Effect of Perineural or Intravenous Betamethasone on Femoral Nerve Block Outcomes in Knee Arthroplasty: A Randomized, Controlled Study.

OBJECTIVES: Despite the use of multimodal analgesia, patients undergoing knee arthroplasty still encounter residual moderate pain. The addition of betamethasone to local anesthetic has been shown to improve postoperative pain. However, it remains uncertain whether the positive effects of perineural or intravenous administration of betamethasone on analgesia outcomes lead to better early mobility and postoperative recovery. METHODS: Between June 2022 and February 2023, a total of 159 patients who were undergoing knee arthroplasty were included in this study. These patients were allocated randomly into three groups: (i) the NS group, received ropivacaine 0.375% and intravenous 3mL 0.9% normal saline; (ii) the PNB group, received ropivacaine 0.375% plus perineural betamethasone (12mg) 3mL and intravenous 3mL 0.9% normal saline; and (iii) the IVB group, received ropivacaine 0.375% and intravenous betamethasone (12mg) 3mL. RESULTS: Both perineural and intravenous administration of betamethasone led to improved median (IQR) numeric rating scale (NRS) scores on the 6-meter walk test, with a score of 1.0 (1.0-2.0) for both groups, compared with 2.0 (1.0-2.0) for the NS group (p = 0.003). Compared to the NS group, both the PNB and IVB groups showed significant reductions in NRS scores at 24 and 36 h after surgery, along with a significant increase in ROM at 24, 36, and 48 h post-operation. Additionally, it exhibited lower levels of cytokine IL-1ß and TNF-α in fluid samples, as well as lower level of HS-CRP in blood samples in the PNB and IVB groups compared to the NS group. CONCLUSION: The administration of perineural and intravenous betamethasone demonstrated an enhanced analgesic effect following knee arthroplasty. Furthermore, it was associated with reduced levels of IL-1ß, TNF-α, and HS-CRP, as well as enhanced knee ROM, which is conducive to early ambulation and postoperative rehabilitation after knee arthroplasty.

Impact of semaglutide on high-sensitivity C-reactive protein: exploratory patient-level analyses of SUSTAIN and PIONEER randomized clinical trials.

BACKGROUND: Exploratory analysis to determine the effect of semaglutide versus comparators on high-sensitivity C-reactive protein (hsCRP) in subjects with type 2 diabetes. METHODS: Trials of once-weekly subcutaneous (SUSTAIN 3) and once-daily oral (PIONEER 1, 2, 5) semaglutide with hsCRP data were analyzed. Subjects with type 2 diabetes (N = 2482) received semaglutide (n = 1328) or comparators (placebo, n = 339; exenatide extended-release, n = 405; empagliflozin, n = 410). hsCRP ratio to baseline at end-of-treatment was analyzed overall, by clinical cutoff (< 1.0, ≥ 1.0 to ≤ 3.0, or > 3.0 mg/L), by tertile, and by estimated glomerular filtration rate in PIONEER 5 (a trial which was conducted in a population with type 2 diabetes and chronic kidney disease [CKD]). Mediation analyses assessed the effect of change in glycated hemoglobin (HbA1c) and/or change in body weight (BW) on hsCRP reductions. RESULTS: Geometric mean baseline hsCRP was similar across trials (range 2.7-3.0 mg/L). Semaglutide reduced hsCRP levels by clinical cutoffs and tertiles from baseline to end-of-treatment in all trials versus comparators (estimated treatment ratios [ETRs] versus comparators: 0.70-0.76; p < 0.01) except versus placebo in PIONEER 5 (ETR [95% CI]: 0.83 [0.67-1.03]; p > 0.05). The effect of semaglutide on hsCRP was partially mediated (20.6-61.8%) by change in HbA1c and BW. CONCLUSIONS: Semaglutide reduced hsCRP ratios-to-baseline versus comparators in subjects with type 2 diabetes (not significant with CKD). This effect was partially mediated via reductions in HbA1c and BW and potentially by a direct effect of semaglutide. Semaglutide appears to have an anti-inflammatory effect, which is being further investigated in ongoing trials. TRIAL REGISTRATIONS: ClinicalTrials.gov identifiers: NCT01885208 (first registered June 2013), NCT02906930 (first registered September 2016), NCT02863328 (first registered August 2016), NCT02827708 (first registered July 2016).

