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Studies investigating autistic community research priorities indicate a mismatch between what autism research focuses on and what autistic people want to see researched. Furthermore, there has not been a research priority-setting exercise specifically with autistic people in Scotland, where there are unique cultural, political and social contexts. Using a community-based participatory design, we aimed to identify the research priorities of autistic adults living in Scotland. Autistic and non-autistic researchers designed and conducted a survey where 225 autistic adults rated and ranked research topics in order of importance and provided qualitative feedback on issues and questions important to them. The top five research priorities were mental health/well-being, identification and diagnosis of autistic people, support services, knowledge and attitudes towards autistic people and issues impacting autistic women. There were differences in priorities according to different intersections of identity, and qualitative responses indicated a desire for research to focus on support and understanding. The bottom three priorities concerned genetics, treatments and interventions and causes. These findings emphasise the need to address the gap between what autism research focuses on and the everyday lives of autistic people. Although research has the potential to improve autistic people's lives, lots of funding goes towards research looking at topics which autistic people say has little impact in their everyday lives. Autistic people's lives can be different depending on where they live, and Scotland is a unique country in many ways. We wanted to find out which topics autistic people in Scotland want to see research on. Our team of autistic and non-autistic researchers (including university-based and community researchers) created a survey where 225 autistic adults rated and ranked the importance of possible research topics and shared their thoughts on what topics mattered to them. The five most important topics were mental health and well-being, identifying and diagnosing autistic people, support services (including healthcare and social care), non-autistic people's knowledge and attitudes and issues impacting autistic women. The three least important topics were genetics or biological aspects of autism, autism treatments/interventions and causes of autism. Our findings indicate that autistic people in Scotland want research to focus on things that matter to their day-to-day lives. Also, the Scottish government says they will be listening to autistic people in their latest policy plans, and we believe that considering autistic people's research priorities is an important part of this. Our findings also add to growing calls for change to happen in how and what autism researchers do research on. [ABSTRACT FROM AUTHOR]

The purpose of this scoping review was to identify and map knowledge on different types of transitional support interventions currently available to support transition to independent living for care leavers. An extensive search using four research databases was undertaken, resulting in 36 relevant articles for inclusion. Findings were organised thematically into four broad areas: (1) Extended care; (2) A Helping Relationship; (3) Family; and (4) Employment, Education and Training. Findings show that offering a combination of targeted interventions can contribute to a more successful transition. Effective relationship‐based practices are critical to the success of transitional support interventions. [ABSTRACT FROM AUTHOR]

In this article, the authors examine the mathematics identity development of six Black male students over the course of a 4-year The Algebra Project Cohort Model (APCM) initiative. Mathematics identity here is defined as participation through interactions and positioning of self and others. Data collection included nearly 450 minutes of video recordings of small-group, mathematics problem solving in which student actions, coded as acts of participation, were tallied. These tallied actions were conceptualized descriptively in terms of mathematics identity using the lenses of agency, accountability, and work practices. The analyses suggest that the APCM students' confidence in self and peers increased over the 4 years, they consistently chose to engage in mathematics, and their reliance on knowledgeable others lessened. Opportunities for future research and implications for policy makers and other stakeholders are discussed.

This article centers on the nonprofit landscape in Vancouver, Canada, a city that occupies the territories of the xʷməθkʷəy̓əm (Musqueam), sḵwx̱wú7mesh (Squamish), and səlilwətaɬ (Tsleil-Waututh) nations, which have never been ceded to the colonial occupation of Canada. Vancouver has a competitive nonprofit field, with an estimated 1600+ nonprofits operating within city limits. This descriptive review starts by defining what a nonprofit industrial complex (NPIC) is, then outlines an abbreviated history of the nonprofit sector on the aforementioned lands. The article then explores issues related to colonialism, anti-poor legislation, neoliberal governance, the fusing of the public and private sectors, and the bureaucratization of social movements and care work as mechanisms to uphold the status quo social order and organization of power. Focusing on under-examined issues related to the business imperatives of nonprofit organizations in the sectors of housing, health and social services, community policing, and research, this work challenges the positive default framing of nonprofits and charities. Instead, we contend that Vancouver’s NPIC allows the government and the wealthy to shirk responsibility for deepening health and social inequities, while shaping nonprofits’ revenue-generating objectives and weakening their accountability to the community.

