Academisch Medisch Centrum Universiteit van Amsterdam

Background Skeletally immature osteochondral lesions of the talus (OLTs) have a significant impact on the health status and quality of life of pediatric patients and the involved family. the current literature showed success in 4 out of 10 patients but it is currently unknown which type of non-operative management showed better clinical- and radiological outcomes. The aim of this study is to compare immobilization and supervised rehabilitation with a ‘skillful’’ neglect in the treatment for skeletally immature patients with an OLT. The hypothesis is that a period of immobilization and supervised rehabilitation will lead to better clinical and radiological outcomes compared to ‘’skillful’’ neglect. Methods Multicenter, prospective, comparative study. Skeletally immature children with an OLT will be assigned to the intervention or control group after a shared decision-making process. Patients in the intervention group will undergo a 4-week period of immobilization with normal casting and non-weightbearing, which is followed by 4 weeks of immobilization with a removable cast and weight bearing boot. Afterwards, they will receive a protocolled period of rehabilitation under supervision of a physical therapist. The control group will have a ‘skillful’’ neglect treatment. The main study outcome is the difference between the two groups on the Oxford Ankle and Foot Questionnaire for Children (OxAFQ-C). Secondary study outcomes are radiologic changes in terms of morphology and lesion size. Numeric Rating Scale (NRS) during weight bearing and quality of life measured with a Pediatrics Quality of Life (Peds-QL) and EuroQol-5 Dimension youth (EQ-5D-y). Discussion This protocol reports on the study design of the CARE Study and it aims to setup a study for evaluating different types of non-operative management in pediatric patients suffering an OLT. This study will compare clinical and radiological outcomes between two different non-operative strategies for treating OLTs in the skeletally immature population. Based on the results of this study, an evidence-based treatment protocol for non-operative management for pediatric OLTs can be provided. Trial registration This study is registered in the International Clinical Trial Registry Platform (ICTRP) with trial number NLOMON54282, date of registration 05192023.

Purpose This study aimed to provide a comprehensive overview of the existing literature on Self-administered Outpatient Parenteral Antimicrobial Therapy (S-OPAT), focusing on safety and clinical outcomes, factors influencing these outcomes, and the experiences of patients and caregivers. Methods We searched the databases MEDLINE, CINAHL, Embase and Cochrane library. Publications were included if they reported on the clinical outcomes, safety, and/or experiences of patients and caregivers with S-OPAT. Study selection and data extraction were performed independently by two reviewers. Quantitative and qualitative data were summarized in data charting forms. Results Forty-four studies were included: 41 primary studies, 2 systematic reviews and 1 clinical guideline. Clinical outcomes were reported in 17 and safety in 23 primary studies. Eleven studies compared S-OPAT to other OPAT delivery models. These studies showed that all models were generally comparable regarding clinical outcomes, but two studies reported an increased number of adverse events with S-OPAT. Nine studies, exploring a total of 7 potential risk factors, identified older age, comorbidities and Staphylococcus aureus infections as contributors to adverse events. The results of 14 studies on patient-centred outcomes showed that patients and caregivers considered S-OPAT a suitable alternative to other OPAT delivery models. Conclusion We conclude that S-OPAT is a viable model of care, demonstrating favourable clinical outcomes, although some safety concerns have been reported. The growing care demand now and in the future urges further development of S-OPAT care. Gaps of knowledge still exist, and we provide recommendations for future research.

The evidence‐ and consensus‐based living guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. The original EuroGuiDerm Guideline on atopic eczema was published in June 2022. Since then, the part of the guideline dealing with systemic therapy has been updated twice. This paper summarizes the results of the second update. Twenty‐eight experts (including clinicians and patient representatives) from 12 European countries participated. The updated guideline provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab and tralokinumab) and Janus kinase (JAK) inhibitors (abrocitinib, baricitinib and upadacitinib). Additionally, the updated guidelines address considerations for paediatric, adolescent, pregnant and breastfeeding patients. For all other aspects, please refer to the 2022 version.

