Systemic immune-inflammation index as a novel predictor of major adverse cardiovascular events in patients undergoing percutaneous coronary intervention: a meta-analysis of cohort studies.

BACKGROUND: The Systemic Immune-Inflammation Index (SII), a novel marker of inflammation based on neutrophil, platelet, and lymphocyte counts, has demonstrated potential prognostic value in patients undergoing percutaneous coronary intervention (PCI). Our aim was to assess the correlation between the SII and major adverse cardiovascular events following percutaneous coronary intervention. METHODS: We searched PubMed, Web of Science, Embase, and The Cochrane Library from inception to November 20, 2023, for cohort studies investigating the association between SII and the occurrence of MACEs after PCI. Statistical analysis was performed using Revman 5.3, with risk ratios (RRs) and 95% confidence intervals (CIs) as relevant parameters. RESULTS: In our analysis, we incorporated a total of 8 studies involving 11,117 participants. Our findings revealed that a high SII is independently linked to a increased risk of MACEs in PCI patients (RR: 2.08,95%CI: 1.87-2.32, I2 = 42%, p < 0.00001). Additionally, we demonstrated the prognostic value of SII in all-cause mortality, heart failure, and non-fatal myocardial infarction. CONCLUSIONS: Elevated SII may serve as a potential predictor for subsequent occurrence of MACEs in patients undergoing PCI. TRIAL REGISTRATION: Our protocol was registered in PROSPERO (registration number: CRD42024499676).

Analysis of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios as inflammatory biomarkers in chronic kidney disease: impact of parathyroidectomy.

INTRODUCTION: Secondary hyperparathyroidism (SHPT) is one of the causes for inflammation in CKD. We assessed the impact of parathyroidectomy (PTX) on neutrophil-to-lymphocyte (N/L) and platelet-to-lymphocyte (P/L) ratios in SHPT patients. METHODS: A total of 118 patients [hemodialysis (HD, n = 81), and transplant recipients (TX, n = 37)] undergoing PTX between 2015 and 2021 were analyzed. RESULTS: There was a significant reduction in calcium and PTH levels in both groups, in addition to an increase in vitamin D. In the HD group, PTX did not alter N/L and P/L ratios. In the TX group, there was a reduction in N/L and P/L ratios followed by a significant increase in total lymphocyte count. CONCLUSION: N/L and P/L ratios are not reliable biomarkers of inflammation in SHPT patients undergoing PTX. Uremia, which induces a state of chronic inflammation in dialysis patients, and the use of immunosuppression in kidney transplant recipients are some of the confounding factors that prevent the use of this tool in clinical practice.

Intracerebral hemorrhage-induced brain injury in mice: The role of peroxiredoxin 2-Toll-like receptor 4 inflammatory axis.

BACKGROUND: Peroxiredoxin 2 (Prx2), an intracellular protein that regulates redox reactions, released from red blood cells is involved in inflammatory brain injury after intracerebral hemorrhage (ICH). Toll-like receptor 4 (TLR4) may be crucial in this process. This study investigated the role of the Prx2-TLR4 inflammatory axis in brain injury following experimental ICH in mice. METHODS: First, C57BL/6 mice received an intracaudate injection of autologous arterial blood or saline and their brains were harvested on day 1 to measure Prx2 levels. Second, mice received an intracaudate injection of either recombinant mouse Prx2 or saline. Third, the mice were co-injected with autologous arterial blood and conoidin A, a Prx2 inhibitor, or vehicle. Fourth, the mice received a Prx2 injection and were treated with TAK-242, a TLR4 antagonist, or saline (intraperitoneally). Behavioral tests, magnetic resonance imaging, western blot, immunohistochemistry/immunofluorescence staining, and RNA sequencing (RNA-seq) were performed. RESULTS: Brain Prx2 levels were elevated after autologous arterial blood injection. Intracaudate injection of Prx2 caused brain swelling, microglial activation, neutrophil infiltration, neuronal death, and neurological deficits. Co-injection of conoidin A attenuated autologous arterial blood-induced brain injury. TLR4 was expressed on the surface of microglia/macrophages and neutrophils and participated in Prx2-induced inflammation. TAK-242 treatment attenuated Prx2-induced inflammation and neurological deficits. CONCLUSIONS: Prx2 can cause brain injury following ICH through the TLR4 pathway, revealing the Prx2-TLR4 inflammatory axis as a potential therapeutic target.

