Search

Background: Lithiasis is a common and recurrent disease. Flexible ureteroscopy (fURS) is the cornerstone of laser treatment of kidney stones. Kidney stones destruction requires its laser pulverization into small fragments in order to remove them through the ureter or improve their spontaneous expulsion along the urinary tract. However, most of the time, all the micro-fragments and dust created cannot be extracted using our surgical tools and may stay intra-renally at the end of the procedure. Adjuvant treatments (such as forced diuresis, inversion or mechanical pressure) were previously described to improve the expulsion of stone fragments after extra-corporeal shock wave lithotripsy. Nevertheless, the impact of adjuvant treatment after fURS remains unclear and mainly theoretical., Objective: The primary objective is to show that the injection of 40 mg of furosemide in slow intravenous during 10 min, after the procedure, increases the stone-free rate 3 months after a fURS for destruction of kidney stones with laser., Methods/design: The study will be a two-parallel group randomized, controlled, multicentric trial with a blinding evaluation. Nine French departments of urology will participate. Patients will be randomized in 2 groups: the experimental group (injection of 40 mg of furosemide at the end of the surgery) and a control one (usual care). Patients will be followed up for 3 months (± 2 weeks) after the surgery. Then, we will perform a low dose abdomino-pelvic CT scan. The primary outcome is the stone-free rate at 3 months. A centralized review of the images will be performed by two specialized radiologists, in a blind and crossed way to allow a homogenization of the results. The secondary outcomes will include the rate of early post-operative urinary tract infection (UTI), the evaluation of post-operative pain, and the safety of the use of furosemide in patients treated by fURS for renal stone laser destruction. As secondary objectives, it is also planned to look at the effect of the prescription of an alpha-blocker as usual treatment on stone-free rate and to assess the agreement between the imaging analysis of the urologist and the specialized radiologist., Discussion: Lithiasis is a public health problem. It affects about 10% of the general population. This prevalence is increasing (multiplied by 3 in 40 years), partly due to changes in the population's eating habits over the years. The lithiasis patient is a patient with a chronic disease requiring annual follow-up and who may suffer from multiple recurrences, with a recurrence rate at 5 years of 50%. Recurrences are partly due to residual fragments left in the kidneys at the end of the operation. Other risk factors for recurrence include dietary hygiene and the presence of an associated metabolic disease. The metabolic blood and urine tests recommended by the Association Française d'Urologie (AFU) can be used to manage these last two problems. As far as residual fragments are concerned, their presence leads to an early recurrence of stones because they form the bed for a new aggregation of crystals in the kidneys. Being able to reduce the rate of residual fragments in patients with the use of furosemide at the end of the intervention therefore seems essential in the management of recurrences in our patients. This will also improve our patients' quality of life. Indeed, lithiasis disease leads to chronic pain associated with acute pain that motivates consultations to the emergency for specialized management. This study is the first to evaluate the impact of forced diuresis with the use of furosemide on the stone-free rate after a fURS for destruction of kidney stone with laser., Trial Registration: ClinicalTrials.gov Identifier: NCT05916963 , first received: 22 June 2023. EU Clinical Trials Register EudraCT Number: 2022-502890-40-00., (© 2024. The Author(s).)

