Reexamining the categorical exclusion of pediatric participants from controlled human infection trials

Controlled human infection (CHI) models have been developed for numerous pathogens in order to better understand disease processes and accelerate drug and vaccine testing. In the past, some researchers conducted highly controversial CHIs with vulnerable populations, including children. Ethical frameworks for CHIs now recommend vulnerable populations be excluded because they cannot consent to high risk research. In this paper we argue that CHI studies span a wide spectrum of benefit and risk, and that some CHI studies may involve minimal risk. The categorical exclusion of children from CHIs therefore departs from the standard approach to evaluating research risks, as international regulations and ethical guidance for pediatric research generally permit non-beneficial research with low risks. The paradigm in research ethics has also shifted from focusing on protecting vulnerable participants to recognizing that inclusion can be important as a matter of justice, providing new reasons to question this default exclusion of children from CHIs. Recognizing that pediatric CHIs can raise complex ethical issues and are easy to sensationalize in ways that may threaten the public’s trust in research and sponsor institutions, we conclude by describing additional complexities that must be addressed before pediatric CHIs beyond licensed vaccine studies might be ethically acceptable.     

Effects of the FcRn developmental pharmacology on the pharmacokinetics of therapeutic monoclonal IgG antibody in pediatric subjects using minimal physiologically-based pharmacokinetic modelling

The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab and palivizumab) were used. The adult group contained six subjects with weights from 50 to 100 kg. For pediatric subjects, seven age groups were assumed, with five subjects each having the weight of 95%, 75%, 50%, 25% and 5% percentile of the population. A first evidence-based rating system to evaluate the quality of the source data used to derive pediatric-specific mPBPK model parameter was proposed. A stepwise approach was used to examine the best combination of age/weight effect on the parameters of the mPBPK model in adult and pediatric subjects. IgG synthesis rate (K_syn), extravasation rate (ER) and FcRn were fitted simultaneously to the PK of bevacizumab and native-IgG in both adult and pediatric. All fitting showed good fits based on the graphs and the coefficient of variation of the fitted parameters (< 50%). Estimated weight-normalized K_syn increased while weight-normalized FcRn and ER decreased with increasing age. The age and weight effect on FcRn were successfully estimated from the data. The final mPBPK model developed with native IgG and bevacizumab was able to predict the PK of palivizumab in pediatric subjects. Implementation of the mPBPK model enables us to analyze the relationships of age, weight, FcRn, ER and K_syn in both adult and pediatric subject. This information may benefit the understanding of complex interaction between the FcRn developmental pharmacology and PK parameters, and improve the prediction of the antibody disposition in pediatric subjects.     

Cation shifts in human retina-choroid

Human ocular tissues from 50 donor eyes were elementally and morphologically analyzed in order to correlate the elemental content and distribution of Ca, Ba, Cr, Cu, Zn, and Se with ocular morphology, sex, race, irideal pigmentation, age, time of death, birth weight, presence and severity of diabetes, and other pathologies noted at autopsy. Initially, to facilitate the transport of donor tissue to the laboratory, the eyes were fixed in glutaraldehyde. Because our preliminary data revealed alterations in elemental content following chemical fixation of ocular tissues, all of the subsequent samples were analyzed in their fresh, hydrated (unfixed) condition as soon after enucleation as possible. Samples were elementally analyzed by X-ray fluorescence spectrometry (XRF) and proton-induced X-ray emission spectrometry (PIXE) using high resolution Si(Li) X-ray detectors. Tissue was morphologiscally examined by scanning electron microscopy and light microscopy histoichemistry.     

The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins

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Highlights

• •Proteome of airway secretions derived from mock- and hRSV-infected WD-PBEC cultures.
• •A polarised secretome in uninfected WD-PBECs, skewed in hRSV-infected cultures.
• •CXCL6, CXCL16, CECACAM1 and CSF3 induced only upon hRSV-infection.
• •Detection of CXCL6, CXCL16 and CSF3 in NPAs from hRSV-positive children.