Objectives Phenotypical Extended Spectrum β-Lactamase (ESBL)-production is commonly determined using the combination disk diffusion test or gradient test. This requires overnight incubation, prolonging time-to-detection and increasing duration of empirical treatment for patients with infections caused by gram-negative bacteria. To achieve instant confirmation without incubation, we developed a machine learning (ML)-model that predicts phenotypic ESBL-confirmation using Minimum Inhibitory Concentrations from routine automated antimicrobial susceptibility testing (AST)-results. Methods Data from the Dutch national laboratory-based surveillance system ISIS-AR collected between 2013 and 2022 from 49 laboratories were used: 178,044 isolates of E. coli (141,576), K. pneumoniae (33,088), and P. mirabilis (3,380) that exhibited resistance to cefotaxime and/or ceftazidime, and had available results of phenotypical ESBL-confirmation testing. We evaluated Logistic Regression, Random Forest and XGBoost models and calculated SHAP-values (SHapley Additive exPlanations) to identify most contributing features. We externally validated models using 5,996 isolates collected in Amsterdam University Medical Centres’ between 2013 and 2022. Results XGBoost achieved an AUROC (Area Under Receiver Operating Characteristics) of 0.97, a sensitivity of 0.89 and an accuracy of 0.93. The most contributing features were the antibiotics cefotaxime, cefoxitin and trimethoprim for E. coli and K. pneumoniae, and cefuroxime, imipenem and cefotaxime for P. mirabilis. External validation yielded AUROCs of 0.93 (E. coli), 0.89 (K. pneumoniae) and 0.93 (P. mirabilis). Conclusion ML-models for prediction of ESBL-production using routine AST-system data achieved high performances. Implementing these models in laboratory practice could shorten time-to-detection. Once deployed, this approach could facilitate widespread screening for phenotypic ESBL-production.

Background The results of the Talar OsteoPeriostic grafting from the Iliac Crest (TOPIC) procedure for lateral osteochondral lesions of the talus (OLTs) are unknown. Therefore, the present prospective study aims to assess the numeric rating scale (NRS) of pain during walking at 2-year follow-up. Secondarily, the aim is to assess other clinical, radiologic, and safety outcomes. Methods This is a single-center, nonrandomized prospective cohort study in which all press-fit lateral TOPIC patients for an OLT are included. Patients with a follow-up of at least 2 years without a concomitant osteochondral lesion of the tibial plafond were included. The primary outcome is the NRS of pain during walking. Secondary clinical outcomes included the NRS during rest and during stair climbing. Additionally, the Foot and Ankle Outcome Score (FAOS), the AOFAS ankle-hindfoot score, and the mental and physical component summary of the 36-Item Short Form Health Survey were recorded. Radiologic follow-up was performed using computed tomography (CT) scans. Results After application of the inclusion and exclusion criteria, 7 patients were included in the present study. The median age at time of surgery was 31.1 years. The NRS of pain during walking improved from a median of 5 (4-7) preoperatively to 1 (0-1) at 2 years of follow-up ( P = .02). All FAOS subscales improved significantly, except the FAOS symptoms subscale. Graft consolidation was observed in 100% of the patients and cysts were present in 5 of 6 patients. No complications occurred and no patients complained of donor site morbidity. No reoperations were performed. Conclusion In the first 7 prospectively followed patients who underwent the TOPIC procedure for large osteochondral lesions of the lateral talar dome, an improvement of the NRS of pain during walking from median 5 preoperatively to 1 at 2-year follow-up was observed.

Aims Adult patients with transposition of the great arteries (TGA) and an systemic right ventricle (sRV) are at risk for heart failure (HF). In this study, we investigated risk factors for HF hospitalization and developed a novel risk stratification tool to optimize risk prediction for clinical practice. Methods and results In this international multicentre study, 522 patients with TGA and an sRV, without history of HF hospitalization, were followed retrospectively for a median of 17.9 years (interquartile range [IQR] 12.9–22.1). HF hospitalization was defined as a hospital admission for HF signs and symptoms with initiation or increase of HF medication. Predictors for HF hospitalization were established using a Cox regression analysis and were used to build a 10‐year risk score. Of the 522 patients, 70% had an atrial switch operation and 30% had a congenitally corrected TGA. The median age at time of enrolment was 23.7 years (IQR 19.9–32.1) and 64% were male. During follow‐up, 127 patients (24.3%) had at least one HF hospitalization. A risk stratification tool was built using the following independent predictors associated with a 10‐year risk of HF hospitalization: age, New York Heart Association functional class ≥II, QRS duration >120 ms, atrial fibrillation, moderate/severe right ventricular dysfunction, with a C‐statistic of 0.868 (95% confidence interval 0.823–0.913). Conclusion During follow‐up, 24.3% of sRV patients had at least one HF hospitalization. Five simple, clinically‐accessible variables can be used as a risk score tool to identify patients at higher risk of HF hospitalization.

