Tergooi

Cancer patients have an eleven-fold increased risk of venous thromboembolism (VTE) compared to the general population. In this hypothesis-generating study we investigated plasma protein levels in colorectal cancer patients with and without thrombosis using targeted absolute quantification of 269 plasma proteins. We included samples from 142 patients with stage III/IV colorectal cancer from MICA - a multinational prospective cohort study, and from 98 patients from CATS - a prospective cohort study with stage III/IV colorectal cancer. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. In MICA, 11 (7.7%) developed VTE; in CATS 6 patients (6.1%) developed VTE within 6months, and 10 (10.2%) within 2years. Six differentially abundant proteins (DAPs) were identified in MICA: APOB100, CD5L, IGHG1, IGHM, PRG4, and TF. A model using these six proteins achieved a c-statistic of 0.687 (95% CI: 0.658-0.717) by internal cross-validation with 100 repeats and random 80% training sets. The optimism-corrected c-statistics was 0.675 (95% CI: 0.648-0.701). Using any subset of the DAPs yielded a c-statistics >0.67, with the best model reaching 0.768 (95% CI: 0.746-0.790). This outperformed the Khorana, modified-Vienna, PROTECHT, and CONKO models. The six DAPs had also predictive value in CATS with c-statistics at 0.70 (95% CI:0.671-0.728) for the 6-month, and 0.73 (95% CI:0.702-0.728) for 2-year follow-up. Two proteins showed inverted patterns between cohorts, likely due to chemotherapy. Our findings call for further investigation into the proteins identified, warranting further validation in larger, standardized studies.

Synovial inflammation is a central feature of knee osteoarthritis (OA), linking systemic and local pathogenic pathways with clinical outcomes. This review synthesises current knowledge on synovial structure and function, and the molecular mechanisms that drive synovitis, including metaflammation, mechanoflammation, mechanotransduction, and immune cell polarisation. It further explores how these processes contribute to structural degeneration, pain, and disease progression. Diagnostic approaches are discussed, with emphasis on biochemical biomarkers, imaging modalities, and the limited reliability of pain alone as a disease marker. By integrating clinical phenotypes with molecular endotypes, the review features how precision medicine can reshape OA care. Therapeutic strategies are presented across the translational spectrum, from oral and intra-articular drugs in clinical use to emerging investigational therapies, multitargeting approaches, and novel gene therapies. This review advocates for phenotype- and endotype-informed interventions as a pathway to more effective and personalised management of synovitis-driven knee OA. The translational value of this work lies in integrating molecular mechanisms with clinical strategies to guide early diagnosis, refine therapeutic targeting, and inform the design of future trials.

BackgroundPhysical activity (PA) is associated with improved overall survival (OS) among colorectal cancer (CRC) patients, but research on PA changes after diagnosis remains limited. This study examines associations between OS and changes in PA from CRC diagnosis onward, across stage- and treatment-related subgroups.MethodsData were analyzed from patients in two large CRC cohorts (PLCRC and COLON) enrolled between August 2010 and December 2022 (follow-up until February 1st, 2024). This included 3395 stage I–IIA patients who underwent surgery only, 2406 stage IIB/C–III patients who received (neo-)adjuvant therapy, and 669 metastatic CRC (mCRC) patients. PA was assessed via the validated SQUASH questionnaire at diagnosis (T0), and at 6, 12, and 24 months post-diagnosis (T6 to T24). Moderate-to-vigorous-intensity recreational activity was quantified by calculating Metabolic Equivalent of Task (MET) hours per week. Associations with OS were examined for change (active [tertile 2 and 3] vs inactive [tertile 1]) between timepoints using multivariable Cox proportional hazards models.ResultsAmong surgery-only patients, change from inactivity to activity between T0 and T6 was significantly associated with OS (HR = 0.58, 95% CI = 0.35 to 0.96). For (neo-)adjuvantly treated patients, significant associations were observed between T6 and T12 (HR = 0.53, 95% CI = 0.31 to 0.90). Among mCRC patients, a significant association was observed between T6 and T12 (HR = 0.53, 95% CI = 0.29 to 0.99).ConclusionChanging from inactivity to activity is significantly associated with prolonged survival during the early months post-diagnosis for surgery-only CRC patients, and later for those undergoing (neo-)adjuvant therapy or with metastatic disease. Validation is warranted in interventional studies.

