, vascular changes and loss of certain growth factors, with disease progression. The results demonstrate the feasibility of profiling inflammatory molecules using diseased human brain samples, and have provided additional targets to validate in relation to PD pathology. [ABSTRACT FROM AUTHOR]

As the world population ages, osteoporosis, the most common disease of bone metabolism, affects more than 200 million people worldwide. The etiology is an imbalance in bone remodeling process resulting in more significant bone resorption than bone remodeling. With the advent of the osteoimmunology field, the immune system's role in skeletal pathologies is gradually being discovered. The cytokine interferon-gamma (IFN-γ), a member of the interferon family, is an important factor in the etiology and treatment of osteoporosis because it mediates bone remodeling. This review starts with bone remodeling process and includes the cellular and key signaling pathways of bone remodeling. The effects of IFN-g on osteoblasts, osteoclasts, and bone mass are discussed separately, while the overall effects of IFN-γ on primary and secondary osteoporosis are summarized. The net effect of IFN-γ on bone appears to be highly dependent on the environment, dose, concentration, and stage of cellular differentiation. This review focuses on the mechanisms of bone remodeling and bone immunology, with a comprehensive discussion of the relationship between IFN-γ and osteoporosis. Finding the paradoxical balance of IFN-γ in bone immunology and exploring the potential of its clinical application provide new ideas for the clinical treatment of osteoporosis and drug development. [ABSTRACT FROM AUTHOR]

Introduction: Severe fever with thrombocytopenia syndrome (SFTS) is characterized by a high mortality rate and is associated with immune dysregulation. Cytokine storms may play an important role in adverse disease regression, this study aimed to assess the validity of MCP-3 in predicting adverse outcomes in SFTS patients and to investigate the longitudinal cytokine profile in SFTS patients. Methods: The prospective study was conducted at Yantai Qishan Hospital from May to November 2022. We collected clinical data and serial blood samples during hospitalization, patients with SFTS were divided into survival and nonsurvival groups based on the clinical prognosis. Results: The levels of serum 48 cytokines were measured using Luminex assays. Compared to healthy controls, SFTS patients exhibited higher levels of most cytokines. The non-survival group had significantly higher levels of 32 cytokines compared to the survival group. Among these cytokines, MCP-3 was ranked as the most significant variable by the random forest (RF) model in predicting the poor prognosis of SFTS patients. Additionally, we validated the predictive effects of MCP-3 through receiver operating characteristic (ROC) curve analysis with an AUC of 0.882 (95% CI, 0.787-0.978, P <0.001), and the clinical applicability of MCP-3 was assessed favorably based on decision curve analysis (DCA). The Spearman correlation analysis indicated that the level of MCP-3 was positively correlated with ALT, AST, LDH, α-HBDH, APTT, D-dimer, and viral load (P<0.01). Discussion: For the first time, our study identified and validated that MCP-3 could serve as a meaningful biomarker for predicting the fatal outcome of SFTS patients. The longitudinal cytokine profile analyzed that abnormally increased cytokines were associated with the poor prognosis of SFTS patients. Our study provides new insights into exploring the pathogenesis of cytokines with organ damage and leading to adverse effects. [ABSTRACT FROM AUTHOR]