Search

OBJECTIVES: Chronic inflammation promotes cardiovascular risk in rheumatoid arthritis (RA). Biological disease-modifying antirheumatic drugs (bDMARDs) improve disease activity and cardiovascular disease outcomes. We explored whether bDMARDs influence the impact of disease activity and inflammatory markers on long-term cardiovascular risk in RA. METHODS: We studied 4370 participants without cardiovascular disease in a 10-country observational cohort of patients with RA. Endpoints were (1) major adverse cardiovascular events (MACE) encompassing myocardial infarction, stroke and cardiovascular death; and (2) any ischaemic cardiovascular events (iCVE) including MACE plus revascularisation, angina, transient ischaemic attack and peripheral arterial disease. RESULTS: Over 26 534 patient-years, 239 MACE and 362 iCVE occurred. The interaction between 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and bDMARD use was significant for MACE (p=0.017), suggesting the effect of DAS28-CRP on MACE risk differed among bDMARD users (n=515) and non-users (n=3855). DAS28-CRP (per unit increase) is associated with MACE risk in bDMARD non-users (HR 1.21 (95% CI 1.07 to 1.37)) but not users (HR 0.69 (95% CI 0.40 to 1.20)). The interaction between CRP (per log unit increase) and bDMARD use was also significant for MACE (p=0.011). CRP associated with MACE risk in bDMARD non-users (HR 1.16 (95% CI 1.04 to 1.30)), but not users (HR 0.65 (95% CI 0.36 to 1.17)). No interaction was observed between bDMARD use and DAS28-CRP (p=0.167) or CRP (p=0.237) for iCVE risk. CONCLUSIONS: RA activity and inflammatory markers associated with risk of MACE in bDMARD non-users but not users suggesting the possibility of biological-specific benefits locally on arterial wall independently of effects on systemic inflammation.

Abstract One in five deaths worldwide is associated with sepsis, which is defined as organ dysfunction caused by a dysregulated host response to infection. An increased understanding of the pathophysiology of sepsis could provide improved approaches for early detection and treatment. Here we describe the development and validation of a mechanistic mathematical model of the inflammatory response, making use of a combination of in vitro and human in vivo data obtained from experiments where bacterial lipopolysaccharide (LPS) was used to induce an inflammatory response. The new model can simulate the responses to both acute and prolonged inflammatory stimuli in an experimental setting, as well as the response to infection in the clinical setting. This model serves as a foundation for a sepsis simulation model with a potentially wide range of applications in different disciplines involved with sepsis research.

Abstract Spintronic sensors are uniquely positioned to deliver the next generation of high-performance magnetic field measurement tools with re-configurable key features. In this perspective article, we focus on giant and tunnel magnetoresistance sensors that exploit changes in the electrical resistance of thin films in response to an external magnetic field. We discuss strategies to address ongoing open challenges to improve operation limits. The goal is to meet current technological needs and thus expand the scope of existing applications. We also propose innovative approaches to design sensors with adaptable characteristics and embedded multifunctionality, aiming to create opportunities for future magnetic sensing applications. These solutions leverage the versatility of spintronic sensors, from the thin-film multilayers that form their building blocks, to device fabrication methods and potential integration with other technologies. The outlook of novel applications spans multiple areas, including electric vehicles, robotics, remote detection, or biomedicine.

Abstract West Nile virus (WNV) and Usutu virus (USUV) are closely related flaviviruses with differing capacities to cause neurological disease in humans. WNV is thought to use a transneural route of neuroinvasion along motor neurons and causes severe motor deficits. The potential for use of transneural routes of neuroinvasion by USUV has not been investigated experimentally, and evidence from the few clinical case reports of USUV-associated neuroinvasive disease is lacking. We hypothesised that, compared with WNV, USUV is less able to infect motor neurons, and therefore determined the susceptibility of human induced pluripotent stem cell (iPSC)-derived spinal cord motor neurons to infection. Both viruses could grow to high titres in iPSC-derived neural cultures. However, USUV could not productively infect motor neurons due to restriction by the antiviral response, which was not induced upon WNV infection. Inhibition of the antiviral response allowed for widespread infection and transportation of USUV along motor neurons within a compartmented culture system. These results show a stark difference in the ability of these two viruses to evade initiation of intrinsic antiviral immunity. Our data suggests that USUV cannot infect motor neurons in healthy individuals but in case of immunodeficiency may pose a risk for motor-related neurological disease and transneural invasion.

