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Abstract Background Coronavirus disease 2019 (COVID-19) is a viral pneumonia that can result in serious respiratory illness. It is associated with extensive systemic inflammation, changes to the lung extracellular matrix, and long-term lung impairment such as interstitial lung disease (ILD). In this study, the aim was to investigate whether tissue remodelling, wound healing, and neutrophil activity is altered in patients with COVID-19 and how these relate to the development of post-COVID ILD. Method Serum samples were collected from 63 patients three months after discharge as part of the Research Evaluation Alongside Clinical Treatment study in COVID-19 (REACT COVID-19), 10 of whom developed ILD, and 16 healthy controls. Samples were quantified using neo-epitope specific biomarkers reflecting tissue stiffness and formation (PC3X, PRO-C3, and PRO-C6), tissue degradation (C1M, C3M, and C6M), wound healing (PRO-FIB and X-FIB), and neutrophil activity (CPa9-HNE and ELP-3). Results Mean serum levels of PC3X (p

Abstract Background Despite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats. Methods We evaluated KBP-336’s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology. Results After 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues. Conclusion Overall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.

Objective To assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple injections of M6495, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS‐5) nanobody, in healthy volunteers and patients with osteoarthritis. Methods Two randomized, placebo‐controlled, double‐blind studies were performed. Study 1 enrolled 54 healthy male volunteers who received one subcutaneous (s.c.) injection of M6495 (1‐300 mg) or placebo (ratio 2:1), evaluating safety, PK, and PD as changes in the serum aggrecan fragment alanine‐arginine‐glycine‐serine (ARGS). Study 2 enrolled 32 patients with osteoarthritis with Kellgren–Lawrence grades 2 to 4 and pain greater than or equal to 40 on the Western Ontario and McMaster Universities Arthritis Index pain subscale at screening and evaluated the safety, PK, and PD of three doses every two weeks (75‐300 mg per dose) or six once‐weekly M6495 s.c. doses (300 mg) or placebo (ratio 3:1) over 106 days’ follow‐up. Results M6495 in single and multiple doses of less than or equal to 300 mg s.c. weekly was well tolerated with no clinically significant changes in any safety parameter. Adverse events more frequently reported in the M6495 groups were mostly mild cases of injection site reactions, myalgia, and nausea, which resolved after treatment cessation. The elimination half‐life of single s.c. doses of M6495 ranged from 79 to 267 hours. M6495 administration substantially reduced serum ARGS levels, indicative of target engagement and indicating disease‐modifying potential of M6495. Conclusion Treatment with M6495 in single and multiple doses up to and including 300 mg s.c. was found to be well tolerated and adequately safe for further clinical evaluation of potential disease‐modifying effects.

Abstract Background The incidence of Antimicrobial Resistance (AMR) in uropathogens varies between countries and over time. We aim to study the patterns and potential predictors of AMR among patients with UTIs admitted to the Urology Department at Alexandria University Hospital. Methods An observational retrospective record-based study was conducted on all patients admitted to the Urology department from October 2018 to October 2020. Data collected from patients’ records included: demographic data, diagnosis on admission, history of chronic diseases, duration of hospital stay, insertion of a urinary catheter, duration of the catheter in days, history of the use of antibiotics in the previous three months, and history of urinary tract operations. If UTI was documented, we abstracted data about urine culture, use of antibiotics, results of urine cultures, type of organism isolated, and sensitivity to antibiotics. We conducted a multivariable logistic regression model. We performed Classification and Regression Tree Analysis (CART) for predicting risk factors associated with drug resistance among patients with UTI. Data were analyzed using SPSS statistical package, Version 28.0, and R software (2022). Results This study encompassed 469 patients with UTIs. The most commonly isolated bacterium was Escherichia coli, followed by Klebsiella pneumoniae. Multidrug resistance (MDR) was found in 67.7% (149/220) of patients with hospital-acquired UTIs and in 49.4% (83/168) of patients with community-acquired UTIs. Risk factors independently associated with antimicrobial resistance according to logistic regression analysis were the use of antibiotics within three months (AOR = 5.2, 95% CI 2.19–12.31), hospital-acquired UTI (AOR = 5.7, 95% CI 3.06–10.76), diabetes mellitus (AOR = 3.8, 95% CI 1.24–11.84), age over 60 years (AOR = 2.9, 95% CI 1.27–6.72), and recurrent UTI (AOR = 2.6, 95% CI 1.08–6.20). Classification and regression tree (CART) analysis revealed that antibiotic use in the previous three months was the most significant predictor for developing drug resistance. Conclusion The study concluded a high level of antimicrobial resistance as well as significant MDR predictors among hospitalized patients with UTIs. It is vital to assess resistance patterns in our hospitals frequently to improve rational antibiotic treatment as well as to sustain antimicrobial stewardship programs and a rational strategy in the use of antibiotics. Empirical therapy for UTI treatment should be tailored to the potential pathogens’ susceptibility to ensure optimal treatment. Strategic antibiotic use is essential to prevent further AMR increases. Further research should focus on suggesting new biological systems or designed drugs to combat the resistance of UTI pathogens.

