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Background: Due to the growing number of complex (multimorbid) patients, integrating and coordinating care across medical specialties around patient needs is an urgent theme in current health care. Clinical leadership plays an important role in stimulating coordination both within and between specialty groups, which results in better outcomes in terms of job satisfaction and quality of care., Purpose: In this light, this study aims to understand the relation between physicians' clinical leadership and outcomes, focusing on the sequential mediation of relationships and coordination with physicians within their own medical specialty group and from other specialties., Methodology: A cross-sectional self-administered survey among physicians in a Dutch hospital (n = 107) was conducted to measure clinical leadership, relational coordination at two levels (medical specialty group and between different specialties), quality of care, and job satisfaction., Results: Clinical leadership was related to better quality of care through more relational coordination within the medical specialty group. Clinical leadership was related to more job satisfaction through more relational coordination within the medical specialty group, through more relational coordination between specialties, and sequentially through both kinds of relational coordination., Conclusion: Physicians who act as clinical leaders are important for crossing specialist boundaries and increasing care outcomes., Practical Implications: To improve multidisciplinary collaboration, managers should encourage clinical leadership and pay attention to the strong relationships between physicians from the same specialty., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Braam et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Hospitals have been encouraged to develop more process-oriented designs, structured around patient needs, to better deal with patients suffering from multi-morbidity. However, most hospitals still have traditional designs built around medical specialties. We aimed to understand how hospital designs are currently developing and what the important drivers are. We built a typology to categorize all Dutch general hospitals (61), and we interviewed hospital managers and staff. The inventory showed three types of hospital building blocks: units built around specific medical specialties, clusters housing different medical specialty units, and centers; multi-specialty entities provide the most suitable structure for a process-oriented approach. Only some Dutch hospitals (5) are mainly designed around centers. However, most hospitals are slowly developing towards hybrid designs. Competitive drivers are not important for stimulating these redesigns. Institutional pressures from within the health care sector and institutional 'mimicking' are the main drivers, but the specific path they take is dependent on their 'heritage'. We found that hospital structures are more the result of incremental, path-dependent choices than 'grand-designs'. Although the majority of the Dutch general hospitals still have a general design built around medical specialties, most hospitals are moving towards a more process-oriented design.

In recent years, data have become the main driver of medical innovation. With increased availability and decreased price of storage and computing power, the potential for improvement in care is enormous. Many data-driven explorations have started. However, the actual implementation of artificial intelligence in healthcare remains scarce. We describe essential elements during a computer-to-bedside process in a data science project that support the crucial role of the neonatologist. IMPACT: There is a great potential for data science in neonatal medicine. Multidisciplinary teams form the foundation of a data science project. Domain experts will need to play a pivotal role. We need an open learning environment., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objectives: To determine whether the statistical fragility of randomized controlled trials (RCTs) in high-impact journals has improved in the last decade and to perform an umbrella review of all published data on the Fragility Index (FI) across medical specialties., Study Design and Setting: The FI was calculated for all eligible RCTs published from 2014-2021 in the New England Journal of Medicine, The Lancet, the Journal of the American Medical Association, the British Medical Journal, and the Annals of Internal Medicine. Trials reporting dichotomous, statistically significant, superiority results were eligible. All previously published systematic reviews on the FI were included in the umbrella review and analyzed by medical (sub) specialty., Results: Of 2,544 screened RCTs, 643 were eligible for the FI analysis. These had a median sample size of 625 (interquartile range [IQR]: 265-2,056), a median FI of 12 (IQR: 3-28), and a median Fragility Quotient of 0.015 (IQR: 0.004-0.045). This is an improvement compared with the median FI of 8 (IQR: 3-18) of RCTs published a decade earlier in the same five journals (P < 0.001). The umbrella review included 57 publications across 15 different medical specialties, with a total of between 10 and 692 RCTs for each specialty. The median FI ranged between two and four for all disciplines., Conclusion: In the last decade, the median statistical robustness of RCTs published in high-impact journals has improved, yet the unchanged lower bound of the interquartile range reveals that statistical significance in 25% of trials is still dependent on three or less events. The umbrella review revealed that statistical fragility is prevalent across all medical specialties. The FI is an easy-to-understand metric that can be used to supplement reported P values and help readers look beyond merely reaching statistical significance., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Less attractive specialties in medicine are struggling to recruit and retain physicians. When properly organized and delivered, continuing medical education (CME) activities that include short courses, coaching in the workplace, and communities of practice might offer a solution to this problem. This position paper discusses how educationalists can create CME activities based on the self-determination theory that increase physicians' intrinsic motivation to work in these specialties., Main Content: The authors propose a set of guidelines for the design of CME activities that offer physicians meaningful training experiences within the limits of the available resources and support. First, to increase physicians' sense of professional relatedness, educationalists must conduct a learner needs assessment, evaluate CME's long-term outcomes in work-based settings, create social learning networks, and involve stakeholders in every step of the CME design and implementation process. Moreover, providing accessible, practical training formats and giving informative performance feedback that authentically connects to learners' working life situation increases physicians' competence and autonomy, so that they can confidently and independently manage the situations in their practice contexts. For each guideline, application methods and instruments are proposed, making use of relevant literature and connecting to the self-determination theory., Conclusions: By reducing feelings of professional isolation and reinforcing feelings of competence and autonomy in physicians, CME activities show promise as a strategy to recruit and retain physicians in less attractive specialties.

Objectives: To improve access to specialist outpatient clinics without adding capacity, Dutch hospitals applied the concept of 'Advanced Access'. Our aim was to determine whether initial improvements are sustained for three years and to identify the factors that influence sustainability., Methods: Qualitative case studies in 14 outpatient specialist clinics. Access measurements at the start, finish and three years after the project were compared. Analysis of sustained and new interventions. Interviews with 52 practitioners, analysed with the constant comparative method to identify general factors that influence sustainability., Results: Eleven out of 14 clinics were able to sustain or improve their reduced delays; two did not and for one it is uncertain. The clinics maintained the majority of the interventions and all introduced new interventions. Three generic factors emerged that influenced their ability to sustain the results: increased responsiveness to better match supply and demand; clinical leadership and incentives; and a shared belief that they can and should control access together., Conclusions: Reduction of delays in access can be sustained if the way of thinking and the planning system becomes demand driven and flexible and if care providers experience benefits. Unlike previous studies, senior management support and formal training was not relevant though clinical leadership and informal socialization was. Making multidisciplinary teams responsible for improvement appears to be vital.

Abstract The integration of next-generation sequencing into clinical diagnostics and surveillance initiatives is impeded by the lack of data analysis pipelines that align with privacy legislation and laboratory certification protocols. To address these challenges, we developed Jovian, an open-source, virus-focused, metagenomic analysis workflow for Illumina data. Jovian generates scaffolds enriched with pertinent annotations, including taxonomic classification, combined with metrics needed for quality assessment (coverage depth, average GC content, localization of open reading frames, minority single nucleotide polymorphisms), and incorporates host and disease metadata. Interactive web-based reports with an audit trail are generated. Jovian was employed on four systems, hosted by three institutes, utilizing grid-computers, a high-performance compute singular server, and a Windows10 laptop. All systems yielded identical results with matching MD5sums. Comparison with a commercial online reference tool using viral gastroenteritis samples confirmed the identification of the same pathogens. Jovian provides comparable results to a commercially available online reference tool and generates identical results at different institutes with different IT architectures, proving it is portable and reproducible. Jovian addresses bottlenecks in the deployment of metagenomics within public health and clinical laboratories and has the potential to enhance the breadth of surveillance and testing programs, thereby fostering more effective public health interventions.

