Elevated Systemic Inflammation Research Articles

Socioeconomic adversity, maternal nutrition, and the prenatal programming of offspring cognition and language at two years of age through maternal inflammation

Increasing rates of child neurodevelopmental vulnerability are a significant public health challenge. The adverse effect of socioeconomic adversity on offspring cognition may be mediated through elevated prenatal maternal systemic inflammation, but the role of modifiable antecedents such as maternal nutrition has not yet been clarified. This study aimed to examine (1) whether prenatal factors, with an emphasis on maternal nutrition, were associated with prenatal maternal systemic inflammation at 28 weeks’ gestation, including the metabolomic marker glycoprotein acetyls (GlycA); (2) the extent to which the association between prenatal maternal nutrition and child cognition and language at age two years was mediated by elevated maternal inflammation in pregnancy; (3) the extent to which the associations between prenatal socioeconomic adversity and child neurodevelopment were mediated through prenatal maternal nutrition and GlycA levels. We used a prospective population-derived pre-birth longitudinal cohort study, the Barwon Infant Study (Barwon region of Victoria, Australia), where 1074 mother–child pairs were recruited by 28 weeks’ gestation using an unselected sampling frame. Exposures included prenatal factors such as maternal diet measured by a validated food frequency questionnaire at 28 weeks’ gestation and dietary patterns determined by principal component analysis. The main outcome measures were maternal inflammatory biomarkers (GlycA and hsCRP levels) at 28 weeks’ gestation, and offspring Bayley-III cognition and language scores at age two years. Results showed that the ‘modern wholefoods’ and ‘processed’ maternal dietary patterns were independently associated with reduced and elevated maternal inflammation respectively (GlycA or hsCRP p < 0.001), and also with higher and reduced offspring Bayley-III scores respectively (cognition p ≤ 0.004, language p ≤ 0.009). Associations between dietary patterns and offspring cognition and language were partially mediated by higher maternal GlycA (indirect effect: cognition p ≤ 0.036, language p ≤ 0.05), but were less evident for hsCRP. The maternal dietary patterns mediated 22 % of the association between socioeconomic adversity (lower maternal education and/or lower household income vs otherwise) and poorer offspring cognition (indirect effect p = 0.001). Variation in prenatal GlycA levels that were independent of these dietary measures appeared less important. In conclusion, modifiable prenatal maternal dietary patterns were associated with adverse child neurocognitive outcomes through their effect on maternal inflammation (GlycA). Maternal diet may partially explain the association between socioeconomic adversity and child neurocognitive vulnerability. Maternal diet-by-inflammation pathways are an attractive target for future intervention studies.

Association of Systemic Inflammation Level on Admission with Total and Cardiovascular‑Specific Death in Heart Failure with Preserved Ejection Fraction: A Large Multi‑Center Retrospective Longitudinal Study.

Heart failure with preserved ejection fraction (HFpEF) is inherently a complex inflammatory syndrome, and heightened inflammation is strongly associated with an increased risk of death. However, the association of systemic inflammation levels with total and cardiovascular death among patients with HFpEF remains unknown. We aimed to investigate the prognostic impact of systemic inflammation on all-cause and cardiovascular death among patients with HFpEF. Patients with HFpEF were included in this study. Systemic inflammation response index (SIRI) is defined as the multiplication of neutrophil and monocyte divided by lymphocyte count, and patients were divided into four groups based on SIRI quartiles. Cox regression models and competing risk models were used to examine the relationships between SIRI and total and cardiovascular‑specific mortality, respectively. 9,986 patients with HFpEF were included in five tertiary hospitals. During a median follow-up period of 4.4 years, a total of 2004 patients died, of which 965 were cardiovascular deaths. After fully adjusting for confounders, elevated SIRI level was significantly related to the increased risk of all-cause death (Q2, Q3, Q4: adjusted hazard ratio (aHR) [95 confidence interval (CI)%] =1.17[1.01-1.35], 1.31[1.13-1.52], 1.51[1.30-1.76], respectively; P for trend <0.001). The elevated quartile of SIRI showed higher risks of cardiovascular death, but there was no statistically significant increased risk of cardiovascular death across the lower SIRI quartile (model 3: Q2, Q3, Q4: aHR [95CI%] =1.22[0.99-1.51], 1.50[1.20-1.86], 1.73[1.37-2.18], respectively; P for trend <0.001). Elevated systemic inflammation level on admission was correlated with an increased risk of all-cause and cardiovascular death among patients with HFpEF. The SIRI may serve as a promising marker of risk stratification for patients with HFpEF.

Association between elevated systemic inflammatory markers and the risk of cognitive decline progression: a longitudinal study.