* Context.--Molecular diagnostics play an increasing role in the diagnosis of Ewing sarcoma. The type of molecular testing used in clinical practice has been poorly described. Objective.--To describe patterns of translocation testing for newly diagnosed Ewing sarcoma. Design.--Children's Oncology Group (COG) trial AEWS1221 was a phase III randomized trial enrolling patients with newly diagnosed metastatic Ewing sarcoma from 2014 to 2019. Patients were required to have a histologic diagnosis of Ewing sarcoma, but translocation testing was not required. Sites provided types and results of any molecular diagnostics performed. Results.--Data from 305 enrolled patients were available. The most common type of molecular testing was fluorescence in situ hybridization (FISH) performed on the primary tumor (236 of 305 patients; 77.4%), with positive testing for an EWSR1 or FUS translocation in 211 (89.4%). Reverse transcription-polymerase chain reaction (RT-PCR) on the primary tumor was performed in 61 of 305 patients (20%), with positive results in 48 of 61 patients (78.7%). Next-generation sequencing was reported in 7 patients for the primary tumor and in 3 patients for metastatic sites. For all types of testing on either primary or metastatic tumor, 16 of 305 patients (5.2%) had no reported translocation testing. When evaluating all results from all testing, 44 of 305 patients (14.4%) lacked documentation of an abnormality consistent with a molecular diagnosis of Ewing sarcoma. Conclusions.--COG sites enrolling in a Ewing sarcoma trial have high rates of testing by FISH or PCR. A small proportion of patients have no translocation testing on either primary or metastatic sites. Next-generation sequencing techniques are not yet commonly used in this context., Ewing sarcoma is a translocation-associated sarcoma mainly affecting children, adolescents, and young adults. The most common translocation is EWSR1/FLI1, although any translocation of EWSR1 or FUS with a member of [...]

Effective information transfer requires social communication skills. As autism is clinically defined by social communication deficits, it may be expected that information transfer between autistic people would be particularly deficient. However, the Double Empathy theory would suggest that communication difficulties arise from a mismatch in neurotype; and thus information transfer between autistic people may be more successful than information transfer between an autistic and a non-autistic person. We investigate this by examining information transfer between autistic adults, non-autistic adults and mixed autistic with-non-autistic pairs. Initial participants were told a story which they recounted to a second participant, who recounted the story to a third participant and so on, along a 'diffusion chain' of eight participants (n=72). We found a significantly steeper decline in detail retention in the mixed chains, while autistic chains did not significantly differ from non-autistic chains. Participant rapport ratings revealed significantly lower scores for mixed chains. These results challenge the diagnostic criterion that autistic people lack the skills to interact successfully. Rather, autistic people effectively share information with each other. Information transfer selectively degrades more quickly in mixed pairs, in parallel with a reduction in rapport.

Many autistic people are motivated to have friends, relationships and close family bonds, despite the clinical characterisation of autism as a condition negatively affecting social interaction. Many first-hand accounts of autistic people describe feelings of comfort and ease specifically with other autistic people. This qualitative research explored and contrasted autistic experiences of spending social time with neurotypical and autistic friends and family. In total, 12 autistic adults (10 females, aged 21-51) completed semi-structured interviews focused on time spent with friends and family; positive and negative aspects of time spent with neurotypical and autistic friends and family; and feelings during and after spending time together. Three themes were identified: cross-neurotype understanding, minority status and belonging. Investigation of these themes reveals the benefits of autistic people creating and maintaining social relationships with other autistic people, in a more systematic way than previous individual reports. They highlight the need for autistic-led social opportunities and indicate benefits of informal peer support for autistic adults.

Abstract Background Routinely-collected mental health data could deliver novel insights for mental health research. However, patients’ willingness to share their mental health data remains largely unknown. We investigated factors influencing likelihood of sharing these data for research purposes amongst people with and without experience of mental illness. Methods We collected responses from a diverse sample of UK National Health Service (NHS) users (n = 2187) of which about half (n = 1087) had lifetime experience of mental illness. Ordinal logistic regression was used to examine the influence of demographic factors, clinical service experience, and primary mental illness on willingness to share mental health data, contrasted against physical health data. Results There was a high level of willingness to share mental (89.7%) and physical (92.8%) health data for research purposes. Higher levels of satisfaction with the NHS were associated with greater willingness to share mental health data. Furthermore, people with personal experience of mental illness were more willing than those without to share mental health data, once the variable of NHS satisfaction had been controlled for. Of the mental illnesses recorded, people with depression, obsessive-compulsive disorder (OCD), personality disorder or bipolar disorder were significantly more likely to share their mental health data than people without mental illness. Conclusions These findings suggest that positive experiences of health services and personal experience of mental illness are associated with greater willingness to share mental health data. NHS satisfaction is a potentially modifiable factor that could foster public support for increased use of NHS mental health data in research.