Purpose – Most papers and books on conducting literature reviews primarily emphasize achieving technical quality, ensuring reproducibility and validating results. Notwithstanding the need for technical excellence, there is also a need for relevance. The purpose of this study is to address that need and offer practical and constructive suggestions for enhancing the meaningful contribution of a literature review, thereby increasing its impact and relevance for publication. Design/methodology/approach – In this conceptual paper, the authors explore strategies to enhance the relevance and contribution of a literature review. By clarifying the needs of diverse audiences and the principles of generating new insights, the authors provide a broad range of options without being prescriptive. Recognizing that every literature review is unique, this paper contrasts various approaches to offer flexible and adaptable guidance. Findings – Literature reviews can be enjoyable to read and write, offering a wide range of substantial contributions that meet the expectations of readers and journal editors. This paper offers practical suggestions for prospective authors to make their reviews more relevant, invaluable and engaging, and summarizes these suggestions in a comprehensive checklist. Research limitations/implications – The paper is not exhaustive but rather complements prevalent literature review methodologies. Originality/value – Existing literature offers limited guidance on enhancing a review’s contribution to science, academic inquiry and society. This paper fills that gap by providing both academic considerations and practical recommendations, drawing on the author’s extensive experience in reviewing and conducting literature reviews. Claves para mejorar el impacto de las revisiones de literatura: directrices para realizar contribuciones significativas Objetivo – La mayoría de los artículos y libros sobre la realización de revisiones de literatura enfatizan principalmente la obtención de calidad técnica, asegurando la reproducibilidad y validando resultados. A pesar de la necesidad de excelencia técnica, también existe la necesidad de la relevancia. El presente artículo aborda esa necesidad y tiene como objetivo ofrecer sugerencias prácticas y constructivas para mejorar la contribución significativa de una revisión de literatura, aumentando así su impacto y relevancia para su publicación. Diseño/metodología/enfoque – En este artículo conceptual, los autores exploran estrategias para mejorar la relevancia y la contribución de una revisión de literatura. Al clarificar las necesidades de audiencias diversas y los principios para generar nuevos conocimientos, los autores proporcionan una amplia gama de opciones sin ser prescriptivos. Reconociendo que cada revisión de literatura es única, este artículo contrasta varios enfoques para ofrecer orientación flexible y adaptable. Resultados – Las revisiones de literatura pueden ser placenteras de leer y escribir, ofreciendo una amplia gama de contribuciones sustanciales que satisfacen las expectativas de los lectores y editores de revistas. Este artículo ofrece sugerencias prácticas para que los autores potenciales hagan que sus revisiones sean más relevantes, valiosas y atractivas, y resume estas sugerencias en una lista de verificación integral. Originalidad – La literatura existente ofrece una orientación limitada sobre cómo mejorar la contribución de una revisión a la ciencia, la investigación académica y la sociedad. Este artículo cubre ese vacío proporcionando consideraciones académicas y recomendaciones prácticas, basadas en la extensa experiencia de los autores en la revisión y realización de revisiones de literatura. Limitaciones/implicaciones de la investigación – El artículo no es exhaustivo, sino que complementa las metodologías prevalentes de revisión de literatura. 提升文献综述影响力：提出有意义贡献的指南 目的 – 大多数关于如何进行文献综述的文章和书籍主要强调实现技术质量、确保可重复性和验证结果。尽管技术卓越性至关重要, 但同样需要注重相关性。本文正是为了满足这一需求, 旨在提供实用且建设性的建议, 以增强文献综述的有意义贡献, 从而增加其发表的影响力和相关性。 设计/方法论/途径 – 在这篇概念性文章中, 作者探讨了增强文献综述相关性和贡献的策略。通过阐明多样化受众的需求和生成新见解的原则, 作者提供了广泛的选项, 而不是一味地指示。认识到每篇文献综述都是独一无二的, 本文对比了各种方法, 以提供灵活和适应性的指导。 研究结果 – 文献综述可以既有趣味性又富有实质性贡献, 满足读者和期刊编辑的期望。本文为潜在作者提供了实用的建议, 使他们的综述更具相关性、不可或缺且引人入胜, 并将这些建议总结在一个全面的清单中。 独创性 – 现有文献对如何增强综述对科学、学术研究和社会的贡献提供的指导有限。本文通过结合学术考虑和实际建议, 弥补了这一空白, 基于作者在审阅和进行文献综述方面的丰富经验, 提供了独特的见解。 研究限制/启示 – 该文章并非详尽无遗, 而是对现有文献综述方法的补充。

Abstract Continuous glucose monitoring (CGM) is a promising, minimally invasive alternative to plasma glucose measurements for calibrating physiology-based mathematical models of insulin-regulated glucose metabolism, reducing the reliance on in-clinic measurements. However, the use of CGM glucose, particularly in combination with insulin measurements, to develop personalized models of glucose regulation remains unexplored. Here, we simultaneously measured interstitial glucose concentrations using CGM as well as plasma glucose and insulin concentrations during an oral glucose tolerance test (OGTT) in individuals with overweight or obesity to calibrate personalized models of glucose-insulin dynamics. We compared the use of interstitial glucose with plasma glucose in model calibration, and evaluated the effects on model fit, identifiability, and model parameters’ association with clinically relevant metabolic indicators. Models calibrated on both plasma and interstitial glucose resulted in good model fit, and the parameter estimates associated with metabolic indicators such as insulin sensitivity measures in both cases. Moreover, practical identifiability of model parameters was improved in models estimated on CGM glucose compared to plasma glucose. Together these results suggest that CGM glucose may be considered as a minimally invasive alternative to plasma glucose measurements in model calibration to quantify the dynamics of glucose regulation.

BackgroundThreonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).MethodsMechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).ResultsBAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.ConclusionsDual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.

Objectives Chronic inflammation promotes cardiovascular risk in rheumatoid arthritis (RA). Biological disease-modifying antirheumatic drugs (bDMARDs) improve disease activity and cardiovascular disease outcomes. We explored whether bDMARDs influence the impact of disease activity and inflammatory markers on long-term cardiovascular risk in RA.Methods We studied 4370 participants without cardiovascular disease in a 10-country observational cohort of patients with RA. Endpoints were (1) major adverse cardiovascular events (MACE) encompassing myocardial infarction, stroke and cardiovascular death; and (2) any ischaemic cardiovascular events (iCVE) including MACE plus revascularisation, angina, transient ischaemic attack and peripheral arterial disease.Results Over 26 534 patient-years, 239 MACE and 362 iCVE occurred. The interaction between 28-joint Disease Activity Score with C-reactive protein (DAS28-CRP) and bDMARD use was significant for MACE (p=0.017), suggesting the effect of DAS28-CRP on MACE risk differed among bDMARD users (n=515) and non-users (n=3855). DAS28-CRP (per unit increase) is associated with MACE risk in bDMARD non-users (HR 1.21 (95% CI 1.07 to 1.37)) but not users (HR 0.69 (95% CI 0.40 to 1.20)). The interaction between CRP (per log unit increase) and bDMARD use was also significant for MACE (p=0.011). CRP associated with MACE risk in bDMARD non-users (HR 1.16 (95% CI 1.04 to 1.30)), but not users (HR 0.65 (95% CI 0.36 to 1.17)). No interaction was observed between bDMARD use and DAS28-CRP (p=0.167) or CRP (p=0.237) for iCVE risk.Conclusions RA activity and inflammatory markers associated with risk of MACE in bDMARD non-users but not users suggesting the possibility of biological-specific benefits locally on arterial wall independently of effects on systemic inflammation.

Abstract Background The occurrence of metabolic syndrome (MetS) and the gut microbiota composition are known to differ across ethnicities yet how these three factors are interwoven is unknown. Also, it is unknown what the relative contribution of the gut microbiota composition is to each MetS component and whether this differs between ethnicities. We therefore determined the occurrence of MetS and its components in the multi-ethnic HELIUS cohort and tested the overall and ethnic-specific associations with the gut microbiota composition. Methods We included 16,209 treatment naïve participants of the HELIUS study, which were of Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish, and Moroccan descent to analyze MetS and its components across ethnicities. In a subset (n = 3443), the gut microbiota composition (16S) was associated with MetS outcomes using linear and logistic regression models. Results A differential, often sex-dependent, prevalence of MetS components and their combinations were observed across ethnicities. Increased blood pressure was commonly seen especially in Ghanaians, while South-Asian Surinamese and Turkish had higher MetS rates in general and were characterized by worse lipid-related measures. Regarding the gut microbiota, when ethnic-independent associations were assumed, a higher α-diversity, higher abundance of several ASVs (mostly for waist and triglyceride-related outcomes) and a trophic network of ASVs of Ruminococcaceae, Christensenellaceae, and Methanobrevibacter (RCM) bacteria were associated with better MetS outcomes. Statistically significant ethnic-specific associations were however noticed for α-diversity and the RCM trophic network. Associations were significant in the Dutch but not always in all other ethnicities. In Ghanaians, a higher α-diversity and RCM network abundance showed an aberrant positive association with high blood pressure measures compared to the other ethnicities. Even though adjustment for socioeconomic status-, lifestyle-, and diet-related variables often attenuated the effect size and/or the statistical significance of the ethnic-specific associations, an overall similar pattern across outcomes and ethnicities remained. Conclusions The occurrence of MetS characteristics among ethnicities is heterogeneous. Both ethnic-independent and ethnic-specific associations were identified between the gut microbiota and MetS outcomes. Across multiple ethnicities, a one-size-fits-all approach may thus be reconsidered in regard to both the definition and/or treatment of MetS and its relation to the gut microbiota.

ABSTRACT: In the Netherlands, poultry meat production has been evolving in recent years toward broiler production systems with slow-growing broilers. In this study the effects of season, catching method, and thinning on carcass quality and production parameters in four different broiler production systems in the Netherlands was evaluated. The data for this study were collected from slaughterhouse data in 2018, 2019, and 2020 and contained information about four different broiler production systems: conventional (fast growing) broilers (CONV), 2 different indoor slow-growing broilers (SGB1 and SGB2), and Better Life 1 Star (BLS) concept with slow-growing broilers. The data set consisted of 14,976, 1,730, 3,713, and 1,121 records (flocks) for CONV, SGB1, SGB2, and BLS, respectively. All three production systems with slow-growing broilers had a lower slaughter weight, average daily gain (ADG), first-week mortality, and total mortality than CONV (no-thinning). ADG of SGB2 and BLS was lower than that of SGB1. Slaughter weight and ADG were the lowest when day-old chicks were placed in March/April and the highest when they were placed in September/October. All slow-growing broiler production systems had a lower footpad lesion score and a lower incidence of hock burns, leg hematomas, breast hematomas, dead-on-arrival chickens (DOA), and total rejects than CONV. Autumn flocks had more hock burns, a higher footpad lesion score, and more wing hematomas than spring flocks. More scabby hips and fewer total rejects were found during the summer months than during the winter months. Thinning flocks had more scabby hips, ammonia burns, and DOAs and fewer hock burns, footpad lesions, wing hematomas, leg hematomas, breast hematomas, and total rejects than no-thinning flocks. Mechanically caught flocks had more ammonia burns, DOAs, and total rejects than manually caught flocks. In conclusion, this study showed that all three production systems with slow-growing broilers had a lower first-week mortality and total mortality and better scores on most carcass quality parameters and welfare indicators than CONV.

