Inflammatory Biomarkers Research Articles

Association of Biomarkers of Neuronal Injury and Inflammation With Insomnia Trajectories After Traumatic Brain Injury: A TRACK-TBI Study.

Insomnia affects about one-third of patients with traumatic brain injury and is associated with worsened outcomes after injury. We hypothesized that higher levels of plasma neuroinflammation biomarkers at the time of TBI would be associated with worse 12-month insomnia trajectories. Participants were prospectively enrolled from 18 level-1 trauma centers participating in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury study from February 26, 2014, to August 8, 2018. Plasma glial fibrillary acidic protein (GFAP), high-sensitivity C-reactive protein (hsCRP), S100b, neuron-specific enolase (NSE), and ubiquitin carboxyl-terminal hydrolase-L1 (UCH-L1) were collected on days 1 (D1) and 14 (D14) after TBI. The insomnia severity index was collected at 2 weeks, 3, 6, and 12 months postinjury. Participants were classified into insomnia trajectory classes based on a latent class model. We assessed the association of biomarkers with insomnia trajectories, controlling for medical and psychological comorbidities and demographics. Two thousand twenty-two individuals with TBI were studied. Elevations in D1 hsCRP were associated with persistent insomnia (severe, odds ratio [OR] = 1.33 [1.11, 1.59], p = 0.002; mild, OR = 1.10 [1.02, 1.19], p = 0.011). Similarly, D14 hsCRP elevations were associated with persistent insomnia (severe, OR = 1.27 [1.02, 1.59], p = 0.03). Of interest, D1 GFAP was lower in persistent severe insomnia (median [Q1, Q3]: 154 [19, 445] pg/mL) compared with resolving mild (491 [154, 1,423], p < 0.001) and persistent mild (344 [79, 1,287], p < 0.001). D14 GFAP was similarly lower in persistent (11.8 [6.4, 19.4], p = 0.001) and resolving (13.9 [10.3, 20.7], p = 0.011) severe insomnia compared with resolving mild (20.6 [12.4, 39.6]. Accordingly, increases in D1 GFAP were associated with reduced likelihood of having persistent severe (OR = 0.76 [95% CI 0.63-0.92], p = 0.004) and persistent mild (OR = 0.88 [0.81, 0.96], p = 0.003) compared with mild resolving insomnia. No differences were found with other biomarkers. Elevated plasma hsCRP and, surprisingly, lower GFAP were associated with adverse insomnia trajectories after TBI. Results support future prospective studies to examine their utility in guiding insomnia care after TBI. Further work is needed to explore potential mechanistic connections between GFAP levels and the adverse insomnia trajectories.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Prognostic Biomarkers of Systemic Inflammation in Non-Small Cell Lung Cancer: A Narrative Review of Challenges and Opportunities

Non-small cell lung cancer (NSCLC) is a common malignancy and is associated with poor survival outcomes. Biomarkers of systemic inflammation derived from blood tests collected as part of routine clinical care offer prognostic information for patients with NSCLC that may assist clinical decision making. They are an attractive tool, as they are inexpensive, easily measured, and reproducible in a variety of healthcare settings. Despite the wealth of evidence available to support them, these inflammatory biomarkers are not yet routinely used in clinical practice. In this narrative review, the key inflammatory indices reported in the literature and their prognostic significance in NSCLC are described. Key challenges limiting their clinical application are highlighted, including the need to define the optimal biomarker of systemic inflammation, a lack of understanding of the systemic inflammatory landscape of NSCLC as a heterogenous disease, and the lack of clinical relevance in reported outcomes. These challenges may be overcome with standardised recording and reporting of inflammatory biomarkers, clinicopathological factors, and survival outcomes. This will require a collaborative approach, to which this field of research lends itself. This work may be aided by the rise of data-driven research, including the potential to utilise modern electronic patient records and advanced data-analysis techniques.

