Evidence-based procedures to improve the reliability of circulating miRNA biomarker assays.

Circulating cell-free microRNAs (cfmiRNA) are an emerging class of biomarkers that have shown great promise in the clinical diagnosis, treatment, and monitoring of several pathological conditions, including cancer. However, validation and clinical implementation of cfmiRNA biomarkers has been hindered by the variability introduced during different or suboptimal specimen collection and handling practices. To address the need for standardization and evidence-based guidance, the National Cancer Institute (NCI) developed a new Biospecimen Evidenced-Based Practices (BEBP) document, entitled "Cell-free miRNA (cfmiRNA): Blood Collection and Processing". The BEBP, the fourth in the document series, contains step-by-step procedural guidelines on blood collection, processing, storage, extraction, and quality assessment that are tailored specifically for cfmiRNA analysis of plasma and serum. The workflow outlined in the BEBP is based on the available literature and recommendations of an expert panel. The BEBP contains the level of detail required for development of evidence-based standard operating procedures (SOPs) as well as the flexibility needed to accomodate (i) discovery- and inquiry-based studies and (ii) the different constraints faced by research labs, industry, clinical and academic institutions to foster widespread implementation. Guidance from the expert panel also included recommendations on study design, validating changes in workflow, and suggested quality thresholds to delineate meaningful changes in cfmiRNA levels. The NCI cfmiRNA: Blood Collection and Processing BEBP is available here as supplementary information as well as through the NCI Biorepositories and Biospecimen Research Branch (BBRB) (https://biospecimens.cancer.gov/resources/bebp.asp).

Epidermal nevi and epidermolytic hyperkeratosis: A review of cases, highlighting indications for biopsy and genetics referral.

Epidermal nevi are common benign cutaneous hamartomas that may rarely demonstrate histopathologic evidence of epidermolytic hyperkeratosis (EHK), representing cutaneous mosaicism for pathogenic keratin variants. Rarely, individuals with linear epidermal nevi transmit to their children the inherited form of EHK, also known as epidermolytic ichthyosis, characterized by generalized erythema, blistering, and scaling at birth evolving to widespread hyperkeratosis. We present an updated review of reported cases of linear epidermal nevi with EHK exhibiting transmission of epidermolytic ichthyosis to guide important considerations in the care of individuals with epidermal nevi. Clinical characteristics of linear epidermal nevi do not reliably predict the presence of EHK. All reported cases of transmission to offspring have occurred in individuals with linear epidermal nevi involving more than one anatomic area suggesting increased reproductive risk with involvement of two or more anatomic sites. Therefore, genetics consultation is recommended for these individuals with biopsy-confirmed EHK. For individuals with smaller areas of epidermal nevus involvement, the implications are less well known, though genetics consultation may still be considered for those interested in further discussion of general reproductive risk.

Screening, Brief Intervention, and Referral to Treatment Plus (SBIRT-Plus): A Novel Interprofessional Training for Rehabilitation Science Professional Students.

IMPORTANCE: With the increasing amount of substance use-related health conditions in the United States, it is important for rehabilitation science professionals to receive screening and prevention training. OBJECTIVE: To describe and examine the preliminary effectiveness of a novel educational program, Screening, Brief Intervention, and Referral to Treatment Plus (SBIRT-Plus), that combines traditional SBIRT training with new modules for cannabis, stimulant, and opioid use. DESIGN: Prospective, cohort design. SETTING: Academic institution. PARTICIPANTS: One hundred eighty-one rehabilitation science graduate students. INTERVENTION: SBIRT-Plus curriculum. OUTCOMES AND MEASURES: Outcomes included satisfaction with training, perception of interprofessional training, attitudes, knowledge, and stigma, as assessed with the Readiness for Interprofessional Learning Scale, Alcohol and Alcohol Problems Perception Questionnaire, Drug and Drug Problems Perception Questionnaire, Knowledge Screening Scale, and two stigma instruments. RESULTS: Most students (>80%) expressed satisfaction with their training, would recommend the training to a colleague, and believed that the training would influence and change the way they practiced with patients at risk for substance use disorders. Students' attitudes and knowledge increased from pre- to post-training, and stigma perceptions were significantly reduced. CONCLUSIONS AND RELEVANCE: SBIRT-Plus is an evidence-based interprofessional training that is feasible to implement in graduate-level education programs. Integrating SBIRT-Plus into professional graduate programs may be an optimal and low-cost model for training rehabilitation health care professionals. Plain-Language Summary: Screening, Brief Intervention, and Referral to Treatment Plus (SBIRT-Plus) is an evidence-based interprofessional training that can be easily adopted in curricula to train professional students about the importance of screening for substance use disorders.