Abstract Airway inflammation, a protective response in the human body, can disrupt normal organ function when chronic, as seen in chronic obstructive pulmonary disease (COPD) and asthma. Chronic bronchitis induces goblet cell hyperplasia and metaplasia, obstructing airflow. Traditional animal testing is often replaced by in vitro three-dimensional cultures of human epithelial cells to assess chronic cell responses. However, these cells are cultured horizontally, differing from the tubular structure of the human airway and failing to accurately reproduce airway stenosis. To address this, we developed the Bronchus-on-a-Chip (BoC) system. The BoC uses a novel microfluidic design in a standard laboratory plate, embedding 62 chips in one plate. Human bronchial epithelial cells were cultured against a collagen extracellular matrix for up to 35 days. Characterization included barrier integrity assays, microscopy, and histological examination. Cells successfully cultured in a tubular structure, with the apical side air-lifted. Epithelial cells differentiated into basal, ciliated, and secretory cells, mimicking human bronchial epithelium. Upon exposure to inducers of goblet cell hyperplasia and metaplasia, the BoC system showed mucus hyperproduction, replicating chronic epithelial responses. This BoC system enhances in vitro testing for bronchial inflammation, providing a more human-relevant and high-throughput method.

Abstract Background Congenital heart disease (CHD) is the most common congenital anomaly. Almost 90% of isolated cases have an unexplained genetic etiology after clinical testing. Non-canonical splice variants that disrupt mRNA splicing through the loss or creation of exon boundaries are not routinely captured and/or evaluated by standard clinical genetic tests. Recent computational algorithms such as SpliceAI have shown an ability to predict such variants, but are not specific to cardiac-expressed genes and transcriptional isoforms. Methods We used genome sequencing (GS) (n = 1101 CHD probands) and myocardial RNA-Sequencing (RNA-Seq) (n = 154 CHD and n = 43 cardiomyopathy probands) to identify and validate splice disrupting variants, and to develop a heart-specific model for canonical and non-canonical splice variants that can be applied to patients with CHD and cardiomyopathy. Two thousand five hundred seventy GS samples from the Medical Genome Reference Bank were analyzed as healthy controls. Results Of 8583 rare DNA splice-disrupting variants initially identified using SpliceAI, 100 were associated with altered splice junctions in the corresponding patient myocardium affecting 95 genes. Using strength of myocardial gene expression and genome-wide DNA variant features that were confirmed to affect splicing in myocardial RNA, we trained a machine learning model for predicting cardiac-specific splice-disrupting variants (AUC 0.86 on internal validation). In a validation set of 48 CHD probands, the cardiac-specific model outperformed a SpliceAI model alone (AUC 0.94 vs 0.67 respectively). Application of this model to an additional 947 CHD probands with only GS data identified 1% patients with canonical and 11% patients with non-canonical splice-disrupting variants in CHD genes. Forty-nine percent of predicted splice-disrupting variants were intronic and > 10 bp from existing splice junctions. The burden of high-confidence splice-disrupting variants in CHD genes was 1.28-fold higher in CHD cases compared with healthy controls. Conclusions A new cardiac-specific in silico model was developed using complementary GS and RNA-Seq data that improved genetic yield by identifying a significant burden of non-canonical splice variants associated with CHD that would not be detectable through panel or exome sequencing.

Abstract Background Very few studies to date investigated the prospective association of changes in exposure to the food environment with cardiovascular disease (CVD) risk. We aim to explore if time-varying exposure to the food environment was associated with hospitalization and mortality due to total and specific types of CVD in The Netherlands. Methods In this prospective cohort study, 4,641,435 Dutch adults aged 35 + years who did not change residence in 2002–2018 were identified through registry data. Exposure to the food environment was defined as time-varying Food Environment Healthiness Index (FEHI) scores (range: − 5 to 5) and time-varying kernel density of specific food retailers (e.g., fast food outlets, supermarkets) around the home location between 2004 and 2018. The main outcome measures were hospitalization and mortality due to overall CVD, stroke, HF, and CHD occurring between 2004 and 2020, based on hospital and death registries. Results In Cox regression models, each unit increase in the FEHI was associated with a lower hospitalization and mortality of CVD (hospitalization hazard ratio (HRh) = 0.90 (0.89 to 0.91), mortality hazard ratio (HRm) = 0.85 (0.82 to 0.89)), CHD (HRh = 0.88 (0.85 to 0.91), HRm = 0.80 (0.75 to 0.86)), stroke (HRh = 0.89 (0.84 to 0.93)), HRm = 0.89 (0.82 to 0.98)), and HF (HRh = 0.90 (0.84–0.96), HRm = 0.84 (0.76 to 0.92)). Increased density of local food shops, fast food outlets, supermarkets, and convenience stores and decreased density of food delivery outlets and restaurants were associated with a higher risk of CVD, CHD, stroke, and HF hospitalization and mortality. Conclusions In this observational longitudinal study, changes in exposure to a healthier food environment over 14 years were associated with a risk reduction in CVD hospitalization and mortality, in particular in urbanized areas and for younger adults and those with higher incomes.

Abstract We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Abstract Background While game-based learning has demonstrated positive outcomes for some learners, its efficacy remains variable. Adaptive scaffolding may improve performance and self-regulation during training by optimizing cognitive load. Informed by cognitive load theory, this study investigates whether adaptive scaffolding based on interaction trace data influences learning performance, self-regulation, cognitive load, test performance, and engagement in a medical emergency game. Methods Sixty-two medical students from three Dutch universities played six game scenarios. They received either adaptive or nonadaptive scaffolding in a randomized double-blinded matched pairs yoked control design. During gameplay, we measured learning performance (accuracy, speed, systematicity), self-regulation (self-monitoring, help-seeking), and cognitive load. Test performance was assessed in a live scenario assessment at 2- and 6–12-week intervals. Engagement was measured after completing all game scenarios. Results Surprisingly, the results unveiled no discernible differences between the groups experiencing adaptive and nonadaptive scaffolding. This finding is attributed to the unexpected alignment between the nonadaptive scaffolding and the needs of the participants in 64.9% of the scenarios, resulting in coincidentally tailored scaffolding. Exploratory analyses suggest that, compared to nontailored scaffolding, tailored scaffolding improved speed, reduced self-regulation, and lowered cognitive load. No differences in test performance or engagement were found. Discussion Our results suggest adaptive scaffolding may enhance learning by optimizing cognitive load. These findings underscore the potential of adaptive scaffolding within GBL environments, cultivating a more tailored and effective learning experience. To leverage this potential effectively, researchers, educators, and developers are recommended to collaborate from the outset of designing adaptive GBL or computer-based simulation experiences. This collaborative approach facilitates the establishment of reliable performance indicators and enables the design of suitable, preferably real-time, scaffolding interventions. Future research should confirm the effects of adaptive scaffolding on self-regulation and learning, taking care to avoid unintended tailored scaffolding in the research design. Trial registration This study was preregistered with the Center for Open Science prior to data collection. The registry may be found at https://osf.io/7ztws/ .

ABSTRACT On May 26, 2021, the European Medical Device Regulation (EU-MDR) entered into effect resulting in a major shift in the requirements for assessment of medical devices in Europe. The EU-MDR Cardiovascular Collaboratory (EU-MCVC) was founded to contribute to the development of faster, more efficient, and more effective pathways for innovation of cardiac medical devices. A registry is an organized system that collects uniform data and evaluates specified outcomes in a population defined by a disease, condition, or exposure. Most registries have been created to improve the quality of care and provide feedback to physicians, hospitals, and health providers. Clinical registries represent an ideal construct for scientific, clinical, and policy-making collaboration. We describe diverse experiences from 5 European countries and address the traditional quality components in clinical trials. Continued collaboration is expected among academics, clinical trialists, patient representatives, regulatory experts, research organizations, registry platforms, regulatory bodies, and industry partners. Data quality is a primary concern and registry leaders need to optimize data quality to become regulatory compliant. A collaborative approach among medical device stakeholders may improve quality of care, reduce costs, and provide faster access to innovative technologies, with the common objective of improving cardiovascular care and outcomes.