Predictive model for non-malignant portal vein thrombosis associated with cirrhosis based on inflammatory biomarkers

BACKGROUND Portal vein thrombosis (PVT), a complication of liver cirrhosis, is a major public health concern. PVT prediction is the most effective method for PVT diagnosis and treatment. AIM To develop and validate a nomogram and network calculator based on clinical indicators to predict PVT in patients with cirrhosis. METHODS Patients with cirrhosis hospitalized between January 2016 and December 2021 at the First Hospital of Lanzhou University were screened and 643 patients with cirrhosis who met the eligibility criteria were retrieved. Following a 1:1 propensity score matching 572 patients with cirrhosis were screened, and relevant clinical data were collected. PVT risk factors were identified using the least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression analysis. Variance inflation factors and correlation matrix plots were used to analyze multicollinearity among the variables. A nomogram was constructed to predict the probability of PVT based on independent risk factors for PVT, and its predictive performance was verified using a receiver operating characteristic curve (ROC), calibration curves, and decision curve analysis (DCA). Finally, a network calculator was constructed based on the nomograms. RESULTS This study enrolled 286 cirrhosis patients with PVT and 286 without PVT. LASSO analysis revealed 13 variables as strongly associated with PVT occurrence. Multivariate logistic regression analysis revealed nine indicators as independent PVT risk factors, including etiology, ascites, gastroesophageal varices, platelet count, D-dimer, portal vein diameter, portal vein velocity, aspartate transaminase to neutrophil ratio index, and platelet-to-lymphocyte ratio. LASSO and correlation matrix plot results revealed no significant multicollinearity or correlation among the variables. A nomogram was constructed based on the screened independent risk factors. The nomogram had excellent predictive performance, with an area under the ROC curve of 0.821 and 0.829 in the training and testing groups, respectively. Calibration curves and DCA revealed its good clinical performance. Finally, the optimal cutoff value for the total nomogram score was 0.513. The sensitivity and specificity of the optimal cutoff values were 0.822 and 0.706, respectively. CONCLUSION A nomogram for predicting PVT occurrence was successfully developed and validated, and a network calculator was constructed. This can enable clinicians to rapidly and easily identify high PVT risk groups.

Molecular Pathways of Vulnerable Carotid Plaques at Risk of Ischemic Stroke: A Narrative Review

The concept of vulnerable carotid plaques is pivotal in understanding the pathophysiology of ischemic stroke secondary to large-artery atherosclerosis. In macroscopic evaluation, vulnerable plaques are characterized by one or more of the following features: microcalcification; neovascularization; lipid-rich necrotic cores (LRNCs); intraplaque hemorrhage (IPH); thin fibrous caps; plaque surface ulceration; huge dimensions, suggesting stenosis; and plaque rupture. Recognizing these macroscopic characteristics is crucial for estimating the risk of cerebrovascular events, also in the case of non-significant (less than 50%) stenosis. Inflammatory biomarkers, such as cytokines and adhesion molecules, lipid-related markers like oxidized low-density lipoprotein (LDL), and proteolytic enzymes capable of degrading extracellular matrix components are among the key molecules that are scrutinized for their associative roles in plaque instability. Through their quantification and evaluation, these biomarkers reveal intricate molecular cross-talk governing plaque inflammation, rupture potential, and thrombogenicity. The current evidence demonstrates that plaque vulnerability phenotypes are multiple and heterogeneous and are associated with many highly complex molecular pathways that determine the activation of an immune-mediated cascade that culminates in thromboinflammation. This narrative review provides a comprehensive analysis of the current knowledge on molecular biomarkers expressed by symptomatic carotid plaques. It explores the association of these biomarkers with the structural and compositional attributes that characterize vulnerable plaques.

Evaluation of inflammatory biomarkers and the ratio of hemoglobin-red cell distribution width in patients with rheumatoid arthritis treated with tumor necrosis factor-alpha inhibitors.

