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Background and Aims Transcatheter aortic valve implantation (TAVI) has become the first choice to treat older patients with severe symptomatic aortic stenosis (AS). This study aimed to compare TAVI with surgery in low-risk patients ≤75 years of age, including both tricuspid and bicuspid AS. Methods The Nordic Aortic Valve Intervention (NOTION)-2 trial enrolled and 1:1 randomized low-risk patients aged ≤75 years with severe symptomatic AS to TAVI or surgery. The primary endpoint was a composite of all-cause mortality, stroke, or rehospitalization (related to the procedure, valve, or heart failure) at 12 months. Results A total of 370 patients were enrolled with a mean age of 71.1 years and a median Society of Thoracic Surgeons risk score of 1.1%. A total of 100 patients had bicuspid AS. The 1-year incidence of the primary endpoint was 10.2% in the TAVI group and 7.1% in the surgery group [absolute risk difference 3.1%; 95% confidence interval (CI), −2.7% to 8.8%; hazard ratio (HR) 1.4; 95% CI, 0.7–2.9; P =.3]. Patients with TAVI, when compared to surgery, had lower risk of major bleeding and new-onset atrial fibrillation and higher risk of non-disabling stroke, permanent pacemaker implantation, and moderate or greater paravalvular regurgitation. The risk of the primary composite endpoint was 8.7% and 8.3% in patients with tricuspid AS (HR 1.0; 95% CI, 0.5–2.3) and 14.3% and 3.9% in patients with bicuspid AS (HR 3.8; 95% CI, 0.8–18.5) treated with TAVI or surgery, respectively (P for interaction =.1). Conclusions Among low-risk patients aged ≤75 years with severe symptomatic AS, the rate of the composite of death, stroke, or rehospitalization at 1 year was similar between TAVI and surgery. Transcatheter aortic valve implantation outcomes in young bicuspid AS patients warrant caution and should be further investigated. (NOTION-2, ClinicalTrials.gov , NCT02825134). Trial Registration number ClinicalTrials.gov NCT02825134. [ABSTRACT FROM AUTHOR]

Summary: Wilms’ tumor protein 1 (WT1) is a tumor-associated antigen overexpressed in various cancers. As a self-antigen, negative selection reduces the number of WT1-specific T cell receptors (TCRs). Here, we provide a protocol to generate WT137-45-specific TCRs using healthy human peripheral blood mononuclear cells. We describe the expansion of WT1-specific T cell clones by two consecutive in vitro stimulations with autologous WT137-45-pulsed dendritic cells and peripheral blood lymphocytes. We then detail the detection with human leukocyte antigen/WT137-45 tetramers. : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Background People with mild to borderline intellectual disabilities (MBIDs) face challenges in social functioning, possibly as a result of limited mentalising abilities such as reflecting on the behaviour of themselves and others. Reflective functioning in people with MBIDs has not yet been investigated due to a lack of instruments. The Reflective Functioning Questionnaire (RFQ) is a seemingly easy adaptable, short self-report questionnaire. The aim of the present, explorative study was to adapt the RFQ for people with MBIDs and investigate the psychometric properties and correlations with other mentalising related constructs. The formulation of the items was adapted to the target group and items were added to broaden the scope towards reflection on both the self and other. Method Participants were 159 adults with MBIDs who completed a Dutch-translated and easy-to-read RFQ with five supplemental items, a questionnaire for autistic traits, a self-report questionnaire assessing perspective taking and two performance-based measures assessing emotion recognition and Theory of Mind. Results Confirmatory factor analysis confirmed the factor structure of the RFQ and revealed a two-factor structure with a Self and Other subscale. Generally satisfactory internal consistency and test-retest reliability were found. Explorative results showed correlations of the RFQ-8 and RFQ subscales with autistic traits and between the RFQ Other and perspective taking. Conclusions This explorative study is the first testing psychometric properties of the RFQ as a self-report questionnaire for assessing reflective functioning in adults with MBIDs. This step is relevant in gaining more scientific knowledge on assessing mentalising in people with MBIDs.

