MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

BACKGROUND: Pick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration. METHODS: In this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and ß coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype. FINDINGS: We obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (ß -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (ß 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (ß 2·66 [0·63 to 4·70], p=0·011), H1i (ß -3·66 [-6·83 to -0·48], p=0·025), and H1u (ß -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (ß -0·57 [-1·07 to -0·07], p=0·026). INTERPRETATION: The Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies. FUNDING: Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Comparison of Two Different Alfaxalone Concentrations Combined with Midazolam to Anesthetize Cynomolgus Macaques (Macaca fascicularis) for Plethysmography.

Plethysmography is employed in nonhuman primates (NHPs) to calculate respiratory minute volume and determine the exposure time required to deliver an aerosol at the target dose. Anesthetic drugs can impact breathing parameters like steady-state minute volume (SSMV) central to aerosol dosing. Alfaxalone-midazolam mixtures (AM) provide superior parameters for plethysmography in cynomolgus macaques. An obstacle to the use of AM is the volume required to anesthetize via intramuscular injection. A more concentrated formulation of alfaxalone will reduce injection volumes and refine AM protocols. The purpose of this study was to compare AM using the Indexed 10-mg/mL (AM10) formulation compared with an investigational 40-mg/mL (AM40) formulation for IM administration in cynomolgus macaques undergoing plethysmography. We hypothesized that AM10 and AM40 would show no difference in quality of anesthesia (QA), duration of anesthesia, SSMV, accumulated minute volume (AMV), and side effects. We also hypothesized that female macaques would have a longer duration of anesthesia compared with males using both formulations. The study used 15 cynomolgus macaques comprised of 8 females and 7 males. NHPs were compared between 2 separate and randomized anesthetic events no less than one week apart. Each animal served as its own control and animals were randomized by random number generation. Anesthetized NHPs were placed in a sealed plethysmography chamber, and minute volume measurements were calculated every 10 s to determine SSMV. Once SSMV was achieved for 20 min, the trial ended. There were no statistically significant differences between AM10 and AM40 for duration of anesthesia, SSMV, AMV, side effects, or QA. AM40 had a significantly smaller injection volume. Females did not show a significantly longer median duration of anesthesia using either of the alfaxalone formulations. Overall, AM40 offers a more humane anesthetic than AM10 for plethysmography in cynomolgus macaques.

Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.

Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes.

Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, ß, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, ß, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, ß, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and ß were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1ß1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1ß1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1ß1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1ß1γ4. Moreover, H1ß1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1ß1γ1 to 77% in H1ß1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.

Disentangling and quantifying the relative cognitive impact of concurrent mixed neurodegenerative pathologies.

Neurodegenerative pathologies such as Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and cerebrovascular disease (CVD) frequently coexist, but little is known about the exact contribution of each pathology to cognitive decline and dementia in subjects with mixed pathologies. We explored the relative cognitive impact of concurrent common and rare neurodegenerative pathologies employing multivariate logistic regression analysis adjusted for age, gender, and level of education. We analyzed a cohort of 6,262 subjects from the National Alzheimer's Coordinating Center database, ranging from 0 to 6 comorbid neuropathologic findings per individual, where 95.7% of individuals had at least 1 neurodegenerative finding at autopsy and 75.5% had at least 2 neurodegenerative findings. We identified which neuropathologic entities correlate most frequently with one another and demonstrated that the total number of pathologies per individual was directly correlated with cognitive performance as assessed by Clinical Dementia Rating (CDR®) and Mini-Mental State Examination (MMSE). We show that ADNC, LBD, LATE-NC, CVD, hippocampal sclerosis, Pick disease, and FTLD-TDP significantly impact overall cognition as independent variables. More specifically, ADNC significantly affected all assessed cognitive domains, LBD affected attention, processing speed, and language, LATE-NC primarily affected tests related to logical memory and language, while CVD and other less common pathologies (including Pick disease, progressive supranuclear palsy, and corticobasal degeneration) had more variable neurocognitive effects. Additionally, ADNC, LBD, and higher numbers of comorbid neuropathologies were associated with the presence of at least one APOE ε4 allele, and ADNC and higher numbers of neuropathologies were inversely correlated with APOE ε2 alleles. Understanding the mechanisms by which individual and concomitant neuropathologies affect cognition and the degree to which each contributes is an imperative step in the development of biomarkers and disease-modifying therapeutics, particularly as these medical interventions become more targeted and personalized.

[Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes]. / Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación.