Aim: To evaluate the knowledge, practices and self-confidence of community pharmacists, pharmacy technicians and pharmacy students about infantile haemangioma (IH) and propranolol treatment., Methods: A national survey was conducted in France from May 2022 to October 2022. A 42-item online questionnaire was used to assess pharmacists' knowledge of the epidemiology, clinical features and management of IH and propranolol treatment., Results: The survey included 255 participants. The mean age was 34.9 years (±9.0); 225 (88%) were women. In all, 193 (76%) practised in urban pharmacies. Altogether, 83 participants (33%) had delivered oral propranolol solution for IH in the last 6 months. Participants' median score for self-confidence regarding propranolol dispensing was five (interquartile range, 2.5-6) on a scale of 1 to 10. Overall, 96 (38%) had more than 50% correct answers on the questionnaire. Multinomial regression models showed high scores on the questionnaire associated with high self-confidence when delivering oral propranolol solution, low number of years since graduation and having already delivered propranolol treatment., Conclusion: This study highlights a lack of knowledge of IH and modalities of propranolol treatment by community pharmacists and slight self-confidence when delivering propranolol. Greater cooperation between healthcare professionals could improve the proper use of medicine., (© 2024 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background: Awake prone positioning (APP) of non-intubated patients with acute hypoxaemic respiratory failure (AHRF) has been inconsistently adopted into routine care of patients with COVID-19, likely due to apparent conflicting evidence from recent trials. This short guideline aims to provide evidence-based recommendations for the use of APP in various clinical scenarios., Methods: An international multidisciplinary panel, assembled for their expertise and representativeness, and supported by a methodologist, performed a systematic literature search, summarized the available evidence derived from randomized clinical trials, and developed recommendations using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology., Results: The panel strongly recommends that APP rather than standard supine care be used in patients with COVID-19 receiving advanced respiratory support (high-flow nasal cannula, continuous positive airway pressure or non-invasive ventilation). Due to lack of evidence from randomized controlled trials, the panel provides no recommendation on the use of APP in patients with COVID-19 supported with conventional oxygen therapy, nor in patients with AHRF due to causes other than COVID-19., Conclusion: APP should be routinely implemented in patients with COVID-19 receiving advanced respiratory support., Competing Interests: Declaration of Competing Interest IP discloses an unrestricted research grant and speaker fees from Fisher & Paykel Healthcare Ltd. and an unrestricted research grant from OpenAI Inc. JLi discloses research funding from Fisher & Paykel Healthcare, Aerogen, Rice Foundation, and the American Association for Respiratory Care, and speaker fees from the American Association for Respiratory Care, Aerogen, Heyer, and Fisher & Paykel Healthcare. SE discloses consultancy fees from Aerogen, research support from Aerogen and Fisher & Paykel Healthcare, and travel reimbursements from Aerogen and Fisher & Paykel Healthcare. DV discloses research funding from Teleflex Medical and Rice Foundation. OR discloses a research grant from Hamilton Medical and Fisher & Paykel, and speaker fees from Hamilton Medical, Ambu, Fisher & Paykel and Aerogen, and non-financial research support from Timpel. YP discloses research support and travel reimbursement from Fisher & Paykel Healthcare. JGL discloses consulting fees from Baxter Healthcare and Cellenkos. MS discloses speaker fees from Fisher & Paykel Healthcare Ltd. and consultancy fees from Aerogen. All other authors have no conflicts to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The corpus callosum (CC) is a key brain structure. In children with neurodevelopmental delay, we compared standard qualitative radiological assessments with an automatic quantitative tool., Methods: We prospectively enrolled 73 children (46 males, 63.0%) with neurodevelopmental delay at single university hospital between September 2020 and September 2022. All of them underwent 1.5-T brain magnetic resonance imaging (MRI) including a magnetization-prepared 2 rapid acquisition gradient echoes - MP2RAGE sequence. Two radiologists blindly reviewed the images to classify qualitatively the CC into normal, hypoplasic, hyperplasic, and/or dysgenetic classes. An automatic tool (QuantiFIRE) was used to provide brain volumetry and T1 relaxometry automatically as well as deviations of those parameters compared with a healthy age-matched cohort. The MRI reference standard for CC volumetry was based on the Garel et al. study. Cohen κ statistics was used for interrater agreement. The radiologists and QuantiFIRE's diagnostic accuracy were compared with the reference standard using the Delong test., Results: The CC was normal in 42 cases (57.5%), hypoplastic in 20 cases (27.4%), and hypertrophic in 11 cases (15.1%). T1 relaxometry values were abnormal in 26 children (35.6%); either abnormally high (18 cases, 24.6%) or low (8 cases, 11.0%). The interrater Cohen κ coefficient was 0.91. The diagnostic accuracy of the QuantiFIRE prototype was higher than that of the radiologists for hypoplastic and normal CC (p = 0.003 for both subgroups, Delong test)., Conclusions: An automated volumetric and relaxometric assessment can assist the evaluation of brain structure such as the CC, particularly in the case of subtle abnormalities., Relevance Statement: Automated brain MRI segmentation combined with statistical comparison to normal volume and T1 relaxometry values can be a useful diagnostic support tool for radiologists., Key Points: • Corpus callosum abnormality detection is challenging but clinically relevant. • Automated quantitative volumetric analysis had a higher diagnostic accuracy than that of visual appreciation of radiologists. • Quantitative T1 relaxometric analysis might help characterizing corpus callosum better., (© 2023. European Society of Radiology (ESR).)