Estrés académico asociado a proteína C-reactiva y síndrome metabólico en estudiantes de medicina / Academic stress associated with C - reactive protein and metabolic syndrome in medical students

Introducción: El estrés académico resulta de la confrontación de un individuo con las demandas del medio universitario, lo cual puede producir cambios a nivel neuro-endocrino-inmunológico y generar un estado de inflamación crónica en donde los niveles de proteína C-reactiva aumentan. Objetivo: Determinar los niveles de estrés académico y proteína C-reactiva en estudiantes de medicina y su posible asociación con síndrome metabólico. Métodos: Se realizó un estudio observacional descriptivo de corte longitudinal que determinó el estrés académico en 68 estudiantes de medicina (41 mujeres y 27 hombres). Se obtuvo información sociodemográfica y clínica de cada estudiante. Se aplicó un cuestionario para la evaluación del estrés académico y se obtuvieron dos muestras de sangre para realizar dos pruebas de proteína C-reactiva de alta sensibilidad en dos tiempos diferentes. Resultados: Pese a que se observaron niveles altos de estrés académico y proteína C-reactiva, no hubo una asociación directa; sin embargo, se encontraron relaciones significativas entre proteína C-reactiva y las variables clínicas, además de un riesgo alto de desarrollar síndrome metabólico. Conclusiones: Se observaron altos niveles de estrés académico asociado a las demandas y exigencias de un programa de medicina con acreditación de alta calidad. Los altos niveles de proteína C-reactiva fueron asociados a los altos niveles de obesidad abdominal, lo que hace que un número significativo de estudiantes se encuentre en riesgo de desarrollar enfermedades cardiovasculares y diabetes mellitus tipo 2, sobre todo aquellos en los que se detectó prehipertensión. No se encontró una relación significativa entre el estrés académico y los niveles de proteína C-reactiva(AU)

Introduction: Academic stress results from the confrontation of an individual with the demands of the university environment, which can produce changes at the neuro-endocrine-immunological level and generate a state of chronic inflammation where the levels of C-reactive protein increase. Objective: To determine the levels of academic stress and C-reactive protein in medical students and their possible association with metabolic syndrome. Methods: A longitudinal descriptive observational study was conducted to determine academic stress in 68 medical students (41 women and 27 men). Sociodemographic and clinical information was obtained from each student. A questionnaire was applied to assess academic stress and two blood samples were obtained to perform two high-sensitivity C-reactive protein tests at two different times. Results: Although high levels of academic stress and C-reactive protein were observed, there was no direct association; however, significant relationships were found between C-reactive protein and clinical variables, in addition to a high risk of developing metabolic syndrome. Conclusions: High levels of academic stress associated with the demands and requirements of a medicine program with high quality accreditation were observed. High levels of C-reactive protein were associated with high levels of abdominal obesity, which means that a significant number of students are at risk of developing cardiovascular diseases and type 2 diabetes mellitus, especially those in whom prehypertension was detected. No significant relationship was found between academic stress and C-reactive protein levels(AU)

Efficacy of Persian barley water on clinical outcomes of hospitalized moderate-severity COVID-19 patients: a single-blind, add-on therapy, randomized controlled clinical trial.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is a debilitating disease with numerous medical and non-medical consequences. Our study aimed to evaluate the efficacy of Persian barley water in controlling the clinical outcomes of hospitalized COVID-19 patients. PATIENTS AND METHODS: This was a single-blind, add-on therapy, randomized controlled clinical trial conducted in Shiraz, Iran, from January to March 2021. One hundred hospitalized COVID-19 patients with moderate disease severity were randomly allocated to receive routine treatment (per local protocols) with or without 250 ml of Persian barley water (PBW) daily for two weeks. Clinical outcomes and blood tests were recorded before and after the study period. Multivariable modeling was applied using Stata software for data analysis. RESULTS: The PBW product passed our standardization and safety assessments. Length of hospital stay (LHS) was 4.5 days shorter in the intervention group than the control group regardless of history of cigarette smoking (95% confidence interval: -7.22, -1.79 days). Also, body temperature, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and creatinine significantly dropped in the intervention group compared to the control group. No adverse events related to PBW occurred. CONCLUSIONS: This clinical trial demonstrated the efficacy of PBW in minimizing the LHS, fever, and levels of ESR, CRP, and creatinine among hospitalized COVID-19 patients with moderate disease severity. More robust trials can help find safe and effective herbal formulations as treatments for COVID-19.

Serum C-reactive protein and iron levels following gonadectomy are not modified by perioperative administration of robenacoxib to dogs.