The aim of this study was to examine pre-treatment and post-treatment hemogram-derived inflammatory biomarkers in patients with rheumatoid arthritis (RA) who received anti-tumor necrosis factor (TNF)-α treatment. The data of 1182 patients with RA were screened. Among them, 207 patients who met the eligibility criteria were included in the retrospective study. Demographic parameters, disease activity, and blood cell-derived indexes were evaluated. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and hemoglobin-red cell distribution width (Hb/RDW) rates were evaluated before treatment and at the third month of treatment in patients with RA who received anti-TNF-α treatment. According to the EULAR response criteria, 12.6% of the 207 patients responded to anti-TNF-α treatment as none, 21.3% as good, and 66.2% as moderate, respectively. Post-treatment NLR and PLR values were significantly lower than pre-treatment values (p < 0.001), whereas post-treatment LMR and Hb/RDW values were significantly higher than pre-treatment values (respectively, p = 0.001 and p = 0.012). The difference between pre-treatment and post-treatment values of LMR and Hb/RDW was significantly higher when compared to the moderate + good response groups than the none-response group (p = 0.002 and p = 0.014, respectively). However, in the receiver operating characteristic curve analysis, these parameters were not found to be significant in predicting treatment response. Significant changes were detected in hemogram-derived inflammatory markers of the groups responding to anti-TNF-α treatment. They can be used as a guide during treatment follow-up. Yet, they do not predict treatment response. Key Points • RA may manifest with periods of remission and activation, and regular follow-up is essential. • There is a demand for readily available, reproducible, and cost-effective parameters to assess treatment response. • Hemogram-derived inflammatory markers differ in relation to anti-TNF-α treatment response in RA. • None of those markers demonstrate an acceptable predictive performance in distinguishing patients based on their response to TNF-α inhibitors.

ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways.

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently, there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however, its biological activity has been very little studied. In the present study, we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1 (TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum, and reduce the expression of fibrosis biomarkers confirmed by Masson staining, immunohistochemistry, real-time polymerase chain reaction (RT-PCR), and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore, we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion, ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

Predictive value of the systemic immune-inflammation index on one-year mortality in geriatric hip fractures.

Geriatric hip fractures are associated with a high incidence of mortality. This study examines the predictive value of the systemic immune-inflammation index (SII) on one-year mortality in elderly hip fracture patients. A single-center retrospective study was conducted between February 2017 and October 2020. Three hundred and eleven surgically treated consecutive hip fracture patients were included in the study. Admission, postoperative first day, and postoperative fifth-day SII values were calculated. The receiver operating characteristic (ROC) curve was used to calculate the cut-off values, and patients were divided into high and low groups according to these cut-off values. After univariate Cox regression analysis, significant factors were included in the multivariate Cox proportional hazards model to adjust the effect of covariates and explore independent predictive factors associated with mortality. Further subgroup analysis was performed to evaluate the accuracy of the results for different clinical and biological characteristics. The mean age was 80.7 ± 8.0 years, and women made up the majority (67.8%) of the patients. The one-year mortality rate was 28.0%. After univariate and multivariate analyses, high postoperative fifth-day SII remained an independent predictor of one-year mortality (adjusted HR 2.16, 95% CI 1.38-3.38, p = 0.001). Older age, male gender, Charlson comorbidity index (CCI) ≥ 2, and hypoalbuminemia were found to be other independent predictors. The optimal cut-off value of the postoperative fifth-day SII was calculated at 1751.9 units (p < 0.001). The postoperative fifth-day SII is a simple and useful inflammatory biomarker for predicting one-year mortality in patients with hip fracture.

Urate-lowering therapy, serum urate, inflammatory biomarkers, and renal function in patients with gout following pegloticase discontinuation

