Higher IL-6 Research Articles

An Insight into the Role of IL-10 and Foamy Macrophages in Infectious Diseases.

Dysregulation of lipid homeostasis causes the deposition of lipids in the form of tiny droplets within foamy macrophages (FMs). In FMs, host-derived lipids aid in survival of various intracellular pathogens leading to sustained infection. In several infectious diseases, the transformation of macrophages into a foamy phenotype is linked to the presence of high IL-10, a potent immune-modulatory cytokine. This review aims to understand the role of IL-10 in the signaling events that are crucial in generation of FMs and highlights how various intracellular pathogens targets the IL-10-FM axis for successful establishment of infections. The review also briefly discusses how the IL-10-FM axis can be a target for developing novel therapeutic strategies to prevent intracellular infections.

Single-cell RNA sequencing analysis reveals the dynamic changes in the tumor microenvironment during NMIBC recurrence.

Due to the clinical characteristic of frequent recurrence in urothelial bladder cancer (UBC), patients face significant health impacts and economic burdens. Therefore, understanding the molecular mechanisms involved in UBC recurrence is crucial for reducing its recurrence rate. The aim of our study is to help urologists and clinical researchers gain a deeper understanding of the changes in the tumor microenvironment (TME) during UBC recurrence. We collected 10 samples from primary and recurrent non-muscle-invasive bladder cancer (NMIBC) and performed single-cell RNA sequencing. By distinguishing and annotating cell subpopulations, we identified tissue preferences of some novel cell subgroups. Next, pseudotime trajectory analysis, cell-cell communication analysis, and function enrichment analysis were applied to evaluate the dynamic changes in the TME and biological functions. Finally, we validated the distribution of some of these cell subgroups using multiplex immunofluorescence experiments. We identified a tumor-associated fibroblast (CAF) subtype with high COL18A1 expression that is highly expressed in recurrent NMIBC, suggesting that the stromal component of the tumor may play a crucial role in the recurrence process. Additionally, pseudotime trajectory analysis revealed a macrophage subtype with high IL-6 expression at the terminal stage of macrophage differentiation, exhibiting significant immunosuppressive features. This indicated the presence of immune exhaustion during NMIBC recurrence. Lastly, we found an upregulation of estrogen in recurrent urothelial cancer cells, which may partially explain the gender disparity observed in UBC. This study identified several cell subpopulations influencing NMIBC recurrence, which were heavily infiltrated in the TME of recurrent NMIBC. Additionally, the enrichment of estrogen in urothelial cancer cells from various sources suggested a role of sex hormones in NMIBC recurrence.

Основные противовоспалительные цитокины и интерлейкин 6 у больных ревматоидным артритом: взаимосвязи и клиническое значение

In the pathogenesis of rheumatoid arthritis (RA), an important role is played by dysfunction between the production of the main anti-inflammatory interleukins (IL) IL-4, IL-10 and proinflammatory (IL-6) cytokines. Objective. Determination of IL-4, IL-6 and IL-10 concentrations in RA patients with advanced stage of the disease, assessment of the relationship between them, clinical indices of disease activity, the presence of rheumatoid factor (RF) and antibodies to cyclic citrullinated peptide (CCP). Material and methods. The study included 154 RA patients (41 males and 113 females) of middle age (56.0 (50.0; 64.0) years), disease duration (9.4 (3.0; 13.0) years), seropositive 129 (83.8 %) for IgM RF and/or 106 (68.8 %) ACPP with moderate or high (DAS28-ESR – 5.40 (4.65; 6.00)) disease activity. The concentration of IL-4, IL-6, IL-10 in the blood serum was determined by multiplex technology. Results. In patients with RA, the concentration of IL-4 did not differ significantly from the control, and for IL-6 and IL-10 it was significantly higher than in donors. High values of IL-6 were significantly more common (51.6 %) than IL-4 (12.33 %, p = 0.001) and IL- 10 (16.23%, p = 0.001). Reliable correlations were found between the hyperproduction of IL-4 and IL-6, IL-6 and IL-4, IL-10. For IL-4 and IL-10, such an association was not found. The concentration and frequency of increased IL-4, IL-6, IL-10 did not differ in patients positive or negative for IgM RF. The concentration of IL-4 was significantly higher in the group of patients seronegative for ACPA compared to seropositive ones, and the prevalence of high IL-4 values was also noted in this group. No such association was found for IL-6 and IL-10. The concentration of IL-6 significantly positively correlated with the indices (DAS28-ESR, CDAI, SDAI) of clinical activity of RA, and the level of IL-4 was positively associated with CDAI, SDAI, IgM RF and inversely with ACPA values. The concentration of IL-10 was associated with CDAI, SDAI, IgM RF. Conclusion. In patients with RA in the advanced stage of the disease, the production of IL-6 predominates over the production of IL-4 and IL-10. In the presence of interrelations between these cytokines, there are certain differences in the associations with clinical indices and laboratory indicators of disease activity, IgM RF and ACPA.

