Teaching Peer Imitation to Preschool-Aged Children with Autism Spectrum Disorder Using a Video Modeling Treatment Package

Peer imitation is a skill that serves to promote the acquisition of new play skills, problem-solving skills, and academic skills through observation of one’s peers. Although peer imitation is an important pre-requisite for learning from peers, many autistic children experience deficits in this area. In the present study, we evaluated a video model treatment package to teach autistic children to imitate their peers. Additionally, we conducted free play probes pre- and post-training to assess the transfer of training to a natural play setting. The results of the current study are mixed. One participant’s imitation skills generalized to the in-vivo sessions and to untrained targets after training with only one set of video models. Two participants mastered imitation of one set of video models; however, their skills did not generalize across sets nor to in-vivo conditions. Data from free play probes show that one participant attended to his peer more, but there were only slight changes in imitation across participants following video model training. Hypotheses for these results and ideas for future research are discussed

NOVEL MECHANISM OF ENDOGENOUS PANCREATIC CANCER CELL EXPRESSION OF IMMUNE CHECKPOINT PROGRAMMED CELL-DEATH 1 PROTEIN (PD-1) INDUCING EPITHELIAL-TO-MESENCHYMAL TRANSITION (EMT) THROUGH THE MET PATHWAY AND PROMOTING CANCER PROGRESSION IN AN IMMUNE-INDEPENDENT PROCESS

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with few treatment options, necessitating an urgent need for novel therapeutics. Immuno-oncologic (IO) therapies have revolutionized anti-cancer regimens in the past decade but typically involve reactivation of adaptive immune responses. In particular, immune checkpoint PD-1 is traditionally expressed only on immune cells while PD-L1 (PD-1 ligand) is overexpressed on cancer cells. When tumor-endogenous PD-L1 binds the PD-1 receptor on T-cells, the immune cells undergo anergy resulting in self-tolerance and cancer cell immune evasion. However, contrary to standard dogma, we previously demonstrated tumor-endogenous PD-1 expression in PDAC. Our data indicated that PD-1 proteins are not exclusive to immune cells and have unrecognized signal transduction cascades intrinsic to cancer cells. Building on this paradigm shift, we aimed to further characterize PD-1 expression in PDAC. Here, we demonstrate that tumor-endogenous PD-1 unexpectedly regulates downstream oncogenic pathways in PDAC. However, unlike PD-1 activation in immune cells leading to apoptosis, we found that tumor-endogenous PD-1 signaling instead increased cancer cell growth, proliferation, and migration by regulating the proto-oncogene MET. This process was dependent on hepatocyte growth factor (MET ligand) and not secondary to direct protein interaction. Importantly, the PD-1/MET axis induced epithelial-to-mesenchymal transition (EMT), a hallmark of oncogenic transformation in PDAC. We next observed that combined therapeutic targeting of PDAC cell PD-1 and MET resulted in substantial direct tumor cell cytotoxicity and growth inhibition in PDAC cell lines, patient-derived organoids, and patient-derived xenografts independent of immune cytotoxic responses. These responses represent a form of previously undescribed oncogene addiction depicting tumor-endogenous PD-1 as an unrecognized proto-oncogene. Altogether, we demonstrated that the traditionally immune-specific PD-1 has a non-immunogenic phenotype when expressed on PDAC cells, resulting in activation of oncogenic processes that can be targeted by therapeutic regimens to enable direct tumor cytotoxicity. This is the first report of a PD-1/MET interaction, PD-1 induction of EMT, or PD-1 functioning as a proto-oncogene in any cancer. Given the urgent need for new PDAC therapeutics, our novel mechanism presents a prime target for direct and indirect therapeutic antagonism in PDAC

How do women feel cold water swimming affects their menstrual and perimenopausal symptoms?

OBJECTIVE: This study aimed to determine how women felt cold water swimming affected their menstrual and perimenopausal symptoms. STUDY DESIGN: An online survey that asked women who regularly swim in cold water about their experiences. The survey was advertised for 2 months on social media. Questions related to cold water swimming habits and menstrual and perimenopausal symptoms were analysed. MAIN OUTCOME MEASURES: Quantitative and qualitative data including; frequency of menstrual and menopause symptoms, the effect of cold water swimming on these symptoms. RESULTS: 1114 women completed the survey. Women reported that cold water swimming reduced their menstrual symptoms, notably psychological symptoms such as anxiety (46.7%), mood swings (37.7%) and irritability (37.6%). Perimenopausal women reported a significant improvement in anxiety (46.9%), mood swings (34.5%), low mood (31.1%) and hot flushes (30.3%). The majority of women with symptoms swam specifically to reduce these symptoms (56.4% for period and 63.3% for perimenopause symptoms). Women said they felt it was the physical and mental effects of the cold water that helped their symptoms. For the free text question, five themes were identified: the calming and mood-boosting effect of the water, companionship and community, period improvements, an improvement in hot flushes and an overall health improvement. CONCLUSION: Women felt that cold water swimming had a positive overall effect on menstrual and perimenopause symptoms. Studies on other forms of exercise to relieve menstrual and perimenopause symptoms may show similar findings

