Noninvasive pediatric blood pressure assessment: exploring the clinicians' perspective.

BACKGROUND: Obtaining accurate and reliable blood pressure (BP) readings in pediatric patients is challenging, given difficulties in adhering to measurement guidelines, limited device validation and variable patient cooperation. This study aimed to investigate clinicians' perspectives surrounding noninvasive pediatric BP assessment to identify opportunities for improvement in BP technology and clinical practice. METHOD: Based on an adapted version of the extended Technology Acceptance Model 2, semi-structured interviews were conducted with clinicians involved in noninvasive pediatric BP assessment in a major Australian children's hospital. Transcripts were analyzed thematically and guided by Technology Acceptance Model 2. RESULTS: Clinician responses ( n  = 20) revealed that poor patient tolerance of BP measurement resulting from excessive cuff inflation is a major hindrance to reliable pediatric BP assessment. Clinicians described low trust in BP readings from automated devices, often relating to poor patient tolerance to cuff inflation, thereby diminishing the clinical utility of these readings in informing treatment decisions. Auscultatory measurement was regarded as more trustworthy and better tolerated, but less convenient to perform as compared with oscillometric measurement. CONCLUSION: A dissonance exists between (1) low trust and clinical utility of the most common and easy-to-use BP measurement approach (automated devices), versus (2) higher trust and clinical utility, but efficiency and user-related impediments, for the auscultatory method. Based on our results, we have developed the Blood Pressure Acceptance Model, which can be used to explain and predict clinicians' acceptance of BP technology. Further work is needed to improve the tolerability and accuracy of automated BP devices in real-world pediatric settings.

How developmental coordination disorder affects daily life: The adolescent perspective.

BACKGROUND: Few studies have focused on the implications of developmental coordination disorder (DCD) in the teen years. Understanding the unique needs of adolescents with DCD and the challenges they face are imperative to inform clinical care. AIM: To understand how DCD affects daily life from adolescents living with the disorder. METHODS: Participants were recruited from a database of adolescents who were formally diagnosed with DCD in childhood. Nineteen semi-structured interviews of adolescents with DCD (13-18 years) were conducted and analyzed using an interpretive description approach. RESULTS: Data analysis revealed four overarching themes: (1) Through the years; (2) Standing out, left out, opting out; (3) Rising into Resilience; and (4) Help me to be me. Adolescents with DCD face challenges in physical, cognitive, social, emotional, and mental health domains, but their success can be optimized through provision of support, fostering social connections, the use of strategies, and increasing public understanding. Few services currently exist for adolescents with DCD, as treatment is not standard of care. CONCLUSIONS AND IMPLICATIONS: Insights gained from this study provide client-centred evidence to advocate for intervention for adolescents with DCD, and guide recommendations for clinical care and community support to meet the needs of this under-served population. WHAT THIS PAPER ADDS?: This paper qualitatively explores the lived experience of adolescents with DCD, adding to the limited research within this population. Expanding beyond the typical focus of motor challenges, this paper highlights the widespread influence of DCD on daily life, including in cognitive, mental health, and social-emotional domains. Common environmental contexts that exacerbate challenges during adolescent years are explored, including high school PE class and electives, learning to drive, beginning employment, and preparing for post-secondary education. Through an interpretive description methodology, this paper delves into clinical and practical solutions to support adolescents with DCD, from an individualized and client-centered perspective.

The glycoimmune checkpoint receptor Siglec-7 interacts with T-cell ligands and regulates T-cell activation.

Siglec-7 (sialic acid-binding immunoglobulin-like lectin 7) is a glycan-binding immune receptor that is emerging as a significant target of interest for cancer immunotherapy. The physiological ligands that bind Siglec-7, however, remain incompletely defined. In this study, we characterized the expression of Siglec-7 ligands on peripheral immune cell subsets and assessed whether Siglec-7 functionally regulates interactions between immune cells. We found that disialyl core 1 O-glycans are the major immune ligands for Siglec-7 and that these ligands are particularly highly expressed on naïve T-cells. Densely glycosylated sialomucins are the primary carriers of these glycans, in particular a glycoform of the cell-surface marker CD43. Biosynthesis of Siglec-7-binding glycans is dynamically controlled on different immune cell subsets through a genetic circuit involving the glycosyltransferase GCNT1. Siglec-7 blockade was found to increase activation of both primary T-cells and antigen-presenting dendritic cells in vitro, indicating that Siglec-7 binds T-cell glycans to regulate intraimmune signaling. Finally, we present evidence that Siglec-7 directly activates signaling pathways in T-cells, suggesting a new biological function for this receptor. These studies conclusively demonstrate the existence of a novel Siglec-7-mediated signaling axis that physiologically regulates T-cell activity. Going forward, our findings have significant implications for the design and implementation of therapies targeting immunoregulatory Siglec receptors.

