[Education, can it be done differently? A sketch of a new training structure for medical specialists]. / Opleiden, kan het anders?

A working group of the 'Resident Education 2025' project of the Association Medical Specialists has the task of developing a training structure for future medical specialist, which is more in line with the desired interprofessional collaboration within a network, with the right care on the right place. Responding to the required flexibility and deployment of medical specialists, also outside the intramural environment. In doing so, we want to safeguard and strengthen the enthusiasm of future and current specialists, among other things through a better work-life balance. A sketch of a training structure has been made, in which the new colleagues first broadly orientate themselves in the various options. Subsequently, by choosing a specific path (of EPAs) which can lead into a medical specialty in a more generalist sense and possibly further differentiate into a sub-specialist. Digital education is offered nationally with various themes, which can be choices in terms of subject and time at which this can be followed. This concept will be further elaborated by the working group in consultation with the various stakeholders, while also considering all obstacles that could stand in the way of this change.The working group Training structure hopes to start a discussion about a possible new training structure for the medical specialist of the future.

Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature.

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

A National Process to Enhance the Validity of Entrustment Decisions for Dutch Pediatric Residents.

BACKGROUND: Postgraduate medical education (PGME) has become increasingly individualized, and entrustable professional activities (EPAs) have been adopted to operationalize this. At the same time, the process and content to determine residents' progress using high-stakes summative entrustment decisions by clinical competency committees (CCCs) is not yet well established. OBJECTIVE: We evaluated the experiences with a structured process for assessment of EPAs to attain uniform summative entrustment decisions for a national sample of pediatric residents. METHODS: An EPA-based national PGME program for pediatric residents was introduced in the Netherlands, including a process of uniform summative entrustment decisions, termed the Evaluation and Assessment of Residents by Supervisors (EARS) procedure. To evaluate the program, we assessed survey data and information from invitational conferences. RESULTS: Beginning in January 2017, 125 pediatric residents in all 8 Dutch residency regions started training in the EARS program. The program enabled robust summative entrustment decisions. Preliminary data suggested that faculty, despite increased preparation time, appreciated the comprehensive appraisal of resident qualifications. The EPA-based program was well accepted by residents. Fifty-one percent (57 of 112) had at least 2 EARS procedures per year, and for 75% (84 of 112) the level of supervision was often or always adjusted to their level of training. CONCLUSIONS: A national EPA-based program provided a structured process for summative entrustment decisions by CCCs and enabled individualized stepwise progression of residents toward unsupervised practice. Broader application of these concepts may require adaptations to accommodate different health care systems and specialties.

Cost-effectiveness of FENO-based and web-based monitoring in paediatric asthma management: a randomised controlled trial.

BACKGROUND: In children with asthma, web-based monitoring and inflammation-driven therapy may lead to improved asthma control and reduction in medications. However, the cost-effectiveness of these monitoring strategies is yet unknown. OBJECTIVE: We assessed the cost-effectiveness of web-based monthly monitoring and of 4-monthly monitoring of FENO as compared with standard care. METHODS: An economic evaluation was performed alongside a randomised controlled multicentre trial with a 1-year follow-up. Two hundred and seventy-two children with asthma, aged 4-18 years, were randomised to one of three strategies. In standard care, treatment was adapted according to Asthma Control Test (ACT) at 4-monthly visits, in the web-based strategy also according to web-ACT at 1 month intervals, and in the FENO-based strategy according to ACT and FENO at 4-monthly visits. Outcome measures were patient utilities, healthcare costs, societal costs and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: No statistically significant differences were found in QALYs and costs between the three strategies. The web-based strategy had 77% chance of being most cost-effective from a healthcare perspective at a willingness to pay a generally accepted €40 000/QALY. The FENO-based strategy had 83% chance of being most cost-effective at €40 000/QALY from a societal perspective. CONCLUSIONS: Economically, web-based monitoring was preferred from a healthcare perspective, while the FENO-based strategy was preferred from a societal perspective, although in QALYs and costs no statistically significant changes were found as compared with standard care. As clinical outcomes also favoured the web-based and FENO-based strategies, these strategies may be useful additions to standard care. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR1995).

Monitoring strategies in children with asthma: a randomised controlled trial.