The aim of this study was to evaluate the perioperative effects of robenacoxib on serum C-reactive protein (CRP) and iron concentrations in dogs undergoing gonadectomy. In a prospective, blinded, controlled clinical trial, 60 healthy dogs were randomly assigned to receive preoperative subcutaneous injection of either robenacoxib [2 mg/kg body weight (BW)], meloxicam (0.2 mg/kg BW), or saline (0.04 mL/kg BW), followed by oral administration over 72 h (robenacoxib: 2 to 4 mg/kg BW; meloxicam: 0.1 mg/kg BW; saline: gelatin capsules). Blood samples were taken before surgery and 12, 24, 48, 72 h, and 7 d after surgery. Pain scores were assessed via the short-form Glasgow Composite Pain Scale over 72 h postoperatively. C-reactive protein (CRP) and iron serum levels increased and decreased (P < 0.01, both), respectively, after surgery and returned to baseline within 1 wk. No differences were observed among treatments (P > 0.05) or based on surgery/gender (P > 0.05). Pain assessment revealed a higher incidence of treatment failure in saline (6 females versus 2 and 1 female in robenacoxib and meloxicam, respectively). In conclusion, robenacoxib and meloxicam had no influence on postoperative CRP or iron in dogs, which suggests that these nonsteroidal anti-inflammatory drugs (NSAIDs) do not have a relevant effect on these biomarkers.

Le but de cette étude était d'évaluer les effets périopératoires du robenacoxib sur les concentrations sériques de protéine C réactive (CRP) et de fer chez des chiens subissant une gonadectomie. Dans un essai clinique prospectif, en aveugle et contrôlé, 60 chiens en bonne santé ont été randomisés pour recevoir une injection sous-cutanée préopératoire de robenacoxib [2 mg/kg de poids corporel (PC)], de méloxicam (0,2 mg/kg de poids corporel) ou de solution saline (0,04 mL/kg de poids corporel), suivie d'une administration orale pendant 72 h (robenacoxib : 2 à 4 mg/kg de poids corporel; méloxicam : 0,1 mg/kg de poids corporel; saline : gélules). Des échantillons de sang ont été prélevés avant la chirurgie et 12, 24, 48, 72 h et 7 jours après la chirurgie. Les pointages de douleur ont été évalués via l'échelle abrégée Glasgow Composite Pain Scale sur 72 h après l'opération. Les taux sériques de CRP et de fer ont augmenté et diminué (P < 0,01, les deux), respectivement, après la chirurgie et sont revenus à la valeur de base en 1 semaine. Aucune différence n'a été observée entre les traitements (P > 0,05) ou en fonction de la chirurgie/du sexe (P > 0,05). L'évaluation de la douleur a révélé une incidence plus élevée d'échec du traitement avec la saline (6 femelles contre 2 et 1 femelles pour le robenacoxib et le méloxicam, respectivement). En conclusion, le robenacoxib et le méloxicam n'ont eu aucune influence sur la CRP ou le fer postopératoire chez le chien, ce qui suggère que ces anti-inflammatoires non stéroïdiens (AINS) n'ont pas d'effet pertinent sur ces biomarqueurs.(Traduit par Docteur Serge Messier).

Disruption of the pentraxin 3/CD44 interaction as an efficient therapy for triple-negative breast cancers.

Due to the heterogeneity and high frequency of genome mutations in cancer cells, targeting vital protumour factors found in stromal cells in the tumour microenvironment may represent an ideal strategy in cancer therapy. However, the regulation and mechanisms of potential targetable therapeutic candidates need to be investigated. An in vivo study demonstrated that loss of pentraxin 3 (PTX3) in stromal cells significantly decreased the metastasis and growth of cancer cells. Clinically, our results indicate that stromal PTX3 expression correlates with adverse prognostic features and is associated with worse survival outcomes in triple-negative breast cancer (TNBC). We also found that transforming growth factor beta 1 (TGF-ß1) induces PTX3 expression by activating the transcription factor CCAAT/enhancer binding protein delta (CEBPD) in stromal fibroblasts. Following PTX3 stimulation, CD44, a PTX3 receptor, activates the downstream ERK1/2, AKT and NF-κB pathways to specifically contribute to the metastasis/invasion and stemness of TNBC MDA-MB-231 cells. Two types of PTX3 inhibitors were developed to disrupt the PTX3/CD44 interaction and they showed a significant effect on attenuating growth and restricting the metastasis/invasion of MDA-MB-231 cells, suggesting that targeting the PTX3/CD44 interaction could be a new strategy for future TNBC therapies.

The effects of atorvastatin on emotional processing, reward learning, verbal memory and inflammation in healthy volunteers: An experimental medicine study.