Chronic systemic inflammation is linked to cognitive decline pathogenesis. This study investigates the association between systemic inflammation markers and cognitive decline progression in a clinical cohort. This prospective observational cohort study enrolled 295 participants. Cognitive decline progression was defined by an increase in clinical dementia rating (CDR) scores. The study examines the correlation between systemic inflammation markers, including systemic Inflammation Response Index (SIRI), systemic Immune-Inflammation Index (SII), prognostic Inflammatory and Nutritional Index (PIV), and cognitive impairment progression. The presence of the APOE 4 allele and diabetes mellitus was associated with elevated PIV levels (P < 0.05). Additionally, AD patients had the highest SII levels, indicating increased inflammation compared to individuals with MCI and SCD (P < 0.05). After a mean follow-up of 17 months, 117 patients (51.31%) experienced cognitive decline progression. AD diagnosis, CDR, and SII were significant predictors of cognitive decline progression (All P < 0.05). This study highlights the clinical significance of elevated systemic inflammation markers in identifying individuals at risk of cognitive decline. Addressing inflammation may offer a promising approach to improving cognitive health and mitigating age-related cognitive decline.

Socioeconomic Disadvantage Moderates the Association of Systemic Inflammation With Amygdala Volume in Adolescents Over a 2-Year Interval: An Exploratory Study

BackgroundResearch has demonstrated an association between elevated systemic inflammation and changes in brain function. Affective areas of the brain involved in processing threat (e.g., amygdala) and reward (e.g., nucleus accumbens) appear to be sensitive to inflammation. Early-life stress, such as experiencing low socioeconomic status (SES), may also potentiate this association, but relevant evidence has come primarily from cross-sectional studies of brain function. It is unclear whether similar associations are present between early-life stress, inflammation, and brain structure, particularly in typically developing populations. MethodsWe recruited and assessed 50 adolescents (31 females/19 males) from the community (mean [SD] age = 15.5 [1.1] years, range = 13.1–17.5 years) and examined in exploratory analyses whether changes in C-reactive protein (ΔCRP) from blood spots predict changes in gray matter volume (ΔGMV) in the bilateral amygdala and nucleus accumbens over a 2-year period. We also investigated whether experiencing early-life stress, operationalized using a comprehensive composite score of SES disadvantage at the family and neighborhood levels, significantly moderated the association between ΔCRP and ΔGMV. ResultsWe found that ΔCRP was negatively associated with Δamygdala GMV (i.e., increasing CRP levels were associated with decreasing amygdala volume; β = −0.84, p = .012). This effect was stronger in youths who experienced greater SES disadvantage (β = −0.56, p = .025). ConclusionsThese findings suggest that increases in systemic inflammation are associated with reductions in amygdala GMV in adolescents, potentially signaling accelerated maturation, and that these neuroimmune processes are compounded in adolescents who experienced greater SES disadvantage. Our findings are consistent with theoretical frameworks of neuroimmune associations and suggest that they may influence adolescent neurodevelopment.

Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and non-recovery in ACLF. Here we mapped the single-cell transcriptome of circulating immune cells from ACLF-, acute decompensated (AD) cirrhosis patients and healthy individuals. We further interrogate how these findings as well as immunometabolic- and functional profiles associate with ACLF recovery (ACLF-R) or non-recovery (ACLF-NR). Our analysis unveiled two distinct states of classical monocytes (cMon). Hereto, ACLF-R cMons were characterized by transcripts associated with immune- and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1. Additional metabolomic- and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program and blunted activation among lymphoid populations in ACLF-R patients. Conversely, ACLF-NR cMon featured elevated expression of inflammatory- and stress response genes such as VIM, LGALS2, and TREM1 along with blunted metabolic activity and increased functionality. This study identifies distinct immuno-metabolic cellular states that contribute to disease outcome in ACLF patients. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or non-recovery phenotypes which may be harnessed as potential therapeutic targets in the future.

Reoxygenation Mitigates Intermittent Hypoxia-Induced Systemic Inflammation and Gut Microbiota Dysbiosis in High-Fat Diet-Induced Obese Rats.