BACKGROUND: Asthma guidelines recommend monitoring of asthma control. However, in a substantial proportion of children, asthma is poorly controlled and the best monitoring strategy is not known. OBJECTIVES: We studied two monitoring strategies for their ability to improve asthma outcomes in comparison with standard care (SC): web-based monthly monitoring with the (Childhood) Asthma Control Test (ACT or C-ACT) and 4-monthly monitoring of FENO. METHODS: In this randomised controlled, partly blinded, parallel group multicentre trial with a 1-year follow-up, children aged 4-18 with a doctor's diagnosis of asthma treated in seven hospitals were randomised to one of the three groups. In the web group, treatment was adapted according to ACT obtained via a website at 1-month intervals; in the FENO group according to ACT and FENO, and in the SC group according to the ACT at 4-monthly visits. The primary endpoint was the change from baseline in the proportion of symptom-free days (SFD). RESULTS: Two-hundred and eighty children (mean age 10.4 years, 66% boys) were included; 268 completed the study. Mean changes from baseline in SFD were similar between the groups: -2.1% (web group, n=90), +8.9% (FENO group, n=91) versus 0.15% (SC, n=87), p=0.15 and p=0.78. Daily dose of inhaled corticosteroids (ICS) decreased more in the web-based group compared with both other groups (-200 µg/day, p<0.01), while ACT and SFD remained similar. CONCLUSIONS: The change from baseline in SFD did not differ between monitoring strategies. With web-based ACT monitoring, ICS could be reduced substantially while control was maintained. TRIAL REGISTRATION NUMBER: NTR 1995.

The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial.

Bronchiolitis is a common disorder in young children that often results in hospitalisation. Except for a possible effect of nebulised hypertonic saline (sodium chloride), no evidence-based therapy is available. This study investigated the efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis. In this multicentre, double-blind, randomised, controlled trial, children hospitalised with acute viral bronchiolitis were randomised to receive either nebulised 3%, 6% hypertonic saline or 0.9% normal saline during their entire hospital stay. Salbutamol was added to counteract possible bronchial constriction. The primary endpoint was the length of hospital stay. Secondary outcomes were need for supplemental oxygen and tube feeding. From the 292 children included in the study (median age 3.4 months), 247 completed the study. The median length of hospital stay did not differ between the groups: 69 h (interquartile range 57), 70 h (IQR 69) and 53 h (IQR 52), for 3% (n=84) and 6% (n=83) hypertonic saline and 0.9% (n=80) normal saline, respectively, (p=0.29). The need for supplemental oxygen or tube feeding did not differ significantly. Adverse effects were similar in the three groups. Nebulisation with hypertonic saline (3% or 6% sodium chloride) although safe, did not reduce the length of stay in hospital, duration of supplemental oxygen or tube feeding in children hospitalised with moderate-to-severe viral bronchiolitis.

Monitoring childhood asthma: web-based diaries and the asthma control test.

BACKGROUND: Data from asthma diaries are frequently used as an end point in asthma studies; however, data on the validity of Web-based diaries are scarce. OBJECTIVES: First, we examined the validity of a Web-based diary in assessing asthma control. Second, we determined the cutoff points for well-controlled asthma of the Childhood Asthma Control Test (C-ACT) and the Asthma Control Test (ACT), and calculated the minimal important difference for both tests. METHODS: Children with asthma, ages 4-18 years (n = 228) completed a 4-week Web-based diary, C-ACT, ACT, and an asthma-related quality-of-life questionnaire at baseline and after 1-year follow-up. RESULTS: The completion rate of the Web-based diaries was 89%. The diary scores correlated strongly with C-ACT and ACT scores (r = -0.73, P < .01; r = -0.64, P < .01, respectively) and the changes in diary scores correlated well with changes in C-ACT and ACT scores. The best cutoff points for well-controlled asthma were C-ACT ≥ 22 and ACT ≥ 23. The minimal important differences were 1.9 (95% CI, 1.3-2.5) for ACT and 1.6 (95% CI, 1.1-2.1) for C-ACT, and -0.7 points/d (95% CI, -1.1 to -0.4) for the Web-based diary. CONCLUSIONS: Our Web-based diary was valid for recording asthma symptoms. Cutoff points of ≥22 (C-ACT) and ≥23 (ACT) define well-controlled asthma. We recommend a 2 C-ACT and ACT points difference as minimally important.

Evaluation of interrupter resistance in methacholine challenge testing in children.