Background The association between perceived ethnic discrimination (PED) and mental health conditions is well studied. However, less is known about the association between PED and suicidal ideation, or the role of positive psychosocial factors in this association. Aims To examine the association between PED and suicidal ideation among ethnic minority groups in Amsterdam, The Netherlands, and investigate whether ethnicity and mastery (people's extent of feeling in control of their lives and environment) moderate this association. Method Cross-sectional data from the multi-ethnic HELIUS study were analysed (n = 17 053) for participants of South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin. PED was measured using the Everyday Discrimination Scale, suicidal ideation using item 9 of the Patient Health Questionnaire-9 and mastery using the Pearlin–Schooler Mastery Scale. Results Logistic regression analyses demonstrated a small positive association between PED and suicidal ideation (OR = 1.068, 95% CI 1.059–1.077), which did not differ among ethnic minority groups. Mastery did not moderate the association between PED and suicidal ideation among the ethnic minority groups. Conclusions Our findings support the hypothesis that PED is associated with suicidal ideation and this association does not significantly vary between ethnic minority groups. Although higher levels of mastery were associated with lower suicidal ideation, mastery did not moderate the relationship between PED and suicidal ideation. Besides targeting ethnic discrimination as a societal problem, future longitudinal research is needed to investigate whether interventions aimed at improving mastery could reduce suicidal ideation in ethnic minority groups.

Rheumatic diseases, such as osteoarthritis and rheumatoid arthritis, affect over 750 million people worldwide and contribute to approximately 40% of chronic pain cases. Inflammation and tissue damage contribute to pain in rheumatic diseases, but pain often persists even when inflammation/damage is resolved. Mechanisms that cause this persistent pain are still unclear. Mitochondria are essential for a myriad of cellular processes and regulate neuronal functions. Mitochondrial dysfunction has been implicated in multiple neurological disorders, but its role in sensory processing and pain in rheumatic diseases is relatively unexplored. This review provides a comprehensive understanding of how mitochondrial dysfunction connects inflammation and damage-associated pathways to neuronal sensitization and persistent pain. To provide an overall framework on how mitochondria control pain, we explored recent evidence in inflammatory and neuropathic pain conditions. Mitochondria have intrinsic quality control mechanisms to prevent functional deficits and cellular damage. We will discuss the link between neuronal activity, mitochondrial dysfunction and chronic pain. Lastly, pharmacological strategies aimed at reestablishing mitochondrial functions or boosting mitochondrial dynamics as therapeutic interventions for chronic pain are discussed. The evidence presented in this review shows that mitochondria dysfunction may play a role in rheumatic pain. The dysfunction is not restricted to neuronal cells in the peripheral and central nervous system, but also includes blood cells and cells at the joint level that may affect pain pathways indirectly. Pre-clinical and clinical data suggest that modulation of mitochondrial functions can be used to attenuate or eliminate pain, which could be beneficial for multiple rheumatic diseases.

