Mutational robustness and the role of buffer genes in evolvability.

Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation's phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.

Teaching medical students to apply deliberate reflection.

PURPOSE: Deliberate reflection on initial diagnosis has been found to repair diagnostic errors. We investigated the effectiveness of teaching students to use deliberate reflection on future cases and whether their usage would depend on their perception of case difficulty. METHOD: One-hundred-nineteen medical students solved cases either with deliberate-reflection or without instructions to reflect. One week later, all participants solved six cases, each with two equally likely diagnoses, but some symptoms in the case were associated with only one of the diagnoses (discriminating features). Participants provided one diagnosis and subsequently wrote down everything they remembered from it. After the first three cases, they were told that the next three would be difficult cases. Reflection was measured by the proportion of discriminating features recalled (overall; related to their provided diagnosis; related to alternative diagnosis). RESULTS: The deliberate-reflection condition recalled more features for the alternative diagnosis than the control condition (p = .013) regardless of described difficulty. They also recalled more features related to their provided diagnosis on the first three cases (p = .004), but on the last three cases (described as difficult), there was no difference. CONCLUSION: Learning deliberate reflection helped students engage in more reflective reasoning when solving future cases.

TripleAiM1: a nationwide registry of de novo metastatic hormone-sensitive prostate cancer with prospective quality-of-life assessment.

INTRODUCTION: The treatment landscape for de novo metastatic hormone sensitive prostate cancer (mHSPC) is rapidly evolving. With an abundance of available treatment strategies, selecting the optimal strategy for an individual patient is becoming increasingly challenging. TripleAiM1 aims to evaluate the impact of mHSPC treatments on health-related quality of life (HRQoL) and to provide real-world data insights on diagnostics, treatment strategies, patient subgroups and related healthcare expenditure for mHSPC. The aspirational target of TripleAiM1 is that in the near future, a more tailored therapy can be offered based on the individual patient's wishes and needs in accordance with the overarching principle of value-based healthcare. METHODS AND ANALYSIS: We describe the TripleAiM1 study design; a nationwide registry comprising a retrospective and prospective cohort of patients with de novo mHSPC. Starting in May 2020, eligible patients are identified, selected and recruited in 14 participating hospitals in the Netherlands. Our hypothesis is that, in a real-world setting, differences in clinically meaningful HRQoL deterioration will be observed for treatment strategies over time. HRQoL data, assessed with patient-reported outcome measures, costs and clinical data will be collected for 24 months.For the retrospective cohort, all patients diagnosed with de novo mHSPC from January 2017 onwards are eligible for inclusion. Patient and tumour characteristics, imaging modalities and treatment patterns will be analysed descriptively to provide a real-world overview.Time-to-event endpoints will be assessed using the Kaplan-Meier method and regression models will be employed to analyse baseline characteristics associated with an increased likelihood of death, progression and HRQoL deterioration. Longitudinal mixed-effects models will be employed to assess change of patient-reported outcome scores from baseline until the end of follow-up. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Medical Research Ethics Committee, Twente. Study results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9719.

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

Effect of the P-glycoprotein inhibitor tamoxifen on edoxaban plasma levels in women with breast cancer.

BACKGROUND: Concomitant use of P-glycoprotein inhibitors can reduce clearance of edoxaban and increase its plasma concentration. Caution is advised with simultaneous use of edoxaban and the frequently used P-glycoprotein inhibitor tamoxifen. However, pharmacokinetic data are lacking. OBJECTIVES: This study aimed to assess the effect of tamoxifen on edoxaban clearance. METHODS: This was a prospective, self-controlled, pharmacokinetic study in breast cancer participants starting tamoxifen. Edoxaban was given at a dose of 60 mg once daily for 4 consecutive days, first without tamoxifen and later with concomitant tamoxifen in steady-state. On day 4 of both edoxaban sequences, serial blood samples were taken. A population pharmacokinetic model was developed using nonlinear mixed effects modelling in which the effect of tamoxifen on edoxaban clearance was assessed. Additionally, mean area under the curves (AUC) were estimated. Geometric least square means (GLM) ratios were calculated and no interaction was concluded if the 90 % CI was within the 80-125 % no-effect boundaries. RESULTS: Twenty-four women with breast cancer scheduled for tamoxifen were included. The median age was 56 years (IQR 51-63). The average edoxaban clearance was 32.0 L/h (95 % CI, 11.1-35.0 L/h). There was no effect of tamoxifen on edoxaban clearance, with a fraction of 100 % (95 % CI 92-108) compared to clearance without tamoxifen. The mean AUCs were 1923 ng*h/ml (SD 695) without tamoxifen and 1947 ng*h/ml (SD 595) with tamoxifen (GLM-ratio 100.4; 90 % CI 98.6-102.2). CONCLUSIONS: Concomitant use of the P-glycoprotein inhibitor tamoxifen does not lead to reduced clearance of edoxaban in patients with breast cancer.

