Acute Inflammatory Markers Research Articles

Plasma Biomarkers of Risk of Tuberculosis Recurrence in HIV Co-Infected Patients From South Africa.

There is an urgent need to identify immunological markers of tuberculosis (TB) risk in HIV co-infected individuals. Previously we have shown that TB recurrence in HIV co-infected individuals on ART was associated with markers of systemic inflammation (IL-6, IL1β and IL-1Rα). Here we examined the effect of additional acute inflammation and microbial translocation marker expression on risk of TB recurrence. Stored plasma samples were drawn from the TB Recurrence upon Treatment with HAART (TRuTH) study, in which individuals with previously treated pulmonary TB were screened for recurrence quarterly for up to 4 years. Recurrent TB cases (n = 37) were matched to controls (n = 102) by original trial study arm assignment and ART start date. Additional subsets of HIV infected (n = 41) and HIV uninfected (n = 37) individuals from Improving Recurrence Success (IMPRESS) study were sampled at active TB and post successful treatment completion. Plasma concentrations of soluble adhesion molecules (sMAdCAM, sICAM and sVCAM), lipopolysaccharide binding protein (LBP) and transforming growth factor-beta (TGF-β1, TGF-β2, TGF-β3) were measured by multiplex immunoassays and ELISA. Cytokine data was square root transformed in order to reduce variability. Multivariable analysis adjusted for a number of potential confounders measured at sample time-point: age, BMI, CD4 count, viral load (VL) and measured at baseline: presence or absence of lung cavities, previous history of TB, and WHO disease stage (4 vs 3). The following analytes were associated with increased risk of TB recurrence in the multivariable model: sICAM (aOR 1.06, 95% CI: 1.02-1.12, p = 0.009), LBP (aOR 8.78, 95% CI: 1.23-62.66, p = 0.030) and TGF-β3 (aOR 1.44, 95% CI 1.01-2.05, p = 0.044). Additionally, we observed a positive correlation between LBP and sICAM (r= 0.347, p<0.0001), and LBP and IL-6, identified to be one of the strongest predictors of TB risk in our previous study (r=0.623, p=0.03). These data show that increased risk of TB recurrence in HIV infected individuals on ART is likely associated with HIV mediated translocation of microbial products and the resulting chronic immune activation.

Omega-3 fatty acids ameliorate vascular inflammation: A rationale for their atheroprotective effects

Background and aimsClinical trials have demonstrated reductions in major adverse cardiovascular events with purified high-dose eicosapentaenoic acid (EPA), independent of effects on lipids. We aimed to investigate whether omega-3 fatty acids reduce vascular inflammation, a critical mediator of atherosclerosis, and hypothesised that EPA is superior to docosahexaenoic acid (DHA). MethodsIn a double-blind randomised controlled trial and cell-culture study, 40 healthy volunteers were supplemented with 4 g daily of either EPA, DHA, fish oil (2:1 EPA:DHA), or placebo for 30 days. Serum was incubated with TNF-stimulated human umbilical vein endothelial cells (HUVECs), and markers of acute vascular inflammation (AVI) were measured. The effects of EPA, DHA (600 mg/kg/day), olive oil, or no treatment were also measured in preclinical models of [1] AVI using a periarterial collar (C57Bl/6J; n = 40 mice) and [2] atherosclerosis where ApoE−/− mice (n = 40) were fed a 16-week atherogenic diet. ResultsEPA supplementation reduced expression of C–C motif chemokine ligand 2 (CCL2) by 25% compared to placebo (p = 0.03). In the AVI model, EPA reduced vascular expression of VCAM1 by 43% (p = 0.02) and CCL2 by 41% (p = 0.03). Significant inverse correlations were observed between EPA levels and vascular expression of VCAM1 (r = −0.56, p = 0.001) and CCL2 (r = −0.56, p = 0.001). In ApoE−/- mice, EPA reduced aortic expression of Il1b by 44% (p = 0.04) and Tnf by 49% (p = 0.04), with similar inverse correlations between EPA levels and both Il1b (r = −0.63, p = 0.009) and Tnf (r = −0.50, p = 0.04). ConclusionsSupplementation with EPA, more so than DHA, ameliorates acute and chronic vascular inflammation, providing a rationale for the cardiovascular benefit observed with high dose omega-3 fatty acid administration.