Background/PurposeLittle is known about long-term clinical outcomes or urate-lowering (ULT) therapy use following pegloticase discontinuation. We examined ULT use, serum urate (SU), inflammatory biomarkers, and renal function following pegloticase discontinuation.MethodsWe conducted a retrospective analysis of gout patients who discontinued pegloticase using the Rheumatology Informatics System for Effectiveness (RISE) registry from 1/2016 to 6/2022. We defined discontinuation as a gap ≥ 12 weeks after last infusion. We examined outcomes beginning two weeks after last dose and identified ULT therapy following pegloticase discontinuation. We evaluated changes in lab values (SU, eGFR, CRP and ESR), comparing on- treatment (≤ 15 days of the second pegloticase dose) to post-treatment.ResultsOf the 375 gout patients discontinuing pegloticase, median (IQR) laboratory changes following discontinuation were: SU: +2.4 mg/dL (0.0,6.3); eGFR: -1.9 mL/min (− 8.7,3.7); CRP: -0.8 mg/L (-12.8,0.0); and ESR: -4.0 mm/hr (-13.0,0.0). Therapy post-discontinuation included oral ULTs (86.0%), restarting pegloticase (4.5%), and no documentation of ULT (9.5%), excluding patients with multiple same-day prescriptions (n = 17). Oral ULTs following pegloticase were: 62.7% allopurinol, 34.1% febuxostat. The median (IQR) time to starting/restarting ULT was 92.0 days (55.0,173.0). Following ULT prescribing (≥ 30 days), only 51.0% of patients had SU < 6 mg/dL. Patients restarting pegloticase achieved a median SU of 0.9 mg/dL (IQR:0.2,9.7) and 58.3% had an SU < 6 mg/dL.ConclusionPegloticase treats uncontrolled gout in patients with failed response to xanthine oxidase inhibitors, but among patients who discontinue, optimal treatment is unclear. Based on this analysis, only half of those starting another ULT achieved target SU. Close follow-up is needed to optimize outcomes after pegloticase discontinuation.

Plasma Galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV.

Adolescents with perinatally-acquired HIV (AWH) are at an increased risk of poor cognitive development but the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multi-morbidity in adults with HIV despite anti-retroviral therapy (ART), however, relationship between Gal-9 in AWH and cognition remain unexplored. A cross-sectional study of two independent age-matched cohorts from India [AWH on ART (n = 15), ART-naïve (n = 15), and adolescents without HIV (AWOH; n = 10)] and Myanmar [AWH on ART (n = 54) and AWOH (n = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests. Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann-Whitney U tests to determine group-wise differences, Spearman's correlation for associations and machine learning (ML) to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers. Gal-9 levels were elevated in ART-treated AWH compared to AWOH in both cohorts (all p < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFα, MCP-1, IP-10, IL-10) and activated CD8 T cells (all p < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains (verbal learning, visuospatial learning, memory, motor skills (all p < 0.05). ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents (mean AUC = 0.837). Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV.

Are central and systemic inflammation associated with fatigue in cerebral small vessel disease?

Fatigue is a common symptom in cerebral small vessel disease (SVD), but its pathogenesis is poorly understood. It has been suggested that inflammation may play a role. We determined whether central (neuro) inflammation and peripheral inflammation were associated with fatigue in SVD. Notably, 36 patients with moderate-to-severe SVD underwent neuropsychometric testing, combined positron emission tomography and magnetic resonance imaging (PET-MRI) scan, and blood draw for the analysis of inflammatory blood biomarkers. Microglial signal was taken as a proxy for neuroinflammation, assessed with radioligand 11C-PK11195. Of these, 30 subjects had full PET datasets for analysis. We assessed global 11C-PK11195 binding and hotspots of 11C-PK11195 binding in the normal-appearing white matter, lesioned tissue, and combined total white matter. Peripheral inflammation was assessed with serum C-reactive protein (CRP) and using the Olink cardiovascular III proteomic panel comprising 92 biomarkers of cardiovascular inflammation and endothelial activation. Fatigue was assessed using the fatigue severity scale (FSS), the visual analog fatigue scale, and a subscale of the Geriatric Depression Scale. Mean (SD) age was 68.7 (11.2) years, and 63.9% were male. Of these, 55.6% showed fatigue on the FSS. Fatigued participants had higher disability scores (p = 0.02), higher total GDS scores (p = 0.02), and more commonly reported a history of depression (p = 0.04). 11C-PK11195 ligand binding in the white matter was not associated with any measure of fatigue. Serum CRP was significantly associated with average fatigue score on FSS (ρ = 0.48, p = 0.004); this association persisted when controlling for age, sex, disability score, and depression (β = 0.49, 95% CI (0.17, 2.26), p = 0.03). Blood biomarkers from the Olink panel showed no association with fatigue. In symptomatic SVD patients, neuroinflammation, assessed with microglial marker 11C-PK11195, was not associated with fatigue. We found some evidence for a role of systematic inflammation, evidenced by an association between fatigue severity and raised CRP, but further studies are required to understand this relationship and inform whether it could be therapeutically modified to reduce fatigue severity. Data for this study are available from the corresponding author upon reasonable request.

