The Pediatric Autism Research Cohort (PARC) Study: protocol for a patient-oriented prospective study examining trajectories of functioning in children with autism.

INTRODUCTION: The developmentally variable nature of autism poses challenges in providing timely services tailored to a child's needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child's day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the Pediatric Autism Research Cohort (PARC) Study. In young children (<7 years of age) newly diagnosed with autism, we will: (1) examine variability in trajectories of adaptive functioning from the point of diagnosis into transition to school; and (2) identify factors associated with trajectories of adaptive functioning. METHODS AND ANALYSIS: We aim to recruit 1300 children under 7 years of age with a recent (within 12 months) diagnosis of autism from seven sites: six in Canada; one in Israel. Participants will be followed prospectively from diagnosis to age 8 years, with assessments at 6-month intervals. Parents/caregivers will complete questionnaires administered via a customized online research portal. Following each assessment timepoint, families will receive a research summary report describing their child's progress on adaptive functioning and related domains. Analysis of the longitudinal data will map trajectories and examine child, family and service characteristics associated with chronogeneity (interindividual and intraindividual heterogeneity over time) and possible trajectory turning points around sensitive periods like the transition to school. ETHICS AND DISSEMINATION: Ethics approvals have been received by all sites. All parents/respondents will provide informed consent when enrolling in the study. Using an integrated knowledge translation approach, where stakeholders are directly engaged in the research process, the PARC Study will identify factors associated with trajectories of functioning in children with autism. Resulting evidence will be shared with government policy makers to inform provincial and national programs. Findings will be disseminated at conferences and published in peer-reviewed journals.

Stenosis to stented: decrease in flow disturbances following stent implantation of a diseased arteriovenous fistula.

The arteriovenous fistula (AVF) is commonly faced with stenosis at the juxta-anastomotic (JXA) region of the vein. Implantation of a flexible nitinol stent across the stenosed JXA has led to the retention of functioning AVFs leading to the resulting AVF geometry being distinctly altered, thereby affecting the haemodynamic environment within it. In this study, large eddy simulations of the flow field within a patient-specific AVF geometry before and after stent implantation were conducted to detail the change in flow features. Although the diseased AVF had much lower flow rates, adverse flow features, such as recirculation zones and swirling flow at the anastomosis, and jet flow at the stenosis site were present. Larger velocity fluctuations (leading to higher turbulent kinetic energy) stemming from these flow features were apparent in the diseased AVF compared to the stented AVF. The unsteadiness at the stenosis created large regions of wall shear stress (WSS) fluctuations downstream of the stenosis site that were not as apparent in the stented AVF geometry. The larger pressure drop across the diseased vein, compared to the stented vein, was primarily caused by the constriction at the stenosis, potentially causing the lower flow rate. Furthermore, the WSS fluctuations in the diseased AVF could lead to further disease progression downstream of the stenosis. The change in bulk flow unsteadiness, pressure drop, and WSS behaviour confirms that the haemodynamic environment of the diseased AVF has substantially improved following the flexible stent implantation.

Salinity and Salt-Priming Impact on Growth, Photosynthetic Performance, and Nutritional Quality of Edible Mesembryanthemum crystallinum L.

Mesembryanthemum crystallinum L. is a nutritious edible facultative halophyte. This study aimed to investigate the physiology and quality of M. crystallinum L. grown under different salinities and salt-priming conditions. All plants were first grown in 10% artificial seawater (ASW) for 10 days. After that, some plants remained in 10% ASW while the others were transferred to 20%, 30%, 40%, or 50% ASW for another 10 days. Some plants also underwent a salt priming by transferring them gradually from 10% to 100% ASW over a span of 10 days (defined as salt primed). All plants were green and healthy. However, there were reductions in shoot and root productivity, leaf growth, and water content, but also an increase in leaf succulence after transferring plants to higher salinities. The salt-primed plants showed higher photosynthetic light use efficiency with higher chlorophyll concentration compared to other plants. The concentrations of proline, ascorbic acid (ASC), and total phenolic compounds (TPC) increased as percentages of ASW increased. The salt-primed plants switched from C3 to crassulacean acid metabolism photosynthesis and accumulated the greatest amounts of proline, ASC, and TPC. In conclusion, higher salinities and salt priming enhance the nutritional quality of M. crystallinum L. but compromises productivity.

Comparison of Single and Repeated Dosing of Anti-Inflammatory Human Umbilical Cord Mesenchymal Stromal Cells in a Mouse Model of Polymicrobial Sepsis.