Conductance-based models have played an important role in the development of modern neuroscience. These mathematical models are powerful “tools” that enable theoretical explorations in experimentally untenable situations, and can lead to the development of novel hypotheses and predictions. With advances in cell imaging and computational power, multi-compartment models with morphological accuracy are becoming common practice. However, as more biological details are added, they make extensive explorations and analyses more challenging largely due to their huge computational expense. Here, we focus on oriens-lacunosum/moleculare (OLM) cell models. OLM cells can contribute to functionally relevant theta rhythms in the hippocampus by virtue of their ability to express spiking resonance at theta frequencies, but what characteristics underlie this is far from clear. We converted a previously developed detailed multi-compartment OLM cell model into a reduced single compartment model that retained biophysical fidelity with its underlying ion currents. We showed that the reduced OLM cell model can capture complex output that includes spiking resonance in in vivo-like scenarios as previously obtained with the multi-compartment model. Using the reduced model, we were able to greatly expand our in vivo-like scenarios. Applying spike-triggered average analyses, we were able to to determine that it is a combination of hyperpolarization-activated cation and muscarinic type potassium currents that specifically allow OLM cells to exhibit spiking resonance at theta frequencies. Further, we developed a robust Kalman Filtering (KF) method to estimate parameters of the reduced model in real-time. We showed that it may be possible to directly estimate conductance parameters from experiments since this KF method can reliably extract parameter values from model voltage recordings. Overall, our work showcases how the contribution of cellular biophysical current details could be determined and assessed for spiking resonance. As well, our work shows that it may be possible to directly extract these parameters from current clamp voltage recordings.

Objectives. Fibroblast activation protein alpha (FAP) is highly expressed by cancer-associated fibroblasts in multiple epithelial cancers. The aim of this study was to characterize FAP expression in sarcomas to explore its potential utility as a diagnostic and therapeutic target and prognostic biomarker in sarcomas. Methods. Available tissue samples from patients with bone or soft tissue tumors were identified at the University of California, Los Angeles. FAP expression was evaluated via immunohistochemistry (IHC) in tumor samples (n = 63), adjacent normal tissues (n = 30), and positive controls (n = 2) using semiquantitative systems for intensity (0 = negative; 1 = weak; 2 = moderate; and 3 = strong) and density (none, 75%) in stromal and tumor/nonstromal cells and using a qualitative overall score (not detected, low, medium, and high). Additionally, RNA sequencing data in publicly available databases were utilized to compare FAP expression in samples (n = 10,626) from various cancer types and evaluate the association between FAP expression and overall survival (OS) in sarcoma (n = 168). Results. The majority of tumor samples had FAP IHC intensity scores ≥2 and density scores ≥25% for stromal cells (77.7%) and tumor cells (50.7%). All desmoid fibromatosis, myxofibrosarcoma, solitary fibrous tumor, and undifferentiated pleomorphic sarcoma samples had medium or high FAP overall scores. Sarcomas were among cancer types with the highest mean FAP expression by RNA sequencing. There was no significant difference in OS in patients with sarcoma with low versus high FAP expression. Conclusion. The majority of the sarcoma samples showed FAP expression by both stromal and tumor/nonstromal cells. Further investigation of FAP as a potential diagnostic and therapeutic target in sarcomas is warranted.

Summary: The SARS-CoV-2 Omicron variant of concern (VoC) and its sublineages contain 31–36 mutations in spike and escape neutralization by most therapeutic antibodies. In a pseudovirus neutralization assay, 66 of the nearly 400 candidate therapeutics in the Coronavirus Immunotherapeutic Consortium (CoVIC) panel neutralize Omicron and multiple Omicron sublineages. Among natural immunoglobulin Gs (IgGs), especially those in the receptor-binding domain (RBD)-2 epitope community, nearly all Omicron neutralizers recognize spike bivalently, with both antigen-binding fragments (Fabs) simultaneously engaging adjacent RBDs on the same spike. Most IgGs that do not neutralize Omicron bind either entirely monovalently or have some (22%–50%) monovalent occupancy. Cleavage of bivalent-binding IgGs to Fabs abolishes neutralization and binding affinity, with disproportionate loss of activity against Omicron pseudovirus and spike. These results suggest that VoC-resistant antibodies overcome mutagenic substitution via avidity. Hence, vaccine strategies targeting future SARS-CoV-2 variants should consider epitope display with spacing and organization identical to trimeric spike.

Background Time to reperfusion is an important predictor of outcome in ischaemic stroke from large vessel occlusion (LVO). For patients requiring endovascular thrombectomy (EVT), the transfer times from peripheral hospitals in metropolitan and regional Victoria, Australia to comprehensive stroke centres (CSCs) have not been studied.Aims To determine transfer and journey times for patients with LVO stroke being transferred for consideration of EVT.Methods All patients transferred for consideration of EVT to three Victorian CSCs from January 2017 to December 2018 were included. Travel times were obtained from records matched to Ambulance Victoria and the referring centre via Victorian Stroke Telemedicine or hospital medical records. Metrics of interest included door-in-door-out time (DIDO), inbound journey time and outbound journey time.Results Data for 455 transferred patients were obtained, of which 395 (86.8%) underwent EVT. The median DIDO was 107 min (IQR 84–145) for metropolitan sites and 132 min (IQR 108–167) for regional sites. At metropolitan referring hospitals, faster DIDO was associated with use of the same ambulance crew to transport between hospitals (75 (63–90) vs 124 (99–156) min, p

BackgroundNew prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays.MethodsA NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome.ResultsThe analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels.ConclusionsNGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes.