Mechanism of Saikosaponin D on Lipopolysaccharide-Induced Acute Lung Injury in Neonatal Rats

This study investigates the mechanism of saikosaponin D on lipopolysaccharide (LPS) aspiration pneumonia in neonatal rats. Inhalation lung injury model was constructed and rats were assigned into control group, model group, saikosaponin D (5, 10 or 20 mg/kg) group and dexamethasone 2 mg/kg group (positive control group). The dry and wet mass ratio of lung tissue was measured by wet and dry method. Superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), IL-6, IL-1β and TNF-α were measured by ELISA. HMGB1, TLR4 and p-NF-κB p65 protein expressions were detected by Western blot. Compared with control group, model group had significantly higher wet and dry mass ratio of lung tissue, lower SOD and GSH contents, higher MDA content, higher IL-6/IL-1β/TNF-α levels, higher HMGB1 and TLR4 levels and higher p-NF-κB p65 to NF-κB p65 ratio (P <0.05). Compared with model group, dry and wet mass ratios of lungs in saikosaponin D groups and dexamethasone group were reduced, SOD and GSH contents were increased, and MDA contents were reduced. Meanwhile, IL-6/IL-1β/TNF-α levels were reduced and HMGB1 and TLR4 levels and p-NF-κB p65 ratio were reduced (P < 0.05). In conclusion, saikosaponin D inhibited release of inflammatory factors, improved oxidative stress and HMGB1/TLR4/NF-κB signaling in LPS-induced inhalational lung injury.

Phase I trial and preclinical data of ACT using neoantigen-reactive TIL for patients with advanced epithelial and ICB-resistant solid cancers

Background and PurposeACT of ex vivo expanded TIL can mediate objective tumor regression in 28-49% of metastatic melanoma patients. However, the efficacy of TIL therapy in most epithelial cancers remains limited. We present the design of a phase I clinical study that aims to assess the safety and efficacy of NEXTGEN-TIL, a TIL product selected based on ex vivo neoantigen recognition, in patients with advanced epithelial tumors and ICB-resistant solid tumors. MethodsPreREP TIL cultures expanded in high dose IL-2 (HD-IL-2) from patients with metastatic solid tumors were screened for recognition of autologous TCL and/or neoantigens. 6 GMP validations of preREP TIL expansion were performed and TIL cultures from these 6 intermediate products were selected to perform the clinical scale GMP validation of the REP. ResultsTIL expanded in 82% of patient-derived tumor biopsies across different cancer types and these contained tumor- and neoantigen-reactive T cells. During GMP-validations, a variable number of TILs expanded, constituting the intermediate products (preREP). Three finished products (REP) were manufactured which reached cell doses ranging from 4.3e9 to 1.1e11 and met the established specifications. The NEXTGEN-TIL clinical trial entails a first expansion of TIL from tumor fragments in HD-IL-2 followed by TIL screening for neoantigen-recognition and REP of selected neoantigen-reactive TIL cultures. Treatment involves a classical non-myeloablative lymphodepleting chemotherapy followed by NEXTGEN-TIL product administration together with HD-IL-2. ConclusionsNEXTGEN-TIL consists of selected neoantigen-reactive TIL and aims to potentially improve efficacy in patients with epithelial and ICB-resistant tumors, with a safety profile like traditional TIL.

Monocyte transcriptome signatures of inflammation and enhanced neutrophil recruitment characterize immunopathology in the blood of TB patients

Tuberculosis (TB) is characterized by immunopathology in the blood and monocytes have been shown to be highly sensitive to plasma environment changes in TB patients. Here, we investigated TB plasma effects on ‘reference monocytes’ using RNA sequencing to characterize a potential immunomodulatory role of monocytes in TB. Candidate pathways induced by plasma samples from TB patients (n=99) compared to healthy controls (n=62) were analyzed for changes in signal transduction, phenotype and secreted cytokines by flow cytometry. Finally, potential implications were characterized in blood samples from corresponding patients and controls.Reference monocytes treated with TB plasma showed an enrichment of pathways involved in inflammation and chemotaxis. Inflammatory cytokines were accompanied by enhanced phosphorylation of STAT molecules (i.e., STAT1/3/5) and strong positive correlations were detected for Interleukin (IL)-6 only in TB plasma-treated monocytes. Moreover, monocyte chemokine receptors (i.e., CCR-1, CCR-5) and pro-inflammatory chemokines (i.e., CXCL-1, CXCL-2, CXCL-8, G-CSF, CCL-2) that attract granulocytes and monocytes were significantly higher in TB plasma-treated monocytes. Notably, corresponding clinical samples also showed higher plasma levels for a subset of inflammatory cytokines/chemokines and, in particular, high IL-6 levels correlated positively with accumulation of neutrophil granulocytes in the blood of TB patients. Finally, monocytes from TB patients were characterized by increased chemokine receptor expression, higher proportions of a CCR-2+ subpopulation and aberrant high SOCS3 expression.These results suggest that monocytes may play a significant role in amplifying plasma immunopathology, leading to sustained mobilization and accumulation of neutrophil granulocytes and chronic inflammation in the blood of TB patients.