Reclassification of Cybistrinae Sharp, 1880 in the Neotropical Region (Coleoptera, Adephaga, Dytiscidae), with description of new taxa.

The classification of the Neotropical Cybistrinae Sharp, 1880 (Coleoptera: Adephaga: Dytiscidae) is extensively revised based on a phylogenetic analysis of morphological features of the group. A new genus, Nilssondytesgen. nov. is described for a unique new species, Nilssondytesdiversussp. nov. from Venezuela. The New World genus, Megadytes Sharp, 1882, with several subgenera, was found to not be monophyletic. The type species of Megadytes, Dytiscuslatus Fabricius, 1801 and the species Cybisterparvus Trémouilles, 1984 were found to be monophyletic together, and phylogenetically more closely related to Cybister Curtis, 1827 than to other species assigned to Megadytes sensu stricto, which were found to also be monophyletic. The name Megadytes is here restricted to include only Megadyteslatus and Megadytesparvus. These two species assigned to this newly restricted genus concept are reviewed and diagnosed. A new genus, Metaxydytesgen. nov., is erected to include all the other species currently assigned to Megadytes sensu stricto. The current subgenus names assigned to Megadytes, Bifurcitus Brinck, 1945, Paramegadytes Trémouilles & Bachmann, 1980, and Trifurcitus Brinck, 1945, are elevated to genus rank since they are variously paraphyletic. The two species assigned to Cybister (Neocybister) Miller, Bergsten & Whiting, 2007, Cybister (Neocybister) festae Griffini, 1895, and Cybister (Neocybister) puncticollis (Brullé, 1837) re reviewed and diagnosed with the former redescribed and its type specimens considered for the first time since its description. Another evidently new species and possible new genus, Megadytes species, IR57 (Ribera et al. 2008), from Peru, is also characterized, but not formally treated because of lack of important data for the single, partial specimen. Diagnostic features are illustrated for the entire group.

ResumenLa clasificación de Cybistrinae Sharp, 1880 neotropicales (Coleoptera: Adephaga: Dytiscidae) se revisa ampliamente con base en un análisis filogenético de características morfológicas del grupo. Un nuevo género, Nilssondytesgen. nov. se describe para la única nueva especie Nilssondytesdiversussp. nov. de Venezuela. Se encontró que el género, Megadytes Sharp, 1882, del Nuevo Mundo y con varios subgéneros, no es monofilético. Se encontró que la especie tipo de Megadytes, Dytiscuslatus Fabricius, 1801 y la especie Cybisterparvus Trémouilles, 1984 forman un grupo monofilético y filogenéticamente más estrechamente relacionado con Cybister Curtis, 1827 que con otras especies asignadas a Megadytes sensu stricto, que se encontró que también forman un grupo monofilético. El nombre Megadytes se restringe aquí para incluir solo a Megadyteslatus y Megadytesparvus. Se revisan y diagnostican estas dos especies asignadas a este nuevo concepto restringido del género. Un nuevo nombre, Metaxydytesgen. nov., se erige para incluir a todas las demás especies actualmente asignadas a Megadytes sensu stricto. Los nombres subgenéricos actuales asignados a Megadytes, Bifurcitus Brinck, 1945, Paramegadytes Trémouilles y Bachmann, 1980 y Trifurcitus Brinck, 1945, se elevan al rango de género, nuevo estado, ya que son parafiléticos de diversas formas. Se revisan y diagnostican las dos especies asignadas a Cybister (Neocybister) Miller, Bergsten y Whiting, 2007, Cybister (Neocybister) festae Griffini, 1895 y Cybister (Neocybister) puncticollis, redescribiendo la primera y considerando sus especímenes tipo por primera vez desde su descripción. Otra especie evidentemente nueva y posible nuevo género, Megadytes, IR57 (Ribera et al. 2008), de Perú, también se caracteriza, pero no se trata formalmente debido a la falta de datos importantes para el único espécimen parcial. Las características diagnósticas se ilustran para todo el grupo.