Identification of association fibers using ex vivo diffusion tractography in Alexander disease brains.

BACKGROUND AND PURPOSE: Alexander disease (AxD) is a neurodegenerative disorder caused by heterozygous Glial Fibrillary Acidic Protein mutation. The characteristic structural findings of AxD, such as leukodystrophic features, are well known, while association fibers of AxD remain uninvestigated. The aim of this study was to explore global and subcortical fibers in four brains with AxD using ex vivo diffusion tractography METHODS: High-angular-resolution diffusion magnetic resonance imaging (HARDI) tractography and diffusion-tensor imaging (DTI) tractography were used to evaluate long and short association fibers and compared to histological findings in brain specimens obtained from four donors with AxD and two donors without neurological disorders RESULTS: AxD brains showed impairment of long association fibers, except for the arcuate fasciculus and cingulum bundle, and abnormal trajectories of the inferior longitudinal and fronto-occipital fasciculi on HARDI tractography and loss of multidirectionality in subcortical fibers on DTI tractography. In histological studies, AxD brains showed diffuse low density on Klüver-Barrera and neurofilament staining and sporadic Rosenthal fibers on hematoxylin and eosin staining CONCLUSIONS: This study describes the spatial distribution of degenerations of short and long association fibers in AxD brains using combined tractography and pathological findings.

Bridging Glycomics and Genomics: New Uses of Functional Genetics in the Study of Cellular Glycosylation.

All living cells are coated with a diverse collection of carbohydrate molecules called glycans. Glycans are key regulators of cell behavior and important therapeutic targets for human disease. Unlike proteins, glycans are not directly templated by discrete genes. Instead, they are produced through multi-gene pathways that generate a heterogenous array of glycoprotein and glycolipid antigens on the cell surface. This genetic complexity has sometimes made it challenging to understand how glycosylation is regulated and how it becomes altered in disease. Recent years, however, have seen the emergence of powerful new functional genomics technologies that allow high-throughput characterization of genetically complex cellular phenotypes. In this review, we discuss how these techniques are now being applied to achieve a deeper understanding of glyco-genomic regulation. We highlight specifically how methods like ChIP-seq, RNA-seq, CRISPR genomic screening and scRNA-seq are being used to map the genomic basis for various cell-surface glycosylation states in normal and diseased cell types. We also offer a perspective on how emerging functional genomics technologies are likely to create further opportunities for studying cellular glycobiology in the future. Taken together, we hope this review serves as a primer to recent developments at the glycomics-genomics interface.

Cortical thickness abnormalities in attention deficit hyperactivity disorder revealed by structural magnetic resonance imaging: Newborns to young adults.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental condition for which we have an incomplete understanding, and so brain imaging methods, such as magnetic resonance imaging (MRI), may be able to assist in characterising and understanding the presentation of the brain in an ADHD population. Statistical and computational methods were used to compare participants with ADHD and neurotypical controls at a variety of developmental stages to assess detectable abnormal neurodevelopment potentially associated with ADHD and to assess our ability to diagnose and characterise the condition from real-world clinical MRI examinations. T1-weighted structural MRI examinations (n = 993; 0-31 years old [YO]) were obtained from neurotypical controls, and 637 examinations were obtained from patients with ADHD (0-26 YO). Measures of average (mean) regional cortical thickness were acquired, alongside the first reporting of regional cortical thickness variability (as assessed with the standard deviation [SD]) in ADHD. A comparison between the inattentive and combined (inattentive and hyperactive) subtypes of ADHD is also provided. A preliminary independent validation was also performed on the publicly available ADHD200 dataset. Relative to controls, subjects with ADHD had, on average, lowered SD of cortical thicknesses and increased mean thicknesses across several key regions potentially linked with known symptoms of ADHD, including the precuneus and supramarginal gyrus.

Normative blood pressure response to exercise stress testing in children and adolescents.

OBJECTIVE: To describe normative values for blood pressure (BP) response to maximal exercise in children/adolescents undergoing a treadmill stress test. METHODS: From a retrospective analysis of medical records, patients who had undergone a Bruce protocol exercise stress test, with (1) normal cardiovascular system and (2) a body mass index percentile rank below 95% were included for analysis. Sex, age, height, weight, resting and peak heart rate, resting and peak systolic blood pressure (SBP), test duration, stage of Bruce protocol at termination, reason for undergoing the test and reason for termination of test were collected. Percentiles for exercise-induced changes in SBP were constructed by age and height for each sex with the use of quantile regression models. RESULTS: 648 patients with a median age of 12.4 years (range 6-18 years) were included. Typical indications for stress testing were investigation of potential rhythm abnormalities, syncope/dizziness and chest pain and were deemed healthy by an overseeing cardiologist. Mean test duration was 12.6±2.2 min. Reference percentiles for change in SBP by sex, age and height are presented. CONCLUSION: The presented reference percentiles for the change in SBP for normal children and adolescents will have utility for detecting abnormally high or low BP responses to exercise in these age groups.