Cytokines Levels and Anti-tuberculosis Drug Resistance among HIV Seropositive Patients in Ibadan, Southwest, Nigeria

Susceptibility to TB disease rises on mutations in cytokine receptors which ultimately lead to defective signaling and alter the immune surveillance and bacterial killing. Therefore, this study was undertaken to investigate the association between cytokines and anti-TB drug resistances. A total of 217 people living with human immunodeficiency virus at University College Hospital, Ibadan were recruited. Venous blood and sputum samples were collected. Sputum samples were cultured for Mycobacterium tuberculosis complex and characterized using standard methods. Anti-TB drug resistance was detected using phenotypic and genotypic methods. Cytokines levels (IL-10 and IFN-Y) were estimated using ELISA method. Association between cytokines and anti-TB drug resistance was determined using linear regression analysis. There were 105(48.4%) males and 112(51.6%) females with a mean age of 42.95 ± 8.286 years and a range of 28-65 years. The prevalence of TB among PLHIV was found to be 19.1% with male having higher rate than female (P<0.05), and highest rate among aged ≥40. There was no significant association between cytokines (IL-10 and IFN-y) and sex of the subjects (P>0.05). However, females had higher IFN-y level of 231.06±61.81 IU/ml when compared to 227.53±57.92 IU/ml obtained from males. The prevalence of multi-drug resistance TB was 11.9% with Rifampicin resistance having the highest rate of 5.5%. There was no significant association between cytokines (IL-10 and IFN-y) and sex, but age group >40 years had higher IL-10 and IFN-y level of 226.53±52.39 IU/ml and 232.41±66.63 IU/ml respectively. There was an association between high cytokines levels and anti-TB drug resistance (P<0.05). Highest cytokines levels; IL-10 (401.00±7.07 IU/ml) and IFN-Y (401.00±7.07 IU/ml) were recorded in Levofloxacin resistance. There was an association between high cytokines levels and genotypic anti- TB drug resistance (P<0.05) with highest cytokines levels; IL-10 (400.12±12.37 IU/ml) and IFN-Y (472.87±31.93 IU/ml) recorded in Rifampicin resistance. This entire study revealed that there is high prevalence of MDR-TB among PLHIV, with Rifampicin monoresistance having the highest resistance rate among the drugs tested, and pro and inflammatory cytokines (IL-10 and IFN-y) play significant role in the development of Multi Drug Resistant-Tuberculosis among people living with HIV.

The Interaction of Second Trimester Prenatal Maternal Inflammation and Psychosocial Stress on Offspring Depressive Symptoms in Adolescence

BackgroundHigher second trimester (T2) prenatal maternal inflammation (PNMI) and prenatal maternal psychosocial stress have been shown to independently contribute to offspring depression risk. Similarly, interactions between sources of inflammation and maternal daily life stress in T2, previously have been associated with increased offspring adolescent depressive symptoms. We aimed to extend previous findings by examining the potential interaction between exposure to higher T2 PNMI and maternal daily life stress on offspring depressive symptoms in adolescence. Methods614 mother-offspring dyads from the Child Health and Development Studies (CHDS) had data available for T2 maternal serum interleukin (IL)-6, IL-8, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptor-II (sTNF-RII), presence/absence of maternal reported daily life stress coded from interviews primarily conducted in T2, and adolescent offspring (ages 15-18 years) depressive symptoms assessed via self-report. Interactions were evaluated using hierarchical multiple regressions, controlling for maternal education. ResultsMaternal daily life stress interacted with higher serum levels of maternal T2 IL-6 and T2 IL-8 to predict adolescent offspring depressive symptoms. Higher IL-6 and higher IL-8 were only associated with offspring depression in the presence of daily life stress. Maternal T2 IL-1ra and sTNF-RII were not associated with offspring adolescent depressive symptoms. ConclusionThe interaction of the adverse impacts of maternal daily life stress and higher maternal IL-6 and/or IL-8 levels during the second trimester may contribute significantly to exacerbate depression risk in adolescent offspring. These results have potential implications for multiple targets of future early intervention and prevention research.

