Thermo Fisher Scientific (Sweden)

Abstract Background IgG autoantibodies against integrin αvβ6 have been associated with preclinical ulcerative colitis (UC),1,2 but data on their emergence and validation are still scarce. Therefore, we aimed to establish and validate a cutoff of anti-αvβ6 for predicting future UC across two independent preclinical cohorts. Additionally, we examined their development in early-life, assessed the influence of genetic-, environmental risk factors and inflammation on anti-αvβ6. Methods Within large population-based cohorts (n > 180,000), prediagnostic blood samples from individuals who later in life were diagnosed with UC were compared with age- and sex-matched controls who remained UC-free during follow-up (Figure 1). To explore early-life presence and genetic and shared environmental influences, we analysed serum from ABIS, a population-based birth cohort (n = 17,055) and the Swedish Twin Registry (n > 97,000). Anti-αvβ6 levels were measured using an in-house automated fluorescence enzyme immunoassay. Relative estimates of proteins were measured on the Olink platform3. Results In the discovery cohort (Table 1), anti-αvβ6 antibodies differentiated preclinical UC from controls (area under the curve [AUC]=0.68). Applying the model to the validation cohort yielded an AUC of 0.79, with a sensitivity of 46% and a specificity of 93%, at the optimal cut-off (109 UA/l) derived from the discovery cohort. Predictive capacity increased closer to diagnosis but remained significant for samples collected ≥20 years before UC diagnosis (AUC=0.67). In the birth cohort, anti-αvβ6 levels at birth appeared elevated in children who later developed UC (OR = 2.13; 95%CI, 0.84-5.38), likely reflecting transplacental antibody transfer, but also after 5 years (OR = 2.58; 95%CI, 0.83-8.03) and 8 years (OR = 2.50; 95%CI, 0.30-21.00). When assessing the level of agreement within twin pairs, low intra-class correlation coefficients were observed irrespective of zygosity and disease status, suggesting limited influence of genetic and shared environmental exposures. However, anti-αvβ6 levels differed across smoking categories in the preclinical cohorts, but inclusion of smoking status added little to model performance (AUC=0.82). By calculating a composite proteomic score, a progressive increase in the score was observed from the lowest to highest quartile of αvβ6 levels in preclinical UC, whereas most controls were found in the lowest quartiles for both the proteomic score and autoantibody levels. Conclusion Anti-αvβ6 autoantibodies represent a reproducible biomarker for preclinical UC. Their early-life presence, environmental modulation, and correlation with immuno-inflammatory proteins highlight their potential utility for risk stratification.

Abstract Rationale: Allergic sensitization is common in asthma and has been associated with an increased disease burden. Allergic sensitization is also found in chronic obstructive pulmonary disease (COPD), but less is known about the associations between allergic sensitization and disease severity in COPD, or in patients with both diagnostic labels. The aim of this investigation was to compare the prevalence of allergic sensitization in patients with asthma, asthma+COPD, and COPD and to investigate its association with severity and lung function in the three diagnostic groups. Methods: The NOVEL observational longiTudinal studY (NOVELTY; ClinicalTrials.gov identifier: NCT02760329) is a large global, prospective, observational study of people with physician-assigned diagnoses of asthma and/or COPD from 19 countries. Allergic sensitization was assessed at baseline by measuring serum IgE antibodies to house dust mite, birch, timothy, cat, dog, mugwort, ragweed, olive, wall pellitory, Alternaria, and Cladosporium. With sIgE ≥0.35 kUA/l classified as a positive value. Disease severity was assessed by the physician at baseline as mild, moderate, or severe. Postbronchodilatory forced expiratory volume in one second (FEV1) was expressed as % predicted, using Global Lung Function Initiative reference values. Results: Allergen specific IgE assessments were available for 2,742 participants with asthma, 800 with asthma+COPD, and 1,935 with COPD. The prevalence of allergic sensitization in those with asthma, asthma+COPD, and COPD was 56%, 36%, and 19%, respectively. House dust mite was the most common sensitization, with a prevalence of 40%, 24%, and 12% in the asthma, asthma+COPD, and COPD groups, respectively. In participants with asthma, sensitization to any allergen, mite, or moulds was independently associated with more severe disease and lower FEV1 after adjustment for age, sex, body mass index, smoking history, and geographical region (Figure). In participants with COPD, allergic sensitization to pollens was associated with mild disease, while sensitization to any allergen, olive, mugwort, or ragweed was independently associated with a higher FEV1 (Figure). There were no significant associations between allergic sensitization and disease severity in the group with asthma+COPD. Conclusions: In individuals with physician-assigned diagnoses of asthma, asthma+COPD, and COPD from NOVELTY, allergic sensitization was associated with more severe disease and lower lung function in patients with asthma, while associations in the opposite direction were found in patients with COPD.