The association between new inflammation markers and frequent peritoneal dialysis-associated peritonitis.

OBJECTIVE: To validate an association between new inflammation and frequent peritoneal dialysis-associated peritonitis (PDAP). MATERIALS AND METHODS: In China, retrospective clinical data were collected on 208 patients who received continuous ambulatory peritoneal dialysis (CAPD) between 2010 and 2021. The patients were divided into two groups: non-frequent PDAP (the interval between two peritonitis episodes of more than one year) and frequent PDAP (the interval between two peritonitis episodes of less than one year). Patients with their first episode of peritonitis had their age, gender, history of hypertension, diabetic disease, underlying renal disease, bacterial infection, and laboratory data collected. The outcomes of bacterial dispersion, systemic immune-inflammation index (SII), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), and risk variables associated with frequent PDAP were analyzed. RESULTS: There are differences between the two groups in dialysis time (p = 0.006), hypertensive nephropathy (p = 0.038), staphylococcus (p = 0.035), white blood cells (p = 0.001), neutrophil (p < 0.01), lymphocyte (p < 0.01), platelet(p = 0.01), SII(p < 0.01), CRP/HDL-C (p = 0.002), CRP (p < 0.001), serum creatinine (p = 0.007), blood urea nitrogen (p = 0.05), serum magnesium (0.03), serum potassium (p = 0.007), and dialysate polymorphonuclear cells (p = 0.004). Multifactorial logistic regression analysis found that SII (p < 0.001), CRP/HDL-C (p = 0.041), and Diabetes mellitus (p = 0.027) were independent risk factors for frequent PDAP. The ROC curve analysis revealed that combining SII with CRP/HDL-C resulted in the largest AUC area (AUC = 0.814). CONCLUSIONS: Our findings offer clinical proof of the combination of SII and CRP/HDL-C in patients with frequent PDAP.

[Biomarkers of Inflammation in Predicting the Outcomes of Heart Failure of Ischemic Etiology: the Results of Factor Analysis].

AIM: To study the prognostic significance of inflammatory biomarkers in patients with chronic heart failure (CHF) and stenotic multivessel coronary atherosclerosis, with determination of the biomarker separate set that reflects subclinical inflammation and is associated with the development of cardiovascular complications during prospective observation. MATERIAL AND METHODS: A prospective observational study was conducted that included 80 patients with CHF and ischemic heart disease who were scheduled for coronary artery bypass grafting (CABG) during their current hospitalization. In addition to routine clinical laboratory tests, coagulation parameters were evaluated and the following inflammatory biomarkers were determined: neutrophil gelatinase-associated lipocalin (NGAL), growth/differentiation factor 15 (GDF-15), fibroblast growth factor 23 (FGF-23), transforming growth factor beta-1 (TGF-ß1), and high-sensitivity C-reactive protein. Also, the calculated neutrophil-to-lymphocyte ratio (N LR) was included in the analysis. Follow-up duration was at least 12 months (median 16 [13, 22] months). Statistical analysis of the data was performed with the IBM SPSS Statistics 21 software. RESULTS: The study presented results of a factor analysis of 10 inflammatory biomarkers in patients who were scheduled for CABG. One of the factors identified by the analysis included the levels of NGAL and GDF-15, N LR, and the level of fibrinogen in the blood in CHF patients with stenotic coronary atherosclerosis and was significantly associated with the death rate during prospective observation. Furthermore, this association remained significant even after adjustments for age, glomerular filtration rate, severity of heart and coronary insufficiency, and the presence of diabetes mellitus. CONCLUSION: In patients with CHF and stenotic coronary atherosclerosis, a set of inflammatory markers, including blood NGAL, GDF-15, N LR, and fibrinogen, can be combined into one factor reflecting subclinical inflammation. The value of this factor can be used to predict cardiovascular death in the long term after surgical myocardial revascularization.