Objectives Systematic review and meta-analysis on shortening antibiotic therapy for Lyme borreliosis (LB) patients. Methods Data sources: Medline, Google, and Google Scholar (queried from January 2022-February 2024), following the PRISMA method and the Cochrane Handbook. Eligibility criteria: Randomized clinical trials, comparative studies; clear definitions of LB, duration of antibiotics and outcome; follow-up ≥ 6–12 months. Meta-analysis included studies that examined three outcomes: treatment failure; residual symptoms; adverse events. Intervention: Short vs. extended antibiotic therapy for erythema migrans (≤ 10 days vs. > 10 days) and disseminated LB (≤ 21 days vs. > 21 days). Assessment of risk of bias. Independently, using the Cochrane Tools. Methods of data synthesis. Estimation of treatment effects based on a fixed-effect model (Mantel–Haenszel or Peto method), with odds ratio (OR) and 95% confidence intervals (CI). Results Thirty-eight full-text articles were examined (850 patients): 29 were included in the qualitative analysis; six in the meta-analysis. Heterogeneity was low (I² = 0%). At 12 months, short-term treatment did not differ from long-term treatment in terms of failures (OR1.50, 95%CI[0.43–5.22]) and residual symptoms (OR0.95, 95%CI[0.66–1.37]), albeit with small samples. Conclusion This meta-analysis was underpowered to prove non-inferiority of shorter treatment, but suggests its safety for EM. Studies focusing on antibiotics duration, with sufficient sample sizes and clear outcomes, are warranted. Graphical Abstract

Hair cortisol concentration is a retrospective, long-term measure of cortisol secretion, often used as a biomarker for chronic stress or suspected cyclic Cushing’s syndrome. Various methods for hair cortisol extraction, typically involving intact, minced, or milled hair incubated with methanol or extraction buffers, may not achieve complete extraction. Incomplete extraction can bias results, particularly when comparing hair samples of differing thickness and texture. Additionally, sample-to-sample variation might be caused by inconsistent cutting or grinding of the hair by different technicians. We aimed to achieve complete cortisol extraction through the enzymatic digestion of hair. After digestion and sample clean-up, we analyzed the final extracts using two-dimensional liquid chromatography-mass spectrometry. Complete digestion was observed with an overnight enzymatic reaction. This method demonstrated high reproducibility, with an intra-day precision of 3.6%, and inter-day precision of 6.5% in a homogenized pool. Moreover, duplicate CV% of intact hairlocks ranged from 0.1% to 8.9%. Our protocol does not influence the cortisol concentration. It is less labor-intensive and more consistent than mincing or milling hair. Our extraction yield was higher compared to the commonly used methanol extraction method. Samples extracted with methanol showed, on average, 19% lower cortisol concentrations than those measured in digested aliquots. We have developed and validated a new, superior method for extracting cortisol from hair utilizing enzymatic digestion. This strategy provides a more thorough extraction, greater consistency, and requires less labor than traditional methods. Graphical Abstract

Healthcare professionals (HCPs) encounter various moral challenges in clinical practice. In various countries, clinical ethics support (CES) services are developed to support HCPs. One of these CES services is clinical ethics committees (CECs): they address moral challenges faced in healthcare settings and offer support for HCPs. However, in Tanzania, CECs have not yet been implemented. For implementation purposes, greater knowledge about how healthcare professionals navigate and respond to moral challenges, their understanding of CECs, and what they perceive as key needs for implementing CECs in hospitals, are valuable. This study explores HCPs’ ways of dealing with their moral challenges at the moment and identifies key needs for establishing CECs in Tanzanian healthcare settings in the near future. The findings show that various implicit ways have been acknowledged as being useful in addressing moral challenges (e.g., regular meetings, family conferences, social welfare units, hospital procedures and guidelines, as well as consulting legal and management units). In addition, HCPs reported that a necessity exists for implementing more formal and systematic modalities to address moral challenges in clinical settings. The research in this paper has served as a preparation for establishing the first CEC in Tanzanian healthcare settings.