Abstract P343: Relationship of Infarct Volume to Inflammation and Prognostic Significance in Patients With Acute Ischemic Stroke

Background and Purpose: The diffusion weighted imaging (DWI) lesion volumes in acute ischemic stroke (AIS) can be automatically measured using deep learning-based segmentation algorithms. We aim to explore the prognostic significance of artificial intelligence-predicted infarct volume, and the association of markers of acute inflammation with the infarct volume. Methods: 12,598 AIS/TIA patients were included in this analysis. Intarct volume was automatically measured using a U-Net model for acute ischemic stroke lesion segmentation on DWI. Participants were divided into 5 subgroups according to infarct volume. Spearman’s correlations were employed to study the association between infarct volume and markers of acute inflammation. Multivariable logistic regression and Cox proportional hazards model were performed to explore the relationship between infarct volume and the incidence of poor functional outcome (modified Rankin scale score 3-6), stroke recurrence or combined vascular events at 3 months. Results: The U-Net model prediction correlated and agreed well with manual annotation ground truth for infarct volume (r=0.96; P&lt;0.001). There were positive correlations between the infarct volume and markers of acute inflammation (neutrophil [r=0.175; P&lt;0.001], hs-CRP [r=0.180; P&lt;0.001], and IL-6 [r=0.225; P&lt;0.001]). Compared with those without DWI lesions, patients with the largest infarct volume (4th Quartile) were nearly five times more likely to have poor functional outcome (mRS 3-6) (adjusted odds ratio, 4.70; 95% confidence intervals [CI], 3.29-6.72; P for trend&lt;0.001) after adjustment for confounding factors and markers of acute inflammation. The infarct volume category was significantly associated with stroke recurrence (adjusted hazard ratios [HRs], 1.0, 1.43[0.95,2.17], 2.22[1.49,3.29], 2.06[1.40,3.05], 2.26[1.52,3.36]; P for trend&lt;0.001) and combined vascular events(adjusted HRs, 1.0, 1.38[0.92,2.09], 2.25[1.53,3.32], 2.03[1.38,2.98], 2.28[1.54,3.36]; P for trend&lt;0.001). Conclusions: Infarct volume measured automatically by deep learning-based tool was a strong predictor of poor functional outcome as well as stroke recurrence, with the potential for widespread adoption in both research and clinical settings.

Lower Lymphocyte Count is Associated With Increased Risk of Parkinson's Disease.

Objectives:Patients with established Parkinson’s disease (PD) display differences in peripheral blood markers of immune function, including leukocyte differential counts, compared with controls. These differences may be useful biomarkers to predict PD and may shed light on pathogenesis. We sought to identify whether peripheral immune dysregulation was associated with increased risk of subsequent PD diagnosis.Methods:We examined the relationship between incident PD, baseline differential leukocyte count and other blood markers of acute inflammation in UK Biobank (UKB), a longitudinal cohort with ~500,000 participants. We used a range of sensitivity analyses and Mendelian randomization (MR) to further explore the nature of associations.Results:After excluding individuals with comorbidities which could influence biomarkers of inflammation, 465 incident PD cases and 312,125 controls remained. Lower lymphocyte count was associated with increased risk of subsequent PD diagnosis (per 1-SD decrease in lymphocyte count odds ratio [OR] = 1.18, 95% confidence interval [CI] = 1.07–1.32, padjusted = 0.01). There was some evidence that reductions in eosinophil counts, monocyte counts and C-reactive protein (CRP) were associated with increased PD risk, and that higher neutrophil count was also associated. Only the association between lower lymphocyte count and increased PD risk remained robust to sensitivity analyses. MR suggested that the effect of lower lymphocyte count on PD risk may be causal (per 1-SD decrease in lymphocyte count; ORMR = 1.09, 95% CI = 1.01–1.18, p = 0.02).Interpretation:We provide converging evidence from observational analyses in UKB and MR that lower lymphocyte count is associated with an increased risk of subsequent PD.

The course of cervical spinal cord atrophy rate and its relationship with NEDA in relapsing remitting multiple sclerosis.