Identifying and prioritizing educational content from a malpractice claims database for clinical reasoning education in the vocational training of general practitioners.

Diagnostic reasoning is an important topic in General Practitioners' (GPs) vocational training. Interestingly, research has paid little attention to the content of the cases used in clinical reasoning education. Malpractice claims of diagnostic errors represent cases that impact patients and that reflect potential knowledge gaps and contextual factors. With this study, we aimed to identify and prioritize educational content from a malpractice claims database in order to improve clinical reasoning education in GP training. With input from various experts in clinical reasoning and diagnostic error, we defined five priority criteria that reflect educational relevance. Fifty unique medical conditions from a malpractice claims database were scored on those priority criteria by stakeholders in clinical reasoning education in 2021. Subsequently, we calculated the mean total priority score for each condition. Mean total priority score (min 5-max 25) for all fifty diagnoses was 17,11 with a range from 13,89 to 19,61. We identified and described the fifteen highest scoring diseases (with priority scores ranging from 18,17 to 19,61). The prioritized conditions involved complex common (e.g., cardiovascular diseases, renal insufficiency and cancer), complex rare (e.g., endocarditis, ectopic pregnancy, testicular torsion) and more straightforward common conditions (e.g., tendon rupture/injury, eye infection). The claim cases often demonstrated atypical presentations or complex contextual factors. Including those malpractice cases in GP vocational training could enrich the illness scripts of diseases that are at high risk of errors, which may reduce diagnostic error and related patient harm.

Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers.

AIM: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort. METHODS AND RESULTS: From the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes. The median age of the study population was 65 years (interquartile range 58-70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N-terminal pro-B-type natriuretic peptide and mid-regional pro-A-type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69). In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio [HR] 1.24, 95% confidence interval [CI] 0.93-1.65; p = 0.144). This association, however, was modified by age (p for CHIP-age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new-onset HF (HR 2.07, 95% CI 1.30-3.29; p = 0.002). CONCLUSION: Clonal haematopoiesis of indeterminate potential correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects <65 years of age.

Learning deliberate reflection in medical diagnosis: does learning-by-teaching help?

Deliberate reflection has been found to foster diagnostic accuracy on complex cases or under circumstances that tend to induce cognitive bias. However, it is unclear whether the procedure can also be learned and thereby autonomously applied when diagnosing future cases without instructions to reflect. We investigated whether general practice residents would learn the deliberate reflection procedure through 'learning-by-teaching' and apply it to diagnose new cases. The study was a two-phase experiment. In the learning phase, 56 general-practice residents were randomly assigned to one of two conditions. They either (1) studied examples of deliberate reflection and then explained the procedure to a fictitious peer on video; or (2) solved cases without reflection (control). In the test phase, one to three weeks later, all participants diagnosed new cases while thinking aloud. The analysis of the test phase showed no significant differences between the conditions on any of the outcome measures (diagnostic accuracy, p = .263; time to diagnose, p = .598; mental effort ratings, p = .544; confidence ratings, p = .710; proportion of contradiction units (i.e. measure of deliberate reflection), p = .544). In contrast to findings on learning-by-teaching from other domains, teaching deliberate reflection to a fictitious peer, did not increase reflective reasoning when diagnosing future cases. Potential explanations that future research might address are that either residents in the experimental condition did not apply the learned deliberate reflection procedure in the test phase, or residents in the control condition also engaged in reflection.

Evolution of self-organised division of labour driven by stigmergy in leaf-cutter ants.

