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Background: Arterial catheters are often used for blood pressure monitoring in the intensive care unit (ICU), but they can cause complications. Non-invasive continuous finger blood pressure monitors could serve as an alternative. However, failure to obtain finger blood pressure signals is reported in up to 12% of ICU patients. Objectives: Our primary objective was to identify the success rate of finger blood pressure monitoring in ICU patients. Secondary objectives were to assess whether patient admission characteristics could be used to identify patients unsuitable for non-invasive blood pressure monitoring and to determine the quality of non-invasive blood pressure waveforms. Methods: Retrospective observational study conducted in a cohort of 499 ICU patients. When available, the signal quality of the first hour of finger measurement was determined using an open-source waveform algorithm. Results: Finger blood pressure signals were obtained in 94% of patients. These patients had a high quality blood pressure waveform for 84% of the measurement time. Patients without a finger blood pressure signal significantly more frequently had a history of kidney and vascular disease, were more often treated with inotropic agents, had lower hemoglobin levels, and had higher arterial lactate levels. Conclusions: Finger blood pressure signals were obtained in nearly all ICU patients. Significant differences in baseline characteristics between patients with and without finger blood pressure signals were found, but they were not clinically relevant. The characteristics studied could therefore not be used to identify patients unsuitable for finger blood pressure monitoring.

Experience sampling studies into daily-life affective reactivity indicate that depressed individuals react more strongly to both positive and negative stimuli than non-depressed individuals, particularly on negative affect (NA). Given the different mean levels of both positive affect (PA) and NA between patients and controls, such findings may be influenced by floor/ceiling effects, leading to violations of the normality and homoscedasticity assumptions underlying the used statistical models. Affect distributions in prior studies suggest that this may have particularly influenced NA-reactivity findings. Here, we investigated the influence of floor/ceiling effects on the observed PA- and NA-reactivity to both positive and negative events. Data came from 346 depressed, non-depressed, and remitted participants from the Netherlands Study of Depression and Anxiety (NESDA). In PA-reactivity analyses, no floor/ceiling effects and assumption violations were observed, and PA-reactivity to positive events, but not negative events, was significantly increased in the depressed and remitted groups versus the non-depressed group. However, NA-scores exhibited a floor effect in the non-depressed group and naively estimated models violated model assumptions. When these violations were accounted for in subsequent analyses, group differences in NA-reactivity that had been present in the naive models were no longer observed. In conclusion, we found increased PA-reactivity to positive events but no evidence of increased NA-reactivity in depressed individuals when accounting for violations of assumptions. The results indicate that affective-reactivity results are very sensitive to modeling choices and that previously observed increased NA-reactivity in depressed individuals may (partially) reflect unaddressed assumption violations resulting from floor effects in NA.

Lifelong graph learning deals with the problem of continually adapting graph neural network (GNN) models to changes in evolving graphs. We address two critical challenges of lifelong graph learning in this work: dealing with new classes and tackling imbalanced class distributions. The combination of these two challenges is particularly relevant since newly emerging classes typically resemble only a tiny fraction of the data, adding to the already skewed class distribution. We make several contributions: First, we show that the amount of unlabeled data does not influence the results, which is an essential prerequisite for lifelong learning on a sequence of tasks. Second, we experiment with different label rates and show that our methods can perform well with only a tiny fraction of annotated nodes. Third, we propose the gDOC method to detect new classes under the constraint of having an imbalanced class distribution. The critical ingredient is a weighted binary cross-entropy loss function to account for the class imbalance. Moreover, we demonstrate combinations of gDOC with various base GNN models such as GraphSAGE, Simplified Graph Convolution, and Graph Attention Networks. Lastly, our k-neighborhood time difference measure provably normalizes the temporal changes across different graph datasets. With extensive experimentation, we find that the proposed gDOC method is consistently better than a naive adaption of DOC to graphs. Specifically, in experiments using the smallest history size, the out-of-distribution detection score of gDOC is 0.09 compared to 0.01 for DOC. Furthermore, gDOC achieves an Open-F1 score, a combined measure of in-distribution classification and out-of-distribution detection, of 0.33 compared to 0.25 of DOC (32% increase)., Accepted manuscript (after peer review, before copy-editing). Published article available at https://doi.org/10.1016/j.neunet.2023.04.022

The aims of this study were to investigate the associations of major depressive disorder (MDD) and its subtypes (atypical, melancholic, combined, unspecified) with actigraphy-derived measures of sleep, physical activity and circadian rhythms; and test the potentially mediating role of sleep, physical activity and circadian rhythms in the well-established associations of the atypical MDD subtype with Body Mass Index (BMI) and the metabolic syndrome (MeS). The sample consisted of 2317 participants recruited from an urban area, who underwent comprehensive somatic and psychiatric evaluations. MDD and its subtypes were assessed via semi-structured diagnostic interviews. Sleep, physical activity and circadian rhythms were measured using actigraphy. MDD and its subtypes were associated with several actigraphy-derived variables, including later sleep midpoint, low physical activity, low inter-daily stability and larger intra-individual variability of sleep duration and relative amplitude. Sleep midpoint and physical activity fulfilled criteria for partial mediation of the association between atypical MDD and BMI, and physical activity also for partial mediation of the association between atypical MDD and MeS. Our findings confirm associations of MDD and its atypical subtype with sleep and physical activity, which are likely to partially mediate the associations of atypical MDD with BMI and MeS, although most of these associations are not explained by sleep and activity variables. This highlights the need to consider atypical MDD, sleep and sedentary behavior as cardiovascular risk factors.

Purpose The added value of measuring patient-reported outcomes (PROs) for delivering patient-centered care and assessment of healthcare quality is increasingly evident. However, healthcare system wide data collection initiatives are hampered by the proliferation of patient-reported outcome measures (PROMs) and conflicting data collection standards. As part of a national initiative of the Dutch Ministry of Health, Welfare and Sport we developed a consensus-based standard set of generic PROs and PROMs to be implemented across Dutch medical specialist care. Methods A working group of mandated representatives of umbrella organizations involved in Dutch medical specialist care, together with PROM experts and patient organizations worked through a structured, consensus-driven co-creation process. This included literature reviews, online expert and working group meetings, and feedback from national patient- and umbrella organizations. The ‘PROM-cycle’ methodology was used to select feasible, valid, and reliable PROMs to obtain domain scores for each of the PROs included in the set. Results Eight PROs across different domains of health were ultimately endorsed: symptoms (pain & fatigue), functioning (physical, social/participation, mental [anxiety & depression]), and overarching (quality of life & perceived overall health). A limited number of generic PROMs was endorsed. PROMIS short forms were selected as the preferred instruments for all PROs. Several recommendations were formulated to facilitate healthcare system level adoption and implementation of the standard set. Conclusions We developed a consensus-based standard set of Generic PROMs and a set of recommendations to facilitate healthcare system wide implementation across Dutch medical specialist care.

Background Major Depressive Disorder (MDD) is a heterogenous brain disorder, with potentially multiple psychosocial and biological disease mechanisms. This is also a plausible explanation for why patients do not respond equally well to treatment with first- or second-line antidepressants, i.e., one-third to one-half of patients do not remit in response to first- or second-line treatment. To map MDD heterogeneity and markers of treatment response to enable a precision medicine approach, we will acquire several possible predictive markers across several domains, e.g., psychosocial, biochemical, and neuroimaging. Methods All patients are examined before receiving a standardised treatment package for adults aged 18–65 with first-episode depression in six public outpatient clinics in the Capital Region of Denmark. From this population, we will recruit a cohort of 800 patients for whom we will acquire clinical, cognitive, psychometric, and biological data. A subgroup (subcohort I, n = 600) will additionally provide neuroimaging data, i.e., Magnetic Resonance Imaging, and Electroencephalogram, and a subgroup of patients from subcohort I unmedicated at inclusion (subcohort II, n = 60) will also undergo a brain Positron Emission Tomography with the [11C]-UCB-J tracer binding to the presynaptic glycoprotein-SV2A. Subcohort allocation is based on eligibility and willingness to participate. The treatment package typically lasts six months. Depression severity is assessed with the Quick Inventory of Depressive Symptomatology (QIDS) at baseline, and 6, 12 and 18 months after treatment initiation. The primary outcome is remission (QIDS ≤ 5) and clinical improvement (≥ 50% reduction in QIDS) after 6 months. Secondary endpoints include remission at 12 and 18 months and %-change in QIDS, 10-item Symptom Checklist, 5-item WHO Well-Being Index, and modified Disability Scale from baseline through follow-up. We also assess psychotherapy and medication side-effects. We will use machine learning to determine a combination of characteristics that best predict treatment outcomes and statistical models to investigate the association between individual measures and clinical outcomes. We will assess associations between patient characteristics, treatment choices, and clinical outcomes using path analysis, enabling us to estimate the effect of treatment choices and timing on the clinical outcome. Discussion The BrainDrugs-Depression study is a real-world deep-phenotyping clinical cohort study of first-episode MDD patients. Trial Registration Registered at clinicaltrials.gov November 15th, 2022 (NCT05616559).