The effect of sodium‐glucose cotransporter‐2 (SGLT2) inhibitor ertugliflozin on fluid volume and kidney function was assessed in patients with type 2 diabetes and heart failure. Thirty‐four participants were randomized in this double‐blind, placebo‐controlled, parallel‐group, multicenter study. Physiologic measurements were obtained under clamped euglycemia at baseline, 1 week, and 12 weeks of treatment. The primary outcome was the proximal tubular natriuretic effect of ertugliflozin versus placebo, measured by fractional excretion of lithium (FELi). Ertugliflozin did not increase FELi or total FENa at 1 week or 12 weeks. Ertugliflozin increased both mean 24‐h urinary sodium excretion (47.5 ± 22.1 mmol/day vs. placebo, p = 0.032) and urinary volume (p = 0.009) at 1 week, which was attenuated at Week 12. Reductions in extracellular fluid (−1.9 ± 0.8 L, p = 0.01), estimated plasma volume (−11.9 ± 13.9%, p = 0.02), and supine mean arterial pressure (−6.6 ± 2.7 mmHg, p = 0.02) were significant at Week 12. Compared to placebo, ertugliflozin acutely increased circulating angiotensinogen and angiotensin‐converting enzyme (ACE) levels, as well as urine adenosine and ACE2 activity (p < 0.05). Changes in other neurohormones, sympathetic activity, kidney, and systemic hemodynamics did not differ compared to placebo. Our findings suggest that SGLT2 inhibition shifts systemic volume toward a state of euvolemia, potentially lowering the risk of worsening heart failure.

Various open science practices have been proposed to improve the reproducibility and replicability of scientific research, but not for all practices, there may be evidence they are indeed effective. Therefore, we conducted a scoping review of the literature on interventions to improve reproducibility. We systematically searched Medline, Embase, Web of Science, PsycINFO, Scopus and Eric, on 18 August 2023. Any study empirically evaluating the effectiveness of interventions aimed at improving the reproducibility or replicability of scientific methods and findings was included. We summarized the retrieved evidence narratively and in evidence gap maps. Of the 105 distinct studies we included, 15 directly measured the effect of an intervention on reproducibility or replicability, while the remainder addressed a proxy outcome that might be expected to increase reproducibility or replicability, such as data sharing, methods transparency or pre-registration. Thirty studies were non-comparative and 27 were comparative but cross-sectional observational designs, precluding any causal inference. Despite studies investigating a range of interventions and addressing various outcomes, our findings indicate that in general the evidence base for which various interventions to improve reproducibility of research remains remarkably limited in many respects.

Background/Objective: Evaluating the measurement properties (MPs) of Clinician-Reported Outcome Measures (ClinROMs) is crucial for selecting appropriate instruments for vitiligo assessment. This review critically appraises the existing evidence on the MPs of the ClinROMs used in vitiligo. Methods: A systematic search was conducted in PubMed, Embase, and the Cochrane Library up to 20 February 2024, identifying validated ClinROMs in vitiligo. Studies were included if they provided original data on ClinROM development or analysis, excluding those solely validating other instruments. The assessment of ClinROM quality and risk of bias analysis followed COSMIN guidelines, and ClinROMs with the highest number of sufficiently rated MPs supported by a moderate/high Quality of Evidence (QoE) were identified per construct category (extent/repigmentation and evolution/activity). Results: This review included 22 studies evaluating 12 ClinROMs. For extent/repigmentation, the Vitiligo Area and Severity Index (VASI), Vitiligo Extent Score (VES), and VESplus each had four MPs rated sufficient with a moderate/high QoE. For evolution, the Vitiligo Disease Improvement Score (VDIS) and Vitiligo Disease Activity Score (VDAS) similarly had four MPs rated sufficient with a moderate/high QoE. For activity evaluated based on a single time point, the Vitiligo Signs of Activity Score (VSAS), the only validated ClinROM for visible signs of disease activity, had three MPs rated sufficient with a moderate/high QoE. Conclusions: Six ClinROMs demonstrated the highest quality ratings across two key constructs. However, none underwent a complete evaluation of all their MPs, highlighting the need for further validation and refinement.