Psychological distress among Canadian postsecondary students: a repeated cross-sectional analysis of the Canadian Campus Wellbeing Survey (CCWS) between spring 2020-2023.

Objective: To examine trends in self-reported psychological distress among Canadian postsecondary students between 2020 and 2023. Participants and Methods: Using data collected from postsecondary students (n = 103,936) through the Canadian Campus Wellbeing Survey (CCWS), multilevel regression models were fitted to determine how distress levels, as measured by the Kessler Psychological Distress Scale, differed across six-time points of the CCWS. Results: Across the cycles, students reported high levels of distress (mean across cycles = 26.16, SD = 8.61). Considering the impact of time on distress, when compared to pre-COVID-19 pandemic, Fall 2020 (ß = 1.4, p < .001), Spring 2021 (ß = 1.2, p < .001), Spring 2022 (ß = 1.6, p < .001), and Spring 2023 (ß = 0.80, p < .017) had significantly higher levels of distress. Distress levels were associated with ancestry, age, gender, and sexual orientation. Conclusion: It is imperative to develop strategies and allocate resources to address the high levels of psychological distress among Canadian postsecondary students.

Strontium isotopes in the atmosphere, geosphere and hydrosphere: Developing a systematic "fingerprinting" framework of rocks and water in sedimentary basins in eastern Australia.

Understanding the connection between aquifers, aquitards, and groundwater-dependant ecosystems remains a key challenge when developing a conceptual hydrogeological model. The aim of this study was to develop a systematic strontium isotope (87Sr/86Sr) fingerprinting framework of rocks and water within the sedimentary Surat and Clarence-Moreton basins (SCM basins) in eastern Australia - an area of extensive coal seam gas development and high potential for aquifer and groundwater-surface water connectivity. To do this, new groundwater samples (n = 298) were collected, analyzed and integrated with published data (n = 154) from the basins' major sedimentary, volcanic and alluvial aquifers, including the major coal seam gas target, the Walloon Coal Measures. Samples were also analyzed from rainfall (n = 2) and surface water (n = 40). In addition, rock core samples (n = 39) from exploration and stratigraphic wells were analyzed to determine the range of Sr isotope composition from host rocks. The analyses of cores demonstrate a distinct and systematic contrast in 87Sr/86Sr between different hydrogeological units. The analyses confirm that all major hydrogeological units have a narrow range with unique 87Sr/86Sr population characteristics that are useful for guiding conceptual model development. Comparison with selected hydrochemical and groundwater age tracers (14C and 36Cl) suggests only limited changes of 87Sr/86Sr from recharge beds to the deeper parts of the basins or with a decrease in natural 14C and 36Cl tracer content along flow paths. Stream sampling during baseflow conditions confirms that 87Sr/86Sr in surface waters are similar to those of the underlying bedrock formations. We demonstrated that 87Sr/86Sr analyses of rocks and water provide a powerful hydrostratigraphic and chemostratigraphic fingerprinting framework in the SCM basins, enabling reliable assessments of plausible aquifer and groundwater-surface water interconnectivity pathways. Applied in other complex multi-aquifer sedimentary basins in Australia, and globally, a similar approach can help to constrain conceptual hydrogeological models and facilitate improved water resource management.

Examining the correlates of cigarette smoking, e-cigarette use and dual use among Canadian post-secondary students.