Impact of inflammation and the immune system on hepatocellular carcinoma recurrence after hepatectomy.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Hepatectomy remains the first-line treatment for patients with resectable HCC. However, the reported recurrence rate of HCC at 5 years after surgery is between 50% and 70%. Tumor-related factors, including tumor size, number and differentiation, and underlying liver disease are well-known risk factors for recurrence after treatment. In addition to tumor-related factors, ever-increasing amounts of studies are finding that the tumor microenvironment also plays an important role in the recurrence of HCC, including systemic inflammatory response and immune regulation. Based on this, some inflammatory and immune markers were used in predicting postoperative cancer recurrence. These include neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, cytotoxic T cells, and regulatory T cells, among others. In this review, we summarized the inflammatory and immune markers that affect recurrence after HCC resection in order to provide direction for adjuvant therapy after HCC resection and ultimately achieve the goal of reducing recurrence.

Effects of an artificial pancreas on postoperative inflammation in patients with esophageal cancer.

PURPOSES: Subtotal esophagectomy for esophageal cancer (EC) is associated with high morbidity rates. Tight glycemic control using an artificial pancreas (AP) is one of the promising strategies to reduce postoperative inflammation and morbidities. However, the effects of tight glycemic control using AP in patients with EC are yet to be fully elucidated. METHOD: This study reviewed 96 patients with EC who underwent subtotal esophagectomy. The postoperative inflammation parameters and morbidity rates were compared between patients who used the AP (n = 27) or not (control group, n = 69). AP is a closed-loop system that comprises a continuous glucose monitor and an insulin pump. RESULTS: The numbers of white blood cells (WBC) and Neutrophils (Neut) were noted to be lower in the AP group than in the control group, but with no significant difference. The ratio in which the number of WBC, Neut, and CRP on each postoperative day (POD) was divided by those tested preoperatively was used to standardize the results. The ratio of WBC and Neut on 1POD was significantly lower in the AP group than in the control group. The rate of surgical site infection was lower in the AP group than in the control group. CONCLUSION: AP significantly decreased WBC and Neut on 1POD; this suggests the beneficial effects of AP in alleviating postoperative inflammation.

A break in mitochondrial endosymbiosis as a basis for inflammatory diseases.

Mitochondria retain bacterial traits due to their endosymbiotic origin, but host cells do not recognize them as foreign because the organelles are sequestered. However, the regulated release of mitochondrial factors into the cytosol can trigger cell death, innate immunity and inflammation. This selective breakdown in the 2-billion-year-old endosymbiotic relationship enables mitochondria to act as intracellular signalling hubs. Mitochondrial signals include proteins, nucleic acids, phospholipids, metabolites and reactive oxygen species, which have many modes of release from mitochondria, and of decoding in the cytosol and nucleus. Because these mitochondrial signals probably contribute to the homeostatic role of inflammation, dysregulation of these processes may lead to autoimmune and inflammatory diseases. A potential reason for the increased incidence of these diseases may be changes in mitochondrial function and signalling in response to such recent phenomena as obesity, dietary changes and other environmental factors. Focusing on the mixed heritage of mitochondria therefore leads to predictions for future insights, research paths and therapeutic opportunities. Thus, whereas mitochondria can be considered 'the enemy within' the cell, evolution has used this strained relationship in intriguing ways, with increasing evidence pointing to the recent failure of endosymbiosis being critical for the pathogenesis of inflammatory diseases.

Higher Donor Age and Severe Microvascular Inflammation Are Risk Factors for Chronic Rejection After Treatment of Active Antibody-Mediated Rejection.

Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1 year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59 years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.

Stressed to the Core: Inflammation and Intestinal Permeability Link Stress-Related Gut Microbiota Shifts to Mental Health Outcomes.