This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Este consenso de nomenclatura y clasificación para la válvula aórtica bicúspide congénita y su aortopatía está basado en la evidencia y destinado a ser utilizado universalmente por médicos (tanto pediatras como de adultos), médicos ecocardiografistas, especialistas en imágenes avanzadas cardiovasculares, cardiólogos intervencionistas, cirujanos cardiovasculares, patólogos, genetistas e investigadores que abarcan estas áreas de investigación clínica y básica. Siempre y cuando se disponga de nueva investigación clave y de referencia, este consenso internacional puede estar sujeto a cambios de acuerdo con datos basados en la evidencia1.

Fleischner Society: Glossary of Terms for Thoracic Imaging.

Members of the Fleischner Society have compiled a glossary of terms for thoracic imaging that replaces previous glossaries published in 1984, 1996, and 2008, respectively. The impetus to update the previous version arose from multiple considerations. These include an awareness that new terms and concepts have emerged, others have become obsolete, and the usage of some terms has either changed or become inconsistent to a degree that warranted a new definition. This latest glossary is focused on terms of clinical importance and on those whose meaning may be perceived as vague or ambiguous. As with previous versions, the aim of the present glossary is to establish standardization of terminology for thoracic radiology and, thereby, to facilitate communications between radiologists and clinicians. Moreover, the present glossary aims to contribute to a more stringent use of terminology, increasingly required for structured reporting and accurate searches in large databases. Compared with the previous version, the number of images (chest radiography and CT) in the current version has substantially increased. The authors hope that this will enhance its educational and practical value. All definitions and images are hyperlinked throughout the text. Click on each figure callout to view corresponding image. © RSNA, 2024 Supplemental material is available for this article. See also the editorials by Bhalla and Powell in this issue.

Whole-Genome Sequencing Analysis Reveals New Susceptibility Loci and Structural Variants Associated with Progressive Supranuclear Palsy.

Background: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method: In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results: Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer's disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73×10-3) in PSP. Conclusions: Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Application of a U-Net Neural Network to the Puccinia sorghi-Maize Pathosystem.

Computer vision approaches to analyze plant disease data can be both faster and more reliable than traditional, manual methods. However, the requirement of manually annotating training data for the majority of machine learning applications can present a challenge for pipeline development. Here, we describe a machine learning approach to quantify Puccinia sorghi incidence on maize leaves utilizing U-Net convolutional neural network models. We analyzed several U-Net models with increasing amounts of training image data, either randomly chosen from a large data pool or randomly chosen from a subset of disease time course data. As the training dataset size increases, the models perform better, but the rate of performance decreases. Additionally, the use of a diverse training dataset can improve model performance and reduce the amount of annotated training data required for satisfactory performance. Models with as few as 48 whole-leaf training images are able to replicate the ground truth results within our testing dataset. The final model utilizing our entire training dataset performs similarly to our ground truth data, with an intersection over union value of 0.5002 and an F1 score of 0.6669. This work illustrates the capacity of U-Nets to accurately answer real-world plant pathology questions related to quantification and estimation of plant disease symptoms. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Paralabral Cyst of the Hip Causing Deep Vein Thrombosis Treated with Arthroscopic Decompression and Labral Repair.

In the setting of femoroacetabular impingement of the hip joint, paralabral cysts are well-documented sequelae. These cysts are typically associated with labral tears caused by CAM and/or pincer-type bony lesions. Synovial fluid extravasation through a tear in the labrum, similar to a popliteus cyst, leads to formation of a capsular-based cyst that is usually self-limiting. Few documented cases of these cysts causing compression of nearby neurovascular structures exist. There are several studies documenting arthroscopic decompression of these cysts, but none reporting compression of the femoral vein by a paralabral cyst resulting in deep vein thrombosis. We present the case of a large anterior paralabral cyst causing compression of the right femoral vein in a patient presenting with deep vein thrombosis and hip pain. Treatment consisted of arthroscopic decompression, followed by definitive aspiration by interventional radiology after labral repair and bipolar hip osteoplasty. The purpose of this case report was to document this rare presentation and offer learning points from our experience.

An update on the clinical pharmacology of kratom: uses, abuse potential, and future considerations.