Obstructive sleep apnea (OSA) is a prevalent sleep breathing disorder characterized by intermittent hypoxia (IH), with continuous positive airway pressure (CPAP) as its standard treatment. However, the effects of intermittent hypoxia/reoxygenation (IH/R) on weight regulation in obesity and its underlying mechanism remain unclear. Gut microbiota has gained attention for its strong association with various diseases. This study aims to explore the combined influence of IH and obesity on gut microbiota and to investigate the impact of reoxygenation on IH-induced alterations. Diet-induced obese (DIO) rats were created by 8-week high-fat diet (HFD) feeding and randomly assigned into three groups (n=15 per group): normoxia (NM), IH (6% O2, 30 cycles/h, 8 h/day, 4 weeks), or hypoxia/reoxygenation (HR, 2-week IH followed by 2-week reoxygenation) management. After modeling and exposure, body weight and biochemical indicators were measured, and fecal samples were collected for 16S rRNA sequencing. DIO rats in the IH group showed increased weight gain (p=0.0016) and elevated systemic inflammation, including IL-6 (p=0.0070) and leptin (p=0.0004). Moreover, IH rats exhibited greater microbial diversity (p<0.0167), and significant alterations in the microbial structure (p=0.014), notably the order Clostridiales, accompanied by an upregulation of bile acid metabolism predicted pathway (p=0.0043). Reoxygenation not only improved IH-exacerbated obesity, systemic inflammation, leptin resistance, and sympathetic activation, but also showed the potential to restore IH-induced microbial alterations. Elevated leptin levels were associated with Ruminococcaceae (p=0.0008) and Clostridiales (p=0.0019), while body weight was linked to Blautia producta (p=0.0377). Additionally, the abundance of Lactobacillus was negatively correlated with leptin levels (p=0.0006) and weight (p=0.0339). IH leads to gut dysbiosis and metabolic disorders, while reoxygenation therapy demonstrates a potentially protective effect by restoring gut homeostasis and mitigating inflammation. It highlights the potential benefits of CPAP in reducing metabolic risk among obese patients with OSA.

C-Jun N-Terminal Kinase-2 (JNK2) Plays a Crucial Role in Alcohol and Corticosterone-Induced Dysbiosis of Gut Microbiota and Tissue Injury at the Gut-Liver Axis

Introduction: About 15% of heavy drinkers develop liver disease, suggesting the “Multiple hit hypothesis” of Alcohol-Associated Liver Diseases (AALD). Chronic stress is a potential second hit in AALD pathogenesis. Our recent study showed that alcohol-induced gut and liver injury is exacerbated by chronic restraint stress or corticosterone. JNK2 plays an essential role in stress-induced cell injury. In this study, we investigated the role of JNK2 in ethanol (EtOH) and corticosterone-induced gut and liver injury and microbiota dysbiosis in mice. Methods: Wildtype (WT) and JNK2 knockout (JNK2-KO) mice (male and female; 8-10 wks) were fed a Lieber-DiCarli liquid diet with or without EtOH (0% 2d, 1% 2d, 2% 2d, 4% 1wk, 5% 1wk, &amp; 6% 1wk). Control groups were pair-fed isocaloric EtOH-free diet. One group of pair-fed and EtOH-fed WT and JNK2-KO mice were administered corticosterone (CORT, 25 mg/kg/day; s.c.). Intestinal permeability was measured by vascular-to-luminal flux of FITC-inulin in vivo, tight junction (TJ) and adherens junction (AJ) integrity was assessed by confocal microscopy for occludin, ZO-1, E-cadherin, and β-catenin, and mucosal inflammation by RT-PCR for cytokines/chemokines. Plasma lipopolysaccharide (LPS) and cytokines were measured to evaluate endotoxemia and systemic inflammation. Liver damage was assessed by measuring plasma AST/ALT, liver triglyceride, and cytokine/chemokine mRNA. Gut microbiota was analyzed by 16S rRNA sequencing of colonic flushing followed by bioinformatics analyses. Results and conclusion: In WT mice, EtOH feeding increased intestinal permeability, disrupted epithelial TJ and AJ, and elevated mucosal cytokine expression, indicating epithelial barrier dysfunction and mucosal inflammation. EtOH increased plasma LPS and cytokine/chemokine levels, indicating endotoxemia and systemic inflammation. Plasma AST/ALT and liver triglyceride levels were increased, indicating EtOH-induced liver damage. CORT significantly elevated EtOH-induced intestinal permeability, TJ/AJ disruption, endotoxemia, systemic inflammation, and liver damage in WT mice. These effects of EtOH and CORT were absent in JNK2-KO mice. Microbiota α-diversity was higher in JNK2-KO mice than in WT mice, and β-diversity analysis showed that the microbiota composition in WT mice differed from that of KO mice. Microbiota α- and β-diversities were altered by EtOH and CORT in WT mice but not in JNK2-KO mice. The relative abundance of Nocardiaceae and Verrucomicrobiaceae was high, and Ruminococcaceae and Bacillaceae were low in KO mice. CORT decreased the abundance of Caulobacteriaceae and Ruminococcaceae and increased Verrucomicrobiaceae and Lactobacillaceae in WT but not KO mice. EtOH increased Ruminococcaceae and Bacillaceae and decreased Lactobacillaceae in WT mice but not KO mice. CORT-induced modulation of EtOH-induced microbiota dysbiosis was observed in WT mice but not KO mice. In conclusion, these data demonstrate that JNK2 regulates gut microbiota in mice, and JNK2 deficiency confers resistance to alcohol and corticosterone-induced tissue injury and microbiota dysbiosis. Acknowledgements: NIH/NIAAA - R01AA012307, AA029270; VA - IO1BX003014. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 2516: Influence of pre-treatment nutrition and inflammation on immunotherapy response in non-small cell lung cancer

