What are the autism research priorities of autistic adults in Scotland?

LAY ABSTRACT: 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.

A DLG1-ARHGAP31-CDC42 axis is essential for the intestinal stem cell response to fluctuating niche Wnt signaling.

A central factor in the maintenance of tissue integrity is the response of stem cells to variations in the levels of niche signals. In the gut, intestinal stem cells (ISCs) depend on Wnt ligands for self-renewal and proliferation. Transient increases in Wnt signaling promote regeneration after injury or in inflammatory bowel diseases, whereas constitutive activation of this pathway leads to colorectal cancer. Here, we report that Discs large 1 (Dlg1), although dispensable for polarity and cellular turnover during intestinal homeostasis, is required for ISC survival in the context of increased Wnt signaling. RNA sequencing (RNA-seq) and genetic mouse models demonstrated that DLG1 regulates the cellular response to increased canonical Wnt ligands. This occurs via the transcriptional regulation of Arhgap31, a GTPase-activating protein that deactivates CDC42, an effector of the non-canonical Wnt pathway. These findings reveal a DLG1-ARHGAP31-CDC42 axis that is essential for the ISC response to increased niche Wnt signaling.

Factors associated with preoperative and postoperative seizures in patients undergoing resection of brain metastases.

OBJECTIVE: Epileptic seizures are a common and potentially devastating complication of metastatic brain tumors. Although tumor-related seizures have been described in previous case series, most studies have focused on primary brain tumors and have not differentiated between different types of cerebral metastases. The authors analyzed a large surgical cohort of patients with brain metastases to examine risk factors associated with preoperative and postoperative seizures and to better understand the seizure risk factors of metastatic brain tumors. METHODS: Patients who underwent resection of a brain metastasis at the University of California, San Francisco (UCSF), were retrospectively reviewed. Patients included in the study were ≥ 18 years of age, required resection of a brain metastasis, and were treated at UCSF. Primary cancers included melanoma, non-small cell lung adenocarcinoma, breast adenocarcinoma, colorectal adenocarcinoma, esophageal adenocarcinoma, gastric adenocarcinoma, renal cell carcinoma, urothelial carcinoma, ovarian carcinoma, cervical squamous cell carcinoma, and endometrial adenocarcinoma. Patients were evaluated for primary cancer type and seizure occurrence, as well as need for use of antiepileptic drugs preoperatively, at time of discharge, and at 6 months postoperatively. Additionally, Engel classification scores were assigned to those patients who initially presented with seizures preoperatively. Univariate and multivariate regression analyses were used to assess the association of tumor type with preoperative seizures. RESULTS: Data were retrospectively analyzed for 348 consecutive patients who underwent surgical treatment of brain metastases between 1998 and 2019. The cohort had a mean age of 60 years at the time of surgery and was 59% female. The mean and median follow-up durations after the date of surgery for the cohort were 22 months and 10.8 months, respectively. In univariate analysis, frontal lobe location (p = 0.05), melanoma (p = 0.02), KRAS mutation in lung carcinoma (p = 0.04), intratumoral hemorrhage (p = 0.04), and prior radiotherapy (p = 0.04) were associated with seizure presentation. Postoperative checkpoint inhibitor use (p = 0.002), prior radiotherapy (p = 0.05), older age (p = 0.002), distant CNS progression (p = 0.004), and parietal lobe tumor location (p = 0.002) were associated with seizures at 6 months postoperatively. The final multivariate model confirmed the independent effects of tumor location in the frontal lobe and presence of intratumoral hemorrhage as predictors of preoperative seizures, and checkpoint inhibitor use and parietal lobe location were identified as significant predictors of seizures at 6 months postoperatively. CONCLUSIONS: Within this surgical cohort of patients with brain metastases, seizures were seen in almost a quarter of patients preoperatively. Frontal lobe metastases and hemorrhagic tumors were associated with higher risk of preoperative seizures, whereas checkpoint inhibitor use and parietal lobe tumors appeared to be associated with seizures at 6 months postoperatively. Future research should focus on the effect of metastatic lesion-targeting therapeutic interventions on seizure control in these patients.

Asylum seeker trauma in a student-run clinic: reducing barriers to forensic medical evaluations.

