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Introduction Necrotising enterocolitis is a devastating gastrointestinal disease predominantly affecting preterm infants. In 40% of cases, its rapid progression renders conservative treatment insufficient, necessitating laparotomy as the sole viable option for survival. However, high perioperative and postoperative mortality rates, along with severe future potential disabilities and suffering, can complicate the decision of whether surgery is still in the infant’s best interest. In such cases, palliative care, aimed to minimise suffering, may be considered as an alternative to laparotomy, especially when the infant’s expected quality of life and overall prognosis are concerning. Depending on the sociocultural context, parents are increasingly involved in this decision. However, weighing the risks, benefits and uncertainties can be challenging for them. Therefore, we aim to develop a decision support tool using a novel combination of the Delphi technique and Q-methodology. Ultimately, we anticipate that this approach will contribute to improved family-centred care and optimised outcomes.Methods and analysis The first phase of the study aims to identify key factors guiding Dutch parents’ decisions between laparotomy and palliative care (decision factors). Using a Delphi process, parents with varying perspectives and experiences will evaluate decision factors found in the literature and those self-suggested. The pertinent set of decision factors is defined during a consensus meeting.During the second phase, parents are asked to compare statements about these decision factors using Q-methodology. A by-person factor analysis of these comparisons will identify different parental decision-making profiles, which allows for formulating advice tailored to those profiles.Ultimately, we will build an online decision support tool which facilitates the classification of parent perspectives. The tool will then provide the parents with the relevant advice. In the last phase of the study, the tool’s effectiveness will be evaluated through an online questionnaire, asking parents to imagine using the tool in a real-world scenario.Ethics and dissemination Ethical approval has been obtained from Central Ethics Review Committee of The University Medical Center Groningen (METc 2023/577, CTc UMCG 153660). Participants will be asked to provide their informed consent for the parts of the study that involve non-anonymous data gathering. Findings will be disseminated through academic journals and conferences. Options for long-term data preservation are under consideration.

Abstract BackgroundNeonatal intensive care unit admissions of newborns are emotional and stressful for parents, influencing their mental and physical well-being and resulting in high rates of psychological morbidities. Significant research has been undertaken to understand and quantify the burden of a newborn’s medical journey on parents’ well-being. Simultaneously, an increase has been observed in the development and implementation of telemedicine interventions, defined as the remote delivery of health care. Telemedicine is used as an overarching term for different technological interventions grouped as real-time audio-visual communication, remote patient monitoring, and asynchronous communication. Various telemedicine interventions have been proposed and developed but scarcely with the primary goal of improving parental well-being during their newborn’s medical journey. ObjectiveThis study aims to identify telemedicine interventions with the potential to improve parents’ well-being and to present the methods used to measure their experience. MethodsA scoping review was conducted, including empirical studies evaluating telemedicine in neonatal care that either measured parental well-being or included parents in the evaluation. Abstract and title screening, full-text screening, and data extraction were performed by three researchers. Two researchers were needed to reach decisions on both the inclusion and extraction of articles. ResultsThe review included 50 out of 737 screened articles. Telemedicine interventions focused mainly on daily visits at the neonatal intensive care unit and discharge preparedness for parents. Surveys were the primary tool used for outcome measurement (36/50, 72%). Aspects of parents’ well-being were evaluated in 62% (31/50) of studies. Telemedicine interventions developed to provide education and support showed a potential to improve self-efficacy and discharge preparedness and decrease anxiety and stress when they included a real-time telemedicine component. ConclusionsThis scoping review identified specific telemedicine interventions, such as real-time audio-visual communication and eHealth apps, that have the potential to improve parental well-being by enhancing self-efficacy and discharge preparedness, and reducing anxiety and stress. However, more insights are needed to understand how these interventions affect well-being. Parents should be included in future research in both the development and evaluation stages. It is important to not only measure parents’ perceptions but also focus on the impact of a telemedicine intervention on their well-being.

Objective: To identify parents' information needs about impending very preterm birth and compare these needs to current information practices in the Netherlands. Methods: Step 1: We surveyed N = 203 parents of preterm infants to assess their information needs. Data were analyzed using inductive thematic analysis. Step 2a: We collected information resources from hospitals (N = 9 NICUs) and via an online search. These materials were analyzed using deductive thematic analysis. Step 2b: We compared findings from Steps 1-2a. Results: We identified four themes pertaining to parents' information needs: (1) participation in care, (2) emotional wellbeing, (3) experience/success stories, and (4) practical information about prematurity. Clinicians' communicative skills and time were considered prerequisites for optimal information-provision. Notably, hospital resources provided mainly medical information about prematurity with some emphasis on participation in care, while parent associations mainly focused on emotional wellbeing and experience/success stories. Conclusion: While parents demonstrate clear information needs about impending very preterm birth, current information resources satisfy these partially. Innovation: Our multidisciplinary research team included both scholars and veteran NICU parents. As such, we identified parents' information needs bottom-up. These parent-driven insights will be used to design an innovative, tailored information platform for parents about impending very preterm birth.

Background: COVID-19 patients frequently experience pulmonary embolism (PE), but its long-term consequences remain uncertain. Objectives: To assess the impact of PE in COVID-19 patients on health outcomes at 3 months after hospitalization. Methods: In this multicenter cross-sectional study, we aggregated data from existing databases to evaluate the impact of PE on health outcomes at 3 months after hospitalization. We assessed 1) questionnaires on health-related quality of life (5-level EuroQol 5-dimensional questionnaire [EQ-5D-5L] questionnaire), anxiety, depression, cognitive failure, and posttraumatic stress disorder; 2) pulmonary function tests (diffusing capacity of the lungs for carbon monoxide [DLCO] and spirometry); and 3) radiological abnormalities. We developed 3 models to assess the association between PE and the EQ-5D-5L index and the percentage of predicted DLCO (DLCO%): a crude model (model 1), adjusted for age, sex, and presence of comorbidities (model 2), and model 2 additionally adjusted for intensive care unit admission (model 3). Results: We included 465 patients who had been hospitalized for COVID-19, of whom 102 (21.9%) had developed a PE during admission. Patients with PE had poorer EQ-5D-5L index values, more impairment in pulmonary functions, and more frequent radiological abnormalities than patients without PE. Symptoms of anxiety, depression, cognitive failure, and posttraumatic stress disorder did not differ between the 2 groups. In model 2, PE was associated with lower EQ-5D-5L index and lower DLCO%. After additionally adjusting for intensive care unit admission, the association between PE and lower EQ-5D-5L index (mean difference = −0.069, [95% CI, −0.12 to −0.017]) remained but not between PE and DLCO%. Conclusion: Our findings suggest that PE in COVID-19 patients is associated with reduced health-related quality of life at 3 months after hospitalization. While PE may be a marker of COVID-19 severity, its presence during hospitalization could indicate potential long-term health issues, which may be considered during follow-up care.