From geriatric assessment to inflammation. A pilot, observational, study about frailty components in older patients with persistent atrial fibrillation

BackgroundAtrial fibrillation (AF) is the most common arrhythmia diagnosed at an older age. AF is associated with frailty, a condition possibly justifying the higher rate of complications and mortality in aged individuals. This study was aimed at describing the characteristics correlated to frailty in older AF subjects. MethodsAfter having excluded a < 3 months major surgery procedure, cancer or other conditions associated with activation of inflammation, and a life expectancy < 12 months, we consecutively enrolled patients ≥ 65 years with persistent AF. They underwent a Comprehensive Geriatric Assessment evaluation. In particular, Mini-Mental State Examination, 15-item Geriatric Depression Scale and Short-Physical Performance Battery (SPPB) described, respectively, cognitive profile, depressive symptoms and physical performance. A venous blood sample was collected to measure interleukin-6 (IL-6; marker of low-grade inflammation) and acylcarnitines, expression of mitochondrial dysfunction and abnormal energy production. ResultsOverall, 49 patients (mean age: 76 ± 6 years; women 30.6 %) were studied. Cluster analysis described two different patterns; the second (N = 18, 36.7 %), when compared to the first one (N = 31, 63.3 %), was characterized by a worse phenotype, identified by the simultaneous presence of lower body mass index, higher CHA2DS2-VASc score (index of clinical complexity), worse SPPB functional performance, and high IL-6 levels. Second cluster patients had a higher concentration of 13 of the 35 acylcarnitines evaluated and increased 5-year mortality. All these features can outline a frail condition. ConclusionsBody size, clinical complexity, physical performance and low-grade inflammation seem to rapidly and adequately describe frailty.

Effects of Dietary Cobalt Levels on Growth Performance, Antioxidant Capacity, and Immune Status of Juvenile Largemouth Bass (Micropterus salmoides).

A 9-week experiment investigated the effects of dietary cobalt levels on the growth performance, antioxidant capacity, and immunity of largemouth bass. Six feed groups were designed and each group received different cobalt levels, including 0.129 mg/kg (control group), 0.192 mg/kg, 0.201 mg/kg, 0.233 mg/kg, 0.277 mg/kg, and 0.316 mg/kg. The results show that the control group (0.129 mg/kg diet) had the lowest final body weight (FBW), weight gain rate (WGR), and specific growth rate (SGR), and the highest feed conversion ratio (FCR), when compared to the cobalt supplementation groups. Dietary cobalt levels of 0.192 mg/kg increased the body protein content and decreased the body moisture content. Regarding antioxidant capacity, the highest catalase (CAT) activity was found in the 0.277 mg/kg dietary cobalt group, while the malondialdehyde (MDA) content was significantly diminished; the total antioxidant capacity (T-AOC) content and glutathione peroxidase (GSH-Px) activity exhibited the highest values in the 0.192 mg/kg and 0.233 mg/kg dietary cobalt groups, respectively. Regarding gene expression, compared with the control group, the mRNA expression of sod was upregulated in the 0.192 mg/kg, 0.233 mg/kg, and 0.277 mg/kg dietary cobalt groups, while the mRNA expression of gpx was diminished when dietary cobalt levels were below 0.233 mg/kg. In addition, the highest il-10 and tgf-β mRNA expression levels were observed in the 0.201 mg/kg and 0.233 mg/kg dietary cobalt groups, respectively. According to the quadratic regression analysis based on the SGR and FCR, the optimal requirement was 0.24 and 0.26 mg/kg of dietary cobalt, respectively.

Real-world predictors of dupilumab prescription in patients with chronic rhinosinusitis with nasal polyps.