Abstract The problem of artifacts in whole slide image acquisition, prevalent in both clinical workflows and research-oriented settings, necessitates human intervention and re-scanning. Overcoming this challenge requires developing quality control algorithms, that are hindered by the limited availability of relevant annotated data in histopathology. The manual annotation of ground-truth for artifact detection methods is expensive and time-consuming. This work addresses the issue by proposing a method dedicated to augmenting whole slide images with artifacts. The tool seamlessly generates and blends artifacts from an external library to a given histopathology dataset. The augmented datasets are then utilized to train artifact classification methods. The evaluation shows their usefulness in classification of the artifacts, where they show an improvement from 0.10 to 0.01 AUROC depending on the artifact type. The framework, model, weights, and ground-truth annotations are freely released to facilitate open science and reproducible research.

Abstract Chronic disease management and follow-up are vital for realizing sustained patient well-being and optimal health outcomes. Recent advancements in wearable technologies, particularly wrist-worn devices, offer promising solutions for longitudinal patient monitoring, replacing subjective, intermittent self-reporting with objective, continuous monitoring. However, collecting and analyzing data from wearables presents several challenges, such as data entry errors, non-wear periods, missing data, and wearable artifacts. In this work, we explore these data analysis challenges using two real-world datasets (mBrain21 and ETRI lifelog2020). We introduce practical countermeasures, including participant compliance visualizations, interaction-triggered questionnaires to assess personal bias, and an optimized pipeline for detecting non-wear periods. Additionally, we propose a visualization-oriented approach to validate processing pipelines using scalable tools such as tsflex and Plotly-Resampler. Lastly, we present a bootstrapping methodology to evaluate the variability of wearable-derived features in the presence of partially missing data segments. Prioritizing transparency and reproducibility, we provide open access to our detailed code examples, facilitating adaptation in future wearable research. In conclusion, our contributions provide actionable approaches for improving wearable data collection and analysis.

Abstract The healthy lifestyle index (HLI), defined as the unweighted sum of individual lifestyle components, was used to investigate the combined role of lifestyle factors on health-related outcomes. We introduced weighted outcome-specific versions of the HLI, where individual lifestyle components were weighted according to their associations with disease outcomes. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), we examined the association between the standard and the outcome-specific HLIs and the risk of T2D, CVD, cancer, and all-cause premature mortality. Estimates of the hazard ratios (HRs), the Harrell’s C-index and the population attributable fractions (PAFs) were compared. For T2D, the HR for 1-SD increase of the standard and T2D-specific HLI were 0.66 (95% CI: 0.64, 0.67) and 0.43 (0.42, 0.44), respectively, and the C-index were 0.63 (0.62, 0.64) and 0.72 (0.72, 0.73). Similar, yet less pronounced differences in HR and C-index were observed for standard and outcome-specific estimates for cancer, CVD and all-cause mortality. PAF estimates for mortality before age 80 were 57% (55%, 58%) and 33% (32%, 34%) for standard and mortality-specific HLI, respectively. The use of outcome-specific HLI could improve the assessment of the role of lifestyle factors on disease outcomes, thus enhancing the definition of public health recommendations.

Abstract As SARS-CoV-2 continues to spread worldwide, tractable primary airway cell models that recapitulate the cell-intrinsic response to arising viral variants are needed. Here we describe an adult stem cell-derived human airway organoid model overexpressing the ACE2 receptor (ACE2-OE) that supports robust viral replication while maintaining 3D architecture and cellular diversity of the airway epithelium. ACE2-OE organoids were infected with SARS-CoV-2 variants and subjected to single-cell RNA-sequencing. Interferon-lambda was upregulated in cells with low-level infection while the NF-kB inhibitor alpha gene (encoding IkBa) was consistently upregulated in infected cells, and its expression positively correlated with infection levels. Confocal microscopy showed more IkBa expression in infected than bystander cells, but found concurrent nuclear translocation of NF-kB that IkBa usually prevents. Overexpressing a nondegradable IkBa mutant reduced NF-kB translocation and increased viral infection. These data demonstrate the functionality of ACE2-OE organoids in SARS-CoV-2 research and underscore that the strength of the NF-kB feedback loop in infected cells controls viral replication.

Abstract Background The practice of palliative sedation continues to raise ethical questions among people, which in turn leads to its varied acceptance and practice across regions. As part of the Palliative Sedation European Union (EU) project, the aim of the present study was to determine the perceptions of palliative care experts regarding the practice of palliative sedation in eight European countries (The Netherlands, Belgium, Germany, UK, Italy, Spain, Hungary, and Romania). Methods A specifically designed survey, including questions on the most frequently used medications for palliative sedation, their availability per countries and settings, and the barriers and facilitators to the appropriate practice of palliative sedation was sent to expert clinicians involved and knowledgeable in palliative care in the indicated countries. A purposive sampling strategy was used to select at least 18 participating clinicians per consortium country. Descriptive statistical analysis was conducted on the survey data. Results Of the 208 expert clinicians invited to participate, 124 participants completed the survey. Midazolam was perceived to be the most frequently used benzodiazepine in all eight countries. 86% and 89% of expert clinicians in Germany and Italy, respectively, perceived midazolam was used “almost always”, while in Hungary and Romania only about 50% or less of the respondents perceived this. Levomepromazine was the neuroleptic most frequently perceived to be used for palliative sedation in the Netherlands, Spain, Germany, and the United Kingdom. Between 38- 86% of all eight countries´ expert clinicians believed that opioid medications were “almost always” used during palliative sedation. The perceived use of IV hydration and artificial nutrition “almost always” was generally low, while the country where both IV hydration and artificial nutrition were considered to be “very often” given by a third of the expert clinicians, was in Hungary, with 36% and 27%, respectively. Conclusions Our study provides insight about the differences in the perceived practice of medication during palliative sedation between eight European countries. In countries where palliative care services have been established longer perceptions regarding medication use during palliative sedation were more in line with the recommended European guidelines than in Central and Eastern European countries like Romania and Hungary.

Abstract Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen leading to structural damage. The application of intraluminal oxygen has been successfully tested in small-animal series during storage and transport of the organ but have been so far clinically unrelatable. In this study, we tested whether a simple and clinically approachable method of intraluminal oxygen application could prevent ischemic damage in a large animal model, during warm ischemia time. We utilised a local no-flow ischemia model of the small intestine in pigs. A low-flow and high-pressure intraluminal oxygen deliverance system was applied in 6 pigs and 6 pigs served as a control group. Mucosal histopathology, hypoxia and barrier markers were evaluated after two hours of no-flow conditions, in both treatment and sham groups, and in healthy tissue. Macro- and microscopically, the luminal oxygen delivered treatment group showed preserved small bowel’s appearance, viability, and mucosal integrity. A gradual deterioration of histopathology and barrier markers and increase in hypoxia-inducible factor 1-α expression towards the sites most distant from the oxygen application was observed. Intraluminal low-flow, high oxygen delivery can preserve the intestinal mucosa during total ischemia of the small intestine. This finding can be incorporated in methods to overcome small bowel ischemia and improve intestinal preservation for transplantation.

