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Comment on: Robotic retrohepatic inferior vena cava thrombectomy using the caudate lobectomy technique: indications and initial outcomes
No full textWhy Trivialist Platonism Cannot be Both Trivialist and Platonist
No full textPlatonism is the view according to which entities such as numbers and properties, characterized as abstract objects, exist. Agust & iacute;n Rayo argues that the truth conditions for statements about mathematical objects and properties make no demands on the world and are, in this way, trivial. The result is trivialist platonism. In this paper, we question the stability of the two central features of the view: it cannot be both trivialist and platonist.</p
The NeuroBioBank whole-genome catalogue of human brain donors with central nervous system disorders
No full textCNS diseases are a prevailing cause of morbidity and mortality worldwide, and are influenced by environmental and biological factors, including genetic risk. Here, we generated genome-wide genetic data on a large cohort of brain tissue donors with in-depth clinical and neuropathological phenotyping, allowing for broad investigations into the risk and mechanisms of these neurological, neurodevelopmental, and psychiatric conditions. This resource consists of 9,663 donors with array-based genotyping and 9,543 donors with whole-genome sequencing completed. The clinical diagnoses of these donors include 148 central nervous system diseases clustered into 15 broad categories by International Classification of Diseases-10 (ICD-10) coding. These donors were collected by six repositories comprising the National Institutes of Health NeuroBioBank, with an average participant age of 60 years. While primarily older individuals of European descent, the cohort also contains younger donors and individuals from non-European backgrounds. Variants were detected in whole-genome sequencing (WGS), normalized and annotated to describe their functional impact, resulting in 171,121,209 unique variants and 1,078,774 non-silent variants. These raw and normalized data have been made available as a neurogenomics resource in the National Institute of Mental Health Data Archive (NIMH NDA) (nda.nih.gov), combined with donor-matched deep demographic and phenotypic data from the NeuroBioBank Portal (neurobiobank.nih.gov). To illustrate applications, we replicated the strong association observed in previous studies between pathogenic CAG nucleotide repeat expansions in the HTT gene with the clinical diagnosis of Huntington's disease, as well as associations of the APOE gene with Alzheimer's disease, and examined the association of polygenic risk scores with the three most common disease diagnoses in the cohort
Demographic, Racial and Geographic Disparities in Mortality and Place of Death Among Patients with Gastrointestinal Cancers: A National Population-Based Study
No full textExpanding the Molecular Signature of Papillary Craniopharyngioma: FGFR2 Fusion in a BRAF-Wildtype Suprasellar Neoplasm
No full textInvesting in AI Interpretability, Control, and Robustness
No full textArtificial intelligence (AI) powers breakthroughs in language processing, computer vision, and scientific discovery; yet, the increasing complexity of frontier models makes their reasoning opaque. This opacity undermines public trust, complicates deployment in safety-critical settings, and frustrates compliance with emerging regulations. In response to initiatives such as the White House AI Action Plan, we synthesize the scientific foundations and policy landscape for interpretability, control, and robustness. We clarify key concepts and survey intrinsically interpretable and post-hoc explanation techniques, discuss human-centered evaluation and governance, and analyze how adversarial threats and distributional shifts motivate robustness research. An empirical case study compares logistic regression, random forests, and gradient boosting on a synthetic dataset with a binary-sensitive attribute using accuracy, \u1d4391score, and group-fairness metrics, and illustrates trade-offs between performance and fairness. We integrate ethical and policy perspectives, including recommendations from America’s AI Action Plan and recent civil rights frameworks, and conclude with guidance for researchers, practitioners, and policymakers on advancing trustworthy AI
Phase 1, dose-escalation study of KTX-2001 (an NSD2 inhibitor) alone and in combination with darolutamide for metastatic castration-resistant prostate cancer
No full textTPS276Background: Metastatic castration-resistant prostate cancer (mCRPC) can evolve into a neuroendocrine-like subtype with aggressive behavior and poor outcomes (1). Nuclear Receptor-Binding SET Domain Protein 2 (NSD2) is overexpressed in prostate cancer and is a driver of both androgen-receptor (AR)-dependent signaling and of neuroendocrine differentiation, where cancer cells lose AR dependence and response to AR pathway inhibitors (ARPIs) (2,3,4). In studies of patient-derived neuroendocrine prostate cancer (NEPC) models, genetic depletion of NSD2 led to restoration of AR expression, reversal of adeno-to-neuroendocrine differentiation, and re-sensitization to ARPI (4). We hypothesize that NSD2 inhibition can reverse resistance to ARPIs in patients with progressive mCRPC, including with neuroendocrine differentiation. KTX-2001 is an oral, potent and selective small molecule inhibitor of NSD2. It is the sponsor’s second NSD2 inhibitor to enter the clinic. The sponsor’s first in class NSD2 inhibitor, KTX-1001, was shown to be tolerable and have preliminary efficacy in patients with relapsed/refractory multiple myeloma (5). Methods: STRIKE-001 (NCT07103018) is a multicenter, open-label phase 1 dose escalation trial of KTX-2001 monotherapy (Part A) and KTX-2001 + darolutamide (Part B). Key inclusion criteria are males age ≥18 years with mCRPC, progression after receiving ARPI, Eastern Cooperative Oncology Group performance score of 0-1, willingness to undergo biopsy if safe and feasible, and life expectancy of ≥6 months. Participants take KTX-2001 by mouth once daily alone (Part A) or with darolutamide 600 mg twice daily (Part B). Dose escalation of KTX-2001 in Parts A and B will follow a 3+3 design and occur in parallel at multiple planned dose levels. Primary objectives are to assess the safety and tolerability, determine MTD, and determine RP2D(s) for further study of KTX-2001 alone and in combination with darolutamide. Secondary objectives include characterization of efficacy and PK parameters for both KTX-2001 monotherapy and in combination with darolutamide. Exploratory objectives include study of pharmacodynamic effects, circulating tumor cells, and cell-free DNA. 1. Conteduca V, Eur J Cancer 2019. 2. Parolia A, Nat Genet 2024. 3. Aytes A, Nat Commun 2018 4. Li J, bioRxiv 2023.07.18.549585 5. Bories P, Blood Vol 144, Suppl 1,2024. Clinical trial information: NCT07103018
Replication Package for: Household Responses to Phantom Riches
No full textThe package contains code and pseudo-data reproducing the figures and tables in the paper
Effect of Novel Protein-Based Air-Entraining Admixtures on Air-Void System, and Mechanical and Transport Properties of Cementitious Materials Containing Fly Ash and Slag
No full textAn experimental study was conducted to assess the effect of proteins as air-entraining agents in different binary cementitious systems. More specifically, air-entraining performance, mechanical properties and transport characteristics of cement pastes blended with up to 30 % fly ash and slag and air entrained with different proteins were evaluated. The experimental program included measuring the hydrophobization of the cement matrix, microstructure, compressive strength, water absorption, and electrical resistivity. It was found that the air-entraining performance of proteins in blended cement binders is affected, and the degree of this effect depends primarily on the properties of each protein. There appeared to be a general reduction in air-entrained porosity in the blended systems containing fly ash in most protein cases. Although the overall water absorption did not show a correlation with air-entrained porosity, a softening of the transition point between initial and secondary absorption was observed and attributed to a wider distribution in void sizes in the pastes air entrained with proteins. In addition, the electrical resistivity of the pastes air-entrained with proteins did not demonstrate a strong correlation with air-entrained porosity indicating a complex influence of proteins on pore structure and pore solution chemistry