Stress levels are surging, alongside the incidence of stress-related psychiatric disorders. Perhaps a related phenomenon, especially in urban areas, the human gut contains fewer bacterial species than ever before. Although the functional implications of this absence are unclear, one consequence may be reduced stress resilience. Preclinical and clinical evidence has shown how stress exposure can alter the gut microbiota and their metabolites, affecting host physiology. Also, stress-related shifts in the gut microbiota jeopardize tight junctions of the gut barrier. In this context, bacteria and bacterial products can translocate from the gut to the bloodstream, lymph nodes, and other organs, thereby modifying systemic inflammatory responses. Heightened circulating inflammation can be an etiological factor in stress-related psychiatric disorders, including some cases of depression. In this review, we detail preclinical and clinical evidence that traces these brain-to-gut-to-brain pathways that underlie stress-related psychiatric disorders and potentially affect their responsivity to conventional psychiatric medications. We also review evidence for interventions that modulate the gut microbiota (e.g., antibiotics, probiotics, prebiotics) to reduce stress responses and psychiatric symptoms. Lastly, we discuss challenges to translation and opportunities for innovations that could impact future psychiatric clinical practice.

Anterior chamber flare and choroidal vascular index as inflammatory markers after uncomplicated phacoemulsification surgery.

PURPOSE: To determine the effect of phacoemulsification surgery, which is one of the types of cataract surgery by using ultrasonic power to break up the crystalline lens and clean it with vacuum, on anterior chamber flare (ACF) and choroidal vascular index (CVI). METHODS: For this cross-sectional study, patients were included if they had cataract with nucleus hardness grade 2 or 3, no systemic inflammatory disease, and not use of anti-inflammatory drugs/prostaglandins preoperatively. ACF using a laser flare meter and CVI in patients underwent uncomplicated phacoemulsification was recorded preoperatively, on the postoperative 1st day, 1st week, and 1st month. RESULTS: Fifty-six eyes were included. ACF was 9.00 ± 2.90 ph/ms preoperatively. Although ACF increased significantly on postoperative day-1 (39.38 ± 23.31ph/ms) and decreased gradually until the 1st month (14.03 ± 6.03ph/ms) after the operation, it was still significantly higher at the 1st month (p < 0.001). Macular and peripapillary CVI increased significantly on postoperative day-1 (0.64 ± 0.03/0.63 ± 0.05) and week-1 (0.64 ± 0.04/0.62 ± 0.04) (p = 0.01, p < 0.001); the postoperative 1st month was similar to the preoperative one (0.59 ± 0.06/0.58 ± 0.06). The relationship between the change in ACF and the change in CVI was not significant. CONCLUSION: Phacoemulsification causes raises in ACF and CVI due to increased intraocular inflammation. The fact that ACF was significantly higher in postoperative month-1 and CVI returned to its preoperative value suggests that the effect of uncomplicated phacoemulsification surgery on the increase in inflammation in the anterior segment lasts longer than in the posterior segment. These results suggest that ACF and CVI follow-up may be clinically important in the follow-up of postoperative inflammation.

Systemic immune-inflammation index and in-stent restenosis in patients with acute coronary syndrome: a single-center retrospective study.

BACKGROUND: In-stent restenosis (ISR) has been shown to be correlated with inflammation. This study aimed to examine the relationship between systemic immune-inflammation index (SII, an innovative inflammatory biomarker) and ISR in acute coronary syndrome (ACS) patients after drug-eluting stent (DES) implantation. METHODS: Subjects who were diagnosed with ACS and underwent DES implantation were enrolled retrospectively. All individuals underwent follow-up coronary angiography at six to forty-eight months after percutaneous coronary intervention (PCI). SII was defined as [(platelet count × neutrophil count)/lymphocyte count], and Ln-transformed SII (LnSII) was carried out for our analysis. Multivariate logistic regression analysis was employed to assess the association between LnSII and DES-ISR. RESULTS: During a median follow-up period of 12 (11, 20) months, 523 ACS patients who underwent follow-up angiography were included. The incidence of DES-ISR was 11.28%, and patients in the higher LnSII tertile trended to show higher likelihoods of ISR (5.7% vs. 12.1% vs. 16.0%; P = 0.009). Moreover, each unit of increased LnSII was correlated with a 69% increased risk of DES-ISR (OR = 1.69, 95% CI 1.04-2.75). After final adjusting for confounders, a significant higher risk of DES-ISR (OR = 2.52, 95% CI 1.23-5.17) was found in participants in tertile 3 (≥ 6.7), compared with those in tertiles 1-2 (< 6.7). Subgroup analysis showed no significant dependence on age, gender, body mass index, current smoking, hypertension, and diabetes for this positive association (all P for interaction > 0.05). CONCLUSION: High levels of SII were independently associated with an increased risk of DES-ISR in ACS patients who underwent PCI. Further prospective cohort studies are still needed to validate our findings.

