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ABSTRACTNeutrophil extracellular traps (NETs) contribute to the pathophysiology of multiple inflammatory and autoimmune diseases. Targeting the NETosis pathway has demonstrated significant therapeutic potency in various disease models. Here, we describe a first-in-class monoclonal antibody (CIT-013) with high affinity for citrullinated histones H2A and H4, which inhibits NETosis and reduces tissue NET burden in vivo with significant anti-inflammatory consequences. We provide a detailed understanding of the epitope selectivity of CIT-013. Detection of CIT-013 epitopes in rheumatoid arthritis (RA) synovium provides evidence that RA is an autoimmune disease with excessive citrullinated NETs that can be targeted by CIT-013. We show that CIT-013 acts upon the final stage of NETosis, binding to its chromatin epitopes when plasma membrane integrity is compromised to prevent NET release. Bivalency of CIT-013 is necessary for NETosis inhibition. In addition, we show that CIT-013 binding to NETs and netting neutrophils enhance their phagocytosis by macrophages in an Fc-dependent manner. This is confirmed using a murine neutrophilic airway inflammation model where a mouse variant of CIT-013 reduced tissue NET burden with significant anti-inflammatory consequences. CIT-013’s therapeutic activity provides new insights for the development of NET antagonists and indicates the importance of a new emerging therapy for NET-driven diseases with unmet therapeutic needs.

This article examines the ways in which distant reading, as a facet of the digital turn in the humanities, has affected the study of literature, with particular attention to the ways the digital turn has impacted the examination of authorship, genre, and style. In the process, it reflects on the ways in which distant reading developed both as a concept in the history of world literature and as a methodological approach that contributed to the evolution of computer-assisted study of literature.Cet article examine les façons dont la lecture à distance, en tant que facette du virage numérique dans les sciences humaines, a affecté l’étude de la littérature, avec une attention particulière aux façons dont le virage numérique a influencé l’examen de la paternité, le genre et le style. Dans le processus, il réfléchit sur les façons dont la lecture à distance a développé à la fois comme un concept dans l’histoire de la littérature mondiale et comme une approche méthodologique qui a contribué à l’évolution de l’étude assistée par ordinateur de la littérature.

Understanding the sensitivity of tidal flats to environmental changes is challenging. Currently, most studies rely on process-based models to systematically explain the morphodynamic evolution of tidal flats. In this study, we proposed an alternative empirical approach to explore tidal flat dynamics using statistical indices based on long-term time series of daily surface elevation development. Surface elevation dynamic (SED) indices focus on the magnitude and period of surface elevation changes, while morphodynamic signature (MDS) indices relate sediment dynamics to environmental drivers. The statistical analyses were applied to an intervention site in the Netherlands to determine the effect of recently constructed groynes on the tidal flat. Using these analyses, we were able to (1) detect a reduction in the daily SED and (2) determine that the changes in the daily SED were predominantly caused by the reduction in wave impact between the groynes rather than the reduction in tidal currents. Overall, the presented results showed that the combination of novel statistical indices provides new insights into the trajectories of tidal flats, ecosystem functioning, and sensitivity to physical drivers (wind and tides). Finally, we suggested how the SED and MDS indices may help to explore the future trajectories and climate resilience of intertidal habitats.

Abstract Background The rapid growth of social networking sites and video sharing platforms has created an opportunity for the alcohol industry to employ advanced advertising and marketing approaches to target their audiences, increasingly blurring the lines between commercial marketing and user-generated content, which poses a challenge for effective regulation. Methods We conducted a systematic search through three peer-reviewed journal databases (WoS, PubMed, Scopus). Studies were included if published in English, after 2004, and assessed statutory regulation or voluntary industry codes, enacted by an EU or nation’s governmental agency or private entity, and with the intent to restrict digital alcohol advertising. In addition, we conducted a manual search of gray literature. Results A total of 4690 records were identified. After duplicate removal and full-text assessment, 14 articles were examined. Our findings indicate that children and adolescents may often be exposed to alcohol advertisements on social media and websites due to industry’s self-regulatory age-affirmation systems being largely ineffective at preventing under-aged access. Cases of self-regulatory violations by the alcohol industry, and increasingly innovative ‘gray-area’ advertising approaches have also been noted. Additionally, research illustrates a lack of developed statutory restrictions of digital alcohol advertising and instead continued reliance on voluntary industry self-regulation. Conclusions There is a substantial need for further research to examine the effectiveness of digital alcohol advertising restrictions in social media, websites and image/video sharing platforms. Moreover, there is a necessity for countries to develop comprehensive statutory frameworks, which would effectively restrict and monitor rapidly advancing digital alcohol advertising practices on new digital media.

Tumour-associated macrophages (TAMs) support tumour development and have emerged as important regulators of therapeutic response to cytostatic agents. To target TAMs, we have developed a novel drug delivery approach which induces drug release as it inhibits cysteine cathepsin activity. This inhibitory prodrug (IPD) approach establishes a self-regulated system where drug release stops after all cysteine cathepsins are inhibited. This could improve the therapeutic window for drugs with severe side effects. We demonstrate and characterise this self-regulation concept with a fluorogenic IPD model. Next, we applied this IPD strategy to deliver cytotoxic drugs, as doxorubicin and monomethyl auristatin E, which are efficiently released and dose-dependently eliminate RAW264.7 macrophages. Lastly, by exploiting the increased cathepsin activity in TAM-like M2-polarised primary macrophages, we show that IPD-Dox selectively eliminates M2 over M1 macrophages. This demonstrates the potential of our IPD strategy for selective drug delivery and modulation of the tumour microenvironment.