Purpose: Intramuscular capillary-type hemangiomas (ICTHs) are rare entities, belonging to the group of intramuscular "hemangiomas." The diagnosis remains challenging. We aimed to assess the diagnostic criteria, treatments and outcomes of ICTHs., Methods: This retrospective study collected all cases of ICTH followed up in 9 French hospital centers, reviewed by an adjudication expert group., Results: Among 133 patients screened, 66 with ICTH were included. The median age of patients at diagnosis was 28.0 years, interquartile range (21.0---36.0). The lesion, mainly presenting as a gradually increasing mass (83.9%), was painless (88.9%) and was located in the head and neck (42.4%). MRI (available in all cases) mainly revealed a well-delineated lesion, isointense to the muscle on T1-weighted images, with enhancement after contrast injection; hyperintense on T2-weighted images; and containing flow voids. Among the 66 cases, 59 exhibited typical ICTH features and 7 shared some imaging features with arteriovenous malformations. These latter were larger than typical ICTHs and more painful and appeared on imaging as less well delimited and more heterogeneous tissue masses, with larger tortuous afferent arteries, earlier draining vein opacification and mild arteriovenous shunting. We propose to name these lesions arteriovenous malformation (AVM)-like ICTH. Pathological reports were similar in typical and AVM-like ICTH, showing capillary proliferation with mainly small-size vessels, negative for GLUT-1 and positive for ERG, AML, CD31 and CD34, with low Ki67 proliferation index (<10%), and adipose tissue. The most frequent treatment for ICTH was complete surgical resection (17/47, 36.2%), preceded in some cases by embolization, which led to complete remission., Conclusions: ICTH can be diagnosed on MRI when it is typical. Biopsy or angiography are required for atypical forms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Awake prone positioning (APP) of patients with acute hypoxaemic respiratory failure gained considerable attention during the early phases of the coronavirus disease 2019 (COVID-19) pandemic. Prior to the pandemic, reports of APP were limited to case series in patients with influenza and in immunocompromised patients, with encouraging results in terms of tolerance and oxygenation improvement. Prone positioning of awake patients with acute hypoxaemic respiratory failure appears to result in many of the same physiological changes improving oxygenation seen in invasively ventilated patients with moderate-severe acute respiratory distress syndrome. A number of randomised controlled studies published on patients with varying severity of COVID-19 have reported apparently contrasting outcomes. However, there is consistent evidence that more hypoxaemic patients requiring advanced respiratory support, who are managed in higher care environments and who can be prone for several hours, benefit most from APP use. We review the physiological basis by which prone positioning results in changes in lung mechanics and gas exchange and summarise the latest evidence base for APP primarily in COVID-19. We examine the key factors that influence the success of APP, the optimal target populations for APP and the key unknowns that will shape future research., Competing Interests: Conflicts of interest: M. Ibarra-Estrada, A. Kharat, D. Cosgrave and C. Guerin report no conflicts of interest. B.A. McNicholas reports consulting fees received personally from Teleflex. Y. Perez reports grants to institution and personal support for attending medical congress from Fisher & Paykel. J. Li reports grants to institution from Fisher & Paykel, Aerogen, Rice Foundation and American Association for Respiratory Care; personal honoraria for lectures from Fisher & Paykel, Aerogen, Heyer lts, and American Association for Respiratory Care. I. Pavlov reports grants to institution from Open AI inc and Fisher & Paykel. D.L. Vines reports grants to institution from Teleflex Medical and Rice Foundation; personal honoraria from Theravance Biopharma; unpaid role as President, National board for Respiratory Care. O. Roca reports grants to institution from Hamilton Medical AG and Fisher & Paykel; personal consulting fees from Aerogen, and honoraria received from Hamilton Medical AG, Fisher & Paykel, Aerogen and Ambu Ltd; unpaid role as chair of Acute Respiratory Failure group of Spanish Society of Intensive Care Medicine; non-funded research support from Timpel Ltd. S. Ehrmann reports grants to institution from Aerogen Ltd and Fisher & Paykel; personal consulting fees from Aerogen Ltd; personal honoraria and support for attending meetings from Aerogen Ltd and Fisher & Paykel; participation on Data Safety Monitoring Board for Aerogen Ltd; receipt of equipment/materials from Aerogen Ltd and Fisher & Paykel. J.G. Laffey reports funding to institution from Science Foundation Ireland; personal consulting fees from Baxter Healthcare; unpaid participation in Data Safety Monitoring Board (investigator trials); unpaid role as chair of Translational Biology Section of European Society of Intensive Care Medicine., (Copyright ©The authors 2023.)

Intramuscular capillary-type haemangiomas (ICTH) are rare vascular anomalies that can easily be misdiagnosed as other entities. A systematic review was performed of all cases of ICTH in the literature since its first description in 1972. An adjudication committee reviewed cases to include only ICTHs. Among 1,143 reports screened, 43 were included, involving 75 patients. The most frequent differential diagnosis was intramuscular venous malformations. The mean age of patients at diagnosis was 21.2 years. ICTH was mainly described as a gradually increasing mass (81.8%), painless (73.9%), that could occur anywhere in the body but most frequently on the head and neck (44.0%). Magnetic resonance imaging (MRI) was mainly used for diagnosis (69.1%) and displayed specific features. The most frequent treatment was complete surgical removal (73.9%), which could be preceded by embolization, and led to complete remission without recurrence in all but 1 case.

Ultrasound is currently recommended as the first-line examination for abdominal symptoms in children. However, a pediatric radiologist is not always available on site, especially during on-call duty. This study was aimed at evaluating the reliability of an innovative 3-D virtual abdominal tele-ultrasonography in this context. A prospective study was conducted between December 2020 and May 2021 that recruited 103 children undergoing ultrasound for abdominal pain. Trauma cases were excluded. Four tridimensional acquisitions were performed with a Smart Sensor 3D device (Canon Medical Systems, Otawara, Japan). Each tele-ultrasonography was secondarily blindly reviewed by two radiologists (one senior and one resident) with Fusion software (Canon Medical Systems). Acceptance and quality of the acquisitions were evaluated on a Likert scale. Inter-rater reliability was quantified using Cohen's κ coefficient and intraclass correlation coefficient. The ultrasound examination was normal in 66 cases (64%), abnormal in 36 cases (35%) and inconclusive in 1 case (1%). The acquisitions were obtained without objections from the children, their parents or the operators in more than 95% of cases. The quality of the acquisitions was considered good to excellent in 84% and 70% of cases. The sensitivity of the senior radiologist and the resident was 86% and 84%, respectively; specificity was 95% and 92%, positive predictive value 92% and 86% and negative predictive value 92 and 91% when comparing the conclusions of the standard and the tele-ultrasound examinations. Cohen's κ coefficients of the diagnosis obtained with the standard and the tele-ultrasound examinations were 0.82 and 0.71, respectively. The inter-rater Cohen's κ coefficient was 0.84. The intraclass correlation coefficient between the standard abdominal examination and the 3-D tele-ultrasound reformatted images for the following quantitative variables on pathological cases was 0.99 (confidence interval: 0.98-0.99). Virtual abdominal tele-ultrasonography is a promising method in pediatric emergencies., Competing Interests: Conflict of interest disclosure The authors declare that they have no competing interests., (Copyright © 2022 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Background: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment)., Methods: This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters., Discussion: Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated., Trial Registration: ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33., (© 2022. The Author(s).)