Exploring the Associations of Inflammatory and Oxidative Stress Biomarkers with Pancreatic Diseases: An Observational and Mendelian Randomisation Study

Identifying biomarkers linked to pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP) is crucial for early detection, treatment, and prevention. Methods: Association analyses of 10 serological biomarkers involved in cell signalling (IFN-γ, IL-6, IL-8, IL-10), oxidative stress (superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzyme activities, total glutathione (GSH), malondialdehyde (MDA) levels), and intestinal permeability proteins (zonulin, I-FABP2) were conducted across PDAC (n = 12), CP (n = 21) and control subjects (n = 23). A Mendelian randomisation (MR) approach was used to assess causality of the identified significant associations in two large genetic cohorts (FinnGen and UK Biobank). Results: Observational results showed a downregulation of SOD and GPx antioxidant enzyme activities in PDAC and CP patients, respectively, and higher MDA levels in CP patients. Logistic regression models revealed significant associations between CP and SOD activity (OR = 0.21, 95% CI [0.05, 0.89], per SD), GPx activity (OR = 0.28, 95% CI [0.10, 0.79], per SD), and MDA levels (OR = 2.05, 95% CI [1.36, 3.08], per SD). MR analyses, however, did not support causality. Conclusions: These findings would not support oxidative stress-related biomarkers as potential targets for pancreatic diseases prevention. Yet, further research is encouraged to assess their viability as non-invasive tools for early diagnosis, particularly in pre-diagnostic CP populations.

Soluble CD27 is an intrathecal biomarker of T-cell-mediated lesion activity in multiple sclerosis

ObjectiveSoluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis.MethodsProtein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features.ResultsWe demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions.InterpretationOur results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes.

The effect of sodium-glucose cotransporter-2 inhibitors on inflammatory biomarkers: A meta-analysis of randomized controlled trials.

To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on inflammatory biomarkers. Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. Thirty-eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow-up of 16 (12-24) weeks. Meta-analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin-6, tumour necrosis factor receptor-1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] -0.85 pg/mL [95% CI -1.32, -0.38], SMD -0.13 [95% CI -0.20, -0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. SMD -0.20 [95% CI -0.33, -0.07], MD -0.83 [95% CI -1.32, -0.33], respectively). There were no significant changes in C-reactive protein (CRP), tumour necrosis factor-α, plasminogen activator inhibitor-1, fibroblast growth factor-21 or monocyte chemoattractant protein-1. Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP.

Effects of Regular Exercise on the Biochemical, Oxidative, and Inflammatory Profiles and Quality of Life in Older Spaniards with Metabolic Syndrome

Metabolic syndrome increases the risk of developing diabetes and cardiovascular disease. The regular practice of physical activity is a crucial factor for healthy aging and for controlling and preventing chronic diseases. To assess the effects of regular physical activity on the biochemical and inflammatory profiles, as well as the quality of life of older adults diagnosed with metabolic syndrome. Participants (aged 55–70 years; living in the Balearic Islands, Spain) were divided into two groups (n = 50 each) according to the degree of physical activity measured by metabolic equivalents of task (METs). Anthropometric parameters, blood pressure, biochemical and hematological parameters, and inflammatory biomarkers were measured. Beck Depression Inventory and adherence to the Mediterranean diet questionnaires, as well as the Dietary Inflammatory Index, chair test, health-related quality of life (HRQoL), and Rapid Assessment of Physical Activity, were also determined. The characterization of the patients was similar in both groups, showing a homogeneous sample. The group with the highest METs experienced a decrease in depression and an increase in the intensity of physical activity. Adherence to the Mediterranean diet and HRQoL physical dimensions increased in participants with the highest METs, also showing a decrease in glycemia and glycosylated hemoglobin values. Inflammatory biomarkers, including tumor necrosis factor alpha, interleukin-6, interleukin-1β, and osteoprotegerin, decreased in patients practicing more physical activity. High levels of physical activity are related to a healthier lifestyle, characterized by high adherence to the Mediterranean diet, decreased depressive behavior, oxidative stress, and inflammatory status in older people with metabolic syndrome.

