Method Validation of Functional Magnetic Resonance Imaging and Electrophysiological Recording to Investigate Mechanisms of Vagus Nerve

Vagus nerve stimulation (VNS) is used clinically to treat epilepsy and depression, but its mechanism of action is unknown. Useful techniques to study this are functional magnetic resonance imaging (fMRI) and the local field potential (LFP). fMRI relies on oxygen use in the brain to show areas where neurons are active. The LFP is an electrical signal created by neuron action potentials and other current moving across cell membranes. The most information can be gained when the two methods are used simultaneously, however, this is difficult to do. This study seeks to validate the technique of fMRI-LFP as applied to study the mechanism of VNS. The rat is used as an animal model. Previously collected data is analyzed to determine effects of stimulation on respiration, since this will affect oxygen levels in the blood. Recording electrodes of different materials are tested to find the artifact size created in an MRI environment. Iridium electrodes were found to have the smallest artifact and therefore the best performance. It is unclear whether the stimulation used affects respiration, so a simultaneous fMRI-LFP experiment is needed to interpret fMR images. More work needs to be done before fMRI-LFP recordings can be taken during VNS

Pancreatic Replacement Therapy for Maladaptive Behaviors in Preschool Children With Autism Spectrum Disorder

IMPORTANCE: There is an urgent unmet need for a treatment addressing the core symptoms and associated maladaptive symptoms of autism spectrum disorder (ASD), especially in preschool populations. OBJECTIVES: To evaluate whether treatment of children with ASD aged 3 to 6 years treated with high-protease pancreatic therapy produces long- and short-term improvements in autism-associated maladaptive behaviors. DESIGN, SETTING, AND PARTICIPANTS: This cohort study at 32 sites across the US used a double-blind parallel group, delayed-start design comprising a 2-week blinded placebo run-in, and a double-blind, randomized, placebo-controlled segment (12 weeks). Children were recruited into the study in 2015, with data collection continuing until 2021. The analyses were completed from June 2021 to February 2022. INTERVENTIONS: All participants were randomly assigned to receive either 900 mg high-protease pancreatic replacement therapy or placebo with food 3 times a day for 12 weeks, followed by all receiving 900 mg high-protease pancreatic replacement therapy for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the irritability/agitation subscale of the Aberrant Behavior Checklist (ABC-I). All potential participants were screened using the Social Communication Questionnaire (SCQ) with diagnosis confirmed by the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) for ASD and the Autism Diagnostic Inventory-Revised (ADI-R). Outcomes were measured at the conclusion of the 12-week double-blind segment and at the conclusion of the 24-week open-label segment (total 36 weeks). RESULTS: A total of 190 participants (150 male [79%]), aged 3 to 6 (mean [SD] age, 4.5 [0.8]) years were randomized. Mixed model for repeated measures analysis performed on ABC-I demonstrated statistically significant differences of -2.49 (95% CI, -4.66 to -0.32; Cohen d = 0.364; P = .03) at the 12-week timepoint and -3.07 (95% CI, -5.81 to -0.33; Cohen d = 0.516; P = .03) at 36-week timepoint. No convergence was noted. Our high-protease pancreatic replacement (CM-AT) was well tolerated with no emergent safety concerns or related serious adverse events noted. CONCLUSIONS AND RELEVANCE: This cohort study of preschool children sustained cumulative reduction in the maladaptive behavior of irritability in autism. This delayed-start analysis, used to demonstrate disease and condition modification, may prove to be an important tool to evaluate treatments for ASD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02410902 and NCT02649959

Regulation of trophoblast beta1-integrin expression by contact with endothelial cells

