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Bertine MJ Flokstra - de Blok,1,2 Thys van der Molen,1,2 Wianda A Christoffers,3 Janwillem WH Kocks,1,2 Richard L Oei,4 Joanne NG Oude Elberink,2,4 Emmy M Roerdink,5 Marie Louise Schuttelaar,3 Jantina L van der Velde,1,2 Thecla M Brakel,1,6 Anthony EJ Dubois2,5 1Department of General Practice, 2GRIAC Research Institute, 3Department of Dermatology, 4Department of Allergology, 5Department of Pediatric Pulmonology and Pediatric Allergy, University of Groningen, University Medical Center Groningen, 6Teaching Unit, Department of Social Psychology, University of Groningen, Groningen, The Netherlands Background: Management of allergic patients in the population is becoming more difficult because of increases in both complexity and prevalence. Although general practitioners (GPs) are expected to play an important role in the care of allergic patients, they often feel ill-equipped for this task. Therefore, the aim of this study was to develop an allergy management support system (AMSS) for primary care. Methods: Through literature review, interviewing and testing in secondary and primary care patients, an allergy history questionnaire was constructed by allergists, dermatologists, GPs and researchers based on primary care and specialists’ allergy guidelines and their clinical knowledge. Patterns of AMSS questionnaire responses and specific immunoglobulin E (sIgE)-test outcomes were used to identify diagnostic categories and develop corresponding management recommendations. Validity of the AMSS was investigated by comparing specialist (gold standard) and AMSS diagnostic categories. Results: The two-page patient-completed AMSS questionnaire consists of 12 (mainly) multiple choice questions on symptoms, triggers, severity and medication. Based on the AMSS questionnaires and sIgE-test outcome of 118 patients, approximately 150 diagnostic categories of allergic rhinitis, asthma, atopic dermatitis, anaphylaxis, food allergy, hymenoptera allergy and other allergies were identified, and the corresponding management recommendations were formulated. The agreement between the allergy specialists’ assessments and the AMSS was 69.2% (CI 67.2–71.2). Conclusion: Using a systematic approach, it was possible to develop an AMSS that allows for the formulation of diagnostic and management recommendations for GPs managing allergic patients. The AMSS thus holds promise for the improvement of the quality of primary care for this increasing group of patients. Keywords: allergy, development, diagnosis, management support system, primary care

Introduction: Integrated care is effective in reducing all-cause mortality in patients with atrial fibrillation (AF) in primary care, though time and resource intensive. The aim of the current study was to assess whether integrated care should be directed at all AF patients equally., Methods: The ALL-IN trial (n = 1,240 patients, median age 77 years) was a cluster-randomized trial in which primary care practices were randomized to provide integrated care or usual care to AF patients aged 65 years and older. Integrated care comprised of (i) anticoagulation monitoring, (ii) quarterly checkups and (iii) easy-access consultation with cardiologists. For the current analysis, cox proportional hazard analysis with all clinical variables from the CHA2DS2-VASc score was used to predict all-cause mortality in the ALL-IN trial. Subsequently, the hazard ratio and absolute risk reduction were plotted as a function of this predicted mortality risk to explore treatment heterogeneity., Results: Under usual care, after a median of 2 years follow-up the absolute risk of all-cause mortality in the highest-risk quarter was 31.0%, compared to 4.6% in the lowest-risk quarter. On the relative scale, there was no evidence of treatment heterogeneity (p for interaction = 0.90). However, there was substantial treatment heterogeneity on the absolute scale: risk reduction in the lowest risk- quarter of risk 3.3% (95% CI -0.4% - 7.0) compared to 12.0% (95% CI 2.7% - 22.0) in the highest risk quarter., Conclusion: While the relative degree of benefit from integrated AF care is similar in all patients, patients with a high all-cause mortality risk have a greater benefit on an absolute scale and should therefore be prioritized when implementing integrated care., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: G.J. Geersing, F.H. Rutten, and M.E.W. Hemels report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. I.C. van Gelder reports consultancy fees from Boston, BMS and Bayer to the institution, unrestricted research grants from the Netherlands Cardiovascular Research Initiative, unrestricted research grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement: EHRA-PATHS (945260). M. Rienstra reports Consultancy fees from Bayer, Microport, InCarda Therapeutics to the institution, an unrestricted research grant from ZonMW and the Dutch Heart Foundation; DECISION project 848090001, unrestricted research grants from the Netherlands Cardiovascular Research Initiative: an initiative with support of the Dutch Heart Foundation; RACE V (CVON 2014–9), RED-CVD (CVON2017-11), an unrestricted research grant from Top Sector Life Sciences & Health to the Dutch Heart Foundation (PPP Allowance; CVON-AI (2018B017)), and an unrestricted research grant from the European Union’s Horizon 2020 research and innovation programme under grant agreement; EHRA-PATHS (945260). S. van Doorn reports an unrestricted institutional grant for performing research in the field of stroke diagnosis from Stoffels-Hornstra. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Trinks-Roerdink et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Diagnostic delay in patients with pulmonary embolism (PE) is typical, yet the proportion of patients with PE that experienced delay and for how many days is less well described, nor are determinants for such delay., Objectives: This study aimed to assess the prevalence and extent of delay in diagnosing PE., Methods: A systematic literature search was performed to identify articles reporting delays in diagnosing PE. The primary outcome was mean delay (in days) or a percentage of patients with diagnostic delay (defined as PE diagnosis more than seven days after symptom onset). The secondary outcome was determinants of delay. Random-effect meta-analyses were applied to calculate a pooled estimate for mean delay and to explore heterogeneity in subgroups., Results: The literature search yielded 10,933 studies, of which 24 were included in the final analysis. The pooled estimate of the mean diagnostic delay based on 12 studies was 6.3 days (95% prediction interval 2.5 to 15.8). The percentage of patients having more than seven days of delay varied between 18% and 38%. All studies assessing the determinants of coughing ( n  = 3), chronic lung disease ( n  = 6) and heart failure ( n  = 8) found a positive association with diagnostic delay. Similarly, all studies assessing recent surgery ( n  = 7) and hypotension ( n  = 6), as well as most studies assessing chest pain ( n  = 8), found a negative association with diagnostic delay of PE., Conclusion: Patients may have symptoms for almost one week before PE is diagnosed and in about a quarter of patients, the diagnostic delay is even longer.