Building Research Capacity in Botswana: A Randomized Trial Comparing Training Methodologies in the Botswana Ethics Training Initiative

Background Little empirical data are available on the extent to which capacity-building programs in research ethics prepare trainees to apply ethical reasoning skills to the design, conduct, or review of research. A randomized controlled trial was conducted in Botswana in 2010 to assess the effectiveness of a case-based intervention using email to augment in-person seminars. Methods University faculty and current and prospective IRB/REC members took part in a semester-long training program in research ethics. Participants attended two 2-day seminars and were assigned at random to one of two on-line arms of the trial. Participants in both arms completed on-line international modules from the Collaborative Institutional Training Initiative. Between seminars, intervention-arm participants were also emailed a weekly case to analyze in response to set questions; responses and individualized faculty feedback were exchanged via email. Tests assessing ethics knowledge were administered at the start of each seminar. The post-test included an additional section in which participants were asked to identify the ethical issues highlighted in five case studies from a list of multiple-choice responses. Results were analyzed using regression and ANOVA. Results Of the 71 participants (36 control, 35 intervention) enrolled at the first seminar, 41 (57.7%) attended the second seminar (19 control, 22 intervention). In the intervention arm, 19 (54.3%) participants fully completed and 8 (22.9%) partially completed all six weekly cases. The mean score was higher on the post-test (30.3/40) than on the pre-test (28.0/40), and individual post- and pre-test scores were highly correlated (r = 0.65, p \u3c 0.0001). Group assignment alone did not have an effect on test scores (p \u3e 0.84), but intervention-arm subjects who completed all assigned cases answered an average of 3.2 more questions correctly on the post-test than others, controlling for pre-test scores (p = 0.003). Conclusions Completion of the case-based intervention improved respondents\u27 test scores, with those who completed all six email cases scoring roughly 10% better than those who failed to complete this task and those in the control arm. There was only suggestive evidence that intensive case work improved ethical issue identification, although there was limited ability to assess this outcome due to a high drop-out rate

Vascular endothelial growth factor-A165b restores normal glomerular water permeability in a diphtheria-toxin mouse model of glomerular injury

BACKGROUND/AIMS:Genetic cell ablation using the human diphtheria toxin receptor (hDTR) is a new strategy used for analysing cellular function. Diphtheria toxin (DT) is a cytotoxic protein that leaves mouse cells relatively unaffected, but upon binding to hDTR it ultimately leads to cell death. We used a podocyte-specific hDTR expressing (Pod-DTR) mouse to assess the anti-permeability and cyto-protective effects of the splice isoform vascular endothelial growth factor (VEGF-A165b). METHODS:The Pod-DTR mouse was crossed with a mouse that over-expressed VEGF-A165b specifically in the podocytes (Neph-VEGF-A165b). Wild type (WT), Pod-DTR, Neph-VEGF-A165b and Pod-DTR X Neph-VEGF-A165b mice were treated with several doses of DT (1, 5, 100, and 1,000 ng/g bodyweight). Urine was collected and the glomerular water permeability (LpA/Vi) was measured ex vivo after 14 days. Structural analysis and podocyte marker expression were also assessed. RESULTS: Pod-DTR mice developed an increased glomerular LpA/Vi 14 days after administration of DT (all doses), which was prevented when the mice over-expressed VEGF-A165b. No major structural abnormalities, podocyte ablation or albuminuria was observed in Pod-DTR mice, indicating this to be a mild model of podocyte disease. However, a change in expression and localisation of nephrin within the podocytes was observed, indicating disruption of the slit diaphragm in the Pod-DTR mice. This was prevented in the Pod-DTR X Neph-VEGF-A165b mice. CONCLUSION: Although only a mild model of podocyte injury, over-expression of the anti-permeability VEGF-A165b isoform in the podocytes of Pod-DTR mice had a protective effect. Therefore, this study further highlights the therapeutic potential of VEGF-A165b in glomerular disease

Do Older Parents have More Self-Regulated Children?

Strong self-regulation in early childhood is a key predictor of academic and social success from elementary school through college (McClelland et al., 2012). This study analyzed the influence of the age of the child’s parent on the child’s self-regulation as measured by the HTKS (Head-Toes-Knees-Shoulders) measure. Relations between children’s self-regulation scores and their parent’s age were initially examined and then were tested again after controlling for family income and child age. Higher child self-regulation was significantly related to having older parents. However, this correlation lost significance after family income (Head Start status) and child age were controlled. These results suggest that although parent age and child self-regulation are significantly related, family income and child age are stronger predictors of children’s self-regulation

A drug-repositioning screen using splicing-sensitive fluorescent reporters identifies novel modulators of VEGF-A splicing with anti-angiogenic properties.