Most existing TWAS tools require individual-level eQTL reference data and thus are not applicable to summary-level reference eQTL datasets. The development of TWAS methods that can harness summary-level reference data is valuable to enable TWAS in broader settings and enhance power due to increased reference sample size. Thus, we develop a TWAS framework called OTTERS (Omnibus Transcriptome Test using Expression Reference Summary data) that adapts multiple polygenic risk score (PRS) methods to estimate eQTL weights from summary-level eQTL reference data and conducts an omnibus TWAS. We show that OTTERS is a practical and powerful TWAS tool by both simulations and application studies. Godkänd;2023;Nivå 0;2023-04-06 (hanlid);Funder: for more funders see the article https://doi.org/10.1038/s41467-023-36862-w

Background Physical activity (PA) levels might be a simple overall physical function indicator of recovery in acutely hospitalized older adults; however it is unknown which amount and level of PA is associated with recovery. Our objective was to evaluate the amount and level of post discharge PA and its optimum cut-off values associated with recovery among acutely hospitalized older adults and stratified for frailty. Methods We performed a prospective observational cohort study including acutely hospitalized older adults (≥ 70 years). Frailty was assessed using Fried’s criteria. PA was assessed using Fitbit up to one week post discharge and quantified in steps and minutes light, moderate or higher intensity. The primary outcome was recovery at 3-months post discharge. ROC-curve analyses were used to determine cut-off values and area under the curve (AUC), and logistic regression analyses to calculate odds ratios (ORs). Results The analytic sample included 174 participants with a mean (standard deviation) age of 79.2 (6.7) years of whom 84/174 (48%) were frail. At 3-months, 109/174 participants (63%) had recovered of whom 48 were frail. In all participants, determined cut-off values were 1369 steps/day (OR: 2.7, 95% confidence interval [CI]: 1.3–5.9, AUC 0.7) and 76 min/day of light intensity PA (OR: 3.9, 95% CI: 1.8–8.5, AUC 0.73). In frail participants, cut-off values were 1043 steps/day (OR: 5.0, 95% CI: 1.7–14.8, AUC 0.72) and 72 min/day of light intensity PA (OR: 7.2, 95% CI: 2.2–23.1, AUC 0,74). Determined cut-off values were not significantly associated with recovery in non-frail participants. Conclusions Post-discharge PA cut-offs indicate the odds of recovery in older adults, especially in frail individuals, however are not equipped for use as a diagnostic test in daily practice. This is a first step in providing a direction for setting rehabilitation goals in older adults after hospitalization.

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

Background Major depressive disorder (MDD) is a heterogeneous psychiatric disorder. Childhood trauma (CT, emotional/physical/sexual abuse or neglect before the age of 18) is one of the largest and most consistent risk factors for development and poor course of MDD. Overactivity of the HPA-axis and the stress hormone cortisol is thought to play a role in the vulnerability for MDD following exposure to CT. Rodent experiments showed that antagonism of the glucocorticoid receptor (GR) at adult age reversed the effects of early life stress. Similarly, we aim to target MDD in individuals with CT exposure using the GR antagonist mifepristone. Methods The RESET-medication study is a placebo-controlled double-blind randomized controlled trial (RCT) which aims to include 158 adults with MDD and CT. Participants will be randomized (1:1) to a 7-day treatment arm of mifepristone (1200 mg/day) or a control arm (placebo). Participants are allowed to receive usual care for MDD including antidepressants. Measurements include three face-to-face meetings at baseline (T0), day 8 (T1), week 6 (T2), and two online follow-up meetings at 12 weeks (T3) and 6 months (T4). A subgroup of participants (N = 80) are included in a fMRI sub-study (T0, T2). The main study outcome will be depressive symptom severity as measured with the Inventory of Depressive Symptomatology—Self Rated (IDS-SR) at T2. Secondary outcomes include, among others, depressive symptom severity at other time points, disability, anxiety, sleep and subjective stress. To address underlying mechanisms mifepristone plasma levels, cortisol, inflammation, epigenetic regulation and fMRI measurements are obtained. Discussion The RESET-medication study will provide clinical evidence whether GR antagonism is a disease-modifying treatment for MDD in individuals exposed to CT. If effective, this hypothesis-driven approach may extend to other psychiatric disorders where CT plays an important role. Trial registration The trial protocol has been registered 01–02-2022 on ClinicalTrials.gov with ID “NCT05217758”.

The diagnostic accuracy of a screening tool is often characterized by its sensitivity and specificity. An analysis of these measures must consider their intrinsic correlation. In the context of an individual participant data meta-analysis, heterogeneity is one of the main components of the analysis. When using a random-effects meta-analytic model, prediction regions provide deeper insight into the effect of heterogeneity on the variability of estimated accuracy measures across the entire studied population, not just the average. This study aimed to investigate heterogeneity via prediction regions in an individual participant data meta-analysis of the sensitivity and specificity of the Patient Health Questionnaire-9 for screening to detect major depression. From the total number of studies in the pool, four dates were selected containing roughly 25%, 50%, 75% and 100% of the total number of participants. A bivariate random-effects model was fitted to studies up to and including each of these dates to jointly estimate sensitivity and specificity. Two-dimensional prediction regions were plotted in ROC-space. Subgroup analyses were carried out on sex and age, regardless of the date of the study. The dataset comprised 17,436 participants from 58 primary studies of which 2322 (13.3%) presented cases of major depression. Point estimates of sensitivity and specificity did not differ importantly as more studies were added to the model. However, correlation of the measures increased. As expected, standard errors of the logit pooled TPR and FPR consistently decreased as more studies were used, while standard deviations of the random-effects did not decrease monotonically. Subgroup analysis by sex did not reveal important contributions for observed heterogeneity; however, the shape of the prediction regions differed. Subgroup analysis by age did not reveal meaningful contributions to the heterogeneity and the prediction regions were similar in shape. Prediction intervals and regions reveal previously unseen trends in a dataset. In the context of a meta-analysis of diagnostic test accuracy, prediction regions can display the range of accuracy measures in different populations and settings.

Background: Thoracic ultrasound is a valuable tool that helps diagnose cardiopulmonary disorders and guide management in intensive care unit patients. Intensive care unit nurses were trained to perform thoracic ultrasound examinations, after which they were named ‘UltraNurses’ for clinical recognizability. UltraNurses demonstrated rapid learning trajectories, but the impact on clinical-decision making remained unknown. The aim of this study was to investigate the effects of UltraNurse ultrasound on clinical management. Methods: This was a prospective observational single center study within a mixed medical and surgical intensive care unit. All adult patients with an indication for UltraNurse thoracic ultrasound were included. The study consisted of three steps: pre- and post- data collection, with the ultrasound examination conducted in-between these two steps. The examination consisted of a standardized ultrasound protocol aimed at the lungs and cardiac output. Primary outcome was what percentage of ultrasounds led to a change of management. Secondary outcomes included: percentage of changes executed within first 8 hours, frequency of pathology found, percentage of diagnosis change, and frequency of UltraNurse ultrasounds per shift. Results: A total of 102 ultrasound examinations were performed in 65 patients (89% mechanically-ventilated). Ultrasound examinations suggested changes of management in 26% of cases, of which 96% were executed within 8 hours. Most changes were within the nursing scope (56%), specifically: 44% of examinations changed fluid management. UltraNurse ultrasound detected pathology in 97% of cases. In 7% of cases, the diagnosis was changed, sometimes leading to life-saving interventions. UltraNurses performed one thoracic ultrasound examination per four shifts. Conclusion: In adult intensive care unit patients, UltraNurse thoracic ultrasound led to a change of management in more than a quarter of the cases, of which almost all were executed within the first 8 hours. Study registration: Netherlands Trial Registration NL9047, VUmc 2020.011