BackgroundZalunfiban is a glycoprotein IIb/IIIa (integrin αIIbβ3) inhibitor designed for subcutaneous administration on first medical contact with patients with suspected ST-segment elevation myocardial infarction (STEMI).MethodsAn international, double-blind, placebo-controlled trial randomly assigned patients with STEMI in a 1:1:1 ratio to receive a single subcutaneous injection of zalunfiban (0.11 mg/kg or 0.13 mg/kg) or placebo. The primary efficacy end point was a hierarchical proportional odds model ranking seven end points from worst to best: all-cause death, stroke, recurrent myocardial infarction, acute stent thrombosis, new-onset or rehospitalization for heart failure, larger infarct size, or no end point through 30 days. The primary safety end point was the occurrence of severe or life-threatening bleeding as per the global use of strategies to open occluded coronary arteries (GUSTO) criteria.ResultsThe trial randomly assigned 2467 patients (853 to zalunfiban 0.11 mg/kg, 818 to zalunfiban 0.13 mg/kg, and 796 to placebo). The primary efficacy end point was significantly improved by zalunfiban (adjusted odds ratio 0.79; 95% confidence interval, 0.65 to 0.98; P=0.028). GUSTO severe bleeding was similar between those who received zalunfiban versus placebo (1.2% vs. 0.8%; P=0.40), but GUSTO mild to moderate bleeding was increased (6.4% vs. 2.5%; P<0.001). Angiography showed faster coronary blood flow with zalunfiban versus placebo (corrected frame count of the infarct-related artery 109 [interquartile range 35 to 176] vs. 176 [interquartile range 40 to 176]; P=0.012).ConclusionsIn patients with STEMI, zalunfiban administered at first medical contact significantly improved preintervention infarct-related patency and reduced the likelihood of a worse 30-day multicomponent hierarchical clinical end point. Zalunfiban was not associated with increased severe or life-threatening bleeding but was associated with increased mild to moderate bleeding. (Funded by CeleCor Therapeutics; CELEBRATE ClinicalTrials.gov number, NCT04825743.)

BackgroundThe preferred timing of treatment of nonculprit lesions in patients with ST-segment elevation myocardial infarction (STEMI) remains uncertain. A comparison of immediate percutaneous coronary intervention (PCI) guided by instantaneous wave-free ratio (iFR) and deferred PCI guided by cardiac stress magnetic resonance imaging (MRI) in patients with STEMI and multivessel disease is warranted.MethodsIn this international, investigator-initiated, open-label, randomized, controlled trial, patients with STEMI and at least one nonculprit lesion who had undergone successful primary PCI were randomly assigned in a 1:1 ratio to immediate iFR-guided PCI (in lesions with >50% stenosis and an iFR of ≤0.89 [normal value, >0.89]) or deferred cardiac stress MRI–guided PCI within 6 weeks after randomization. The primary end point was a composite of death from any cause, recurrent myocardial infarction, or hospitalization for heart failure at 3-year follow-up.ResultsThe trial included 1146 patients (558 in the iFR group and 588 in the MRI group) with a mean (±SD) age of 63±11 years; 78% were men. A total of 237 of 556 patients (42.6%) in the iFR group and 110 of 587 patients (18.7%) in the MRI group underwent nonculprit-lesion coronary-artery PCI. A primary-end-point event occurred in 50 patients (9.3%) in the iFR group and in 55 patients (9.8%) in the MRI group (hazard ratio, 0.95; 95% confidence interval, 0.65 to 1.40; P=0.81). Serious adverse events occurred in 145 patients in the iFR group and in 181 in the MRI group.ConclusionsAmong patients with STEMI who have undergone successful primary PCI, immediate iFR-guided PCI was not superior to deferred cardiac stress MRI–guided PCI of nonculprit coronary-artery lesions with respect to death from any cause, recurrent myocardial infarction, or hospitalization for heart failure at 3 years. (Funded by Philips Volcano and others; iMODERN ClinicalTrials.gov number, NCT03298659.)