Abstract Purpose: Immune checkpoint inhibitor therapy (ICI) is effective in non-small-cell lung cancer (NSCLC) but only a minority respond, likely due in part to the gut microbiome. Given the coupling of host nutritional status and gut microbiota composition, we investigated the pre-treatment associations of nutritional status and biomarkers with ICI treatment response and survivals. Methods: We recruited stage III-IV NSCLC patients. Pre-ICI treatment clinical information and blood samples were obtained. Clinician assessed ICI response and survival data were recorded. The nutritional/inflammatory indicators were compared based on treatment response and survivals. ICI Clinical Benefit was defined as 12-month progression free survival. Pearson Chi-square or Fisher’s Exact test was used to compare categorical metrics; non-parametric analysis compared continuous metrics by treatment response. Overall survivals were assessed using multivariable Cox proportional hazards models to estimate associations. Results: Of the 76 patients recruited, all were ECOG performance status 0 (14.5%) or 1 (85.5%). 36 (47%) had Clinical Benefit with median survival 21.3 mo. vs. 6.6 mo. among the No Clinical Benefit patients (p&amp;lt;0.01). Non-responders had significantly more often weight loss, lower serum albumin, elevated red cell distribution index (RDW) and worse scores for Frailty Index, Geriatric Nutritional Risk Index and Mini-Nutritional Assessment (MNA). Non-responders had significantly more inflammation with a higher Systemic Immune Response Index (SIRI) and RDW. Overall survival was negatively correlated with: 1. weight loss; 2. low serum albumin; 3. low serum sodium; 4. high RDW; 5. elevated total neutrophils, total white blood cells, total monocytes, neutrophil to lymphocyte ratio, and monocyte to lymphocyte ratio; 6. adverse MNA and Geriatric Nutritional Risk Index; 7. elevated SIRI and Systemic Immune Inflammation Index (SII). ICI response prediction accuracy using a solely MNA-based model was significantly high in terms of AUROC of 0.85 [95% CI= (0.76, 0.93); p&amp;lt;0.05]. In multivariable analysis, the predictor of immunotherapy response and survival was the 6-measure MNA which strongly correlates with weight loss, low serum albumin and depressed Frailty Index. Conclusions: An adverse nutritional status with accompanying chronic inflammation is strong predictor of non-response to ICI. Since lung cancer patients with depressed pre-treatment nutrition have a low likelihood of an ICI response, they should be promptly referred for dietician consultation for intensive nutritional therapy which may improve their clinical outlook. Considering the negative association of malnutrition/inflammation with response to ICI treatment in NSCLC patients who still qualify as ECOG performance status 0-1 patients, prospective clinical trials should also stratify their results by nutritional status. Citation Format: Lary A. Robinson, Youngchul Kim, Acadia Buro, Stephanie R. Hogue, Alexis Bailey, Gina M. DeNicola, Christine Pierce, Mark Umbarger, Doratha A. Byrd. Influence of pre-treatment nutrition and inflammation on immunotherapy response in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2516.

Chronic Gut Inflammation and Dysbiosis in IBS: Unraveling Their Contribution to Atopic Dermatitis Progression.

Emerging evidence suggests a link between atopic dermatitis (AD) and gastrointestinal disorders, particularly in relation to gut microbial dysbiosis. This study explored the potential exacerbation of AD by gut inflammation and microbial imbalances using an irritable bowel syndrome (IBS) mouse model. Chronic gut inflammation was induced in the model by intrarectal injection of 2,4,6-trinitrobenzene sulfonic acid (TNBS), followed by a 4-week development period. We noted significant upregulation of proinflammatory cytokines in the colon and evident gut microbial dysbiosis in the IBS mice. Additionally, these mice exhibited impaired gut barrier function, increased permeability, and elevated systemic inflammation markers such as IL-6 and LPS. A subsequent MC903 challenge on the right cheek lasting for 7 days revealed more severe AD symptoms in IBS mice compared to controls. Further, fecal microbial transplantation (FMT) from IBS mice resulted in aggravated AD symptoms, a result similarly observed with FMT from an IBS patient. Notably, an increased abundance of Alistipes in the feces of IBS mice correlated with heightened systemic and localized inflammation in both the gut and skin. These findings collectively indicate that chronic gut inflammation and microbial dysbiosis in IBS are critical factors exacerbating AD, highlighting the integral relationship between gut and skin health.