Abstract Background Supermarket interventions are promising to promote healthier dietary patterns, but not all individuals may be equally susceptible. We explored whether the effectiveness of nudging and pricing strategies on diet quality differs by psychological and grocery shopping characteristics. Methods We used data of the 12-month Supreme Nudge parallel cluster-randomised controlled supermarket trial, testing nudging and pricing strategies to promote healthier diets. Participants were Dutch speaking adults aged 30–80 years and regular shoppers of participating supermarkets (n = 12) in socially disadvantaged neighbourhoods. Data on psychological characteristics (food-related behaviours; price sensitivity; food decision styles; social cognitive factors; self-control) and grocery shopping characteristics (time spent in the supermarket; moment of the day; average supermarket visits; shopping at other retailers; supermarket proximity) were self-reported at baseline. These characteristics were tested for their moderating effects of the intervention on diet quality (scored 0–150) in linear mixed models. Results We included 162 participants from intervention supermarkets and 199 from control supermarkets (73% female, 58 (± 10.8) years old, 42% highly educated). The interventions had no overall effect on diet quality. Only five out of 23 potential moderators were statistically significant. Yet, stratified analyses of these significant moderators showed no significant effects on diet quality for one of the subgroups and statistically non-significant negative effects for the other. Negative effects were suggested for individuals with lower baseline levels of meal planning (β − 2.6, 95% CI − 5.9; 0.8), healthy shopping convenience (β − 3.0, 95% CI − 7.2; 1.3), and healthy food attractiveness (β − 3.5, 95% CI − 8.3; 1.3), and with higher levels of price consciousness (β − 2.6, 95% CI − 6.2; 1.0) and weekly supermarket visits (β − 2.4, 95% CI − 6.8; 1.9). Conclusions Adults with varying psychological and grocery shopping characteristics largely seem equally (un)susceptible to nudging and pricing strategies. It might be that certain characteristics lead to adverse effects, but this is not plausible, and the observed negative effects were small and statistically non-significant and may be explained by chance findings. Verification of these findings is needed in real-world trials based on larger sample sizes and with the use of more comprehensive interventions. Trial registration Dutch Trial Register ID NL7064, 30th of May, 2018, https://onderzoekmetmensen.nl/en/trial/20990

Abstract Structural brain network topology can be altered in case of a brain tumor, due to both the tumor itself and its treatment. In this study, we explored the role of structural whole-brain and nodal network metrics and their association with cognitive functioning. Fifty WHO grade 2–3 adult glioma survivors (> 1-year post-therapy) and 50 matched healthy controls underwent a cognitive assessment, covering six cognitive domains. Raw cognitive assessment scores were transformed into w-scores, corrected for age and education. Furthermore, based on multi-shell diffusion-weighted MRI, whole-brain tractography was performed to create weighted graphs and to estimate whole-brain and nodal graph metrics. Hubs were defined based on nodal strength, betweenness centrality, clustering coefficient and shortest path length in healthy controls. Significant differences in these metrics between patients and controls were tested for the hub nodes (i.e. n = 12) and non-hub nodes (i.e. n = 30) in two mixed-design ANOVAs. Group differences in whole-brain graph measures were explored using Mann–Whitney U tests. Graph metrics that significantly differed were ultimately correlated with the cognitive domain-specific w-scores. Bonferroni correction was applied to correct for multiple testing. In survivors, the bilateral putamen were significantly less frequently observed as a hub (p bonf 0.573, p bonf 0.794, p bonf

Abstract Snakebite envenomation is a major public health issue which causes severe morbidity and mortality, affecting millions of people annually. Of a diverse range of clinical manifestations, local and systemic haemorrhage are of particular relevance, as this may result in ischemia, organ failure and even cardiovascular shock. Thus far, in vitro studies have failed to recapitulate the haemorrhagic effects observed in vivo. Here, we present an organ-on-a-chip approach to investigate the effects of four different snake venoms on a perfused microfluidic blood vessel model. We assess the effect of the venoms of four snake species on epithelial barrier function, cell viability, and contraction/delamination. Our findings reveal two different mechanisms by which the microvasculature is being affected, either by disruption of the endothelial cell membrane or by delamination of the endothelial cell monolayer from its matrix. The use of our blood vessel model may shed light on the key mechanisms by which tissue-damaging venoms exert their effects on the capillary vessels, which could be helpful for the development of effective treatments against snakebites.

Summary: Background: Currently, there is no licensed treatment for chronic norovirus infections, but the use of intra-duodenally-delivered immunoglobulins is promising; nevertheless, varying results have limited their wide use. Little is known about the relationship between norovirus genetic diversity and treatment efficacy. Methods: We analyzed the norovirus within-host diversity and evolution in a cohort of 20 immunocompromised individuals using next-generation sequencing (NGS) and clone-based sequencing of the capsid (VP1) gene. Representative VP1s were expressed and their glycan receptor binding affinity and antigenicity were evaluated. Findings: The P2 domain, within the VP1, accumulated up to 30-fold more non-synonymous mutations than other genomic regions. Intra-host virus populations in these patients tended to evolve into divergent lineages that were often antigenically distinct. Several of these viruses were widely resistant to binding-blocking antibodies in immunoglobulin preparations. Notably, for one patient, a single amino-acid substitution in the P2 domain resulted in an immune-escape phenotype, and it was likely the main contributor to treatment failure. Furthermore, we found evidence for transmission of late-stage viruses between two immunocompromised individuals. Interpretation: The findings demonstrated that within-host noroviruses in chronic infections tend to evolve into antigenically distinct subpopulations. This antigenic evolution was likely caused by the remaining low immunity levels exerted by immunocompromised individuals, possibly undermining antiviral treatment. Our observations provide insights into norovirus (within-host) evolution and treatment. Funding: Erasmus MC grant mRACE, the European Union's Horizon 2020 research and innovation program under grant agreement No. 874735 (VEO), and the NWO STEVIN award (Koopmans).

Introduction Differential target multiplexed spinal cord stimulation (DTM SCS) is a new stimulation paradigm for chronic pain management with the aim of modulating glial cells and neurons in order to rebalance their interactions. Animal studies revealed positive effects of this type of stimulation; however, studies in humans are still scarce, pointing towards the need for an evaluation of the effectiveness and safety of DTM SCS in clinical settings. Furthermore, the differential target multiplexed (DTM) algorithm consists of a combination of several programmes, which will presumably consume more energy from the spinal cord stimulation (SCS) battery. Therefore, the objective of DETECT is to investigate the feasibility, effectiveness and safety of DTM SCS in patients with Persistent Spinal Pain Syndrome Type II through a longitudinal cohort study.Methods and analysis DETECT is a prospective multicentre cohort study (n≥250) with a follow-up until 12 months after receiving DTM SCS. The study initiated in October 2021 and is currently still recruiting patients. Self-reporting outcome variables were evaluated at baseline (before SCS) and at 1, 6 and 12 months of DTM SCS. The primary effectiveness endpoint is overall pain intensity, measured with the visual analogue scale. Secondary effectiveness outcome measures are back pain intensity, leg pain intensity, disability, health-related quality of life, pain medication use, functional disability, clinical holistic responder status, self-management, impression of change, work status, pain catastrophising, symptoms of central sensitisation, anxiety, depression and healthcare utilisation. Time spent in different body postures and SCS stimulation parameters will be read out from the pulse generator. The prevalence of technical issues, recharge frequency, (serious) adverse events and the proportion of successful DTM trials will be collected as well. Longitudinal mixed models will be calculated to evaluate the effectiveness of DTM SCS over time.Ethics and dissemination The study protocol was approved by the central Ethics Committee of the Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel (B.U.N.1432021000563) and the Ethics Committees of each participating centre. Research findings will be disseminated to key stakeholders through peer-reviewed publications in scientific journals and presentations to clinical audiences.Trial registration number NCT05068011.