Social insects owe their widespread success to their ability to efficiently coordinate behaviour to carry out complex tasks. Several leaf-cutter ant species employ an advanced type of division of labour known as task partitioning, where the task of retrieving leaves is distributed between workers that cut and drop and those that collect the fallen leaves. It is not entirely clear how such highly coordinated behaviour can evolve, as it would seem to require the simultaneous mutations of multiple traits during the same generation. Here, we use an agent-based simulation model to show how task partitioning in leaf-cutter ants can gradually evolve by exploiting stigmergy (indirect coordination through the environment) through gravity (leaves falling from the treetop on the ground forming a cache). Our simple model allows independent variation in two core behavioural dimensions: the tendency to drop leaves and the tendency to pick up dropped leaves. Task partitioning readily evolves even under these minimal assumptions through adaptation to an arboreal environment where traveling up and down the tree is costly. Additionally, we analyse ant movement dynamics to demonstrate how the ants achieve efficient task allocation through task switching and negative feedback control.

Misrepresentation of group contributions undermines conditional cooperation in a human decision making experiment.

Cooperative behaviour can evolve through conditional strategies that direct cooperation towards interaction partners who have themselves been cooperative in the past. Such strategies are common in human cooperation, but they can be vulnerable to manipulation: individuals may try to exaggerate their past cooperation to elicit reciprocal contributions or improve their reputation for future gains. Little is known about the prevalence and the ramifications of misrepresentation in human cooperation, neither in general nor about its cultural facets (self-sacrifice for the group is valued differently across cultures). Here, we present a large-scale interactive decision making experiment (N = 870), performed in China and the USA, in which individuals had repeated cooperative interactions in groups. Our results show that (1) most individuals from both cultures overstate their contributions to the group if given the opportunity, (2) misrepresentation of cooperation is detrimental to cooperation in future interactions, and (3) the possibility to build up a personal reputation amplifies the effects of misrepresentation on cooperation in China, but not in the USA. Our results suggest that misrepresentation of cooperation is likely to be an important factor in (the evolution of) human social behaviour, with, depending on culture, diverging impacts on cooperation outcomes.

A professional knowledge base for collaborative reflection education: a qualitative description of teacher goals and strategies.

INTRODUCTION: For several decades, educational experts have promoted reflection as essential to professional development. In the medical setting, collaborative reflection has gained significant importance across the curriculum. Collaborative reflection has a unique edge over individual reflection, but many medical teachers find facilitating group reflection sessions challenging and there is little documentation about the didactics of teaching in such collaborative reflection settings. To address this knowledge gap, we aim to capture the professional knowledge base for facilitating collaborative reflection by analyzing the formal and perceived goals and strategies of this practice. METHODS: The professional knowledge base consists of formal curricular materials as well as individual teacher expertise. Using Template Analysis, we analyzed the goals and strategies of collaborative reflection reported in institutional training documents and video-stimulated interviews with individual teachers across all Dutch general practitioner training institutes. RESULTS: The analysis resulted in a highly diverse overview of educational goals for residents during the sessions, teacher goals that contribute to those educational goals, and a myriad of situation-specific teacher strategies to accomplish both types of goals. Teachers reported that the main educational goal was for residents to learn and develop and that the teachers' main goal was to facilitate learning and development by ensuring everyone's participation in reflection. Key teacher strategies to that end were to manage participation, to ensure a safe learning environment, and to create conditions for learning. DISCUSSION: The variety of strategies and goals that constitute the professional knowledge base for facilitating collaborative reflection in postgraduate medical education shows how diverse and situation-dependent such facilitation can be. Our analysis identifies a repertoire of tools that both novice and experienced teachers can use to develop their professional skill in facilitating collaborative reflection.

Improving medical residents' self-assessment of their diagnostic accuracy: does feedback help?

When physicians do not estimate their diagnostic accuracy correctly, i.e. show inaccurate diagnostic calibration, diagnostic errors or overtesting can occur. A previous study showed that physicians' diagnostic calibration for easy cases improved, after they received feedback on their previous diagnoses. We investigated whether diagnostic calibration would also improve from this feedback when cases were more difficult. Sixty-nine general-practice residents were randomly assigned to one of two conditions. In the feedback condition, they diagnosed a case, rated their confidence in their diagnosis, their invested mental effort, and case complexity, and then were shown the correct diagnosis (feedback). This was repeated for 12 cases. Participants in the control condition did the same without receiving feedback. We analysed calibration in terms of (1) absolute accuracy (absolute difference between diagnostic accuracy and confidence), and (2) bias (confidence minus diagnostic calibration). There was no difference between the conditions in the measurements of calibration (absolute accuracy, p = .204; bias, p = .176). Post-hoc analyses showed that on correctly diagnosed cases (on which participants are either accurate or underconfident), calibration in the feedback condition was less accurate than in the control condition, p = .013. This study shows that feedback on diagnostic performance did not improve physicians' calibration for more difficult cases. One explanation could be that participants were confronted with their mistakes and thereafter lowered their confidence ratings even if cases were diagnosed correctly. This shows how difficult it is to improve diagnostic calibration, which is important to prevent diagnostic errors or maltreatment.