Many Canadians use nicotine products such as cigarettes and e-cigarettes. A particular subpopulation of concern is post-secondary students given they have a higher prevalence of use. Many correlates of cigarette smoking and e-cigarette use have been identified. However, less focus has been on examining the correlates of cigarette smoking, e-cigarette use and dual use. This study explores the correlates of different nicotine modality use in post-secondary students. Using data from the Canadian Campus Wellbeing Survey (CCWS; n = 27,164), a multi-level nominal regression assessed the correlates of nicotine modality use. In comparison to individuals who were <20, individuals 20-24 (OR = .448, 95% CI .321, .625), 25-29 (OR = .140, 95% CI .093, .212), 30-34 (OR = .076, 95% CI .046, .125) and over 35 (OR = .041, 95% CI .024, .071) had lower odds of e-cigarette use compared to cigarette smoking. Identifying as a woman (OR = 1.553, 95% CI 1.202, 2.006), non-heterosexual (OR = .642, 95% CI = .485,0.851), current cannabis user (OR = 1.651, 95% CI 1.296, 2.104), and being an international student (OR = .350, 95% CI .251, .487) also impacted the odds of e-cigarette use vs only cigarette smoking. When considering dual use vs cigarette smoking, individuals aged 20-24 (OR = .491, 95% CI .337, .717), 25-29 (OR = .221, 95% CI .137, .357), 30-34 (OR = .163, 95% CI .091, .292) and over 35 (OR = .122, 95% CI .065, .230) had lower odds than individuals <20. Current cannabis use (OR = 1.680, 95% CI = 1.209, 2.138), binge drinking (OR = 1.885, 95% CI 1.384, 2.568), and international student status (OR = .689, 95% CI .476, .996) also impacted cigarette smoking vs dual-use. Overall, a minority of young adults (11.5%) at post-secondary institutions in our sample use nicotine products, and the higher prevalence of e-cigarette use warrants continued monitoring. Health promotion campaigns addressing e-cigarette use are required. Additionally, tailored intervention efforts could prioritize the treatment needs of international students studying in Canada.

RGS10 mitigates high glucose-induced microglial inflammation via the reactive oxidative stress pathway and enhances synuclein clearance in microglia.

Microglia play a critical role in maintaining brain homeostasis but become dysregulated in neurodegenerative diseases. Regulator of G-protein Signaling 10 (RGS10), one of the most abundant homeostasis proteins in microglia, decreases with aging and functions as a negative regulator of microglia activation. RGS10-deficient mice exhibit impaired glucose tolerance, and high-fat diet induces insulin resistance in these mice. In this study, we investigated whether RGS10 modulates microglia activation in response to hyperglycemic conditions, complementing our previous findings of its role in inflammatory stimuli. In RGS10 knockdown (KD) BV2 cells, TNF production increased significantly in response to high glucose, particularly under proinflammatory conditions. Additionally, glucose uptake and GLUT1 mRNA levels were significantly elevated in RGS10 KD BV2 cells. These cells produced higher ROS and displayed reduced sensitivity to the antioxidant N-Acetyl Cysteine (NAC) when exposed to high glucose. Notably, both BV2 cells and primary microglia that lack RGS10 exhibited impaired uptake of alpha-synuclein aggregates. These findings suggest that RGS10 acts as a negative regulator of microglia activation not only in response to inflammation but also under hyperglycemic conditions.

Hemostatic Efficacy and Safety of Weight-Based Versus Fixed-Dose 4F-PCC for Vitamin K Antagonist Reversal.

Background: Four-factor prothrombin complex concentrate (4F-PCC) is indicated for vitamin K antagonist (VKA) reversal but is associated with thrombotic events (TE). In 2018, the institution revised 4F-PCC dosing for VKA reversal from INR and weight-based dosing to a fixed-dose of 1500 units. Objective: The purpose of this study was to compare hemostatic efficacy and TE rate of fixed-dose 4PCC to weight-based dosing. Methods: This was a retrospective, single-center, quasi-experimental study of adult patients who received 4F-PCC for VKA reversal from January 2014 through May 2016 (INR and weight-based dosing) or April through October 2018 (fixed-dosing). The primary endpoint was hemostatic efficacy, defined by achieving an INR of ≤1.4, or an INR of ≤1.7 with evidence of hemostasis. The key secondary endpoint was TE within 14 days of 4F-PCC administration. Data were analyzed using descriptive statistics, chi-squared for nominal data and Mann-Whitney U for ordinal and continuous data. Results: The study included 163 patients who received weight-based dosing and 45 who received fixed-dose 4F-PCC. Hemostatic efficacy was 76.9% of patients in the weight-based group and 77.4% of patients in the fixed-dose group (P = .229). TE occurred in 13.5% of the weight-based vs 6.7% of the fixed-dose group (P = .181). Conclusion: This study found no difference in hemostatic efficacy with fixed-dose 4F-PCC for VKA reversal compared to INR and weight-based dosing. The occurrence of TE was reduced by 50% with the 4F-PCC fixed-dose strategy; however, this difference was not statistically significant. Further randomized studies are needed to confirm these results.