Unveiling the Effects of Left Hemispheric Intracerebral Hemorrhage on Long-term Potentiation and Inflammation in the Bilateral Hippocampus: A Preclinical Study.

OBJECTIVE: Changes in cognition and memory are common complications of intracerebral hemorrhage (ICH), although the exact cause of this phenomenon is still unknown. The objectives of our project were to assess the changes in long-term potentiation, inflammation, and cell damage in the bilateral hippocampus following striatal intracerebral hemorrhage at different time points. MATERIALS AND METHODS: Unilateral ICH was induced in the striatum of 96 Wistar rats (6 control groups and 6 ICH groups). We measured changes in synaptic inputs in the bilateral hippocampus using the field potential recording method on days 3, 7, and 14 after ICH. After staining the section with hematoxylin, the volume and number of hippocampal cells were measured. The number of NF-κB positive cells was evaluated using the immunohistochemistry method. RESULTS: There was a significant change in the amplitude and slope of the hippocampal excitatory potential in the ICH group compared to the sham group, but only on the 7th day after surgery. Specifically, the ipsilateral hippocampus in the ICH-7 group showed an increase in stimulation recording in 90 minutes compared to the sham-7 group (p<0.0001), while the contralateral hippocampus in the ICH-7 group exhibited a decrease in potential recording compared to the sham-7 group (p<0.0001). By day 14, the ICH group had a lower cell density in both the ipsilateral (p<0.05) and contralateral hippocampus (p<0.05) compared to the sham group, but there was no significant change in the hippocampal volume between the groups at any time interval. Furthermore, our immunohistochemical analysis revealed that the number of NF-kB-positive cells in both hemispheres of the ICH groups was significantly greater than that of the sham groups across all time intervals. CONCLUSIONS: These findings suggest that striatal injury may lead to inflammation and cell death in the bilateral hippocampus, which can impair cognitive function after ICH.

Association between systemic immune inflammation Index and all-cause mortality in incident peritoneal dialysis-treated CKD patients: a multi-center retrospective cohort study.

BACKGROUND: Chronic inflammatory disorders in peritoneal dialysis (PD) contribute to the adverse clinical outcome. Systemic immune inflammation index (SII) is the novel and convenient measurement that is positively associated with various diseases. However, scarce is known regarding the association between SII with all-cause mortality among PD patients. METHODS: In this multi-center retrospective cohort study, 1,677 incident patients with PD were enrolled. Eligible patients were stratified into groups based on SII level: tertile 1(< 456.76), tertile 2(456.76 to 819.03), and tertile 3(> 819.03). The primary endpoint was the all-cause mortality. Both Cox regression analysis and competing risk models were used to examine the association between SII and all-cause mortality. Subgroup analysis was performed to assess the influence of the SII tertiles on all-cause mortality in different subgroups. RESULTS: During the follow-up period of 30.5 ± 20.0 months, 26.0% (437/1,677) patients died, of whom the SII tertile 3 group accounted for 39.1% (171/437) of the deaths. Patients in the SII tertile 3 group had a higher all-cause mortality rate than patients in the SII tertile 1 and 2 groups (log-rank = 13.037, P < 0.001). The SII tertile 3 group was significantly associated with 80% greater risk (95% confidence interval:1.13 to 2.85; P = 0.013) compared with the SII tertile 1 group in multivariable Cox regression analysis. The competing risk model also indicated that the relationship between SII tertiles and all-cause mortality remains (subdistribution hazard ratio: 1.86; 95% confidence interval: 1.15 to 2.02, P = 0.011). Furthermore, the relationship between the log-transformed SII and all-cause mortality in patients with PD was nearly linear (P = 0.124). CONCLUSION: A close relationship was observed between the SII and all-cause mortality in patients undergoing PD, suggesting that more attention should be paid to the SII, which is a convenient and effective measurement in clinical practice.