Structural and Diffusion MRI Analyses With Histological Observations in Patients With Lissencephaly.

The development of cortical convolutions, gyri and sulci, is a complex process that takes place during prenatal development. Lissencephaly, a rare genetic condition characterized by the lack of cortical convolutions, offers a model to look into biological processes that lead to the development of convolutions. Retrospective, qualitative, and quantitative analyses of structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were performed in patients with lissencephaly (N = 10) and age-/sex-matched controls (N = 10). In order to identify microstructural correlates of structural MRI and DTI findings, postmortem brains of patients with lissencephaly (N = 4) and age-matched controls (N = 4) were also examined with histology. Patients with lissencephaly had significantly smaller gyrification index and volumes of hemispheric white and gray matter, compared to the age-/sex-matched control group. However, there was no significant difference between groups in the subcortical gray matter volumes. Although the majority of patients with lissencephaly had a preserved normal-like appearance of major fissures and primary sulci, the spatial distribution of agyric cortical regions was different in patients with lissencephaly-1 (LIS1) and doublecortin (DCX) mutations. Lastly, in patients with lissencephaly, the spatiotemporal distribution of projection pathways was preserved while short- to medium-range cortico-cortical pathways were absent or fewer in number. Our results indicate that in the patients with lissencephaly cortical system is affected more than the subcortical one.

Structural magnetic resonance imaging demonstrates abnormal cortical thickness in Down syndrome: Newborns to young adults.

Down syndrome (DS) is a genetic disorder caused by an extra copy of all or part of chromosome 21 and is characterized by intellectual disability. We performed a retrospective analysis of 47 magnetic resonance imaging (MRI) examinations of participants with DS (aged 5 to 22 years) and compared them with a large cohort of 854 brain MRIs obtained from neurotypical participants (aged 5 to 32 years) with the objective of assessing the clinical presentation of Down syndrome, towards better understanding the neurological development associated with the condition. An additional cohort of 26 MRI exams from patients with DS and 139 exams from neurotypical participants (aged 0-5 years) are included as part of a supplementary analysis. Regionally distributed cortical thickness measurements, including average measurements as well as standard deviations (intra-regional cortical thickness variability) were extracted from each examination. The largest effect sizes observed were associated with increased average cortical thickness in the postcentral gyrus with specific abnormalities observed in Brodmann's areas 1 and 3b in DS, which was observed across all age ranges. We also observed strong effect sizes associated with decreased cortical thickness variability in the lateral orbitofrontal gyrus, the postcentral gyrus and more in DS participants. Findings suggest regionally irregular gray matter development in DS that can be detected with MRI.

Structural Magnetic Resonance Imaging Demonstrates Abnormal Regionally-Differential Cortical Thickness Variability in Autism: From Newborns to Adults.

Autism is a group of complex neurodevelopmental disorders characterized by impaired social interaction and restricted/repetitive behavior. We performed a large-scale retrospective analysis of 1,996 clinical neurological structural magnetic resonance imaging (MRI) examinations of 781 autistic and 988 control subjects (aged 0-32 years), and extracted regionally distributed cortical thickness measurements, including average measurements as well as standard deviations which supports the assessment of intra-regional cortical thickness variability. The youngest autistic participants (<2.5 years) were diagnosed after imaging and were identified retrospectively. The largest effect sizes and the most common findings not previously published in the scientific literature involve abnormal intra-regional variability in cortical thickness affecting many (but not all) regions of the autistic brain, suggesting irregular gray matter development in autism that can be detected with MRI. Atypical developmental patterns have been detected as early as 0 years old in individuals who would later be diagnosed with autism.

Absence of cytotoxic and inflammatory effects following in vitro exposure of chondrogenically-differentiated human mesenchymal stem cells to adenosine, lidocaine and Mg2+ solution.