BackgroundChild maltreatment is a common negative experience and has potential long-lasting adverse consequences for mental and physical health, including increased risk for major depressive disorder (MDD) and metabolic syndrome. In addition, child maltreatment may increase the risk for comorbid physical health conditions to psychiatric conditions, with inflammation as an important mediator linking child maltreatment to poor adult health. However, it remains unresolved whether experiencing child maltreatment increases the risk for the development of comorbid metabolic syndrome to MDD. Therefore, we investigated whether child maltreatment increased the risk for comorbid metabolic syndrome to depressed mood. Subsequently, we examined whether C-reactive protein (CRP), as an inflammatory marker, mediated this association. In addition, we investigated whether effects differed between men and women.MethodsAssociations were examined within cross-sectional data from the multiethnic HELIUS study (N = 21,617). Adult residents of Amsterdam, Netherlands, self-reported on child maltreatment (distinct and total number of types experienced before the age of 16 years) as well as current depressed mood (PHQ-9 score ≥ 10), and underwent physical examination to assess metabolic syndrome. The CRP levels were assessed in N = 5,998 participants. Logistic and linear regressions were applied for binary and continuous outcomes, respectively. All analyses were adjusted for relevant demographic, socioeconomic, and lifestyle characteristics, including ethnicity.ResultsA higher number of maltreatment types as well as distinct types of emotional neglect, emotional abuse, and sexual abuse were significantly associated with a higher risk for current depressed mood. Child maltreatment was not significantly associated with the risk for metabolic syndrome in the whole cohort, nor within individuals with depressed mood. As child maltreatment was not significantly associated with the CRP levels, subsequent mediation analyses were not performed. No significant moderating effects by sex were observed.ConclusionIn this multiethnic urban cohort, child maltreatment was associated with a higher risk for depressed mood. Contrary to our expectations, child maltreatment was not significantly associated with an increased risk for metabolic syndrome, neither in the whole cohort nor as a comorbid condition in individuals with depressed mood. As the data were cross-sectional and came from a non-clinical adult population, longitudinal perspectives in relation to various stages of the investigated conditions were needed with more comprehensive assessments of inflammatory markers.

Only very few enzymes are known to catalyze protein histidine methylation. Here, the authors show that METTL9 is responsible for most 1-methylhistidine modifications in mouse and human proteomes, and characterize METTL9′s substrate specificity and potential cellular functions.

Remnant natural forests act as a source of wild pollinators that are potentially relevant for crop pollination for sustaining the food production system of smallholder farms. In the Ethiopian highlands, sacred forests scattered within agricultural landscapes harbour wild pollinators. The contribution of wild pollinators to crop pollination services to surrounding smallholder agricultural farms is largely unknown. In this study, we empirically assessed the effects of Ethiopian church forest habitats on crop flower visitation by pollinators on smallholder farms in Lake Tana basin, Ethiopia. Crop flower visitation rates were recorded in 72 crop fields along distance gradients within a 1500 m buffer zone around 15 church forest patches. We constructed cross-validated generalized additive mixed models (GAMMs) to fit the crop flower visitation rates with fixed effect explanatory variables (distance from forest, forest patch size, forest age, forest functional diversity index, forest proximity index and crop type) that are known to potentially influence pollinator visitation in crop fields. Total flower visitation rates decreased with distance to the forest patches across an agricultural landscape. Visitation rates increased with increasing forest patch size, functional richness, proximity index, and age of church forest patches. Overall, we found that the rate of crop flower visitation varies with pollinator-dependent crop types and wild pollinator groups. An in-depth understanding of the forest biodiversity, cultural value, food security nexus enables the promotion of ongoing church forest stewardship in local and regional policies.

The end of the first working program of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES) provided an opportunity to draw lessons from its work. This perspective paper captures insights from ecosystem services (ES) researchers and practitioners, largely drawing from the European context (referred to herein as ‘ES community’), on this key science–policy interface. We synthesize reflections from a workshop on how (i) IPBES can engage the ES community; (ii) the ES community can engage with IPBES; and (iii) individual scientists can contribute. We note that IPBES constitutes a great advancement towards multidisciplinarity and inclusivity in ES research and practice. Key reflections for IPBES are that funding and visibility at ES research events could be improved, the contribution and selection processes could be more transparent, and communication with experts improved. Key reflections for the ES community include a need to improve policy-relevance by integrating more social scientists, researchers from developing countries, early-career scientists and policy-makers. Key reflections directed towards individual scientists include contributing (pro)actively to science–policy interface initiatives such as IPBES and increasing transdisciplinary research. These reflections intend to contribute to the awareness of challenges and opportunities for institutions, groups and individuals working on ES.