Introduction The Semantic Web community provides a common Resource Description Framework (RDF) that allows representation of resources such that they can be linked. To maximize the potential of linked data - machine-actionable interlinked resources on the Web - a certain level of quality of RDF resources should be established, particularly in the biomedical domain in which concepts are complex and high-quality biomedical ontologies are in high demand. However, it is unclear which quality metrics for RDF resources exist that can be automated, which is required given the multitude of RDF resources. Therefore, we aim to determine these metrics and demonstrate an automated approach to assess such metrics of RDF resources. Methods An initial set of metrics are identified through literature, standards, and existing tooling. Of these, metrics are selected that fulfil these criteria: (1) objective; (2) automatable; and (3) foundational. Selected metrics are represented in RDF and semantically aligned to existing standards. These metrics are then implemented in an open-source tool. To demonstrate the tool, eight commonly used RDF resources were assessed, including data models in the healthcare domain (HL7 RIM, HL7 FHIR, CDISC CDASH), ontologies (DCT, SIO, FOAF, ORDO), and a metadata profile (GRDDL). Results Six objective metrics are identified in 3 categories: Resolvability (1), Parsability (1), and Consistency (4), and represented in RDF. The tool demonstrates that these metrics can be automated, and application in the healthcare domain shows non-resolvable URIs (ranging from 0.3% to 97%) among all eight resources and undefined URIs in HL7 RIM, and FHIR. In the tested resources no errors were found for parsability and the other three consistency metrics for correct usage of classes and properties. Conclusion We extracted six objective and automatable metrics from literature, as the foundational quality requirements of RDF resources to maximize the potential of linked data. Automated tooling to assess resources has shown to be effective to identify quality issues that must be avoided. This approach can be expanded to incorporate more automatable metrics so as to reflect additional quality dimensions with the assessment tool implementing more metrics.

Background Major depressive disorder (MDD) is a common, recurrent mental disorder and a leading cause of disability worldwide. A large part of adult MDD patients report a history of childhood trauma (CT). Patients with MDD and CT are assumed to represent a clinically and neurobiologically distinct MDD subtype with an earlier onset, unfavorable disease course, stress systems’ dysregulations and brain alterations. Currently, there is no evidence-based treatment strategy for MDD that specifically targets CT. Given the central role of trauma in MDD patients with CT, trauma-focused therapy (TFT), adjunctive to treatment as usual (TAU), may be efficacious to alleviate depressive symptoms in this patient population. Methods The RESET-psychotherapy study is a 12-week, single-blind, randomized controlled trial testing the efficacy of TFT in 158 adults with moderate to severe MDD, as a ‘stand-alone’ depression diagnosis or superimposed on a persistent depressive disorder (PDD), and CT. TFT (6–10 sessions of Eye Movement Desensitization and Reprocessing and/or imagery rescripting) + TAU is compared to TAU only. Assessments, including a wide range of psychological/psychiatric and biological characteristics, take place before randomization (T0), during treatment (T1), at post-treatment (T2) and at 6-month follow-up (T3). Pre-post treatment stress-related biomarkers in hair (cortisol) and blood (epigenetics and inflammation) will be assessed to better understand working mechanisms of TFT. A subgroup of 60 participants will undergo structural and functional Magnetic Resonance Imaging (MRI) assessments to determine pre-post treatment brain activity. The primary outcome is self-reported depression symptom severity at post-treatment, measured with the 30-item Inventory of Depressive Symptomatology – Self Report (IDS-SR). Discussion If adjunctive TFT efficaciously alleviates depressive symptoms in MDD patients with CT, this novel treatment strategy could pave the way for a more personalized and targeted MDD treatment. Trial registration ClinicalTrials.gov, registered at 08–12-2021, number of identification: NCT05149352.

This study is a simple illustration of the benefit of averaging over cohorts, rather than developing a prediction model from a single cohort. We show that models trained on data from multiple cohorts can perform significantly better in new settings than models based on the same amount of training data but from just a single cohort. Although this concept seems simple and obvious, no current prediction model development guidelines recommend such an approach.

BackgroundDepression during pregnancy and after the birth of a child is highly prevalent and an important public health problem. Psychological interventions are the first-line treatment and, although a considerable number of randomized trials have been conducted, no recent comprehensive meta-analysis has evaluated treatment effects.MethodsWe used an existing database of randomized controlled trials of psychotherapies for adult depression and included studies aimed at perinatal depression. Random effects models were used in all analyses. We examined the effects of the interventions in the short and long term, and also examined secondary outcomes.ResultsForty-three studies with 49 comparisons and 6270 participants between an intervention and control group were included. The overall effect size was g = 0.67 [95% confidence interval (CI) 0.45~0.89; numbers needed-to-be-treated = 4.39] with high heterogeneity (I2 = 80%; 95% CI 75~85). This effect size remained largely unchanged and significant in a series of sensitivity analyses, although some publication bias was found. The effects remained significant at 6–12 months follow-up. Significant effects were also found for social support, anxiety, functional limitations, parental stress and marital stress, although the number of studies for each outcome was low. All results should be considered with caution because of the high levels of heterogeneity in most analyses.ConclusionsPsychological interventions are probably effective in the treatment of perinatal depression, with effects that last at least up to 6–12 months and probably also have effects on social support, anxiety, functional impairment, parental stress, and marital stress.

Objective:Birth weight, fetal growth and placental function influence cognitive development. The gradient of these associations is understudied, especially among those with a birth weight considered appropriate-for-gestational age. The aim of this study was to evaluate the associations between birth-weight centile and intellectual development in term/near-term infants across the entire birth-weight spectrum, in order to provide a basis for better understanding of the long-term implications of fetal growth restriction and reduced placental function.Methods:This was a population-based cohort study of 266 440 liveborn singletons from uncomplicated pregnancies, delivered between 36 and 42 weeks of gestation. Perinatal data were obtained from the Dutch Perinatal Registry over the period 2003–2008 and educational data for children aged approximately 12 years were obtained from Statistics Netherlands over the period 2016–2019. Regression analyses were conducted to assess the association of birth-weight centile with school performance. The primary outcomes were mean school performance score, on a scale of 501–550, and proportion of children who reached higher secondary school level.Results:Mean school performance score increased gradually with increasing birth-weight centile, from 533.6 in the 1st–5th birth-weight-centile group to 536.8 in the 81st–85th birth-weight-centile group. Likewise, the proportion of children at higher secondary school level increased with birth-weight centile, from 43% to 57%. Compared with the 81st–85th birth-weight-centile group, mean school performance score and proportion of children at higher secondary school level were significantly lower in all birth-weight-centile groups below the 80th centile, after adjusting for confounding factors.Conclusions:Birth-weight centile is associated positively with school performance at 12 years of age across the entire birth-weight spectrum, well beyond the conventional and arbitrary cut-offs for suspected fetal growth restriction. This underlines the importance of developing better tools to diagnose fetal growth restriction and reduced placental function, and to identify those at risk for associated short- and long-term consequences. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVES: The aim of this study was to evaluate employee return-to-work (RTW) rates and examine predictors of absence duration after COVID-19. RTW rates were referenced against RTW rates after absence due to flu-like symptoms and assessed over the course of the pandemic. METHODS: Routinely collected data from a nationally operating Dutch occupational health service was used. The data were retrieved from employees who reported sick due to COVID-19 (N=30 396) or flu-like symptoms (N=15 862). Data consisted of responses to a triage survey combined with longitudinal register-based information on sickness absence. RTW rates after COVID-19 were evaluated through Kaplan-Meier estimates and compared to RTW rates for flu-like symptoms, and between three periods with different dominant virus variants. Predictors for absence duration were examined through Cox proportional hazards models. RESULTS: RTW after COVID-19 was found to be notably later than after flu-like symptoms (median RTW=10 versus 6 days, respectively). On average, 5.5% of employees who contracted COVID-19 were absent for over 12 weeks. Time-to-RTW shortened as different virus variants became dominant over time. The main predictors contributing to later RTW were older age, female sex, belonging to a risk group, and the symptoms shortness of breath and fatigue. CONCLUSIONS: Estimates of the RTW rate after COVID-19 and identification of predictors may aid healthcare professionals in gaining insight into variations in the disease course and rehabilitation process. The present findings can help employers and policy-makers grasp the impact of COVID-19 on the workplace.