Introduction This research, through the analysis of the case-law of the Inter-American Court of Human Rights (IACtHR), seeks to shed light on the nexus between families of the missing' claims, their agency and State compliance with reparations. The IACtHR has a unique follow-up system in the area of reparations, where victims can directly address the judges during hearings. This paper suggests that victims' participation - before and after the judgment- pervades the legal rigidity of international jurisdictions and contributes to a better understanding of reparations. INTRODUCTION: The number of forcibly displaced immigrants seeking asylum in the United States continues to rapidly increase. Movement from Latin America to the United States was the third-largest migration worldwide in 2017 (Leyva-Flores et al., 2019). As migration patterns change, understanding the background and trauma profile of newly displaced populations is essential to meet their health needs and aid successful resettlement. University-affiliated student-run asylum clinics conduct a growing number of forensic medical evaluations of asylum seekers and provide a vital lens to study changes in this population's profile over time. METHODS: A retrospective review was conducted of the first 102 asylum seekers receiving forensic medical evaluations between 2019 and 2021 at a university-affiliated student- run clinic, reporting demographics; trauma, medical, and mental health histories; referral patterns; and legal outcomes. Bivariate statistics were used to investigate the relationship between past trauma and mental health outcomes. RESULTS: Clients reported an average of 4.4 different types of physical, psychological, and sexual ill-treatment per person. The current mental health burden was extensive with 86.9 percent of clients reporting symptoms of PTSD and/or depression. Clinician-student teams evaluated clients within a clinic structure deploying a continuous improvement model to reduce common barriers to forensic evaluations and promote longitudinal follow- up and referrals. DISCUSSION: This study demonstrates the complexity of trauma exposure reported by asylum seekers, contributes to the evidence on how trauma results in mental health outcomes, and describes trauma-centred clinic adaptations that reduce barriers to forensic evaluations known to improve the rates of legal protection.

Cellular shape reinforces niche to stem cell signaling in the small intestine.

Niche-derived factors regulate tissue stem cells, but apart from the mechanosensory pathways, the effect of niche geometry is not well understood. We used organoids and bioengineered tissue culture platforms to demonstrate that the conical shape of Lgr5+ small intestinal stem cells (ISCs) facilitate their self-renewal and function. Inhibition of non-muscle myosin II (NM II)-driven apical constriction altered ISC shape and reduced niche curvature and stem cell capacity. Niche curvature is decreased in aged mice, suggesting that suboptimal interactions between old ISCs and their niche develop with age. We show that activation of NM IIC or physical restriction to young topology improves in vitro regeneration by old epithelium. We propose that the increase in lateral surface area of ISCs induced by apical constriction promotes interactions between neighboring cells, and the curved topology of the intestinal niche has evolved to maximize signaling between ISCs and neighboring cells.

Salvage Surgery for Local Control of Brain Metastases After Previous Stereotactic Radiosurgery: A Single-Center Series.

BACKGROUND: Although overall survival (OS) has improved in patients with brain metastases (BMs), control of recurrent BMs remains a therapeutic challenge. Salvage surgery may achieve acceptable control rates in the setting of progression after previous stereotactic radiosurgery (SRS), yet it remains a question how additional adjuvant therapies may affect outcomes and how patient selection for salvage surgery may be optimized. METHODS: Patients receiving salvage surgery for BM progression after previous SRS were retrospectively reviewed from a single center. Outcomes of interest included local tumor progression, leptomeningeal dissemination, and OS. Cox proportional hazard models and nominal logistic regression were applied to determine factors associated with outcomes of interest. RESULTS: A total of 43 patients with 50 BMs were included. After salvage surgery, local progression was observed for 17 BMs (34%), leptomeningeal dissemination was observed in 17 patients (39.5%), and censored median OS was 17.9 months. On multivariate analysis, use of brachytherapy was associated with improved local control (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04-0.6; P = 0.008). For patients treated with SRS ≥4.5 months before salvage surgery, both brachytherapy (HR, 0.07; 95% CI, 0.01-0.39; P = 0.002) and postoperative adjuvant SRS (HR, 0.14; 95% CI, 0.02-1.00; P = 0.05) were associated with improved local control compared with no adjuvant radiation therapy. Presence of extracranial malignancy (HR, 6.70; 95% CI, 2.58-17.42; P < 0.0001) was associated with shorter survival. Graded prognostic assessment underestimated survival in 79.1% of patients, with a mean difference of 18.9 months between graded prognostic assessment-estimated and actual OS. CONCLUSIONS: In properly selected patients, salvage surgery may be an appropriate therapy for BM progression after previous SRS. Adjuvant brachytherapy and repeat SRS can offer significant benefit for local control with salvage resection.

