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We sought to determine if corticosteroid administration is associated with a SARS-CoV-2 nucleic acid test-positive result and to describe therapies administered to SARS-CoV-2 infected children.We collected cross-sectional data from participants recruited in 41 pediatric emergency departments (ED) in 10 countries between March 2020 and June 2021. Participants were18 years old, had signs or symptoms of, or risk factors for acute SARS-CoV-2 infection, and had nucleic acid testing performed. To determine if SARS-CoV-2 test status was independently associated with corticosteroid administration, we used a multivariable conditional logistic regression model matched by study site to compare treatments administered based on SARS-CoV-2 test and disposition status. This analysis was repeated for the subgroup of study participants who were hospitalized.30.3% (3,121/10,315) of participants were SARS-CoV-2-positive. Although remdesivir was more commonly administered to SARS-CoV-2-positive children, use was infrequent (25/3120 [0.8%] vs 1/7188 [0.01%]; P = .001). Corticosteroid use was less common among SARS-CoV-2-positive children (219/3120 [7.0%] vs 759/7190 [10.6%]; P.001). Among hospitalized children, there were no differences in provision of inotropes, respiratory support, chest drainage or extracorporeal membrane oxygenation between groups. Corticosteroid administration was associated with age, history of asthma, wheezing, study month, hospitalization and intensive care unit admission; it was not associated with a positive SARS-CoV-2 test result overall (aOR: 0.91; 95%CI: 0.74, 1.12) or among the subgroup of those hospitalized (aOR: 1.04; 95%CI: 0.75, 1.44).Few disease-specific treatments are provided to SARS-CoV-2-positive children; clinical trials evaluating therapies in children are urgently needed.

Radiograph use contributes to low-value care for children in emergency departments (EDs), but little is known about systemic factors associated with their use. This study compares low-value radiograph use across ED settings by hospital type, pediatric volumes and physician specialty.This is a cross-sectional study of routinely collected administrative data. We included children (age 0-18 yr) discharged from EDs in Ontario, Canada, between 2010 and 2019 with diagnoses of bronchiolitis, asthma, abdominal pain and constipation. Multiple clinical practice guidelines recommend against routine radiograph use in these conditions. Logistic regression evaluated odds of low-value radiograph by ED setting (pediatric academic [referent], adult academic, community with or without pediatric consultation services), pediatric volume and physician specialty (pediatric emergency medicine [PEM, referent], emergency medicine [EM], family medicine with EM training, pediatrics, family medicine), adjusting for demographic, clinical and provider characteristics. We used generalized estimating equations to account for clustering by ED.Of the total 9 862 787 eligible pediatric ED discharges in Ontario, 60 914 children had bronchiolitis, 141 921 asthma, 333 332 abdominal pain and 110 514 constipation; 26.0% received low-value radiographs. Compared with pediatric EDs and PEM physicians (referents), patients with bronchiolitis were most likely to have a chest radiograph in adult academic EDs (adjusted odds ratio [OR] 5.1 [95% confidence interval (CI) 4.6-5.6]) and by family physicians with EM training (adjusted OR 4.8 [95% CI 4.5-5.1]). Patients with asthma were more likely to have a chest radiograph in adult academic EDs (adjusted OR 3.0 [95% CI 2.8-3.2]) and by EM physicians (adjusted OR 2.8 [95% CI 2.6-3.0]). Patients with abdominal pain and constipation were more likely to have abdominal radiographs in community hospitals with pediatric consultation (adjusted OR 1.6 [95% CI 1.6-1.7] and 2.3 [95% CI 2.3-2.4], respectively) and by family physicians with EM training (adjusted OR 1.6 [95% CI 1.6-1.7] and 2.1 [95% CI 2.0-2.2], respectively).Over the decade-long study period, low-value radiograph use was frequent for children with 4 common conditions seen in Ontario EDs. Quality improvement initiatives aimed at reducing unnecessary radiographs in children should focus on EM physicians practising in EDs that primarily treat adult patients.

