Human iPSC-Derived Cerebellar Neurons from a Patient with Ataxia-Telangiectasia Reveal Disrupted Gene Regulatory Networks

Ataxia-telangiectasia (A-T) is a rare genetic disorder caused by loss of function of the ataxia-telangiectasia-mutated kinase and is characterized by a predisposition to cancer, pulmonary disease, immune deficiency and progressive degeneration of the cerebellum. As animal models do not faithfully recapitulate the neurological aspects, it remains unclear whether cerebellar degeneration is a neurodevelopmental or neurodegenerative phenotype. To address the necessity for a human model, we first assessed a previously published protocol for the ability to generate cerebellar neuronal cells, finding it gave rise to a population of precursors highly enriched for markers of the early hindbrain such as EN1 and GBX2, and later more mature cerebellar markers including PTF1α, MATH1, HOXB4, ZIC3, PAX6, and TUJ1. RNA sequencing was used to classify differentiated cerebellar neurons generated from integration-free A-T and control induced pluripotent stem cells. Comparison of RNA sequencing data with datasets from the Allen Brain Atlas reveals in vitro-derived cerebellar neurons are transcriptionally similar to discrete regions of the human cerebellum, and most closely resemble the cerebellum at 22 weeks post-conception. We show that patient-derived cerebellar neurons exhibit disrupted gene regulatory networks associated with synaptic vesicle dynamics and oxidative stress, offering the first molecular insights into early cerebellar pathogenesis of ataxia-telangiectasia

The Other Fifty Percent: Expressions From Special Education Teachers About Why They Persist in the Profession

We examined reasons special educators are motivated to persist in the profession despite challenges that often lead to attrition for this group. Participants were 21 special education teachers with six or more years of teaching experience across multiple grade levels. Data were collected via the Zoom virtual meeting platform with four focus groups. Semi-structured interview techniques were used, and data were analyzed using deductive coding procedures. Participants shared external, employment, and personal factors associated with Billingsley’s (1993) career decision framework that influenced their persistence, such as supports from school administrators with expertise in special education law, passion for students and their achievement, and stressors related to the workforce that motivated them to persist in the profession. Implications for educational practice and future research are discussed

Neural measures of social attention across the first years of life: characterizing typical development and markers of autism risk

We would like to thank the Infant Sibling Project staff, past and present, for their hard work in collecting these data. We are very grateful for the assistance of Brandon Keehn, Alexandra Libby and Ella Kipervasser with data processing, and we thank Vanessa Vogel-Farley for her constant guidance. Finally, we want to acknowledge the very dedicated families who committed years of their lives to the Infant Sibling Project and who made this work possible. Funding was provided by NIH (R21DC08637) to H.T-F., NIDCD (1R01DC010290-01) to C.A.N. and H. T-F., the Simons Foundation (137186) to C.A.N. and the Autism Speaks Pilot Grants Program to H.T-F. (R21DC08637 - NIH; 1R01DC010290-01 - NIDCD; 137186 - Simons Foundation; Autism Speaks Pilot Grants Program)Published versio

The improving outcomes in intermittent exotropia study: outcomes at 2 years after diagnosis in an observational cohort

Background: The purpose of this study was to investigate current patterns of management and outcomes of intermittent distance exotropia [X(T)] in the UK. Methods: This was an observational cohort study which recruited 460 children aged < 12 years with previously untreated X(T). Eligible subjects were enrolled from 26 UK hospital ophthalmology clinics between May 2005 and December 2006. Over a 2-year period of follow-up, clinical data were prospectively recorded at standard intervals from enrolment. Data collected included angle, near stereoacuity, visual acuity, control of X(T) measured with the Newcastle Control Score (NCS), and treatment. The main outcome measures were change in clinical outcomes (angle, stereoacuity, visual acuity and NCS) in treated and untreated X(T), 2 years from enrolment (or, where applicable, 6 months after surgery). Change over time was tested using the chi-square test for categorical, Wilcoxon test for non-parametric and paired-samples t-test for parametric data. Results: At follow-up, data were available for 371 children (81% of the original cohort). Of these: 53% (195) had no treatment; 17% (63) had treatment for reduced visual acuity only (pure refractive error and amblyopia); 13% (50) had non surgical treatment for control (spectacle lenses, occlusion, prisms, exercises) and 17% (63) had surgery. Only 0.5% (2/371) children developed constant exotropia. The surgically treated group was the only group with clinically significant improvements in angle or NCS. However, 8% (5) of those treated surgically required second procedures for overcorrection within 6 months of the initial procedure and at 6-month follow-up 21% (13) were overcorrected. Conclusions: Many children in the UK with X(T) receive active monitoring only. Deterioration to constant exotropia, with or without treatment, is rare. Surgery appears effective in improving angle of X(T) and NCS, but rates of overcorrection are high