INTRODUCTION: Kratom (Mitragyna speciosa) has generated substantial clinical and scientific interest as a complex natural product. Its predominant alkaloid mitragynine and several stereoisomers have been studied for activity in opioid, adrenergic, and serotonin receptors. While awaiting clinical trial results, the pre-clinical evidence suggests a range of potential therapeutic applications for kratom with careful consideration of potential adverse effects. AREAS COVERED: The focus of this review is on the pharmacology, pharmacokinetics, and potential drug-drug interactions of kratom and its individual alkaloids. A discussion on the clinical pharmacology and toxicology of kratom is followed by a summary of user surveys and the evolving concepts of tolerance, dependence, and withdrawal associated with kratom use disorder. EXPERT OPINION: With the increasing use of kratom in clinical practice, clinicians should be aware of the potential benefits and adverse effects associated with kratom. While many patients may benefit from kratom use with few or no reported adverse effects, escalating dose and increased use frequency raise the risk for toxic events in the setting of polysubstance use or development of a use disorder.

Tau seeding without tauopathy.

Neurodegenerative tauopathies such as Alzheimer's disease (AD) are caused by brain accumulation of tau assemblies. Evidence suggests tau functions as a prion, and cells and animals can efficiently propagate unique, transmissible tau pathologies. This suggests a dedicated cellular replication machinery, potentially reflecting a normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would contain seeding activity. We have recently developed a novel monoclonal antibody (MD3.1) specific for tau seeds. We used this antibody to immunopurify tau from the parietal and cerebellar cortices of 19 healthy subjects without any neuropathology, ranging 19 to 65 years. We detected seeding in lysates from the parietal cortex, but not in the cerebellum. We also detected no seeding in brain homogenates from wildtype or human tau knockin mice, suggesting that cellular/genetic context dictates development of seed-competent tau. Seeding did not correlate with subject age or brain tau levels. We confirmed our essential findings using an orthogonal assay, real-time quaking-induced conversion, which amplifies tau seeds in vitro. Dot blot analyses revealed no AT8 immunoreactivity above background levels in parietal and cerebellar extracts and ∼1/100 of that present in AD. Based on binding to a panel of antibodies, the conformational characteristics of control seeds differed from AD, suggesting a unique underlying assembly, or structural ensemble. Tau's ability to adopt self-replicating conformations under nonpathogenic conditions may reflect a normal function that goes awry in disease states.

Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy.

INTRODUCTION: Alzheimer's disease (AD) and primary age-related tauopathy (PART) both harbor 3R/4R hyperphosphorylated-tau (p-tau)-positive neurofibrillary tangles (NFTs) but differ in the spatial p-tau development in the hippocampus. METHODS: Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT-bearing and non-NFT-bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS: Proteomic measures of synaptic health were inversely correlated with the subregional p-tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aß) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION: These results suggest subfield-specific proteome differences that may explain some of the differences in Aß and p-tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aß in the pathologic process. HIGHLIGHTS: Synaptic health is inversely correlated with local p-tau burden. The proteome of NFT- and non-NFT-bearing neurons is influenced by the presence of Aß in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.

Metastatic Pulmonary Calcification: Single-Center Review of Typical and Atypical Imaging Features.

PURPOSE: The purpose of this study is to bring attention to an atypical form of metastatic pulmonary calcification, which is conventionally described as a metabolic process with upper lobe predominance in patients with a specific clinical history, which has not been reported as a distinct entity. METHODS: Patients with metastatic pulmonary calcification (MPC) were first identified with mPower keyword search, including MPC or metastatic calcifications on computed tomography chest radiological reports. Patients were then filtered on likelihood of MPC based off imaging reports. Images were then reviewed by three senior radiologists for pertinent characteristics such as location of MPC, degree of calcifications and pleural effusions. Based on the predominant location of MPC, cases were labeled as either typical or atypical. Clinical and imaging characteristics relevant to MPC were noted and compared across typical and atypical cases. RESULTS: In our study, we describe 25 patients with MPC, 13 defined as typical MPC and 12 with atypical MPC. Through consensus of senior radiologists, MPC was deemed to be mild (52%), moderate (44%), or severe (4%). Twenty-three patients (92%) had underlying renal disease including 21 requiring dialysis at the time of diagnosis. Outside of age at diagnosis, there was no significant clinical difference between the two groups. Evaluation of imaging characteristics (average HU attenuation, 267; range, 186-295), pattern and distribution of calcification, and clinical history strongly supported a diagnosis of atypical MPC. CONCLUSION: This study presents several cases of lower lobe subpleural MPC associated with pleural effusions, which has not been reported as a distinct entity, despite comprising a significant portion of MPC cases at our institution.