It is crucial to understand the underlying pathophysiology of obstructive sleep apnea (OSA). Upper airway collapsibility is an important pathophysiological factor that affects the upper airway in OSA. The aim of the current study was to review the existing body of knowledge on the pharyngeal collapsibility in OSA. After a thorough search through Medline, PubMed, Scopus, and Web of science, the relevant articles were found and used in this study. Critical closing pressure (Pcrit) is the gold standard measure for the degree of collapsibility of the pharyngeal airway. Various physiological factors and treatments affect upper airway collapsibility. Recently, it has been shown that the baseline value of Pcrit is helpful in the upfront selection of therapy options. The standard techniques to measure Pcrit are labor-intensive and time-consuming. Therefore, despite the importance of Pcrit, it is not routinely measured in clinical practice. New emerging surrogates, such as finite element (FE) modeling or the use of peak inspiratory flow measurements during a routine overnight polysomnography, may enable clinicians to have an estimate of the pharyngeal collapsibility. However, validation of these techniques is needed.

Study Objectives: Obstructive sleep apnea (OSA) is increasingly recognized as a complex and heterogenous disorder. As a result, a “one-size-fits-all” management approach should be avoided. Therefore, evaluation of pathophysiological endotyping in OSA patients is emphasized, with upper airway collapse during sleep as one of the main features. To assess the site(s) and pattern(s) of upper airway collapse, natural sleep endoscopy (NSE) is defined as the gold standard. As NSE is labor-intensive and time-consuming, it is not feasible in routine practice. Instead, drug-induced sleep endoscopy (DISE) is the most frequently used technique and can be considered as the clinical standard. Flow shape and snoring analysis are non-invasive measurement techniques, yet are still evolving. Although DISE is used as the clinical alternative to assess upper airway collapse, associations between DISE and NSE observations, and associated flow and snoring signals, have not been quantified satisfactorily. In the current project we aim to compare upper airway collapse identified in patients with OSA using endoscopic techniques as well as flow shape analysis and analysis of tracheal snoring sounds between natural and drug-induced sleep.Methods: This study is a blinded prospective comparative multicenter cohort study. The study population will consist of adult patients with a recent diagnosis of OSA. Eligible patients will undergo a polysomnography (PSG) with NSE overnight and a DISE within 3 months. During DISE the upper airway is assessed under sedation by an experienced ear, nose, throat (ENT) surgeon using a flexible fiberoptic endoscope in the operating theater. In contrast to DISE, NSE is performed during natural sleep using a pediatric bronchoscope. During research DISE and NSE, the standard set-up is expanded with additional PSG measurements, including gold standard flow and analysis of tracheal snoring sounds.Conclusions: This project will be one of the first studies to formally compare collapse patterns during natural and drug-induced sleep. Moreover, this will be, to the authors' best knowledge, the first comparative research in airflow shape and tracheal snoring sounds analysis between DISE and NSE. These novel and non-invasive diagnostic methods studying upper airway mechanics during sleep will be simultaneously validated against DISE and NSE.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04729478.

A new method for automated sleep stage scoring of polysomnographies is proposed that uses a random forest approach to model feature interactions and temporal effects. The model mostly relies on features based on the rules from the American Academy of Sleep Medicine, which allows medical experts to gain insights into the model. A common way to evaluate automated approaches to constructing hypnograms is to compare the one produced by the algorithm to an expert's hypnogram. However, given the same data, two expert annotators will construct (slightly) different hypnograms due to differing interpretations of the data or individual mistakes. A thorough evaluation of our method is performed on a multi-labeled dataset in which both the inter-rater variability as well as the prediction uncertainties are taken into account, leading to a new standard for the evaluation of automated sleep stage scoring algorithms. On all epochs, our model achieves an accuracy of 82.7%, which is only slightly lower than the inter-rater disagreement. When only considering the 63.3% of the epochs where both the experts and algorithm are certain, the model achieves an accuracy of 97.8%. Transition periods between sleep stages are identified and studied for the first time. Scoring guidelines for medical experts are provided to complement the certain predictions by scoring only a few epochs manually. This makes the proposed method highly time-efficient while guaranteeing a highly accurate final hypnogram.