Background and AimsThe diagnostic and prognostic properties of anti-integrin αvβ6 immunoglobulin G (IgG) autoantibodies in ulcerative colitis (UC) are poorly understood. We aimed to assess the diagnostic performance of anti-integrin αvβ6 autoantibodies and examine their association with disease outcomes.MethodsSerum samples from a Swedish inception cohort of patients with suspected inflammatory bowel disease (IBD, n = 473) were analyzed using an in-house fluorescence enzyme immunoassay based on EliA technology. Findings were validated in a Norwegian population-based inception cohort (n = 570). Diagnostic performance was assessed by calculating the area under the curve (AUC) with 95% confidence intervals and determining sensitivity and specificity. Reclassification was evaluated using the net reclassification index.ResultsIn the discovery cohort, patients with UC, IBD-unclassified, or colonic Crohn’s disease exhibited higher median autoantibody levels compared to symptomatic and healthy controls. In the validation cohort, the autoantibody demonstrated 79% sensitivity and 94% specificity for UC vs symptomatic controls at a cut-off of 400 UA/l. Its diagnostic performance (AUC = 0.92, 95% CI, 0.89-0.95) was superior to hs-CRP (AUC = 0.65, 95% CI, 0.60-0.70, P < .001) and faecal calprotectin (fcalpro) (AUC = 0.88, 95% CI, 0.84-0.92, P = .09). Combining the autoantibody with fcalpro further improved diagnostic accuracy (AUC = 0.97, 95% CI, 0.95-0.98) and patient reclassification (P < .001). Autoantibody positivity was associated with a severe phenotype of UC, characterised by increased inflammatory activity and higher IL-17A and granzyme B levels. Higher autoantibody levels were linked to an aggressive disease course, remaining stable in aggressive UC but decreasing in indolent disease (P = .003).ConclusionsAnti-integrin αvβ6 is a reliable diagnostic and prognostic marker for UC, with potential clinical implementation.

This study presents an alloy design perspective guided by elemental segregation during solidification to determine the site-specific chemistry and related local thermodynamic properties of dendritic microstructures. This was accomplished via manipulation of the microsegregation behavior by means of nominal alloy composition and thermal conditions of the solidification processes, including modified cooling rates spanning over six orders of magnitudes using ingot casting, directed energy deposition (DED-LB/M) additive manufacturing (AM) and laser powder bed fusion (PBF-LB/M) AM processes. Our approach was demonstrated by computationally designing a novel Al x Co 25 Fe (50-x) Ni 25 multi-principal element alloy (MPEA) as a model system, employing a combination of CALPHAD, Scheil, and multiphase-field simulations, and by experimentally validating the resulting microstructure evolution. The lower Al content (x = 10.5) was designated to generate a supersaturated single-phase fcc matrix suitable for heat-treatments to trigger local phase transformations. The higher Al content (x = 14.5) was selected to define the size and morphology of dual-phase microstructures by controlling phase nucleation and growth through segregation during solidification. Our results showcased how selective enrichment of the desired elements in interdendritic regions can be employed to induce local phase transformations during solidification or post heat-treatments, while their size can be flexibly controlled by the degree of undercooling during solidification. The suggested segregation-guided design approach can be transferred to other alloy systems, enabling effective tuning of local functional, structural, kinetic, and, as shown in this study, thermodynamic properties of dendritic microstructures by predetermining the nature of the alloy matrix through tailored solidification behavior.