Due to protean presentations, poor sensitivity of radiographs and variable reliability of synovial fluid analysis, diagnosis of Calcium pyrophosphate deposition disease (CPPD) is a challenge. This study addressed the diagnostic performance of musculoskeletal ultrasound (MSK-USG) in identifying CPPD features in hyaline cartilage, fibrocartilage, tendon, and synovial fluid. We compared ultrasound findings in CPPD to those in osteoarthritis (OA) and gout and healthy control. In this retrospective exploratory study, MSK-USG performed between February 2022 and July 2023 were reviewed. Patients retrospectively fulfilled the ACR/ EULAR classification criteria 2023 (score ≥ 56) were included (n = 16). Clinical phenotypes included acute CPP arthritis (44%), CPPD with OA (44%), and chronic CPP arthritis (12%). Ultrasound images were evaluated at common CPPD target sites: hyaline cartilage and fibrocartilage of the knee, wrist triangular fibrocartilage, metacarpophalangeal joints, joint capsules, tendons, and synovial membranes. Ultrasound images of CPPD cases were compared to those of OA, gout, and healthy controls. Sensitivity, specificity, and predictive values were calculated for Ultrasound features. Compared to healthy controls, Ultrasound features showed a sensitivity of 94.12% (CI: 71.31–99.85), specificity of 100% (CI: 86.77–100), positive predictive value of 100%, and negative predictive value of 99.59% in diagnosing CPPD. Ultrasound findings in hyaline cartilage showed a sensitivity & a specificity of 100% each. Fibrocartilage involvement showed a sensitivity of 93.75% and specificity of 86.67%. Whereas these figures were lowest for tendons with sensitivity of 12.5% (CI: 1.55–38.35) and specificity of 86.67% (CI: 69.28–96.24), respectively. Compared to OA, sensitivity and specificity were 100% and 93.75%, respectively. Specificity was lower when compared to gout (40%). MSK-USG demonstrated high diagnostic accuracy in identifying CPPD, especially in hyaline cartilage and fibrocartilage. While these findings support the use of Ultrasound as an adjunctive diagnostic tool, particularly in distinguishing CPPD from OA, the small sample size and retrospective design limit generalizability. Prospective studies with larger cohorts and crystal-confirmed cases are needed for validation.

# shared last authors Severe asthma in children is difficult to manage due to its clinical and biological heterogeneity. Since nasal transcriptomic profiles can mirror lower airway inflammation, this study explores their potential as a non-invasive approach to identify molecular subgroups. Nasal brushing samples were collected at baseline from children with severe asthma (GINA step ≥3) recruited in two Dutch hospitals, as part of the PANDA cohort. Bulk RNA-sequencing data from nasal brushings were normalized and analyzed. Principal component analysis and hierarchical clustering was used to identify distinct transcriptomic clusters. Differential gene expression analysis was performed, followed by gene set enrichment analysis (GSEA) with Gene Ontology, biological patways database. We investigated 35 children (mean age 12.4 ± 3.3 years, 60% boys). Unsupervised clustering identified 2 different molecular subgroups. The smallest cluster (n=4) was characterized by upregulation of genes linked to airway inflammation and epithelial remodeling (e.g. IL18, EDN1, ISG15), and downregulation of genes suggesting impaired mucociliary function (SCIN, ST6GAL1). In addition, these patients showed enrichment in gene expression profiles related to cilium movement and fluid transport, while pathways associated with keratinocyte differentiation and keratinization were downregulated, suggesting altered epithelial function. These findings support nasal transcriptomics as a non-invasive tool to explore molecular heterogeneity in pediatric severe asthma and highlight its potential for biomarker discovery and personalized treatment.