IntroductionThe relationship between carotid artery stenosis (CAS) and ipsilateral silent brain ischemia (SBI) remains unclear, with uncertain therapeutic implications. The present study, part of the TAXINOMISIS project (nr. 755,320), aimed to investigate SBIs in patients with asymptomatic CAS, correlating them with clinical, carotid ultrasonographic data, and CFD analyses.MethodsThe TAXINOMISIS clinical trial study (nr. NCT03495830) involved six vascular surgery centers across Europe, enrolling patients with asymptomatic and symptomatic CAS ranging from 50 to 99%. Patients underwent carotid ultrasound and magnetic resonance imaging (MRI), including brain diffusion-weighted, T2-weighted/FLAIR, and T1-weighted sequences. Brain MRI scans were analyzed for the presence of SBI according to established definitions. Ultrasound assessments included Doppler and CFD analysis. Only asymptomatic patients were included in this substudy.ResultsAmong 195 asymptomatic patients, the mean stenosis (NASCET) was 64.1%. Of these, a total of 33 patients (16.9%) had at least one SBI detected on a brain MRI scan. Specifically, 19 out of 33 patients (57.6%) had cortical infarcts, 4 out of 33 patients (12.1%) had ipsilateral lacunar infarcts, 6 out of 33 patients had (18.2%) subcortical infarcts, 1 out of 33 patients (3.0%) had both cortical and lacunar infarcts, and 3 out of 33 patients (9.1%) both cortical and subcortical infarcts. Patients with SBIs exhibited significantly higher risk factors, including a higher body mass index (28.52 ± 9.38 vs. 26.39 ± 3.35, p = 0.02), diastolic blood pressure (80.87 ± 15.73 mmHg vs. 80.06 ± 8.49 mmHg, p = 0.02), creatinine levels (93.66 ± 34.61 μmol/L vs. 84.69 ± 23.67 μmol/L, p = 0.02), and blood triglycerides (1.8 ± 1.06 mmol/L vs. 1.48 ± 0.78 mmol/L, p = 0.03). They also had a higher prevalence of cardiovascular interventions (29.6% vs. 13.8%, p = 0.04), greater usage of third/fourth-line antihypertensive treatment (50%vs16%, p = 0.03), and anticoagulant medications (60% vs. 16%, p = 0.01). Additionally, the number of contralateral cerebral infarcts was higher in patients with SBIs (35.5% vs. 13.4%, p

Background: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R–SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R–SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19. Methods: Baseline serum R–SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R–SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS. Results: Baseline albumin-adjusted serum R–SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R–SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = −9.48, p = 0.023). Conclusion: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R–SH as a monitoring biomarker and a potential therapeutic target in the development of PCS.

Abstract Background Preterm born infants are at risk for brain injury and subsequent developmental delay. Treatment options are limited, but optimizing postnatal nutrition may improve brain- and neurodevelopment in these infants. In pre-clinical animal models, combined supplementation of docosahexaenoic acid (DHA), choline, and uridine-5-monophosphate (UMP) have shown to support neuronal membrane formation. In two randomized controlled pilot trials, supplementation with the investigational product was associated with clinically meaningful improvements in cognitive, attention, and language scores. The present study aims to assess the effect of a similar nutritional intervention on brain development and subsequent neurodevelopmental outcome in infants born very and extremely preterm. Methods This is a randomized, placebo-controlled, double-blinded, parallel-group, multi-center trial. A total of 130 infants, born at less than 30 weeks of gestation, will be randomized to receive a test or control product between term-equivalent age and 12 months corrected age (CA). The test product is a nutrient blend containing DHA, choline, and UMP amongst others. The control product contains only fractions of the active components. Both products are isocaloric powder supplements which can be added to milk and solid feeds. The primary outcome parameter is white matter integrity at three months CA, assessed using diffusion-tensor imaging (DTI) on MRI scanning. Secondary outcome parameters include volumetric brain development, cortical thickness, cortical folding, the metabolic and biochemical status of the brain, and product safety. Additionally, language, cognitive, motor, and behavioral development will be assessed at 12 and 24 months CA, using the Bayley Scales of Infant Development III and digital questionnaires (Dutch version of the Communicative Development Inventories (N-CDI), Ages and Stages Questionnaire 4 (ASQ-4), and Parent Report of Children’s Abilities – Revised (PARCA-R)). Discussion The investigated nutritional intervention is hypothesized to promote brain development and subsequent neurodevelopmental outcome in preterm born infants who have an inherent risk of developmental delay. Moreover, this innovative study may give rise to new treatment possibilities and improvements in routine clinical care. Trial registration WHO International Clinical Trials Registry: NL-OMON56181 (registration assigned October 28, 2021).

Abstract The effect of family socioeconomic status (SES) on academic achievement in literacy and numeracy has been extensively studied with educational inequalities already witnessed in preschoolers. This is presumably explained by the effect of family SES on cognitive and socioemotional abilities associated with academic achievement. Metacognition which refers to knowledge and regulation skills involving reflexivity about one's own cognitive processes is one of these abilities. However, most of the studies investigating the association between metacognition and academic achievement have focused on school-aged students and studies with younger students are only emerging. Meanwhile, the association between family SES and metacognition abilities has surprisingly received little attention regardless of participants’ age. The aim of this study was to explore the associations between family SES, metacognition, language and mathematical abilities in preschoolers aged 5 to 6. We provide the first evidence that the effect of family SES on preschoolers’ language and mathematical abilities is mediated by the effect of family SES on their metacognitive abilities. The implications for future research, education and policies aiming at reducing educational inequalities are discussed.

Abstract Tumors are highly complex and heterogenous ecosystems where malignant cells interact with healthy cells and the surrounding extracellular matrix (ECM). Solid tumors contain large ECM deposits that can constitute up to 60% of the tumor mass. This supports the survival and growth of cancerous cells and plays a critical role in the response to immune therapy. There is untapped potential in targeting the ECM and cell-ECM interactions to improve existing immune therapy and explore novel therapeutic strategies. The most abundant proteins in the ECM are the collagen family. There are 28 different collagen subtypes that can undergo several post-translational modifications (PTMs), which alter both their structure and functionality. Here, we review current knowledge on tumor collagen composition and the consequences of collagen PTMs affecting receptor binding, cell migration and tumor stiffness. Furthermore, we discuss how these alterations impact tumor immune responses and how collagen could be targeted to treat cancer.

Summary: Regulatory T cells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4+ thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs. TNFR2-co-stimulated effector tTregs and Tconvs are both glycolytic, but only in tTregs are glycolysis and the tricarboxylic acid (TCA) cycle linked to a boost in fatty acid (FA) synthesis (FAS), supported by relevant gene expression. FA chains in tTregs are longer and more unsaturated than in Tconvs. In contrast to Tconvs, tTregs effectively use either lactate or glucose for FAS and rely on this process for proliferation. FASN and SCD1, enzymes responsible for FAS and FA desaturation, prove essential for the ability of tTregs to suppress Tconvs. These data illuminate how effector tTregs can thrive in inflamed or cancerous tissues with limiting glucose but abundant lactate levels.

This paper presents PREDICTOR (PREDICting Take-Over Response time): an interactive open-source research software tool to predict the timing of various stages of a transition of control, or take-over, in semi-automated driving. Although previous work has investigated extensively what factors affect the minimum time needed for a successful take-over by the driver, less is known about how specific stages within the take-over process are affected by those factors. PREDICTOR applies a theoretical framework that describes the take-over process as interruption handling through a series of stages. It then ties this theory to a database that summarizes results from previous take-over studies. PREDICTOR can be used to interactively predict through simulation how specific human factors (e.g., alert modality, alert onset time) impact four distinct stages of the take-over response process. The tool simulates and visualizes expected reaction time distributions for each stage of the take-over process. The use of distributions also highlights the likelihood of an accident – as long responses (“outliers”) are quantifiable. Moreover, it can help understand at which stage drivers might take relatively longer or shorter, and which stages are most impacted by a specific factor (e.g., alert modality). PREDICTOR also allows users to add their own data, and to define their own dependent variables for analysis. As a tool that allows exploration of various scenarios, PREDICTOR can aid in the prediction and analysis of potential future accidents.