Correlates of Quality of Life in Autistic Individuals.

Background: Quality of life is an important outcome to autistic individuals. However, the correlates of quality of life in this population are not well known. The purpose of this project was to investigate the extent to which employment, depression, anxiety, and social participation were associated with quality of life in autistic individuals. We also explored potential associations between emotion dysregulation and quality of life. Method: Baseline data from two randomized control trials were used for analysis. A total of 125 autistic adolescents and adults aged 16-45 (M = 25.40) participated. Linear regression models were constructed to investigate whether employment, depression, anxiety, and social participation were associated with five domains of quality of life: overall, physical health, psychological, social relationships, and environment. Additional linear regression models explored whether emotion dysregulation was associated with the same quality of life domains. Results: Surprisingly, employment was not significantly associated with any quality of life domain. Greater depression severity was significantly associated with poorer quality of life across all domains. Greater social participation was associated with better quality of life, but only for individuals with lower anxiety. More severe dysphoria was associated with poorer overall quality of life and the psychological and physical health domains. Conclusions: Results suggest that mental health and emotion dysregulation are important predictors of quality of life for autistic people. They also suggest that anxiety symptoms may attenuate the beneficial effects of social participation. This study provides insight into the unique experiences of autistic individuals and highlights potential unmet need.

Helping Practitioners Stop, Drop, and Roll: Suggestions to Help Improve Responses to Intense Clinical Events.

Community practitioners inconsistently implement evidence-based interventions. Implementation science emphasizes the importance of some practitioner characteristics, such as motivation, but factors such as practitioners' emotion regulation and cognitive processing receive less attention. Practitioners often operate in stressful environments that differ from those in which they received training. They may underestimate the impact of their emotional state on their ability to deliver evidence-based interventions. This "hot-cold state empathy gap" is not well studied in mental health care. In this Open Forum, the authors describe scenarios where this gap is affecting practitioners' ability to implement evidence-based practices. The authors provide suggestions to help practitioners plan for stressful situations.

Notable Histologic Findings in a "Normal" Cohort: The National Institutes of Health Genotype-Tissue Expression (GTEx) Project

CONTEXT.­: The National Institutes of Health (NIH) Genotype-Tissue Expression (GTEx) project was designed to evaluate how genetic variation and epigenetic effects influence gene expression in normal tissue. OBJECTIVE.­: To ensure that the grossly normal-appearing tissues collected were free from disease, each specimen underwent histologic evaluation. DESIGN.­: In total, nearly 30 000 tissue aliquots collected from almost 1000 postmortem donors underwent histologic review by project pathologists, and detailed observations of any abnormalities or lesions present were recorded. RESULTS.­: Despite sampling of normal-appearing tissue, in-depth review revealed incidental findings among GTEx samples that included neoplastic, autoimmune, and genetic conditions; the incidence of some of these conditions among GTEx donors differed from those previously reported for other populations. A number of age-related abnormalities observed during histologic review of tissue specimens are also described. CONCLUSIONS.­: Histologic findings from the GTEx project may serve to improve populational awareness of several conditions and present a unique opportunity for others to explore age- and gender-influenced conditions. Resources from the study, including histologic image and sequencing data, are publicly available for research.