Despite increasing dupilumab use for chronic rhinosinusitis with nasal polyps (CRSwNP), little is known about the factors influencing its use in real-world practice. We aimed to identify factors that may predict dupilumab prescription in CRSwNP patients who have undergone endoscopic sinus surgery (ESS). A single-institution, retrospective cohort study of patients who underwent ESS for CRSwNP between 2015 and 2023 was conducted. Demographics, comorbidities, 22-item sinonasal outcome test (SNOT-22) scores, and dupilumab prescription date were extracted from patient records. Intraoperative nasal mucus cytokine levels were measured using a multiplex bead assay. Univariate logistic regression analysis was performed to identify factors associated with dupilumab prescription, and multivariate logistic regression was used to adjust for surgery date. A total of 299 CRSwNP patients were included, including seventy (23.4%) who were prescribed dupilumab postoperatively. Patients were more likely to be prescribed dupilumab if they had asthma (odds ratio [OR] 2.304), aspirin-exacerbated respiratory disease (AERD, OR 3.375), elevated tissue eosinophils (OR 1.005), and higher 3-month postoperative SNOT-22 scores (OR 1.027). Patients prescribed dupilumab also had greater odds of having elevated mucus interleukin (IL)-5 (OR 1.128) and IL-13 (OR 1.213). When adjusting for surgery date, associated factors included: asthma (OR 2.444), AERD (OR 3.750), allergic rhinitis (OR 1.833), higher tissue eosinophils (OR 1.005), elevated 3-month SNOT-22 scores (OR 1.028), and higher IL-5 (OR 1.123) and IL-13 (OR 1.202) levels. Asthma, AERD, allergic rhinitis, and elevated tissue eosinophil, IL-5, and IL-13 levels are predictive of dupilumab prescription in CRSwNP patients. These may serve as clinical and inflammatory biomarkers and can aid in counseling patients about expected disease trajectory.

Olaparib enhancing radiosensitization and anti-metastatic effect of oral cancer by targeting IL-17A signal

PurposeWe tested whether the PARP inhibitor, Olaparib, can effectively enhance radiosensitivity while inhibiting OSCC growth and metastasis in vitro and in vivo. Patient samples were used for survival validation.MethodsThe present study investigated the effect of Olaparib and ionizing radiation (IR) on clonogenic, migratory, and invasive ability in human IR-sensitive (OML1) and IR-resistant (OML1-R) OSCC cell lines. We next explored the underlying mechanism with ELISA and a Western blotting assay. Two in vivo mouse models were established to investigate the efficacy of Olaparib combined with radiotherapy (RT) on local tumor growth and lung metastasis. IL-17 A expression was confirmed in tissue specimens of OSCC patients by immunohistochemistry.ResultsWe found that Olaparib, in combination with IR, substantially inhibited cell growth, migration, and invasion in vitro. Mechanistically, the Olaparib treatment significantly reduced the secretion of IL-17 A in irradiated OSCC cells by attenuating NF-κB and p38 activity. Consistently, Olaparib enhanced the radiosensitivity and, with RT, synergistically reduced both tumor growth and lung metastasis in mice. In addition, OSCC patients with high IL-17 A expression were substantially associated with an increased risk of lymph node involvement and worse survival.ConclusionsThis study has highlighted that Olaparib displays radiosensitizing and antimetastatic effects by inhibiting the IL-17 A-dependent signal. Remarkably, Olaparib could provide a remarkable anticancer efficacy to improve treatment response in OSCC patients with recurrent/metastatic disease after RT.

Characterization of the Biological Variability of the Angiome Biomarkers over Time in Healthy Subjects.

Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in cancer patients, little is known regarding the natural variation of biomarkers in healthy populations. Here we conducted a clinical study to evaluate the natural variability of biomarkers over time in healthy participants. The angiome multiplex array, a panel of 25 circulating protein biomarkers, was assessed in 28 healthy participants across 8 timepoints over the span of 60 days. We utilized the intraclass correlation coefficient (ICC) to quantify the reliability of the biomarkers. Adjusted ICC values were calculated under the framework of a linear mixed-effects model, taking into consideration age, sex, body mass index (BMI), fasting status, and sampling factors. ICC was calculated to determine the reliability of each biomarker. HGF was the most stable marker (ICC=0.973), while PDGF-BB was the most variable marker (ICC=0.167). In total, ICC analyses revealed that 22 out of 25 measured biomarkers display good (≥0.4) to excellent (>0.75) ICC values. Three markers (PDGF-BB, TGF-1, PDGF-AA) had ICC values <0.4. Greater age was associated with higher IL-6 (p=0.0114). Higher BMI was associated with higher levels of IL-6 (p=0.0003) and VEGF-R3 (p=0.0045). Of the 25 protein biomarkers measured over this short time period, 22 markers were found to have good or excellent ICC values, providing additional validation for this biomarker assay. This data further supports the validation of the angiome biomarker assay and its application as an integrated biomarker in clinical trial testing.

Dysregulation of Regulatory T Cells and Autoimmune Sequelae in DRESS: Insights From Flow Cytometry and NanoString Analysis.