Numerous lipids are heterogeneously distributed among organelles. Most lipid trafficking between organelles is achieved by a group of lipid transfer proteins (LTPs) that carry lipids using their hydrophobic cavities. The human genome encodes many intracellular LTPs responsible for lipid trafficking and the function of many LTPs in defining cellular lipid levels and distributions is unclear. Here, we created a gene knockout library targeting 90 intracellular LTPs and performed whole-cell lipidomics analysis. This analysis confirmed known lipid disturbances and identified new ones caused by the loss of LTPs. Among these, we found major sphingolipid imbalances in ORP9 and ORP11 knockout cells, two proteins of previously unknown function in sphingolipid metabolism. ORP9 and ORP11 form a heterodimer to localize at the ER-trans-Golgi membrane contact sites, where the dimer exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Consequently, loss of either protein causes phospholipid imbalances in the Golgi apparatus that result in lowered sphingomyelin synthesis at this organelle. Overall, our LTP knockout library toolbox identifies various proteins in control of cellular lipid levels, including the ORP9-ORP11 heterodimer, which exchanges PS and PI(4)P at the ER-Golgi membrane contact site as a critical step in sphingomyelin synthesis in the Golgi apparatus.

Abstract Coronary artery disease (CAD) often leads to adverse events resulting in significant disease burdens. Underlying risk factors often remain inapparent prior to disease incidence and the cardiovascular (CV) risk is not exclusively explained by traditional risk factors. Platelets inherently promote atheroprogression and enhanced platelet functions and distinct platelet lipid species are associated with disease severity in patients with CAD. Lipidomics data were acquired using mass spectrometry and processed alongside clinical data applying machine learning to model estimates of an increased CV risk in a consecutive CAD cohort (n = 595). By training machine learning models on CV risk measurements, stratification of CAD patients resulted in a phenotyping of risk groups. We found that distinct platelet lipids are associated with an increased CV or bleeding risk and independently predict adverse events. Notably, the addition of platelet lipids to conventional risk factors resulted in an increased diagnostic accuracy of patients with adverse CV events. Thus, patients with aberrant platelet lipid signatures and platelet functions are at elevated risk to develop adverse CV events. Machine learning combining platelet lipidome data and common clinical parameters demonstrated an increased diagnostic value in patients with CAD and might improve early risk discrimination and classification for CV events.

Abstract Background First-void urine (FVU) provides a non-invasive method for collecting a wide range of biomarkers found in genital tract secretions. To optimize biomarker collection in FVU, this study investigated the impact of naturally present and supplemented precipitating agents: uromodulin (UMOD) and polyethylene glycol (PEG), on the concentration of human papillomavirus (HPV) pseudovirions (PsV), cell-free DNA (cfDNA), and cellular genomic DNA (gDNA) through centrifugation. Methods FVU samples from ten healthy female volunteers, along with a control sample, were spiked with seal herpesvirus 1 (PhHV-1) DNA, HPV16 plasmid DNA, and HPV16 PsV with an enhanced green fluorescent protein (EGFP) reporter. The samples were subjected to various concentration protocols involving PEG precipitation, low-speed centrifugation (5 min at 1000×g), and medium-speed centrifugation (1 h at 3000×g). Subsequently, quantitative PCR (qPCR) was used to assess cellular and cell-free glyceraldehyde-3-phosphate dehydrogenase (GAPDH) DNA, cell-free PhHV-1 and HPV16 DNA, and PsV (EGFP) DNA. In addition, UMOD levels were measured. Results The findings revealed that PEG significantly increased the concentration of cfDNA and gDNA in the pellet after centrifugation, with the most pronounced effect observed for cfDNA. Moreover, low-speed centrifugation without PEG effectively depleted cellular gDNA while preserving cfDNA in the supernatants. Pseudovirions were consistently pelleted, even with low-speed centrifugation, and a positive but not significant effect of PEG on PsV (EGFP) DNA yield in the pellet was observed. Additionally, a significant correlation was observed between UMOD and GAPDH, HPV16, and PsV (EGFP) DNA quantities in the pellet. Furthermore, large variations among the FVU samples were observed. Conclusions With this study, we provide novel insights into how various biomarker precipitation protocols, including both the properties of FVU and the use of PEG as a precipitating agent, influence the concentration of cfDNA, cellular gDNA, and pseudovirions.

Abstract Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.

Objective: Large language models and artificial intelligence (AI) based chatbots have brought new insights in healthcare, but they also raise major concerns. Their applications in vascular surgery have scarcely been investigated to date. This international survey aimed to evaluate the perceptions and feedback from vascular surgeons on the use of AI chatbots in vascular surgery. Methods: This international open e-survey comprised 50 items that covered participant characteristics, their perceptions on the use of AI chatbots in vascular surgery, and their user experience. The study was designed in accordance with the Checklist for reporting Results of Internet E-Surveys and was critically reviewed and approved by international members of the European Vascular Research Collaborative (EVRC) prior to distribution. Participation was open to self reported health professionals specialised (or specialising) in vascular surgery, including residents or fellows. Results: Of the 342 individuals who visited the survey page, 318 (93%) agreed to participate; 262 (82.4%) finished the survey and were included in the analysis. Most were consultants or attending physicians (64.1%), most declared not having any training or education related to AI in healthcare (221; 84.4%), and 198 (75.6%) rated their knowledge about the abilities of AI chatbots between average to very poor. Interestingly, 95 participants (36.3%) found that AI chatbots were very useful or somewhat useful in clinical practice at this stage and 229 (87.4%) agreed that they should be systematically validated prior to being used. Eighty participants (30.5%) had specifically tested it for questions related to clinical practice and 59 (73.8%) of them experienced issues or limitations. Conclusion: This international survey provides an overview of perceptions of AI chatbots by vascular surgeons and highlights the need to improve knowledge and training of health professionals to better evaluate, define, and implement their use in vascular surgery.

Abstract We investigated whether urinary vascular non-inflammatory molecule-1 (vanin-1), a promising early-onset tubular injury marker, correlates with other established tubular injury markers and is associated with graft failure in kidney transplant recipients (KTR). We measured 24 h urinary vanin-1 excretion in 656 KTR (age 53 ± 13 years, 43% female, estimated glomerular filtration rate (eGFR) 53 ± 21 mL/min/1.73 m2) who had undergone kidney transplantation ≥ 1 year. The median 24 h urinary vanin-1 excretion was 145 [51–331] pmol/24 h. 24 h urinary vanin-1 excretion correlated weakly but significantly with other tubular injury markers (ρ = 0.14, p

Fifteen to 20% of patients with an acute ischaemic stroke have a tandem lesion defined by the combination of an intracranial large vessel thrombo-embolic occlusion and a high grade stenosis or occlusion of the ipsilateral internal carotid artery. These patients tend to have worse outcomes than patients with isolated intracranial occlusions, with higher rates of disability and death. The introduction of endovascular thrombectomy to treat the intracranial lesion clearly improved the outcome compared with treatment with intravenous thrombolysis alone. However, the best treatment strategy for managing the extracranial carotid artery lesion in patients with tandem lesions remains unknown. Current guidelines recommend carotid endarterectomy for patients with transient ischaemic attack or non-disabling stroke and moderate or severe stenosis of the internal carotid artery, within two weeks of the initial event, to prevent major stroke recurrence and death. Alternatively, the symptomatic carotid artery could be treated by endovascular placement of a stent during endovascular thrombectomy (EVT). This would negate the need for a second procedure, immediately reduce the risk of stroke recurrence, increase patient satisfaction, and could be cost effective. However, the administration of dual antiplatelet therapy could potentially increase the risk of symptomatic intracranial haemorrhage in patients with acute ischaemic stroke. Randomised controlled trials evaluating the efficacy and safety of immediate carotid artery stenting during EVT in acute stroke patients with tandem lesions are currently ongoing and will impact the current guidelines regarding the treatment of patients with acute ischaemic stroke due to these tandem lesions.