Background Telephone triage is fully integrated in Dutch out-of-hours primary care (OOH-PC). Patients presenting with chest pain are initially assessed according to a standardized protocol (“Netherlands Triage Standard” [NTS]). Nevertheless, little is known about its (diagnostic) performance, nor on the impact of subsequent clinical judgements made by triage assistants and general practitioners (GPs). Objective To evaluate the performance of the current NTS chest pain protocol. Methods Observational, retrospective cohort study of adult patients with chest pain who contacted a regional OOH-PC facility in the Netherlands, in 2017. The clinical outcome measure involved the occurrence of a “major event,” which is a composite of all-cause mortality and urgent cardiovascular and noncardiovascular conditions, occurring ≤6 weeks of initial contact. We assessed the performance using diagnostic and discriminatory properties. Results In total, 1,803 patients were included, median age was 54.0 and 57.5% were female. Major events occurred in 16.2% of patients with complete follow-up, including 99 (6.7%) cases of acute coronary syndrome and 22 (1.5%) fatal events. NTS urgency assessment showed moderate discriminatory abilities for predicting major events (c-statistic 0.66). Overall, NTS performance showed a sensitivity and specificity of 83.0% and 42.4% with a 17.0% underestimated major event rate. Triage assistants’ revisions hardly improved urgency allocation. Further consideration of the clinical course following OOH-PC contact did generate a more pronounced improvement with a sensitivity of 89.4% and specificity of 61.9%. Conclusion Performance of telephone triage of chest pain appears moderate at best, with acceptable safety yet limited efficiency, even after including further work-up by GPs.

Objective: To assess whether migraine may be genetically and/or causally associated with inflammatory bowel disease (IBD) or celiac disease. Background: Migraine has been linked to IBD and celiac disease in observational studies, but whether this link may be explained by a shared genetic basis or could be causal has not been established. The presence of a causal association could be clinically relevant, as treating one of these medical conditions might mitigate the symptoms of a causally linked condition. Methods: Linkage disequilibrium score regression and two-sample bidirectional Mendelian randomization analyses were performed using summary statistics from cohort-based genome-wide association studies of migraine (59,674 cases; 316,078 controls), IBD (25,042 cases; 34,915 controls) and celiac disease (11,812 or 4533 cases; 11,837 or 10,750 controls). Migraine with and without aura were analyzed separately, as were the two IBD subtypes Crohn's disease and ulcerative colitis. Positive control analyses and conventional Mendelian randomization sensitivity analyses were performed. Results: Migraine was not genetically correlated with IBD or celiac disease. No evidence was observed for IBD (odds ratio [OR] 1.00, 95% confidence interval [CI] 0.99-1.02, p = 0.703) or celiac disease (OR 1.00, 95% CI 0.99-1.02, p = 0.912) causing migraine or migraine causing either IBD (OR 1.08, 95% CI 0.96-1.22, p = 0.181) or celiac disease (OR 1.08, 95% CI 0.79-1.48, p = 0.614) when all participants with migraine were analyzed jointly. There was some indication of a causal association between celiac disease and migraine with aura (OR 1.04, 95% CI 1.00-1.08, p = 0.045), between celiac disease and migraine without aura (OR 0.95, 95% CI 0.92-0.99, p = 0.006), as well as between migraine without aura and ulcerative colitis (OR 1.15, 95% CI 1.02-1.29, p = 0.025). However, the results were not significant after multiple testing correction. Conclusions: We found no evidence of a shared genetic basis or of a causal association between migraine and either IBD or celiac disease, although we obtained some indications of causal associations with migraine subtypes. Keywords: Mendelian randomization; celiac disease; gastrointestinal disease; genetic correlation; inflammatory bowel disease; migraine.

Participatory action research (PAR) is a form of community-driven qualitative research which aims to collaboratively take action to improve participants’ lives. This is generally achieved through cognitive, reflexive learning cycles, whereby people ultimately enhance their wellbeing. This approach builds on two assumptions: (1) participants are able to reflect on and prioritize difficulties they face; (2) collective impetus and action are progressively achieved, ultimately leading to increased wellbeing. This article complicates these assumptions by analyzing a two-year PAR project with mothers of disabled children from a South African urban settlement. Participant observation notes, interviews, and a group discussion served as primary data. We found that mothers’ severe psychological stress and the strong intersectionality of their daily challenges hampered participation. Consequently, mothers considered the project ‘inactionable’. Yet, many women quickly started expressing important individual and collective wellbeing transformations. To understand these ‘unlikely’ transformations, a feminist relational account, in particular, that of relational wellbeing, proves essential. We reflect on the consequences of these findings for the dominant PAR methodology and operationalization, and propose to sensitize future PAR with marginalized women by employing relational wellbeing as an overarching ontological awareness.

Addition of placental histopathology studies to obstetric trials is likely to be cost-effective and may reveal structural changes suggestive of functional dysfunction to explain the success or failure of a clinical intervention. We share our recent experience in adding placental pathological examination to two clinical trials, retrospectively in one and at the outset in the other, so that other clinical trial investigators may benefit from it. The practical issues can be summarised as being regulatory and ethical, operational and reporting. Prospective inclusion of placental pathological examination as part of a clinical trial protocol is easier than retrospective, and is facilitated by fully-costed funding.

Background and Aims Paediatric inflammatory bowel disease [IBD] is characterized by altered immunological and metabolic pathways. Metabolomics may therefore increase pathophysiological understanding and could develop into characterization of biomarkers for diagnosis and IBD treatment response. However, no uniform metabolomic profiles have been identified to date. This systematic review aimed to identify faecal metabolomic signatures in paediatric IBD vs controls, and to describe metabolites associated with disease activity and treatment response. Methods A literature search was performed in Embase, Medline, Web of Science and Cochrane Library. Studies assessing faecal metabolomics in paediatric patients < 18 years with IBD [de novo, active, inactive] with comparative groups [IBD vs non-IBD; responders vs non-responders] were included. The quality of included studies was assessed according to the Newcastle–Ottawa Scale. Results Nineteen studies were included [540 patients with IBD, 386 controls], assessing faecal short-chain fatty acids [SCFA] [five studies], amino acids [AA] [ten studies], bile acids [BA] [eight studies] and other metabolites [nine studies] using various methodologies. Significantly increased levels of AA [particularly phenylalanine], primary BA and lower levels of secondary BA were described in paediatric IBD compared to controls. Faecal SCFA results varied across studies. Additionally, responders and non-responders to exclusive enteral nutrition and infliximab showed differences in baseline faecal metabolites [based on BA, AA]. Conclusions This systematic review provides evidence for distinct faecal metabolomic profiles in paediatric IBD. However, results varied across studies, possibly due to differences in study design and applied analytical techniques. Faecal metabolomics could provide more insight into host–microbial interactions in IBD, but further studies with standardized methodologies and reporting are needed.

BackgroundThe COVIH study is a prospective coronavirus disease 2019 (COVID-19) vaccination study in 1154 people with HIV (PWH), of whom 14% showed reduced antibody levels after primary vaccination. We evaluated whether an additional vaccination boosts immune responses in these hyporesponders.MethodsThe primary end point was the increase in antibodies 28 days after additional mRNA-1273 vaccination. Secondary end points included neutralizing antibodies, S-specific T-cell and B-cell responses, and reactogenicity.ResultsOf the 66 participants, 40 previously received 2 doses ChAdOx1-S, 22 received 2 doses BNT162b2, and 4 received a single dose Ad26.COV2.S. The median age was 63 years (interquartile range [IQR], 60–66), 86% were male, and median CD4+ T-cell count was 650/μL (IQR, 423–941). The mean S1-specific antibody level increased from 35 binding antibody units (BAU)/mL (95% confidence interval [CI], 24–46) to 4317 BAU/mL (95% CI, 3275–5360) (P < .0001). Of all participants, 97% showed an adequate response and the 45 antibody-negative participants all seroconverted. A significant increase in the proportion of PWH with ancestral S-specific CD4+ T cells (P = .04) and S-specific B cells (P = .02) was observed.ConclusionsAn additional mRNA-1273 vaccination induced a robust serological response in 97% of PWH with a hyporesponse after primary vaccination.Clinical Trials Registration. EUCTR2021-001054-57-N.