Severe coagulopathy and inflammation occurred after resection of giant right ventricular intimal sarcoma with cardiopulmonary bypass: a case report.

BACKGROUND: Primary malignant cardiac tumors are rare in clinic, and surgical resection under cardiopulmonary bypass (CPB) remains the main treatment. The non-physiological perfusion process of CPB leads to contact activation, and the resulting coagulopathy and systemic inflammatory response syndrome (SIRS) are common complications. However, it is difficult to predict the impact of foreign tumor fragments on this pathophysiological process once they enter the bloodstream, making this phenomenon more complex and challenging. CASE PRESENTATION: We report a case of cardiac intimal sarcoma who developed severe coagulopathy and widespread inflammation after excision of massive right ventricular tumor and replacement of tricuspid valve by median sternotomy under CPB. Although the procedure was expected to cause tumor cell necrosis and precautions were taken, uncontrolled massive postoperative bleeding, persistent fever, abnormally elevated inflammatory markers, and recurrent malignant arrhythmias occurred after surgery. In addition to common factors, the most possible underlying mechanism is contact activation triggered following surgical procedure for intimal sarcoma with CPB. CONCLUSION: Patients with intracardiac malignant tumors are at a high risk for serious contact activation during CPB. Preventive application of comprehensive anti-inflammatory measures such as drugs and adsorptive CPB technology, as well as point-of-care (POC) monitoring of coagulation status will be helpful for individualized guidance and optimization of CPB management, and improvement of patient prognosis.

Omental coating attenuates implant-induced foreign body reaction in rats.

The objective of this study is to clarify whether the omental coating can effectively attenuate foreign body reaction (FBR) induced by implanted materials. Male Sprague-Dawley rats were injected with polydextran particle slurry intraperitoneally to activate the omentum. 7 days later, polyether polyurethane sponge discs were implanted subcutaneously on each side of the rat's back as the foreign implants to induce FBR. The next day, omental transposition were performed. The disc on the left side of each rat's back was wrapped with omental flap (omental group); the disc on the right side was untreated (control group). All discs were removed 21 days after implantation and assessed by determining the components of the fibrovascular tissue (angiogenesis, inflammation, foreign body giant cells (FBGCs) aggregation and fibrogenesis). In implants in omental group, micro vessel density (MVD), Hemoglobin (Hb) content and VEGF levels (pro-angiogenic cytokine) were increased when compared with implants from control group. Inflammatory parameters (IL-1ß; macrophage accumulation-NAG activity; neutrophil accumulation- MPO levels) were decreased in implants after omental coating. Also, collagen deposition, fibrous capsule thickness, and FBGCs decreased in implants from omental group. However, intra-implant levels of TNF-α and TGF-ß1 were not different after omental coating. Our findings showed for the first time that the omental coating around the implants attenuate the adverse FBR, it may be critical in developing new strategies to control FBR and improve the function and performance of the implanted materials.

Dynamics of inflammation-associated plasma proteins following faecal microbiota transplantation in patients with psoriatic arthritis and healthy controls: exploratory findings from the FLORA trial.

OBJECTIVES: The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins. METHODS: This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel). RESULTS: Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p<0.05), of which 10 proteins were elevated in PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, and IL-2. In the FMT group, levels of 12 proteins changed significantly across all timepoints (tumour necrosis factor (TNF), CDCP1, IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences in protein levels between FMT and sham-treated patients were observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell factor (p=0.024), matrix metalloproteinase-1 (p=0.038), and SLAMF1 (p=0.042). FMT had the largest positive effect on IFN-γ, Axin-1 and CCL25 and the largest negative effect on CCL19 and IL-6. CONCLUSIONS: Patients with active PsA have a distinct immunological plasma protein signature compared with HC pre-FMT. FMT affects several of these disease markers, including sustained elevation of IFN-γ. TRIAL REGISTRATION NUMBER: NCT03058900.

Persistent inflammation, immunosuppression, and catabolism syndrome (PICS): a review of definitions, potential therapies, and research priorities.

Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS) is a clinical endotype of chronic critical illness. PICS consists of a self-perpetuating cycle of ongoing organ dysfunction, inflammation, and catabolism resulting in sarcopenia, immunosuppression leading to recurrent infections, metabolic derangements, and changes in bone marrow function. There is heterogeneity regarding the definition of PICS. Currently, there are no licensed treatments specifically for PICS. However, findings can be extrapolated from studies in other conditions with similar features to repurpose drugs, and in animal models. Drugs that can restore immune homeostasis by stimulating lymphocyte production could have potential efficacy. Another treatment could be modifying myeloid-derived suppressor cell (MDSC) activation after day 14 when they are immunosuppressive. Drugs such as interleukin (IL)-1 and IL-6 receptor antagonists might reduce persistent inflammation, although they need to be given at specific time points to avoid adverse effects. Antioxidants could treat the oxidative stress caused by mitochondrial dysfunction in PICS. Possible anti-catabolic agents include testosterone, oxandrolone, IGF-1 (insulin-like growth factor-1), bortezomib, and MURF1 (muscle RING-finger protein-1) inhibitors. Nutritional support strategies that could slow PICS progression include ketogenic feeding and probiotics. The field would benefit from a consensus definition of PICS using biologically based cut-off values. Future research should focus on expanding knowledge on underlying pathophysiological mechanisms of PICS to identify and validate other potential endotypes of chronic critical illness and subsequent treatable traits. There is unlikely to be a universal treatment for PICS, and a multimodal, timely, and personalised therapeutic strategy will be needed to improve outcomes for this growing cohort of patients.

FSH Is Responsible for Androgen Deprivation Therapy-Associated Atherosclerosis in Mice by Exaggerating Endothelial Inflammation and Monocyte Adhesion.

BACKGROUND: Androgen deprivation therapy (ADT) is the mainstay treatment for advanced prostate cancer. But ADTs with orchiectomy and gonadotropin-releasing hormone (GnRH) agonist are associated with increased risk of cardiovascular diseases, which appears less significant with GnRH antagonist. The difference of follicle-stimulating hormone (FSH) in ADT modalities is hypothesized to be responsible for ADT-associated cardiovascular diseases. METHODS: We administered orchiectomy, GnRH agonist, or GnRH antagonist in male ApoE-/- mice fed with Western diet and manipulated FSH levels by testosterone and FSH supplementation or FSH antibody to investigate the role of FSH elevation on atherosclerosis. By combining lipidomics, in vitro study, and intraluminal FSHR (FSH receptor) inhibition, we delineated the effects of FSH on endothelium and monocytes and the underlying mechanisms. RESULTS: Orchiectomy and GnRH agonist, but not GnRH antagonist, induced long- or short-term FSH elevation and significantly accelerated atherogenesis. In orchiectomized and testosterone-supplemented mice, FSH exposure increased atherosclerosis. In GnRH agonist-treated mice, blocking of short FSH surge by anti-FSHß antibody greatly alleviated endothelial inflammation and delayed atherogenesis. In GnRH antagonist-treated mice, FSH supplementation aggravated atherogenesis. Mechanistically, FSH, synergizing with TNF-α (tumor necrosis factor alpha), exacerbated endothelial inflammation by elevating VCAM-1 (vascular cell adhesion protein 1) expression through the cAMP/PKA (protein kinase A)/CREB (cAMP response element-binding protein)/c-Jun and PI3K (phosphatidylinositol 3 kinase)/AKT (protein kinase B)/GSK-3ß (glycogen synthase kinase 3 beta)/GATA-6 (GATA-binding protein 6) pathways. In monocytes, FSH upregulated CD29 (cluster of differentiation 29) expression via the PI3K/AKT/GSK-3ß/SP1 (specificity protein 1) pathway and promoted monocyte-endothelial adhesion both in vitro and in vivo. Importantly, FSHR knockdown by shRNA in endothelium of carotid arteries markedly reduced GnRH agonist-induced endothelial inflammation and atherosclerosis in mice. CONCLUSIONS: FSH is responsible for ADT-associated atherosclerosis by exaggerating endothelial inflammation and promoting monocyte-endothelial adhesion.