This study aimed to compare the annualized segmental cervical spinal cord atrophy rate (ASCAR) in the early and late stages of relapsing remitting multiple sclerosis (RRMS), and to investigate the relationship between ASCAR and no evidence of disease activity (NEDA) in RRMS. Participants in this study included early stage MS (EMSg) patients, late stage MS (LMSg) patients, and healthy controls. All of the included participants (n = 175 subjects) were followed up for 14months, and an MRI was performed on each participant at the beginning and at the end of the study. Cervical spinal cord average segmental area (CSCA) was measured by a semi-automated method, and ASCAR (mm2/year) was calculated. Data from the EMSg (n = 81 subjects) and LMSg (n = 94 subjects) patient groups were compared with each other and with the control group (n = 43 subjects). Examination of the initial CSCA values revealed that the baseline CSCA of the control group was larger than that of the EMSg (p < 0.001), and the baseline CSCA of the EMSg was larger than that of the LMSg (p < 0.001). The ASCAR of the control group, LMSg, and EMSg were 0.48, 0.93, and 1.81mm2 (p < 0.001), respectively. Regression analysis revealed that disability increase was associated with ASCAR, while MRI activity and relapse presence were unrelated to ASCAR. In both patient groups, ASCAR was slower in those who fulfilled NEDA but this relationship was not significant. Cervical spinal cord atrophy progression over time occurs at a greater rate in the early stages of RRMS disease compared to the late stages. ASCAR was unrelated to MRI activity and relapse, which are clinical markers of acute inflammation.

The results of investigating the efficacy and safety of non-medical switching from the original rituximab to its biosimilar in rheumatoid arthritis patients (AMBIRA study)

Wide usage of biologic disease-modifying anti-rheumatic drugs (DMARDs) biosimilars in clinical practice has greatly increased the availability of biologic therapy for rheumatic patients. Nevertheless, not only economic expediency but efficacy and safety are the key principals of any treatment including biologic DMARDs. Objective . To investigate the efficacy and safety of switching from the original rituximab (MabThera®, “F. Hoffmann-La Roche Ltd.”, Switzerland) to its biosimilar (Acellbia®, “BIOCAD”, Russia) by non-medical reasons in rheumatoid arthritis patients. Subjects and methods . 40 rheumatoid arthritis patients on basic therapy who had taken at least one course of original rituximab (MabThera®) 1000 mg twice in 2 weeks more than 6 months ago were included. They were switched to equal-dose biosimilar (Acellbia®) by non-medical reasons and were observed throughout the year. At 12, 24 weeks and one year after switching dynamics of the next parameters were evaluated: pain level according to visual analogue scale (VAS), tender joint count (TJC), swollen joint count (SJC), acute inflammatory and immunological markers, disease activity score (DAS28) calculated using erythrocyte sedimentation rate (DAS28-ESR) or C-reactive protein (DAS28-CRP), health assessment questionnaire (HAQ) index and safety profile. Results . All the data are presented as median of indicator in the moment of measurement after switching therapy (Meperiod). In 12-week period TJC [(Me]_0=9.50, Me_12=6.0, p&lt; 0.01) and SJC (Me_0=2,0, Me_12=1,0, p&lt;0.01) were decreased with positive dynamics on the 24 and 48 weeks. Also, similar results were observed in the VAS pain level. DAS28 showed significant decreasing during observation: Me0=4.38, Me24=3.55, Meyear=3.49, p&lt;0.01 for DAS28-ESR; and Me0=3.91, Me24=3.15, Meyear=3.03, p&lt;0.01 for DAS28-CRP. Immunological markers were increased or stable during the first months after switching, but then they were significantly decreased: Me0=45.0 U/ml, Meyear=23.0 U/ml, p&lt;0.01 for rheumatoid factor; and Me0=88.0 U/ml, Meyear=50.5 U/ml, p&lt;0.01 for anti-cyclic citrullinated peptide. HAQ index was stabilized during 1 year: Me0=1.00, Meyear=0.75, p&lt;0.01. Severe infusion reactions on Acellbia® were not observed, safety profile was similar to MabThera®. Conclusion . Our investigation revealed that non-medical switching from original rituximab (MabThera®, “F. Hoffmann-La Roche Ltd.”, Switzerland) to its biosimilar (Acellbia®, “BIOCAD”, Russia) has no significant influence on the therapy efficacy and safety.

IntraIndividual Variability in Serum Alpha-1 Antitrypsin Levels.