Background: Awake prone positioning has been broadly utilised for non-intubated patients with COVID-19-related acute hypoxaemic respiratory failure, but the results from published randomised controlled trials (RCTs) in the past year are contradictory. We aimed to systematically synthesise the outcomes associated with awake prone positioning, and evaluate these outcomes in relevant subpopulations., Methods: In this systematic review and meta-analysis, two independent groups of researchers searched MEDLINE, Embase, PubMed, Web of Science, Scopus, MedRxiv, BioRxiv, and ClinicalTrials.gov for RCTs and observational studies (with a control group) of awake prone positioning in patients with COVID-19-related acute hypoxaemic respiratory failure published in English from Jan 1, 2020, to Nov 8, 2021. We excluded trials that included patients intubated before or at enrolment, paediatric patients (ie, younger than 18 years), or trials that did not include the supine position in the control group. The same two independent groups screened studies, extracted the summary data from published reports, and assessed the risk of bias. We used a random-effects meta-analysis to pool individual studies. We used the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the certainty and quality of the evidence. The primary outcome was the reported cumulative intubation risk across RCTs, and effect estimates were calculated as risk ratios (RR;95% CI). The analysis was primarily conducted on RCTs, and observational studies were used for sensitivity analyses. No serious adverse events associated with awake prone positioning were reported. The study protocol was prospectively registered with PROSPERO, CRD42021271285., Findings: A total of 1243 studies were identified, we assessed 138 full-text articles and received the aggregated results of three unpublished RCTs; therefore, after exclusions, 29 studies were included in the study. Ten were RCTs (1985 patients) and 19 were observational studies (2669 patients). In ten RCTs, awake prone positioning compared with the supine position significantly reduced the need for intubation in the overall population (RR 0·84 [95% CI 0·72-0·97]). A reduced need for intubation was shown among patients who received advanced respiratory support (ie, high-flow nasal cannula or non-invasive ventilation) at enrolment (RR 0·83 [0·71-0·97]) and in intensive care unit (ICU) settings (RR 0·83 [0·71-0·97]) but not in patients receiving conventional oxygen therapy (RR 0·87 [0·45-1·69]) or in non-ICU settings (RR 0·88 [0·44-1·76]). No obvious risk of bias and publication bias was found among the included RCTs for the primary outcome., Interpretation: In patients with COVID-19-related acute hypoxaemic respiratory failure, awake prone positioning reduced the need for intubation, particularly among those requiring advanced respiratory support and those in ICU settings. Awake prone positioning should be used in patients who have acute hypoxaemic respiratory failure due to COVID-19 and require advanced respiratory support or are treated in the ICU., Funding: OpenAI, Rice Foundation, National Institute for Health Research, and Oxford Biomedical Research Centre., Competing Interests: Declaration of interests SE discloses consultancy fees from Aerogen, research support from Aerogen and Fisher & Paykel Healthcare, and travel reimbursements from Aerogen and Fisher & Paykel Healthcare. JL discloses research funding from Fisher & Paykel Healthcare, Aerogen, and Rice Foundation, and speaker fees from American Association for Respiratory Care, Aerogen, Heyer, and Fisher & Paykel Healthcare. IP discloses a research grant and speaker fees from Fisher & Paykel Healthcare. YP discloses research support from Fisher & Paykel Healthcare. OR discloses a research grant from Hamilton Medical and speaker fees from Hamilton Medical, Ambu, Fisher & Paykel and Aerogen, and non-financial research support from Timpel and Masimo. DV discloses research funding from Teleflex Medical and Rice Foundation, and speaker fees from Theravance Biopharma. MT discloses consulting fees from Fisher & Paykel Healthcare. JRM discloses research support from Fisher & Paykel Healthcare, and speaker fees from Fisher & Paykel Healthcare, Gilead, Dextro and Linet. JGL discloses consulting fees from Baxter Healthcare and GlaxoSmithKline. KM is the primary investigator for the industry funded trial NCT03808922. MF is a consultant for a start-up company (ProofDx) developing a CRISPR based diagnostic test for COVID-19. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Awake prone positioning (APP) improves oxygenation in coronavirus disease (COVID-19) patients and, when successful, may decrease the risk of intubation. However, factors associated with APP success remain unknown. In this secondary analysis, we aimed to assess whether APP can reduce intubation rate in patients with COVID-19 and to focus on the factors associated with success., Methods: In this multicenter randomized controlled trial, conducted in three high-acuity units, we randomly assigned patients with COVID-19-induced acute hypoxemic respiratory failure (AHRF) requiring high-flow nasal cannula (HFNC) oxygen to APP or standard care. Primary outcome was intubation rate at 28 days. Multivariate analyses were performed to identify the predictors associated to treatment success (survival without intubation)., Results: Among 430 patients randomized, 216 were assigned to APP and 214 to standard care. The APP group had a lower intubation rate (30% vs 43%, relative risk [RR] 0.70; CI 95 0.54-0.90, P = 0.006) and shorter hospital length of stay (11 interquartile range [IQR, 9-14] vs 13 [IQR, 10-17] days, P = 0.001). A respiratory rate ≤ 25 bpm at enrollment, an increase in ROX index > 1.25 after first APP session, APP duration > 8 h/day, and a decrease in lung ultrasound score ≥ 2 within the first 3 days were significantly associated with treatment success for APP., Conclusion: In patients with COVID-19-induced AHRF treated by HFNC, APP reduced intubation rate and improved treatment success. A longer APP duration is associated with APP success, while the increase in ROX index and decrease in lung ultrasound score after APP can also help identify patients most likely to benefit., Trial Registration: This study was retrospectively registered in ClinicalTrials.gov at July 20, 2021. Identification number NCT04477655. https://clinicaltrials.gov/ct2/show/NCT04477655?term=PRO-CARF&draw=2&rank=1., (© 2022. The Author(s).)