It is widely recognized that airspace capacity must increase over the coming years. It is also commonly accepted that meeting this challenge while balancing concerns around safety, efficiency, and workforce issues will drive greater reliance on automation. However, if automation is not properly developed and deployed, it represents something of a double-edged sword, and has been linked to several human–machine system performance issues. In this article, we argue that human–automation function and task allocation may not be the way forward, as it invokes serialized interactions that ultimately push the human into a problematic supervisory role. In contrast, we propose a flight-based allocation strategy in which a human controller and digital colleague each have full control authority over different flights in the airspace, thereby creating a parallel system. In an exploratory human-in-the-loop simulation exercise involving six operational en route controllers, it was found that the proposed system was considered acceptable after the users gained experience with it during simulation trials. However, almost all controllers did not follow the initial flight allocations, suggesting that allocation schemes need to remain flexible and/or be based on criteria capturing interactions between flights. In addition, the limited capability of and feedback from the automation contributed to this result. To advance this concept, future work should focus on substantiating flight-centric complexity in driving flight allocation schemes, increasing automation capabilities, and facilitating common ground between humans and automation.

This article proposes a novel framework for the rapid implementation of automation programs in industrial heating and cooling systems. The global push for sustainability necessitates significant infrastructural transformations within these systems, which currently rely heavily on fossil fuels and are responsible for 75% of industrial final energy consumption. Our research highlights the critical role of design patterns and object-oriented programming principles to address the complex integration of additional energy converters and storage into automation programs. By leveraging design patterns, our framework encapsulates the intricacies of various components, such as actuators, sensors, and storage, within a comprehensive object-oriented model that also allows the integration of different control strategies. Qualitatively, this approach enhances the reusability, scalability, and adaptability of automation programs. Therefore, quantitatively, our framework enables a more resilient and efficient energy system. The framework is validated through its application to a complex, cross-linked industrial heating and cooling system at the ETA Research Factory of the Technical University of Darmstadt. Using the developed framework reduces implementation effort significantly due to its consistent and modular structure resulting from the reusable design patterns.

Yaws, caused by Treponema pallidum ssp. pertenue, remains a significant public health concern in tropical regions of West Africa and the South Pacific, primarily affecting children in remote areas with limited access to hygiene and sanitation. In this study, conducted in three endemic countries of West Africa where yaws remains a significant public health concern (Ghana, Cameroon, and Côte d'Ivoire), we aimed to assess the knowledge, attitudes, and practices related to yaws among community members, community health workers (CHWs), and traditional healers. The study revealed variations in the perception of causes of yaws among community members: the majority or participants in Ghana attributed yaws to germs (60.2%); in Cameroon the most reported form of transmission was contact with or drinking infected water sources (44.6%); and in Côte d'Ivoire both of these answers were also the most prevalent (60.3% germs and 93.% water sources). A substantial proportion of participants in Côte d'Ivoire also associated yaws with witchcraft and divine punishment (44.8%). Only a small proportion of individuals in Ghana and Côte d'Ivoire correctly identified contact with an infected person as a form of transmission (11.9% and 20.7%, respectively) and less than half in Cameroon (42.6%), although more than 98% of all participants reported avoidance behaviours towards yaws infected people due to fear of getting infected. Most participants expressed a preference for seeking care at hospitals (49.2%, 60.6%, 86.2%) or health care professionals including doctors and nurses (58.5%, 41,5% and 17.2%) if they were diagnosed with yaws, although a quarter of participants in Côte d'Ivoire also sought support from traditional healers. The CHWs interviewed were generally well-trained on yaws causes and treatment options, although they often reported low availability of treatment and diagnostic tests for yaws. Our findings underscore the need for community education, awareness campaigns, ongoing CHW training, and improved access to yaws treatment and diagnostic resources. The data also suggest that collaboration with traditional healers, who usually hold a highly esteemed position in the society, such as giving training on yaws causes and transmission or exchanging knowledge on treatment options, could be beneficial in certain regions, particularly in Côte d'Ivoire.

ABSTRACT Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation.

The intraparietal sulcus (IPS) has been associated with numerical processing. A recent study reported that the IPS sulcal pattern was associated with arithmetic and symbolic number abilities in children and adults. In the present study, we evaluated the link between numerical abilities and the IPS sulcal pattern in children with Developmental Dyscalculia (DD) and typically developing children (TD), extending previous analyses considering other sulcal features and the postcentral sulcus (PoCS). First, we confirm the longitudinal sulcal pattern stability of the IPS and the PoCS. Second, we found a lower proportion of left sectioned IPS and a higher proportion of a double-horizontal IPS shape bilaterally in DD compared to TD. Third, our analyses revealed that arithmetic is the only aspect of numerical processing that is significantly related to the IPS sulcal pattern (sectioned vs not sectioned), and that this relationship is specific to the left hemisphere. And last, correlation analyses of age and arithmetic in children without a sectioned left IPS indicate that although they may have an inherent disadvantage in numerical abilities, these may improve with age. Thus, our results indicate that only the left IPS sulcal pattern is related to numerical abilities and that other factors co-determine numerical abilities.

Introduction Twin pregnancies have a high risk of extreme preterm birth (PTB) at less than 28 weeks of gestation, which is associated with increased risk of neonatal morbidity and mortality. Currently there is a lack of effective treatments for women with a twin pregnancy and a short cervix or cervical dilatation. A possible effective surgical method to reduce extreme PTB in twin pregnancies with an asymptomatic short cervix or dilatation at midpregnancy is the placement of a vaginal cerclage.Methods and analysis We designed two multicentre randomised trials involving eight hospitals in the Netherlands (sites in other countries may be added at a later date). Women older than 16 years with a twin pregnancy at

Having two ears enables us to localize sound sources by exploiting interaural time differences (ITDs) in sound arrival. Principal neurons of the medial superior olive (MSO) are sensitive to ITD, and each MSO neuron responds optimally to a best ITD (bITD). In many cells, especially those tuned to low sound frequencies, these bITDs correspond to ITDs for which the contralateral ear leads, and are often larger than the ecologically relevant range, defined by the ratio of the interaural distance and the speed of sound. Using in vivo recordings in gerbils, we found that shortly after hearing onset the bITDs were even more contralaterally leading than found in adult gerbils, and travel latencies for contralateral sound-evoked activity clearly exceeded those for ipsilateral sounds. During the following weeks, both these latencies and their interaural difference decreased. A computational model indicated that spike timing-dependent plasticity can underlie this fine-tuning. Our results suggest that MSO neurons start out with a strong predisposition toward contralateral sounds due to their longer neural travel latencies, but that, especially in high-frequency neurons, this predisposition is subsequently mitigated by differential developmental fine-tuning of the travel latencies.