Aims: To evaluate the extent and determinants of off-label non-vitamin K oral anticoagulant (NOAC) dosing in newly diagnosed Dutch AF patients., Methods and Results: In the DUTCH-AF registry, patients with newly diagnosed AF (<6 months) are prospectively enrolled. Label adherence to NOAC dosing was assessed using the European Medicines Agency labelling. Factors associated with off-label dosing were explored by multivariable logistic regression analyses. From July 2018 to November 2020, 4500 patients were registered. The mean age was 69.6 ± 10.5 years, and 41.5% were female. Of the 3252 patients in which NOAC label adherence could be assessed, underdosing and overdosing were observed in 4.2% and 2.4%, respectively. In 2916 (89.7%) patients with a full-dose NOAC recommendation, 4.6% were underdosed, with a similar distribution between NOACs. Independent determinants (with 95% confidence interval) were higher age [odds ratio (OR): 1.01 per year, 1.01-1.02], lower renal function (OR: 0.96 per ml/min/1.73 m 2 , 0.92-0.98), lower weight (OR: 0.98 per kg, 0.97-1.00), active malignancy (OR: 2.46, 1.19-5.09), anaemia (OR: 1.73, 1.08-2.76), and concomitant use of antiplatelets (OR: 4.93, 2.57-9.46). In the 336 (10.3%) patients with a reduced dose NOAC recommendation, 22.9% were overdosed, most often with rivaroxaban. Independent determinants were lower age (OR: 0.92 per year, 0.88-0.96) and lower renal function (OR: 0.98 per ml/min/1.73 m 2 , 0.96-1.00)., Conclusion: In newly diagnosed Dutch AF patients, off-label dosing of NOACs was seen in only 6.6% of patients, most often underdosing. In this study, determinants of off-label dosing were age, renal function, weight, anaemia, active malignancy, and concomitant use of antiplatelets., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Introduction: Anticoagulation therapy is pivotal in the management of stroke prevention in atrial fibrillation (AF). Prospective registries, containing longitudinal data are lacking with detailed information on anticoagulant therapy, treatment adherence and AF-related adverse events in practice-based patient cohorts, in particular for non-vitamin K oral anticoagulants (NOAC). With the creation of DUTCH-AF, a nationwide longitudinal AF registry, we aim to provide clinical data and answer questions on the (anticoagulant) management over time and of the clinical course of patients with newly diagnosed AF in routine clinical care. Within DUTCH-AF, our current aim is to assess the effect of non-adherence and non-persistence of anticoagulation therapy on clinical adverse events (eg, bleeding and stroke), to determine predictors for such inadequate anticoagulant treatment, and to validate and refine bleeding prediction models. With DUTCH-AF, we provide the basis for a continuing nationwide AF registry, which will facilitate subsequent research, including future registry-based clinical trials., Methods and Analysis: The DUTCH-AF registry is a nationwide, prospective registry of patients with newly diagnosed 'non-valvular' AF. Patients will be enrolled from primary, secondary and tertiary care practices across the Netherlands. A target of 6000 patients for this initial cohort will be followed for at least 2 years. Data on thromboembolic and bleeding events, changes in antithrombotic therapy and hospital admissions will be registered. Pharmacy-dispensing data will be obtained to calculate parameters of adherence and persistence to anticoagulant treatment, which will be linked to AF-related outcomes such as ischaemic stroke and major bleeding. In a subset of patients, anticoagulation adherence and beliefs about drugs will be assessed by questionnaire., Ethics and Dissemination: This study protocol was approved as exempt for formal review according to Dutch law by the Medical Ethics Committee of the Leiden University Medical Centre, Leiden, the Netherlands. Results will be disseminated by publications in peer-reviewed journals and presentations at scientific congresses., Trial Registration Number: Trial NL7467, NTR7706 (https://www.trialregister.nl/trial/7464)., Competing Interests: Competing interests: GC and EMT-R are supported by a research grant of ZonMW (project numbers 848050006 and 848050007). JS is supported by a grant from the Dutch Federation of Anticoagulation Clinics (FNT), outside the submitted work. FAK has received research support from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, MSD, Daiichi Sankyo, Actelion, the Dutch Thrombosis Association and the Dutch Heart foundation. JRdG reports research grants from Abbott, AtriCure, Boston Scientific, Medtronic and Bayer. He received speaker/consultancy honoraria from AtriCure, Bayer, Daiichi Sankyo, Johnson & Johnson, Servier and Novartis; all outside the scope of this work. JGM received consultancy