Background: Awake prone positioning (APP) has been advocated to improve oxygenation and prevent intubation of patients with acute hypoxemic respiratory failure due to coronavirus disease 2019 (COVID-19). This paper aims to synthesize the available evidence on the efficacy of APP., Methods: We performed a systematic review of proportional outcomes from observational studies to compare intubation rate in patients treated with APP or with standard care., Results: A total of 46 published and 4 unpublished observational studies that included 2,994 subjects were included, of which 921 were managed with APP and 870 were managed with usual care. APP was associated with significant improvement of oxygenation parameters in 381 cases of 19 studies that reported this outcome. Among the 41 studies assessing intubation rates (870 subjects treated with APP and 852 subjects treated with usual care), the intubation rate was 27% (95% CI 19-37%) as compared to 30% (95% CI 20-42%) ( P = .71), even when duration of application, use of adjunctive respiratory assist device (high-flow nasal cannula or noninvasive ventilation), and severity of oxygenation deficit were taken into account. There appeared to be a trend toward improved mortality when APP was compared with usual care (11% vs 22%), which was not statistically significant., Conclusions: APP was associated with improvement of oxygenation but did not reduce the intubation rate in subjects with acute respiratory failure due to COVID-19. This finding is limited by the high heterogeneity and the observational nature of included studies. Randomized controlled clinical studies are needed to definitively assess whether APP could improve key outcome such as intubation rate and mortality in these patients., (Copyright © 2022 by Daedalus Enterprises.)

Background: Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial., Methods: In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov, NCT04325906, NCT04347941, NCT04358939, NCT04395144, NCT04391140, and NCT04477655., Findings: Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75-0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62-0·91), and the HR for mortality was 0·87 (0·68-1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups., Interpretation: Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula., Funding: Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interrégional, Appel d'Offre 2020, Groupement Interrégional de Recherche Clinique et d'Innovation Grand Ouest, Association pour la Promotion à Tours de la Réanimation Médicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd., Competing Interests: Declaration of interests SE discloses consultancies from Aerogen Ltd, research support from Aerogen Ltd, Fisher & Paykel Healthcare Ltd, Hamilton medical, travel reimbursements from Aerogen Ltd and Fisher & Paykel Healthcare Ltd. JL discloses research funding from Fisher & Paykel Healthcare Ltd, Aerogen Ltd, and Rice Foundation, and speaker fees from AARC and Fisher & Paykel Healthcare Ltd. IP discloses a research grant and speaker fees from Fisher & Paykel Healthcare Ltd. YP discloses research support from Fisher & Paykel Healthcare Ltd. OR discloses a research grant from Hamilton Medical and speaker fees from Hamilton Medical, Ambu and Aerogen Ltd, and non-financial research support from Timpel and Masimo Corporation. His institution received fees for consultancy from Hamilton Medical. DV discloses research funding from Teleflex Medical, Inc and Rice Foundation, and speaker fees from Theravance Biopharma. MWT discloses consulting fees from Fisher and Paykel. JRM discloses research support from Fisher & Paykel, and speaker fees from Fisher & Paykel, Gilead, Dextro, and Linet. JGL discloses consulting fees from Baxter Healthcare and Glaxosmithkline. All other authors have no competing interests to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Ultrasonographic quantitative measurements enable characterizing the stiffness and viscosity of liver parenchyma. Normal Shear Wave Elastography (SWE) values have been reported in adults and children. The Attenuation Imaging (ATI) coefficient is a measure of local sound energy loss thought to reflect steatosis in adults. The aim of our study was to provide normal SWE and ATI liver values in healthy children., Methods: A prospective monocentric study was conducted recruiting 86 children (45 boys and 41 girls) from a single University Hospital between January 2019 and June 2020, having a clinically indicated ultrasound examination, without a known or documented history of liver disease. Examinations were performed using an Aplio i800 (Canon Medical Systems) ultrasound system with an i8CX1 transducer. SWE measurements were obtained using a color map showing an automated measurement area grid overlay. ATI coefficients were generated automatically for each region of interest in the right liver., Results: Overall median age for the pediatric population was 106 months (1-180 months; SD 49 months). Children were normal weighted. Liver SWE was available for all children. The median liver SWE was 4.6 kPa [3.3-6.6]. ATI yielded valid measurements in 77 patients. The median ATI coefficient was 0.65 [0.5-0.81] dB/cm/MHz. No impact of age, sex, weight and Body Mass Index was observed., Conclusion: SWE and ATI liver values were provided in healthy children. The normative quantitative data might be useful to characterize liver parenchyma in children better., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Introduction: The use of peripheral indwelling arterial catheter for haemodynamic monitoring is widespread in the intensive care unit and is recommended in patients with shock. However, there is no evidence that the arterial catheter could improve patient's outcome, whereas the burden of morbidity generated is significant (pain, thrombosis, infections). We hypothesise that patients with shock may be managed without an arterial catheter., Methods and Analysis: The EVERDAC study is an investigator-initiated, pragmatic, multicentre, randomised, controlled, open-label, non-inferiority clinical trial, comparing a less invasive intervention (ie, no arterial catheter insertion until felt absolutely needed, according to predefined safety criteria) or usual care (ie, systematic arterial catheter insertion in the early hours of shock). 1010 patients will be randomised with a 1:1 ratio in two groups according to the strategy. The primary outcome is all-cause mortality by 28 days after inclusion. A health economic analysis will be carried out., Ethics and Dissemination: The study has been approved by the Ethics Committee (Comité de Protection des Personnes Île de France V, registration number 61606 CAT 2, 19 july 2018) and patients will be included after informed consent. The results will be submitted for publication in peer-reviewed journals., Trial Registration Number: NCT03680963., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A marked increase in frequency of acute acral eruptions (AAE) was observed in children during the COVID-19 pandemic in the spring period., Objectives: In this observational multicenter study, based on children with AAE, we aimed to assess the proportion of household members possibly infected by SARS-CoV-2., Methods: We collected data from all children observed with AAE, prospectively from April 7, 2020 to June 22, 2020, and retrospectively since February 28, 2020. The primary outcome was the household infection rate, defined as the proportion of family clusters having at least one member with COVID-19 infection other than the child with AAE ("index child"). The definition of a case was based on characteristic clinical signs and a positive PCR or serology., Results: The study included 103 children in 10 French departments and in Quebec. The median age was 13 years and the interquartile range [8-15], with a female-to-male ratio of 1/1.15. In children with AAE, all PCR tests were negative (n=18), and serology was positive in 2/14 (14.3%) cases. We found no significant anomalies in the lab results. A total of 66 of the 103 families (64.1%) of included children had at least one other infected member apart from the index child. The total number of household members was 292, of whom 119 (40.8%) were considered possibly infected by SARS-CoV-2. No index children or households exhibited severe COVID-19., Discussion: Among the 103 households included, 64.1% had at least one infected member. Neither children with AAE nor their households showed severe COVID-19., (Copyright © 2021. Published by Elsevier Masson SAS.)