Abstract Kidney transplant recipients (KTR) have impaired health-related quality of life (HRQoL) and suffer from intestinal dysbiosis. Increasing evidence shows that gut health and HRQoL are tightly related in the general population. Here, we investigate the association between the gut microbiome and HRQoL in KTR, using metagenomic sequencing data from fecal samples collected from 507 KTR. Multiple bacterial species are associated with lower HRQoL, many of which have previously been associated with adverse health conditions. Gut microbiome distance to the general population is highest among KTR with an impaired physical HRQoL (R = −0.20, P = 2.3 × 10−65) and mental HRQoL (R = −0.14, P = 1.3 × 10−3). Physical and mental HRQoL explain a significant part of variance in the gut microbiome (R 2 = 0.58%, FDR = 5.43 × 10−4 and R 2 = 0.37%, FDR = 1.38 × 10−3, respectively). Additionally, multiple metabolic and neuroactive pathways (gut brain modules) are associated with lower HRQoL. While the observational design of our study does not allow us to analyze causality, we provide a comprehensive overview of the associations between the gut microbiome and HRQoL while controlling for confounders.

Abstract Background Over the years, the knowledge translation (KT) field has moved from promoting linearized models to embracing the importance of interaction and learning. Likewise, there is now increased attention on the transfer of KT approaches to new environments. Some scholars, however, have warned that ideas about transferability still hinge on linear thinking and doing. In the current study, we therefore sought to use a more reflexive approach to KT and to study how actors align KT approaches with their local environments. Methods Our (auto) ethnographic study took place in a wider KT project. This project intended to combine three components: (1) co-organizing demand-driven, locally led and embedded KT cycles in Cameroon, Jordan, and Nigeria, (2) building upon established KT methods and (3) equipping and empowering local teams. We conducted 63 semi-structured interviews with key KT actors, observed 472 h of KT practices, and collected a paper trail of documents. At the same time, we also compiled project exchanges, such as project documents, plans, protocols, field notes, meeting notes and an archive of (email) correspondence between project members. We analysed all data abductively. Results We show that there were numerous moments where the design of our project indeed enabled us to align with local practices and needs. Yet this often did not suffice, and the project design sometimes conflicted with other logics and values. By analysing these tensions, we want to show that doing KT work which acts upon different values and knowledges and is sensitive towards the different effects that it produces demands both structuring projects in a specific way and requires significant alignment work of KT actors in practice. Conclusions We show that practising KT more reflexively relies on two important conditions. First, KT projects have to be structured with sufficient discretionary space. Second, even though the structure of a project is important, there will be continuous need for alignment work. It is important to facilitate such alignment work and to further support it. In the discussion of this paper, we therefore articulate three design principles and three sensitivities. These elements can be used to make future KT projects more reflexive and sensitive to (social) complexity.

Sleep hypoventilation (SH) is common in COPD patients with diurnal hypercapnia, however there are little data on the presence of SH in COPD patients with diurnal normocapnia. In this study the prevalence of SH in stable normocapnic COPD patients with severe or very severe obstruction (GOLD stages III and IV) was evaluated across body mass index (BMI) classes and associations between SH and body composition measures were explored. A total of 56 diurnal normocapnic COPD patients, of whom 17 normal-weight (COPDNW), 18 overweight (COPDOW) and 21 obese (COPDOB), underwent polysomnography to objectify SH and bioelectrical impedance analysis to assess body composition. The overall prevalence of SH was 66.1% and was not different across BMI classes. Logistic regression models indicated that SH was not associated with waist-to-hip ratio, body fat percentage and fat-free mass index. Our data indicate that SH is common in diurnal normocapnic COPD patients with severe or very severe obstruction and is not associated with BMI or body composition.

Abstract NAD is a coenzyme central to metabolism that also serves as a 5′-terminal cap for bacterial and eukaryotic transcripts. Thermal degradation of NAD can generate nicotinamide and ADP-ribose (ADPR). Here, we use LC-MS/MS and NAD captureSeq to detect and identify NAD-RNAs in the thermophilic model archaeon Sulfolobus acidocaldarius and in the halophilic mesophile Haloferax volcanii. None of the four Nudix proteins of S. acidocaldarius catalyze NAD-RNA decapping in vitro, but one of the proteins (Saci_NudT5) promotes ADPR-RNA decapping. NAD-RNAs are converted into ADPR-RNAs, which we detect in S. acidocaldarius total RNA. Deletion of the gene encoding the 5′−3′ exonuclease Saci-aCPSF2 leads to a 4.5-fold increase in NAD-RNA levels. We propose that the incorporation of NAD into RNA acts as a degradation marker for Saci-aCPSF2. In contrast, ADPR-RNA is processed by Saci_NudT5 into 5′-p-RNAs, providing another layer of regulation for RNA turnover in archaeal cells.

Abstract The accumulation of erythrocyte membranes within an atherosclerotic plaque may contribute to the deposition of free cholesterol and thereby the enlargement of the necrotic core. Erythrocyte membranes can be visualized and quantified in the plaque by immunostaining for the erythrocyte marker glycophorin C. Hence, we theorized that the accumulation of erythrocytes quantified by glycophorin C could function as a marker for plaque vulnerability, possibly reflecting intraplaque hemorrhage (IPH), and offering predictive value for pre-procedural neurological symptoms. We employed the CellProfiler-integrated slideToolKit workflow to visualize and quantify glycophorin C, defined as the total plaque area that is positive for glycophorin C, in single slides of culprit lesions obtained from the Athero-Express Biobank of 1819 consecutive asymptomatic and symptomatic patients who underwent carotid endarterectomy. Our assessment included the evaluation of various parameters such as lipid core, calcifications, collagen content, SMC content, and macrophage burden. These parameters were evaluated using a semi-quantitative scoring method, and the resulting data was dichotomized as predefined criteria into categories of no/minor or moderate/heavy staining. In addition, the presence or absence of IPH was also scored. The prevalence of IPH and pre-procedural neurological symptoms were 62.4% and 87.1%, respectively. The amount of glycophorin staining was significantly higher in samples from men compared to samples of women (median 7.15 (IQR:3.37, 13.41) versus median 4.06 (IQR:1.98, 8.32), p

Human cytomegalovirus (HCMV) represents a highly medically important pathogen which has constantly been the subject of both molecular and clinical investigations. HCMV infections, especially those in high-risk patients, still raise many unanswered questions, so current investigations are focused on viral pathogenesis, vaccine development, and options for antiviral drug targeting. To this end, the use of suitable viral strains as well as recombinant reporter constructs in cultured cells and model systems has specific significance. We previously reported on the application of various herpesviruses that express green, red, or related fluorescent proteins, especially in the fields of virus–host interaction and antiviral research. Here, we characterized a recombinant version of the clinically relevant and cell type-adaptable HCMV strain TB40, which expresses firefly luciferase as a quantitative reporter of viral replication (TB40-FLuc). The data provide evidence for five main conclusions. First, HCMV TB40-FLuc is employable in multiple settings in primary human cells. Second, viral reporter signals are easily quantifiable, even at early time points within viral replication. Third, the FLuc reporter reflects the kinetics of viral intracellular replication, cascade-like viral IE-E-L protein production, and progeny release. Fourth, as relates to specific applications of the TB40-FLuc system, we demonstrated the reliability of quantitative antiviral compound determination in multi-well formats and its independence from fluorescence-based measurements in the case of autofluorescent inhibitors. Finally, we illustrated increased reporter sensitivity in comparison to other recombinant HCMVs. In essence, recombinant HCMV TB40-FLuc combines several molecular properties that are considered beneficial in studies on viral host tropism, replication efficiency, and antiviral drug assessment.