Summary: Background: The inflammatory response in patients with traumatic brain injury (TBI) offers opportunities for stratification and intervention. Previous unselected approaches to immunomodulation in patients with TBI have not improved patient outcomes. Methods: Serum and plasma samples from two prospective, multi-centre observational studies of patients with TBI were used to discover (Collaborative European NeuroTrauma Effectiveness Research [CENTER-TBI], Europe) and validate (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI] Pilot, USA) individual variations in the immune response using a multiplex panel of 30 inflammatory mediators. Mediators that were associated with unfavourable outcomes (Glasgow outcome score-extended [GOS-E] ≤ 4) were used for hierarchical clustering to identify patients with similar signatures. Findings: Two clusters were identified in both the discovery and validation cohorts, termed early-inflammatory and pauci-inflammatory. The early-inflammatory phenotype had higher concentrations of interleukin-6 (IL-6), IL-15, and monocyte chemoattractant protein 1 (MCP1). Patients with the early-inflammatory phenotype were older and more likely to have an unfavourable GOS-E at 6 months. There were no differences in the baseline injury severity scores between patients in each phenotype. A combined IL-15 and MCP1 signature identified patients with the early-inflammatory phenotype in both cohorts. Inflammatory processes mediated outcomes in older patients with moderate-severe TBI. Interpretation: Our findings offer a precision medicine approach for future clinical trials of immunomodulation in patients with TBI, by using inflammatory signatures to stratify patients. Funding: CENTER-TBI study was supported by the European Union 7th Framework Programme. TRACK-TBI is supported by the National Institute of Neurological Disorders and Stroke.

BackgroundDigital technologies have penetrated most workplaces. However, it is unclear how such digital technologies affect the physical health of older workers. ObjectiveThis scoping review aims to examine and summarize the evidence from scientific literature concerning the impact of digital technology on the physical health of older workers. MethodsThis scoping review will be conducted following recommendations outlined by Levac et al and will adhere to the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews) guidelines for reporting. Peer-reviewed papers written in English will be searched in the following databases: MEDLINE, Cochrane, ProQuest, Web of Science, Scopus, APA PsycInfo, and ERIH PLUS. The web-based systematic review platform Covidence will be used to create a data extraction template. It will cover the following items: study and participant characteristics, health measures, digital tool characteristics and usage, and research findings. Following the Population, Concept, and Context (PCC) framework, our review will focus on studies involving older workers aged 50 years or older, any form of digital technology (including teleworking and the use of digital tools at work), and how digital technologies affect physical health (such as vision loss, musculoskeletal disorders, and migraines). Studies that focus only on mental health will be excluded. Study selection based on title and abstract screening (first stage), full-text review (second stage), and data extraction (third stage) will be performed by a group of researchers, whereby each paper will be reviewed by at least 2 people. Any conflict regarding the inclusion or exclusion of a study and the data extraction will be resolved by discussion between the researchers who evaluated the papers; a third researcher will be involved if consensus is not reached. ResultsA preliminary search of MEDLINE, Epistemonikos, Cochrane, PROSPERO, and JBI Evidence Synthesis was conducted, and no current or ongoing systematic reviews or scoping reviews on the topic were identified. The results of the study are expected in April 2025. ConclusionsOur scoping review will seek to provide an overview of the available evidence and identify research gaps regarding the effect of digital technology and the use of digital tools in the work environment on the physical health of older workers. International Registered Report Identifier (IRRID)PRR1-10.2196/59900

Introduction The predominant provider payment models in healthcare, particularly fee-for-service, hinder the delivery of high-value care and can encourage healthcare providers to prioritise the volume of care over the value of care. To address these issues, healthcare providers, payers and policymakers are increasingly experimenting with alternative payment models (APMs), such as shared savings (SS) and bundled payment (BP). Despite a growing body of literature on APMs, there is still limited insight into what works in developing and implementing successful APMs, as well as how, why and under what circumstances. This paper presents the protocol for a study that aims to (1) identify these circumstances and reveal the underlying mechanisms through which outcomes are achieved and (2) identify transferrable lessons for successful APMs in practice.Methods and analysis Drawing on realist evaluation principles, this study will employ an iterative three-step approach to elicit a programme theory that describes the relationship between context, mechanisms and outcomes of APMs. The first step involves a literature review to identify the initial programme theory. The second step entails empirical testing of this theory via a multiple case study design including seven SS and BP initiatives in Dutch hospital care. We will use various qualitative and quantitative methods, including interviews with involved stakeholders, document analysis and difference-in-differences analyses. In the final step, these data and the applicable formal theories will be combined to test and refine the (I)PT and address the research objectives.Ethics and dissemination Ethical approval has been granted by the Research Ethics Review Committee of Erasmus School of Health Policy and Management (Project ID ETH2122-0170). Where necessary, informed consent will be obtained from study participants. Among other means, study results will be disseminated through a publicly available manual for stakeholders (eg, healthcare providers and payers), publications in peer-reviewed scientific journals and (inter)national conference presentations.

Immunoglobulins for intravenous use (IVIgs) and subcutaneous use (SCIgs) can prevent recurrent and severe infections in patients with secondary antibody deficiencies that are frequently linked to haematological/oncological malignancies as well as other clinical conditions and their respective treatments. Even so, as IVIgs and SCIgs are costly and their supply is limited, their clinical use must be optimised. The aim of this position paper is to provide structured practical guidance on the optimal use of IVIgs and SCIgs in secondary antibody deficiencies, particularly in haematological and oncological practice. The authors agree that the occurrence of severe infections is a prerequisite for the use of IVIgs. Serum IgG levels in general as well as IgG subclass levels can be additional indicators of whether a patient could benefit from IVIgs. Responsiveness to vaccines can help to identify immunodeficiency. Patients with chronic lymphocytic leukaemia or multiple myeloma who are receiving respective treatment, especially B-cell depletion therapy, but also some patients with autoimmune diseases are prone to antibody deficiencies and need IVIgs. For the optimal use of IVIgs and to maximise their potential benefit, the indication must be individually assessed for each patient. As a primary treatment goal, the authors define a sufficient prophylaxis of severe infections, which can be supported by normalising IgG levels. If the initiated treatment is insufficient or linked to intolerable adverse reactions, switching the product within the class of IVIgs or changing to a different batch of the same product can be considered. Pausing treatment can also be considered if there are no infections, which happens more frequently in summer, but treatment needs to be resumed once infections return. These structured recommendations for IVIg treatment in patients with secondary antibody deficiency may provide guidance for clinical practice and therefore help to allocate IVIgs to those who will benefit the most, without overusing valuable resources.

BackgroundOral anticoagulation therapy (OAC) is the cornerstone treatment for preventing venous thromboembolism and stroke in patients with nonvalvular atrial fibrillation (NVAF). Despite its significance, challenges in adherence and persistence to OAC regimens have been reported, leading to severe health complications. Central to addressing these challenges is the concept of self-efficacy (SE) in medication management. Currently, there is a noticeable gap in available tools specifically designed to measure SE in OAC self-care management, while such tools are crucial for enhancing patient adherence and overall treatment outcomes. ObjectiveThis study aims to develop and validate a novel scale aimed to measure self-care self-efficacy (SCSE) in patients with NVAF under OAC, which is the patients’ Self-Care Self-Efficacy Index in Oral Anticoagulation Therapy Management (SCSE-OAC), for English- and Italian-speaking populations. We also seek to assess patients’ SE in managing their OAC treatment effectively and to explore the relationship between SE levels and sociodemographic and clinical variables. MethodsUsing a multiphase, mixed methods observational study design, we first conceptualize the SCSE-OAC through literature reviews, patient focus groups, and expert consensus. The scale’s content validity will be evaluated through patient and expert reviews, while its construct validity is assessed using exploratory and confirmatory factor analyses, ensuring cross-cultural applicability. Criterion validity will be examined through correlations with clinical outcomes. Reliability will be tested via internal consistency and test-retest reliability measures. The study will involve adult outpatients with NVAF on OAC treatment for a minimum of 3 months, using both e-surveys and paper forms for data collection. ResultsIt is anticipated that the SCSE-OAC will emerge as a reliable and valid tool for measuring SE in OAC self-care management. It will enable identifying patients at risk of poor adherence due to low SE, facilitating targeted educational interventions. The scale’s validation in both English and Italian-speaking populations will underscore its applicability in diverse clinical settings, contributing significantly to personalized patient-centered care in anticoagulation management. ConclusionsThe development and validation of the SCSE-OAC represent a significant advancement in the field of anticoagulation therapy. Validating the index in English- and Italian-speaking populations will enable personalized patient-centered educational interventions, ultimately improving OAC treatment outcomes. The SCSE-OAC’s focus on SCSE introduces a novel approach to identifying and addressing individual patient needs, promoting adherence, and ultimately improving health outcomes. Future endeavors will seek to extend the validation of the SCSE-OAC across diverse cultural and linguistic landscapes, broadening its applicability in global clinical and research settings. This scale-up effort is crucial for establishing a universal standard for measuring SCSE in OAC management, empowering clinicians and researchers worldwide to tailor effective and culturally sensitive interventions. Trial RegistrationClinicalTrials.gov NCT05820854; https://tinyurl.com/2mmypey7 International Registered Report Identifier (IRRID)PRR1-10.2196/51489