Objective To determine if low household income is associated with disease severity following emergency department (ED) discharge in children with acute gastroenteritis (AGE). Methods We conducted a secondary analysis employing data collected in 10 US-based tertiary-care, pediatric EDs between 2014 and 2017. Participants were aged 3 to 48 months and presented for care due to AGE. Income status was defined based on 1) home ZIP Code median annual home income and 2) percentage of home ZIP Code households below the poverty threshold. The primary outcome was moderate-to-severe AGE, defined by a post-ED visit Modified Vesikari Scale (MVS) score ≥9. Secondary outcomes included in-person revisits, revisits with intravenous rehydration, hospitalization, and etiologic pathogens. Results About 943 (97%) participants with a median age of 17 months (interquartile range 10, 28) completed follow-up. Post-ED visit MVS scores were lower for the lowest household income group (adjusted: -0.60; 95% confidence interval [CI]: -1.13, -0.07). Odds of experiencing an MVS score ≥9 did not differ between groups (adjusted odds ratio: 0.91; 95% CI: 0.54, 1.52). No difference in the post-ED visit MVS score or the proportion of participants with scores ≥9 was observed using the national poverty threshold definition. For both income definitions, there were no differences in terms of revisits following discharge, hospitalizations, and intravenous rehydration. Bacterial enteropathogens were more commonly identified in the lowest socioeconomic group using both definitions. Conclusions Lower household income was not associated with increased disease severity or resource use. Economic disparities do not appear to result in differences in the disease course of children with AGE seeking ED care.

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children's pre-injury and 1-month post-injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion-weighted imaging at post-acute (2-33 days post-injury) and chronic (3 or 6 months via random assignment) post-injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, -0.58 (-1.04, -0.11), and superior longitudinal fasciculus, -0.49 (-0.90, -0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post-injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes.

ObjectiveTo assess the co-occurrence and clustering of post-concussive symptoms in children, and to identify distinct patient phenotypes based on symptom type and severity.MethodsWe performed a secondary analysis of the prospective, multicentre Predicting and Preventing Post-concussive Problems in Pediatrics (5P) cohort study, evaluating children 5–17 years of age presenting within 48 hours of an acute concussion. Our primary outcome was the simultaneous occurrence of two or more persistent post-concussive symptoms on the Post-Concussion Symptom Inventory at 28 days post-injury. Analyses of symptom and patient clusters were performed using hierarchical cluster analyses of symptom severity ratings.Results3063 patients from the parent 5P study were included. Median age was 12.1 years (IQR: 9.2–14.6 years), and 1857 (60.6%) were male. Fatigue was the most common persistent symptom (21.7%), with headache the most commonly reported co-occurring symptom among patients with fatigue (55%; 363/662). Headache was common in children reporting any of the 12 other symptoms (range: 54%–72%). Physical symptoms occurred in two distinct clusters: vestibular-ocular and headache. Emotional and cognitive symptoms occurred together more frequently and with higher severity than physical symptoms. Fatigue was more strongly associated with cognitive and emotional symptoms than physical symptoms. We identified five patient groups (resolved/minimal, mild, moderate, severe and profound) based on symptom type and severity.ConclusionPost-concussive symptoms in children occur in distinct clusters, facilitating the identification of distinct patient phenotypes based on symptom type and severity. Care of children post-concussion must be comprehensive, with systems designed to identify and treat distinct post-concussion phenotypes.

OBJECTIVES: Although most acute gastroenteritis (AGE) episodes in children rapidly self-resolve, some children go on to experience more significant and prolonged illness. We sought to develop a prognostic score to identify children at risk of experiencing moderate-to-severe disease after an index emergency department (ED) visit. METHODS: Data were collected from a cohort of children 3 to 48 months of age diagnosed with AGE in 16 North American pediatric EDs. Moderate-to-severe AGE was defined as a Modified Vesikari Scale (MVS) score ≥9 during the 14-day post-ED visit. A clinical prognostic model was derived using multivariable logistic regression and converted into a simple risk score. The model’s accuracy was assessed for moderate-to-severe AGE and several secondary outcomes. RESULTS: After their index ED visit, 19% (336/1770) of participants developed moderate-to-severe AGE. Patient age, number of vomiting episodes, dehydration status, prior ED visits, and intravenous rehydration were associated with MVS ≥9 in multivariable regression. Calibration of the prognostic model was strong with a P value of 0.77 by the Hosmer-Lemenshow goodness-of-fit test, and discrimination was moderate with an area under the receiver operator characteristic curve of 0.68 (95% confidence interval [CI] 0.65–0.72). Similarly, the model was shown to have good calibration when fit to the secondary outcomes of subsequent ED revisit, intravenous rehydration, or hospitalization within 72 hours after the index visit. CONCLUSIONS: After external validation, this new risk score may provide clinicians with accurate prognostic insight into the likely disease course of children with AGE, informing disposition decisions, anticipatory guidance, and follow-up care.