Due to the positive effects of rehabilitation declining over time, the aim of this study was to investigate the long-term physical activity level (PAL) following inpatient rehabilitation in relation to the use of a smartphone-based after-care program. 202 patients (mean Body Mass Index (BMI): 30,8 kg/m2; 61% female) with chronic diseases (e.g., diabetes mellitus, obesity, chronic low back pain, depression) were recruited between 08/2020 and 08/2021 in this single-arm observational study. All patients underwent a 3-week inpatient rehabilitation program. PAL (in total activity minutes/week) was measured with a validated (online) questionnaire (Freiburger Questionnaire on PA) after 3, 6, 9, and 12 months. App usage (online time, completion of a course) was recorded automatically and used to evaluate the app user behavior (adherence). A variety of socio-economic factors (age, sex, education level, income etc.) were collected to identify possible barriers of app use. Except for sex, no significant difference was observed for socio-economic factors regarding app usage behavior. Median PAL significantly increased after rehabilitation in the total cohort from 360 min/week (before rehabilitation) to 460 min/week 6 months after rehabilitation, then declined to 420 min/week 9 months after rehabilitation before falling below baseline level after 12 months. There was no significant difference in PAL between app users (45%, 91/202) and non-users (55%, 111/202), although app users tended to retain higher activity levels after 3 and 6 months, respectively. Overall, our study emphasizes the effectiveness of a 3-week rehabilitation program on PAL and the acceptance and usability of a smartphone-based after-care program in this patient group. The adherence to this 3-months after-care app program was acceptable (30%), with modest evidence supporting the effectiveness of app use to sustain PAL in the short term.

Abstract Background Creeping fat is a pathological feature of small bowel Crohn’s disease (CD), with literature suggesting that bowel resection with extended mesenteric resection is related to less postoperative recurrences. Conventional imaging is unable to accurately quantify the disease involvement (i.e., fibrosis) of creeping fat. Quantification of disease involvement could be useful in decision-making for additional extended mesenteric resection. We investigated the feasibility of magnetic resonance elastography (MRE) of the mesentery and if MRE is capable to detect fibrotic disease involvement of mesentery in active CD. Methods Multifrequency MRE yielded spatial stiffness (shear wave speed, SWS, |G*|) and fluidity maps (φ). Viscoelastic properties of seven CD patients’ mesentery were compared to age- and sex-matched healthy volunteers (HV) (Mann–Whitney U-test). Within CD patients, the affected and “presumably” unaffected mesentery were compared (Wilcoxon-signed rank test). Repeatability was tested in 15 HVs (Bland–Altman analysis, coefficient of variation [CoV]). Spearman rank correlations were used to investigate the relation between microscopically scored amount of mesenteric fibrosis and viscoelastic parameters. Results SWS, |G*|, and φ of affected mesentery in CD were higher compared to HV (p = 0.017, p = 0.001, p = 0.017). Strong correlations were found between percentage of area of mesenteric fibrosis and SWS and |G*| (p

Abstract Magnetic imaging using nitrogen-vacancy (NV) spins in diamonds is a powerful technique for acquiring quantitative information about sub-micron scale magnetic order. A major challenge for its application in the research on two-dimensional (2D) magnets is the positioning of the NV centers at a well-defined, nanoscale distance to the target material required for detecting the small magnetic fields generated by magnetic monolayers. Here, we develop a diamond “dry-transfer” technique akin to the state-of-the-art 2D-materials assembly methods and use it to place a diamond micro-membrane in direct contact with the 2D interlayer antiferromagnet CrSBr. We harness the resulting NV-sample proximity to spatially resolve the magnetic stray fields generated by the CrSBr, present only where the CrSBr thickness changes by an odd number of layers. From the magnetic stray field of a single uncompensated ferromagnetic layer in the CrSBr, we extract a monolayer magnetization of M CSB = 0.46(2) T, without the need for exfoliation of monolayer crystals or applying large external magnetic fields. The ability to deterministically place NV-ensemble sensors into contact with target materials and detect ferromagnetic monolayer magnetizations paves the way for quantitative analysis of a wide range of 2D magnets assembled on arbitrary target substrates.

Abstract Background and aim Sex differences in atherosclerosis have been described with female plaques being mostly perceived as stable and fibrous. Sex-specific mechanisms such as mosaic loss of the Y chromosome in men have been linked to cardiovascular health. In women, X-linked mechanisms such as X chromosome inactivation (XCI) skewing is common in several tissues. Yet, information on the role of XCI in female atherosclerotic plaques is lacking. Here, we investigated the presence of XCI skewing in advanced atherosclerotic lesions and its association with cardiovascular risk factors, histological plaque data, and clinical data. Methods XCI skewing was quantified in 154 atherosclerotic plaque and 55 blood DNA samples of women included in the Athero-Express study. The skewing status was determined performing the HUMARA assay. Then, we studied the relationship of XCI skewing in female plaque and cardiovascular risk factors using regression models. In addition, we studied if plaque XCI predicted plaque composition, and adverse events during 3-years follow-up using Cox proportional hazard models. Results XCI skewing was detected in 76 of 154 (49.4%) plaques and in 27 of 55 (67%) blood samples. None of the clinical risk factors were associated with plaque skewing. Plaque skewing was more often detected in plaques with a plaque hemorrhage (OR [95% CI]: 1.44 [1.06–1.98], P = 0.02). Moreover, skewed plaques were not associated with a higher incidence of composite and major events but were specifically associated with peripheral artery events during a 3-year follow-up period in a multivariate model (HR [95%CI]: 1.46 [1.09–1.97]; P = 0.007). Conclusions XCI skewing is common in carotid plaques of females and is predictive for the occurrence of peripheral artery events within 3 years after carotid endarterectomy.

Abstract BackgroundThe prevalence of chronic wounds is predicted to increase within the aging populations in industrialized countries. Patients experience significant distress due to pain, wound secretions, and the resulting immobilization. As the number of wounds continues to rise, their adequate care becomes increasingly costly in terms of health care resources worldwide. eHealth support systems are being increasingly integrated into patient care. However, to date, no systematic analysis of such apps for chronic wounds has been published. ObjectiveThe aims of this study were to systematically identify and subjectively assess publicly available German- or English-language mobile apps for patients with chronic wounds, with quality assessments performed by both patients and physicians. MethodsTwo reviewers independently conducted a systematic search and assessment of German- or English-language mobile apps for patients with chronic wounds that were available in the Google Play Store and Apple App Store from April 2022 to May 2022. In total, 3 apps met the inclusion and exclusion criteria and were reviewed independently by 10 physicians using the German Mobile App Rating Scale (MARS) and the System Usability Scale (SUS). The app with the highest mean MARS score was subsequently reviewed by 11 patients with chronic wounds using the German user version of the MARS (uMARS) and the SUS. Additionally, Affinity for Technology Interaction (ATI) scale scores were collected from both patients and physicians. ResultsThis study assessed mobile apps for patients with chronic wounds that were selected from a pool of 118 identified apps. Of the 73 apps available in both app stores, 10 were patient oriented. After excluding apps with advertisements or costs, 3 apps were evaluated by 10 physicians. Mean MARS scores ranged from 2.64 (SD 0.65) to 3.88 (SD 0.65) out of 5, and mean SUS scores ranged from 50.75 (SD 27) to 80.5 (SD 17.7) out of 100. WUND APP ConclusionsThe quality ratings from physicians and patients were comparable and indicated mediocre app quality. Technical affinity, as assessed by using the ATI scale, was slightly lower for patients. Adequate apps for patients with chronic wounds remain limited, emphasizing the need for improved app development to meet patient needs. The ATI scale proved valuable for assessing technical affinity among different user groups.

