Brief Report: An evaluation of an Australian autism-specific, early intervention programme

There is a relative paucity of evidence examining the effectiveness of early intervention for young children with Autism Spectrum Disorder, in particular those delivered through educationally-based programmes. This study aimed to evaluate the real world effectiveness of a community-based autism-specific early learning and intervention programme in Australia. Children enrolled between February 2010 and May 2013 who had a diagnosis of an Autism Spectrum Disorder was eligible to participate in the study. Fifty-nine children with a mean age of 3.98 years participated. Cognitive ability, language, autistic symptoms, and motor skills were assessed at baseline and follow up (12 months or at programme exit) using standardised measures. Pre- and post-measures were compared using paired sample t-tests. Significant improvements were found in receptive and expressive language, autism symptoms, and overall adaptive behaviour. No significant change was found in motor skills. Children with Autism Spectrum Disorder attending the community-based programme had significant gains particularly in domains of cognition and language. Study limitations are discussed

HbA1c variability in adults with type 1 diabetes on continuous subcutaneous insulin infusion (CSII) therapy compared to multiple daily injection (MDI) treatment

Objective To determine if continuous subcutaneous insulin infusion (CSII) therapy is associated with lower glycated haemoglobin (HbA1c) variability (long-term glycaemic variability; GV) relative to multiple daily injection (MDI) treatment in adults with type 1 diabetes mellitus (T1DM). Design Retrospective audit. Setting and participants Clinic records from 506 adults with T1DM from two tertiary Australian hospitals. Outcome measures Long-term GV was assessed by HbA1c SD and coefficient of variation (CV) in adults on established MDI or CSII therapy, and in a subset changing from MDI to CSII. Results Adults (n=506, (164 CSII), 50% women, mean±SD age 38.0±15.3 years, 17.0±13.7 years diabetes, mean HbA1c 7.8%±1.2% (62±13 mmol/mol) on CSII, 8.0%±1.5% (64±16 mmol/mol) on MDI) were followed for 4.1±3.6 years. CSII use was associated with lower GV (HbA1c SD: CSII vs MDI 0.5%±0.41% (6±6 mmol/mol) vs 0.7%±0.7% (9±8 mmol/mol)) and CV: CSII vs MDI 6.7%±4.6% (10±10 mmol/mol) vs 9.3%±7.3% (14±13 mmol/mol), both p<0.001. Fifty-six adults (73% female, age 36±13 years, 16±13 years diabetes, HbA1c 7.8%±0.8% (62±9 mmol/mol)) transitioned from MDI to CSII. Mean HbA1c fell by 0.4%. GV from 1 year post-CSII commencement decreased significantly, HbA1c SD pre-CSII versus post-CSII 0.7%±0.5% (8±5 mmol/mol) vs 0.4%±0.4% (5±4 mmol/mol); p<0.001, and HbA1c CV 9.2%±5.5% (13±8 mmol/mol) vs 6.1%±3.9% (9±5 mmol/mol); p<0.001. Conclusions In clinical practice with T1DM adults relative to MDI, CSII therapy is associated with lower HbA1c GV

Interleukin‐5 drives glycolysis and reactive oxygen species‐dependent citric acid cycling by eosinophils

Introduction Eosinophils have been long implicated in antiparasite immunity and allergic diseases and, more recently, in regulating adipose tissue homeostasis. The metabolic processes that govern eosinophils, particularly upon activation, are unknown. Methods Peripheral blood eosinophils were isolated for the analysis of metabolic processes using extracellular flux analysis and individual metabolites by stable isotope tracer analysis coupled to gas chromatography‐mass spectrometry following treatment with IL‐3, IL‐5 or granulocyte‐macrophage colony‐stimulating factor (GM‐CSF). Eosinophil metabolism was elucidated using pharmacological inhibitors. Results Human eosinophils engage a largely glycolytic metabolism but also employ mitochondrial metabolism. Cytokine stimulation generates citric acid cycle (TCA) intermediates from both glucose and glutamine revealing this previously unknown role for mitochondria upon eosinophil activation. We further show that the metabolic programme driven by IL‐5 is dependent on the STAT5/PI3K/Akt signalling axis and that nicotinamide adenine dinucleotide phosphate oxidase (NOX)‐dependent ROS production might be a driver of mitochondrial metabolism upon eosinophil activation. Conclusion We demonstrate for the first time that eosinophils are capable of metabolic plasticity, evidenced by increased glucose‐derived lactate production upon ROS inhibition. Collectively, this study reveals a role for both glycolysis and mitochondrial metabolism in cytokine‐stimulated eosinophils. Selective targeting of eosinophil metabolism may be of therapeutic benefit in eosinophil‐mediated diseases and regulation of tissue homeostasis

Continuous subcutaneous insulin infusion alters microRNA expression and glycaemic variability in children with type 1 diabetes

To determine whether continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) therapy from near-diagnosis of type 1 diabetes is associated with reduced glycaemic variability (GV) and altered microRNA (miRNAs) expression. Adolescents (74% male) within 3-months of diabetes diagnosis (n = 27) were randomized to CSII (n = 12) or MDI. HbA1c, 1-5-Anhydroglucitol (1,5-AG), high sensitivity C-peptide and a custom TaqMan qPCR panel of 52 miRNAs were measured at baseline and follow-up (median (LQ-UQ); 535 (519-563) days). There were no significant differences between groups in baseline or follow-up HbA1c or C-peptide, nor baseline miRNAs. Mean +/- SD 1,5-AG improved with CSII vs. MDI (3.1 +/- 4.1 vs. - 2.2 +/- - 7.0 mg/ml respectively, P = 0.029). On follow-up 11 miRNAs associated with diabetes vascular complications had altered expression in CSII-users. Early CSII vs. MDI use is associated with lower GV and less adverse vascular-related miRNAs. Relationships with future complications are of interest