Background: Existing studies on disease course usually apply relatively short follow-up periods and narrow definitions of disease course resulting in too optimistic views on disease prognosis. This study explores the relevance of using a longer and broader (cross-disorder) perspective. Methods: Respondents with a 12-month disorder at baseline and available at 3-, 6- and 9-year follow-up were selected (major depressive disorder, MDD: n = 208; anxiety disorder: n = 220) from a general population study (N = 6646). DSM-IV disorders were assessed with the Composite International Diagnostic Interview. Disease course was described using a short and narrow perspective (i.e., 3-year follow-up, and considering presence of the index disorder only) and a long and broad perspective (9-year follow-up, and considering presence of any mood, anxiety or substance use disorder as outcome). Results: The recovery rates of both MDD and anxiety disorder reduced by half when the perspective switched from short and narrow (MDD: 74.0 %; anxiety disorder: 79.5 %) to long and broad (35.6 % and 40.0 % respectively). At 9-year follow-up, the rates of a persistent disorder (a disorder at each follow-up assessment) tripled when the perspective switched from narrow to broad (MDD: from 4.8 % to 13.9 %; anxiety disorder: from 4.5 % to 15.5 %). Limitations: The findings are not generalizable to the most severe depressed and anxious patients. Conclusions: Most people with MDD or anxiety disorder in the general population have a rather favourable prognosis when a narrow perspective is applied, but an unfavourable prognosis when a long-term and broad perspective is applied. Consequently, MDD and anxiety disorder should not merely be perceived as episodic disorders, and require longer-term disease monitoring and management.

BackgroundDietary interventions did not prevent depression onset nor reduced depressive symptoms in a large multi-center randomized controlled depression prevention study (MooDFOOD) involving overweight adults with subsyndromal depressive symptoms. We conducted follow-up analyses to investigate whether dietary interventions differ in their effects on depressive symptom profiles (mood/cognition; somatic; atypical, energy-related).MethodsBaseline, 3-, 6-, and 12-month follow-up data from MooDFOOD were used (n = 933). Participants received (1) placebo supplements, (2) food-related behavioral activation (F-BA) therapy with placebo supplements, (3) multi-nutrient supplements (omega-3 fatty acids and a multi-vitamin), or (4) F-BA therapy with multi-nutrient supplements. Depressive symptom profiles were based on the Inventory of Depressive Symptomatology.ResultsF-BA therapy was significantly associated with decreased severity of the somatic (B = −0.03, p = 0.014, d = −0.10) and energy-related (B = −0.08, p = 0.001, d = −0.13), but not with the mood/cognition symptom profile, whereas multi-nutrient supplementation was significantly associated with increased severity of the mood/cognition (B = 0.05, p = 0.022, d = 0.09) and the energy-related (B = 0.07, p = 0.002, d = 0.12) but not with the somatic symptom profile.ConclusionsDifferentiating depressive symptom profiles indicated that food-related behavioral interventions are most beneficial to alleviate somatic symptoms and symptoms of the atypical, energy-related profile linked to an immuno-metabolic form of depression, although effect sizes were small. Multi-nutrient supplements are not indicated to reduce depressive symptom profiles. These findings show that attention to clinical heterogeneity in depression is of importance when studying dietary interventions.

STUDY OBJECTIVE: To compare the prognostic accuracy of clinical judgment for frailty in older patients at the emergency department with a validated screening instrument and patient-perceived frailty.METHODS: A prospective cohort study in patients 70 years of age and older in 2 Dutch EDs with a follow-up of 3 months. A dichotomous question was asked to the physician and patient: "Do you consider the patient / yourself to be frail?" The Identification of Seniors At Risk-Hospitalized Patients (ISAR-HP) was used as a validated screening instrument. The primary composite outcome consisted of either functional decline, institutionalization, or mortality.RESULTS: A total of 736 patients were included. The physician identified 59% as frail, compared with 49% by ISAR-HP and 43% by patients themselves. The level of agreement was fair (Fleiss Kappa, 0.31). After 3 months, 31% of the patients experienced at least 1 adverse health outcome. The sensitivity was 79% for the physician, 72% for ISAR-HP, 61% for the patient, and 48% for all 3 combined. The specificity was 50% for the physician, 63% for ISAR-HP, 66% for the patient, and 85% for all 3 positive. The highest positive likelihood ratio was 3.03 (physician, ISAR-HP, patient combined), and the lowest negative likelihood ratio was 0.42 (physician). The areas under the receiver operating curves were all poor: 0.68 at best for ISAR-HP.CONCLUSION: Clinical judgment for frailty showed fair agreement with a validated screening instrument and patient-perceived frailty. All 3 instruments have poor prognostic accuracy, which does not improve when combined. These findings illustrate the limited prognostic value of clinical judgment as a frailty screener in older patients at the ED.

Background: Childhood trauma is a common and potent risk factor for developing major depressive disorder in adulthood, associated with earlier onset, more chronic or recurrent symptoms, and greater probability of having comorbidities. Some studies indicate that evidence-based pharmacotherapies and psychotherapies for adult depression might be less efficacious in patients with a history of childhood trauma than patients without childhood trauma, but findings are inconsistent. Therefore, we examined whether individuals with major depressive disorder, including chronic forms of depression, and a reported history of childhood trauma, had more severe depressive symptoms before treatment, had more unfavourable treatment outcomes following active treatments, and were less likely to benefit from active treatments relative to a control condition, compared with individuals with depression without childhood trauma. Methods: We did a comprehensive meta-analysis (PROSPERO CRD42020220139). Study selection combined the search of bibliographical databases (PubMed, PsycINFO, and Embase) from Nov 21, 2013, to March 16, 2020, and full-text randomised clinical trials (RCTs) identified from several sources (1966 up to 2016–19) to identify articles in English. RCTs and open trials comparing the efficacy or effectiveness of evidence-based pharmacotherapy, psychotherapy, or combination intervention for adult patients with depressive disorders and the presence or absence of childhood trauma were included. Two independent researchers extracted study characteristics. Group data for effect-size calculations were requested from study authors. The primary outcome was depression severity change from baseline to the end of the acute treatment phase, expressed as standardised effect size (Hedges' g). Meta-analyses were done using random-effects models. Findings: From 10 505 publications, 54 trials met the inclusion criteria, of which 29 (20 RCTs and nine open trials) contributed data of a maximum of 6830 participants (age range 18–85 years, male and female individuals and specific ethnicity data unavailable). More than half (4268 [62%] of 6830) of patients with major depressive disorder reported a history of childhood trauma. Despite having more severe depression at baseline (g=0·202, 95% CI 0·145 to 0·258, I2=0%), patients with childhood trauma benefitted from active treatment similarly to patients without childhood trauma history (treatment effect difference between groups g=0·016, –0·094 to 0·125, I2=44·3%), with no significant difference in active treatment effects (vs control condition) between individuals with and without childhood trauma (childhood trauma g=0·605, 0·294 to 0·916, I2=58·0%; no childhood trauma g=0·178, –0·195 to 0·552, I2=67·5%; between-group difference p=0·051), and similar dropout rates (risk ratio 1·063, 0·945 to 1·195, I2=0%). Findings did not significantly differ by childhood trauma type, study design, depression diagnosis, assessment method of childhood trauma, study quality, year, or treatment type or length, but differed by country (North American studies showed larger treatment effects for patients with childhood trauma; false discovery rate corrected p=0·0080). Most studies had a moderate to high risk of bias (21 [72%] of 29), but the sensitivity analysis in low-bias studies yielded similar findings to when all studies were included. Interpretation: Contrary to previous studies, we found evidence that the symptoms of patients with major depressive disorder and childhood trauma significantly improve after pharmacological and psychotherapeutic treatments, notwithstanding their higher severity of depressive symptoms. Evidence-based psychotherapy and pharmacotherapy should be offered to patients with major depressive disorder regardless of childhood trauma status. Funding: None.