fees from BMS/Pfizer and Daiichi Sankyo. FS received consultancy fees from Daiichi Sankyo and BMS, and restricted institutional grants from Daiichi Sankyo. RGT reports grants and personal fees from Boehringer Ingelheim, Bayer, Pfizer, Bristol Meyer Squibb and Daiichi Sankyo. FHR and GJG received unrestricted institutional grants from Bayer, BMS/Pfizer, Boehringer Ingelheim and Daiichi Sankyo. MEWH received consultancy fees from Bayer, BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo and Roche, and received a research grant from Federation of Dutch Thrombosis Services. MVH reports unrestricted grants from and personal fees from Boehringer Ingelheim, Pfizer/BMS, Bayer Health Care, Aspen and Daiichi Sankyo, outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years, as more and more experience has been gained with prescribing direct oral anticoagulants (DOACs), new research initiatives have emerged in the Netherlands to improve the safety and appropriateness of DOAC treatment for stroke prevention in patients with atrial fibrillation (AF). These initiatives address several contemporary unresolved issues, such as inappropriate dosing, non-adherence and the long-term management of DOAC treatment. Dutch initiatives have also contributed to the development and improvement of risk prediction models. Although fewer bleeding complications (notably intracranial bleeding) are in general seen with DOACs in comparison with vitamin K antagonists, to successfully identify patients with high bleeding risk and to tailor anticoagulant treatment accordingly to mitigate this increased bleeding risk, is one of the research aims of recent and future years. This review highlights contributions from the Netherlands that aim to address these unresolved issues regarding the anticoagulant management in AF in daily practice, and provides a narrative overview of contemporary stroke and bleeding risk assessment strategies.

Background: Atopic dermatitis (AD) and food allergy frequently coexist in children., Objective: To examine the association between food allergy and AD., Methods: Between 2001 and 2011, children referred to our tertiary care center underwent double-blind, placebo-controlled food challenges (DBPCFCs) for one or more suspected food allergies as part of regular care. Immediate reactions were observed and recorded by allergy nursing staff, whereas late reactions were ascertained by semistructured telephone interview 48 hours after challenge. To test to which degree specific IgE results were predictive in the outcome of DBPCFCs in children with and without (previous and current) AD, logistic regression analysis was performed., Results: A total of 1186 DBPCFCs were studied. Sensitization to foods occurred significantly more often in children with previous AD. The association between specific IgE results and the outcome of DBPCFCs was significant for children with and without (previous and current) AD but stronger for children without current AD. The positivity rate of DBPCFCs in children with mild, moderate, and severe AD was 53.3%, 51.7%, and 100%, respectively. Children with AD and a history of worsening AD as their only symptom reacted as often to placebo as to challenge food., Conclusion: Children with current AD are more frequently asymptomatically sensitized to the foods in question than those without AD. In addition, children suspected of food allergy should be considered for testing, regardless of the severity of their AD. Our results suggest that children with exacerbation of AD in the absence of other allergic symptoms are unlikely to be food allergic., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The aim of the study was to estimate the prevalence of probable food allergy in adolescents aged 11-20 and to examine the frequency of epinephrine autoinjector (EAI) ownership among high-risk individuals. Adolescents were screened followed by a more detailed telephone questionnaire inquiring about suspected food(s), symptoms, diagnosis, and use of an EAI. The participating adolescents were classified as probably or unlikely to be food-allergic. The need for an EAI was assessed. In total, 2284 adolescents completed the screening questionnaire, of which 396 indicated food to be a problem and 168 agreed to be interviewed. Forty-eight adolescents were classified as probably food-allergic, of which eight were not aware of their food allergy. Twenty-three adolescents were considered candidates for an EAI, whereas only two of them had been prescribed this medication. The calculated questionnaire-based prevalence of EAI need was 3.0% (minimal prevalence at least 1.0%), whereas the EAI ownership was 0.09%. In conclusion, we found an alarming under prescription of EAIs in school-going adolescents., (© 2011 John Wiley & Sons A/S.)