Drug reactions with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are severe cutaneous adverse hypersensitivity reactions with distinct clinical manifestations. Regulatory T (Treg) cells may behave differently in these syndromes, contributing to their diverse clinical features and outcomes. This study compared Treg dynamics between DRESS and SJS/TEN patients during the acute and recovery phases. Flow cytometry quantitatively analysed and defined the immunophenotype of CD4+CD25+CD127-FoxP3+ Tregs in blood from DRESS and SJS/TEN patients indicated that Treg percentages were lowest in DRESS patients during the acute phase compared to those in the recovery phase in DRESS patients and the acute phase in SJS/TEN patients. During the acute phase, CTLA-4 expression in Tregs in both DRESS patients with and without autoimmune sequelae was significantly increased, while only DRESS patients without autoimmune sequelae had elevated OX40 expression compared to the healthy controls. High IL-10 expression in Tregs during the acute phase in SJS/TEN patients was also observed. The suppressive function of Tregs was lower in DRESS compared to SJS/TEN, which was determined using a suppression assay by co-culturing autologous Treg and effector T cells. Furthermore, NanoString technology explored mRNA profiles in Tregs. Genes associated with the JAK/STAT pathway were found to be downregulated during the acute phase in DRESS patients who later developed autoimmune sequelae. Our findings evidenced impaired Treg function in DRESS compared to SJS/TEN. The early disturbance of the JAK/STAT pathway may serve as a prognostic marker for autoimmune development in DRESS patients.

Community-Associated MRSA—Not So Innocent Sibling per Se: A Case Report

Background: Methicillin-resistant S. aureus (MRSA) is a major healthcare burden and is classified as healthcare-associated (HA-MRSA) and community-associated (CA-MRSA). While HA-MRSA is clinically feared, CA-MRSA is often considered less pathogenic. This case report highlights the serious course of illness due to CA-MRSA infection and provides a treatment strategy for the management of such cases. Case description: A 41-year-old male presented with fever and breathlessness for five days. Upon admission, he was provided empirical treatment for atypical infections and vasopressor support for hypotension. His condition deteriorated, necessitating ventilator support. Although the initial tracheal Bio Fire test indicated MRSA, his clinical manifestations did not match MRSA pneumonia symptoms; however, CA-MRSA was confirmed within 12 h. Skin legions developed within 16 h and progressed gradually from ecchymosis, petechial, and palpable purpura to bullous lesions over 72 h. The antibiotic regimen was modified and optimized with the addition of Clindamycin, Vancomycin, and Meropenem–Colistin. Owing to high IL-6 levels, dual vasopressor support, and acute kidney failure, he was started on early (within 12 h) continuous renal replacement therapy (CRRT) with CytoSorb filter (for 3 days) for cytokine removal. IL-6 levels decreased after two days of CytoSorb use. Subsequently, the patient stabilized with reduced dependence on vasopressor and ventilator assistance. Discussion: Early diagnosis of CA-MRSA and management with CRRT using CytoSorb may help improve patient outcomes. To our knowledge, this is the first report of clinical management of CA-MRSA with CytoSorb therapy in India that resulted in positive outcomes.

Biomarkers of microbial translocation and generalized inflammation are associated with frailty among people with HIV.

Frailty occurs at higher rates and younger ages among people with HIV (PWH) compared to the general population and is often attributed to chronic inflammation and subsequent immune exhaustion. We assessed how inflammatory biomarkers are associated with frailty among PWH. The Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort is comprised of adult PWH in care at 10 sites, and harmonizes demographic, clinical, and patient-reported outcomes (PRO) data. A panel of 13 inflammatory biomarkers was collected from a subset of virally suppressed PWH once per person between 2010-2018. Frailty was measured with a validated PRO phenotype, scored 0-4, from biomarker collection date through July 2022. With adjusted linear mixed models, we estimated longitudinal associations between standard deviation-scaled log2-transformed biomarkers and frailty score. Among 273 PWH, most were male (91%), average age at baseline was 45, 42% were non-Hispanic White while 35% were non-Hispanic Black, and average follow-up time was 5.5 years. Several biomarkers were associated with higher frailty, including those linked to microbial translocation (sCD14, LBP, KT ratio) and systemic inflammation (CRP, IL-6, suPAR, sTNFR1, sTNFR2). Higher IL-6 was associated with a 0.25-point higher frailty score (95%CI:0.12-0.39). Higher sTNFR1 (0.35 [0.13-0.56]), sCD14 (0.21 [0.11-0.31]), and suPAR (0.24 [0.11-0.36]) levels were also associated with higher frailty scores over follow-up. Higher levels of biomarkers linked to microbial translocation and systemic inflammation are associated with higher average frailty scores over time in a cohort of virally suppressed PWH, highlighting these pathways as potential interventional targets for mitigating frailty in PWH.