Childhood Maltreatment and Immune Cell Gene Regulation during Adolescence: Transcriptomics Highlight Non-Classical Monocytes.

Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13-17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function.

Complete Blood Cell Count-Derived Inflammation Biomarkers and the Need for Laser Capsulotomy Due to Posterior Capsule Opacification Following Cataract Surgery.

Inflammation plays a significant role in the proliferation, migration, and differentiation of lens epithelial cells after cataract surgery, clinically manifested as posterior capsule opacification (PCO). This condition is typically treated with neodymium: yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy. Our objective is to evaluate the association between blood-derived inflammatory markers and the development of clinically significant PCO necessitating treatment with laser capsulotomy. We conducted a retrospective review of charts for all patients who underwent Nd:YAG laser capsulotomy in our department between January 2021 and December 2022. The study included 70 patients who diagnosed with clinically significant PCO requiring treatment with Nd:YAG laser capsulotomy following cataract surgery, as well as 70 pseudophakic controls with no signs of PCO. Complete blood cell count parameters were obtained from medical records and the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) were calculated. The mean age of the Nd:YAG laser capsulotomy and control group was 71.83±8.46 and 72.27±9.98 years, respectively. The preoperative NLR scores for the Nd:YAG laser capsulotomy group (mean rank = 34.43) were statistically significantly higher than those of the control group (mean rank = 25.41) (p = 0.044). However, after adjusting for preoperative measurements, no statistically significant differences were observed between the groups for the other parameters. Preoperative NLR scores were higher in patients who developed clinically significant PCO requiring treatment with Nd:YAG laser capsulotomy. This finding suggests that patients with elevated systemic inflammation may be at an increased risk of developing PCO following cataract surgery. Further research is needed to evaluate the role of systemic inflammation in the pathogenesis of PCO.

Socioeconomic and Inflammatory Correlates of Plasma Cortisol Among Individuals with Sickle Cell Disease

Introduction: Cortisol plays a critical role in the biological link between stress and health outcomes. It is frequently investigated in the association between socioeconomic stress and morbidity, and the hypothesized biological mechanism by which socioeconomic stress and cortisol impact health is through chronically elevated systemic inflammation. This research is relevant to individuals with sickle cell disease (SCD) for several reasons. First, up to 40% of children and adolescents with SCD are impacted by neighborhood poverty. Furthermore, individuals with SCD are faced with significant disease-related morbidities, such as chronic and acute pain, renal injury, and cerebrovascular disease that are further complicated by elevated inflammatory markers. Finally, cortisol is heavily understudied in this population, with no research investigating socioeconomic or inflammatory correlates. The purpose of this study was to investigate plasma cortisol and its association with neighborhood-level socioeconomic factors (income and poverty) and immunomodulatory cytokines (IL-6, IL-10), among individuals with SCD. Method: Plasma from individuals with SCD within Children's Hospital of Philadelphia (CHOP) and University of Pennsylvania School of Medicine (Penn Medicine) BioBanks were identified. A cortisol radioimmunoassay was used to determine plasma cortisol levels. The Olink immune response panel was used to measure plasma levels of 92 proteins involved in inflammatory pathways. Home address collected from electronic health records was used to determine neighborhood census tract geoid, which was then used to collect data on median neighborhood income and percentage of families living in poverty from the 2020 American Census Survey. Bivariate and multivariate analyses were conducted across 4 subgroups in the total sample: pediatric patients, adult patients, SCA (HbSS/HbSß 0), and other SCD genotypes (HbSC/HbSß +). Control samples (healthy and sickle cell trait; n = 22) without neighborhood information were also available for comparison. Results: Fifty-four independent outpatient samples were identified after excluding duplicates and siblings. Twenty-seven samples were from children and adolescents receiving pediatric care at CHOP (Range age = .8 to 21; Mage= 13.6, SD = 5.3; 51.9% female, 74.1% SCA) and 27 samples were from adults receiving care at Penn Medicine (Range age = 19 to 56; Mage= 35.8, SD = 10.1; 51.9% female, 51.9% SCA). There were no significant differences in cortisol levels across each subgroup ( Mpeds= 16.6, SDpeds = 6.2; Madult= 13.4, SDadult = 6.9; MSCA= 15.1, SDSCA = 7.1; MSCD= 14.9, SDSCD = 6.3). Neighborhood income and poverty did not differ across pediatric and adult patients, and income did not differ across SCD types. However, neighborhood poverty was lower among patients with SCA ( M = 13.9; SD = 11.9) relative to other SCD genotypes ( M = 21.7; SD = 13.5; p = .041). Bivariate Spearman analyses found that neighborhood variables were not correlated with cortisol or cytokines in the total sample or subgroups. Yet, multivariate analyses controlling for sex and time of blood draw showed a positive main effect for patient age ( p = .019) and a significant age by poverty interaction ( p = .041) predicting cortisol among pediatric patients. Cortisol levels were higher with age, yet the association among poverty and cortisol was strongest in younger patients. Analyses also showed a sex*poverty interaction among pediatric patients that approached significance ( p = .081), such that poverty only predicted cortisol in male patients. There were no significant differences for immunomodulatory cytokines across each SCD subgroups; however, IL-6 and IL-10 were elevated in patients with SCA relative to healthy controls ( p IL6 = .021; p IL10 = .003). Bivariate Spearman correlations showed that cortisol was positively related to IL-6 (rho [ρ]= .38, p = .027) and IL-10 (ρ= .34, p = .048) among patients with SCA. There were no additional significant bivariate or multivariate effects. Conclusion: Neighborhood factors likely have downstream effects on the biological stress response and inflammation in SCD. Further research must be conducted to elucidate concurrent and prospective associations among neighborhood socioeconomic factors, stress-related cortisol response, and inflammatory outcomes when extending this work to investigate the impact of stress on SCD morbidity and mortality.

