The Superficial White Matter in Autism and Its Role in Connectivity Anomalies and Symptom Severity.

In autism spectrum disorders (ASDs), the majority of neuroimaging studies have focused on the analysis of cortical morphology. White matter changes remain less understood, particularly their association to cortical structure and function. Here, we focused on region that has gained only little attention in ASD neuroimaging: the superficial white matter (SWM) immediately beneath the cortical interface, a compartment playing a prominent role in corticogenesis that incorporates long- and short-range fibers implicated in corticocortical connectivity. Studying a multicentric dataset of ASD and neurotypical controls, we harnessed surface-based techniques to aggregate microstructural SWM diffusion features. Multivariate analysis revealed SWM anomalies in ASD compared with controls in medial parietal and temporoparietal regions. Effects were similar in children and adolescents/adults and consistent across sites. Although SWM anomalies were more confined when correcting for cortical thickness and surface area, findings were overall robust. Diffusion anomalies modulated functional connectivity reductions in ASD and related to symptom severity. Furthermore, mediation models indicated a link between SWM changes, functional connectivity, and symptom load. Analyses targeting the SWM offer a novel perspective on the interplay between structural and functional network perturbations in ASD, highlighting a potentially important neurobiological substrate contributing to its diverse behavioral phenotype.

Anti-apoptotic Effects of Human Wharton's Jelly-derived Mesenchymal Stem Cells on Skeletal Muscle Cells Mediated via Secretion of XCL1.

The role of Wharton's jelly-derived human mesenchymal stem cells (WJ-MSCs) in inhibiting muscle cell death has been elucidated in this study. Apoptosis induced by serum deprivation in mouse skeletal myoblast cell lines (C2C12) was significantly reduced when the cell lines were cocultured with WJ-MSCs. Antibody arrays indicated high levels of chemokine (C motif) ligand (XCL1) secretion by cocultured WJ-MSCs and XCL1 protein treatment resulted in complete inhibition of apoptosis in serum-starved C2C12 cells. Apoptosis of C2C12 cells and loss of differentiated C2C12 myotubes induced by lovastatin, another muscle cell death inducer, was also inhibited by XCL1 treatment. However, XCL1 treatment did not inhibit apoptosis of cell lines other than C2C12. When XCL1-siRNA pretreated WJ-MSCs were cocultured with serum-starved C2C12 cells, apoptosis was not inhibited, thus confirming that XCL1 is a key factor in preventing C2C12 cell apoptosis. We demonstrated the therapeutic effect of XCL1 on the zebrafish myopathy model, generated by knock down of a causative gene ADSSL1. Furthermore, the treatment of XCL1 resulted in significant recovery of the zebrafish skeletal muscle defects. These results suggest that human WJ-MSCs and XCL1 protein may act as promising and novel therapeutic agents for treatment of myopathies and other skeletal muscle diseases.

A scoping review of current non-pharmacological treatment modalities for phantom limb pain in limb amputees.

PURPOSE: Phantom limb pain (PLP) is a chronic neuropathic pain condition of a missing limb following amputation. Pain management is multi-modal, including various non-pharmacological therapies. The purpose of this scoping review was to investigate the evidence surrounding current non-pharmacological treatment modalities for PLP and provide insight into their clinical feasibility. METHOD: A systematic search was conducted using four databases (Medline, Embase, PsychInfo, and CINAHL) following the PRISMA-ScR method. Results from papers meeting the inclusion criteria were charted to summarize findings, demographics, and use of neuroimaging. RESULTS: A total of 3387 papers were identified, and full texts of 142 eligible papers were assessed. Eleven treatment modalities for PLP were identified with varying levels of evidence. Overall, there were 25 RCTs, 58 case reports, and 59 a combination of pilot, quasi-experimental, observational, and other study designs. CONCLUSIONS: Currently, the evidence surrounding most treatment modalities is limited and only a fraction of studies are supported by strong evidence. The findings of this review demonstrated a clear need to conduct more rigorous research with diverse study designs to better understand which modalities provide the most benefit and to incorporate neuroimaging to better determine the neural correlates of PLP and mechanisms of various treatments.Implications for RehabilitationPhantom limb pain (PLP) is a prevalent and debilitating condition following amputation and health care professionals should incorporate an evidence-based pain management protocol into their rehabilitation program.There exist a number of different non-pharmacological therapies to address PLP, however the scientific rigor and levels of evidence vary across modalities.Prescription of interventions for PLP should consider individual patient differences, accessibility to the patient, and quite possibly, a multi-modal approach, particularly for those who also experience residual limb pain.Imagery-based therapies provide the highest level of current evidence based on robust and large randomized control trials, are readily accessible, and are thus most recommended for relief of PLP.

Prospective preference assessment for the Comparison of Analgesic Regimen Effectiveness and Safety in Surgery (CARES) trial.