Incorrect recombination partner associations contribute to meiotic instability of neo-allopolyploid Arabidopsis suecica.

Combining two or more related homoeologous genomes in a single nucleus, newly formed allopolyploids must rapidly adapt meiosis to restore balanced chromosome segregation, production of euploid gametes and fertility. The poor fertility of such neo-allopolyploids thus strongly selects for the limitation or avoidance of genetic crossover formation between homoeologous chromosomes. In this study, we have reproduced the interspecific hybridization between Arabidopsis thaliana and Arabidopsis arenosa leading to the allotetraploid Arabidopsis suecica and have characterized the first allopolyploid meioses. First-generation neo-allopolyploid siblings vary considerably in fertility, meiotic behavior and levels of homoeologous recombination. We show that centromere dynamics at early meiosis is altered in synthetic neo-allopolyploids compared with evolved A. suecica, with a significant increase in homoeologous centromere interactions at zygotene. At metaphase I, the presence of multivalents involving homoeologous chromosomes confirms that homoeologous recombination occurs in the first-generation synthetic allopolyploid plants and this is associated with a significant reduction in homologous recombination, compared to evolved A. suecica. Together, these data strongly suggest that the fidelity of recombination partner choice, likely during the DNA invasion step, is strongly impaired during the first meiosis of neo-allopolyploids and requires subsequent adaptation.

A Single-Nucleus Transcriptome-Wide Association Study Implicates Novel Genes in Depression Pathogenesis.

BACKGROUND: Depression, a common psychiatric illness and global public health problem, remains poorly understood across different life stages, which hampers the development of novel treatments. METHODS: To identify new candidate genes for therapeutic development, we performed differential gene expression analysis of single-nucleus RNA sequencing data from the dorsolateral prefrontal cortex of older adults (n = 424) in relation to antemortem depressive symptoms. Additionally, we integrated genome-wide association study results for depression (n = 500,199) along with genetic tools for inferring the expression of 14,048 unique genes in 7 cell types and 52 cell subtypes to perform a transcriptome-wide association study of depression followed by Mendelian randomization. RESULTS: Our single-nucleus transcriptome-wide association study analysis identified 68 candidate genes for depression and showed the greatest number being in excitatory and inhibitory neurons. Of the 68 genes, 53 were novel compared to previous studies. Notably, gene expression in different neuronal subtypes had varying effects on depression risk. Traits with high genetic correlations with depression, such as neuroticism, shared more transcriptome-wide association study genes than traits that were not highly correlated with depression. Complementing these analyses, differential gene expression analysis across 52 neocortical cell subtypes showed that genes such as KCNN2, SCAI, WASF3, and SOCS6 were associated with late-life depressive symptoms in specific cell subtypes. CONCLUSIONS: These 2 sets of analyses illustrate the utility of large single-nucleus RNA sequencing data both to uncover genes whose expression is altered in specific cell subtypes in the context of depressive symptoms and to enhance the interpretation of well-powered genome-wide association studies so that we can prioritize specific susceptibility genes for further analysis and therapeutic development.

Defining the Cynomolgus Macaque (Macaca fascicularis) Animal Model for Aerosolized Venezuelan Equine Encephalitis: Importance of Challenge Dose and Viral Subtype.

Venezuelan equine encephalitis virus (VEEV) outbreaks occur sporadically. Additionally, VEEV has a history of development as a biothreat agent. Yet, no FDA-approved vaccine or therapeutic exists for VEEV disease. The sporadic outbreaks present a challenge for testing medical countermeasures (MCMs) in humans; therefore, well-defined animal models are needed for FDA Animal Rule licensure. The cynomolgus macaque (CM) model has been studied extensively at high challenge doses of the VEEV Trinidad donkey strain (>1.0 × 108 plaque-forming units [PFU]), doses that are too high to be a representative human dose. Based on viremia of two subtypes of VEEV, IC, and IAB, we found the CM infectious dose fifty (ID50) to be low, 12 PFU, and 6.7 PFU, respectively. Additionally, we characterized the pattern of three clinical parameters (viremia, temperature, and lymphopenia) across a range of doses to identify a challenge dose producing consistent signs of infection. Based on these studies, we propose a shift to using a lower challenge dose of 1.0 × 103 PFU in the aerosol CM model of VEEV disease. At this dose, NHPs had the highest viremia, demonstrated a fever response, and had a measurable reduction in complete lymphocyte counts-biomarkers that can demonstrate MCM efficacy.