Mixed method research in school psychology: a mixed methods investigation of trends

This article illustrates the utility of mixed methods research (i.e., combining quantitative and qualitative techniques) to the field of school psychology. First, the use of mixed methods approaches in school psychology practice is discussed. Second, the mixed methods research process is described in terms of school psychology research. Third, the current state of affairs with respect to mixed methods designs in school psychology research is illustrated through a mixed methods analysis of the types of empirical studies published in the four leading school psychology journals between 2001 and 2005. Only 13.7% of these studies were classified as representing mixed methods research. We conclude that this relatively small proportion likely reflects the fact that only 3.5% of graduatelevel school psychology programs appear to require that students enroll in one or more qualitative and/or mixed methods research courses, and only 19.3% appear to offer one or more qualitative courses as an elective. Finally, the utility of mixed methods research is illustrated by critiquing select monomethod (i.e., qualitative or quantitative) and mixed methods studies conducted on the increasingly important topic of bullying. We demonstrate how using mixed methods techniques results in richer data being collected, leading to a greater understanding of underlying phenomena

Paying clinicians to join clinical trials : a review of guidelines and interview study of trialists

Background: The motivations of clinicians to participate in clinical trials have been little studied. This project explored the potential role of payment for participation in publicly funded clinical trials in the UK. The aims were to review relevant guidelines and to collate and analyse views of clinical trialists on the role of payments and other factors that motivated clinicians to join clinical trials. Methods: Review of guidelines governing payments to clinicians for recruitment to trials. Semistructured interviews with a range of NHS clinical trial leaders, analysed using qualititative methods. Results: While UK guidelines had little to say specifically on payments linked to recruitment, all payments have become highly regulated and increasingly transparent. Interview participants believed that expenses arising from research should be covered. Payments in excess of expenses were seen as likely to increase participation but with the risk of reducing quality. Motivations such as interest in the topic, the scope for patients to benefit and intellectual curiosity were considered more important. Barriers to involvement included bureaucracy and lack of time. Discussion: Limited scope exists for paying clinicians over-and-above the cost of their time to be involved in research. Most trialists favour full payment of all expenses related to research. Conclusion: Payment of clinicians beyond expenses is perceived to be a less important motivating factor than researching important, salient questions, and facilitating research by reducing bureaucracy and delay

Health Assessment and Seroepidemiologic Survey of Potential Pathogens in Wild Antillean Manatees (Trichechus manatus manatus)

The Antillean manatee (Trichechus manatus manatus), a subspecies of the West Indian manatee, inhabits fresh, brackish, and warm coastal waters distributed along the eastern border of Central America, the northern coast of South America, and throughout the Wider Caribbean Region. Threatened primarily by human encroachment, poaching, and habitat degradation, Antillean manatees are listed as endangered by the International Union for the Conservation of Nature. The impact of disease on population viability remains unknown in spite of concerns surrounding the species' ability to rebound from a population crash should an epizootic occur. To gain insight on the baseline health of this subspecies, a total of 191 blood samples were collected opportunistically from wild Antillean manatees in Belize between 1997 and 2009. Hematologic and biochemical reference intervals were established, and antibody prevalence to eight pathogens with zoonotic potential was determined. Age was found to be a significant factor of variation in mean blood values, whereas sex, capture site, and season contributed less to overall differences in parameter values. Negative antibody titers were reported for all pathogens surveyed except for Leptospira bratislava, L. canicola, and L. icterohemorrhagiae, Toxoplasma gondii, and morbillivirus. As part of comprehensive health assessment in manatees from Belize, this study will serve as a benchmark aiding in early disease detection and in the discernment of important epidemiologic patterns in the manatees of this region. Additionally, it will provide some of the initial tools to explore the broader application of manatees as sentinel species of nearshore ecosystem health

Immunomodulation by imiquimod in patients with high-risk primary melanoma.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted

Compliance or pragmatism: How do academics deal with managerialism in higher education? A comparative study in three countries

Universities throughout Europe have adopted organisational strategies, structures, technologies, management instruments and values that are commonly found in the private sector. While these alleged managerial measures may be considered useful, and have a positive effect on the quality of teaching and research, there is also evidence of detrimental effects on primary tasks. The consequences of such managerial measures were investigated through 48 interviews with staff members at 10 universities in the Netherlands, Sweden and the UK. The results were analysed and interpreted within the framework of institutional and professional theory, by linking them to three central themes: 'symbolic compliance', 'professional pragmatism' and 'formal instrumentality'. These themes explain why and how the respondents dissociated themselves from the managerial measures imposed upon them. This occurred often for pragmatic and occasionally for principled reasons. © 2012 Society for Research into Higher Education