Bronchial hyperresponsiveness (BHR) is a key feature of asthma and is assessed using bronchial provocation tests. The primary outcome in such tests (a 20% decrease in forced expiratory volume in 1 sec (FEV1)) is difficult to measure in young patients. This study evaluated the sensitivity and specificity of the interrupter resistance (Rint ) technique, which does not require active patient participation, by comparing it to the primary outcome measure. Methacholine challenge tests were performed in children with a history of moderate asthma and BHR. Mean and individual changes in Rint and FEV1 were studied. A receiver operating characteristic (ROC) curve was used to describe sensitivity and specificity of Rint . Seventy-three children (median age: 9.2 years; range: 6.3-13.4 years) participated. There was a significant (P < 0.01) increase in mean Rint with increasing methacholine doses. However, individual changes of Rint showed large fluctuations. There was great overlap in change of Rint between children who did and did not reach the FEV1 endpoint. A ROC curve showed an area under the curve of 0.65. Because of low sensitivity and specificity, the use of Rint to diagnose BHR in individual patients seems limited.

Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma.

RATIONALE: For children with symptomatic asthma despite low to moderate doses of inhaled corticosteroids, evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of inhaled corticosteroids. OBJECTIVE: To evaluate whether salmeterol/fluticasone propionate (SFP), 50/100 µg twice a day, is noninferior regarding symptom control compared with fluticasone propionate (FP), 200 µg twice a day Diskus in children with symptomatic asthma. METHODS: A multicenter, randomized, parallel-group, double-blind study was performed comparing SFP and FP treatment during 26 weeks on asthma control and lung function. MEASUREMENTS AND MAIN RESULTS: A total of 158 children, 6-16 years old, still symptomatic on FP, 100 µg twice a day, during a 4-week run-in period, were included. Percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups (per protocol analysis: adjusted mean difference [FP minus SFP] 2.6%; 95% confidence interval, -8.1 to 13.4). Both groups showed substantial improvements of about 25 percent points in symptom-free days (both P < 0.001 from baseline). Lung function measurements (FEV(1), FVC, PEF rate, and maximal expiratory flow) did not differ between groups except for a slight advantage in maximal expiratory flow in the SFP group at 1 week. No differences were found between FP and SFP regarding exacerbation rates, adverse events, or growth. CONCLUSIONS: In our study the efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid.

Structural lung changes, lung function, and non-invasive inflammatory markers in cystic fibrosis.

Cystic fibrosis (CF) lung disease is characterized by chronic airway inflammation and recurrent infections, resulting in (ir)reversible structural lung changes and a progressive decline in lung function. The objective of this study was to investigate the relationship between non-invasive inflammatory markers (IM) in exhaled breath condensate (EBC), lung function indices and structural lung changes, visualized by high resolution computed tomography (HRCT) scans in CF. In 34 CF patients, lung function indices (forced expiratory volume in 1 s, forced vital capacity [FVC], residual volume, and total lung capacity [TLC]) and non-invasive IM (exhaled nitric oxide, and condensate acidity, nitrate, nitrite, 8-isoprostane, hydrogen peroxide, interferon-gamma) were assessed. HRCT scans were scored in a standardized and validated way, a composite score and component scores were calculated. In general, the correlations between non-invasive IM and structural lung changes, and between IM and lung function were low (correlation coefficients <0.40). Patients with positive sputum Pseudomonas cultures had higher EBC nitrite levels and higher parenchymal HRCT subscores than patients with Pseudomonas-negative cultures (p < 0.05). Multiple linear regression models demonstrated that FVC was significantly predicted by hydrogen peroxide in EBC, and the scores of bronchiectasis and mosaic perfusion (Pearson correlation coefficient R = 0.78, p < 0.001). TLC was significantly predicted by 8-isoprostane, nitrate, hydrogen peroxide in EBC, and the mucous plugging subscore (R = 0.92, p < 0.01). Static and dynamic lung function indices in this CF group were predicted by the combination of non-invasive IM in EBC and structural lung changes on HRCT imaging. Future longitudinal studies should reveal whether non-invasive monitoring of airway inflammation in CF adds to better follow-up of patients.

Biomarkers in exhaled breath condensate indicate presence and severity of cystic fibrosis in children.