Summary: Background: Traumatic brain injury is conventionally categorised as mild, moderate, or severe on the Glasgow Coma Scale (GCS). Recently developed biomarkers can provide more objective and nuanced measures of the extent of brain injury. Methods: Exposure–response relationships were investigated in 2479 patients aged ≥16 enrolled in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) prospective observational cohort study. Neurofilament protein-light (NFL), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and glial fibrillary acidic protein (GFAP) were assayed from serum sampled in the first 24 h; concentrations were divided into quintiles within GCS severity groups. Relationships with the Glasgow Outcome Scale-Extended were examined using modified Poisson regression including age, sex, major extracranial injury, time to sample, and log biomarker concentration as covariates. Findings: Within severity groups there were associations between biomarkers and outcomes after adjustment for covariates: GCS 13–15 and negative CT imaging (relative risks [RRs] from 1.28 to 3.72), GCS 13–15 and positive CT (1.21–2.81), GCS 9–12 (1.16–2.02), GCS 3–8 (1.09–1.94). RRs were associated with clinically important differences in expectations of prognosis. In patients with GCS 3 (RRs 1.51–1.80) percentages of unfavourable outcome were 37–51% in the lowest quintiles of biomarker levels and reached 90–94% in the highest quintiles. Similarly, for GCS 15 (RRs 1.83–3.79), the percentages were 2–4% and 19–28% in the lowest and highest biomarker quintiles, respectively. Interpretation: Conventional TBI severity classification is inadequate and underestimates heterogeneity of brain injury and associated outcomes. The adoption of circulating biomarkers can add to clinical assessment of injury severity. Funding: European Union 7th Framework program (EC grant 602150), Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, Neuro-Trauma Sciences, NIHR Rosetrees Trust.

Objectives: In March 2023, all societal-level COVID-19 control measures were lifted by the Dutch government. This study was performed to understand the self-experienced burden of this new phase of COVID-19 on the perspectives and behaviors of severely immunocompromised individuals. Methods: This is an observational, descriptive, cross-sectional study in The Netherlands. An online survey was completed by severely immunocompromised individuals, to capture their general well-being (score from 1 = worst to 10 = best), mental and physical health, and daily and social activities during survey conduct and retrospectively for before onset of COVID-19. The survey was open for completion from May 24th until August 7nd, 2023. Results: Of the 236 respondents, 96.6 % had been vaccinated against COVID-19 and 24.6 % were shielding to avoid COVID-19 during survey conduct. The general well-being score for all respondents was 7.5 (±1.2 SD) before onset of the COVID-19 pandemic and 6.9 (±1.6 SD) during survey conduct (P

Abstract Settlement is a critical period in the life cycle of marine invertebrates with a planktonic larval stage. For reef-building invertebrates such as oysters and corals, settlement rates are predictive for long-term reef survival. Increasing evidence suggests that marine invertebrates use information from ocean soundscapes to inform settlement decisions. Sessile marine invertebrates with a planktonic stage are particularly reliant on environmental cues to direct them to ideal habitats. As gregarious settlers, oysters prefer to settle amongst members of the same species. It has been hypothesized that oyster larvae from species Crassostrea virginica and Ostrea angasi use distinct conspecific oyster reef sounds to navigate to ideal habitats. In controlled laboratory experiments we exposed Pacific Oyster Magallana gigas larvae to anthropogenic sounds from conspecific oyster reefs, vessels, combined reef-vessel sounds as well as off-reef and no speaker controls. Our findings show that sounds recorded at conspecific reefs induced higher percentages of settlement by about 1.44 and 1.64 times compared to off-reef and no speaker controls, respectively. In contrast, the settlement increase compared to the no speaker control was non-significant for vessel sounds (1.21 fold), combined reef-vessel sounds (1.30 fold), and off-reef sounds (1.18 fold). This study serves as a foundational stepping stone for exploring larval sound feature preferences within this species.

Abstract Background Healthy lifestyles are inversely associated with the risk of noncommunicable diseases, which are leading causes of death. However, few studies have used longitudinal data to assess the impact of changing lifestyle behaviours on all-cause and cancer mortality. Methods Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, lifestyle profiles of 308,497 cancer-free adults (71% female) aged 35–70 years at recruitment across nine countries were assessed with baseline and follow-up questionnaires administered on average of 7 years apart. A healthy lifestyle index (HLI), assessed at two time points, combined information on smoking status, alcohol intake, body mass index, and physical activity, and ranged from 0 to 16 units. A change score was calculated as the difference between HLI at baseline and follow-up. Associations between HLI change and all-cause and cancer mortality were modelled with Cox regression, and the impact of changing HLI on accelerating mortality rate was estimated by rate advancement periods (RAP, in years). Results After the follow-up questionnaire, participants were followed for an average of 9.9 years, with 21,696 deaths (8407 cancer deaths) documented. Compared to participants whose HLIs remained stable (within one unit), improving HLI by more than one unit was inversely associated with all-cause and cancer mortality (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.81, 0.88; and HR: 0.87; 95% CI: 0.82, 0.92; respectively), while worsening HLI by more than one unit was associated with an increase in mortality (all-cause mortality HR: 1.26; 95% CI: 1.20, 1.33; cancer mortality HR: 1.19; 95% CI: 1.09, 1.29). Participants who worsened HLI by more than one advanced their risk of death by 1.62 (1.44, 1.96) years, while participants who improved HLI by the same amount delayed their risk of death by 1.19 (0.65, 2.32) years, compared to those with stable HLI. Conclusions Making healthier lifestyle changes during adulthood was inversely associated with all-cause and cancer mortality and delayed risk of death. Conversely, making unhealthier lifestyle changes was positively associated with mortality and an accelerated risk of death.

Abstract Background In patients without a family history, Duchenne muscular dystrophy (DMD) is typically diagnosed at around 4–5 years of age. It is important to diagnose DMD during infancy or toddler stage in order to have timely access to treatment, opportunities for reproductive options, prevention of potential fatal reactions to inhaled anesthetics, awareness of a child’s abilities needed for good parenting, and opportunities for enrolment in clinical trials. Method We aimed to develop a short risk assessment tool based on developmental milestones that may contribute to the early detection of boys with DMD in primary care. As part of the case-control 4D-DMD study (Detection by Developmental Delay in Dutch boys with DMD), data on developmental milestones, symptoms and therapies for 76 boys with DMD and 12,414 boys from a control group were extracted from the health records of youth health care services and questionnaires. Multiple imputation, diagnostic validity and pooled backward logistic regression analyses with DMD (yes/no) as the dependent variable and attainment of 26 milestones until 36 months of age (yes/no) as the independent variable were performed. Descriptive statistics on symptoms and therapies were provided. Results A tool with seven milestones assessed at specific ages between 12 and 36 months resulted in a sensitivity of 79% (95CI:67–88%), a specificity of 95.8% (95%CI:95.3–96.2), and a positive predictive value of 1:268 boys. Boys with DMD often had symptoms (e.g. 43% had calf muscle pseudohypertrophy) and were referred to therapy (e.g. 59% for physical therapy) before diagnosis. Discussion This tool followed by the examination of other DMD-related symptoms could be used by youth health care professionals during day-to-day health assessments in the general population to flag children who require further action. Conclusions The majority of boys (79%) with DMD can be identified between 12 and 36 months of age with this tool. It increases the initial a priori risk of DMD from 1 in 5,000 to approximately 1 in 268 boys. We expect that other neuromuscular disorders and disabilities can also be found with this tool.