Migration is associated with a substantial change in environmental exposures and health outcomes. We aimed to investigate the shift in gut microbiota composition and the associations with cardiometabolic outcomes in the RODAM-Pros cohort spanning multiple research sites across continents. We determined gut microbiota composition of 1,177 Ghanaian participants in rural Ghana, urban Ghana, and Amsterdam, the Netherlands, using 16S rRNA sequencing. We observed a clear gradient in gut microbiota composition and alpha and beta diversity from rural Ghana to urban Ghana, to Amsterdam. We used pairwise XGBoost machine learning classification models to identify which microbes were most distinct between locations in prevalence and abundance. The associations between these microbes and the locations could partly be explained by differences in confounders such as dietary intake. Groups of microbes that emerged or disappeared along the migration axis were associated with cardiometabolic outcomes, including higher body mass index, higher HbA1c and higher diastolic blood pressure. Concluding, we identified associations between a shift in gut microbiota composition and cardiometabolic risk along the migration axis, underscoring the relevance of gut health in the context of migration-associated adverse health outcomes.

Background Over 6 million people have fled their homes in response to the full-scale invasion of Russian armed forces into Ukraine and are forcibly displaced since the start on 4 February 2022. Refugees, both adults and children, have a high risk of developing mental health disorders, in particular post-traumatic stress disorder, depression and anxiety disorders. Research into the mental health of Ukrainian families and their needs is urgently needed. The primary aim of this study is to increase our understanding of the consequences of potentially traumatic events for the mental health of parents and children. This may inform the development of mental health and psychosocial support interventions which can be readily implemented in the family context. Methods and analysis We will conduct a four-wave longitudinal online survey study among Ukrainian families displaced to the Netherlands. This study is a part of the Nadiya data collection, intended to assess the mental health responses of Ukrainian refugee families to the stress of war, forced migration, family separation and adaptation to new circumstances in their hosting country. Participants are assessed at four time points, approximately 6 months apart. Data collection for T1 started in May 2023. We aim to recruit a total of n=1500 participants at T1, of which n=1000 adults (18 years and older) and n=500 children (8–11 years) and teenagers (12–17 years). To investigate symptom profiles and associated risk and protective factors among parents and children, we will use latent class growth modelling. Ethics and dissemination The data collection procedure has been approved by the Ethical Committee of the Faculty of Social Sciences of Utrecht University. Data will be deposited, stored and shared using Utrecht University’s institutional research data repository Yoda. This research project is part of the Global Collaboration on Traumatic Stress; all authors are affiliated with this network. The findings will be published in peer-reviewed, open access journals and further disseminated through conference presentations, news updates at the project website and on the websites of the Dutch Society for Traumatic Stress Studies ( www.ntvp.nl ), and the European Society of Traumatic Stress Studies, as well as through media contributions. Trial registration number The current study was registered on 26 March 2024 on The Open Science Framework (OSF): https://doi.org/10.17605/OSF.IO/9FP7U .

Samenvatting Verschillende risicoclassificatiesystemen (RCS) worden wereldwijd gebruikt om patiënten met nieuw gediagnosticeerde prostaatkanker in prognostische groepen in te delen. Deze studie onderzocht de voorspellende waarde van risicogroepen (laag, intermediair en hoog risico) binnen vier RCS (EAU, NCCN, CPG en CAPRA) voor het detecteren van metastasen op PSMA-PET/CT. Metastasen werden gevonden bij 35 % (931/2.630) van de patiënten. De prevalentie in intermediair- en hoogrisicogroepen varieerde tussen 12 % tot 46 %. Twee RCS deelden deze groepen verder op: metastasen werden gevonden bij 5,8 %, 13 %, 22 % en 62 % voor respectievelijk gunstig intermediair-, ongunstig intermediair-, hoog- en zeerhoogrisicoprostaatkanker (NCCN); en bij 6,9 %, 13 %, 21 % en 60 % voor de overeenkomstige CPG-groepen. Deze studie benadrukt het belang van gedetailleerde risicostratificatie. Primaire PSMA-PET/CT wordt geadviseerd voor patiënten met ongunstig intermediairrisicoprostaatkanker of hoger.