Background This study aimed to compare laparoscopic lavage and sigmoidectomy as treatment for perforated diverticulitis with purulent peritonitis during a 36 month follow-up of the LOLA trial. Methods Within the LOLA arm of the international, multicentre LADIES trial, patients with perforated diverticulitis with purulent peritonitis were randomised between laparoscopic lavage and sigmoidectomy. Outcomes were collected up to 36 months. The primary outcome of the present study was cumulative morbidity and mortality. Secondary outcomes included reoperations (including stoma reversals), stoma rates, and sigmoidectomy rates in the lavage group. Results Long-term follow-up was recorded in 77 of the 88 originally included patients, 39 were randomised to sigmoidectomy (51%) and 38 to laparoscopic lavage (49%). After 36 months, overall cumulative morbidity (sigmoidectomy 28/39 (72%) versus lavage 32/38 (84%), p = 0·272) and mortality (sigmoidectomy 7/39 (18%) versus lavage 6/38 (16%), p = 1·000) did not differ. The number of patients who underwent a reoperation was significantly lower for lavage compared to sigmoidectomy (sigmoidectomy 27/39 (69%) versus lavage 17/38 (45%), p = 0·039). After 36 months, patients alive with stoma in situ was lower in the lavage group (proportion calculated from the Kaplan–Meier life table, sigmoidectomy 17% vs lavage 11%, log-rank p = 0·0268). Eventually, 17 of 38 (45%) patients allocated to lavage underwent sigmoidectomy. Conclusion Long-term outcomes showed that laparoscopic lavage was associated with less patients who underwent reoperations and lower stoma rates in patients alive after 36 months compared to sigmoidectomy. No differences were found in terms of cumulative morbidity or mortality. Patient selection should be improved to reduce risk for short-term complications after which lavage could still be a valuable treatment option. Graphical abstract

Background: Infection control practitioners face several challenges when implementing infection control link nurse (ICLN) programmes. Identification of strategies to address these can improve the impact of current ICLN programmes and guide their future implementation. Aim: We aimed to identify implementation strategies for ICLN programmes in acute-care hospitals with the Consolidated Framework for Implementation Research (CFIR)-Expert Recommendations for Implementing Change (ERIC) Implementation Strategy Matching tool. Methods: An expert panel matched 19 implementation and sustainment barriers, identified in our previous studies, to the most fitting CFIR constructs. Subsequently, we applied the CFIR-ERIC Matching Tool and generated a list of implementation strategies to address these barriers. Findings: Barriers were predominantly found within the CFIR domains ‘inner setting’ (characteristics of the implementing organization) and ‘process’ (stages of implementation). With the ERIC Matching Tool, we identified the 10 most important strategies to address barriers of implementation of ICLN programmes: identify and prepare champions, conduct local consensus discussions, assess for readiness and identify barriers and facilitators, inform local opinion leaders, use facilitation, create a learning collaborative, conduct local needs assessments, develop a formal implementation blueprint, build a coalition, and identify early adopters. Conclusion: The CFIR domains ‘inner setting’ and ‘process’ appeared to be the most important to impede implementation of ICLN programmes in acute-care hospitals. Application of the CFIR-ERIC tool highlighted the identification and preparation of champions as the leading strategy for the successful implementation of these programmes. With this tool, strategies can be specifically tailored towards local implementation and sustainment barriers.

Children with traumatic brain injury are at risk of neurocognitive and behavioural impairment. Although there is evidence for abnormal brain activity in resting-state networks after TBI, the role of resting-state network organisation in paediatric TBI outcome remains poorly understood. This study is the first to investigate the impact of paediatric TBI on resting-state network organisation using graph theory, and its relevance for functional outcome. Participants were 8–14 years and included children with (i) mild TBI and risk factors for complicated TBI (mildRF+, n = 20), (ii) moderate/severe TBI (n = 15), and (iii) trauma control injuries (n = 27). Children underwent resting-state functional magnetic resonance imaging (fMRI), neurocognitive testing, and behavioural assessment at 2.8 years post-injury. Graph theory was applied to fMRI timeseries to evaluate the impact of TBI on global and local organisation of the resting-state network, and relevance for neurocognitive and behavioural functioning. Children with TBI showed atypical global network organisation as compared to the trauma control group, reflected by lower modularity (mildRF + TBI and moderate/severe TBI), higher smallworldness (mildRF + TBI) and lower assortativity (moderate/severe TBI ps < .04, Cohen's ds: > .6). Regarding local network organisation, the relative importance of hub regions in the network did not differ between groups. Regression analyses showed relationships between global as well as local network parameters with neurocognitive functioning (i.e., working memory, memory encoding; R2 = 23.3 - 38.5%) and behavioural functioning (i.e., externalising problems, R2 = 36.1%). Findings indicate the impact of TBI on global functional network organisation, and the relevance of both global and local network organisation for long-term neurocognitive and behavioural outcome after paediatric TBI. The results suggest potential prognostic value of resting-state network organisation for outcome after paediatric TBI.

Background: Childhood trauma (CT) is a risk factor for depressive and anxiety disorders. However, whether CT is more strongly linked to specific clinical features of these disorders remains inconclusive. The current study comprehensively examined cross-sectional and longitudinal associations between CT and depressive/anxiety symptomatology in a large adult sample with current and remitted depressive and/or anxiety disorders. Methods: Baseline (n = 1803), 2-year (n = 1735), 4-year (n = 1585), and 6-year follow-up (n = 1475) data from the Netherlands Study of Depression and Anxiety were used. CT (emotional neglect, emotional/physical/sexual abuse) was assessed at baseline, while depressive/anxiety symptomatology with relevant dimensions (e.g., mood/cognitive, melancholic, general distress, and somatic depression) was assessed at each wave using self-reported questionnaires. Linear regressions and linear mixed models determined cross-sectional and longitudinal associations. Results: Individuals with CT, especially, severe CT, compared to those without CT, had significantly higher scores in overall depressive symptomatology (Cohen's d = 0.674), mood/cognitive depression (d = 0.691), melancholic depression (d = 0.587), general distress (d = 0.561), and somatic depression severity (d = 0.549). Differences were lower, but still highly significant for anxiety (d = 0.418), worry (d = 0.362), and fear/phobic symptomatology (d = 0.359). Effects were consistent across CT types and maintained over six years. Limitations: Retrospectively-reported CT. Conclusions: CT is a risk factor for depressive and anxiety symptomatology across all dimensions and enduring over multiple years. Screening for CT is essential to identify individuals at risk for more severe and chronic manifestations of affective disorders.

Background: Structural brain alterations are observed in major depressive disorder (MDD). However, MDD is a highly heterogeneous disorder and specific clinical or biological characteristics of depression might relate to specific structural brain alterations. Clinical symptom subtypes of depression, as well as immuno-metabolic dysregulation associated with subtypes of depression, have been associated with brain alterations. Therefore, we examined if specific clinical and biological characteristics of depression show different brain alterations compared to overall depression. Method: Individuals with and without depressive and/or anxiety disorders from the Netherlands Study of Depression and Anxiety (NESDA) (328 participants from three timepoints leading to 541 observations) and the Mood Treatment with Antidepressants or Running (MOTAR) study (123 baseline participants) were included. Symptom profiles (atypical energy-related profile, melancholic profile and depression severity) and biological indices (inflammatory, metabolic syndrome, and immuno-metabolic indices) were created. The associations of the clinical and biological profiles with depression-related structural brain measures (anterior cingulate cortex [ACC], orbitofrontal cortex, insula, and nucleus accumbens) were examined dimensionally in both studies and meta-analysed. Results: Depression severity was negatively associated with rostral ACC thickness (B = -0.55, pFDR = 0.03), and melancholic symptoms were negatively associated with caudal ACC thickness (B = -0.42, pFDR = 0.03). The atypical energy-related symptom profile and immuno-metabolic indices did not show a consistent association with structural brain measures across studies. Conclusion: Overall depression- and melancholic symptom severity showed a dose-response relationship with reduced ACC thickness. No associations between immuno-metabolic dysregulation and structural brain alterations were found, suggesting that although both are associated with depression, distinct mechanisms may be involved.