Summary: The manifestation of metabolic deteriorations that accompany overweight and obesity can differ greatly between individuals, giving rise to a highly heterogeneous population. This inter-individual variation can impede both the provision and assessment of nutritional interventions as multiple aspects of metabolic health should be considered at once. Here, we apply the Mixed Meal Model, a physiology-based computational model, to characterize an individual’s metabolic health in silico. A population of 342 personalized models were generated using data for individuals with overweight and obesity from three independent intervention studies, demonstrating a strong relationship between the model-derived metric of insulin resistance (ρ = 0.67, p

Abstract Background In the Diabetes domain, events such as meals and exercises play an important role in the disease management. For that, many studies focus on automatic meal detection, specially as part of the so-called artificial $$\beta$$ β -cell systems. Meals are associated to blood glucose (BG) variations, however such variations are not peculiar to meals, it mostly comes as a combination of external factors. Thus, general approaches such as the ones focused on glucose signal rate of change are not enough to detect personalized influence of such factors. By using a data-driven individualized approach for meal detection, our method is able to fit real data, detecting personalized meal responses even when such external factors are implicitly present. Methods The method is split into model training and selection. In the training phase, we start observing meal responses for each individual, and identifying personalized patterns. Occurrences of such patterns are searched over the BG signal, evaluating the similarity of each pattern to each possible signal subsequence. The most similar occurrences are then selected as possible meal event candidates. For that, we include steps for excluding less relevant neighbors per pattern, and grouping close occurrences in time globally. Each candidate is represented by a set of time and response signal related qualitative variables. These variables are used as input features for different binary classifiers in order to learn to classify a candidate as Meal or Non-Meal. In the model selection phase, we compare all trained classifiers to select the one that performs better with the data of each individual. Results The results show that the method is able to detect daily meals, providing a result with a balanced proportion between detected meals and false alarms. The analysis on multiple patients indicate that the approach achieves good outcomes when there is enough reliable training data, as this is reflected on the testing results. Conclusions The approach aims at personalizing the meal detection task by relying solely on data. The premise is that a model trained with data that contains the implicit influence of external factors is able to recognize the nuances of the individual that generated the data. Besides, the approach can also be used to improve data quality by detecting meals, opening opportunities to possible applications such as detecting and reminding users of missing or wrongly informed meal events.

ABSTRACT Purpose: To review and compare the effectivity of novel minimally invasive treatments (MITs) to transurethral resection of the prostate (TURP) for the treatment of lower urinary tract symptoms (LUTS) in men. Methods: Medline, Embase, and Cochrane databases were searched from January 2010 to December 2022 for randomized controlled trials (RCTs) evaluating MITs, compared to TURP or sham, in men with LUTS. Studies were assessed by risk of bias tool, and evidence by GRADE. Functional outcomes by means of uroflowmetry and IPSS were the primary outcomes, safety and sexual function were secondary outcomes. As part of this review, a network meta-analysis (NMA) was conducted. MITs were ranked based on functional outcome improvement probability. Results: In total, 10 RCTs were included, evaluating aquablation, prostatic urethral lift, prostatic artery embolization (PAE), convective water vapor thermal treatment or temporary implantable nitinol device. All MITs showed a better safety profile compared to TURP. Functional outcome improvement following aquablation were comparable to TURP. In the NMA, aquablation was ranked highest, PAE followed with the second highest probability to improve functional outcomes. Other novel MITs resulted in worse functional outcomes compared to TURP. Level of evidence was low to very low. Conclusions: Five MITs for treatment of LUTS were identified. Aquablation is likely to result in functional outcomes most comparable to TURP. Second in ranking was PAE, a technique that does not require general or spinal anesthesia. MITs have a better safety profile compared to TURP. However, due to high study heterogeneity, results should be interpreted with caution.