Identification of Mitral Valve Prolapse on Non-electrocardiography-gated Enhanced Chest Computed Tomography.

PURPOSE: The primary imaging modality for the diagnosis of mitral valve prolapse (MVP) is echocardiography supplemented by electrocardiography (ECG)-gated cardiac computed tomography (CT) angiography. However, we have recently encountered patients with MVP who were initially identified on non-ECG-gated enhanced chest CT. The purpose of this study is to evaluate the diagnostic accuracy of non-ECG-gated enhanced chest CT to predict the presence of MVP. PATIENTS AND METHODS: Of 92 patients (surgically confirmed MVP who underwent non-ECG-gated chest CT), 27 patients were excluded for motion artifact or insufficient surgical correlation, and 65 patients were ultimately included. As a control, 65 patients with dyspnea and without MVP (non-ECG-gated chest CT and echocardiography were performed within 1 month) were randomly selected. We retrospectively analyzed an asymmetric double line sign on axial CT images for the presence of MVP. The asymmetric double line sign was defined as the presence of a linear structure, not located in the plane traversing the mitral annulus. RESULTS: Use of the asymmetric double line sign to predict MVP on non-ECG-gated CT showed modest sensitivity, high specificity, modest negative predictive value, and high positive predictive value of 59% (38/65), 99% (64/65), 70% (64/91), and 97% (38/39), respectively. CONCLUSION: The asymmetric double line sign on non-ECG-gated enhanced chest CT may be a valuable finding to predict the presence of MVP. Familiarity with this CT finding may lead to prompt diagnosis and proper management of MVP.

Histopathologic brain age estimation via multiple instance learning.

Understanding age acceleration, the discordance between biological and chronological age, in the brain can reveal mechanistic insights into normal physiology as well as elucidate pathological determinants of age-related functional decline and identify early disease changes in the context of Alzheimer's and other disorders. Histopathological whole slide images provide a wealth of pathologic data on the cellular level that can be leveraged to build deep learning models to assess age acceleration. Here, we used a collection of digitized human post-mortem hippocampal sections to develop a histological brain age estimation model. Our model predicted brain age within a mean absolute error of 5.45 ± 0.22 years, with attention weights corresponding to neuroanatomical regions vulnerable to age-related changes. We found that histopathologic brain age acceleration had significant associations with clinical and pathologic outcomes that were not found with epigenetic based measures. Our results indicate that histopathologic brain age is a powerful, independent metric for understanding factors that contribute to brain aging.

Lung-Reporting and Data System 2.0: Impact of the Updated Approach to Juxtapleural Nodules During Lung Cancer Screening Using the National Lung Cancer Screening Trial Data Set.

PURPOSE: To determine the frequency of malignancy of nonperifissural juxtapleural nodules (JPNs) measuring 6 to < 10 mm in a subset of low-dose chest computed tomographies from the National Lung Cancer Screening Trial and the rate of down-classification of such nodules in Lung-Reporting and Data System (RADS) 2.0 compared with Lung-RADS 1.1. MATERIALS AND METHODS: A secondary analysis of a subset of the National Lung Screening Trial was performed. An exemption was granted by the Institutional Review Board. The dominant noncalcified nodule measuring 6 to <10 mm was identified on all available prevalence computed tomographies. Nodules were categorized as pleural or nonpleural. Benign or malignant morphology was recorded. Initial and updated categories based on Lung-RADS 1.1 and Lung-RADS 2.0 were assigned, respectively. The impact of the down-classification of JPN was assessed. Both classification schemes were compared using the McNemar test (P < 0.01). RESULTS: A total of 2813 patients (62 ± 5 y, 1717 men) with 4408 noncalcified nodules were studied. One thousand seventy-three dominant nodules measuring 6 to <10 mm were identified. Three hundred forty-eight (32.4%) were JPN. The updated scheme allowed down-classification of 310 JPN from categories 3 (n = 198) and 4A (n = 112) to category 2. We, therefore, estimate a 4.8% rate of down-classification to category 2 in the entire National Lung Screening Trial screening group. Two/348 (0.57%) JPN were malignant, both nonbenign in morphology. The false-positive rate decreased in the updated classification (P < 0.01). CONCLUSION: This study demonstrates the low malignant potential of benign morphology JPN measuring 6 mm to <10 mm. The Lung-RADS 2.0 approach to JPN is estimated to reduce short-term follow-ups and false-positive results.