Abstract Predictive modelling of cancer outcomes using radiomics faces dimensionality problems and data limitations, as radiomics features often number in the hundreds, and multi-institutional data sharing is ()often unfeasible. Federated learning (FL) and feature selection (FS) techniques combined can help overcome these issues, as one provides the means of training models without exchanging sensitive data, while the other identifies the most informative features, reduces overfitting, and improves model interpretability. Our proposed FS pipeline based on FL principles targets data-driven radiomics FS in a multivariate survival study of non-small cell lung cancer patients. The pipeline was run across datasets from three institutions without patient-level data exchange. It includes two FS techniques, Correlation-based Feature Selection and LASSO regularization, and Cox Proportional-Hazard regression with Overall Survival as endpoint. Trained and validated on 828 patients overall, our pipeline yielded a radiomic signature comprising "intensity-based energy" and "mean discretised intensity". Validation resulted in a mean Harrell C-index of 0.59, showcasing fair efficacy in risk stratification. In conclusion, we suggest a distributed radiomics approach that incorporates preliminary feature selection to systematically decrease the feature set based on data-driven considerations. This aims to address dimensionality challenges beyond those associated with data constraints and interpretability concerns.

Abstract Programmed death-ligand 1 (PD-L1) expression is currently used in the clinic to assess eligibility for immune-checkpoint inhibitors via the tumor proportion score (TPS), but its efficacy is limited by high interobserver variability. Multiple papers have presented systems for the automatic quantification of TPS, but none report on the task of determining cell-level PD-L1 expression and often reserve their evaluation to a single PD-L1 monoclonal antibody or clinical center. In this paper, we report on a deep learning algorithm for detecting PD-L1 negative and positive tumor cells at a cellular level and evaluate it on a cell-level reference standard established by six readers on a multi-centric, multi PD-L1 assay dataset. This reference standard also provides for the first time a benchmark for computer vision algorithms. In addition, in line with other papers, we also evaluate our algorithm at slide-level by measuring the agreement between the algorithm and six pathologists on TPS quantification. We find a moderately low interobserver agreement at cell-level level (mean reader-reader F1 score = 0.68) which our algorithm sits slightly under (mean reader-AI F1 score = 0.55), especially for cases from the clinical center not included in the training set. Despite this, we find good AI-pathologist agreement on quantifying TPS compared to the interobserver agreement (mean reader-reader Cohen’s kappa = 0.54, 95% CI 0.26–0.81, mean reader-AI kappa = 0.49, 95% CI 0.27—0.72). In conclusion, our deep learning algorithm demonstrates promise in detecting PD-L1 expression at a cellular level and exhibits favorable agreement with pathologists in quantifying the tumor proportion score (TPS). We publicly release our models for use via the Grand-Challenge platform.

Abstract Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable. This study aims to understand the genotype–phenotype relationship in affected individuals with CNNM2 variants by phenotypic, functional and structural analysis of new as well as previously reported variants. This results in the identification of seven variants that significantly affect CNNM2-mediated Mg2+ transport. Pathogenicity of these variants is further supported by structural modelling, which predicts CNNM2 structure to be affected by all of them. Strikingly, seizures and intellectual disability are absent in 4 out of 7 cases, indicating these phenotypes are caused either by specific CNNM2 variant only or by additional risk factors. Moreover, in line with sporadic observations from previous reports, CNNM2 variants might be associated with disturbances in parathyroid hormone and Ca2+ homeostasis.

Abstract The Caribbean region is prone to the strong winds and low air pressures of tropical cyclones and their corresponding storm surge that driving coastal flooding. To protect coastal communities from the impacts of tropical cyclones, it is important to understand how this impact of tropical cyclones might change towards the future. This study applies the storyline approach to show what tropical cyclones Maria (2017) and Dorian (2019) could look like in a 2 °C and 3.4 °C warmer future climate. These two possible future climates are simulated with a high-resolution regional climate model using the pseudo global warming approach. Using the climate response from these simulations we apply a Delta-quantile mapping technique to derive future changes in wind speed and mean sea level pressure. We apply this Delta technique to tropical cyclones Maria and Dorian’s observed wind and pressure fields to force a hydrodynamic model for simulating storm surge levels under historical and future climate conditions. Results show that the maximum storm surge heights of Maria and Dorian could increase by up to 0.31 m and 0.56 m, respectively. These results clearly show that future changes in storm surge heights are not negligible compared to end-of-the-century sea level rise projections, something that is sometimes overlooked in large-scale assessments of future coastal flood risk.

Abstract The spike protein (S) of SARS-CoV-2 induces neutralizing antibodies and is the key component of current COVID-19 vaccines. The most efficacious COVID-19 vaccines are genetically-encoded spikes with a double proline substitution in the hinge region to stabilize S in the prefusion conformation (S-2P). A subunit vaccine can be a valuable addition to mRNA and viral vector-based vaccines but requires high stability of spike. In addition, further stabilization of the prefusion conformation of spike might improve immunogenicity. To test this, five spike proteins were designed and characterized, ranging from low to high stability. The immunogenicity of these proteins was assessed in mice, demonstrating that a spike (S-closed-2) with a high melting temperature, which still allowed ACE2 binding, induced the highest neutralization titers against homologous and heterologous strains (up to 16-fold higher than the least stabilized spike). In contrast, the most stable spike variant (S-locked), in which the receptor binding domains (RBDs) were locked in a closed conformation and thus not able to breathe, induced relatively low neutralizing antibody titers against heterologous strains. These data demonstrate that S protein stabilization with RBDs exposing highly conserved epitopes may be needed to increase the immunogenicity of spike proteins for future COVID-19 vaccines.

A neurocysticercosis-like lesion in an 11-year-old boy in the Netherlands was determined to be caused by the zoonotic Taenia martis tapeworm. Subsequent testing revealed that 15% of wild martens tested in that region were infected with T. martis tapeworms with 100% genetic similarity; thus, the infection source was most likely local.

Abstract: In Mexico, the economically active population aged over 50 years has been increasing in recent years. Due to their age, these workers may experience health deterioration and require some form of care. However, only formal employment is associated with better access to health services and pensions. At the same time, these workers may also need to care for children, sick partners or dependent older adults, which limits their time available for employment. This study examined the association between disability, receiving and providing care and access to health services, and economic activity among adults aged 50 to 69 in Mexico in 2015 and 2018. Multilevel modeling was conducted using data from the Mexican Health and Aging Study (MHAS). The MHAS is a longitudinal panel study of adults aged 50 years and older. The study sample included data from 8,831 observations from 2015 and 10,445 observations from 2018. Those living with some degree of disability and receiving care were found to be less likely to be economically active than those living with disability and not receiving care. Similarly, individuals who care for someone were also found to be less likely to be employed. Furthermore, the data suggested that individuals without access to health services were more likely to be economically active. For individuals aged 50 to 69 years, health and care issues were factors that limited economic activity status. In family-oriented societies with weak welfare states, the right to health is partial for the population and care is traditionally the responsibility of women, which exacerbates gender inequalities and has a differential impact on paid work for men and women.