Background: Transperineal focal laser ablation (TPLA) treatment for prostate cancer (PCa) is an experimental focal ablative therapy modality with low morbidity. However, a dosimetry model for TPLA is lacking. Objective: To determine (1) the three-dimensional (3D) histologically defined ablation zone of single- and multifiber TPLA treatment for PCa correlated with magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS) and (2) a reliable imaging modality of ablation zone volumetry. Design, setting, and participants: This was a prospective, multicenter, and interventional phase I/II pilot study with an ablate-and-resect design. TPLA was performed in 12 patients with localized prostate cancer divided over four treatment regimens to evaluate potential variation in outcomes. Intervention: TPLA was performed approximately 4 wk prior to robot-assisted radical prostatectomy (RARP) in a daycare setting using local anesthesia. Outcome measurements and statistical analysis: Four weeks after TPLA, ablation zone volumetry was determined on prostate MRI and CEUS by delineation and segmentation into 3D models and correlated with whole-mount RARP histology using the Pearson correlation index. Results and limitations: Twelve office-based TPLA procedures were performed successfully under continuous transrectal ultrasound guidance using local perineal anesthesia. No serious adverse events occurred. A qualitative analysis showed a clear demarcation of the ablation zone on T2-weighted MRI, dynamic contrast-enhanced MRI, and CEUS. On pathological evaluation, no remnant cancer was observed within the ablation zone. Ablation zone volumetry on CEUS and T2-weighted MRI compared with histology had a Pearson correlation index of r = 0.94 (95% confidence interval [CI] 0.74–0.99, p

Dose reduction (DR) of first-generation biologics for plaque psoriasis (TNF-alpha inhibitors (i) and interleukin (IL)-12/23i) has been described in a previous scoping review. The literature on the DR of the newest generation of biologics (IL-17/23i) was scarce. The current review provides a literature update on the previous scoping review on the DR of all biologics, including the newest generation, with a focus on the uptake and implementation of DR in practice. The current literature search on DR revealed 14 new articles in addition to those in the previous review. Four of the newly found articles tested DR strategies, mostly focusing on first-generation biologics; only guselkumab (IL-23i) was included in one study. The other 10 studies showed data on regaining response after failure of DR, safety, cost-effectiveness, and uptake and implementation, as well as information about IL-17/23i. The eligibility criteria to start DR included both absolute and relative Psoriasis Area and Severity Index (PASI) scores (PASI ≤3/≤5/PASI 75–100) and/or Dermatology Life Quality Index (DLQI) ≤3/≤5, or BSA ≤1/≤2, or Physician Global Assessment (PGA) ≤1/0–2 during a period ranging from 12 weeks to ≥1 year. Most studies used PASI ≤5 and/or DLQI ≤5 or PGA ≤1 for ≥6 months. DR strategies were mostly performed by stepwise interval prolongation in two steps (to 67% of the standard dose, followed by 50%). Some studies of IL-17/23i reduced the dose to ±25%. The tested DR strategies on stepwise or fixed DR on TNF-αi and IL-12/23i (three studies), as well as one “on-demand” dosing study on IL-23i guselkumab, were successful. In the case of relapse of DR on TNF-αi and IL-12/23i, clinical effectiveness was regained by retreatment with the standard dose. All studies showed substantial cost savings with the biologic DR of TNF-αi and IL-12/23i. The identified barriers against the implementation of DR were mainly a lack of guidelines and scientific evidence on effectiveness and safety, and a lack of time and (technical) support. The identified facilitators were mainly clear guidelines, feasible protocols, adequate education of patients and physicians, and cost reduction. In conclusion, DR seems promising, but a research gap still exists in randomized, prospective studies testing DR strategies, especially of IL-17/23i, hampering the completion of guidelines on DR. Taking into account the identified barriers and facilitators most likely results in a more successful implementation of biologic DR in practice.

Highly pathogenic avian influenza viruses (HPAIVs) cause severe hemorrhagic disease in terrestrial poultry and are a threat to the poultry industry, wild life, and human health. HPAIVs arise from low pathogenic avian influenza viruses (LPAIVs), which circulate in wild aquatic birds. HPAIV emergence is thought to occur in poultry and not wild aquatic birds, but the reason for this species-restriction is not known. We hypothesized that, due to species-specific tropism and replication, intrahost HPAIV selection is favored in poultry and disfavored in wild aquatic birds. We tested this hypothesis by co-inoculating chickens, representative of poultry, and ducks, representative of wild aquatic birds, with a mixture of H7N7 HPAIV and LPAIV, mimicking HPAIV emergence in an experimental setting. Virus selection was monitored in swabs and tissues by RT-qPCR and immunostaining of differential N-terminal epitope tags that were added to the hemagglutinin protein. HPAIV was selected in four of six co-inoculated chickens, whereas LPAIV remained the major population in co-inoculated ducks on the long-term, despite detection of infectious HPAIV in tissues at early time points. Collectively, our data support the hypothesis that HPAIVs are more likely to be selected at the intrahost level in poultry than in wild aquatic birds and point towards species-specific differences in HPAIV and LPAIV tropism and replication levels as possible explanations.