Measuring alpha-1 antitrypsin (AAT) serum levels is often the first step when investigating for alpha-1 antitrypsin deficiency (AATD). The purpose of this study was to determine the test-retest reproducibility of AAT serum levels and to determine if between-measurements variability was associated with acute phase markers of inflammation. We retrospectively analyzed a sample of 255 patients from a community respirology practice with chronic obstructive pulmonary disease (COPD) in whom AAT serum levels were measured twice, on separate visits. White blood cell count and fibrinogen were also measured at the time of the second blood sampling as markers of acute phase inflammation. Intraclass correlation coefficient (ICC), Pearson correlation coefficient, and Bland-Altman analysis were used to document test-retest reproducibility. Regression analyses were used to identify potential correlates of test-retest AAT level differences. Although the 2 AAT serum levels were significantly correlated, the between-measurement agreement was weak (ICC of 0.38 [95% confidence interval (CI), 0.27 to 0.48]; Pearson correlation coefficient of 0.34 [95% CI, 0.23 to 0.44]) and Bland-Altman analysis revealed wide 95% limits of agreement. Considering that an AAT serum level below 1.13g/L should trigger further investigations to confirm the AAT status, discrepancies between the test-retest AAT levels resulted in reconsidering requirement for further investigation in 22% of patients. A significant correlation between the fibrinogen value and the second AAT level was found (r=0.21, p=0.004 [n=173]). Serum AAT levels showed weak intra-individual reproducibility which could lead to AATD status misclassification and potentially a missed diagnosis of AATD.

Prophylactic Use of Meloxicam and Paracetamol in Peripartal Sows Suffering From Postpartum Dysgalactia Syndrome

Postpartum dysgalactia syndrome (PPDS) is a major economic problem in modern sow farms. General treatment of PPDS consists of the use of oxytocin to promote milk ejection and non-steroidal anti-inflammatory drugs (NSAIDs) to alleviate inflammatory processes. So far, studies investigated the use of a single administration of NSAIDs after parturition in healthy and non-healthy sows. The current study investigated whether administration of meloxicam or paracetamol in sows prior to parturition improves sow and piglet health as well as performance in a farm with PPDS problems in sows. Sixty sows and 978 piglets from a Belgian farrow-to-finish farm were enrolled. Sows were randomly divided into three groups: a non-treated control group, a meloxicam-treated group and a paracetamol-treated group. Treatment was administered orally for 7 days from gestation day 113 onwards. Performance and health parameters investigated in sows were gestation length, farrowing duration, litter characteristics, colostrum yield and quality (Immunoglobulin G), litter weight gain, weaning-to-estrus interval, pregnancy rate, rectal temperature, acute phase proteins and inflammatory markers serum amyloid A, haptoglobin, interferon γ, interleukin 1β and 6 backfat, constipation and feed refusal. Performance and health parameters in piglets were birthweight, average daily weight gain, colostrum intake and mortality. Paracetamol-treated sows showed a significantly (P = 0.04) lower rectal temperature (mean ± SD: 38.09 ± 0.18°C) than the meloxicam-treated sows (38.24 ± 0.18°C), but not than the control group (38.22 ± 0.18°C). Sows of the paracetamol-treated group had a significantly (P = 0.001) longer gestation length (116.3 ± 0.9 days) than sows of the control group (115.3 ± 0.6 days), but not than meloxicam-treated sows (115.9 ± 0.9 days). No significant differences between the three groups were found for all the other parameters. In conclusion, the prophylactic oral administration of either meloxicam or paracetamol for 7 days starting 2 days prior to farrowing did not show beneficial effects on both health and performance parameters of sows and piglets.

Circulating antioxidant vitamins and copper in Azorean coronary artery disease patients under preventive medication – A case study

Background and aimOxidative stress and inflammation are conditions that are deeply involved in atherosclerosis and consequent coronary artery disease (CAD). Therefore, the aim of this study was to assess the relationship among circulating antioxidant vitamins (C, A, E), copper, and other pro- or antioxidant/inflammation markers in patients with and without CAD under preventive medication. Subjects and methods174 Azorean subjects symptomatic for CAD (age 56 ± 9y; 68 % men) submitted to coronary angiography were split into 2 groups: one formed by CAD patients (≥50 % stenosis in at least one major coronary vessel) and the other by non-CAD patients (<50 % stenosis). Both groups were age-, sex- and BMI-matched. Plasma levels of vitamins or copper were measured by HPLC and AAS, respectively. Results and conclusionsLower vitamin C levels were observed in CAD patients (mainly in women, who exhibited a high rate of diabetes mellitus) as compared to the non-CAD ones. Also, CAD patients (mainly men) exhibited significantly higher concentrations of plasma copper than their non-CAD counterparts (1.17 ± 0.3 mg/L vs. 1.09 ± 0.3 mg/L, p = 0.030). In bivariate analysis, plasma copper levels were positively associated with serum LDL-cholesterol (r=0.22; p = 0.004) and chiefly with C-reactive protein (r=0.40; p < 0.001). Furthermore, they were significantly lower in recurrent vs. non recurrent CAD patients (1.07±0.2 vs. 1.24±0.3 mg/L, p = 0.004). ROC analysis showed that plasma copper, whenever >1.06 mg/L, was an independent risk factor for CAD in primary prevention for men, which suggests that its levels can fluctuate with medical therapy (such as anti-inflammatory), thus indicating that copper is not a reliable marker for CAD. Moreover, plasma copper concentration was not associated with CAD severity. Yet, results do suggest that, even within its reference concentration range, it could be useful as an acute inflammation marker in CAD management.