Influence of Lp(a) and systemic inflammation on all-cause mortality in a primary prevention population: data from our clinic database

Abstract Background Epidemiological, pathophysiological, and genetic studies have established Lp(a) as a causal risk factor for development of cardiovascular (CVD) and valvular heart disease. However, there is controversy about how inflammation can modulate Lp(a) risk and major adverse cardiovascular events. We aim to investigate the influence of elevated Lp(a) and systemic inflammation on all-cause mortality in a primary prevention setting. Method We analyzed data obtained from the Preventive Cardiology Information System (PreCis), a database of clinical and laboratory information on 8,136 primary prevention patients seen at our clinic preventive cardiology clinic between 1st Jan 1999-12th Dec 2018. Primary prevention was defined as having no history of coronary artery disease (CAD), coronary and peripheral arterial revascularization, nor atherosclerosis. Lp(a) ≥50 mg/dL was considered as clinically elevated. The association between Lp(a) and the demographic and clinical variables of interest was examined using the student’s t-test or Chi-squared test. All-cause mortality was assessed using Kaplan-Meier estimates, and adjusted Cox proportional hazards models. All statistical analyses were conducted using SAS version 9.4. Result In the overall primary prevention population (n=8,136), the median age was 54 years, with 56.9% women and 84.8% being Caucasian. In this cohort, 21% had hypertension, and 5.5% had diabetes. The median Lp(a) was 21 mg/dL (interquartile interval 7-57 mg/dL). Lp(a) was ≥50 mg/dL in 29% of the population. Of those with elevated Lp(a) (n=2,368), 1,751 (73.9%) patients had hsCRP drawn. In this group, 782 patients (44.7%) had hsCRP &amp;lt;2 mg/L and 969 (55.3%) had hsCRP ≥2 mg/L. The all-cause mortality rate in individuals with elevated Lp(a) and hsCRP ≥2mg/L was 9.2% compared to 4.2% in those with elevated Lp(a) and hsCRP &amp;lt;2mg/L. In a multivariable Cox proportional hazard regression model adjusted for age and gender, in patients with elevated Lp(a), hsCRP ≥2 mg/L was significantly associated with all-cause mortality (HR 2.35, 95% CI (1.57-3.53), p&amp;gt;0.001) (Figure 1). Conclusion In a primary prevention population without established atherosclerosis, elevated Lp(a), increased systemic inflammation was associated with increased all-cause mortality. This finding supports the need for risk classification and targeted primary prevention management of higher risk patients with elevated Lp(a).