A novel simplified biomechanical assessment of the heel pad during foot plantarflexion

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Ultra-Widefield Imaging of the Retinal Macrovasculature in Parkinson Disease Versus Controls With Normal Cognition Using Alpha-Shapes Analysis

Purpose: To investigate retinal vascular characteristics using ultra-widefield (UWF) scanning laser ophthalmoscopy in Parkinson disease (PD).Methods: Individuals with an expert-confirmed clinical diagnosis of PD and controls with normal cognition without PD underwent UWF imaging (California, Optos). Patients with diabetes, uncontrolled hypertension, glaucoma, dementia, other movement disorders, or known retinal or optic nerve pathology were excluded. Images were analyzed using Vasculature Assessment and Measurement Platform for Images of the Retina (VAMPIRE-UWF; Universities of Edinburgh and Dundee, UK) software which described retinal vessel width gradient and tortuosity, vascular network fractal dimension, as well as alpha-shape analysis to further characterize vascular morphology [complexity (Opαmin) and spread (OpA)].Results: In the PD cohort, 53 eyes of 38 subjects, and in the control cohort, 51 eyes of 33 subjects were assessed. Eyes with PD had more tortuous retinal arteries in the superotemporal quadrant (p = 0.043). In eyes with PD, alpha-shape analysis revealed decreased OpA, indicating less retinal vasculature spread compared to controls (p = 0.032). Opαmin was decreased in PD (p = 0.044), suggesting increased vascular network complexity. No differences were observed in fractal dimension in any ROI.Conclusions: This pilot study suggests that retinal vasculature assessment on UWF images using alpha-shape analysis reveals differences in retinal vascular network spread and complexity in PD and may be a more sensitive metric compared to fractal dimension.Translational Relevance: Retinal vasculature assessment using these novel methods may be useful in understanding ocular manifestations of PD and the development of retinal biomarkers

Ultra-Widefield Imaging of the Retinal Macrovasculature in Parkinson Disease Versus Controls With Normal Cognition Using Alpha-Shapes Analysis

PURPOSE: To investigate retinal vascular characteristics using ultra-widefield (UWF) scanning laser ophthalmoscopy in Parkinson disease (PD).METHODS: Individuals with an expert-confirmed clinical diagnosis of PD and controls with normal cognition without PD underwent Optos California UWF imaging. Patients with diabetes, uncontrolled hypertension, glaucoma, dementia, other movement disorders, or known retinal or optic nerve pathology were excluded. Images were analyzed using Vasculature Assessment and Measurement Platform for Images of the Retina (VAMPIRE-UWF) software, which describes retinal vessel width gradient and tortuosity, provides vascular network fractal dimensions, and conducts alpha-shape analysis to further characterize vascular morphology (complexity, Opαmin; spread, OpA).RESULTS: In the PD cohort, 53 eyes of 38 subjects were assessed; in the control cohort, 51 eyes of 33 subjects were assessed. Eyes with PD had more tortuous retinal arteries in the superotemporal quadrant (P = 0.043). In eyes with PD, alpha-shape analysis revealed decreased OpA, indicating less retinal vasculature spread compared to controls (P = 0.032). Opαmin was decreased in PD (P = 0.044), suggesting increased vascular network complexity. No differences were observed in fractal dimension in any region of interest.CONCLUSIONS: This pilot study suggests that retinal vasculature assessment on UWF images using alpha-shape analysis reveals differences in retinal vascular network spread and complexity in PD and may be a more sensitive metric compared to fractal dimension.TRANSLATIONAL RELEVANCE: Retinal vasculature assessment using these novel methods may be useful in understanding ocular manifestations of PD and the development of retinal biomarkers.</p

Potently neutralizing and protective anti-human metapneumovirus antibodies target diverse sites on the fusion glycoprotein

Human metapneumovirus (hMPV) is a leading cause of acute lower respiratory tract infections in high-risk populations, yet there are no vaccines or anti-viral therapies approved for the prevention or treatment of hMPV-associated disease. Here, we used a high-throughput single-cell technology to interrogate memory B cell responses to the hMPV fusion (F) glycoprotein in young adult and elderly donors. Across all donors, the neutralizing antibody response was primarily directed to epitopes expressed on both pre- and post-fusion F conformations. However, we identified rare, highly potent broadly neutralizing antibodies that recognize pre-fusion-specific epitopes and structurally characterized an antibody that targets a site of vulnerability at the pre-fusion F trimer apex. Additionally, monotherapy with neutralizing antibodies targeting three distinct antigenic sites provided robust protection against lower respiratory tract infection in a small animal model. This study provides promising monoclonal antibody candidates for passive immunoprophylaxis and informs the rational design of hMPV vaccine immunogens.We acknowledge the Immune Monitoring and Flow Cytometry Resource (IMFCSR) at the Norris Cotton Cancer Center at Dartmouth supported by NCI Cancer Center Support Grant 5P30CA023108-41. This work was funded in part by Welch Foundation grant number F-0003-19620604.S

X-rays Studies of the Solar System

X-ray observatories contribute fundamental advances in Solar System studies by probing Sun-object interactions, developing planet and satellite surface composition maps, probing global magnetospheric dynamics, and tracking astrochemical reactions. Despite these crucial results, the technological limitations of current X-ray instruments hinder the overall scope and impact for broader scientific application of X-ray observations both now and in the coming decade. Implementation of modern advances in X-ray optics will provide improvements in effective area, spatial resolution, and spectral resolution for future instruments. These improvements will usher in a truly transformative era of Solar System science through the study of X-ray emission.Comment: White paper submitted to Astro2020, the Astronomy and Astrophysics Decadal Surve