Impaired autophagy following ex vivo heating at physiologically relevant temperatures in peripheral blood mononuclear cells from elderly adults.

With the increasing threat of climate change and the accompanying rise in the frequency and severity of extreme heat events, there are growing health concerns for heat-vulnerable elderly adults. Elderly adults are at increased risk of developing heat-related injuries, in part due to age-related declines in thermoregulatory and cellular function. Regarding the latter, the process of autophagy is activated as a cellular protective mechanism to counter heat-induced stress, but the extent that heat stress activates autophagy in elderly adults is not known. Further, the interplay between autophagy, the heat shock response (HSR), the acute inflammatory response, and apoptosis remains poorly understood in elderly adults. Therefore, the purpose of this study was to examine changes in autophagy, the HSR, inflammation, and apoptosis following increasing levels of ex vivo heat stress representative of physiologically relevant increases in body core temperatures (37-41°C). Whole blood from 20 elderly adults (72±4 years; 14 men, 6 women) was heated (via water immersion) to temperatures representative of normal resting conditions (normothermia; 37°C), in addition to moderate and severe heat stress conditions (39, and 41°C, respectively) for 90 min. Peripheral blood mononuclear cells (PBMC) were isolated and protein markers of autophagy, the HSR, acute inflammation, and apoptosis were examined. No significant increases in markers of autophagy or the HSR were observed following any temperature condition. However, an increase in acute inflammation was observed above baseline following moderate heat stress (39°C), with further increases in inflammation and apoptosis observed during severe heat stress (41°C). Our findings indicate that PBMCs from elderly adults do not exhibit increases in autophagy or the HSR following severe heat stress, potentially contributing to the elevated risk of cellular dysfunction seen in elderly adults during heat stress.

System-Wide Strategies Were Associated With Improved Outcome in Critically Ill Patients With Coronavirus Disease 2019: Experience From a Large Health-Care Network

The coronavirus disease 2019 (COVID-19)-associated critical illness poses an unprecedented challenge to ICU capacity and resources1,2 with an estimated mortality rate of 41.6% and a long ICU stay.3 Initial data have linked multiple patient-level risk factors with worse clinical outcomes4,5 and include older age, preexisting conditions (diabetes mellitus, hypertension, and obesity), initial illness severity, acute inflammation markers, and coagulation.4,5 However, few studies reported the impact of hospital-level factors on ICU outcome.

Immune biomarkers link air pollution exposure to blood pressure in adolescents

BackgroundChildhood exposure to air pollution contributes to cardiovascular disease in adulthood. Immune and oxidative stress disturbances might mediate the effects of air pollution on the cardiovascular system, but the underlying mechanisms are poorly understood in adolescents. Therefore, we aimed to identify immune biomarkers linking air pollution exposure and blood pressure levels in adolescents.MethodsWe randomly recruited 100 adolescents (mean age, 16 years) from Fresno, California. Using central-site data, spatial-temporal modeling, and distance weighting exposures to the participant’s home, we estimated average pollutant levels [particulate matter (PM), polyaromatic hydrocarbons (PAH), ozone (O3), carbon monoxide (CO) and nitrogen oxides (NOx)]. We collected blood samples and vital signs on health visits. Using proteomic platforms, we quantitated markers of inflammation, oxidative stress, coagulation, and endothelial function. Immune cellular characterization was performed via mass cytometry (CyTOF). We investigated associations between pollutant levels, cytokines, immune cell types, and blood pressure (BP) using partial least squares (PLS) and linear regression, while adjusting for important confounders.ResultsUsing PLS, biomarkers explaining most of the variance in air pollution exposure included markers of oxidative stress (GDF-15 and myeloperoxidase), acute inflammation (C-reactive protein), hemostasis (ADAMTS, D-dimer) and immune cell types such as monocytes. Most of these biomarkers were independently associated with the air pollution levels in fully adjusted regression models. In CyTOF analyses, monocytes were enriched in participants with the highest versus the lowest PM2.5 exposure. In both PLS and linear regression, diastolic BP was independently associated with PM2.5, NO, NO2, CO and PAH456 pollution levels (P ≤ 0.009). Moreover, monocyte levels were independently related to both air pollution and diastolic BP levels (P ≤ 0.010). In in vitro cell assays, plasma of participants with high PM2.5 exposure induced endothelial dysfunction as evaluated by eNOS and ICAM-1 expression and tube formation.ConclusionsFor the first time in adolescents, we found that ambient air pollution levels were associated with oxidative stress, acute inflammation, altered hemostasis, endothelial dysfunction, monocyte enrichment and diastolic blood pressure. Our findings provide new insights on pollution-related immunological and cardiovascular disturbances and advocate preventative measures of air pollution exposure.