A retrospective cohort study of genetic referral and diagnosis of Birt-Hogg-Dubé Syndrome in patients with Trichodiscoma and Fibrofolliculoma skin lesions.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a genetic condition caused by pathogenic variants in the FLCN gene resulting in benign skin lesions, spontaneous pneumothorax, and increased risk for a variety of renal tumors. Skin manifestations of BHD include trichodiscoma (TD) and fibrofolliculoma (FF), which may represent the same pathologic entity. These lesions can identify BHD patients, who upon positive genetic testing can be considered for life-long surveillance for renal neoplasms. OBJECTIVE: To characterize patients diagnosed with TD and FF including rates and outcomes of genetics referral. METHODS: Retrospective chart reviews of patients with confirmed or possible diagnosis of TD or FF at the University of Michigan from September 2002 through October 2020 to assess pathologic findings, personal and family history of BHD manifestations, referral for genetic evaluation, and genetic testing results. RESULTS: 64 patients had a pathologic diagnosis of TD or FF, 16 of whom (25%) were referred to cancer genetics. Fourteen patients completed genetic evaluation, 9 of whom were diagnosed with BHD (64%), with 6 unique pathogenic variants in FLCN. CONCLUSION: Providers should consider referral for genetic evaluation for patients with biopsy-proven TD or FF, as early diagnosis of BHD provides the opportunity for early detection and treatment of other BHD-associated conditions.

Language-discordant care in pediatric neurosurgery: parent and provider perspectives on challenges and multilevel solutions to reduce disparities.

OBJECTIVE: In the United States, Spanish is the second most spoken language, with nearly 42 million individuals speaking Spanish at home. Spanish speakers have been noted to have higher rates of unfavorable neurosurgical outcomes; however, to the authors' knowledge, no study has explored the experiences of patients, caregivers, and providers receiving or delivering neurosurgical care in language-discordant settings. In this study, the authors sought to identify challenges faced by pediatric neurosurgery providers and Spanish-speaking parents communicating with a language barrier and propose solutions to address those challenges. METHODS: Spanish-speaking parents and pediatric neurosurgery providers were invited to participate in semistructured interviews. Purposeful sampling was used to recruit Spanish-speaking parents whose child had recently undergone neurological surgery at the authors' institution and to identify pediatric neurosurgery clinical team members to interview, including physicians, advanced practice providers, and interpreters. Codes were inductively developed and applied to transcripts by two researchers. Thematic analysis was conducted to identify challenges faced by parents and providers. RESULTS: Twenty individuals were interviewed, including parents (n = 8), advanced practice providers (n = 5), physicians (n = 3), interpreters (n = 2), a social worker (n = 1), and a nurse (n = 1). Three challenges were identified. 1) Compared with English-speaking parents, providers noted that Spanish-speaking parents were less likely to ask questions or raise new concerns. Concurrently, Spanish-speaking parents expressed a desire to better understand their child's future medical needs, care, and development. 2) There is a dearth of high-quality resources available in the Spanish language to supplement patient and parent neurosurgical education. 3) Both parents and providers invariably prefer in-person interpreters; however, their availability is limited. CONCLUSIONS: Three challenges were identified by Spanish-speaking parents of pediatric neurosurgery patients and providers when receiving or delivering care through a language barrier. The authors discuss multilevel solutions that, if deployed, could directly address these shared challenges. Furthermore, optimizing communication may help mitigate the disparities experienced by non-English-speaking Hispanic/Latino individuals when receiving neurosurgical care.

Distinctive CD56dim NK subset profiles and increased NKG2D expression in blood NK cells of Parkinson's disease patients.

Mounting data suggest an important role for the immune system in Parkinson's disease (PD). Previous evidence of increased natural killer (NK) cell populations in PD suggests a potential role of NK cells in the pathogenesis of the disease. Previous studies have analyzed NK cell populations using aggregation by variable expression of CD56 and CD16. It remains unknown what differences may exist between NK cell subpopulations when stratified using more nuanced classification. Here, we profile NK cell subpopulations and elucidate the expressions of activating, NKG2D, inhibitory, NKG2A, and homing, CX3CR1, receptors on NK cell subpopulations in PD and healthy controls (HC). We analyzed cryopreserved PMBC samples using a 10-color flow cytometry panel to evaluate NK cell subpopulations in 31 individuals with sporadic PD and 27 HC participants. Here we identified significant differences in the CD56dim NK subset that changes with disease severity in PD. Furthermore, the expressions of NKG2D in all three NK cell subsets were significantly elevated in PD patients compared to HC. Notably, NKG2A expression in the CD56bright NK subset increased in PD patients with longer disease duration but there were no changes in CX3CR1. In summary, our data suggests that changes in NK cells may be influenced by the clinical severity and duration of PD.