Purpose: The purpose of this study was to identify in the EPIRMEX cohort the correlations between MRI brain metrics, including diffuse excessive high signal intensities (DEHSI) obtained with an automated quantitative method and neurodevelopmental outcomes at 2 years., Materials and Methods: A total of 390 very preterm infants (gestational age at birth≤32 weeks) who underwent brain MRI at term equivalent age at 1.5T (n=338) or 3T (n=52) were prospectively included. Using a validated algorithm, automated metrics of the main brain surfaces (cortical and deep gray matter, white matter, cerebrospinal fluid) and DEHSI with three thresholds were obtained. Linear adjust regressions were performed to assess the correlation between brain metrics with the ages and stages questionnaire (ASQ) score at 2 years., Results: Basal ganglia and thalami, cortex and white matter surfaces positively and significantly correlated with the global ASQ score. For all ASQ sub-domains, basal ganglia and thalami surfaces significantly correlated with the scores. DEHSI was present in 289 premature newborns (74%) without any correlation with the ASQ score. Metrics of DEHSI were greater at 3T than at 1.5T., Conclusion: Brain MRI metrics obtained in our multicentric cohort correlate with the neurodevelopmental outcome at 2 years of age. The quantitative detection of DEHSI is not predictive of adverse outcomes. Our automated algorithm might easily provide useful predictive information in daily practice., (Copyright © 2020 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Competing Interests: Declaration of Competing Interest JL discloses research support from Fisher & Paykel Healthcare for another research project. IP has been a speaker for Fisher & Pakyel Healthcare within the last 3 years. All compensation was paid to the charitable foundation at the hospital where he works, and he did not personally receive any compensation. OR provides consultancy to Hamilton Medical but he did not receieved any personal fee. All compensations were received by the Institute of Research of his Institution. He received speaker fees by Air Liquide. SE received unrestricted research grants, travel fee reimbursements and speaker fees from Fisher & Paykel Healthcare, consulting fees from La Diffusion Technique Française, consulting fees and unrestricted research grants from Aerogen Ltd., and an unrestricted research grant from Hamilton medical. Other authors have no conflict of interest to declare.