An increase in pediatric cases of invasive group A streptococcus (iGAS) disease was noted in the Netherlands starting in early 2022. GAS disease can range from mild to life-threatening invasive infections. Clinical and public health decisions rely on timely and detailed reporting of clinical data. To determine risk factors associated with severe pediatric iGAS, defined as requiring admission to an intensive care unit and/or death, and to analyze pediatric iGAS incidence, presentations, and outcome between pre-COVID-19 pandemic (January 2015 to March 2020), COVID-19 pandemic (April 2020 to December 2021), and post-COVID-19 pandemic (January 2022 to June 2024) periods. This observational, retrospective and prospective cohort study in 20 hospitals (tertiary and nontertiary) in the Netherlands was conducted from January 2015 to June 2024, with real-time reporting of data on the study website since January 2022. Children aged 0 to 17 years with iGAS (positive culture or polymerase chain reaction test and/or clinical presentation) were included. iGAS infection. The primary outcome was risk factors for severe iGAS; secondary outcomes included iGAS incidence rate and clinical phenotypes prior, during, and after the COVID-19 pandemic. Risk factors for severity and mortality were analyzed using univariable and multivariable logistic regression analyses, and incidence rate ratios (IRRs) between pre-COVID-19 and postCOVID-19 pandemic periods were calculated using Poisson regression. Of 617 children included, 351 (56.9%) were aged 0 to 4 years. For the 192 participants with detailed data collection, median (IQR) age was 4.2 (1.7-7.1) years and 91 (47.4%) were male. iGAS cases decreased during the COVID-19 pandemic and increased significantly in the post-COVID-19 period (IRR, 2.93; 95%, 2.46-3.49), as compared with the pre-COVID-19 pandemic period. By late 2023, the incidence of iGAS returned to pre-COVID-19 pandemic levels. Factors associated with increased risk of severe disease included a post-COVID-19 pandemic diagnosis (odds ratio [OR], 3.49; 95% CI, 2.31-6.26), pulmonary involvement (OR, 8.64; 95% CI, 5.50-13.55), streptococcal toxic shock syndrome (STSS; OR, 11.71; 95% CI, 4.39-31.18), and meningitis or encephalitis (OR, 4.38; 95% CI, 4.39-31.18). Clinical factors associated with increased risk of severe disease were reduced consciousness (OR, 7.61; 95% CI, 1.84-34.41), dyspnea (OR, 9.89; 95% CI, 3.04-32.14), abnormal auscultation (OR, 6.32; 95% CI, 2.18-18.32), and elevated C-reactive protein (OR, 6.32; 95% CI, 2.18-18.32), while estimated glomerular filtration rate was associated with a decreased risk (OR, 0.64; 95% CI, 0.49-0.84). Disease severity increased in post-COVID-19-pandemic cases, with higher mortality (13 of 294 cases [4.4%] vs 3 of 218 cases [1.4%]) and intensive care admission rates (113 of 294 cases [38.4%] vs 34 of 218 cases [15.6%]), as compared with pre-COVID-19 pandemic cases. Severity of pulmonary iGAS was similar in both periods. In the post-COVID-19 pandemic period, there was a significant increase in the incidence of pulmonary infections (IRR, 5.04; 95% CI, 3.27-7.97) , STSS (IRR, 10.30; 95% CI, 3.88-35.60), meningitis or encephalitis (IRR, 12.30; 95% CI, 4.14-52.70), and necrotizing fasciitis (IRR, 26.10; 95% CI, 5.14-475.00). In this cohort study, risk factors for a complicated course of iGAS in children included pulmonary or central nervous system involvement, STSS, reduced consciousness or pulmonary clinical signs, elevated CRP, and decreased eGFR. Awareness of these risk factors is important to improve timely recognition of at-risk cases and improve clinical outcomes.