CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials

Development of Quality Indicators to Evaluate the Appropriateness of Empiric Antimicrobial Use in Pediatric Patients

Background: Use of quality indicators is one strategy recommended to assess antimicrobial prescribing for pediatric inpatients. Objective: To achieve consensus from infectious diseases clinicians on quality indicators that characterize appropriate empiric antimicrobial use for the management of infectious syndromes in pediatric inpatients. Methods: This study was completed using the Delphi technique. The research team developed an initial list of quality indicators, informed by a literature search. A multidisciplinary group of health care providers with expertise in infectious diseases was invited to participate. The list was disseminated to this panel of experts using Opinio survey software. The experts were asked to rate the indicators on a 9-point Likert scale in relation to the following criterion: “The importance of each item in determining appropriateness considering benefit or harm at the individual or population level”. Consensus was defined as at least 75% agreement and a median score of 7 or higher. Results: Twelve of 31 invited experts completed at least 1 round of the survey, and 10 completed all rounds. Consensus was achieved on 28 of 31 proposed indicators after 3 rounds. Indicators with consensus were categorized under “empiric choice” (n = 12 indicators), “dose” (n = 5), “duration” (n = 2), “administration” (n = 4), “diagnosis” (n = 2), and “documentation” (n = 3). Six of the indicators for which consensus was achieved were rephrased by the experts. Conclusions: Consensus was achieved on quality indicators to assess the appropriateness of empiric antimicrobial use in pediatric patients. Clinicians and researchers can use these consensus-based indicators to assess adherence to best practice. RÉSUMÉ Contexte : L’utilisation d’indicateurs de qualité est l’une des stratégies recommandées pour évaluer la prescription d’antimicrobiens aux patients pédiatriques hospitalisés. Objectif : Parvenir à un consensus, entre les cliniciens des maladies infectieuses, portant sur les indicateurs de qualité qui caractérisent l’utilisation empirique appropriée des antimicrobiens pour la prise en charge des syndromes infectieux chez les patients pédiatriques hospitalisés. Méthodes : Cette étude a été réalisée à l’aide de la technique Delphi. L’équipe de recherche a dressé une liste initiale d’indicateurs de qualité éclairée par une recherche documentaire. Un groupe multidisciplinaire de prestataires de soins de santé ayant une expertise dans le domaine des maladies infectieuses a été invité à participer. La liste a été diffusée à ce panel d’experts à l’aide du logiciel d’enquête Opinio. Les experts ont été invités à noter les indicateurs sur une échelle de Likert de 9 points par rapport au critère suivant : « L’importance de chaque élément pour déterminer la pertinence compte tenu du bienfait ou du dommage à l’échelle individuelle ou de la population ». Le consensus était défini comme « Un accord d’au moins 75 % et un score médian d’au moins 7 ». Résultats : Douze des 31 experts invités ont terminé au moins 1 cycle de l’enquête et 10 les ont tous terminés. Un consensus a été atteint pour 28 des 31 indicateurs proposés après 3 cycles. Les indicateurs qui ont atteint le consensus ont été classés en « choix empirique » (n = 12 indicateurs), « dose » (n = 5), « durée » (n = 2), « administration » (n = 4), « diagnostic » (n = 2) et « documentation » (n = 3). Six indicateurs faisant consensus ont été reformulés par les experts. Conclusions : Un consensus a été atteint pour les indicateurs de qualité visant à évaluer l’utilisation empirique appropriée des antimicrobiens chez les patients pédiatriques. Les cliniciens et les chercheurs peuvent utiliser ces indicateurs basés sur le consensus pour évaluer le respect des meilleures pratiques

Multicenter initial guidance on use of antivirals for children with coronavirus disease 2019/Severe acute respiratory syndrome coronavirus 2

BackgroundAlthough coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion.ResultsGiven the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated

Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2

BackgroundAlthough coronavirus disease 2019 (COVID-19) is mild in nearly all children, a small proportion of pediatric patients develop severe or critical illness. Guidance is therefore needed regarding use of agents with potential activity against severe acute respiratory syndrome coronavirus 2 in pediatrics.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 18 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of best available evidence and expert opinion.ResultsGiven the typically mild course of pediatric COVID-19, supportive care alone is suggested for the overwhelming majority of cases. The panel suggests a decision-making framework for antiviral therapy that weighs risks and benefits based on disease severity as indicated by respiratory support needs, with consideration on a case-by-case basis of potential pediatric risk factors for disease progression. If an antiviral is used, the panel suggests remdesivir as the preferred agent. Hydroxychloroquine could be considered for patients who are not candidates for remdesivir or when remdesivir is not available. Antivirals should preferably be used as part of a clinical trial if available.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For those rare cases of severe or critical disease, this guidance offers an approach for decision-making regarding antivirals, informed by available data. As evidence continues to evolve rapidly, the need for updates to the guidance is anticipated

Multicenter interim guidance on use of antivirals for children with COVID-19/SARS-CoV-2

BackgroundAlthough coronavirus disease 2019 (COVID-19) is a mild infection in most children, a small proportion develop severe or critical illness. Data describing agents with potential antiviral activity continue to expand such that updated guidance is needed regarding use of these agents in children.MethodsA panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion.ResultsGiven the typically mild course of COVID-19 in children, supportive care alone is suggested for most cases. For children with severe illness, defined as a supplemental oxygen requirement without need for noninvasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO), remdesivir is suggested, preferably as part of a clinical trial if available. Remdesivir should also be considered for critically ill children requiring invasive or noninvasive mechanical ventilation or ECMO. A duration of 5 days is appropriate for most patients. The panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for COVID-19 in children.ConclusionsAntiviral therapy for COVID-19 is not necessary for the great majority of pediatric patients. For children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir

Initial Guidance on Use of Monoclonal Antibody Therapy for Treatment of COVID-19 in Children and Adolescents

BackgroundIn November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for 2 novel virus-neutralizing monoclonal antibody therapies, bamlanivimab and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate coronavirus disease 2019 (COVID-19) in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products.MethodsA panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion.ResultsThe course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high-risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis.ConclusionsBased on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence and ensure the implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities

The effectiveness of Early Head Start for 3-year-old children and their parents

Early Head Start, a federal program begun in 1995 for low-income pregnant women and families with infants and toddlers, was evaluated through a randomized trial of 3,001 families in 17 programs. Interviews with primary caregivers, child assessments, and observations of parent-child interactions were completed when children were 3 years old. Caregivers were diverse in race-ethnicity, language, and other characteristics. Regression-adjusted impact analyses showed that 3-year-old program children performed better than did control children in cognitive and language development, displayed higher emotional engagement of the parent and sustained attention with play objects, and were lower in aggressive behavior. Compared with controls, Early Head Start parents were more emotionally supportive, provided more language and learning stimulation, read to their children more, and spanked less. The strongest and most numerous impacts were for programs that offered a mix of home-visiting and center-based services and that fully implemented the performance standards early

The effectiveness of Early Head Start for 3-year-old children and their parents

Early Head Start, a federal program begun in 1995 for low-income pregnant women and families with infants and toddlers, was evaluated through a randomized trial of 3,001 families in 17 programs. Interviews with primary caregivers, child assessments, and observations of parent-child interactions were completed when children were 3 years old. Caregivers were diverse in race-ethnicity, language, and other characteristics. Regression-adjusted impact analyses showed that 3-year-old program children performed better than did control children in cognitive and language development, displayed higher emotional engagement of the parent and sustained attention with play objects, and were lower in aggressive behavior. Compared with controls, Early Head Start parents were more emotionally supportive, provided more language and learning stimulation, read to their children more, and spanked less. The strongest and most numerous impacts were for programs that offered a mix of home-visiting and center-based services and that fully implemented the performance standards early