Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant\u27s maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health

Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus

© 2019 The Authors Objective: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. Methods: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). Results: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03–1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). Conclusion: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease

Osteopontin and disease activity in patients with recent-onset systemic Lupus Erythematosus: Results from the SLICC Inception Cohort

Copyright © 2019. All rights reserved. Objective. In cross-sectional studies, elevated osteopontin (OPN) levels have been proposed to reflect, and/or precede, progressive organ damage and disease severity in systemic lupus erythematosus (SLE). We aimed, in a cohort of patients with recent-onset SLE, to determine whether raised serum OPN levels precede damage and/or are associated with disease activity or certain disease phenotypes. Methods. We included 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who had 5 years of followup data available. All patients fulfilled the 1997 American College of Rheumatology (ACR) criteria. Baseline sera from patients and from age- and sex-matched population-based controls were analyzed for OPN using ELISA. Disease activity and damage were assessed at each annual followup visit using the SLE Disease Activity Index 2000 (SLEDAI-2K) and the SLICC/ACR damage index (SDI), respectively. Results. Compared to controls, baseline OPN was raised 4-fold in SLE cases (p \u3c 0.0001). After relevant adjustments in a binary logistic regression model, OPN levels failed to significantly predict global damage accrual defined as SDI ≥ 1 at 5 years. However, baseline OPN correlated with SLEDAI-2K at enrollment into the cohort (r = 0.27, p \u3c 0.0001), and patients with high disease activity (SLEDAI-2K ≥ 5) had raised serum OPN (p \u3c 0.0001). In addition, higher OPN levels were found in patients with persistent disease activity (p = 0.0006), in cases with renal involvement (p \u3c 0.0001) and impaired estimated glomerular filtration rate (p = 0.01). Conclusion. The performance of OPN to predict development of organ damage was not impressive. However, OPN associated significantly with lupus nephritis and with raised disease activity at enrollment, as well as over time

Effect of Location on Tracheal Intubation Safety in Cardiac Disease—Are Cardiac ICUs Safer?

Copyright © 2017 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies Objectives: Evaluate differences in tracheal intubation–associated events and process variances (i.e., multiple intubation attempts and oxygen desaturation) between pediatric cardiac ICUs and noncardiac PICUs in children with underlying cardiac disease. Design: Retrospective cohort study using a multicenter tracheal intubation quality improvement database (National Emergency Airway Registry for Children). Setting: Thirty-six PICUs (five cardiac ICUs, 31 noncardiac ICUs) from July 2012 to March 2016. Patients: Children with medical or surgical cardiac disease who underwent intubation in an ICU. Interventions: None. Measurements and Main Results: Our primary outcome was the rate of any adverse tracheal intubation–associated event. Secondary outcomes were severe tracheal intubation–associated events, multiple tracheal intubation attempt rates, and oxygen desaturation. There were 1,502 tracheal intubations in children with underlying cardiac disease (751 in cardiac ICUs, 751 in noncardiac ICUs) reported. Cardiac ICUs and noncardiac ICUs had similar proportions of patients with surgical cardiac disease. Patients undergoing intubation in cardiac ICUs were younger (median age, 1 mo [interquartile range, 0–6 mo]) compared with noncardiac ICUs (median 3 mo [interquartile range, 1–11 mo]; p \u3c 0.001). Tracheal intubation–associated event rates were not different between cardiac ICUs and noncardiac ICUs (16% vs 19%; adjusted odds ratio, 0.74; 95% CI, 0.54–1.02; p = 0.069). However, in a sensitivity analysis comparing cardiac ICUs with mixed ICUs (i.e., ICUs caring for children with either general pediatric or cardiac diseases), cardiac ICUs had decreased odds of adverse events (adjusted odds ratio, 0.71; 95% CI, 0.52–0.97; p = 0.033). Rates of severe tracheal intubation–associated events and multiple attempts were similar. Desaturations occurred more often during intubation in cardiac ICUs (adjusted odds ratio, 1.61; 95% CI, 1.04–1.15; p = 0.002). Conclusions: In children with underlying cardiac disease, rates of adverse tracheal intubation–associated events were not lower in cardiac ICUs as compared to noncardiac ICUs, even after adjusting for differences in patient characteristics and care models

Impact of Just-in-Time and Just-in-Place Simulation on Intern Success With Infant Lumbar Puncture

BACKGROUND AND OBJECTIVE: Simulation-based skill trainings are common; however, optimal instructional designs that improve outcomes are not well specified. We explored the impact of just-in-time and just-in-place training (JIPT) on interns\u27 infant lumbar puncture (LP) success. METHODS: This prospective study enrolled pediatric and emergency medicine interns from 2009 to 2012 at 34 centers. Two distinct instructional design strategies were compared. Cohort A (2009-2010) completed simulation-based training at commencement of internship, receiving individually coached practice on the LP simulator until achieving a predefined mastery performance standard. Cohort B (2010-2012) had the same training plus JIPT sessions immediately before their first clinical LP. Main outcome was LP success, defined as obtaining fluid with first needle insertion andanalgesia, early stylet removal, and overall attempts. RESULTS: A total of 436 first infant LPs were analyzed. The LP success rate in cohort A was 35% (13/37), compared with 38% (152/399) in cohort B (95% confidence interval for difference [CI diff], -15% to +18%). Cohort B exhibited greater analgesia use (68% vs 19%; 95% CI diff, 33% to 59%), early stylet removal (69% vs 54%; 95% CI diff, 0% to 32%), and lower mean number of attempts (1.4 +/- 0.6 vs 2.1 +/- 1.6, P \u3c .01) compared with cohort A. CONCLUSIONS: Across multiple institutions, intern success rates with infant LP are poor. Despite improving process measures, adding JIPT to training bundles did not improve success rate. More research is needed on optimal instructional design strategies for infant LP

Managing Chronic Cough as a Symptom in Children and Management Algorithms: CHEST Guideline and Expert Panel Report

© 2020 American College of Chest Physicians Background: Cough is one of the most common presenting symptoms to general practitioners. The objective of this article is to collate the pediatric components of the CHEST chronic cough guidelines that have recently updated the 2006 guidelines to assist general and specialist medical practitioners in the evaluation and management of children who present with chronic cough. Methods: We reviewed all current CHEST Expert Cough Panel\u27s statements and extracted recommendations and suggestions relating to children aged ≤ 14 years with chronic cough (\u3e 4 weeks duration). Additionally, we undertook systematic reviews to update other sections we considered relevant and important. Results: The eight recent CHEST guidelines relevant to children, based on systematic reviews, reported some high-quality evidence in the management of chronic cough in children (eg, use of algorithms and management of wet/productive cough using appropriate antibiotics). However, much evidence is still inadequate, particularly in the management of non-specific cough in the community. Conclusions: The recommendations and suggestions related to the management of chronic cough in the pediatric age group have been based upon high-quality systematic reviews and are summarized in this article. Compared to the 2006 Cough Guidelines, there is now high-quality evidence for some aspects of the management of chronic cough in children. However, further studies particularly in primary health care are required