Mesenchymal stromal cells (MSCs) ameliorate pre-clinical sepsis and sepsis-associated acute kidney injury (SA-AKI) but clinical trials of single-dose MSCs have not indicated robust efficacy. This study investigated immunomodulatory effects of a novel MSC product (CD362-selected human umbilical cord-derived MSCs [hUC-MSCs]) in mouse endotoxemia and polymicrobial sepsis models. Initially, mice received intra-peritoneal (i.p.) lipopolysaccharide (LPS) followed by single i.p. doses of hUC-MSCs or vehicle. Next, mice underwent cecal ligation and puncture (CLP) followed by intravenous (i.v.) doses of hUC-MSCs at 4 h or 4 and 28 h. Analyses included serum/plasma assays of biochemical indices, inflammatory mediators and the AKI biomarker NGAL; multi-color flow cytometry of peritoneal macrophages (LPS) and intra-renal immune cell subpopulations (CLP) and histology/immunohistochemistry of kidney (CLP). At 72 h post-LPS injections, hUC-MSCs reduced serum inflammatory mediators and peritoneal macrophage M1/M2 ratio. Repeated, but not single, hUC-MSC doses administered at 48 h post-CLP resulted in lower serum concentrations of inflammatory mediators, lower plasma NGAL and reversal of sepsis-associated depletion of intra-renal T cell and myeloid cell subpopulations. Hierarchical clustering analysis of all 48-h serum/plasma analytes demonstrated partial co-clustering of repeated-dose hUC-MSC CLP animals with a Sham group but did not reveal a distinct signature of response to therapy. It was concluded that repeated doses of CD362-selected hUC-MSCs are required to modulate systemic and local immune/inflammatory events in polymicrobial sepsis and SA-AKI. Inter-individual variability and lack of effect of single dose MSC administration in the CLP model are consistent with observations to date from early-phase clinical trials.

Investigating the Associations Between Child Autistic Symptoms, Socioeconomic Context, and Family Life: A Pilot Study.

Objective: The day-to-day experience of families with an Autistic child may be shaped by both, child characteristics and available resources, which often are influenced by the socioeconomic context of the family. Using a socioecological approach, this study explored the quantitative associations between child autistic symptoms, family socioeconomic status, and family life. Methods: Data came from the Pediatric Autism Research Cohort-PARC Study (pilot). Parents of children with a recent diagnosis of autism completed a set of assessments, including the Autism Family Experience Questionnaire, Autism Impact Measure, and a Sociodemographic Questionnaire. A series of multiple, iterative linear regression models were constructed to ascertain quantitative associations between child autistic symptoms, socioeconomic context, and family life. Results: A total of 50 children (mean age: 76 months; SD: 9.5 months; and 84% male) with data on the variables of interest were included in the analysis. The frequency of child autistic symptoms was associated with family life outcomes (p = 0.02 and R 2 = 24%). Once autistic symptom frequency, symptom impact, and sociodemographic variables were considered, parents of higher educational attainment reported worse family life outcomes compared to their lesser-educated counterparts. This cumulative regression model had considerable explanatory capability (p = 0.01, R 2 = 40%). Conclusion: This study demonstrates the utility of using a socioecological approach to examine the dynamic interplay between child characteristics and family circumstances. Our findings suggest that family life for parents (of an autistic child) who have obtained higher education is reported (by the parents themselves) as less satisfactory compared to that of parents without higher education, once adjusted for the autistic symptom frequency of child, symptom impact, and income. These findings can inform the design and delivery of more family-centered care pathways during the years following a diagnosis of autism.

Sleep Well Be Well: Pilot of a digital intervention to improve child behavioural sleep problems.

AIM: To investigate whether a digital sleep intervention improves child and care giver sleep and psychosocial outcomes. METHODS: A total of 120 families with children aged 2-13 years, reporting moderate to severe child behavioural sleep problems, were recruited from a hospital sleep clinic waitlist or the community. Children from non-English speaking families, with known intellectual disability (IQ < 70) or severe medical problems excluded. Tailored behavioural sleep strategies were delivered to primary care givers via a smart phone app and complementary website. Eligible families completed a baseline questionnaire and child 'sleep check' then received the digital sleep intervention for 5 weeks, and then completed a post questionnaire. OUTCOMES: care giver report of child sleep as no/mild versus moderate/severe problem over past month (primary outcome); problem child sleep patterns (Brief Infant Sleep Questionnaire or Child Sleep Habits Questionnaire), child temperament, care giver mental health (Kessler 6), care giver sleep, health service use for their child's sleep and time off work/activities to access services. RESULTS: At follow up, care givers reported fewer moderate/severe child sleep problems (84.6-40.7%), improved problem child sleep patterns, better temperament and improved care giver mental health. Care giver sleep quality and quantity remained unchanged. Health service use (averaged over a 6-month period pre- and post-intervention) fell from 18.9% pre- to 14.1% post-intervention. CONCLUSION: A digital sleep intervention appears promising in improving sleep in children with moderate/severe behavioural sleep problems, and care giver mental health. It may be a useful alternative to face-to-face management of behavioural sleep problems.