Achtergrond Bij thuiswonende ouderen wordt functieverlies mogelijk uitgesteld door preventieve interventies. Het herkennen van ouderen met een verhoogd risico op functieverlies is een belangrijke eerste stap. Dit onderzoek heeft als doelstellingen: (1) om het Identification of Seniors At Risk (ISAR) screeningsinstrument te optimaliseren en te valideren in een eerstelijnspopulatie (ISARPrimary Care) en (2) om selectie van ouderen met verhoogd risico, vastgesteld met behulp van de ISAR-PC te vergelijken met selectie op basis van alleen leeftijd. Methode In de prospectieve ontwikkelings- en validatiecohorten namen respectievelijk 790 en 2573 thuiswonende ouderen (≥ 70 jaar) deel. Functieverlies was gedefinieerd als minimaal één punt achteruitgang op de gemodificeerde Katz-activiteiten van de dagelijks leven index na twaalf maanden ten opzichte van de score bij inclusie, dan wel sterfte. Resultaten Drie diagnostische kenmerken waren het meest voorspellend voor functieverlies: leeftijd (odds ratio (OR) 1,06 per toegevoegd jaar; 95 %- BI = 1,02–1,10), afhankelijkheid bij instrumentele activiteiten van het dagelijks leven (OR = 2,17; 95 %-BI = 1,46–3,22), en geheugenproblemen (OR = 2,22; 95 %-BI = 1,41–3,51). Het onderscheidend vermogen uitgedrukt in de AUC-range van de ISAR-PC was 0,67–0,70, en de kalibratie was goed. Van de deelnemende ouderen werd 40,6 % geclassificeerd als ouderen met een verhoogd risico op functieverlies. In het validatiecohort was de AUC range 0,63–0,64. De AUC range van leeftijd ≥ 75 jaar alleen in het validatiecohort was 0,56–0,57 en 65,0 % van de deelnemende ouderen werd daarbij geclassificeerd met een verhoogd risico op functieverlies. Conclusie Het discriminerend vermogen van de ISAR-PC is redelijk en de kalibratie goed. Selectie van ouderen met een verhoogd risico op functieverlies op basis van ISAR-PC is efficiënter dan selectie op basis van alleen leeftijd.

Introduction The prevalence of non-alcoholic fatty liver disease (NAFLD) ranges from 25% in the general population to 90% in patients with obesity scheduled for bariatric surgery. NAFLD can progress towards non-alcoholic steatohepatitis (NASH) associated with complications such as cirrhosis, hepatocellular carcinoma and cardiovascular disease. To date, losing weight and lifestyle modifications are the best known treatments for NASH. Bariatric surgery significantly improves NAFLD/NASH in the short term. However, the extent of this improvement is not yet clear and long-term data on the natural course of NAFLD/NASH after bariatric surgery are lacking. The factors involved in NAFLD/NASH regression after bariatric surgery have not been elucidated.Methods and analysis This is an observational prospective cohort study including patients scheduled for bariatric surgery. Extensive metabolic and cardiovascular analyses will be carried out including measurements of carotid intima media thickness and pulse wave velocity. Genomic, proteomic, lipidomic and metabolomic studies will be done. Microbioma analyses before and 1 year after surgery will be done. Transient elastography measurements will be performed before and at 1, 3 and 5 years after surgery. For those with an elevated preoperative transient elastography measurement by Fibroscan, a laparoscopic liver biopsy will be performed during surgery. Primary outcome measures are the change of steatosis and liver fibrosis 5 years after surgery. Secondary outcome measure is the comparison of the transient elastography measurements with the NAFLD Activity Score from the biopsies.Ethics and dissemination The protocol has been approved by the Medical Research Ethics Committees United, Nieuwegein, on 1 March 2022 (registration code R21.103/NL79423.100.21). The study results will be submitted for publication in peer-reviewed journals and data will be presented at scientific meetings.Trial registration number NCT05499949.

IntroductionAccelerated by the coronavirus pandemic, the healthcare landscape is rapidly evolving, with a shift towards hybrid care models combining in-person and online care. To support this shift, the Radboudumc, an academic hospital in the Netherlands, decided to redesign an existing space facilitating the conduction of video consultations.MethodThe design process involved participation of end-users to ensure that the physical space met their needs. The look and feel of the area was based on evidence-based design guidelines. Two prototype setups were built and tested, and the feedback informed the final design of the Garden Room.ResultsIdentified end-user needs were divided into 3 major categories entailing consultation room setup, optimal use of technology and practical issues involving room availability. Combined with the look and feel of the hospital, final design requirements were developed. The Garden Room consists of 18 video consultation rooms, 4 shared workspaces, relaxation area with kitchen, and meeting rooms. Specific attention is given to the ergonomics, technology and privacy in the rooms to facilitate optimal video conversations between patients and healthcare providers. In the Garden Room, natural elements and an open design supports working in a healing environment.DiscussionNext challenge will be optimizing the use of the Garden Room, which may be hindered by various barriers like resistance to change, existing work processes, and lack of skills training. To address these barriers and support use of the Garden Room, the hospital should focus on the implementation of education, changes in work processes, and the presence of advocates for telehealth.