Despite clear testing recommendations for herpes simplex virus (HSV) infection in infants, few data exist on the comprehensiveness of HSV testing in practice. In a 23-center study of 112 infants with confirmed HSV disease, less than one-fifth had all recommended testing performed, highlighting the need for increased awareness of and adherence to testing recommendations for this vulnerable population.

Over the past decade, visits to American and Canadian emergency departments (EDs) for child and youth mental health care have increased substantially.

OBJECTIVE Describe the clinical presentation, prevalence of concurrent serious bacterial infection (SBI), and outcomes among infants with omphalitis. METHODS Within the Pediatric Emergency Medicine Collaborative Research Committee, 28 sites reviewed records of infants ≤90 days of age with omphalitis seen in the emergency department from January 1, 2008, to December 31, 2017. Demographic, clinical, laboratory, treatment, and outcome data were summarized. RESULTS Among 566 infants (median age 16 days), 537 (95%) were well-appearing, 64 (11%) had fever at home or in the emergency department, and 143 (25%) had reported fussiness or poor feeding. Blood, urine, and cerebrospinal fluid cultures were collected in 472 (83%), 326 (58%), and 222 (39%) infants, respectively. Pathogens grew in 1.1% (95% confidence interval [CI], 0.3%–2.5%) of blood, 0.9% (95% CI, 0.2%–2.7%) of urine, and 0.9% (95% CI, 0.1%–3.2%) of cerebrospinal fluid cultures. Cultures from the site of infection were obtained in 320 (57%) infants, with 85% (95% CI, 80%–88%) growing a pathogen, most commonly methicillin-sensitive Staphylococcus aureus (62%), followed by methicillin-resistant Staphylococcus aureus (11%) and Escherichia coli (10%). Four hundred ninety-eight (88%) were hospitalized, 81 (16%) to an ICU. Twelve (2.1% [95% CI, 1.1%–3.7%]) had sepsis or shock, and 2 (0.4% [95% CI, 0.0%–1.3%]) had severe cellulitis or necrotizing soft tissue infection. There was 1 death. Serious complications occurred only in infants aged CONCLUSIONS In this multicenter cohort, mild, localized disease was typical of omphalitis. SBI and adverse outcomes were uncommon. Depending on age, routine testing for SBI is likely unnecessary in most afebrile, well-appearing infants with omphalitis.

We compared the perfomance of SARS-CoV-2 reverse transcriptase real-time polymerase chain reaction (RT-PCR) to droplet digital PCR (ddPCR). 95% and 40% of positive and negative RT-PCR specimens, respectively, were positive on ddPCR yielding sensitivities of 84% (95% CI: 74, 91) and 97% (95% CI: 89, 99), for RT-PCR and ddPCR, respectively. We found that SARS-CoV-2 RT-PCR testing in children has a concerning false-negative rate at lower nucleocapsid gene copy numbers.