The feasibility of using smartphone apps to manage self-harm and suicidal acts in adolescents admitted to an inpatient mental health ward.

OBJECTIVE: The aim of this study is to assess the feasibility (uptake, retention and adherence) and acceptability of a combination of smartphone apps to deliver a digitized safety plan, BeyondNow, and personalized management strategies, BlueIce, with adolescents discharged from a mental health inpatient ward following self-harm, suicidal ideation and/or behavior. METHODS: Participants in this pre-post pilot study included 20 adolescents between 13-18 years, presenting with self-harming or suicidal behaviors in an inpatient psychiatric ward at a tertiary pediatric hospital. Participants were familiarized with the apps and completed baseline measures prior to discharge. They used the apps for six weeks before completing the follow-up survey, which measured feasibility and acceptability of the apps, as well as suicide resilience. RESULTS: Seventeen participants completed the pilot. Most of the sample accessed both apps at least once, three accessed the BeyondNow safety plan five times or more, and six used the BlueIce toolbox five times or more. A total of 73.5% of the sample that experienced a crisis used at least one of the apps at least once. Forty seven percent felt that the apps would not keep them safe when in crisis, although almost all of the sample rated both apps as easy to use (94% for BeyondNow, and 82% for BlueIce). Medium to large effect sizes were also found with regard to improvements in suicide resilience. CONCLUSION: Both apps were found to be feasible and acceptable in this population, and easy to use, although no conclusions can be drawn regarding the clinical efficacy of the apps.

Differential effects of propofol and dexmedetomidine on neuroinflammation induced by systemic endotoxin lipopolysaccharides in adult mice.

Propofol and dexmedetomidine are commonly used in clinical situations where neuroinflammation may be imminent or even established but comparative data on their effects on neuroinflammatory and cognitive parameters are lacking. Using a murine model of neuroinflammation induced by systemic lipopolysaccharide (LPS), this study compared the effects of these two agents on cognitive function, neuroinflammatory parameters, oxidative stress and neurotransmission. Male adult C57BL/6 N mice were anaesthetised with propofol or dexmedetomidine prior to intraperitoneal injection of LPS. Cognitive and motor function were assessed by the Y-maze and Rotarod tests respectively. Inflammatory responses were evaluated by relative levels of cytokine mRNA and immunoreactivity of glia cells. LPS caused a marked elevation in IL-1ß and TNF-α levels both peripherally and in the brain, together with microglia activation (p < 0.05) and cognitive impairment. These changes were accompanied by an increase in 8-hydroxy-2'-deoxyguanosine (8-OHdG) (p < 0.05). Dexmedetomidine attenuated microglia activation (p < 0.05) and the elevation in 8-OHdG level (p < 0.05). Propofol did not affect cognition. However, both drugs lowered the number of vesicular glutamate transporter 1 (VGLUT 1), but was associated with higher levels of apoptosis and 8-OHdG (p < 0.05). Data from this study suggest dexmedetomidine and propofol have different anti-neuroinflammatory and neuroprotective profiles. However, neither drug can fully attenuate the effects of LPS induced cognitive impairment.

Fluoro-substituted cyanine for reliable in vivo labelling of amyloid-ß oligomers and neuroprotection against amyloid-ß induced toxicity.

Alzheimer's disease (AD) is the most prevalent but still incurable neurodegenerative form of dementia. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. We herein report a novel fluoro-substituted cyanine, F-SLOH, which exhibits good Aß oligomer selectivity with a high binding affinity, attributed to the synergistic effect of strong π-π stacking and intermolecular CH···O and CH···F interactions. The selectivity towards the Aß oligomers in the brain was ascertained by in vitro labelling on tissue sections and in vivo labelling through the systemic administration of F-SLOH in 7 month APP/PS1 double transgenic (Tg) and APP/PS1/Tau triple Tg mouse models. F-SLOH also shows remarkably effective inhibition on Aß aggregation and highly desirable neuroprotective effects against Aß-induced toxicities, including the inhibition of ROS production and Ca2+ influx. Its excellent blood-brain barrier (BBB) penetrability and low bio-toxicity further support its tremendous potential as a novel theranostic agent for both early diagnosis and therapy of AD.

Effect of Continuous Propofol Infusion in Rat on Tau Phosphorylation with or without Temperature Control.