ABSTRACT Enterovirus D68 (EV-D68) is predominantly associated with mild respiratory infections, but can also cause severe respiratory disease and extra-respiratory complications, including acute flaccid myelitis. Systemic dissemination of EV-D68 is crucial for the development of extra-respiratory diseases, but it is currently unclear how EV-D68 spreads systemically (viremia). We hypothesize that immune cells contribute to the systemic dissemination of EV-D68, as this is a mechanism commonly used by other enteroviruses. Therefore, we investigated the susceptibility and permissiveness of human primary immune cells for different EV-D68 isolates. In human peripheral blood mononuclear cells inoculated with EV-D68, only B cells were susceptible but virus replication was limited. However, in B cell-rich cultures, such as Epstein–Barr virus-transformed B-lymphoblastoid cell line (BLCL) and primary lentivirus-transduced B cells, which better represent lymphoid B cells, were productively infected. Subsequently, we showed that dendritic cells (DCs), particularly immature DCs, are susceptible and permissive for EV-D68 infection and that they can spread EV-D68 to autologous BLCL. Altogether, our findings suggest that immune cells, especially B cells and DCs, could play an important role in the pathogenesis of EV-D68 infection. Infection of these cells may contribute to systemic dissemination of EV-D68, which is an essential step toward the development of extra-respiratory complications.IMPORTANCEEnterovirus D68 (EV-D68) is an emerging respiratory virus that has caused outbreaks worldwide since 2014. EV-D68 infects primarily respiratory epithelial cells resulting in mild respiratory diseases. However, EV-D68 infection is also associated with extra-respiratory complications, including polio-like paralysis. It is unclear how EV-D68 spreads systemically and infects other organs. We hypothesized that immune cells could play a role in the extra-respiratory spread of EV-D68. We showed that EV-D68 can infect and replicate in specific immune cells, that is, B cells and dendritic cells (DCs), and that virus could be transferred from DCs to B cells. Our data reveal a potential role of immune cells in the pathogenesis of EV-D68 infection. Intervention strategies that prevent EV-D68 infection of immune cells will therefore potentially prevent systemic spread of virus and thereby severe extra-respiratory complications.

The objective was to examine the prevalence of atherosclerotic cardiovascular disease (ASCVD) and its risk factors among patients with RA with diabetes mellitus (RA-DM) and patients with RA without diabetes mellitus (RAwoDM), and to evaluate lipid and blood pressure (BP) goal attainment in RA-DM and RAwoDM in primary and secondary prevention. The cohort was derived from the Survey of Cardiovascular Disease Risk Factors in Patients with Rheumatoid Arthritis from 53 centres/19 countries/3 continents during 2014-2019. We evaluated the prevalence of cardiovascular disease (CVD) among RA-DM and RAwoDM. The study population was divided into those with and without ASCVD, and within these groups we compared risk factors and CVD preventive treatment between RA-DM and RAwoDM. The study population comprised of 10 543 patients with RA, of whom 1381 (13%) had DM. ASCVD was present in 26.7% in RA-DM compared with 11.6% RAwoDM (p

The prevalence of bacterial vaginosis (BV) among women of reproductive age is 29%. BV arises from a vaginal imbalance marked by reduced levels of lactic acid-producing lactobacilli and an overgrowth of pathogenic anaerobes. The multifactorial nature of BV’s pathogenesis complicates its treatment. Current antibiotic therapy exhibits a recurrence rate of about 60% within a year. Recurrence can be caused by antibiotic treatment failure (e.g., due to antimicrobial resistance), the persistence of residual infections (e.g., due to biofilm formation), and re-infection. Because of the high recurrence rates, alternative therapies are required. Medical-grade honey (MGH), known for its antimicrobial and wound healing properties in wound care, emerges as a potential novel therapy for BV. MGH exerts broad-spectrum antimicrobial activity, employing multiple mechanisms to eliminate the risk of resistance. For example, the low pH of MGH and the production of hydrogen peroxide benefit the microbiota and helps restore the natural vaginal balance. This is supported by in vitro studies demonstrating that MGH has an antibacterial effect on several pathogenic bacteria involved in the pathophysiology of BV, while lactobacilli and the vaginal microenvironment can be positively affected. In contrast to antibiotics, MGH exerts anti-biofilm activity, affects the microbiome as pre- and probiotic, and modulates the vaginal microenvironment through its anti-inflammatory, anti-oxidative, physicochemical, and immunomodulatory properties. More clinical research is required to confirm the positive effect of MGH on BV and to investigate the long-term cure rate.

In the dynamic interplay between people and their physical environments, the Global South stands as a mosaic undergoing a multitude of transformative influences in architecture and urbanism, within which examining social sustainability becomes imperative. While the prevailing attention remains on environmental and economic sustainability, this study addresses a persistent gap in the urban literature by focusing on the dynamic and manifold nature of social sustainability. Positioning itself within the context of sustainable development, the study links the pursuit of social aspects of sustainability with selected unique urban contexts from the Global South. Five cases, including Alexandria (Egypt), Tripoli (Libya), Basra (Iraq), Lilongwe (Malawi), and Accra (Ghana), are discussed through multi-layered investigations which involve attitude surveys, interviews, focus groups, participatory systematic observations, and behavioral mapping, engaging directly with inhabitants and stakeholders. Uncovering people–place narratives in the identified contexts, the cases are developed into five knowledge typologies that serve as practical tools for planning and design decision-making, policy formulation, and academic discourse. Discussions are conceived to demonstrate the transformative role people–place narratives play in fostering a more sustainable and equitable urban future. Conclusions are drawn to offer practical insights for stakeholders involved in various capacities in shaping the urban landscape of the Global South.