INTRODUCTION:Neutrophilic calprotectin (CP) and myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and eosinophil-derived neurotoxin (EDN) are suggested proxy markers for gut inflammation. However, there are insufficient supporting data for MPO, NGAL, and EDN.METHODS:In a cross-sectional investigation including adult patients, we studied the ability of CP, MPO, NGAL, and EDN, measured in fecal and serum samples, to differentiate between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and to predict disease activity.RESULTS:Fifty-nine patients had ulcerative colitis (UC), 38 had Crohn's disease, and 100 patients had IBS. The protein concentrations were higher in patients with IBD in the fecal samples (P < 0.001) and the serum samples (P < 0.01), and they correlated weakly (rs ≤0.38) between the sample sources. Fecal EDN was higher in patients with Crohn's disease compared with UC (1.79 vs 0.50 mg/kg, P = 0.016). The neutrophilic proteins were superior to EDN in the fecal samples for differentiating between patients with IBD and IBS. Fecal MPO (cutoff: 0.86 mg/kg) had the highest sensitivity (74.7%) and specificity (84.6%). Combining fecal CP and MPO increased the sensitivity to 82.3% (specificity: 73.6%). NGAL (cutoff: 196.9 μg/L) showed the best discriminating performance in serum (sensitivity: 62.9%; specificity: 68.0%). Serum NGAL (cutoff: 272.4 μg/L) predicted active disease in UC (Partial Mayo Score ≥2) with a sensitivity and specificity of 57.1% and 83.3%, respectively.DISCUSSION:Fecal MPO and serum NGAL are promising novel biomarkers, in addition to fecal CP, for differentiating between IBD and IBS. Serum NGAL may also predict disease activity in patients with UC.

Background:Rheumatic? is an online symptom checker developed collaboratively by designers, engineers, clinical experts and patients. It is designed to identify individuals at high risk of developing rheumatic diseases and patients with immune-mediated rheumatic diseases (IRD). After completion of the questionnaire, Rheumatic? gives a weighted score based on expert assessments of the clinical significance of the answers[1]. A previous retrospective study has demonstrated the potential to distinguish IRD from osteoarthritis(OA) and gout, where clinicians filled out the questionnaire based on the medical notes[2]. In order to use a questionnaire in real life, it should be tested on real life participants, as they may describe their symptoms differently than experts.In order to evaluate the performance of the current Rheumatic? score, to differentiate between IRDs and non-IRDs we conducted a prospective real-world study in the Netherlands and assessed the differences in Rheumatic? total scores between individuals diagnosed with IRD and non-IRD.Objectives:Examine the difference in scores of Rheumatic? between IRD (Rheumatoid arthritis, Psoriatic arthritis, Myositis, Sjogren’s syndrome, SLE, Spondyloarthritis and Polymyalgia rheumatica) and non-IRD(OA, Gout, Fibromyalgia and other) diagnoses.Methods:We analyzed data submitted by Dutch participants recruited via multiple channels between July 2021 and July 2022. After completing the online questionnaire Rheumatic? participants received four follow-up surveys at 1 week, 3, 6 and 12 months asking, among other things, for previous and novel diagnoses. The theoretical total score for the participant was determined using the current, expert developed, risk assessment model post collection of all data[1,2].We used t-test and analysis of variance (ANOVA) to compared the observed differences in mean and median of total scores among these groups.Results:8,727 participants were included, of which 6861(79%) were female. The distribution of self-reported diagnoses is shown in Figure 1A. Variations in total scores across diagnosis groups is shown in Figure 1B. Among the participants, 4,146 (48%) did not receive a diagnosis (Table 1), 1,449 (17%) reported an IRD diagnosis, 1,410 (16%) fibromyalgia, and 2,976 (34%) OA or gout. Sex distribution differed between these four diagnostic categories: 78%, 70%, 94% and 80% respectively. 35% had a diagnosis in more than one disease category (Figure 1A). 24% of the people with OA/gout also reported fibromyalgia. For IRDs this was 17.5%.Patients without a diagnosis had a median score of 210 (Figure 1B). Consistent with the previous study, patients with only an IRD had a significantly higher score than patients with only OA or gout (IRDonly 250 versus AO/Goutonly 207, P<0.001)2. However, this difference was less marked for patients with multiple diagnoses (IRDmultiple 311 and OA/Goutmultiple 305, P=0.57). This was majorly caused by fibromyalgia patients whose median score was even higher than of people with an IRD (330 and 347 for FMonly and FMmultiple).Conclusion:Our study is the first to test an online symptom checker by following real-life patients. Rheumatic? is capable of capturing different patterns between patients with and without immune-mediated rheumatic diseases by scoring IRDs higher than non-IRDs. However, the magnitude of the difference is obscured by people having multiple diagnoses in particular fibromyalgia.REFERENCES:[1] Knitza J, et al. DOI: 10.2196/17507.[2] Knevel R, et al. DOI: 10.3389/fmed.2022.774945.Table 1. Patient characteristics and self-reported diagnoses.IRD = immune mediate rheumatic diseases, OA = osteoarthritis, FM = fibromyalgia, only = selection of patients with only a diagnosis in the specified category, multiple = diagnoses in multiple disease categories, all = all patients with a specified category diagnosisFigure 1.Other = joint infection, pseudogout and overload for musculoskeletal systemAcknowledgements:This study was supported by Horizon-EU within the SPIDERR project (activity No.101080711), and the DigiPrevent program (funded in April 2022) from EIT Health. The project has further received funding from the Dutch Organization for Health Research and Development (ZonMw) via the Klinische Fellow No. 40-00703-97-19069, and Open Competition, No. 09120012110075. A special thank you to David Steeman for data management.Disclosure of Interests:Ling Qin: None declared, Floor Zegers: None declared, Daniyal Selani: None declared, Erik B. van den Akker: None declared, Reinhard Bos: None declared, Saskia Le Cessie: None declared, Isabel Gehring Thermo Fisher Scientific, Herman Kasper Glas: None declared, Martina Johannesson: None declared, Johannes Knitza: None declared, Linda Mathsson-Alm Thermo Fisher Scientific, Marcel J.T. Reinders: None declared, Ewout Steyerberg: None declared, Astrid van Tubergen: None declared, Lise M. Verhoef: None declared, Barbara Axnäs ELSA Science AB, Lars Klareskog: None declared, Rachel Knevel: None declared.

