We Need to Share a Dream

In lieu of an abstract, below is the essay\u27s first paragraph. I have a dream that one day my fellow Black Americans will open their eyes to the world filled with self-hatred that they themselves have perpetuated throughout the years. I also have a dream that tomorrow the sun will rise on a new generation of prosperous young black people will emerge from the shadows that once consumed our future and rise up against the stereotype. We fail to realize that the foundation laid down for us by the great freedom fighters in our past is crumbling right below our feet and will continue to do so until we see that we are a part of the problem. As a race, we struggle with the concept of our own fight for freedom and equality; and I am not referring to freedom from “the Man” as is usually presumed. I am, however, referring to freedom from the mental blocks that we and society have put in place and that our youth grow up believing. In the year 1963, Martin Luther King Jr. whilst giving his I Have a Dream speech said, “We must forever conduct our struggle on the high plane of dignity and discipline. We must not allow our creative protest to degenerate into physical violence. Again and again we must rise to the majestic heights of meeting physical force with soul force.” These are noble words that seem simple to follow and live by, but yet we fail to do so; and it is not because we are unable, but because we are unwilling. We are willing to accept that we are not good enough to achieve the same goals as the White community due to the color of our skin and while this may not necessarily encompass every racial situation, this is one prominent problem that needs to be addressed

Addressing the Language Binding Problem With Dynamic Functional Connectivity During Meaningful Spoken Language Comprehension

During speech, how does the brain integrate information processed on different timescales and in separate brain areas so we can understand what is said? This is the language binding problem. Dynamic functional connectivity (brief periods of synchronization in the phase of EEG oscillations) may provide some answers. Here we investigate time and frequency characteristics of oscillatory power and phase synchrony (dynamic functional connectivity) during speech comprehension. Twenty adults listened to meaningful English sentences and non-sensical “Jabberwocky” sentences in which pseudo-words replaced all content words, while EEG was recorded. Results showed greater oscillatory power and global connectivity strength (mean phase lag index) in the gamma frequency range (30–80 Hz) for English compared to Jabberwocky. Increased power and connectivity relative to baseline was also seen in the theta frequency range (4–7 Hz), but was similar for English and Jabberwocky. High-frequency gamma oscillations may reflect a mechanism by which the brain transfers and integrates linguistic information so we can extract meaning and understand what is said. Slower frequency theta oscillations may support domain-general processing of the rhythmic features of speech. Our findings suggest that constructing a meaningful representation of speech involves dynamic interactions among distributed brain regions that communicate through frequency-specific functional networks

Effects of Renal Denervation vs Sham in Resistant Hypertension after Medication Escalation:Prespecified Analysis at 6 Months of the RADIANCE-HTN TRIO Randomized Clinical Trial

IMPORTANCE: Although early trials of endovascular renal denervation (RDN) for patients with resistant hypertension (RHTN) reported inconsistent results, ultrasound RDN (uRDN) was found to decrease blood pressure (BP) vs sham at 2 months in patients with RHTN taking stable background medications in the Study of the ReCor Medical Paradise System in Clinical Hypertension (RADIANCE-HTN TRIO) trial. OBJECTIVES: To report the prespecified analysis of the persistence of the BP effects and safety of uRDN vs sham at 6 months in conjunction with escalating antihypertensive medications. DESIGN, SETTING, AND PARTICIPANTS: This randomized, sham-controlled, clinical trial with outcome assessors and patients blinded to treatment assignment, enrolled patients from March 11, 2016, to March 13, 2020. This was an international, multicenter study conducted in the US and Europe. Participants with daytime ambulatory BP of 135/85 mm Hg or higher after 4 weeks of single-pill triple-combination treatment (angiotensin-receptor blocker, calcium channel blocker, and thiazide diuretic) with estimated glomerular filtration rate (eGFR) of 40 mL/min/1.73 m(2 )or greater were randomly assigned to uRDN or sham with medications unchanged through 2 months. From 2 to 5 months, if monthly home BP was 135/85 mm Hg or higher, standardized stepped-care antihypertensive treatment starting with aldosterone antagonists was initiated under blinding to treatment assignment. INTERVENTIONS: uRDN vs sham procedure in conjunction with added medications to target BP control. MAIN OUTCOMES AND MEASURES: Six-month change in medications, change in daytime ambulatory systolic BP, change in home systolic BP adjusted for baseline BP and medications, and safety. RESULTS: A total of 65 of 69 participants in the uRDN group and 64 of 67 participants in the sham group (mean [SD] age, 52.4 [8.3] years; 104 male [80.6%]) with a mean (SD) eGFR of 81.5 (22.8) mL/min/1.73 m(2) had 6-month daytime ambulatory BP measurements. Fewer medications were added in the uRDN group (mean [SD], 0.7 [1.0] medications) vs sham (mean [SD], 1.1 [1.1] medications; P = .045) and fewer patients in the uRDN group received aldosterone antagonists at 6 months (26 of 65 [40.0%] vs 39 of 64 [60.9%]; P = .02). Despite less intensive standardized stepped-care antihypertensive treatment, mean (SD) daytime ambulatory BP at 6 months was 138.3 (15.1) mm Hg with uRDN vs 139.0 (14.3) mm Hg with sham (additional decreases of −2.4 [16.6] vs −7.0 [16.7] mm Hg from month 2, respectively), whereas home SBP was lowered to a greater extent with uRDN by 4.3 mm Hg (95% CI, 0.5-8.1 mm Hg; P = .03) in a mixed model adjusting for baseline and number of medications. Adverse events were infrequent and similar between groups. CONCLUSIONS AND RELEVANCE: In this study, in patients with RHTN initially randomly assigned to uRDN or a sham procedure and who had persistent elevation of BP at 2 months after the procedure, standardized stepped-care antihypertensive treatment escalation resulted in similar BP reduction in both groups at 6 months, with fewer additional medications required in the uRDN group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0264942

Scaling Autoregressive Multi-Modal Models: Pretraining and Instruction Tuning

We present CM3Leon (pronounced "Chameleon"), a retrieval-augmented, token-based, decoder-only multi-modal language model capable of generating and infilling both text and images. CM3Leon uses the CM3 multi-modal architecture but additionally shows the extreme benefits of scaling up and tuning on more diverse instruction-style data. It is the first multi-modal model trained with a recipe adapted from text-only language models, including a large-scale retrieval-augmented pre-training stage and a second multi-task supervised fine-tuning (SFT) stage. It is also a general-purpose model that can do both text-to-image and image-to-text generation, allowing us to introduce self-contained contrastive decoding methods that produce high-quality outputs. Extensive experiments demonstrate that this recipe is highly effective for multi-modal models. CM3Leon achieves state-of-the-art performance in text-to-image generation with 5x less training compute than comparable methods (zero-shot MS-COCO FID of 4.88). After SFT, CM3Leon can also demonstrate unprecedented levels of controllability in tasks ranging from language-guided image editing to image-controlled generation and segmentation

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

SYNGAP1 encephalopathy:A distinctive generalized developmental and epileptic encephalopathy

Objective To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. Methods Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. Results We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). Conclusions SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.</p