Objective Clinical observation suggests that vascular activation and autoimmunity precede remodelling of the extracellular matrix (ECM) in systemic sclerosis (SSc). We challenge this paradigm by hypothesising that ECM biomarkers are already disturbed in patients with very early SSc (veSSc) when fibrosis is not yet clinically detectable.Methods 42 patients with veSSc, defined as the presence of Raynaud’s phenomenon and at least one of puffy fingers, positive antinuclear antibodies or pathological nailfold capillaroscopy, not meeting the 2013 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for SSc, were compared with healthy controls (HCs, n=29). ECM degradation (BGM, C3M, C4M and C6M) and ECM formation biomarkers (PRO-C3, PRO-C4 and PRO-C5) were measured in serum using ELISAs. A cross-sectional analysis at baseline and a longitudinal analysis was performed.Results Compared with HC, veSSc patients showed a strongly dysregulated turnover of type III and IV collagens (higher C3M, C4M, both p

The importance of the research topic is established by the problems that occur in structural buildings when exposed to fire accidents, where the concrete loses much part of its mechanical properties and therefore becomes out of service. Because reconstruction of damaged buildings has a high financial cost, it is necessary to focus on the restoration of damaged concrete members with performant techniques and proven efficiency in terms of increasing the strength of concrete and its resistance to high temperatures. The authors conduct a numerical investigation on the use of carbon fiber-reinforced polymer sheeting CFRP to restore various structural concrete elements such as beams, columns, and slabs damaged in fire accidents for two types of normal and high-strength concrete, in addition to studying the behavior of concrete after strengthening it with CFRP sheets. The results by showed that load capacity, stiffness index, and absorption energy index have been improved

Abstract Citrullinated vimentin has been linked to several chronic and autoimmune diseases, but how citrullinated vimentin is associated with disease prevalence and genetic variants in a clinical setting remains unknown. The aim of this study was to obtain a better understanding of the genetic variants and pathologies associated with citrullinated and MMP-degraded vimentin. Patient Registry data, serum samples and genotypes were collected for a total of 4369 Danish post-menopausal women enrolled in the Prospective Epidemiologic and Risk Factor study (PERF). Circulating citrullinated and MMP-degraded vimentin (VICM) was measured. Genome-wide association studies (GWAS) and phenome wide association studies (PheWAS) with levels of VICM were performed. High levels of VICM were significantly associated with the prevalence of chronic pulmonary diseases and death from respiratory and cardiovascular diseases (CVD). GWAS identified 33 single nucleotide polymorphisms (SNPs) with a significant association with VICM. These variants were in the peptidylarginine deiminase 3/4 (PADI3/PADI4) and Complement Factor H (CFH)/KCNT2 gene loci on chromosome 1. Serum levels of VICM, a marker of citrullinated and MMP-degraded vimentin, were associated with chronic pulmonary diseases and genetic variance in PADI3/PADI4 and CFH/ KCNT2. This points to the potential for VICM to be used as an activity marker of both citrullination and inflammation, identifying responders to targeted treatment and patients likely to experience disease progression.

Objective To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab.Methods In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering.Results Based on all three studies, we identified two orthogonal dimensions reflecting: (1) inflammation and neutrophil activity (driven by C1M and CPa9-HNE) and (2) collagen turnover (driven by PRO-C2). Three endotypes were identified: high inflammation endotype (Endotype1), low inflammation endotype (Endotype 2) and high collagen turnover endotype (Endotype3). Endotype1 showed higher disease activity (Ankylosing Spondylitis Disease Activity Score (ASDAS)) at baseline compared with Endotype2 and Endotype3 and higher percentage of patients responding to adalimumab based on ASDAS clinical improvement at week 24. Endotype3 showed higher percentage of patients with 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index response at week 24 compared with Endotype2.Conclusion These endotypes differ in their tissue remodelling profile and may in the future have utility for patient stratification and treatment tailoring.

Abstract Background Eosinophilic esophagitis (EoE) is a chronic progressive inflammatory disease of the esophagus, characterized by extracellular matrix remodeling and fibrotic stricture formation. Disease monitoring requires multiple re-endoscopies with esophageal biopsies. Hence non-invasive methods for determining tissue fibrosis and treatment efficacy are warranted. Aims To investigate the ability of extracellular matrix proteins in serum as potential biomarkers of tissue remodeling and clinical, endoscopic, and histological disease outcomes in adult EoE patients. Methods Protein-fingerprint assays were used to measure neo-epitope specific fragments of collagen remodeling, human-neutrophil elastase degraded calprotectin, and citrullinated or non-citrullinated vimentin in the serum of an adult EoE-cohort. Biomarker analysis, symptoms, endoscopic features and histological disease activity (eosinophils(eos) per high-power-field(hpf)) were evaluated at baseline and after six weeks of dietary intervention. Results Patients with a baseline (Endoscopic Reference score) EREFS fibrosis subscore ≥ 2 presented with increased fibrolysis of cross-linked type III collagen (CTX-III) (p