Outcomes Associated with the use of High Dose Corticosteroids and IL-6 Inhibitors for the Treatment of Acute Respiratory Distress Syndrome Secondary to SARS COV-2.

During the COVID-19 pandemic, treatment strategies evolved rapidly. The RECOVERY trial established corticosteroids as the standard care for reducing mortality in COVID-19 patients. However, some critical care clinicians began using doses higher than those recommended in RECOVERY. To characterize the use of high-dose corticosteroids and IL-6 inhibitors in critically ill COVID-19 patients and examine their association with adverse drug events (ADEs). A retrospective cohort study of 320 electronic health records (January 1, 2020 - June 30, 2022) was conducted on COVID-19 patients requiring high-flow oxygen or mechanical ventilation. Patients were categorized based on corticosteroid dose: "high dose dexamethasone" (daily dose greater than 12 mg and/or for longer than 10 days), "low dose dexamethasone" (daily dose 12 mg or less for 10 days or less), and "no dexamethasone" (no corticosteroid therapy). Subgroups were created based on IL-6 inhibitor use. High-dose dexamethasone was associated with increased odds of ADEs compared to low dose (OR 2.55, 95% CI 1.45 to 4.49) and no dexamethasone (OR 6.29, 95% CI 2.08 to 19.03). No additional efficacy benefit was observed in patients receiving high dose corticosteroids when compared to low dose corticosteroids. Patients receiving both an IL-6 inhibitor and high-dose dexamethasone had further increased odds of ADEs. High-dose dexamethasone was also associated with increased mortality compared to low dose (OR 3.78, 95% CI 1.97-7.25) and no dexamethasone (OR 15.22, 95% CI 3.27-70.74). Acknowledging the risk for residual confounding, higher doses of dexamethasone were associated with increased ADEs and mortality. These findings highlight the need for careful consideration of the use of high-dose dexamethasone.

Inflammation is associated with pain and fatigue in older adults

IntroductionIncreasing evidence suggests that inflammation may play a pivotal role in the development of chronic pain and fatigue in aging individuals. This study investigated the relationship between three inflammatory markers (IL-6, CRP, and TNFα) and pain and fatigue, both cross-sectionally and longitudinally, in a sample of older adults from the Saint Louis Personality and Aging (SPAN) study. MethodsSPAN study participants provided blood samples at two in-person sessions approximately 2 years apart for the analysis of the inflammatory biomarkers IL-6, CRP, and TNFα. Pain and fatigue were assessed using the RAND-36 Health Status Inventory. Correlations (with false discovery rate correction for multiple testing) and follow-up linear regressions including potentially confounding demographic (e.g., annual household income) and health (e.g., BMI, medication use) covariates were used to estimate cross sectional and longitudinal associations. Analytic ns ranged from 533 to 815. ResultsCross-sectional analyses revealed that higher IL-6 and CRP were associated with greater reported pain and fatigue, even after accounting for covariates (βs > .098, ps < .05). TNFα was associated with greater fatigue only (β = .100, p = .012). Longitudinally, CRP and IL-6 predicted future pain and fatigue, although only the relationship between CRP and future fatigue survived the inclusion of covariates (β = .104, p = .022). Both pain and fatigue predicted higher levels of IL-6 and CRP approximately 2 years later, although only the associations with IL-6 survived the inclusion of covariates (βs > .12, ps < .01). DiscussionOur study adds to a growing body of literature showing that inflammation is associated with greater pain and fatigue in older adults. Our longitudinal data showing temporal bidirectional associations is consistent with evidence from non-human animal models that heightened inflammation causally contributes to fatigue and also suggests that the experience of pain and fatigue may contribute to inflammation. It will be important for future work to identify how lifestyle factors associated with pain and fatigue (e.g., physical activity) may contribute to these associations.

Retrieval of Normal Sleep for Two Weeks Normalized Adiposity and Minimized Insulin Resistance Induced by 4-Week Insomnia in Aged Female Rats

