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Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. [https://www.selleckchem.com/products/AZD2281(Olaparib).html Olaparib clinical trial] This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.<br />Bright IDEAS (BI) is a problem-solving skills training (PSST) program that has been demonstrated in earlier randomized controlled trials (RCTs) to be an effective and specific intervention for improving problem-solving skills and reducing negative affect in caregivers of children with cancer. The objectives of this study were to (a) offer an approach to defining meaningful treatment response and to determine the rates of responsivity to PSST; and (b) identify characteristics of PSST responders and nonresponders.<br />Data from 154 mothers receiving the BI intervention were analyzed. Drawing on the literature on minimal clinically important differences, two criteria for determining responsivity were calculated for the primary outcome of problem-solving skills (a) The reliable change index (RCI) based on group data, and; (b) The effect size (ES) of each participant's pre/postintervention change score as a function of the group's baseline SD.<br />Thirty-three percent of the sample met both responsivity criteria immediately posttreatment (39% at follow-up) and 38% (39% at follow-up) met neither. An additional 29% demonstrated a small or greater ES (≥ 0.2) but did not meet the RCI criteria, suggesting possible benefit. The single consistent predictor of responsivity was participants' pretreatment problem-solving skills, with lower skills at baseline predicting greater improvement (p &lt; .001).<br />These findings highlight the need to go beyond group data in interpreting RCTs and to incorporate measures of meaningful treatment response. Our ability to predict and screen for meaningful treatment response is critical to more precise targeting, enhanced outcomes, and better resource allocation.<br />These findings highlight the need to go beyond group data in interpreting RCTs and to incorporate measures of meaningful treatment response. Our ability to predict and screen for meaningful treatment response is critical to more precise targeting, enhanced outcomes, and better resource allocation.<br />Glioblastoma is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during GBM progression.<br />Using In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAV and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model.<br />Using a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed in our mouse model that TDECs are a rare subpopulation that contributes to vessels within the tumor, albeit to a limited degree. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogenous populations are also present in human glioma.<br />Our findings show extensive endothelial heterogeneity within the tumor and tumor microenvironment, and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.<br />Our findings show extensive endothelial heterogeneity within the tumor and tumor microenvironment, and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.<br />Open notes invite patients and families to read ambulatory visit notes through the patient portal. Little is known about the extent to which they identify and speak up about perceived errors. Understanding the barriers to speaking up can inform quality improvements.<br />To describe patient and family attitudes, experiences, and barriers related to speaking up about perceived serious note errors.<br />Mixed method analysis of a 2016 electronic survey of patients and families at 2 northeast US academic medical centers. Participants had active patient portal accounts and at least 1 note available in the preceding 12 months.<br />6913 adult patients (response rate 28%) and 3672 pediatric families (response rate 17%) completed the survey. In total, 8724/9392 (93%) agreed that reporting mistakes improves patient safety. Among 8648 participants who read a note, 1434 (17%) perceived ≥1 mistake. 627/1434 (44%) reported the mistake was serious and 342/627 (56%) contacted their provider. Participants who self-identified as Black or African American, Asian, "other," or "multiple" race(s) (OR 0.