BACKGROUND: Growing evidence from clinical trials and epidemiological studies suggests that statins can have clinically significant antidepressant effects, potentially related to anti-inflammatory action on several neurobiological structures. However, the underlying neuropsychological mechanisms of these effects remain unexplored. AIMS: In this experimental medicine trial, we investigated the 7-day effects of the lipophilic statin, atorvastatin on a battery of neuropsychological tests and inflammation in healthy volunteers. METHODS: Fifty healthy volunteers were randomised to either 7 days of atorvastatin 20 mg or placebo in a double-blind design. Participants were assessed with psychological questionnaires and a battery of well-validated behavioural tasks assessing emotional processing, which is sensitive to putative antidepressant effects, reward learning and verbal memory, as well as the inflammatory marker, C-reactive protein. RESULTS: Compared to placebo, 7-day atorvastatin increased the recognition (p = 0.006), discriminability (p = 0.03) and misclassifications (p = 0.04) of fearful facial expression, independently from subjective states of mood and anxiety, and C-reactive protein levels. Otherwise, atorvastatin did not significantly affect any other psychological and behavioural measure, nor peripheral C-reactive protein. CONCLUSIONS: Our results reveal for the first time the early influence of atorvastatin on emotional cognition by increasing the processing of anxiety-related stimuli (i.e. increased recognition, discriminability and misclassifications of fearful facial expression) in healthy volunteers, in the absence of more general effects on negative affective bias. Further studies exploring the effects of statins in depressed patients, especially with raised inflammatory markers, may clarify this finding and inform future clinical trials.

Comparative study evaluating antihistamine versus leukotriene receptor antagonist as adjuvant therapy for rheumatoid arthritis.

PURPOSE: Investigating the efficacy and safety of rupatadine (RUP) versus montelukast (MON) as adjuvant therapy for patients with rheumatoid arthritis (RA). METHODS: From December 2018 to December 2019, 75 patients with active RA were enrolled in this randomized double-blind placebo-controlled study. The patients were randomized into three groups (n = 25 in each group); methotrexate (MTX) group which received MTX 15-25 mg/week plus placebo tablet once daily; MTX/RUP group which received MTX plus RUP 10 mg once daily; and MTX/MON group which received MTX plus MON 10 mg once daily. The treatment duration was 3 months. At baseline and 3 months after treatment, blood samples were collected for the biochemical analysis of high-sensitivity C-reactive protein (hs-CRP), interleukins 8 and 17 (IL-8, IL-17), E-selectin, and clusterin (CLU) levels. Clinical and functional assessments using Disease Activity Score-CRP (DAS28-CRP) and Multidimensional Health Assessment Questionnaire (MDHAQ) were performed. RESULTS: Both RUP and MON produced clinical and functional improvements which were translated by significant improvements in DAS28-CRP score and MDHAQ. Rupatadine significantly reduced all measured parameters (P < 0.05) except for IL-17 and CLU. Montelukast significantly decreased all measured variables (P < 0.05) except for E-selectin. Interleukin-8 was positively correlated with IL-17 and CLU, while hs-CRP was positively correlated with E-selectin and body mass index (BMI). Both drugs were well tolerated; somnolence was the common side effect for RUP. No neuropsychiatric events were reported with MON. CONCLUSION: Rupatadine or montelukast may serve as a potential adjuvant therapy for patients with rheumatoid arthritis secondary to the preliminary evidence of efficacy and safety. ClinicalTrials.gov identifier NCT03770923, December 10, 2018.

IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: IL-6 has emerged as a pivotal factor in atherothrombosis. Yet, the safety and efficacy of IL-6 inhibition among individuals at high atherosclerotic risk but without a systemic inflammatory disorder is unknown. We therefore addressed whether ziltivekimab, a fully human monoclonal antibody directed against the IL-6 ligand, safely and effectively reduces biomarkers of inflammation and thrombosis among patients with high cardiovascular risk. We focused on individuals with elevated high-sensitivity CRP and chronic kidney disease, a group with substantial unmet clinical need in whom previous studies in inflammation inhibition have shown efficacy for cardiovascular event reduction. METHODS: RESCUE is a randomised, double-blind, phase 2 trial done at 40 clinical sites in the USA. Inclusion criteria were age 18 years or older, moderate to severe chronic kidney disease, and high-sensitivity CRP of at least 2 mg/L. Participants were randomly allocated (1:1:1:1) to subcutaneous administration of placebo or ziltivekimab 7·5 mg, 15 mg, or 30 mg every 4 weeks up to 24 weeks. The primary outcome was percentage change from baseline in high-sensitivity CRP after 12 weeks of treatment with ziltivekimab compared with placebo, with additional biomarker and safety data collected over 24 weeks of treatment. Primary analyses were done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. The trial is registered with ClinicalTrials.gov, NCT03926117. FINDINGS: Between June 17, 2019, and Jan 14, 2020, 264 participants were enrolled into the trial, of whom 66 were randomly assigned to each of the four treatment groups. At 12 weeks after randomisation, median high-sensitivity CRP levels were reduced by 77% for the 7·5 mg group, 88% for the 15 mg group, and 92% for the 30 mg group compared with 4% for the placebo group. As such, the median pairwise differences in percentage change in high-sensitivity CRP between the ziltivekimab and placebo groups, after aligning for strata, were -66·2% for the 7·5 mg group, -77·7% for the 15 mg group, and -87·8% for the 30 mg group (all p<0·0001). Effects were stable over the 24-week treatment period. Dose-dependent reductions were also observed for fibrinogen, serum amyloid A, haptoglobin, secretory phospholipase A2, and lipoprotein(a). Ziltivekimab was well tolerated, did not affect the total cholesterol to HDL cholesterol ratio, and there were no serious injection-site reactions, sustained grade 3 or 4 neutropenia or thrombocytopenia. INTERPRETATION: Ziltivekimab markedly reduced biomarkers of inflammation and thrombosis relevant to atherosclerosis. On the basis of these data, a large-scale cardiovascular outcomes trial will investigate the effect of ziltivekimab in patients with chronic kidney disease, increased high-sensitivity CRP, and established cardiovascular disease. FUNDING: Novo Nordisk.

The Impact of Telmisartan on Cardiometabolic Risk Factors in Hypertensive Male Siblings of Women With Polycystic Ovary Syndrome.

Brothers of women with polycystic ovary syndrome (PCOS) were found to be at increased risk for cardiometabolic disorders. This risk may be exacerbated by concurrent poorly controlled hypertension. Angiotensin II receptor blockers are the most frequently used antihypertensive drugs. The aim of the present study was to compare blood pressure-lowering and pleiotropic effects of telmisartan between male siblings of PCOS probands and unrelated men. The study included 2 age-, blood pressure-, and mass index-matched groups of men with grade 1 hypertension: 24 brothers of women with PCOS (group A) and 26 brothers of healthy women (group B). All subjects were treated with telmisartan (80 mg daily). Blood pressure, glucose homeostasis markers, and plasma lipids, as well as plasma levels of total testosterone, bioavailable testosterone, androstenedione, uric acid, high-sensitivity C-reactive protein (hsCRP), homocysteine, fibrinogen, and 25-hydroxyvitamin D were measured before and after 12 weeks of therapy. At entry, there were between-group differences in the degree of insulin resistance, plasma levels of high-density lipoprotein-cholesterol, triglycerides, calculated bioavailable testosterone, androstenedione, hsCRP, and 25-hydroxyvitamin D. Although telmisartan reduced blood pressure in both study groups, this effect was stronger in group B. Irrespective of the study group, the drug improved insulin sensitivity and reduced circulating levels of uric acid and homocysteine, but these effects were more pronounced in group B than group A. Only in group B, telmisartan decreased hsCRP and fibrinogen, as well as increased 25-hydroxyvitamin D. The obtained results suggest that hypertensive male relatives of PCOS probands may gain less benefit from telmisartan treatment than unrelated hypertensive men.

The effect of insulin pump combined with ulinastatin on the levels of PCT, TG, PTX-3, and CX3CL1 in patients with diabetic ketoacidosis and pancreatitis.