Although more guideline-adherent care has been described in pediatric compared to adult trauma centers, we aimed to provide a more detailed characterization of management and resource utilization of children with intra-abdominal injury (IAI) within pediatric centers. Our primary objective was to describe the epidemiology, diagnostic evaluation, and management of children with IAI across U.S. children's hospitals. Our secondary objective was to describe the interhospital variation in surgical management of children with IAI.We conducted a cross-sectional study of 33 hospitals in the Pediatric Health Information System. We included children aged18 years evaluated in the emergency department from 2010 to 2019 with IAI, as defined by ICD coding, and who underwent an abdominal computed tomography (CT). Our primary outcome was abdominal surgery. We categorized IAI by organ system and described resource utilization data. We used generalized linear regression to calculate adjusted hospital-level proportions of abdominal surgery, with a random effect for hospital.We studied 9265 children with IAI. Median (IQR) age was 9.0 (6.0-13.0) years. Abdominal surgery was performed in 16% (n = 1479) of children, with the lowest proportion of abdominal surgery observed in children aged5 years. Liver (38.6%) and spleen (32.1%) were the most common organs injured. A total of 3.1% of children with liver injuries and 2.8% with splenic injuries underwent abdominal surgery. Although there was variation in rates of surgery across hospitals (p 0.001), only three of 33 hospitals had rates that were statistically different from the aggregate mean of 16%.Most children with IAI are managed nonoperatively, and most children's hospitals manage children with IAI similarly. These data can be used to inform future benchmarking efforts across hospitals to assess concordance with guidelines for the management of children with IAI.

This study investigates whether acute treatment with ibuprofen, acetaminophen, or both is associated with resolution of headache or reduction of headache pain at 7 days post-concussion in children and youth.A secondary analysis of the Predicting and Preventing Post-concussive Problems in Pediatrics (5P) prospective cohort study was conducted. Individuals aged 5-18 years with acute concussion presenting to nine Canadian pediatric emergency departments (ED) were enrolled from August 2013 to June 2015. The primary outcome was the presence of headache at 7 days, measured using the Post-Concussion Symptom Inventory. The association between acute administration of ibuprofen, acetaminophen, or both and headache presence at 7 days was investigated with propensity scores and adjusted multivariate regression models.2277 (74.3%) of 3063 participants had headache upon ED presentation. Of these participants, 1543 (67.8%) received an analgesic medication before or during their ED visit [ibuprofen 754 (33.1%), acetaminophen 445 (19.5%), both 344 (15.1%); or no medication 734 (32.2%)]. Multivariate analysis pertained to 1707 participants with propensity scores based on personal characteristics and symptoms; 877 (51.4%) reported headache at 7 days post-concussion. No association emerged between treatment and presence of headache at 7 days [ibuprofen vs. untreated: (relative risk (RR) = 1.12 (95% CI 0.99,1.26); acetaminophen vs untreated RR = 1.02 (95% CI 0.87,1.22); both vs untreated RR = 1.02 (95% CI 0.86,1.18)].Exposure to ibuprofen, acetaminophen, or both in the acute phase does not decrease the risk of headache at 7 days post-concussion. Non-opioid analgesics like ibuprofen or acetaminophen may be prescribed for short-term headache relief but clinicians need to be cautious with long-term medication overuse in those whose headache symptoms persist.RéSUMé: OBJECTIF: Cette étude vise à déterminer si un traitement aigu à l'ibuprofène, à l'acétaminophène ou aux deux est associé à la résolution des maux de tête ou à la réduction de la douleur des maux de tête 7 jours après la commotion cérébrale chez les enfants et les adolescents. MéTHODES: Une analyse secondaire de l'étude de cohorte prospective Predicting and Preventing Post-concussive Problems in Pediatrics (5P) a été réalisée. Des personnes âgées de 5 à 18 ans souffrant d'une commotion cérébrale aiguë se présentant dans neuf services d'urgence pédiatriques (SU) canadiens ont été inscrites d'août 2013 à juin 2015. Le résultat primaire était la présence de maux de tête à 7 jours, mesurée à l'aide du Post-Concussion Symptom Inventory. L'association entre l'administration aiguë d'ibuprofène, d'acétaminophène ou des deux et la présence de maux de tête à 7 jours a été étudiée à l'aide de scores de propension et de modèles de régression multivariés ajustés. RéSULTATS: 2277 (74,3%) des 3063 participants avaient des maux de tête lors de la présentation aux urgences. Parmi ces participants, 1 543 (67,8%) ont reçu un médicament analgésique avant ou pendant leur visite aux urgences [ibuprofène 754 (33,1%), acétaminophène 445 (19,5%), les deux 344 (15,1%); ou aucun médicament 734 (32,2%)]. L'analyse multivariée a porté sur 1707 participants avec des scores de propension basés sur les caractéristiques personnelles et les symptômes; 877 (51,4%) ont signalé des maux de tête 7 jours après la commotion cérébrale. Aucune association n'est apparue entre le traitement et la présence de céphalées à 7 jours [ibuprofène vs non traité: (risque relatif (RR) = 1,12 (95%CI:0,99,1,26); acétaminophène vs non traité RR = 1,02 (95% IC: 0,87,1,22); les deux vs non traité RR = 1,02 (95% IC: 0,86,1,18)]. CONCLUSIONS: L'exposition à l'ibuprofène, à l'acétaminophène ou aux deux dans la phase aiguë ne diminue pas le risque de céphalées 7 jours après la commotion. Les analgésiques non opioïdes comme l'ibuprofène ou l'acétaminophène peuvent être prescrits pour soulager les maux de tête à court terme, mais les cliniciens doivent faire attention à la surconsommation de médicaments à long terme chez les personnes dont les symptômes de maux de tête persistent.