Abstract Background Insomnia affects the energy metabolism components which may alter the body’s metabolic functions. Sleep disturbances, both quantitative and qualitative, may increase the risk of developing chronic conditions, such as obesity, metabolic disorders, diabetes, and cardiovascular disease. Aim This study was carried out to investigate the effect of insomnia on glucose homeostasis in aged female rats, and to elucidate the possible underlying mechanism(s), as well as the potential metabolic recovery after retrieval to the normal sleep pattern. Methods 60 Sprague Dawley aged female rats were randomly divided into two main groups: Control group (C) and Insomnia group (I). The latter was further subdivided into two subgroups, 10 rats each: Group Iins. which was subjected to insomnia four hours daily, five days /week for 4 weeks, and Group Іins, Rec. that was subjected to insomnia like Iins. group with retrieval to normal sleep for two weeks. Rats in all groups were subjected to estimation of Body weight (BW), Body mass index (BMI) and Waist circumference at the beginning of the study. The intraperitoneal glucose tolerance test (IPGTT) was measured at the beginning of the study and was monitored every two weeks. By the end of fourth week (for groups C and Iins.) &amp; By the end of the sixth week (for group Iins.rec). BW, BMI, Waist circumference, intraperitoneal glucose tolerance test (IPGTT), peak glycemia (PG) and area under the curve (AUC), Fasting blood glucose (FBG), Insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA- IR), Total cholesterol (TC), Triglycerides (TG), Low density lipoprotein cholesterol (LDL-C), High density lipoprotein cholesterol (HDL-C), Adiponectin, IL6 and Caspase 3 were estimated. Results After four weeks, Iins. rats exhibited a significantly higher change in BW, BMI, WC, FBG, blood glucose levels at 30 min., 60 min, 90 min., 120 min, PG and AUC of IPGGT, insulin level and HOMA-IR, serum (TGs), (TC), (LDL-C), serum IL6 &amp; caspase3 but showed significant decrease in serum level of (HDL-C) and adiponectin in comparison to C rats, After two week recovery from insomnia, Iins.rec. rats exhibited a significantly lower values of WC, FBG, insulin, HOMA-IR, (TGs), (TC), (LDL-C), serum IL6 &amp; caspase3 with insignificant change in BW, BMI, blood glucose levels at 30 min., 60 min, 90 min., 120 min, PG, AUC of IPGGT &amp; serum (HDL-C) with significantly higher values of adiponectin when compared to Iins.rats, and exhibited insignificant change in BW, BMI, WC, FBG, blood glucose levels at 60 min. and at 90 min, (TC), (LDL-C) and adiponectin with significantly higher values of blood glucose levels at 30 min., 120 min, PG and AUC of IPGGT insulin level, HOMA-IR, serum (TGs), serum IL6 &amp; caspase3 with significantly lower values serum (HDL-C) in comparison to the C rats. Conclusion Four-week insomnia in aged female rats resulted in increased blood glucose, insulin resistance, dyslipidemia and enhanced inflammatory and apoptotic states. Retrieval of normal sleep for two weeks normalized body adiposity, fasting blood glucose, total cholesterol and LDL-C and minimized the insulin resistance, hypertriglyceridemia and the decrease in HDL-C as well as inflammation and apoptosis.

Predictive nomogram of the clinical outcomes of colorectal cancer based on methylated SEPT9 and intratumoral IL-10+ Tregs infiltration

BackgroundGene methylation and the immune-related tumor microenvironment (TME) are highly correlated in tumor progression and therapeutic efficacy. Although both of them can be used to predict the clinical outcomes of colorectal cancer (CRC) patients, their predictive value is still unsatisfactory. Whether a combination risk model comprising these two prediction parameters performs better predictive effectiveness than independent factor is still unclear. Methylated Septin9 (mSEPT9) is an early diagnosis biomarker of CRC, in this study, we aimed to investigate mSEPT9-related biomarkers of immunosuppressive TME and identify the value of the combination risk model in predicting the clinical outcomes of CRC.MethodsImmunofluorescence staining was performed to clarify the correlation between intratumoral IL-10+ Treg infiltration and mSEPT9 in peripheral blood. Survival time, response to 5-fluorouracil (5-FU)-based chemotherapy and PD-1 blockade, and the probability of recurrence or metastasis were analyzed in study (197 CRC samples) and validation (195 CRC samples) sets to evaluate the efficacy of combination risk model. Potential mechanisms were explored by mRNA sequencing.ResultsHypermethylated SEPT9 in the peripheral blood of patients with CRC (stage I-III, and stage IV with resectable M1) before radical resection was positively correlated with high intratumoral IL-10+ Treg infiltration. The high-risk model revealed poor overall survival and progression-free survival, inferior therapeutic response to 5-FU-based chemotherapy and PD-1 blockade, and high probability of recurrence or metastasis. The underlying mechanisms may be associated with the increase in mSEPT9 and mediation of IL-10 via methionine metabolic reprogramming-induced infiltration of IL-10+ Tregs in the TME, which promotes tumor progression and resistance to 5-FU-based chemotherapy and PD-1 blockade.ConclusionsThe combination risk model of peripheral mSETP9 and intratumoral IL-10+ Treg infiltration in CRC can effectively predict prognosis, responsiveness to 5-FU-based chemotherapy and PD-1 blockade, and the probability of recurrence or metastasis. Therefore, this model can be used for precision treatment of CRC.