BackgroundIn younger individuals, low absolute risk of cardiovascular disease (CVD) may conceal an increased risk age and relative risk of CVD. Calculation of risk age is proposed as an adjuvant to absolute CVD risk estimation in European guidelines. We aimed to compare the discriminative ability of available risk age models in prediction of CVD in rheumatoid arthritis (RA). Secondly, we also evaluated the performance of risk age models in subgroups based on RA disease characteristics.MethodsRA patients aged 30-70 years were included from an international consortium named A Trans-Atlantic Cardiovascular Consortium for Rheumatoid Arthritis (ATACC-RA). Prior CVD and diabetes mellitus were exclusion criteria. The discriminatory ability of specific risk age models was evaluated using c-statistics and their standard errors after calculating time until fatal or non-fatal CVD or last follow-up.ResultsA total of 1974 patients were included in the main analyses, and 144 events were observed during follow-up, the median follow-up being 5.0 years. The risk age models gave highly correlated results, demonstrating R2 values ranging from 0.87 to 0.97. However, risk age estimations differed > 5 years in 15-32% of patients. C-statistics ranged 0.68-0.72 with standard errors of approximately 0.03. Despite certain RA characteristics being associated with low c-indices, standard errors were high. Restricting analysis to European RA patients yielded similar results.ConclusionsThe cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive.

ObjectivesSmoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients.MethodsDisease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status.ResultsOf the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5-6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P

Abstract Background Binge eating disorder (BED), as the most prevalent eating disorder, is strongly related to obesity and other somatic and psychiatric morbidity. Despite evidence-based treatments a considerable number of BED patients fail to recover. There is preliminary evidence for the association between psychodynamic personality functioning and personality traits on treatment outcome. However, research is limited and results are still contradictory. Identifying variables associated with treatment outcome could improve treatment programs. The aim of the study was to explore whether personality functioning or personality traits are associated with Cognitive Behavioral Therapy (CBT) outcome in obese female patients with BED or subthreshold BED. Methods Eating disorder symptoms and clinical variables were assessed in 168 obese female patients with DSM-5 BED or subthreshold BED, referred to a 6-month outpatient CBT program in a pre-post measurement design. Personality functioning was assessed by the Developmental Profile Inventory (DPI), personality traits by the Temperament and Character Inventory (TCI). Treatment outcome was assessed by the Eating Disorder Examination-Questionnaire (EDE-Q) global score and self-reported binge eating frequency. According to the criteria of clinical significance, 140 treatment completers were categorized in four outcome groups (recovered, improved, unchanged, deteriorated). Results EDE-Q global scores, self-reported binge eating frequency and BMI significantly decreased during CBT, where 44.3% of patients showed clinically significant change in EDE-Q global score. Treatment outcome groups showed significant overall differences on the DPI Resistance and Dependence scales and the aggregated ‘neurotic’ scale. Significant overall differences were found between groups on TCI Harm avoidance, although post hoc t-tests were non-significant. Furthermore, multiple logistic regression analysis, controlling for mild to moderate depressive disorder and TCI harm avoidance showed that ‘neurotic’ personality functioning was a significant negative predictor of clinically significant change. Conclusion Maladaptive (‘neurotic’) personality functioning is significantly associated with a less favorable outcome after CBT in patients with binge eating. Moreover, ‘neurotic’ personality functioning is a predictor of clinically significant change. Assessment of personality functioning and personality traits could support indication for more specified or augmented care, tailored towards the patients’ individual strengths and vulnerabilities. Trial registration This study protocol was retrospectively evaluated and approved on 16-06-2022 by the Medical Ethical Review Committee (METC) of the Amsterdam Medical Centre (AMC). Reference number W22_219#22.271.

Abstract Tick-borne encephalitis virus (TBEV) may cause tick-borne encephalitis (TBE), a potential life-threatening infection of the central nervous system in humans. Phylogenetically, TBEVs can be subdivided into three main subtypes, which differ in endemic region and pathogenic potential. In 2016, TBEV was first detected in the Netherlands. One of two detected strains, referred to as Salland, belonged to the TBEV-Eu subtype, yet diverged ≥ 2% on amino acid level from other members of this subtype. Here, we report the successful rescue of this strain using infectious subgenomic amplicons and its subsequent in vitro characterization by comparison to two well-characterized TBEV-Eu strains; Neudoerfl and Hypr. In the human alveolar epithelial cell line A549, growth kinetics of Salland were comparable to the high pathogenicity TBEV-Eu strain Hypr, and both strains grew considerably faster than the mildly pathogenic strain Neudoerfl. In the human neuroblastoma cell line SK-N-SH, Salland replicated faster and to higher infectious titers than both reference strains. All three TBEV strains infected primary human monocyte-derived dendritic cells to a similar extent and interacted with the type I interferon system in a similar manner. The current study serves as the first in vitro characterization of the novel, divergent TBEV-Eu strain Salland.