Several studies suggest a relationship between anesthesia-induced tau hyperphosphorylation and the development of postoperative cognitive dysfunction. This study further characterized the effects of continuous propofol infusion on tau protein phosphorylation in rats, with or without temperature control. Propofol was administered intravenously to 8-10-week-old male Sprague-Dawley rats and infused to the loss of the righting reflex for 2 h continuously. Proteins from cortex and hippocampus were examined by western blot and immunohistochemistry. Rectal temperature was significantly decreased during propofol infusion. Propofol with hypothermia significantly increased phosphorylation of tau at AT8, AT180, Thr205, and Ser199 in cortex and hippocampus except Ser396. With temperature maintenance, propofol still induced significant elevation of AT8, Thr205, and Ser199 in cortex and hippocampus; however, increase of AT180 and Ser396 was only found in hippocampus and cortex, respectively. Differential effects of propofol with or without hypothermia on multiple tau related kinases, such as Akt/GSK3ß, MAPK pathways, or phosphatase (PP2A), were demonstrated in region-specific manner. These findings indicated that propofol increased tau phosphorylation under both normothermic and hypothermic conditions, and temperature control could partially attenuate the hyperphosphorylation of tau. Further studies are warranted to determine the long-term impact of propofol on the tau pathology and cognitive functions.

Dexmedetomidine directly increases tau phosphorylation.

Exposure to anesthetic agents has been linked to abnormal tau protein phosphorylation, an antecedent to the development of neurofibrillary tangles. This study evaluates the direct and indirect effects of dexmedetomidine. Primary culture of cortical neurons established from Sprague-Dawley (SD) rat embryos were exposed to dexmedetomidine for 1 or 6 hours, and the degree of tau phosphorylation at the AT8, AT180, and S396 sites was assessed by western blot analysis. To assess and compare their relative in vivo effects, the same agent was administered intravenously to 8 to 10 week old male SD rats and titrated to the loss of the righting reflex for 2 hours. After 1 hour of recovery, the rats were sacrificed and samples taken from the cortex and hippocampus were subjected to western blot and immunohistochemical analysis. The in vitro studies reviewed significant hyperphosphorylation only at the S396 site, and these changes have largely disappeared at 6 hours. With temperature maintenance, dexmedetomidine induced significant changes in hyperphosphorylation at the AT8 site in the cortex and hippocampus and at the AT180 in the hippocampus. The direct effect of anesthetic agents on fully differentiated cortical neurons is epitope-specific and short-lived. The in vivo effects are comparatively more complicated and depend not only on the phosphorylation site but the regions of the brain examined. These findings suggest that dexmedetomidine increases tau phosphorylation both in vitro and in vivo under normothermic conditions, and further studies are warranted to determine the long-term impact of this anesthetic on the tau pathology and even cognitive function.

Small interfering RNA specific for N-methyl-D-aspartate receptor 2B offers neuroprotection to dopamine neurons through activation of MAP kinase.

In the present study, N-methyl-D-aspartate receptor 2B (NR2B)-specific siRNA was applied in parkinsonian models. Our previous results showed that reduction in expression of N-methyl-D-aspartate receptor 1 (NR1), the key subunit of N-methyl-D-aspartate receptors, by antisense oligos ameliorated the motor symptoms in the 6-hydroxydopamine (6-OHDA)-lesioned rat, an animal model of Parkinson's disease (PD).

N-Acetyl-l-cysteine capped quantum dots offer neuronal cell protection by inhibiting beta (1-40) amyloid fibrillation.

This is the first work that revealed the neuro-protective effect of functionalized quantum dots against the cytotoxicity induced by beta-amyloid peptides. This study gives insight into the future treatment of Alzheimer's disease. It opens many avenues for the development of the next generation nanotechnology for biomedical and therapeutic applications.

Errorless academic compliance training: a school-based application for young students with autism.

Errorless academic compliance training is a graduated, noncoercive approach to treating oppositional behavior in children. In the present study, three teaching staff in a special education classroom were trained to conduct this intervention with three male students diagnosed with autism spectrum disorders. During baseline, staff delivered a range of academic and other classroom requests and recorded student compliance. A hierarchy of compliance probabilities was then calculated, ranging from Level 1 (requests yielding high levels of compliance) to Level 4 (those typically yielding noncompliance). At treatment initiation, teaching staff delivered high densities of Level 1 requests and provided reinforcement for compliance. Subsequent request levels were faded in over time, at a slow enough rate to ensure continued high compliance. By intervention end, all three students demonstrated substantially improved compliance to classroom requests that had commonly yielded noncompliance before intervention. Covariant improvement in on-task skills was also evident.

Fe3O4-in-silica super crystal of defined interstices for single protein molecules entrapment under magnetic flux.

Confocal fluorescence demonstrates that single molecules of dye-labelled Cytochrome C or B5 containing paramagnetic Fe(III) can be magnetically placed into the interstices of super-crystal which is composed of three dimensional regular arrays of Fe(3)O(4) nanoparticles.