Elevated Biomarkers of Inflammation and Vascular Dysfunction Are Associated with Distal Sensory Polyneuropathy in People with HIV

Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown. This study aimed to determine whether DSP signs and symptoms were associated with a panel of plasma biomarkers of inflammation (d-dimer, sTNFRII, MCP-1, IL-6, IL-8, IP-10, sCD14) and vascular I integrity (ICAM-1, VCAM-1, uPAR, MMP-2, VEGF, uPAR, TIMP-1, TIMP-2) and differed between PWH and people without HIV (PWoH). A cross-sectional study was conducted among 143 participants (69 PWH and 74 PWoH) assessed by studies at the UC San Diego HIV Neurobehavioral Research Program. DSP signs and symptoms were clinically assessed for all participants. DSP was defined as two or more DSP signs: bilateral symmetrically reduced distal vibration, sharp sensation, and ankle reflexes. Participant-reported symptoms were neuropathic pain, paresthesias, and loss of sensation. Factor analyses reduced the dimensionality of the 15 biomarkers among all participants, yielding six factors. Logistic regression was used to assess the associations between biomarkers and DSP signs and symptoms, controlling for relevant demographic and clinical covariates. The 143 participants were 48.3% PWH, 47 (32.9%) women, and 47 (33.6%) Hispanics, with a mean age of 44.3 ± 12.9 years. Among PWH, the median (IQR) nadir and current CD4+ T-cells were 300 (178–448) and 643 (502–839), respectively. Participants with DSP were older but had similar distributions of gender and ethnicity to those without DSP. Multiple logistic regression showed that Factor 2 (sTNFRII and VCAM-1) and Factor 4 (MMP-2) were independently associated with DSP signs in both PWH and PWoH (OR [95% CI]: 5.45 [1.42–21.00], and 15.16 [1.07–215.22]), respectively. These findings suggest that inflammation and vascular integrity alterations may contribute to DSP pathogenesis in PWH, but not PWoH, possibly through endothelial dysfunction and axonal degeneration.

Development and Validation of an Inflammatory Prognostic Index to Predict Outcomes in Advanced/Metastatic Urothelial Cancer Patients Receiving Immune Checkpoint Inhibitors

Background: Immune checkpoint inhibitors (ICIs) improve overall survival (OS) in advanced/metastatic urothelial cancer (a/mUC) patients. Preliminary evidence suggests a prognostic role of inflammatory biomarkers in this setting. We aimed to develop a disease-specific prognostic inflammatory index for a/mUC patients on ICIs. Methods: Fifteen variables were retrospectively correlated with OS and progression-free survival (PFS) in a development (D, n = 264) and a validation (V, n = 132) cohort of platinum-pretreated a/mUC pts receiving ICIs at L2 or further line. A nomogram and inflammatory prognostic index (U-IPI) were developed. The index was also tested in a control cohort of patients treated with chemotherapy only (C, n = 114). Results: The strongest predictors of OS were baseline platelet/lymphocyte (PLR) and neutrophil/lymphocyte (NLR) ratios, and lactate dehydrogenase (LDH), NLR, and albumin changes at 4 weeks. These were used to build the U-IPI, which can distinctly classify patients into good or poor response groups. The nomogram scoring is significant for PFS and OS (p &lt; 0.001 in the D, V, and combined cohorts) for the immunotherapy (IO) cohort, but not for the control cohort. Conclusions: The lack of a baseline systemic inflammatory profile and the absence of early serum inflammatory biomarker changes are associated with significantly better outcomes on ICIs in a/mUC pts. The U-IPI is an easily applicable dynamic prognostic tool for PFS and OS, allowing for the early identification of a sub-group with dismal outcomes that would not benefit from ICIs, while distinguishing another that draws an important benefit.

Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1

Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023. CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices. Incident AF. A total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index. Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.

Association of circulating biomarkers with illness severity measures differentiates myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 condition: a prospective pilot cohort study.