ABSTRACT: The aim of this research is to observe the effect of insulin pump combined with Ulinastatin on the levels of procalcitonin (PCT), triglycerides (TG), pentraxin-3(PTX-3), and C-X3-C motif chemokine ligand 1 (CX3CL1) in patients with diabetic ketoacidosis and pancreatitis.A total of 72 patients with diabetic ketoacidosis and pancreatitis who were admitted to our hospital from February 2016 to February 2020 were selected as the research subjects. They were divided into study groups (36 cases, given insulin pump combined Ulinastatin treatment) and control group (36 cases, given insulin pump treatment). Statistics of changes in blood amylase (AMS), blood glucose, blood ketones, glycosylated hemoglobin (HbA1c), PCT, TG, PTX-3, and chemokine CX3CL in pancreatic tissue before and after treatment.After treatment, the clinical efficacy of the study group was significantly higher than that of the control group (94.44% vs 75.00%), the difference was significant (P < .05). After treatment, the clinical symptoms (abdominal distension, abdominal pain, body temperature, blood sugar, HbA1c and blood amylase) in the study group were significantly less time-to-normal than in the control group, and the difference was significant (P < .05). After treatment, the AMS, blood sugar, HbA1c, and blood ketones of the 2 groups were all lower than before treatment, and the study group's AMS, blood sugar, HbA1c, and blood ketones were all lower In the control group, the difference was significant (P < .05). After treatment, the 2 groups of PCT, TG, PTX-3, and CX3CL were all lower than before treatment, among which the study group PCT, TG, PTX-3, and CX3CL1 were lower than the control group, the difference was significant (P < .05). After treatment, the total adverse reaction rate of the 2 groups was not significantly different (P > .05), but the total adverse reaction rate of the study group was lower than that of the control group.The combination of insulin pump and ulinastatin in the treatment of patients with diabetic ketoacidosis complicated with acute pancreatitis has a effect, which can shorten the recovery time of clinical symptoms, reduce the levels of PCT, TG, PTX-3, and CX3CL1, and has fewer adverse reactions. It is worthy of clinical application.

Effect of Serum Urate Lowering With Allopurinol on Blood Pressure in Young Adults: A Randomized, Controlled, Crossover Trial.

OBJECTIVE: To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS: We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and <160 mm Hg or diastolic BP ≥80 and <100 mm Hg, and serum urate ≥5.0 mg/dl for men or ≥4.0 mg/dl for women were enrolled. Main exclusion criteria included chronic kidney disease, gout, or past use of urate-lowering therapies. Participants received oral allopurinol (300 mg daily) or placebo for 1 month followed by a 2-4 week washout and then were crossed over. Study outcome measures were change in systolic BP from baseline, endothelial function estimated as flow-mediated dilation (FMD), and high-sensitivity C-reactive protein (hsCRP) levels. Adverse events were assessed. RESULTS: Ninety-nine participants were randomized, and 82 completed all visits. The mean ± SD age was 28.0 ± 7.0 years, 62.6% were men, and 40.4% were African American. In the primary intent-to-treat analysis, systolic BP did not change during the allopurinol treatment phase (mean ± SEM -1.39 ± 1.16 mm Hg) or placebo treatment phase (-1.06 ± 1.08 mm Hg). FMD increased during allopurinol treatment periods compared to placebo treatment periods (mean ± SEM 2.5 ± 0.55% versus -0.1 ± 0.42%; P < 0.001). There were no changes in hsCRP level and no serious adverse events. CONCLUSION: Our findings indicate that urate-lowering therapy with allopurinol does not lower systolic BP or hsCRP level in young adults when compared with placebo, despite improvements in FMD. These findings do not support urate lowering as a treatment for hypertension in young adults.

Randomized Controlled Trial: Subcutaneous vs Intravenous Infliximab CT-P13 Maintenance in Inflammatory Bowel Disease.

BACKGROUND & AIMS: This study compared pharmacokinetics, symptomatic and endoscopic efficacy, safety, and immunogenicity of a subcutaneous formulation of the infliximab biosimilar CT-P13 (CT-P13 SC) vs intravenous CT-P13 (CT-P13 IV) in patients with inflammatory bowel disease (IBD). METHODS: This randomized, multicenter, open-label, parallel-group, phase 1 study enrolled tumor necrosis factor inhibitor-naïve patients with active ulcerative colitis (total Mayo score 6-12 points with endoscopic subscore ≥2) or Crohn's disease (Crohn's Disease Activity Index 220-450 points) at 50 centers. After CT-P13 IV induction at Week (W) 0/W2, patients were randomized (1:1) to receive CT-P13 SC every 2 weeks (q2w) from W6 to W54 or CT-P13 IV every 8 weeks from W6 to W22. At W30, all patients receiving CT-P13 IV switched to CT-P13 SC q2w until W54. The primary endpoint was noninferiority of CT-P13 SC to CT-P13 IV for observed predose CT-P13 concentration at W22 (Ctrough,W22), concluded if the lower bound of the 2-sided 90% confidence interval (CI) for the ratio of geometric least-squares means exceeded 80%. RESULTS: Overall, 66 and 65 patients were randomized to CT-P13 SC and CT-P13 IV, respectively. The primary endpoint of noninferiority was met with a geometric least-squares means ratio for Ctrough,W22 of 1154.17% (90% CI 786.37-1694.00; n = 59 [CT-P13 SC]; n = 57 [CT-P13 IV]). W30/W54 clinical remission rates were comparable between arms. Other efficacy, safety, and immunogenicity assessments were also broadly comparable between arms, including after switching. CONCLUSIONS: The pharmacokinetic noninferiority of CT-P13 SC to CT-P13 IV, and the comparable efficacy, safety, and immunogenicity profiles, support the potential suitability of CT-P13 SC treatment in IBD. ClinicalTrials.gov ID: NCT02883452.