Minimizing the average distance to a closest leaf in a phylogenetic tree.

When performing an analysis on a collection of molecular sequences, it can be convenient to reduce the number of sequences under consideration while maintaining some characteristic of a larger collection of sequences. For example, one may wish to select a subset of high-quality sequences that represent the diversity of a larger collection of sequences. One may also wish to specialize a large database of characterized "reference sequences" to a smaller subset that is as close as possible on average to a collection of "query sequences" of interest. Such a representative subset can be useful whenever one wishes to find a set of reference sequences that is appropriate to use for comparative analysis of environmentally derived sequences, such as for selecting "reference tree" sequences for phylogenetic placement of metagenomic reads. In this article, we formalize these problems in terms of the minimization of the Average Distance to the Closest Leaf (ADCL) and investigate algorithms to perform the relevant minimization. We show that the greedy algorithm is not effective, show that a variant of the Partitioning Around Medoids (PAM) heuristic gets stuck in local minima, and develop an exact dynamic programming approach. Using this exact program we note that the performance of PAM appears to be good for simulated trees, and is faster than the exact algorithm for small trees. On the other hand, the exact program gives solutions for all numbers of leaves less than or equal to the given desired number of leaves, whereas PAM only gives a solution for the prespecified number of leaves. Via application to real data, we show that the ADCL criterion chooses chimeric sequences less often than random subsets, whereas the maximization of phylogenetic diversity chooses them more often than random. These algorithms have been implemented in publicly available software.

Nestly--a framework for running software with nested parameter choices and aggregating results.

UNLABELLED: The execution of a software application or pipeline using various combinations of parameters and inputs is a common task in bioinformatics. In the absence of a specialized tool to organize, streamline and formalize this process, scientists must write frequently complex scripts to perform these tasks. We present nestly, a Python package to facilitate running tools with nested combinations of parameters and inputs. nestly provides three components. First, a module to build nested directory structures corresponding to choices of parameters. Second, the nestrun script to run a given command using each set of parameter choices. Third, the nestagg script to aggregate results of the individual runs into a CSV file, as well as support for more complex aggregation. We also include a module for easily specifying nested dependencies for the SCons build tool, enabling incremental builds. AVAILABILITY: Source, documentation and tutorial examples are available at http://github.com/fhcrc/nestly. nestly can be installed from the Python Package Index via pip; it is open source (MIT license).

Reconciling taxonomy and phylogenetic inference: formalism and algorithms for describing discord and inferring taxonomic roots.

BACKGROUND: Although taxonomy is often used informally to evaluate the results of phylogenetic inference and the root of phylogenetic trees, algorithmic methods to do so are lacking. RESULTS: In this paper we formalize these procedures and develop algorithms to solve the relevant problems. In particular, we introduce a new algorithm that solves a "subcoloring" problem to express the difference between a taxonomy and a phylogeny at a given rank. This algorithm improves upon the current best algorithm in terms of asymptotic complexity for the parameter regime of interest; we also describe a branch-and-bound algorithm that saves orders of magnitude in computation on real data sets. We also develop a formalism and an algorithm for rooting phylogenetic trees according to a taxonomy. CONCLUSIONS: The algorithms in this paper, and the associated freely-available software, will help biologists better use and understand taxonomically labeled phylogenetic trees.

A format for phylogenetic placements.

We have developed a unified format for phylogenetic placements, that is, mappings of environmental sequence data (e.g., short reads) into a phylogenetic tree. We are motivated to do so by the growing number of tools for computing and post-processing phylogenetic placements, and the lack of an established standard for storing them. The format is lightweight, versatile, extensible, and is based on the JSON format, which can be parsed by most modern programming languages. Our format is already implemented in several tools for computing and post-processing parsimony- and likelihood-based phylogenetic placements and has worked well in practice. We believe that establishing a standard format for analyzing read placements at this early stage will lead to a more efficient development of powerful and portable post-analysis tools for the growing applications of phylogenetic placement.