Background: Epidemiological studies suggest sex differences in the prevalence and characteristics of unrecognized and recognized myocardial infarction (uMI, rMI). Despite increasingly diverse populations, observations are limited in multiethnic contexts. Gaining better understanding may inform policy makers and healthcare professionals on populations at risk of uMI who could benefit from preventive measures. Methods: We used baseline data from the multiethnic population-based HELIUS cohort (2011–2015; Amsterdam, the Netherlands). Using logistic regressions, we studied sex differences in the prevalence and proportion of uMIs across ethnic groups. Next, we studied whether symptoms, clinical parameters, and sociocultural factors were associated with uMIs. Finally, we compared secondary preventive therapies in women and men with a uMI or rMI. We relied on pathological Q-waves on a resting electrocardiogram as the electrocardiographic signature for (past) MI. Results: Overall, and in Turkish and Moroccan subgroups, the prevalence of uMIs was higher in men than women. The proportion of uMIs was similar in women (21.0%) and men (18.4%), yet varied by ethnicity. In women and men, symptoms (chest pain, dyspnea) and clinical parameters (hypertension, hypercholesterolemia), and in women also lower educational level and diabetes were associated with lower odds of uMIs. Women (0.0%) and men (3.6%) with uMI were unlikely to receive secondary preventive therapies compared to those with rMI (28.1–40.9%). Conclusions: The prevalence of uMIs was higher in men than women, and sex differences in the proportion of uMIs varied somewhat across ethnic groups. People with uMIs did not receive adequate preventative medications, posing a risk for recurrent events.

Mycobacteroides abscessus is one of the most resistant bacteria so far known and causes severe and hard to treat lung infections in predisposed patients such as those with Cystic Fibrosis (CF). Further, it causes nosocomial infections by forming biofilms on medical devices or water reservoirs. An eye-catching feature of M. abscessus is the growth in two colony morphotypes. Depending on the presence or absence of glycopeptidolipids on the cell surface, it forms smooth or rough colonies. In this study, a porous glass bead biofilm model was used to compare biofilm formation, biofilm organization and biofilm matrix composition in addition to the antimicrobial susceptibility of M. abscessus biofilms versus suspensions of isogenic (smooth and rough) patient isolates. Both morphotypes reached the same cell densities in biofilms. The biofilm architecture, however, was dramatically different with evenly distributed oligo-layered biofilms in smooth isolates, compared to tightly packed, voluminous biofilm clusters in rough morphotypes. Biofilms of both morphotypes contained more total biomass of the matrix components protein, lipid plus DNA than was seen in corresponding suspensions. The biofilm mode of growth of M. abscessus substantially increased resistance to the antibiotics amikacin and tigecycline. Tolerance to the disinfectant peracetic acid of both morphotypes was increased when grown as biofilm, while tolerance to glutaraldehyde was significantly increased in biofilm of smooth isolates only. Overall, smooth colony morphotypes had more pronounced antimicrobial resistance benefit when growing as biofilm than M. abscessus showing rough colony morphotypes.

The impact of pre-transplant parathyroid hormone (PTH) levels on early or long-term kidney function after kidney transplantation is subject of debate. We assessed whether severe hyperparathyroidism is associated with delayed graft function (DGF), death-censored graft failure (DCGF), or all-cause mortality. In this single-center cohort study, we studied the relationship between PTH and other parameters related to bone and mineral metabolism, including serum alkaline phosphatase (ALP) at time of transplantation with the subsequent risk of DGF, DCGF and all-cause mortality using multivariable logistic and Cox regression analyses. In 1,576 kidney transplant recipients (51.6 ± 14.0 years, 57.3% male), severe hyperparathyroidism characterized by pre-transplant PTH ≥771 pg/mL (>9 times the upper limit) was present in 121 patients. During 5.2 [0.2–30.0] years follow-up, 278 (15.7%) patients developed DGF, 150 (9.9%) DCGF and 432 (28.6%) died. A higher pre-transplant PTH was not associated with DGF (HR 1.06 [0.90–1.25]), DCGF (HR 0.98 [0.87–1.13]), or all-cause mortality (HR 1.02 [0.93–1.11]). Results were consistent in sensitivity analyses. The same applied to other parameters related to bone and mineral metabolism, including ALP. Severe pre-transplant hyperparathyroidism was not associated with an increased risk of DGF, DCGF or all-cause mortality, not supporting the need of correction before kidney transplantation to improve graft or patient survival.

Volume electron microscopy together with computer-based image analysis are yielding neural circuit diagrams of ever larger regions of the brain. These datasets are usually represented in a cell-to-cell connectivity matrix and contain important information about prevalent circuit motifs allowing to directly test various theories on the computation in that brain structure. Of particular interest are the detection of cell assemblies and the quantification of feedback, which can profoundly change circuit properties. While the ordering of cells along the rows and columns doesn't change the connectivity, it can make special connectivity patterns recognizable. For example, ordering the cells along the flow of information, feedback and feedforward connections are segregated above and below the main matrix diagonal, respectively. Different algorithms are used to renumber matrices such as to minimize a given cost function, but either their performance becomes unsatisfying at a given size of the circuit or the CPU time needed to compute them scales in an unfavorable way with increasing number of neurons. Based on previous ideas, I describe an algorithm which is effective in matrix reordering with respect to both its performance as well as to its scaling in computing time. Rather than trying to reorder the matrix in discrete steps, the algorithm transiently relaxes the integer program by assigning a real-valued parameter to each cell describing its location on a continuous axis ('smooth-index') and finds the parameter set that minimizes the cost. I find that the smooth-index algorithm outperforms all algorithms I compared it to, including those based on topological sorting.