Chronic airway inflammation is present in cystic fibrosis (CF). Non-invasive inflammometry may be useful in disease management. The aim of the present cross-sectional study was to investigate: (i) the ability of fractional exhaled nitric oxide and inflammatory markers (IM) [exhaled breath condensate (EBC) acidity, nitrite, nitrate, hydrogen peroxide (H(2)O(2)), 8-isoprostane, Th1/Th2 cytokines] to indicate (exacerbations of) CF; and (ii) the ability of these non-invasive IM to indicate CF disease severity. In 98 children (48 CF/50 controls), exhaled nitric oxide was measured using the NIOX, and condensate was collected using a glass condenser. In CF interferon (IFN-gamma) and nitrite concentrations were significantly higher, whereas exhaled nitric oxide levels were significantly lower compared with controls (3.3 +/- 0.3 pg/ml, 2.2 +/- 0.2 microM, 10.0 +/- 1.2 p.p.b. vs. 2.6 +/- 0.2 pg/ml, 1.4 +/- 0.1 microM, 15.4 +/- 1.4 p.p.b. respectively). Using multivariate logistic regression models, the presence of CF was best indicated by 8-isoprostane, nitrite and IFN-gamma [sensitivity 78%, specificity 83%; area under receiver operating characteristic curve (AUC) 0.906, p < 0.001]. An exacerbation of CF was best indicated by 8-isoprostane and nitrite (sensitivity 40%, specificity 97%, AUC curve 0.838, p = 0.009). Most indicative biomarkers of CF severity were exhaled nitric oxide, and condensate acidity (sensitivity 96%, specificity 67%; AUC curve 0.751, p = 0.008). In this cross-sectional study, the combination of different exhaled IM could indicate (exacerbations of) CF, and severity of the disease in children. Longitudinal data are necessary to further confirm the role of these markers for the management of CF in children.

A novel microdeletion in 1(p34.2p34.3), involving the SLC2A1 (GLUT1) gene, and severe delayed development.

A de novo 4.1-megabase microdeletion of chromosome 1p34.2p34.3 has been identified by array-based comparative genomic hybridization in a young male with severely delayed development, microcephaly, pronounced hypotonia, and facial dysmorphism. The deleted region encompasses 48 genes, among them the glucose transporter 1 (SLC2A1 or GLUT1) gene. The deletion of the GLUT1 gene was in line with the abnormal ratio of cerebrospinal fluid (CSF) glucose to blood glucose, indicative of GLUT1 deficiency syndrome (MIM #606777). GLUT1 deficiency syndrome is characterized by therapy-resistant infantile seizures, developmental delay, acquired microcephaly, spasticity, ataxia, and a low concentration of glucose in the CSF. It is known that a ketogenic diet can lead to better control of seizures. This case study shows that identifying a microdeletion as the cause of learning disability is not only important for genetic counselling but might also lead to therapeutic intervention.

Management of blunt tracheal trauma in children: a case series and review of the literature.

Blunt tracheal trauma seldom develops in children because of their anatomy and the mobility of the cartilage. It has the potential to be overlooked, either because of the severity of concomitant injuries or because of the unfamiliarity of paediatricians with this type of injury. However, tracheal injury might be lethal due to airway compromise. Early bronchoscopy may be necessary to anticipate complications and prevent permanent dysfunction. We present a retrospective, double-institution case series over a 5-year period, describing five children, aged 3 to 14 years, with tracheal injury after blunt cervical trauma. All patients showed emphysema with pneumomediastinum. After explorative bronchoscopy, all patients were successfully treated with antibiotics and/or supportive ventilation. In summary, minimal lesions due to blunt tracheal trauma could be treated conservatively in children. Since the external signs of tracheal injury are not indicative of the extent of the trauma, a high index of suspicion is warranted in these patients.

Poor adherence to self-medication instructions in children with asthma and their parents.

This study describes a self-treatment program for parents of children with asthma. The aim was to prevent asthma exacerbations by learning to recognise prodromal signs and acting upon them by increasing inhaled corticosteroids (ICS). The study questions were: (1) can we teach parents and children to recognise prodromal signs? (2) are instructions to increase inhalation medication followed? (3) will frequency and severity of asthma attacks diminish subsequently? Due to physicians' changed attitude towards prescription of ICS, fewer children could be recruited who were "ICS-naive" than expected. Twenty-nine children of the age of 4-11 years with moderate asthma, participated in a one year prospective randomised study. Structured information was given to all patients on asthma, symptoms and medication. The experimental group received additional information on recognising prodromal signs and doubling ICS during one week. Only in 25% of the patients who recognised prodromal signs the dose of ICS was doubled (as prescribed), in 75% inadequately or not at all. Recognition of prodromal signs was poor as well as compliance to increase as-needed medication. No significant decrease of asthma symptoms occurred in the experimental group. Clinical implications are important for self-treatment instructions: an individually tailored and multi-component program should be offered by health care providers in order to help the patient to recognise early alarm symptoms, comply to self-treatment instructions and to make adaptations for continuous self-regulation.