Developing a Measure of Key Adult Outcomes in Adults with Developmental Disabilities: Conceptual Model and Item Generation of the REALS (Relationships, Employment, Autonomy, and Life Satisfaction).

Employment, social relationships, and autonomy are priorities to people with intellectual and developmental disabilities (IDDs). However, few validated measures exist to systematically assess these key adult outcomes in this population. This research includes first steps to develop self- and proxy report measures of life outcomes for adults with IDDs-the Relationships, Employment, Autonomy, and Life Satisfaction (REALS). A literature search identified existing adult outcome measures, and comparison of their domains informed initial conceptual model development. External consultants revised the model, and items were generated. Autistic adults (n = 15), adults with other IDDs (n = 7), caregivers of autistic adults (n = 13), and caregivers of adults with other IDDs (n = 10) completed in-depth cognitive interviews to assess comprehension of items and response categories, factors influencing how participants respond to items, and the inclusiveness of the item pool. A final conceptual model was generated with three subdomains (social relationships, employment, and autonomy), including assessment of life satisfaction within each domain. Cognitive interviews revealed that response set restructuring and item-level revisions were needed to capture the complexity of adult life and make the measure more accessible across a range of abilities. This study developed a conceptual model of relationships, work, and autonomy specific to adults with IDDs. Future work will involve collecting data from 800 + self-reporters with IDDs and 800 + caregivers of adults with IDDs to conduct psychometric analyses. Improving measurement in this area is critical to better understanding the needs of adults with IDDs and improving services available to them.

Automated intracranial vessel segmentation of 4D flow MRI data in patients with atherosclerotic stenosis using a convolutional neural network.

Introduction: Intracranial 4D flow MRI enables quantitative assessment of hemodynamics in patients with intracranial atherosclerotic disease (ICAD). However, quantitative assessments are still challenging due to the time-consuming vessel segmentation, especially in the presence of stenoses, which can often result in user variability. To improve the reproducibility and robustness as well as to accelerate data analysis, we developed an accurate, fully automated segmentation for stenosed intracranial vessels using deep learning. Methods: 154 dual-VENC 4D flow MRI scans (68 ICAD patients with stenosis, 86 healthy controls) were retrospectively selected. Manual segmentations were used as ground truth for training. For automated segmentation, deep learning was performed using a 3D U-Net. 20 randomly selected cases (10 controls, 10 patients) were separated and solely used for testing. Cross-sectional areas and flow parameters were determined in the Circle of Willis (CoW) and the sinuses. Furthermore, the flow conservation error was calculated. For statistical comparisons, Dice scores (DS), Hausdorff distance (HD), average symmetrical surface distance (ASSD), Bland-Altman analyses, and interclass correlations were computed using the manual segmentations from two independent observers as reference. Finally, three stenosis cases were analyzed in more detail by comparing the 4D flow-based segmentations with segmentations from black blood vessel wall imaging (VWI). Results: Training of the network took approximately 10 h and the average automated segmentation time was 2.2 ± 1.0 s. No significant differences in segmentation performance relative to two independent observers were observed. For the controls, mean DS was 0.85 ± 0.03 for the CoW and 0.86 ± 0.06 for the sinuses. Mean HD was 7.2 ± 1.5 mm (CoW) and 6.6 ± 3.7 mm (sinuses). Mean ASSD was 0.15 ± 0.04 mm (CoW) and 0.22 ± 0.17 mm (sinuses). For the patients, the mean DS was 0.85 ± 0.04 (CoW) and 0.82 ± 0.07 (sinuses), the HD was 8.4 ± 3.1 mm (CoW) and 5.7 ± 1.9 mm (sinuses) and the mean ASSD was 0.22 ± 0.10 mm (CoW) and 0.22 ± 0.11 mm (sinuses). Small bias and limits of agreement were observed in both cohorts for the flow parameters. The assessment of the cross-sectional lumen areas in stenosed vessels revealed very good agreement (ICC: 0.93) with the VWI segmentation but a consistent overestimation (bias ± LOA: 28.1 ± 13.9%). Discussion: Deep learning was successfully applied for fully automated segmentation of stenosed intracranial vasculatures using 4D flow MRI data. The statistical analysis of segmentation and flow metrics demonstrated very good agreement between the CNN and manual segmentation and good performance in stenosed vessels. To further improve the performance and generalization, more ICAD segmentations as well as other intracranial vascular pathologies will be considered in the future.