Objectives This study investigated changes in the length of stay (LoS) at a level III/IV neonatal intensive care unit (NICU) and level II neonatology departments until discharge home for very preterm infants and identified factors influencing these trends.Design Retrospective cohort study based on data recorded in the Netherlands Perinatal Registry between 2008 and 2021.Setting A single level III/IV NICU and multiple level II neonatology departments in the Netherlands.Participants NICU-admitted infants (n=2646) with a gestational age (GA)

Summary: Background: Consumption of fibre, fruits and vegetables have been linked with lower colorectal cancer (CRC) risk. A genome-wide gene-environment (G × E) analysis was performed to test whether genetic variants modify these associations. Methods: A pooled sample of 45 studies including up to 69,734 participants (cases: 29,896; controls: 39,838) of European ancestry were included. To identify G × E interactions, we used the traditional 1--degree-of-freedom (DF) G × E test and to improve power a 2-step procedure and a 3DF joint test that investigates the association between a genetic variant and dietary exposure, CRC risk and G × E interaction simultaneously. Findings: The 3-DF joint test revealed two significant loci with p-value

Abstract Background Context-specific interventions may contribute to sustained behaviour change and improved health outcomes. We evaluated the real-world effects of supermarket nudging and pricing strategies and mobile physical activity coaching on diet quality, food-purchasing behaviour, walking behaviour, and cardiometabolic risk markers. Methods This parallel cluster-randomised controlled trial included supermarkets in socially disadvantaged neighbourhoods across the Netherlands with regular shoppers aged 30–80 years. Supermarkets were randomised to receive co-created nudging and pricing strategies promoting healthier purchasing (N = 6) or not (N = 6). Nudges targeted 9% of supermarket products and pricing strategies 3%. Subsequently, participants were individually randomised to a control (step counter app) or intervention arm (step counter and mobile coaching app) to promote walking. The primary outcome was the average change in diet quality (low (0) to high (150)) over all follow-up time points measured with a validated 40-item food frequency questionnaire at baseline and 3, 6, and 12 months. Secondary outcomes included healthier food purchasing (loyalty card-derived), daily step count (step counter app), cardiometabolic risk markers (lipid profile and HbA1c via finger prick, and waist circumference via measuring tape), and supermarket customer satisfaction (questionnaire-based: very unsatisfied (1) to very satisfied (7)), evaluated using linear mixed-models. Healthy supermarket sales (an exploratory outcome) were analysed via controlled interrupted time series analyses. Results Of 361 participants (162 intervention, 199 control), 73% were female, the average age was 58 (SD 11) years, and 42% were highly educated. Compared to the control arm, the intervention arm showed no statistically significant average changes over time in diet quality (β − 1.1 (95% CI − 3.8 to 1.7)), percentage healthy purchasing (β 0.7 ( − 2.7 to 4.0)), step count (β − 124.0 ( − 723.1 to 475.1), or any of the cardiometabolic risk markers. Participants in the intervention arm scored 0.3 points (0.1 to 0.5) higher on customer satisfaction on average over time. Supermarket-level sales were unaffected (β − 0.0 (− 0.0 to 0.0)). Conclusions Co-created nudging and pricing strategies that predominantly targeted healthy products via nudges were unable to increase healthier food purchases and intake nor improve cardiometabolic health. The mobile coaching intervention did not affect step count. Governmental policy measures are needed to ensure more impactful supermarket modifications that promote healthier purchases. Trial registration Dutch Trial Register ID NL7064, 30 May 2018, https://www.onderzoekmetmensen.nl/en/trial/20990

Abstract Background To diagnose the full spectrum of hereditary and congenital diseases, genetic laboratories use many different workflows, ranging from karyotyping to exome sequencing. A single generic high-throughput workflow would greatly increase efficiency. We assessed whether genome sequencing (GS) can replace these existing workflows aimed at germline genetic diagnosis for rare disease. Methods We performed short-read GS (NovaSeq™6000; 150 bp paired-end reads, 37 × mean coverage) on 1000 cases with 1271 known clinically relevant variants, identified across different workflows, representative of our tertiary diagnostic centers. Variants were categorized into small variants (single nucleotide variants and indels

Abstract Background Tertiary lymphoid structures (TLSs) are dense accumulations of lymphocytes in inflamed peripheral tissues, including cancer, and are associated with improved survival and response to immunotherapy in various solid tumors. Histological TLS quantification has been proposed as a novel predictive and prognostic biomarker, but lack of standardized methods of TLS characterization hampers assessment of TLS densities across different patients, diseases, and clinical centers. Methods We introduce an approach based on HookNet-TLS, a multi-resolution deep learning model, for automated and unbiased TLS quantification and identification of germinal centers in routine hematoxylin and eosin stained digital pathology slides. We developed HookNet-TLS using n = 1019 manually annotated TCGA slides from clear cell renal cell carcinoma, muscle-invasive bladder cancer, and lung squamous cell carcinoma. Results Here we show that HookNet-TLS automates TLS quantification across multiple cancer types achieving human-level performance and demonstrates prognostic associations similar to visual assessment. Conclusions HookNet-TLS has the potential to be used as a tool for objective quantification of TLS in routine H&E digital pathology slides. We make HookNet-TLS publicly available to promote its use in research.

Abstract Whole-mount sectioning is a technique in histopathology where a full slice of tissue, such as a transversal cross-section of a prostate specimen, is prepared on a large microscope slide without further sectioning into smaller fragments. Although this technique can offer improved correlation with pre-operative imaging and is paramount for multimodal research, it is not commonly employed due to its technical difficulty, associated cost and cumbersome integration in (digital) pathology workflows. In this work, we present a computational tool named PythoStitcher which reconstructs artificial whole-mount sections from digitized tissue fragments, thereby bringing the benefits of whole-mount sections to pathology labs currently unable to employ this technique. Our proposed algorithm consists of a multi-step approach where it (i) automatically determines how fragments need to be reassembled, (ii) iteratively optimizes the stitch using a genetic algorithm and (iii) efficiently reconstructs the final artificial whole-mount section on full resolution (0.25 µm/pixel). PythoStitcher was validated on a total of 198 cases spanning five datasets with a varying number of tissue fragments originating from different organs from multiple centers. PythoStitcher successfully reconstructed the whole-mount section in 86–100% of cases for a given dataset with a residual registration mismatch of 0.65–2.76 mm on automatically selected landmarks. It is expected that our algorithm can aid pathology labs unable to employ whole-mount sectioning through faster clinical case evaluation and improved radiology-pathology correlation workflows.

Abstract A two-step strategy combining assisted benchmark testing (entry controls) and External Quality Assessments (EQAs) with blinded simulated clinical specimens to enhance and maintain the quality of nucleic acid amplification testing was developed. This strategy was successfully applied to 71 diagnostic laboratories in The Netherlands when upscaling the national diagnostic capacity during the SARS-CoV-2 pandemic. The availability of benchmark testing in combination with advice for improvement substantially enhanced the quality of the laboratory testing procedures for SARS-CoV-2 detection. The three subsequent EQA rounds demonstrated high quality testing with regard to specificity (99.6% correctly identified) and sensitivity (93.3% correctly identified). Even with the implementation of novel assays, changing workflows using diverse equipment and a high degree of assay heterogeneity, the overall high quality was maintained using this two-step strategy. We show that in contrast to the limited value of Cq value for absolute proxies of viral load, these Cq values can, in combination with metadata on strategies and techniques, provide valuable information for laboratories to improve their procedures. In conclusion, our two-step strategy (preparation phase followed by a series of EQAs) is a rapid and flexible system capable of scaling, improving, and maintaining high quality diagnostics even in a rapidly evolving (e.g. pandemic) situation.