Alternative splicing of the vascular endothelial growth factor A (VEGF-A) terminal exon generates two protein families with differing functions. Pro-angiogenic VEGF-Axxxa isoforms are produced via selection of the proximal 3' splice site of the terminal exon. Use of an alternative distal splice site generates the anti-angiogenic VEGF-Axxxb proteins. A bichromatic splicing-sensitive reporter was designed to mimic VEGF-A alternative splicing and was used as a molecular tool to further investigate this alternative splicing event. Part of VEGF-A's terminal exon and preceding intron were inserted into a minigene construct followed by the coding sequences for two fluorescent proteins. A different fluorescent protein is expressed depending on which 3' splice site of the exon is used during splicing (dsRED denotes VEGF-Axxxa and EGFP denotes VEGF-Axxxb). The fluorescent output can be used to follow splicing decisions in vitro and in vivo. Following successful reporter validation in different cell lines and altering splicing using known modulators, a screen was performed using the LOPAC library of small molecules. Alterations to reporter splicing were measured using a fluorescent plate reader to detect dsRED and EGFP expression. Compounds of interest were further validated using flow cytometry and assessed for effects on endogenous VEGF-A alternative splicing at the mRNA and protein level. Ex vivo and in vitro angiogenesis assays were used to demonstrate the anti-angiogenic effect of the compounds. Furthermore, anti-angiogenic activity was investigated in a Matrigel in vivo model. To conclude, we have identified a set of compounds that have anti-angiogenic activity through modulation of VEGF-A terminal exon splicing

Teleneurology service provided via tablet technology: 3-year outcomes and physician satisfaction

© James Cook University. Introduction: This study aimed to demonstrate that teleneurology consultations conducted via tablet technology are an efficient and cost-effective means of managing acute neurologic emergencies at community-based hospitals and that utilizing such technology yields high community physician satisfaction. Method: During a 39-month period, Vanderbilt University Medical Center in Tennessee USA, provided teleneurology services to 10 community-based hospitals that lacked adequate neurology coverage. Hospitalists at one community-based hospital were not comfortable treating any patient with a neurologic symptom, resulting in 100% of those patients being transferred. This facility now retains more than 60% of neurology patients. For less than US$1200, these hospitals were able to meet the only capital expenditure required to launch this service: the purchase of handheld tablet computers. Real-time teleneurology consultations were conducted via tablet using two-way video conferencing, radiologic image sharing, and medical record documentation. Community physicians were regularly surveyed to assess satisfaction. Results: From February 2014 to May 2017, 3626 teleneurology consultations were conducted. Community physicians, in partnership with neurologists, successfully managed 87% of patients at the community-based hospital. Only 13% of patients required transfer to another facility for a higher level of care. The most common diagnoses included stroke (34%), seizure (11%), and headache/migraine (6%). The average time for the neurologist to answer a request for consultation page and connect with the community physician was 10.6 minutes. Ninety-one percent of community physicians were satisfied or somewhat satisfied with the overall service. Conclusion: In the assessment of neurology patients, tablets are a more cost-effective alternative to traditional telehealth technologies. The devices promote efficiency in consultations through ease of use and low transfer rates, and survey results indicate community physician satisfaction

A drug-repositioning screen using splicing-sensitive fluorescent reporters identifies novel modulators of VEGF-A splicing with anti-angiogenic properties.

Alternative splicing of the vascular endothelial growth factor A (VEGF-A) terminal exon generates two protein families with differing functions. Pro-angiogenic VEGF-Axxxa isoforms are produced via selection of the proximal 3' splice site of the terminal exon. Use of an alternative distal splice site generates the anti-angiogenic VEGF-Axxxb proteins. A bichromatic splicing-sensitive reporter was designed to mimic VEGF-A alternative splicing and was used as a molecular tool to further investigate this alternative splicing event. Part of VEGF-A's terminal exon and preceding intron were inserted into a minigene construct followed by the coding sequences for two fluorescent proteins. A different fluorescent protein is expressed depending on which 3' splice site of the exon is used during splicing (dsRED denotes VEGF-Axxxa and EGFP denotes VEGF-Axxxb). The fluorescent output can be used to follow splicing decisions in vitro and in vivo. Following successful reporter validation in different cell lines and altering splicing using known modulators, a screen was performed using the LOPAC library of small molecules. Alterations to reporter splicing were measured using a fluorescent plate reader to detect dsRED and EGFP expression. Compounds of interest were further validated using flow cytometry and assessed for effects on endogenous VEGF-A alternative splicing at the mRNA and protein level. Ex vivo and in vitro angiogenesis assays were used to demonstrate the anti-angiogenic effect of the compounds. Furthermore, anti-angiogenic activity was investigated in a Matrigel in vivo model. To conclude, we have identified a set of compounds that have anti-angiogenic activity through modulation of VEGF-A terminal exon splicing