Introduction: Prone positioning (PP) is an effective first-line intervention to treat patients with moderate to severe acute respiratory distress syndrome (ARDS) receiving invasive mechanical ventilation, as it improves gas exchanges and reduces mortality. The use of PP in awake spontaneous breathing patients with ARDS secondary to COVID-19 was reported to improve oxygenation in few retrospective trials with small sample size. High-level evidence of awake PP for hypoxaemic patients with COVID-19 patients is still lacking., Methods and Analysis: The protocol of this meta-trial is a prospective collaborative individual participant data meta-analysis of randomised controlled open label superiority trials. This design is particularly adapted to a rapid scientific response in the pandemic setting. It will take place in multiple sites, among others in USA, Canada, Ireland, France and Spain. Patients will be followed up for 28 days. Patients will be randomised to receive whether awake PP and nasal high flow therapy or standard medical treatment and nasal high flow therapy. Primary outcome is defined as the occurrence rate of tracheal intubation or death up to day 28. An interim analysis plan has been set up on aggregated data from the participating research groups., Ethics and Dissemination: Ethics approvals were obtained in all participating countries. Results of the meta-trial will be submitted for publication in a peer-reviewed journal. Each randomised controlled trial was registered individually, as follows: NCT04325906, NCT04347941, NCT04358939, NCT04395144 and NCT04391140., Competing Interests: Competing interests: IP has been a speaker for Fisher & Pakyel Healthcare within the last 3 years. All compensation was paid to the charitable foundation at the hospital where he works, and he did not personally receive any compensation. JL discloses research support from Fisher & Paykel Healthcare for another research project. SE received unrestricted research grants, travel fee reimbursements and speaker fees from Fisher & Paykel Healthcare, consulting fees from La Diffusion Technique Française, consulting fees and unrestricted research grants from Aerogen Ltd and an unrestricted research grant from Hamiton medical. OR provides consultancy to Hamilton Medical but he did not receive any personal fee. All compensation were received by the Institute of Research of his Institution. He received speaker fees by Air Liquide. J-PF reports grants from the French Ministry of Health; grants, personal fees and non-financial support from Fisher & Paykel Heathcare; personal fees and non-financial support from SOS oxygene, 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.)

Background: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults., Methods: This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm 2 ., Discussion: For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment., Trial Registration: ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11.

Introduction: Atopic dermatitis (AD) is a chronic inflammatory disease affecting 10%-15% of children in Europe. There is a need for new primary preventive therapeutic strategies in at-risk populations. Recent research has indicated that atopic diseases are associated with a disrupted gut microbial 'balance' in early life raising the possibility that interventions which yield optimal patterns of microflora could improve host's health. Prebiotics, sugars with immunomodulatory properties that stimulate the diversity of the digestive microbiota, are ideal candidates for such research. So far, most clinical trials have focused on improving infant gut colonisation postnatally. However, prenatal life is a crucial period during which different tolerance mechanisms are put in place. We aim to determine whether antenatal prebiotics supplementation prevents AD in high-risk children., Methods and Analysis: This is a randomised, multicentre, double-blind, trial to evaluate the effectiveness of antenatal prebiotic maternal supplementation (galacto-oligosaccharide/inulin) in pregnant women versus placebo on the occurrence of AD at 1 year of age in at-risk children (defined as having a maternal history of atopic disease). Participating women will be randomised to daily ingestion of a prebiotics or placebo (maltodextrin) from 20 weeks' gestation until delivery. The primary outcome is the prevalence of AD at 1 year of age, using the version of the UK Working Party Diagnostic Criteria optimised for preventive studies. Key secondary endpoints are AD severity, quality of life and prebiotics tolerance. The target sample size is 376 women (188 patients per group) which will provide 80% power to detect a 33% reduction of the risk of AD in the verum group (α=0.05). The primary analysis will be based on the intention-to-treat principle., Ethics and Dissemination: Results will be presented in peer-reviewed journals and at international conferences. Ethics approval for the study was obtained from the institutional ethical review board of 'Comité de Protection des Personnes Sud Ouest-Outre-Mer III' of the University Hospital Centre of Bordeaux (2017/13)., Trial Registration Number: NCT03183440; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Systemic mammalian target of rapamycin (mTOR) inhibitors are currently used in many dermatologic indications. Their topical use is recent and poorly codified., Objective: To provide an overview of the topical use of mTOR inhibitors in dermatologic conditions and evaluate their efficacy and safety., Methods: A literature search was performed in January 2017. Reports of all studies investigating the use of topical mTOR inhibitors in any dermatology diseases were included. The exclusion criteria were systemic use and mucosal administration., Results: We included 40 studies with a total of 262 patients. In all, 11 dermatologic conditions were found, the most frequent being angiofibromas linked to tuberous sclerosis complex (157 patients). Topical mTOR inhibitors were significantly more efficient than placebo for angiofibromas (relative risk, 2.52; 95% confidence interval, 1.27-5.00; I 2  = 0%). The median concentration of sirolimus was 0.1%, with a median treatment duration of 12 weeks. Topical mTOR inhibitors were well tolerated, with only mild or moderate local side effects (mostly irritative) reported. Blood level of sirolimus was not detected in 90% of patients., Limitations: High heterogeneity in most studies., Conclusion: This systematic review supports the efficacy of topical sirolimus for angiofibromas linked to tuberous sclerosis complex, with only local side effects reported. Other indications require further research., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes., Objective: The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs., Methods/design: This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor)., Discussion: The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study)., Trial Registration: ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.