Accumulating evidence suggests that autonomic dysfunction and persistent systemic inflammation are common clinical features in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID. However, there is limited knowledge regarding their potential association with circulating biomarkers and illness severity in these conditions. This single-site, prospective, cross-sectional, pilot cohort study aimed to distinguish between the two patient populations by using self-reported outcome measures and circulating biomarkers of endothelial function and systemic inflammation status. Thirty-one individuals with ME/CFS, 23 individuals with long COVID, and 31 matched sedentary healthy controls were included. All study participants underwent non-invasive cardiovascular hemodynamic challenge testing (10min NASA lean test) for assessment of orthostatic intolerance. Regression analysis was used to examine associations between outcome measures and circulating biomarkers in the study participants. Classification across groups was based on principal component and discriminant analyses. Four ME/CFS patients (13%), 1 with long COVID (4%), and 1 healthy control (3%) presented postural orthostatic tachycardia syndrome (POTS) using the 10-min NASA lean test. Compared with matched healthy controls, ME/CFS and long COVID subjects showed higher levels of ET-1 (p < 0.05) and VCAM-1 (p < 0.001), and lower levels of nitrites (NOx assessed as NO2- + NO3-) (p < 0.01). ME/CFS patients also showed higher levels of serpin E1 (PAI-1) and E-selectin than did both long COVID and matched control subjects (p < 0.01 in all cases). Long COVID patients had lower TSP-1 levels than did ME/CFS patients and matched sedentary healthy controls (p < 0.001). As for inflammation biomarkers, both long COVID and ME/CFS subjects had higher levels of TNF-α than did matched healthy controls (p < 0.01 in both comparisons). Compared with controls, ME/CFS patients had higher levels of IL-1β (p < 0.001), IL-4 (p < 0.001), IL-6 (p < 0.01), IL-10 (p < 0.001), IP-10 (p < 0.05), and leptin (p < 0.001). Principal component analysis supported differentiation between groups based on self-reported outcome measures and biomarkers of endothelial function and inflammatory status in the study population. Our findings revealed that combining biomarkers of endothelial dysfunction and inflammation with outcome measures differentiate ME/CFS and Long COVID using robust discriminant analysis of principal components. Further research is needed to provide a more comprehensive characterization of these underlying pathomechanisms, which could be promising targets for therapeutic and preventive strategies in these conditions.

Pathophysiologic Mapping of Chronic Liver Diseases With Longitudinal Multiparametric MRI in Animal Models.

Chronic liver diseases (CLDs) have diverse etiologies. To better classify CLDs, we explored the ability of longitudinal multiparametric MRI (magnetic resonance imaging) in depicting alterations in liver morphology, inflammation, and hepatocyte and macrophage activity in murine high-fat diet (HFD)- and carbon tetrachloride (CCl4)-induced CLD models. Mice were either untreated, fed an HFD for 24 weeks, or injected with CCl4 for 8 weeks. Longitudinal multiparametric MRI was performed every 4 weeks using a 7 T MRI scanner, including T1/T2 relaxometry, morphological T1/T2-weighted imaging, and fat-selective imaging. Diffusion-weighted imaging was applied to assess fibrotic remodeling and T1-weighted and T2*-weighted dynamic contrast-enhanced MRI and dynamic susceptibility contrast MRI using gadoxetic acid and ferucarbotran to target hepatocytes and the mononuclear phagocyte system, respectively. Imaging data were associated with histopathological and serological analyses. Principal component analysis and clustering were used to reveal underlying disease patterns. The MRI parameters significantly correlated with histologically confirmed steatosis, fibrosis, and liver damage, with varying importance. No single MRI parameter exclusively correlated with 1 pathophysiological feature, underscoring the necessity for using parameter patterns. Clustering revealed early-stage, model-specific patterns. Although the HFD model exhibited pronounced liver fat content and fibrosis, the CCl4 model indicated reduced liver fat content and impaired hepatocyte and macrophage function. In both models, MRI biomarkers of inflammation were elevated. Multiparametric MRI patterns can be assigned to pathophysiological processes and used for murine CLD classification and progression tracking. These MRI biomarker patterns can directly be explored clinically to improve early CLD detection and differentiation and to refine treatments.