Beyond social learning.

Cultural evolution requires the social transmission of information. For this reason, scholars have emphasized social learning when explaining how and why culture evolves. Yet cultural evolution results from many mechanisms operating in concert. Here, we argue that the emphasis on social learning has distracted scholars from appreciating both the full range of mechanisms contributing to cultural evolution and how interactions among those mechanisms and other factors affect the output of cultural evolution. We examine understudied mechanisms and other factors and call for a more inclusive programme of investigation that probes multiple levels of the organization, spanning the neural, cognitive-behavioural and populational levels. To guide our discussion, we focus on factors involved in three core topics of cultural evolution: the emergence of culture, the emergence of cumulative cultural evolution and the design of cultural traits. Studying mechanisms across levels can add explanatory power while revealing gaps and misconceptions in our knowledge. This article is part of the theme issue 'Foundations of cultural evolution'.

A participant perspective on collaborative reflection: video-stimulated interviews show what residents value and why.

The potential of reflection for learning and development is broadly accepted across the medical curriculum. Our understanding of how exactly reflection yields its educational promise, however, is limited to broad hints at the relation between reflection and learning. Yet, such understanding is essential to the (re)design of reflection education for learning and development. In this qualitative study, we used participants' video-stimulated comments on actual practice to identify features that do or do not make collaborative reflection valuable to participants. In doing so, we focus on aspects of the interactional process that constitute the educational activity of reflection. To identify valuable and less valuable features of collaborative reflection, we conducted one-on-one video-stimulated interviews with Dutch general practice residents about collaborative reflection sessions in their training program. Residents were invited to comment on any aspect of the session that they did or did not value. We synthesized all positively and negatively valued features and associated explanations put forward in residents' narratives into shared normative orientations about collaborative reflection: what are the shared norms that residents display in telling about positive and negative experiences with collaborative reflection? These normative orientations display residents' views on the aim of collaborative reflection (educational value for all) and the norms that allegedly contribute to realizing this aim (inclusivity and diversity, safety, and efficiency). These norms are also reflected in specific educational activities that ostensibly contribute to educational value. As such, the current synthesis of normative orientations displayed in residents' narratives about valuable and less valuable elements of collaborative reflection deepen our understanding of reflection and its supposed connection with educational outcomes. Moreover, the current empirical endeavor illustrates the value of video-stimulated interviews as a tool to value features of educational processes for future educational enhancements.

How the incentive to contribute affects contributions in the one-shot public goods game.

Enmeshed in various social structures, humans must often weigh their own interest against the interest of others-including the common interest of groups they belong to. The Public Goods Game (PGG), which succinctly pits individual interest against group interest, has been a staple of research into how people make such decisions. It has been studied in many variations, in the laboratory and (increasingly) online. One of the defining parameters of the PGG is the marginal per capita return of the group project (MPCR), which determines the incentive for contributing to the group project relative to the incentive of keeping points in the personal account. The effect of MPCR on contributions has been investigated before, but its effects have never been characterised with high resolution. Here, we present a systematic and high-resolution investigation of the effect of MPCR in groups of three. We do this in a large-scale online decision making experiment recruiting participants from Amazon Mechanical Turk. Our results provide a fine-grained account of the relationship between incentive to cooperate on the one hand and cooperation on the other, and can help to provide a basis for choosing MPCR magnitudes for future research endeavours using online PGG studies.

Health-related Quality of Life and Pain in a Real-world Castration-resistant Prostate Cancer Population: Results From the PRO-CAPRI Study in the Netherlands.