Effect of synbiotics and probiotics supplementation on autoimmune diseases: A systematic review and meta-analysis of clinical trials.

BACKGROUND & AIMS: Today synbiotics are considered as immunomodulatory agents. The current systematic review and meta-analysis investigated the effect of synbiotics and probiotics on inflammatory and oxidative stress markers in autoimmune disease. MATERIALS & METHODS: The English literature search was performed using PubMed, Scopus, Web of Science, and the Central Cochrane Library through March 2020. Random effects models and generic inverse variance methods were used to synthesize quantitative data by STATA14. RESULTS: From a total of 623 entries identified via searches, ten RCTs (n = 440; 216 as intervention, 224 as controls) were included. An additional eleven studies with same intervention and different markers were also explained systematically. The pooled effect size showed that Interleukin (IL)-6 (WMD = -7.79 pg/ml; 95% CI = -13.81, -1.77, P = 0.011), Tumor Necrosis Factor (TNF)-α (WMD = -1.05 pg/ml; 95% CI = -2.01, -0.10, P = 0.030), high sensitivity C-Reactive Protein (hs-CRP) (SMD = -0.58; 95% CI = -0.79, -0.37, P < 0.001), Malondialdehyde (MDA) (SMD = -0.36; 95% CI = -0.68, -0.04; P = 0.026), Homeostasis Model of Assessment-estimated Insulin Resistance (HOMA-IR) (WMD = -0.71; 95% CI = -1.05, -0.37, P < 0.001), and beta cell function (HOMA-ß) (WMD = -15.18; 95% CI = -22.08, -8.28, P < 0.001) changed following probiotics (or synbiotics) supplementation. Also supplementation with doses more than 2 billion CFU could reduce IL-10 concentrations (WMD = -1.84; 95% CI = -2.23, 1.87; P < 0.001). Glutathione (GSH) and Total Antioxidant Capacity (TAC) levels did not influence by synbiotics and probiotics; insignificancy was remained after subgrouping for participants' age, study duration, and disease duration. CONCLUSION: Our findings revealed that synbiotics and probiotics supplementation has significant effect on some inflammatory and oxidative stress markers; although, the number of trials was too small to powerful conclusion and further investigations may be needed.

Cryo-Electron Microscopy and Biochemical Analysis Offer Insights Into the Effects of Acidic pH, Such as Occur During Acidosis, on the Complement Binding Properties of C-Reactive Protein.

The pentraxin family of proteins includes C-reactive protein (CRP), a canonical marker for the acute phase inflammatory response. As compared to normal physiological conditions in human serum, under conditions associated with damage and inflammation, such as acidosis and the oxidative burst, CRP exhibits modulated biochemical properties that may have a structural basis. Here, we explore how pH and ligand binding affect the structure and biochemical properties of CRP. Cryo-electron microscopy was used to solve structures of CRP at pH 7.5 or pH 5 and in the presence or absence of the ligand phosphocholine (PCh), which yielded 7 new high-resolution structures of CRP, including pentameric and decameric complexes. Structures previously derived from crystallography were imperfect pentagons, as shown by the variable angles between each subunit, whereas pentameric CRP derived from cryoEM was found to have C5 symmetry, with subunits forming a regular pentagon with equal angles. This discrepancy indicates flexibility at the interfaces of monomers that may relate to activation of the complement system by the C1 complex. CRP also appears to readily decamerise in solution into dimers of pentamers, which obscures the postulated binding sites for C1. Subtle structural rearrangements were observed between the conditions tested, including a putative change in histidine protonation that may prime the disulphide bridges for reduction and enhanced ability to activate the immune system. Enzyme-linked immunosorbent assays showed that CRP had markedly increased association to the C1 complex and immunoglobulins under conditions associated with acidosis, whilst a reduction in the Ca2+ concentration lowered this pH-sensitivity for C1q, but not immunoglobulins, suggesting different modes of binding. These data suggest a model whereby a change in the ionic nature of CRP and immunological proteins can make it more adhesive to potential ligands without large structural rearrangements.