Background: Genetic and nutritional factors have been linked to the risk of aggressive prostate cancer (PCa). The fatty acid (FA) composition of peri-prostatic adipose tissue (PPAT), which reflects the past FA intake, is potentially involved in PCa progression. We analysed the FA composition of PPAT, in correlation with the ethno-geographical origin of the patients and markers of tumour aggressiveness., Methods: From a cohort of 1000 men treated for PCa by radical prostatectomy, FA composition of PPAT was analysed in 156 patients (106 Caucasians and 50 African-Caribbeans), 78 with an indolent tumour (ISUP group 1 + pT2 + PSA <10 ng/mL) and 78 with an aggressive tumour (ISUP group 4-5 + pT3). The effect of FA extracted from PPAT on in-vitro migration of PCa cells DU145 was studied in 72 patients, 36 Caucasians, and 36 African-Caribbeans., Results: FA composition differed according to the ethno-geographical origin. Linoleic acid, an essential n-6 FA, was 2-fold higher in African-Caribbeans compared with Caucasian patients, regardless of disease aggressiveness. In African-Caribbeans, the FA profile associated with PCa aggressiveness was characterised by low level of linoleic acid along with high levels of saturates. In Caucasians, a weak and negative association was observed between eicosapentaenoic acid level (an n-3 FA) and disease aggressiveness. In-vitro migration of PCa cells using PPAT from African-Caribbean patients was associated with lower content of linoleic acid., Conclusion: These results highlight an important ethno-geographical variation of PPAT, in both their FA content and association with tumour aggressiveness., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Genetics discoveries have allowed for a better understanding of capillary malformations (CMs) associated with overgrowth syndrome. However, molecular analyses are still not easy to perform or interpret. Other analytical methods are needed., Objectives: To identify clinical and haemodynamic factors associated with leg length discrepancy (LLD) in children with CMs of the lower limbs., Methods: Data were obtained from the multicentre French national cohort CONAPE (COhorte Nationale d'enfants atteints d'Angiome Plan de membrE inférieur), from children aged 2-12 years old with CMs of the lower limbs. Clinical characteristics were prospectively collected. Haemodynamic factors were measured by an sonographer who calculated the arterial blood flow (ABF) in both lower limbs. An ABF difference ≥ 50% between the two lower limbs was considered relevant. LLD ≥ 2% was determined by the same radiologist on centralized radiographs., Results: We analysed data at baseline for 96 children. The mean ± SD age was 5·6 ± 3·1 years; 49 (51%) were male; and 14 (15%) showed LLD. In total, 32 patients (33%) had venous anomalies, 13 (14%) lymphatic anomalies and in one child a diagnosis of Parkes Weber syndrome was made. Only an increased circumference above the knee was more frequent with than without LLD (43% vs. 13%, P = 0·02). In all, 10/79 patients (13%) showed a difference in ABF ≥ 50%: four had LLD. The frequency of differences in ABF ≥ 50% was greater with than without LLD [33% (n = 4/12) vs. 9% (n = 6/67), P = 0·04]., Conclusions: ABF measured by Duplex ultrasonography is a simple, low-cost and noninvasive complementary examination for help in detecting LLD, with a difference of ≥ 50% possibly associated., (© 2017 British Association of Dermatologists.)

Parents are increasingly placing amber necklaces on their infants or toddlers to prevent teething pain. The use of the necklaces can pose a risk of death by strangulation, however, there are no data on the potential infectious risk linked to bacterial colonisation associated with the necklaces. We aimed to analyse bacterial colonisation of amber necklaces worn by children during hospital consultations. This prospective observational study included all children wearing a teething necklace at consultation in the Paediatric Dermatology and the Paediatric Emergency Department of our hospital from April to December 2014. The study included 27 children (median age: 10.7 months; 70.4% female). The surface of necklaces underwent bacteriological analyses using three different agar cultures. Parents completed a brief questionnaire to provide reasons for using necklaces and express awareness of risks. One child had a history of impetigo. All necklaces were colonised by bacteria (median: four species per necklace [range: 1-9]); 32 different species were found, the most frequent being coagulase-negative staphylococci (Staphylococcus epidermidis in 88.9% of cases). In three cases, methicillin-sensitive Staphylococcus aureus was found. The most frequent reason for wearing a necklace was to prevent teething pain (n = 17; 63.0%); the necklace was judged effective (moderately/highly effective) in 74.1% of cases, however, 70.4% of parents considered the use of the necklace to be risky. Amber necklaces may be highly colonised by commensal germs of the skin, mainly coagulase-negative staphylococci. Although these bacteria are saprophytes, they may become pathogenic in particular conditions.

We sought to explore the architecture of trials of calcineurin inhibitors for atopic eczema to document the extent to which comparisons with active treatments such as topical corticosteroids might have been included or avoided. We identified all eligible randomized controlled trials using the Global Resource for EczemA Trials (GREAT) database. Network plots were produced where the nodes represented a treatment type and the lines between the nodes represented the number of trials or participants involved in the various treatment comparisons. A total of 174 randomized controlled trials for atopic eczema treatments were identified in which pimecrolimus, tacrolimus, or topical corticosteroids were compared with another intervention or a vehicle/emollient. Of 39 trials involving pimecrolimus and 41 trials involving tacrolimus, 8 (20.5%) and 13 (31.7%), respectively, made comparisons with topical corticosteroids, and 25 (64.1%) and 15 (36.6%), respectively, were vehicle-controlled studies. The high rate of comparisons with vehicle controls in randomized controlled trials that assessed the efficacy of pimecrolimus or tacrolimus long after efficacy had been established is a matter of concern. Active comparators (mild topical corticosteroids for pimecrolimus and moderate to potent topical corticosteroids for tacrolimus) are best placed to determine how topical calcineurin inhibitors compare with established clinical practice., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)