BACKGROUND: The purpose of this study was to determine generic, cancer-specific, and prostate cancer-specific health-related quality of life (HRQoL), pain and changes over time in patients with metastatic castration-resistant prostate cancer (mCRPC) in daily practice. PATIENTS AND METHODS: PRO-CAPRI is an observational, prospective study in 10 hospitals in the Netherlands. Patients with mCRPC completed the EQ-5D, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and Brief Pain Inventory-Short Form (BPI-SF) every 3 months and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Prostate Cancer Module (EORTC QLQ-PR25) every 6 months for a maximum of 2 years. Subgroups were identified based on chemotherapy pretreatment. Outcomes were generic, cancer-specific, and prostate cancer-specific HRQoL and self-reported pain. Descriptive statistics were performed including changes over time and minimal important differences (MID) between subgroups. RESULTS: In total, 151 included patients answered 873 questionnaires. The median follow-up from the start of the study was 19.5 months, and 84% were treated with at least 1 life-prolonging agent. Overall, patients were in good clinical condition (Eatern Cooperative Oncology Group performance status 0-1 in 78%) with normal baseline hemoglobin, lactate dehydrogenase, and alkaline phosphatase. At inclusion, generic HRQoL was high with a mean EQ visual analog score of 73.2 out of 100. The lowest scores were reported on role and physical functioning (mean scores of 69 and 76 of 100, respectively), and fatigue, pain, and insomnia were the most impaired domains. These domains deteriorated in > 50% of patients. CONCLUSION: Although most patients were treated with new treatments during follow-up, mCRPC has a negative impact on HRQoL with deterioration in all domains over time, especially role and physical functioning. These domains need specific attention during follow-up to maintain HRQoL as long as possible by timely start of adequate supportive care management.

A Historical-Genetic Reconstruction of Human Extra-Pair Paternity.

Paternity testing using genetic markers has shown that extra-pair paternity (EPP) is common in many pair-bonded species [1, 2]. Evolutionary theory and empirical data show that extra-pair copulations can increase the fitness of males as well as females [3, 4]. This can carry a significant fitness cost for the social father, who then invests in rearing offspring that biologically are not his own [5]. In human populations, the incidence and correlates of extra-pair paternity remain highly contentious [2, 6, 7]. Here, we use a population-level genetic genealogy approach [6, 8] to reconstruct spatiotemporal patterns in human EPP rates. Using patrilineal genealogies from the Low Countries spanning a period of over 500 years and Y chromosome genotyping of living descendants, our analysis reveals that historical EPP rates, while low overall, were strongly impacted by socioeconomic and demographic factors. Specifically, we observe that estimated EPP rates among married couples varied by more than an order of magnitude, from 0.4% to 5.9%, and peaked among families with a low socioeconomic background living in densely populated cities of the late 19th century. Our results support theoretical predictions that social context can strongly affect the outcomes of sexual conflict in human populations by modulating the incentives and opportunities for engaging in extra-pair relationships [9-11]. These findings show how contemporary genetic data combined with in-depth genealogies open up a new window on the sexual behavior of our ancestors.

Different potencies of topical corticosteroids for a better treatment strategy in children with atopic dermatitis (the Rotterdam Eczema study): protocol for an observational cohort study with an embedded randomised open-label controlled trial.

INTRODUCTION: Topical corticosteroids (TCS) of different potencies are the main treatment to control atopic dermatitis (AD). The Dutch guideline on AD for general practitioners (GPs) recommends a stepwise approach in which treatment steps are tailored to the severity of the disease, starting with the lowest possible potency of TCS. However, it remains unclear whether the recommended stepwise approach is most efficient. This randomised open-label controlled trial aims to determine whether a potent TCS is more effective than a low-potency TCS in the initial treatment of children with a moderate flare-up of AD in primary care. In the observational cohort, the overall aim is to determine the frequency, burden and determinants of flare-ups of AD during follow-up. METHODS AND ANALYSIS: The study is an observational cohort study with an embedded pragmatic randomised controlled, open-label trial. Eligible are patients diagnosed with AD (aged 12 weeks to 18 years) who visited the GP for AD or received repeated prescriptions for AD in the previous 12 months; follow-up of the cohort is 1 year. Children are enrolled in the trial if they have a flare-up of AD during follow-up in the cohort. Eligible children are randomised to the intervention group (with a potent TCS once daily) or to the GP guideline group (with a low potency TCS once daily). Primary outcome is the difference in average subjective disease severity over 24 weeks follow-up in the trial, measured with the patient-oriented eczema measure. As secondary outcome, the Eczema Area and Severity Index is measured. ETHICS AND DISSEMINATION: This study tests the hypothesis that immediate treatment with a potent TCS during a flare-up of AD leads to faster and more efficacious results as compared with starting with a TCS with low potency with less overall use of TCS. The study protocol is approved by the Medical Ethics Committee (MEC) of the Erasmus Medical Center Rotterdam, the Netherlands (MEC-2017-328). The results of the study will be published in international peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NTR: 6679; Pre-results.