Objective: To address the growing need for effective data reuse in health research, healthcare institutions need to make their data Findable, Accessible, Interoperable, and Reusable (FAIR). A prevailing method to model databases for interoperability is the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM), developed by the Observational Health Data Sciences and Informatics (OHDSI) initiative. A European repository for OMOP CDM-converted databases called the “European Health Data & Evidence Network (EHDEN) portal” was developed, aiming to make these databases Findable and Accessible. This paper aims to assess the FAIRness of databases on the EHDEN portal. Materials and methods: Two researchers involved in the OMOP CDM conversion of separate Dutch Intensive Care Unit (ICU) research databases each manually assessed their own database using seventeen metrics. These were defined by the FAIRsFAIR project as a list of minimum requirements for a database to be FAIR. Each metric is given a score from zero to four based on how well the database adheres to the metric. The maximum score for each metric varies from one to four based on the importance of the metric. Results: Fourteen out of the seventeen metrics were unanimously rated: seven were rated the highest score, one was rated half of the highest score, and five were rated the lowest score. The remaining three metrics were assessed differently for the two use cases. The total scores achieved were 15.5 and 12 out of a maximum of 25. Conclusion: The main omissions in supporting FAIRness were the lack of globally unique identifiers such as Uniform Resource Identifiers (URIs) in the OMOP CDM and the lack of metadata standardization and linkage in the EHDEN portal. By implementing these in future updates, the EHDEN portal can be more FAIR.

Objective: This study aimed to acquire insight into the perceived user friendliness, accessibility and inclusiveness of a personalized digital care pathway. Materials & methods: Usability of the tool was tested in an experimental setting. Mixed methods data collection consisted of scenario-based eye tracking tests in a web- or mobile-based prototype of the tool, followed by a questionnaire assessing user friendliness (System Usability Scale; SUS) and a structured interview. Inclusiveness was assessed by subgroup comparisons based on language proficiency, age and education level. Via purposive sampling a heterogeneous population of users (N = 24) was recruited. Eye tracking was used to measure gaze behavior. Results: Overall, participants were satisfied with the tool (scale 0–10, 7.5; SD = 1.29). User friendliness of the mobile version (68.3; SD = 21.6) was higher than the web version (50.9; SD = 17.3) measured by SUS score (0–100). With regard to accessibility, eye tracking scenarios showed that the menu bar was hard to find (17% mobile, 55% web). In all scenario's, information was found faster in the mobile version than the web version. Attention was easily drawn to images. Regarding inclusiveness of the tool, we found significantly longer completing time of the scenario tasks for low language proficiency (p-value = 0.029) and higher age subgroups (p-value = 0.049). Lower language proficiency scored a significant lower SUS score (p-value = 0.012). Conclusions: Overall, user friendliness and accessibility were positively evaluated. Assessment of inclusiveness emphasized the need for tailoring digital tools to those with low language proficiency and/or an older age. Co-creation of digital care tools with users is therefore important to match users’ needs, make tools easily understandable and accessible to all users, and ultimately result in better uptake and impact.

Introduction and objective: The Dutch university medical centres (UMC's) are on the forefront when it comes to validation, implementation and research of telemonitoring. To aid the UMC's in their effort, the Dutch Government has supported the UMC's by fostering the ‘Citrien eHealth program’. This program aims at nationwide implementation and upscaling of telemonitoring via a collaborative network. To quantify the success of this program, this study aims to provide insights into the current adoption of telemonitoring by health care professionals (HCP) within Dutch UMC's. Methods: Based on the evaluation framework as adapted from the Normalization Process Theory (NPT) a cross-sectional study was conducted in all Dutch UMC's. Thirty healthcare professionals (HCPs) per UMC were invited to complete the 23-item Normalization MeAsure Development (NoMAD) questionnaire, a tool to assess the degree of normalisation of telemonitoring. Results: The over-all response rate was 52.4% (124/240). Over 80% of respondents agreed or strongly agreed that they understand how telemonitoring affects the nature of their work, with a mean score of 1.49 (N = 117, SD 0.74). HCPs reported to believe telemonitoring will become a normal part of their work in the near future (N = 124, mean = 8.67, SD = 1.38). Using the Wilcoxon signed-rank test, the difference between current practise and future use of telemonitoring predicts to be statistically significant (Z = − 7.505, p ≤ 0.001). Mean scores for appropriate training and sufficient resources are relatively low (2.39 and 2.70 respectively), indicating a barrier for collective action. Conclusion: This is the first study to assess the implementation of telemonitoring as standard practise across Dutch UMCs. The HCPs in this study are the frontrunners, believing that telemonitoring will become standard practise in the future despite the fact that it is currently not. Based on the results of this study, both educational and implementation strategies including practical skills training are highly recommended in order to scale up telemonitoring widely.

International audience; ObjectiveThe aim of this study was to compare outcomes of single or multistage approach during fenestrated-branched endovascular aortic repair (FB-EVAR) of extensive thoracoabdominal aortic aneurysms (TAAAs).MethodsWe reviewed the clinical data of consecutive patients treated by FB-EVAR for extent I to III TAAAs in 24 centers (2006-2021). All patients received a single brand manufactured patient-specific or off-the-shelf fenestrated-branched stent grafts. Staging strategies included proximal thoracic aortic repair, minimally invasive segmental artery coil embolization, temporary aneurysm sac perfusion and combinations of these techniques. Endpoints were analyzed for elective repair in patients who had a single- or multistage approach before and after propensity score adjustment for baseline differences, including the composite 30-day/in-hospital mortality and/or permanent paraplegia, major adverse event, patient survival, and freedom from aortic-related mortality.ResultsA total of 1947 patients (65% male; mean age, 71 ± 8 years) underwent FB-EVAR of 155 extent I (10%), 729 extent II (46%), and 713 extent III TAAAs (44%). A single-stage approach was used in 939 patients (48%) and a multistage approach in 1008 patients (52%). A multistage approach was more frequently used in patients undergoing elective compared with non-elective repair (55% vs 35%; P < .001). Staging strategies were proximal thoracic aortic repair in 743 patients (74%), temporary aneurysm sac perfusion in 128 (13%), minimally invasive segmental artery coil embolization in 10 (1%), and combinations in 127 (12%). Among patients undergoing elective repair (n = 1597), the composite endpoint of 30-day/in-hospital mortality and/or permanent paraplegia rate occurred in 14% of single-stage and 6% of multistage approach patients (P < .001). After adjustment with a propensity score, multistage approach was associated with lower rates of 30-day/in-hospital mortality and/or permanent paraplegia (odds ratio, 0.466; 95% confidence interval, 0.271-0.801; P = .006) and higher patient survival at 1 year (86.9±1.3% vs 79.6±1.7%) and 3 years (72.7±2.1% vs 64.2±2.3%; adjusted hazard ratio, 0.714; 95% confidence interval, 0.528-0.966; P = .029), compared with a single stage approach.ConclusionStaging elective FB-EVAR of extent I to III TAAAs was associated with decreased risk of mortality and/or permanent paraplegia at 30 days or within hospital stay, and with higher patient survival at 1 and 3 years.

OBJECTIVE: Older adults at the Emergency Department (ED) often present with nonspecific complaints (NSC) such as 'weakness' or 'feeling unwell'. Health care workers may underestimate illness in patients with NSC, leading to adverse health outcomes. This study compares characteristics and outcomes of NSC-patients versus specific complaints (SC) patients.METHODS: Cohort study in patients ≥ 70 years in two Dutch EDs. NSC was classified according to the BANC-study-framework based on the medical history in the ED letter, before additional diagnostics took place. A second classification was performed at the end of the ED visit/hospital admission. Primary outcomes were functional decline, institutionalization, and mortality at 30 days.RESULTS: 26% (n = 228) of a total of 888 included patients presented with NSC. Compared with SC-patients, NSC-patients were older, more frail, and more frequently female. NSC-patients had a higher risk of functional decline and institutionalization at 30 days (adjusted ORs 1.84, 95% CI 1.27 - 2.72, and 2.46, 95% CI 1.51-4.00, respectively), but not mortality (adjusted OR 1.26, 95% CI 0.58 - 2.73). Reclassification to a specific complaint after the ED visit or hospital admission occurred in 54% of NSC-patients.CONCLUSION: NSC occur especially in older, frail female patients and are associated with an increased risk of functional decline and institutionalization, even after adjustment for worse baseline status. In half of the patients, a specific complaint revealed during ED or hospital stay. Physicians at the ED should consider NSC as a red flag needing appropriate observation and evaluation of underlying serious conditions and needs of this vulnerable patient group.

In the original publication, one of the co-author names was mistakenly misspelled as "Jan Hazelet" instead of "Jan Hazelzet". It is updated in this correction.