Study objective This study aimed to explore oral ondansetron usage and impact on outcomes in clinical practice. Methods This observational study was a planned secondary analysis of 2 trials conducted in 10 US and 6 Canadian institutions between 2014 and 2017. Children 3 to 48 months old with gastroenteritis and ≥3 episodes of vomiting in the 24 hours preceding emergency department (ED) presentation were included. Oral ondansetron was administered at the discretion of the provider. The principal outcomes were intravenous fluid administration and hospitalization at the index visit and during the subsequent 72 hours and diarrhea and vomiting frequency during the 24 hours following the ED visit. Results In total, 794 children were included. The median age was 16.0 months (interquartile range 10.0 to 26.0), and 50.1% (398/794) received oral ondansetron. In propensity-adjusted analysis (n=528), children administered oral ondansetron were less likely to receive intravenous fluids at the index visit (adjusted odds ratio [aOR] 0.50; 95% confidence interval [CI] 0.29 to 0.88). There were no differences in the frequencies of intravenous fluid administration within the first 72 hours (aOR 0.65; 95% CI 0.39 to 1.10) or hospitalization at the index visit (aOR 0.31; 95% CI 0.09 to 1.10) or the subsequent 72 hours (aOR 0.52; 95% CI 0.21 to 1.28). Episodes of vomiting (aRR 0.86; 95% CI 0.63 to 1.19) and diarrhea (aRR 1.11; 95% CI 0.93 to 1.32) during the 24 hours following ED discharge also did not differ. Conclusion Among preschool-aged children with gastroenteritis seeking ED care, oral ondansetron administration was associated with a reduction in index ED visit intravenous fluid administration; it was not associated with intravenous fluids administered within 72 hours, hospitalization, or vomiting and diarrhea in the 24 hours following discharge.

Although the passage of blood in stools in children represents a medical emergency, children seeking emergency department (ED) care remain poorly characterized. Our primary objective was to compare clinical characteristics and etiologic pathogens in children with acute diarrhea with and without caregiver-reported hematochezia. Secondary objectives were to characterize interventions and resource utilization.We conducted a secondary analysis of the Alberta Provincial Pediatric EnTeric Infection TEam (APPETITE) database. Children18 years presenting to two pediatric EDs within a 24-hour period and7 days of symptoms were consecutively recruited.Of 1,061 participants, 115 (10.8%) reported hematochezia at the enrollment visit at which time those with hematochezia, compared to those without, had more diarrheal episodes/24-hour period (9 vs. 6; difference: 2; 95% confidence interval [CI]: 2.0, 4.0; p 0.001), and were less likely to have experienced vomiting (54.8% vs. 80.2%; difference: -25.4; 95% CI: -34.9, -16.0; p 0.001). They were more likely to receive intravenous fluids (33.0% vs. 17.9%; difference: 15.2; 95% CI: 6.2, 24.1; p 0.001) and require repeat health care visits (45.5% vs. 34.7%; difference: 10.7; 95% CI: 0.9, 20.6; p = 0.03). A bacterial pathogen was identified in 33.0% of children with hematochezia versus 7.9% without (difference: 25.1; 95% CI: 16.3, 33.9; p 0.001); viruses were detected in 31.3% of children with hematochezia compared to 72.3% in those without (difference: -41.0%, 95% CI: -49.9, -32.1; p 0.001).In children with acute diarrhea, caregiver report of hematochezia, compared to the absence of hematochezia, was associated with more diarrheal but fewer vomiting episodes, and greater resource consumption. The former group of children was also more likely to have bacteria detected in their stool.