Uropathogenic Escherichia coli (UPEC) and avian pathogenic Escherichia coli (APEC) are extraintestinal pathogenic Escherichia coli (ExPEC) that infect dogs and poultry. These agents occur both as single-species infections and, commonly, in co-infection with Enterococcus faecalis (EF); however, it is unclear how EF co-infections modulate ExPEC virulence. Genetic drivers of interspecies interactions affecting virulence were identified using macrocolony co-culture, chicken embryo co-infection experiments, and whole-genome sequence analysis of ExPEC and EF clinical isolates. Ten of 11 UPEC strains originally co-isolated with EF exhibited a growth advantage when co-cultured with EF on iron-limited, semi-solid media in contrast to growing alone (P < 0.01). Phylogenetic analyses of these UPEC and 18 previously screened APEC indicated the growth-response phenotype was conserved in ExPEC despite strain diversity. When genomes of EF-responsive ExPEC were compared to non-responsive ExPEC genomes, EF-induced growth was associated with siderophore, exopolysaccharide (EPS), and plasmid conjugative transfer genes. Two matched pairs of EF-responsive and non-responsive ExPEC were selected for further characterization by macrocolony proximity and chicken embryo lethality assays. EF-responsive ExPEC produced 5 to 16 times more EPS in proximity to EF and were more lethal to embryos alone and during co-infection with EF compared to non-responsive ExPEC (P < 0.05). A responsive APEC strain cured of its conjugative plasmid lost the enhanced growth and EPS production response to EF. These data demonstrate that ExPEC growth augmentation by EF occurs in UPEC and APEC strains and is linked to conjugative virulence plasmids and EPS production, which are widely conserved ExPEC virulence determinants.

IntroductionThere is a lack of comprehensive and uniform data on head and neck paragangliomas (HNPGLs), and research is challenging due to its rarity and the involvement of multiple medical specialties. To improve current research data collection, we initiated the Head and Neck Paraganglioma Registry (HNPGL Registry). The aim of the HNPGL Registry is to a) collect extensive data on all HNPGL patients through a predefined protocol, b) give insight in the long term outcomes using patient reported outcome measures (PROMs), c) create uniformity in the diagnostic and clinical management of these conditions, and thereby d) help provide content for future (randomized) research.Methods and analysisThe HNPGL Registry is designed as a prospective longitudinal observational registry for data collection on HNPGL patients and carriers of (likely) pathogenic variants causative of HNPGLs. All patients, regardless of the received treatment modality, can be included in the registry after informed consent is obtained. All relevant data regarding the initial presentation, diagnostics, treatment, and follow-up will be collected prospectively in an electronic case report form. In addition a survey containing the EuroQol 5D-5L (EQ-5D-5L), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), Modified Fatigue Impact Scale (MFIS), Short QUestionnaire to Assess Health-enhancing physical activity (SQUASH), Cancer Worry Scale (CWS) and Hospital Anxiety and Depression Scale (HADS) will be sent periodically. The registry protocol was approved by the Medical Ethical Review Board of the University Medical Center Utrecht.ConclusionThe HNPGL Registry data will be used to further establish the optimal management for HNPGL patients and lay the foundation for guideline recommendations and the outline of future research.

BackgroundDespite Antiplatelet therapy (APT), cardiovascular patients undergoing revascularisation remain at high risk for thrombotic events. Individual response to APT varies substantially, resulting in insufficient protection from thrombotic events due to high on-treatment platelet reactivity (HTPR) in ≤40% of patients. Individual variation in platelet response impairs APT guidance on a single patient level. Unfortunately, little is known about individual platelet response to APT over time, timing for accurate residual platelet reactivity measurement, or the optimal test to monitor residual platelet reactivity.AimsTo investigate residual platelet reactivity variability over time in individual patients undergoing carotid endarterectomy (CEA) treated with clopidogrel.MethodsPlatelet reactivity was determined in patients undergoing CEA in a prospective, single-centre, observational study using the VerifyNow (change in turbidity from ADP-induced binding to fibrinogen-coated beads), the VASP assay (quantification of phosphorylation of vasodilator-stimulated phosphoprotein), and a flow-cytometry-based assay (PACT) at four perioperative time points. Genotyping identified slow (CYP2C19*2 and CYP2C19*3) and fast (CYP2C19*17) metabolisers.ResultsBetween December 2017 and November 2019, 50 patients undergoing CEA were included. Platelet reactivity measured with the VerifyNow (p = < .001) and VASP (p = .029) changed over time, while the PACT did not. The VerifyNow identified patients changing HTRP status after surgery. The VASP identified patients changing HTPR status after eight weeks (p = .018). CYP2C19 genotyping identified 13 slow metabolisers.ConclusionIn patients undergoing CEA, perioperative platelet reactivity measurements fluctuate over time with little agreement between platelet reactivity assays. Consequently, HTPR status of individual patients measured with the VerifyNow and VASP assay changed over time. Therefore, generally used perioperative platelet reactivity measurements seem unreliable for adjusting perioperative APT strategy.

IntroductionThe risk of major bleeding complications in catheter directed thrombolysis (CDT) for acute limb ischemia (ALI) remains high, with reported major bleeding complication rates in up to 1 in every 10 treated patients. Fibrinogen was the only predictive marker used for bleeding complications in CDT, despite the lack of high quality evidence to support this. Therefore, recent international guidelines recommend against the use of fibrinogen during CDT. However, no alternative biomarkers exist to effectively predict CDT-related bleeding complications. The aim of the POCHET biobank is to prospectively assess the rate and etiology of bleeding complications during CDT and to provide a biobank of blood samples to investigate potential novel biomarkers to predict bleeding complications during CDT.MethodsThe POCHET biobank is a multicentre prospective biobank. After informed consent, all consecutive patients with lower extremity ALI eligible for CDT are included. All patients are treated according to a predefined standard operating procedure which is aligned in all participating centres. Baseline and follow-up data are collected. Prior to CDT and subsequently every six hours, venous blood samples are obtained and stored in the biobank for future analyses. The primary outcome is the occurrence of non-access related major bleeding complications, which is assessed by an independent adjudication committee. Secondary outcomes are non-major bleeding complications and other CDT related complications. Proposed biomarkers to be investigated include fibrinogen, to end the debate on its usefulness, anti-plasmin and D-Dimer.Discussion and conclusionThe POCHET biobank provides contemporary data and outcomes of patients during CDT for ALI, coupled with their blood samples taken prior and during CDT. Thereby, the POCHET biobank is a real world monitor on biomarkers during CDT, supporting a broad spectrum of future research for the identification of patients at high risk for bleeding complications during CDT and to identify new biomarkers to enhance safety in CDT treatment.

To study how the nervous system processes visual information, experimenters must record neural activity while delivering visual stimuli in a controlled fashion. In animals with a nearly panoramic field of view, such as flies, precise stimulation of the entire visual field is challenging. We describe a projector-based device for stimulation of the insect visual system under a microscope. The device is based on a bowl-shaped screen that provides a wide and nearly distortion-free field of view. It is compact, cheap, easy to assemble, and easy to operate using the included open-source software for stimulus generation. We validate the virtual reality system technically and demonstrate its capabilities in a series of experiments at two levels: the cellular, by measuring the membrane potential responses of visual interneurons; and the organismal, by recording optomotor and fixation behavior of Drosophila melanogaster in tethered flight. Our experiments reveal the importance of stimulating the visual system of an insect with a wide field of view, and we provide a simple solution to do so.

Zellweger Syndrome is a peroxisomal disorder that can lead to elevation of long chain fatty acids and epilepsy, which can be drug resistant. The treatment of drug resistant epilepsy can include the ketogenic diet in appropriately chosen patients. Typically, the ketogenic diet is contraindicated in individuals with defects in fatty acid metabolism because of the diet’s reliance on medium and long chain fatty acids. To our knowledge this is the first publication outlining the use of the ketogenic diet in patients with defects in beta oxidation of very long chain fatty acids. We present two patients with Zellweger Syndrome who were placed on a ketogenic diet for drug resistant epilepsy.Safety and tolerance of the ketogenic diet in patients with Zellweger Syndrome.