     

Excess neuropeptides in lung signal through endothelial cells to impair gas exchange

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Neuroblastoma differentiation in vivo excludes cranial tumors

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Proteomics applied to pediatric medicine: opportunities and challenges

Introduction: Care in pediatrics often refers to treatments directed to adults. However, childhood is a specific life period, with molecular pathways connected to development and thereby it requires distinctive considerations and special treatments under disease. Proteomics can help to elucidate the molecular mechanisms underlying the human development and disease onset in pediatric age and this review is devoted to underline the results recently obtained in the field.

Areas covered: The contribution of proteomics to the characterization of physiological modifications occurring during human development is presented. The proteomic studies carried out to elucidate the molecular mechanisms underlying different pediatric pathologies and to discover new markers for early diagnosis and prognosis of disease, comprising genetic and systemic pathologies, sepsis and pediatric oncology are thereafter reported. The investigations concerning milk composition in human and farm mammals are also presented. Finally, the chances offered by the integration of different -omic platforms are discussed.

Expert commentary: The growing utilization of holistic technologies such as proteomics, metabolomics and microbiomics will allow, in the near future, to define at the molecular level the complexity of human development and related diseases, with great benefit for future generations.     

Outcomes Following Primary Anterior Cruciate Ligament Reconstruction Using a Partial Transphyseal (Over-the-Top) Technique in Skeletally Immature Patients

BackgroundThe incidence of anterior cruciate ligament (ACL) injuries in skeletally immature patients is increasing, with ACL reconstruction preferred in this population due to reported chondroprotective benefits. Due to concerns with growth disturbance following ACL reconstruction in skeletally immature patients, various physealsparing and partial transphyseal techniques have been developed. Currently, there is no consensus on the most effective ACL reconstruction technique in skeletally immature patients. The purpose of the current study was to report the outcomes of a partial-transphyseal over-the-top (OTT) ACL reconstruction in a cohort of skeletally immature patients.MethodsAll patients with radiographic evidence of open tibial and femoral physes that underwent primary ACL reconstruction using a partial-transphyseal OTT technique between 2009-2018 at a single tertiary-care institution with at least twelve months of clinical follow-up were retrospectively reviewed. Patient demographics, physical examination findings, graft ruptures, return to sport, and Tegner activity levels were analyzed. Statistical significance was defined as p<0.05.ResultsOverall, 11 males and 1 female (12 knees) with a mean age of 12.8±1.8 (range: 10-16) years were included in the study. The mean postoperative follow-up of the cohort was 2.3±1.2 (range: 1.1-5.2) years. All ACLs were reconstructed with hamstring autograft with allograft augmentation utilized in a single patient. There were two cases of ACL graft rupture (16.7%). All patients were able to return to the same or higher level of sporting activity at an average of 7.4+2.7 months. There were no cases of clinically significant longitudinal or angular growth disturbance.ConclusionPartial transphyseal ACL reconstruction using a transphyseal tibial tunnel and an extra-articular OTT technique on the femur in skeletally immature patients affords minimal risk of growth disturbance with a graft rupture rate consistent with what has been reported in this high-risk population. All patients were able to return to sport at the same or higher level. Level of Evidence: IV     

Using BRAFV600E as a marker of autophagy dependence in pediatric brain tumors

Autophagy inhibition is a potential therapeutic strategy in central nervous system (CNS) tumors. The BRAF^V600E mutation is known to affect autophagy. Our studies indicate CNS tumor cells with BRAF^V600E mutant cells (but not wild type) display high rates of induced autophagy, are sensitive to autophagy inhibition, and display synergy when chloroquine is combined with the RAF kinase inhibitor vemurafenib or standard chemotherapeutics. Our studies also indicate chloroquine can improve vemurafenib sensitivity in intrinsically resistant cells and in a patient with induced-vemurafenib resistance. These findings suggest CNS tumors with BRAF^V600E are autophagy-dependent and that identification of BRAF^V600E may be a marker to identify pediatric patients with the best potential response to autophagy inhibition.