BACKGROUND: Clinical trials face major barriers such as under-enrollment and selective enrollment, which threaten study completion and undermine validity and generalizability. Thus, we conducted a prospective preference assessment (PPA) prior to commencing the Comparison of Analgesic Regimen Effectiveness and Safety in Surgery (CARES) trial-a randomized controlled study comparing the outcomes of managing acute postoperative pain between opioid-sparing and opioid-based therapies. This PPA aimed to (1) determine the patients' willingness to participate in the CARES trial, (2) identify the areas for improvement, and (3) assess the differences between willing and unwilling patients. METHODS: Patients undergoing elective laparoscopic cholecystectomy were recruited between August 2019 and February 2020 from two academic hospitals. A survey was administered to each patient consisting of (1) a vignette describing the trial, (2) an assessment of the patients' understanding of the trial, (3) open-ended questions assessing the attitudes towards the trial, and (4) patient-completed questionnaires. Data were analyzed qualitatively with thematic analysis and quantitatively with the Wilcoxon signed-rank and chi-square tests. RESULTS: Forty-two patients were enrolled and grouped based on the 6-point Likert scale into willing (4-6, 71%) and not willing (1-3, 29%) to participate in the CARES trial. There were no significant differences with respect to all variables: age, education, sex, visible minority status, previous research, previous surgery, regular use of pain medications, surgical concerns, previous discussions on pain management, significant pain within the past 3 months, and significant use of pain medication within the past month. Factors that motivated participation were contributing to scientific research (45%), altruism (29%), and improving personal pain (24%). Common discouraging factors were negative perceptions of opioids (29%), side effects (21%), being blinded to the study medication (21%), and poor pain management (19%). CONCLUSIONS: This PPA revealed that two key discouraging factors for patients were being blinded to the type of pain medication being taken and the potential for poor pain management as a consequence of participation. Modifications to improve patient acceptance of the CARES trial include ensuring sufficient rescue medicine and follow-up visits consistent with current standards of care for all patients, as well as patient education surrounding safe administration and side effects of the study medications.

The negative impact of chronic rhinosinusitis on the health-related quality of life among adult patients with cystic fibrosis.

BACKGROUND: With improved survival in cystic fibrosis (CF) patients, it is crucial to evaluate the impact of chronic co-morbidities such as chronic rhinosinusitis (CRS). The objectives were 1) To determine the prevalence of CRS with a large series of CF patients 2) To evaluate the impact of CRS on the Health-Related Quality of Life (HRQoL) of CF patients and 3) To compare CRS-specific, CF-specific and general HRQoL instruments. METHODS: Consecutive CF patients from the Toronto Adult Cystic Fibrosis Centre were recruited between March 2018 and January 2020. Participants completed the 22-Item Nasal Outcome Test (SNOT-22), Cystic Fibrosis Questionnaire-Revised for adolescents and adults over 14 years of age (CFQ-R), Cystic Fibrosis Quality of Life Evaluative Self-administered Test (CF-QUEST) and the 36-Item Short Form Survey (SF-36). HRQoL scores were correlated using Spearman's correlation coefficients. RESULTS: Out of 195 patients eligible for analysis, the prevalence of CRS with positive endoscopic findings was 42.6% (95% confidence interval: 35.5-49.8%). CRS patients reported significantly lower HRQoL with higher SNOT-22 scores and lower scores in the respiratory domain of CFQ-R and physical health domains of CF-QUEST and SF-36. The physical (ρ= -0.63) and mental (ρ= -0.66) domains of SF-36 and CF-QUEST (ρ= -0.76) had a strong correlation with SNOT-22. Higher scores of SNOT-22 nasal subdomains correlated with lower scores of SF-36, CFQ-R and CF-QUEST. CONCLUSION: CRS is a prevalent co-morbidity of CF patients, which significantly reduces HRQoL. SNOT-22, CFQ-R, CF-QUEST and SF-36 were strongly correlated. Severity of sinonasal symptoms have a strong correlation with HRQoL in CF patients.

Distribution of human umbilical cord blood-derived mesenchymal stem cells in the Alzheimer's disease transgenic mouse after a single intravenous injection.

The aim of this study was to track the migration of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) administered through a single intravenous injection and to observe the consequential therapeutic effects in a transgenic Alzheimer's disease mouse model. Ten-month-old APP/PS1 mice received a total injection of 1×10 cells through the lateral tail vein and were killed 1, 4, and 7 days after administration. On the basis of immunohistochemical analysis, hUCB-MSCs were not detected in the brain at any of the time points. Instead, most of the injected mesenchymal stem cells were found to be distributed in the lung, heart, and liver. In terms of the molecular effects, statistically significant differences in the amyloid ß protein, neprilysin, and SOX2 levels were not observed among the groups. On the basis of the results from this study, we suggest that single intravenously administered hUCB-MSCs are not delivered to the brain and also do not have a significant influence on Alzheimer's disease pathology.

Distribution of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in canines after intracerebroventricular injection.

In this study, we investigated the distribution of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) administered via intracerebroventricular (ICV) injection in a canine model. Ten beagles (11-13 kg per beagle) each received an injection of 1 × 106 cells into the right lateral ventricle and were sacrificed 7 days after administration. Based on immunohistochemical analysis, hUCB-MSCs were observed in the brain parenchyma, especially along the lateral ventricular walls. Detected as far as 3.5 mm from the cortical surface, these cells migrated from the lateral ventricle toward the cortex. We also observed hUCB-MSCs in the hippocampus and the cervical spinal cord. According to real-time polymerase chain reaction results, most of the hUCB-MSCs were found distributed in the brain and the cervical spinal cord but not in the lungs, heart, kidneys, spleen, and liver. ICV administered hUCB-MSCs also enhanced the endogenous neural stem cell population in the subventricular zone. These results highlighted the ICV delivery route as an optimal route to be performed in stem cell-based clinical therapies for neurodegenerative diseases.