Red Hair Color Is Associated with Elevated CRP Levels among US Women

Red Hair Color Is Associated with Elevated CRP Levels among US Women

Usefulness of Elevated Troponin to Predict Death in Patients With COVID-19 and Myocardial Injury

Elevations in troponin levels have been shown to predict mortality in patients with coronavirus disease 2019 (COVID-19). The role of inflammation in myocardial injury remains unclear. We sought to determine the association of elevated troponin with mortality in a large, ethnically diverse population of patients hospitalized with COVID-19, and to determine the association of elevated inflammatory markers with increased troponin levels. We reviewed all patients admitted at our health system with COVID-19 from March 1 to April 27, 2020, who had a troponin assessment within 48 hours of admission. We used logistic regression to calculate odds ratios (ORs) for mortality during hospitalization, controlling for demographics, co-morbidities, and markers of inflammation. Of 11,159 patients hospitalized with COVID-19, 6,247 had a troponin assessment within 48 hours. Of these, 4,426 (71%) patients had normal, 919 (15%) had mildly elevated, and 902 (14%) had severely elevated troponin. Acute phase and inflammatory markers were significantly elevated in patients with mildly and severely elevated troponin compared with normal troponin. Patients with elevated troponin had significantly increased odds of death for mildly elevated compared with normal troponin (adjusted OR, 2.06; 95% confidence interval, 1.68 to 2.53; p < 0.001) and for severely elevated compared with normal troponin (OR, 4.51; 95% confidence interval, 3.66 to 5.54; p < 0.001) independently of elevation in inflammatory markers. In conclusion, patients hospitalized with COVID-19 and elevated troponin had markedly increased mortality compared with patients with normal troponin levels. This risk was independent of cardiovascular co-morbidities and elevated markers of inflammation.

Inflammation and Coagulation during Critical Illness and Long-Term Cognitive Impairment and Disability.

Rationale: The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear.Objectives: To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability.Methods: We obtained plasma samples from adults with respiratory failure or shock on Study Days 1, 3, and 5 and measured concentrations of CRP (C-reactive protein), IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, MMP-9 (matrix metalloproteinase-9), TNF-α (tumor necrosis factor-α), soluble TNF receptor 1, and protein C. At 3 and 12 months after discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models).Measurements and Main Results: We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment Sequential Organ Failure Assessment score of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes.Conclusions: Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.

Hyponatremia as a predictor of perforated acute appendicitis in pediatric population: A prospective study