BACKGROUND: ALM solution, a combination of adenosine, lidocaine and Mg2+, is an emerging small volume therapy that has been shown to prevent and correct coagulopathy and surgery-related inflammation in preclinical models, though its application in orthopaedic surgery is yet to be demonstrated. The effect of ALM solution on chondrocytes is unknown. The aim of this preliminary study was to investigate the effect of ALM solution on viability and inflammatory responses of chondrogenically-differentiated human bone marrow-derived mesenchymal stem cells (chondro-MSC), in vitro. METHODS: Chondro-MSC were exposed to media only, saline (0.9% NaCl or 1.3% NaCl) only, or saline containing ALM (1 mM adenosine, 3 mM lidocaine, 2.5 mM Mg2+) or tranexamic acid (TXA, 100 mg/ml) for 1 or 4 h. Responses to ALM solutions containing higher lidocaine concentrations were also compared. Chondrocyte viability was determined using WST-8 colorimetric assays and inflammatory cytokine (TNF-α, IL-1ß, IL-8) and matrix metalloproteinases (MMP-3, MMP-12, MMP-13) concentrations using multiplex bead arrays. RESULTS: The viability of chondro-MSC was significantly greater after 1 h treatment with ALM compared to saline (96.2 ± 7.9 versus 75.6 ± 7.3%). Extension of exposure times to 4 h had no significant adverse effect on cell viability after treatment with ALM (1 h, 85.4 ± 5.6 v 4 h, 74.0 ± 15.2%). Cytotoxicity was evident following exposure to solutions containing lidocaine concentrations greater than 30 mM. There were no significant differences in viability (80 ± 5.4 v 57.3 ± 16.2%) or secretion of IL-8 (60 ± 20 v 160 ± 50 pg/ml), MMP-3 (0.95 ± 0.6 v 3.4 ± 1.6 ng/ml), and MMP-13 (4.2 ± 2.4 v 9.2 ± 4.3 ng/ml) in chondro-MSC exposed to saline, ALM or TXA. CONCLUSIONS: Short-term, in vitro exposure to clinically-relevant concentrations of ALM solution had no adverse inflammatory or chondrotoxic effects on human chondro-MSC, with responses comparable to saline and TXA. These findings provide support for continued evaluation of ALM solution as a possible therapeutic to improve outcomes following orthopaedic procedures.

Regional volumetric abnormalities in pediatric autism revealed by structural magnetic resonance imaging.

Autism is a group of complex neurodevelopmental disorders characterized by impaired social interaction, restricted and repetitive behavior. We performed a large-scale retrospective analysis of 1,996 structural magnetic resonance imaging (MRI) examinations of the brain from 1,769 autistic and neurologically typically developing patients (aged 0-32 years), and extracted regional volumetric measurements distributed across 463 brain regions of each patient. The youngest autistic patients (<2.5 years) were diagnosed after imaging and identified retrospectively. Our study demonstrates corpus callosum volumetric abnormalities among autistic patients that are associated with brain overgrowth in early childhood (0-5 years old), followed by a shift towards known decreased volumes in later ages. Results confirm known increases in ventricular volumes among autistic populations and extends those findings to increased volumes of the choroid plexus. Our study also demonstrates distributed volumetric abnormalities among autistic patients that affect a variety of key regional white and grey matter areas of the brain potentially associated with known symptoms of autism.

A Sorting Statistic with Application in Neurological Magnetic Resonance Imaging of Autism.

Effect size refers to the assessment of the extent of differences between two groups of samples on a single measurement. Assessing effect size in medical research is typically accomplished with Cohen's d statistic. Cohen's d statistic assumes that average values are good estimators of the position of a distribution of numbers and also assumes Gaussian (or bell-shaped) underlying data distributions. In this paper, we present an alternative evaluative statistic that can quantify differences between two data distributions in a manner that is similar to traditional effect size calculations; however, the proposed approach avoids making assumptions regarding the shape of the underlying data distribution. The proposed sorting statistic is compared with Cohen's d statistic and is demonstrated to be capable of identifying feature measurements of potential interest for which Cohen's d statistic implies the measurement would be of little use. This proposed sorting statistic has been evaluated on a large clinical autism dataset from Boston Children's Hospital, Harvard Medical School, demonstrating that it can potentially play a constructive role in future healthcare technologies.

Cerebellar Pathways in Mouse Model of Purkinje Cell Degeneration Detected by High-Angular Resolution Diffusion Imaging Tractography.

Cerebellar MR imaging has several challenging aspects, due to the fine, repetitive layered structure of cortical folia with underlying axonal pathways. In this MR study, we imaged with high-angular resolution diffusion imaging (HARDI) abnormal cerebellar cortical structure (gray matter) and myelinated axonal pathways (white matter) of a mouse spontaneous mutation, Purkinje cell degeneration (pcd), in which almost all Purkinje neurons degenerate, mainly between postnatal days 20 and 35. Mouse brains at postnatal day 20 (P20) and at 8 months were scanned, and known or expected abnormalities, such as reduction of the white matter volume, disorganized pathways likely linked to parallel fibers, mossy fibers, and other fibers running from/to the cerebellar cortex were observed in mutant mice. Such abnormalities were detected at both an early and a fully advanced degeneration stage. These results suggest that our diffusion MR tractography is useful for early detection and tracking of neuropathology in the cerebellum.