Nowadays, parents, caretakers, teachers and researchers have an increasing interest in the development and consequences of problematic social media use, especially among adolescents. A growing body of research investigates factors that may influence the development of problematic social media use. This study examined the role of the broader context of parental (time spent with parents and family support), peer (peer support and peer pressure), and individual factors (perceived self-control) in the development of adolescents' risky and problematic social media use (ref = normative), as well as the moderating role of self-control by using a longitudinal design. Adolescents (N = 1384) aged 11–19 years (Mage = 14.1, SD = 1.03) were included and completed a self-report questionnaire twice (6-month interval). A Multinomial Logistic Regression showed that parent and peer factors predicted risky social media use, but not problematic use of social media. Adolescents’ level of self-control did not modify these relationships. However, low self-control did increase the odds of developing risky or problematic social media use directly. In conclusion, this study provides preliminary evidence that general parent and peer factors can help to prevent risky social media use, but to a lesser extent problematic use of social media. For the latter, the individual factor self-control, however, seems to play a role.

PURPOSE: To investigate drug-related causes attributed to acute kidney injury (DAKI) and their documentation in patients admitted to the Intensive Care Unit (ICU). METHODS: This study was conducted in an academic hospital in the Netherlands by reusing electronic health record (EHR) data of adult ICU admissions between November 2015 to January 2020. First, ICU admissions with acute kidney injury (AKI) stage 2 or 3 were identified. Subsequently, three modes of DAKI documentation in EHR were examined: diagnosis codes (structured data), allergy module (semi-structured data), and clinical notes (unstructured data). RESULTS: n total 8124 ICU admissions were included, with 542 (6.7%) ICU admissions experiencing AKI stage 2 or 3. The ICU physicians deemed 102 of these AKI cases (18.8%) to be drug-related. These DAKI cases were all documented in the clinical notes (100%), one in allergy module (1%) and none via diagnosis codes. The clinical notes required the highest time investment to analyze. CONCLUSIONS: Drug-related causes comprise a substantial part of AKI in the ICU patients. However, current unstructured DAKI documentation practice via clinical notes hampers our ability to gain better insights about DAKI occurrence. Therefore, both automating DAKI identification from the clinical notes and increasing structured DAKI documentation should be encouraged.

Objective: The aim of this study was to compare the short and long term clinical outcomes of endovascular (EVAR) vs. open surgical repair (OSR) of juxtarenal (JAAAs) and pararenal abdominal aortic aneurysms (PAAAs) in five high volume European academic centres. Methods: This was a retrospective multicentre cohort study of five high volume European academic centres (> 50 open or 50 endovascular abdominal aortic aneurysm repairs annually) including 834 consecutive patients who were operated on and prospectively followed. Using propensity score matching (PSM) each patient who underwent OSR was matched with one patient who underwent EVAR in a 1:1 ratio (145 patients per group). The primary endpoint was long term all cause mortality, while the secondary endpoint was freedom from aortic related re-intervention. Results: After a follow up of 87 months, no difference in overall survival between the two groups was observed (38.6% for EVAR vs. 42.1% for OSR; p =.88). Patients undergoing EVAR underwent aortic related re-interventions more frequently (24.1% vs. 6.9%; p

OBJECTIVES: Although the Modified Early Warning Score (MEWS) is increasingly being used in the acute care chain to recognize disease severity, its superiority compared with clinical gestalt remains unproven. Therefore, the aim of this study was to compare the accuracy of medical caregivers and MEWS in predicting the development of critical illness. DESIGN: This was a multicenter observational prospective study. SETTING: It was performed in a level-1 trauma center with two different sites and emergency departments (EDs) with a combined capacity of about 50.000 patients annually. PATIENTS: It included all adult patients presented to the ED by Emergency Medical Services (EMS). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For all patients, the acute caregivers were asked several standardized questions regarding clinical predicted outcome (clinical gestalt), and the MEWS was calculated. The primary outcome was the occurrence of critical illness, defined as ICU admission, serious adverse events, and mortality within 72 hours. The sensitivity, specificity, and discriminative power of both clinical gestalt and MEWS for the occurrence of critical illness were calculated as the area under the receiver operating characteristic curve (AUROC). Among the total of 800 included patients, 113 patients (14.1%) suffered from critical illness. The specificity for predicting three-day critical illness for all caregivers (for EMS nurses, ED nurses, and physicians) was 93.2%; 97.3%, and 96.8%, respectively, and was significantly (p < 0.01) better than an MEWS score of 3 or higher (70.4%). The sensitivity was significantly lower for EMS and ED nurses, but not significantly different for physicians compared with MEWS. The AUROCs for prediction of 3-day critical illness by both the ED nurses (AUROC = 0.809) and the physicians (AUROC = 0.848) were significantly higher (p = 0.032 and p = 0.010, respectively) compared with MEWS (AUROC = 0.731). CONCLUSIONS: For patients admitted to the ED by EMS, medical professionals can predict the development of critical illness within 3 days significantly better than the MEWS. Although MEWS is able to correctly predict those patients that become critically ill, its use leads to overestimation due to a substantial number of false positives.

Introduction: Spontaneous iliac vein rupture (SIVR) is an uncommon disease with less than sixty cases reported before. This disease often requires surgical intervention. SIVR has never been imaged in the literature. This report shows how to image this diagnosis. Case report: A 71-year-old female was diagnosed with SIVR with the use of CT venography. Endovascular repair with 2 endografts and a sinus XL stent was performed. Postoperatively, the patient developed abdominal compartment syndrome and a large part of the intestines had to be removed because of ischemia. Discussion: This is the first report that shows SIVR before and after endovascular treatment with the use of CT venography by injecting a contrast bolus in the femoral vein. This information is of high interest for a broad range of clinicians to show or exclude a venous abdominal bleeding in an early stage.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. Xiang Zhu is supported by the Stein Fellowship from Stanford University and Institute for Computational and Data Sciences Seed Grant from The Pennsylvania State University. C.D.B. is supported by the NIH (R01-HL133218). Funding for the Global Lipids Genetics Consortium was provided by the NIH (R01-HL127564). This research was conducted using the UK Biobank Resource under application number 24460. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards 2I01BX003362-03A1 and 1I01BX004821-01A1. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We thank Bethany Klunder for administrative support. Study-specific acknowledgments are provided in the supplemental information.

Background The number of studies applying machine learning (ML) to predict acute kidney injury (AKI) has grown steadily over the past decade. We assess and critically appraise the state of the art in ML models for AKI prediction, considering performance, methodological soundness, and applicability. Methods We searched PubMed and ArXiv, extracted data, and critically appraised studies based on the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD), Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS), and Prediction Model Risk of Bias Assessment Tool (PROBAST) guidelines. Results Forty-six studies from 3166 titles were included. Thirty-eight studies developed a model, five developed and externally validated one, and three studies externally validated one. Flexible ML methods were used more often than deep learning, although the latter was common with temporal variables and text as predictors. Predictive performance showed an area under receiver operating curves ranging from 0.49 to 0.99. Our critical appraisal identified a high risk of bias in 39 studies. Some studies lacked internal validation, whereas external validation and interpretability of results were rarely considered. Fifteen studies focused on AKI prediction in the intensive care setting, and the US-derived Medical Information Mart for Intensive Care (MIMIC) data set was commonly used. Reproducibility was limited as data and code were usually unavailable. Conclusions Flexible ML methods are popular for the prediction of AKI, although more complex models based on deep learning are emerging. Our critical appraisal identified a high risk of bias in most models: Studies should use calibration measures and external validation more often, improve model interpretability, and share data and code to improve reproducibility.

OBJECTIVE: Faster and cheaper next generation sequencing technologies have enabled expansion of carrier screening for recessive disorders, potentially facilitating population-based implementation regardless of ancestry or family history. Little is known, however, about the attitudes regarding population-based carrier screening among families with genetic disorders. This study assessed views among parents and patients with a recessive disorder and parents of children with Down syndrome (DS) on expanded carrier screening (ECS).METHOD: In total, 85 patients with various recessive disorders, 110 parents of a child with a recessive disorder and 89 parents of a child with DS participated in an online survey in the Netherlands. Severity of recessive disorders was classified as mild/moderate or severe/profound.RESULTS: The majority of the (parents of) patients with a recessive disorder had a positive attitude towards population-based ECS, including screening for their own or their child's disorder. DS parents were significantly less positive towards ECS. Subgroup analyses showed that the severity of the disorder, rather than being a patient or parent, influences the attitudes, beliefs and intention to participate in ECS.CONCLUSION: Our findings have important implications for future implementation initiatives as they demonstrate the different perspectives from people with experiential knowledge with genetic disorders.