Pharmacokinetics and Pharmacodynamics of Subcutaneous Sarilumab and Intravenous Tocilizumab Following Single-Dose Administration in Patients With Active Rheumatoid Arthritis on Stable Methotrexate.

We assessed pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships of interleukin-6 (IL-6), soluble IL-6 receptor, and C-reactive protein (CRP) in serum, and absolute neutrophil count (ANC) in blood following single doses of subcutaneous sarilumab versus intravenous tocilizumab (NCT02097524) from patients with rheumatoid arthritis (RA) who are inadequate responders to methotrexate (MTX) and on a stable dose of MTX. Patients with RA randomized (1:1:1:1) to single-dose sarilumab (150 or 200 mg subcutaneously) or tocilizumab (4 or 8 mg/kg intravenously) were included (n = 101), and PK, PD, and PK/PD relationships and safety were assessed over 6 weeks postdose. PK profiles for both drugs are described by parallel linear and nonlinear target-mediated clearance pathways. PD markers showed similar onset of effect during the first week postdose, regardless of dose or route of administration. CRP and ANC decreased, with median postdose nadirs at 7-15 days for CRP and 3-5 days for ANC. Both drugs at low and high doses achieved the same nadir for ANC and a similar return toward baseline within 2 weeks postdose, suggesting a saturation of effect. Safety profiles of sarilumab and tocilizumab were generally similar. In conclusion, despite differences in PK, the onset of the decrease in CRP (efficacy) and ANC (safety) after a single dose were similar for subcutaneous sarilumab and intravenous tocilizumab. PD effects and safety were consistent with previous studies.

Primary adjunctive corticosteroid therapy is associated with improved outcomes for patients with Kawasaki disease with coronary artery aneurysms at diagnosis.

OBJECTIVE: Patients with Kawasaki disease (KD) with coronary artery enlargement at diagnosis are at the highest risk for persistent coronary artery aneurysms (CAAs) and may benefit from primary adjunctive anti-inflammatory therapy beyond intravenous immunoglobulin (IVIG). We evaluate the effect of primary adjunctive corticosteroid therapy on outcomes in patients with CAA at diagnosis. DESIGN: Single-centre, retrospective review. PATIENTS: Patients with KD diagnosed within 10 days of fever onset and with baseline CA z-score ≥2.5. INTERVENTIONS: Primary treatment with IVIG (n=162) versus IVIG plus corticosteroids (n=48). MAIN OUTCOME MEASURES: Treatment resistance (persistent fever >36 hours after initial treatment), CAA regression rate. RESULTS: Of the 92 patients with KD who received corticosteroids at our institution from 2012 to 2019, 48 met the inclusion criteria for primary adjunctive therapy. The corticosteroid group was younger and had larger baseline CAAs compared with historical controls. Demographics and laboratory values were otherwise similar between groups. The corticosteroid group had a less treatment resistance (4% vs 30%, p=0.003) and a greater improvement in C reactive protein. After adjusting for baseline CA z-score, age and baseline bilateral versus unilateral CAA, the corticosteroid group had a higher odds of (OR 2.77 (1.04, 7.42), p=0.042) and a shorter time to CAA regression (HR 1.94 (1.27, 2.96), p=0.002). CONCLUSION: Primary adjunctive corticosteroid therapy is associated with decreased initial treatment resistance, greater improvement in inflammatory markers and higher likelihood of CAA regression in patients who have CAA at diagnosis. Multi-centre, randomised controlled trials are needed to confirm the benefits of corticosteroids in patients with CAA at diagnosis and to compare corticosteroids with other adjunctive therapies.

COVID-19 and non-COVID ARDS patients demonstrate a distinct response to low dose steroids- A retrospective observational study.

Patients with COVID-19 ARDS have distinct physiological and immunological phenotypes compared to patients with non-COVID ARDS. Patients with COVID-19 ARDS (n = 32) had a significant improvement in PaO2: FiO2 ratio (p = 0.046) following low-dose steroid treatment, unlike patients with non-COVID ARDS (n = 16) (p = 0.529). Patients with COVID-19 ARDS had a greater fall in CRP compared to patients with non-COVID ARDS, albeit not statistically significant (p = 0.07). Our novel findings highlight differences in the underlying physiological and immunological phenotypes between COVID-19 and non-COVID ARDS, with implications for future ARDS studies.

Differential Binding of Sarilumab and Tocilizumab to IL-6Rα and Effects of Receptor Occupancy on Clinical Parameters.

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6-mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.