BackgroundThe aim of this study was to investigate hyponatremia as a new biochemical marker associated with complicated appendicitis in the pediatric population. MethodsPediatric patients (n = 184) with acute appendicitis confirmed by histopathology were enrolled in a prospective cohort study from January 2019 to May 2020. Medical history, demographic and clinical data were recorded in the study protocol. Blood samples for biochemical analysis, electrolytes and acute inflammatory markers were taken before surgery.Patients were further divided in two groups, those with non-perforated (n = 148; 79%) and perforated appendicitis (n = 38; 21%). ResultsThe mean serum sodium level in patients with complicated appendicitis was significantly lower compared to patients with non-complicated appendicitis (132.2 mmol/L vs. 139.2 mmol/L, p < 0.001). The receiver operating characteristic curve of plasma sodium concentration in patients who were diagnosed with perforated acute appendicitis showed an area under the curve of 0.983 (95% CI, 0.963–1.00). A cut-off-value of plasma sodium concentration of ≤135 mmol/L was shown to give the best possible sensitivity and specificity, 94.7% (95% CI: 82.2–99.3) and 88.5% (95% CI: 88.2–93.2) respectively (p < 0.001). Patients with complicated appendicitis were more likely to be younger than five years of age (10.5% vs. 1.4%, p = 0.005), have a duration of symptoms for >24 h (97.4% vs. 59.6%, p < 0.001), sodium serum concentration ≤135 mmol/L (89.5% vs. 5.5%, p < 0.001), body temperature >38.5 °C (47.4% vs. 11.0%, p < 0.001) and CRP serum concentration >62 mg/L (26% vs. 2%, p < 0.001). ConclusionHyponatremia is a novel and very discriminative marker of complicated appendicitis in the pediatric population, and is therefore recommended in appendicitis diagnostic and treatment planning. Type of studyProspective comparative study Level of evidenceII

A specific dietary fibre supplementation improves cognitive performance-an exploratory randomised, placebo-controlled, crossover study.

The impact of the microbiota on the gut-brain axis is increasingly appreciated. A growing body of literature demonstrates that use of dietary fibre and prebiotics can manipulate the microbiota and affect host health. However, the influence on cognition and acute stress response is less well understood. The objective of this study was to investigate the efficacy of a dietary fibre, polydextrose (PDX), in improving cognitive performance and acute stress responses through manipulation of the gut microbiota in a healthy population. In this double-blind, randomised, placebo-controlled, crossover design study, 18 healthy female participants received 12.5 g Litesse®Ultra (> 90% PDX polymer) or maltodextrin for 4 weeks. Cognitive performance, mood, acute stress responses, microbiota composition, and inflammatory markers were assessed pre- and post-intervention. PDX improved cognitive flexibility as evidenced by the decrease in the number of errors made in the Intra-Extra Dimensional Set Shift (IED) task. A better performance in sustained attention was observed through higher number of correct responses and rejections in the Rapid Visual Information Processing (RVP) task. Although there was no change in microbial diversity, abundance of Ruminiclostridium 5 significantly increased after PDX supplementation compared with placebo. PDX supplementation attenuated the increase of adhesion receptor CD62L on classical monocytes observed in the placebo group. Supplementation with the PDX resulted in a modest improvement in cognitive performance. The results indicate that PDX could benefit gut-to-brain communication and modulate behavioural responses.

Etiologic Subtypes of Ischemic Stroke in SARS-CoV-2 Patients in a Cohort of New York City Hospitals.

Objective: To describe the ischemic stroke subtypes related to coronavirus disease 2019 (COVID-19) in a cohort of New York City hospitals and explore their etiopathogenesis.Background: Most neurological manifestations are non-focal, but few have reported the characteristics of ischemic strokes or investigated its pathophysiology.Methods: Data were collected prospectively April 1-April 15, 2020 from two centers in New York City to review possible ischemic stroke types seen in COVID-19-positive patients. Patient presentation, demographics, related vascular risk factors, associated laboratory markers, as well as imaging and outcomes were collected.Results: The age of patients ranged between 27 and 82 years. Approximately 81% of patients had known vascular risk factors, the commonest being hypertension (75%) followed by diabetes (50%) coronary disease or atrial fibrillation. Eight patients presented with large vessel occlusion (LVO) with median age 55 years (27-82) and all were male. Eight patients presented with non-LVO syndromes, with median age 65.5 years (59–82) and most were female (62.5%). Both groups were 50% African Americans and 37.5% South Asian. Both groups had similar D-dimer levels although other acute phase reactants/disease severity markers (Ferritin, CRP, procalcitonin) were higher in the LVO group. The LVO group also had a significantly higher mortality compared to the non-LVO group. The most common etiology was cryptogenic (6 patients) followed by small vessel occlusion (3 patients) and undetermined-unclassified (3 patients). For the remaining 4 patients, 2 were identified as cardioembolic and 2 with large artery atherosclerosis.Conclusion: COVID-19-related ischemic events can present as small vessel occlusions, branch emboli or large vessel occlusions. The most common etiology is cryptogenic. Patients with LVO syndromes tend to be younger, male and may have elevated acute inflammatory markers.

The Effect of Prickly Pear, Pumpkin, and Linseed Oils on Biological Mediators of Acute Inflammation and Oxidative Stress Markers.