Inflammatory biomarkers link perceived stress with metabolic dysregulation

ObjectivePerceived stress has been identified as a risk factor for metabolic syndrome. However, the intermediate pathways underlying this relationship are not well understood. Inflammatory responses may be one process by which stress leads to metabolic dysregulation. Prior work has shown that chronic stress is associated with elevated systemic inflammation and that altered inflammatory activity contributes to the pathogenesis of metabolic syndrome. The current analyses tested this hypothesis by examining inflammation as a pathway by which perceived stress affects metabolic health. MethodsData from the Midlife in the United States Study (MIDUS) (N = 648; Mean age = 52.3) provided measures of perceived stress, inflammatory biomarkers [C-reactive protein (CRP), interleukin-6 (IL-6), E-selectin, fibrinogen, intracellular adhesion molecule-1 (ICAM-1)] and metabolic health markers. Confirmatory factor analysis (CFA) was used to confirm the fit of a hierarchical model of metabolic syndrome in our sample. Structural equation modeling (SEM) was used to test the assumption that inflammation mediates the association between perceived stress and the latent factor representing metabolic syndrome. ResultsThe CFA of metabolic syndrome demonstrated excellent goodness of fit to our sample [CFI = 0.97, TLI = 0.95, RMSEA = 0.06, SMSR = 0.05]. Mediation analysis with SEM revealed that the indirect pathway linking stress to metabolic dysregulation through inflammation was significant [B = 0.08, SE = 0.01, z = 3.69, p < .001, 95% confidence interval CI (0.04, 0.13)]. ConclusionsThese results suggest that inflammatory biomarkers are a viable explanatory pathway for the relationship between perceived stress and metabolic health consequences. Interventions that target psychosocial stress may serve as cost-effective and accessible treatment options for mitigating inflammatory health risks.

Elevated systemic inflammation level increases the risk of incident cancer mortality among patients with coronary artery disease.

Elevated systemic inflammation level increases the risk of incident cancer mortality among patients with coronary artery disease.

Enhanced inflammasome-mediated inflammation and impaired autophagy in peripheral blood mononuclear cells is associated with non-alcoholic fatty liver disease severity

AimsIdentification of the progress of non-alcoholic fatty liver disease (NAFLD) is crucial for their effective treatment. Circulating peripheral blood mononuclear cells (PBMC) could be a surrogate monitor instead of complicated and expensive biopsies. Changes in immuno-metabolic status in NAFLD patients may be reflected by an expression of different PBMC-specific molecular markers. It was hypothesized that impaired autophagy with enhanced inflammasome activation is a critical molecular event in PBMC that could contribute to systemic inflammation associated with NAFLD progression. Main methodsA cross-sectional study with a sample size of 50 subjects were undertaken from a governmental facility in Kolkata, India. Major anthropometric, biochemical, and dietary parameters were recorded. Cellular and serum samples of NAFLD patients were analyzed for oxidative stress, inflammation, inflammasome activation, and autophagic flux by western blot, flow cytometry, immunocytochemistry. Key findingsBaseline anthropometric and clinical parameters were found associated with NAFLD severity. Elevated systemic inflammation was reflected by higher proinflammatory markers like iNOS, Cox-2, IL-6, TNF-α, IL-1β, hsCRP in the serum of NAFLD subjects (p < 0.05). ROS-induced NLRP3 inflammasomes marker proteins were upregulated (p < 0.05) in PBMC along with NAFLD severity. Expression of autophagic markers such as LC3B, Beclin-1 and its regulator pAMPKα were found diminished (p < 0.05) with a concomitant rise of p62. Colocalization of NLRP3 with LC3B proteins in PBMC was found diminished along NAFLD severity. SignificancePresent data provide mechanistic evidence of impaired autophagy and intracellular ROS triggered inflammasome activation in PBMC, which could potentially exacerbate NAFLD severity.

Elevated C-reactive protein mediates the liver-brain axis: a preliminary study.

Chronic liver diseases of all etiologies exist along a spectrum with varying degrees of hepatic fibrosis. Despite accumulating evidence implying associations between liver fibrosis and cognitive functioning, there is limited research exploring the underlying neurobiological factors and the possible mediating role of inflammation on the liver-brain axis. Using data from the UK Biobank, we examined the cross-sectional association of liver fibrosis (as measured by Fibrosis-4 score) with cognitive functioning and regional grey matter volumes (GMVs) while adjusting for numerous covariates and multiple comparisons. We further performed post-hoc preliminary analysis to investigate the mediating effect of C-reactive protein (CRP) on the association between liver fibrosis and both cognitive functioning and GMVs. We analysed behaviour from up to 447,626 participants (N ranged from 45,055 to 447,533 per specific cognitive metric) 37 years and older. 38,244 participants (age range 44-82 years) had GMV data collected at a median 9-year follow-up. Liver fibrosis showed significant associations with cognitive performance in reasoning, working memory, visual memory, prospective memory, executive function, and processing speed. Subgroup analysis indicated larger effects sizes for symbol digital substitution but smaller effect sizes for trail making in middle-aged people than their old counterparts. Neuroimaging analyses revealed significant associations between liver fibrosis and reduced regional GMVs, primarily in the hippocampus, thalamus, ventral striatum, parahippocampal gyrus, brain stem, and cerebellum. CRP levels were significantly higher in adults with advanced liver fibrosis than those without, indicating an elevated systemic inflammation. Moreover, the serum CRP significantly mediated the effect of liver fibrosis on most cognitive measures and regional GMVs in the hippocampus and brain stem. This study provides a well-powered characterization of associations between liver fibrosis, cognitive impairment, and grey matter atrophy. It also highlights the possibly mediating role of systemic inflammation on the liver-brain axis. Early surveillance and prevention of liver diseases may reduce cognitive decline and brain GMV loss. National Science Foundation, and National Institutes of Health.