BACKGROUND: In human and non-human primates, migratory trophoblasts penetrate the uterine epithelium, invade uterine matrix, and enter the uterine vasculature. Invasive trophoblasts show increased expression of β1 integrin. Since trophoblast migration within the uterine vasculature involves trophoblast attachment to endothelial cells lining the vessel walls, this raises the possibility that cell-cell contact and/or factors released by endothelial cells could regulate trophoblast integrin expression. To test this, we used an in vitro system consisting of early gestation macaque trophoblasts co-cultured on top of uterine microvascular endothelial cells. RESULTS: When cultured alone, trophoblasts expressed low levels of β1 integrin as determined by quantitative immunofluorescence microscopy. When trophoblasts were cultured on top of endothelial cells for 24 h, the expression of trophoblast β1 integrin was significantly increased as determined by image analysis. β1 Integrin expression was not increased when trophoblasts were cultured with endothelial cell-conditioned medium, suggesting that upregulation requires direct contact between trophoblasts and endothelial cells. To identify endothelial cell surface molecules responsible for induction of trophoblast integrin expression, trophoblasts were cultured in dishes coated with recombinant platelet endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), or αVβ3 integrin. Trophoblast β1 integrin expression (assessed by immunofluorescence microscopy and Western blotting) was increased when PECAM-1 or αVβ3 integrin, but not ICAM-1, was used as substrate. CONCLUSIONS: Direct contact between trophoblasts and endothelial cells increases the expression of trophoblast β1 integrin

Rat Stem-Cell Factor Induces Splenocytes Capable Of Regenerating The Thymus

Cytokine regulation of prethymic T-lymphoid progenitor-cell proliferation and/or differentiation has not been well-defined, although much is known of cytokine regulation of hemopoietic stem- and progenitor-cell development. Here we use a recently identified hemopoietic growth factor, stem-cell factor (SCF) (a form of the c-kit ligand), and a transplant model of thymocyte regeneration to assess the effect of SCF on the in vivo generation of prethymic, thymocyte progenitor-cell activity. We show that recombinant rat SCF (rrSCF164 administered to weanling rats selectively induces an increase in thymocyte progenitor activity in the spleens of treated rats as compared to rats treated with vehicle, polyethylene glycol (PEG)-conjugated rat albumin, or recombinant human granulocyte colony-stimulating factor (rhG-CSF). These data demonstrate that administration of SCF in vivo affects extrathymic-origin thymocyte regenerating cells and may influence, directly or indirectly, early prethymic stages of T-cell lymphopoiesis in addition to its known effect on early stages of myelopoiesis and erythropoiesis

Building, scaling, and sustaining a learning health system for surgical quality improvement: A toolkit

This article describes how to start, replicate, scale, and sustain a learning health system for quality improvement, based on the experience of the Michigan Surgical Quality Collaborative (MSQC). The key components to operationalize a successful collaborative improvement infrastructure and the features of a learning health system are explained. This information is designed to guide others who desire to implement quality improvement interventions across a regional network of hospitals using a collaborative approach. A toolkit is provided (under Supporting Information) with practical information for implementation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156156/3/lrh210215.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156156/2/lrh210215-sup-0001-supinfo.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156156/1/lrh210215_am.pd

How should the completeness and quality of curated nanomaterial data be evaluated

Nanotechnology is of increasing significance. Curation of nanomaterial data into electronic databases offers opportunities to better understand and predict nanomaterials’ behaviour. This supports innovation in, and regulation of, nanotechnology. It is commonly understood that curated data need to be sufficiently complete and of sufficient quality to serve their intended purpose. However, assessing data completeness and quality is non-trivial in general and is arguably especially difficult in the nanoscience area, given its highly multidisciplinary nature. The current article, part of the Nanomaterial Data Curation Initiative series, addresses how to assess the completeness and quality of (curated) nanomaterial data. In order to address this key challenge, a variety of related issues are discussed: the meaning and importance of data completeness and quality, existing approaches to their assessment and the key challenges associated with evaluating the completeness and quality of curated nanomaterial data. Considerations which are specific to the nanoscience area and lessons which can be learned from other relevant scientific disciplines are considered. Hence, the scope of this discussion ranges from physicochemical characterisation requirements for nanomaterials and interference of nanomaterials with nanotoxicology assays to broader issues such as minimum information checklists, toxicology data quality schemes and computational approaches that facilitate evaluation of the completeness and quality of (curated) data. This discussion is informed by a literature review and a survey of key nanomaterial data curation stakeholders. Finally, drawing upon this discussion, recommendations are presented concerning the central question: how should the completeness and quality of curated nanomaterial data be evaluated