Enteric methane (CH4 ) production from cattle contributes to global greenhouse gas emissions. Measurement of enteric CH4 is complex, expensive, and impractical at large scales; therefore, models are commonly used to predict CH4 production. However, building robust prediction models requires extensive data from animals under different management systems worldwide. The objectives of this study were to (1) collate a global database of enteric CH4 production from individual lactating dairy cattle; (2) determine the availability of key variables for predicting enteric CH4 production (g/day per cow), yield [g/kg dry matter intake (DMI)], and intensity (g/kg energy corrected milk) and their respective relationships; (3) develop intercontinental and regional models and cross-validate their performance; and (4) assess the trade-off between availability of on-farm inputs and CH4 prediction accuracy. The intercontinental database covered Europe (EU), the United States (US), and Australia (AU). A sequential approach was taken by incrementally adding key variables to develop models with increasing complexity. Methane emissions were predicted by fitting linear mixed models. Within model categories, an intercontinental model with the most available independent variables performed best with root mean square prediction error (RMSPE) as a percentage of mean observed value of 16.6%, 14.7%, and 19.8% for intercontinental, EU, and United States regions, respectively. Less complex models requiring only DMI had predictive ability comparable to complex models. Enteric CH4 production, yield, and intensity prediction models developed on an intercontinental basis had similar performance across regions, however, intercepts and slopes were different with implications for prediction. Revised CH4 emission conversion factors for specific regions are required to improve CH4 production estimates in national inventories. In conclusion, information on DMI is required for good prediction, and other factors such as dietary neutral detergent fiber (NDF) concentration, improve the prediction. For enteric CH4 yield and intensity prediction, information on milk yield and composition is required for better estimation.

Sarcomas of soft tissue and bone are mesenchymal malignancies that can arise in any anatomic location, most commonly the extremity, retroperitoneum, and trunk. Even for lower grade histologic subtypes, local recurrence can cause significant morbidity and even disease-related death. Although surgery remains the cornerstone of local control, perioperative radiation and systemic therapy are often important adjuvants. This review will summarize the current therapeutic approaches for local control of soft tissue and bone sarcomas.

Abstract Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency.

Abstract The diagnosis of antineutrophil cytoplasmic autoantibody‐associated vasculitis in first‐episode strokes is particularly challenging, especially in patients lacking features of systemic vasculitis. We present the case of a 71‐year‐old woman with positive myeloperoxidase antineutrophil cytoplasmic antibodies and negative proteinase 3 autoantibodies. The patient presented with 1 week history of pyramidal weakness in both upper and lower limbs, hyperreflexia, and clonus. Magnetic resonance imaging of the brain demonstrated widespread bihemispheric cortical and deep white matter acute infarcts, which are consistent with features of stroke secondary to vasculitis. Myeloperoxidase antineutrophilic cytoplasmic autoantibody‐positive vasculitis diseases are more commonly associated with renal, pulmonary, and cutaneous manifestations; however, in our patient, the central nervous system features predominated. This case highlights the challenges of diagnosing primary central nervous system vasculitis, in this case, an atypical myeloperoxidase antineutrophilic cytoplasmic autoantibody‐positive disease without the classical disease course and clinical signs.

The isolation and characterization of neutralizing antibodies from infection and vaccine settings informs future vaccine design, and methodologies that streamline the isolation of antibodies and the generation of B cell clones are of great interest. Retroviral transduction to express Bcl-6 and Bcl-xL and transform primary B cells has been shown to promote long-term B cell survival and antibody secretion in vitro, and can be used to isolate antibodies from memory B cells. However, application of this methodology to B cell subsets from different tissues and B cells from chronically infected individuals has not been well characterized. Here, we characterize Bcl-6/Bcl-xL B cell immortalization across multiple tissue types and B cell subsets in healthy and HIV-1 infected individuals, as well as individuals recovering from malaria. In healthy individuals, naïve and memory B cell subsets from PBMCs and tonsil tissue transformed with similar efficiencies, and displayed similar characteristics with respect to their longevity and immunoglobulin secretion. In HIV-1-viremic individuals or in individuals with recent malaria infections, the exhausted CD27-CD21- memory B cells transformed with lower efficiency, but the transformed B cells expanded and secreted IgG with similar efficiency. Importantly, we show that this methodology can be used to isolate broadly neutralizing antibodies from HIV-infected individuals. Overall, we demonstrate that Bcl-6/Bcl-xL B cell immortalization can be used to isolate antibodies and generate B cell clones from different B cell populations, albeit with varying efficiencies.