Acute Limb Ischemia Rutherford Classification III and COVID-19: A Case Report

Background: COVID-19 is caused by SARS-CoV-2 infections, which are responsible for the recent pandemic. COVID-19 infection increases thromboembolic events, including Acute Limb Ischemia (ALI) by causing elevated cytokine levels, systemic inflammation, hypercoagulation state, and hyperinflammation responses. This complication might cause loss of limbs. Case description: We report a case of a 61-year-old male with COVID-19 who developed an ALI. He presented to the emergency department with acute left leg pain since a day before admission and shortness of breath three days before admission. His left foot was bluish-discolored, cold to the touch, and mottled in appearance. Chest x-ray showed bilateral inhomogeneous consolidation. Left lower limb X-ray revealed a gangrenous appearance. CT-Angiography suggested severe distal stenosis of the left femoral artery with complete occlusion of its distal aspect. COVID-19 was diagnosed based on RT-PCR testing. He received antibiotics and anticoagulation. Unfortunately, he underwent an amputation procedure. Conclusion: A high index of suspicion should be maintained for ALI in COVID-19 patients, which is a vascular emergency. Some patients can achieve revascularization with observation or medical and/or surgical intervention, but other patients succumb to either amputation or death.

Central role for neurally dysregulated IL-17A in dynamic networks of systemic and local inflammation in combat casualties

Dynamic Network Analysis (DyNA) and Dynamic Hypergraphs (DyHyp) were used to define protein-level inflammatory networks at the local (wound effluent) and systemic circulation (serum) levels from 140 active-duty, injured service members (59 with TBI and 81 non-TBI). Interleukin (IL)-17A was the only biomarker elevated significantly in both serum and effluent in TBI vs. non-TBI casualties, and the mediator with the most DyNA connections in TBI wounds. DyNA combining serum and effluent data to define cross-compartment correlations suggested that IL-17A bridges local and systemic circulation at late time points. DyHyp suggested that systemic IL-17A upregulation in TBI patients was associated with tumor necrosis factor-α, while IL-17A downregulation in non-TBI patients was associated with interferon-γ. Correlation analysis suggested differential upregulation of pathogenic Th17 cells, non-pathogenic Th17 cells, and memory/effector T cells. This was associated with reduced procalcitonin in both effluent and serum of TBI patients, in support of an antibacterial effect of Th17 cells in TBI patients. Dysregulation of Th17 responses following TBI may drive cross-compartment inflammation following combat injury, counteracting wound infection at the cost of elevated systemic inflammation.

Tumor Necrosis Factor-α Mediates Inflammation-induced Early-Stage Left Ventricular Systolic Dysfunction.

Elevated systemic inflammation contributes to pathogenesis of heart failure with preserved ejection fraction (HFpEF), but molecular mechanisms are poorly understood. Although left ventricular (LV) diastolic dysfunction is the main cause of HFpEF, subclinical systolic dysfunction also contributes. We have previously shown that rats with collagen-induced arthritis (CIA) have systemic inflammation, LV diastolic dysfunction, and that increased circulating TNF-α contributes to inflammation-induced HFpEF pathogenesis, but does not mediate LV diastolic dysfunction in CIA rats. Contribution of systemic inflammation to dysfunction of the active process of LV diastolic and systolic function are unknown. In the present study, we used the CIA rat model to investigate the effects of systemic inflammation and TNF-α blockade on systolic function, and mRNA expression of genes involved in active diastolic relaxation and of myosin heavy chain (MyHC) isoforms. Collagen inoculation and TNF-α blockade did not affect LV mRNA expression of genes that mediate active LV diastolic function. Collagen-induced inflammation impaired LV global longitudinal strain ( P = 0.03) and velocity ( P = 0.04). This impairment of systolic function was prevented by TNF-α blockade. Collagen inoculation decreased mRNA expression of α-MyHC ( Myh6, P = 0.03) and increased expression of β-MyHC ( Myh7, P = 0.0002), a marker, which is upregulated in failing hearts. TNF-α blockade prevented this MyHC isoform-switch. These results show that increased circulating TNF-α changes the relative expression of MyHC isoforms, favoring β-MyHC, which may underlie changes in contractile function that impair systolic function. Our results indicate that TNF-α initiates early-stage LV systolic, rather than LV diastolic dysfunction.