The Omicron BA.1 (B.1.1.529) SARS-CoV-2 variant is characterized by a high number of mutations in the viral genome, associated with immune escape and increased viral spread. It remains unclear whether milder COVID-19 disease progression observed after infection with Omicron BA.1 in humans is due to reduced pathogenicity of the virus or due to pre-existing immunity from vaccination or previous infection. Here, we inoculated hamsters with Omicron BA.1 to evaluate pathogenicity and kinetics of viral shedding, compared to Delta (B.1.617.2) and to animals re-challenged with Omicron BA.1 after previous SARS-CoV-2 614G infection. Omicron BA.1 infected animals showed reduced clinical signs, pathological changes, and viral shedding, compared to Delta-infected animals, but still showed gross- and histopathological evidence of pneumonia. Pre-existing immunity reduced viral shedding and protected against pneumonia. Our data indicate that the observed decrease of disease severity is in part due to intrinsic properties of the Omicron BA.1 variant.

The level of private debt in the Netherlands is exceptional in both historical and comparative terms. High debt ratios inhibit economic growth, induce financial fragility and lead to deeper and more tenacious recessions. Facilitated by fiat money creation, private debt in the modern economy mainly consists of bank credit. Internationally shared causes of the rise in bank money are the decline in cash payments, tax deductions and a narrowed focus in monetary policy. In the Dutch case, liberalized mortgages, the side effects of the funded pension system and the strong concentration of the banking system add to these. It is the confluence of these factors that has made Dutch debt growth since the 1970s exceptional. Some of these, notably the deduction of interest on mortgages and financial deregulation, have dominated the debate on this subject and hence are part of public perception. However, this does not apply to other mechanisms mentioned, such as the role of bank money and that of bank concentration. As a result, policy analysis of the debt problem thus far has been selective. The lessons of Dutch financial development are of importance to the realization of the European banking union and to monetary policy and taxation in the euro area. Our analysis demonstrates the usefulness of applied history.

Dyslipidemia in obesity results from excessive production and impaired clearance of triglyceride-rich (TG-rich) lipoproteins, which are particularly pronounced in the postprandial state. Here, we investigated the impact of Roux-en-Y gastric bypass (RYGB) surgery on postprandial VLDL1 and VLDL2 apoB and TG kinetics and their relationship with insulin-responsiveness indices. Morbidly obese patients without diabetes who were scheduled for RYGB surgery (n = 24) underwent a lipoprotein kinetics study during a mixed-meal test and a hyperinsulinemic-euglycemic clamp study before the surgery and 1 year later. A physiologically based computational model was developed to investigate the impact of RYGB surgery and plasma insulin on postprandial VLDL kinetics. After the surgery, VLDL1 apoB and TG production rates were significantly decreased, whereas VLDL2 apoB and TG production rates remained unchanged. The TG catabolic rate was increased in both VLDL1 and VLDL2 fractions, but only the VLDL2 apoB catabolic rate tended to increase. Furthermore, postsurgery VLDL1 apoB and TG production rates, but not those of VLDL2, were positively correlated with insulin resistance. Insulin-mediated stimulation of peripheral lipoprotein lipolysis was also improved after the surgery. In summary, RYGB resulted in reduced hepatic VLDL1 production that correlated with reduced insulin resistance, elevated VLDL2 clearance, and improved insulin sensitivity in lipoprotein lipolysis pathways.

Introduction Recurrent vulvovaginal candidiasis (RVVC) affects up to 9% of women worldwide. This amount is expected to increase due to lifestyle changes, increased fungal resistance and biofilm formation. Treatment options are limited and in 57% of the cases, relapses occur within 12 months after starting fluconazole therapy (golden standard). The pathogenesis of RVVC is multifactorial and includes fungal biology, the vaginal microenvironment and the immune system. Fluconazole is antimicrobial and effective in inducing short-term remission but a long-term cure is hard to achieve. Medical grade honey (MGH) has antimicrobial, protective, antioxidative and immunomodulatory activity and may therefore be a good alternative treatment. This study aims to investigate the clinical cure rate and long-term efficacy of MGH compared with fluconazole in patients with RVVC.Methods and analysis This study is a multicentre, randomised controlled trial (Maastricht University Medical Centre+ and Zuyderland Medical Centre). A total of 252 eligible women will be randomly assigned to the fluconazole group (control) or the MGH group (L-Mesitran, treatment). The primary objective is to investigate the mycological cure rate after 1 month assessed through a vaginal culture. Secondary objectives are the clinical cure rate regarding symptoms, the prophylactic activity after 6 months of maintenance therapy and the number of relapses within 12 months. Moreover, information about side effects, discomfort and quality of life will be collected with the use of questionnaires.Ethics and dissemination Ethical approval from the Medical Ethics Review Committee of the academic hospital Maastricht/University Maastricht has been obtained (NL 73974.068.21, V.7 on 8 February 2022). Additional approval was obtained from the Ethics Committee of the Zuyderland Medical Centre Heerlen (Z2021141 on 4 March 2022). The first patient was randomised on 22 August 2022. Results will be made available to researchers and healthcare professionals via conferences, meetings and peer-reviewed international publications.Trial registration number NCT05367089.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.