Medicinal plants have been used as a source of effective and safe alternative therapeutic agents for various ailments including inflammation. In fact, the aim of this study is to assess the topical anti-inflammatory and antioxidative potential effects of Cucurbita pepo (pumpkin), Linum usitatissimum (linseed), and Opuntia ficus indica (prickly pear) oils on acute inflammation using carrageenan-induced paw edema model. The study was conducted on 36 rats splitted in 6 groups: a normal control group and 5 carrageenan-treated groups (1%), each treated with either a normal saline, the reference drug (“Inflocine®” 2 mg/paw), pumpkin, linseed, or prickly pear oils (25 μl/paw). The response to these treatments was mainly assessed by the measuring of edema paw size, hematological and biochemical analysis, oxidative stress testing, and histological study. All the studied seed oils especially prickly pear oil proved to be efficient in treating acute inflammation. The oil-treated groups revealed a significant (p < 0.05) decrease in the clinical signs of inflammation, hematological parameters (white blood cells and platelets), concentrations of CRP and fibrinogen, and congestion compared to the normal saline-treated group. The results also showed that the tested oils, endowed with a radical scavenging ability, could significantly increase the activities of SOD, CAT, and GPx in carrageenan-treated skin by reducing the lipid peroxidation and protein oxidation (TBARS, AOPP). The anti-inflammatory effect of the tested oils was closely related to both their antioxidant properties as well as their bioactive compounds (polyunsaturated fatty acids, vitamin E, and phytosterols). For the first time, the findings of the current study highlight the “in vivo” anti-inflammatory property of pumpkin, linseed, and prickly pear oils on carrageenan-induced acute inflammation by regulating inflammatory mediators and oxidative stress markers.

Molecular Imaging of Very Late Antigen-4 in Acute Lung Injury.

Inflammation plays a central role in the pathogenesis of acute lung injury (ALI) during both the acute pneumonitis stage and progression into the chronic fibroproliferative phase, leading to pulmonary fibrosis. Currently, there is an unmet clinical and research need for noninvasive ways to monitor lung inflammation through targeting of immunoregulatory pathways contributing to ALI pathogenesis. In this study, we evaluated the role of targeted imaging of very late antigen-4 (VLA-4), as a key integrin mediating the adhesion and recruitment of immune cells to inflamed tissues, in quantifying lung inflammation in a mouse model of lipopolysaccharide-induced ALI. Methods: ALI was induced by a single intratracheal administration of lipopolysaccharide (10, 20, or 40 μg per mouse) in C57BL/6J mice. Control mice were intratracheally instilled with sterile phosphate-buffered saline. VLA-4-targeted PET/CT was performed 24 h after intravenous injection of a 64Cu-labeled high-affinity peptidomimetic ligand referred to as 64Cu-LLP2A, which is conjugated with the chelator (1,4,8,11-tetraazacyclotetradecane-1-(methane phosphonic acid)-8-(methane carboxylic acid) and a polyethylene glycol 4 linker, at day 2 after the induction of ALI. Ex vivo biodistribution of 64Cu-LLP2A was determined by γ-counting of harvested organs. The severity of lung inflammation was assessed histologically and by measuring the expression of inflammatory markers in the lung tissue lysates using reverse transcription quantitative polymerase chain reaction. Results: Intratracheal lipopolysaccharide instillation led to an acute inflammatory response in the lungs, characterized by increased expression of multiple inflammatory markers and infiltration of myeloid cells, along with a significant and specific increase in 64Cu-LLP2A uptake, predominantly in a peribronchial distribution. There was a strong correlation between the lipopolysaccharide dose and 64Cu-LLP2A uptake, as quantified by in vivo PET (R = 0.69, P < 0.01). Expression levels of both subunits of VLA-4, that is, integrins α4 and β1, significantly correlated with the expression of multiple inflammatory markers, including tumor necrosis factor-α, interleukin-1β, and nitric oxide synthase-2, highlighting the potential of VLA-4 as a surrogate marker of acute lung inflammation. Notably, in vivo 64Cu-LLP2A uptake significantly correlated with the expression of multiple inflammatory markers and VLA-4. Conclusion: Our study demonstrates the feasibility of molecular imaging of VLA-4, as a mechanistically relevant target in ALI, and the accuracy of VLA-4-targeted PET in quantification of ongoing lung inflammation in a murine model.