IntroductionAnaphylaxis is a severe, potentially fatal multiorgan system manifestation of an allergic reaction. The highest incidence of anaphylaxis is in children and adolescents. Biphasic anaphylaxis (BA) is defined as the recurrence of allergic symptoms after resolution of an initial reaction. It has been reported to occur in 10%–20% of cases within 1–48 hours from the onset of the initial reaction. The dilemma for physicians is determining which patients with resolved anaphylaxis should be observed for BA and for how long. Guidelines for duration of postanaphylaxis monitoring vary, are based on limited evidence and can have unintended negative impacts on patient safety, quality of life and healthcare resources. The objectives of this study are to derive a prognostic model for BA and to develop a risk-scoring system that informs disposition decisions of children who present to emergency departments (ED) with anaphylaxis.Methods and analysisThis prospective multicentre cohort study will enrol 1682 patients from seven paediatric EDs that are members of the Paediatric Emergency Research Canada network. We will enrol patients younger than 18 years of age with an allergic reaction meeting anaphylaxis diagnostic criteria. Trained ED research assistants will screen, obtain consent and prospectively collect study data. Research assistants will follow patients during their ED visit and ascertain, in conjunction with the medical team, if the patient develops BA. A standardised follow-up survey conducted following study enrolment will determine if a biphasic reaction occurred after ED disposition. Model development will conform to the broad principles of the PROGRESS (Prognosis Research Strategy) framework and reporting will follow the Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis Statement.Ethics and disseminationEthics approval has been received from all participating centres. Our dissemination plan focuses on informing clinicians, policy makers and parents of the results through publication in peer-reviewed journals and broadcasting on multiple media platforms.Trial registration numberNCT05135377.

ObjectivesDespite a lack of evidence demonstrating superiority to non-steroidal anti-inflammatory drugs, like ketorolac, that are associated with lower risk of harms, opioids remain the most prescribed analgesic for acute abdominal pain. In this pilot trial, we will assess the feasibility of a definitive trial comparing ketorolac with morphine in children with suspected appendicitis. We hypothesise that our study will be feasible based on a 40% consent rate.Methods and analysisA single-centre, non-inferiority, blinded (participant, clinician, investigators and outcome assessors), double-dummy randomised controlled trial of children aged 6–17 years presenting to a paediatric emergency department with ≤5 days of moderate to severe abdominal pain (≥5 on a Verbal Numerical Rating Scale) and are investigated for appendicitis. We will use variable randomised blocks of 4–6 and allocate participants in 1:1 ratio to receive either intravenous (IV) ketorolac 0.5 mg/kg+IV morphine placebo or IV morphine 0.1 mg/kg+IV ketorolac placebo. Analgesic co-intervention will be limited to acetaminophen (commonly used as first-line therapy). Participants in both groups will be allowed rescue therapy (morphine 0.5 mg/kg) within 60 min of our intervention. Our primary feasibility outcome is the proportion of eligible patients approached who provide informed consent and are enrolled in our trial. Our threshold for feasibility will be to achieve a ≥40% consent rate, and we will enrol 100 participants into our pilot trial.Ethics and disseminationOur study has received full approval by the Hamilton integrated Research Ethics Board. We will disseminate our study findings at national and international paediatric research conferences to garner interest and engage sites for a future multicentre definitive trial.Trial registrationNCT04528563, Pre-results.