BackgroundChronic airflow limitation (CAL) is a hallmark of chronic obstructive pulmonary disease but is also present in some patients with asthma. We investigated respiratory symptoms, sleep and health status of participants with and without CAL with particular emphasis on concurrent asthma using data from adult populations in Iceland, Estonia and Sweden investigated within the Burden of Obstructive Lung Disease study.MethodsAll participants underwent spirometry with measurements of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) before and after bronchodilation. CAL was defined as postbronchodilator FEV1/FVC below the lower limit of normal. IgE-sensitisation and serum concentrations of eosinophil-derived neurotoxin (S-EDN) were assessed in a subsample. The participants were divided into four groups: no self-reported doctor’s diagnosed asthma or CAL, asthma without CAL, CAL without asthma and asthma and CAL: χ2 test and analysis of variance were used in bivariable analyses and logistic and linear regression when analysing the independent association between respiratory symptoms, exacerbations, sleep-related symptoms and health status towards CAL, adjusting for centre, age, sex, body mass index, smoking history and educational level.ResultsAmong the 1918 participants, 190 (9.9%) had asthma without CAL, 127 (6.6%) had CAL without asthma and 50 (2.6%) had CAL with asthma. Having asthma with CAL was associated with symptoms such as wheeze (adjusted OR (aOR) 6.53 (95% CI 3.53 to 12.1), exacerbations (aOR 12.8 (95% CI 6.97 to 23.6), difficulties initiating sleep (aOR 2.82 (95% CI 1.45 to 5.48), nocturnal gastro-oesophageal reflux (aOR 3.98 (95% CI 1.79 to 8.82)) as well as lower physical health status. In these analyses, those with no asthma and no CAL were the reference group. The prevalence of IgE-sensitisation was highest in both asthma groups, which also had higher levels of S-EDN.ConclusionIndividuals with self-reported asthma with CAL suffer from a higher burden of respiratory and sleep-related symptoms, higher exacerbation rates and lower health status when compared with participants with asthma alone or CAL alone.

Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field.