Histologic and Quality Assessment of Genotype-Tissue Expression (GTEx) Research Samples: A Large Postmortem Tissue Collection.

CONTEXT.­: The National Institutes of Health Genotype-Tissue Expression (GTEx) project was developed to elucidate how genetic variation influences gene expression in multiple normal tissues procured from postmortem donors. OBJECTIVE.­: To provide critical insight into a biospecimen's suitability for subsequent analysis, each biospecimen underwent quality assessment measures that included evaluation for underlying disease and potential effects introduced by preanalytic factors. DESIGN.­: Electronic images of each tissue collected from nearly 1000 postmortem donors were evaluated by board-certified pathologists for the extent of autolysis, tissue purity, and the type and abundance of any extraneous tissue. Tissue-specific differences in the severity of autolysis and RNA integrity were evaluated, as were potential relationships between these markers and the duration of postmortem interval and rapidity of death. RESULTS.­: Tissue-specific challenges in the procurement and preservation of the nearly 30 000 tissue specimens collected during the GTEx project are summarized. Differences in the degree of autolysis and RNA integrity number were observed among the 40 tissue types evaluated, and tissue-specific susceptibilities to the duration of postmortem interval and rapidity of death were observed. CONCLUSIONS.­: Ninety-five percent of tissues were of sufficient quality to support RNA sequencing analysis. Biospecimens, annotated whole slide images, de-identified clinical data, and genomic data generated for GTEx represent a high-quality and comprehensive resource for the scientific community that has contributed to its use in approximately 1695 articles. Biospecimens and data collected under the GTEx project are available via the GTEx portal and authorized access to the Database of Genotypes and Phenotypes; procedures and whole slide images are available from the National Cancer Institute.

Dynamic and prognostic proteomic associations with FEV1 decline in chronic obstructive pulmonary disease.

Rationale: Identification and validation of circulating biomarkers for lung function decline in COPD remains an unmet need. Objective: Identify prognostic and dynamic plasma protein biomarkers of COPD progression. Methods: We measured plasma proteins using SomaScan from two COPD-enriched cohorts, the Subpopulations and Intermediate Outcomes Measures in COPD Study (SPIROMICS) and Genetic Epidemiology of COPD (COPDGene), and one population-based cohort, Multi-Ethnic Study of Atherosclerosis (MESA) Lung. Using SPIROMICS as a discovery cohort, linear mixed models identified baseline proteins that predicted future change in FEV1 (prognostic model) and proteins whose expression changed with change in lung function (dynamic model). Findings were replicated in COPDGene and MESA-Lung. Using the COPD-enriched cohorts, Gene Set Enrichment Analysis (GSEA) identified proteins shared between COPDGene and SPIROMICS. Metascape identified significant associated pathways. Measurements and Main Results: The prognostic model found 7 significant proteins in common (p < 0.05) among all 3 cohorts. After applying false discovery rate (adjusted p < 0.2), leptin remained significant in all three cohorts and growth hormone receptor remained significant in the two COPD cohorts. Elevated baseline levels of leptin and growth hormone receptor were associated with slower rate of decline in FEV1. Twelve proteins were nominally but not FDR significant in the dynamic model and all were distinct from the prognostic model. Metascape identified several immune related pathways unique to prognostic and dynamic proteins. Conclusion: We identified leptin as the most reproducible COPD progression biomarker. The difference between prognostic and dynamic proteins suggests disease activity signatures may be different from prognosis signatures.

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.