tbuckley/cabot-search huggingface dataset:
CADD-Splice—improving genome-wide variant effect prediction using deep learning-derived splice scores
Authors: Philipp Rentzsch, Max Schubach, Jay Shendure, Martin Kircher
Journal: Genome Medicine (2021)

Abstract Background Splicing of genomic exons into mRNAs is a critical prerequisite for the accurate synthesis of human proteins. Genetic variants impacting splicing underlie a substantial proportion of genetic disease, but are challenging to identify beyond those occurring at donor and acceptor dinucleotides. To address this, various methods aim to predict variant effects on splicing. Recently, deep neural networks (DNNs) have been shown to achieve better results in predicting splice variants than other strategies. Methods It has been unclear how best to integrate such process-specific scores into genome-wide variant effect predictors. Here, we use a recently published experimental data set to compare several machine learning methods that score variant effects on splicing. We integrate the best of those approaches into general variant effect prediction models and observe the effect on classification of known pathogenic variants. Results We integrate two specialized splicing scores into CADD (Combined Annotation Dependent Depletion; cadd.gs.washington.edu ), a widely used tool for genome-wide variant effect prediction that we previously developed to weight and integrate diverse collections of genomic annotations. With this new model, CADD-Splice, we show that inclusion of splicing DNN effect scores substantially improves predictions across multiple variant categories, without compromising overall performance. Conclusions While splice effect scores show superior performance on splice variants, specialized predictors cannot compete with other variant scores in general variant interpretation, as the latter account for nonsense and missense effects that do not alter splicing. Although only shown here for splice scores, we believe that the applied approach will generalize to other specific molecular processes, providing a path for the further improvement of genome-wide variant effect prediction.
Magnetic Resonance Imaging in Patients With Cardiac Implantable Electronic Devices With Abandoned Leads
Authors: Robert D. Schaller, Tamara Brunker, Michael P. Riley, Francis E. Marchlinski, Saman Nazarian, Harold Litt
Journal: JAMA Cardiology (2021)

Magnetic resonance imaging (MRI) is the modality of choice for many conditions. Conditional devices and novel protocols for imaging patients with legacy cardiac implantable electronic devices (CIEDs) have increased access to MRI in patients with devices. However, the presence of abandoned leads remains an absolute contraindication.To assess if the performance of an MRI in the presence of an abandoned CIED lead is safe and whether there are deleterious effects on concomitant active CIED leads.This cohort study included consecutive CIED recipients undergoing 1.5-T MRI with at least 1 abandoned lead between January 2013 and June 2020. MRI scans were performed at the Hospital of the University of Pennsylvania. No patients were excluded.CIEDs were reprogrammed based on patient-specific pacing needs. Electrocardiography telemetry and pulse oximetry were monitored continuously, and live contact with the patient throughout the scan via visual and voice contact was performed if possible. After completion of the MRI, CIED evaluation was repeated and programming returned to baseline or to a clinically appropriate setting.Variation in pre- and post-MRI capture threshold of 50% or more, ventricular sensing 40% or more, and lead impedance 30% or more, as well as clinical sequelae such as pain and sustained tachyarrhythmia were considered significant. Long-term follow-up lead-related data were analyzed if available.A total of 139 consecutive patients (110 men [79%]) with a mean (SD) age of 65.6 (13.4) years underwent 200 MRIs of various anatomic regions including the thorax. Repeat examinations were common with a maximum of 16 examinations for 1 patient. There was a total of 243 abandoned leads with a mean (SD) of 1.22 (0.45) per patient. The mean (SD) number of active leads was 2.04 (0.78) and 64 patients (46%) were pacemaker dependent. A transmit-receive radiofrequency coil was used in 41 patients (20.5%), all undergoing MRI of the brain. There were no abnormal vital signs or sustained tachyarrhythmias. No changes in battery voltage, power-on reset events, or changes of pacing rate were noted. CIED parameter changes including decreased right atrial sensing in 4 patients and decreased left ventricular R-wave amplitude in 1 patient were transiently noted. One patient with an abandoned subcutaneous array experienced sternal heating that subsided on premature cessation of the study.The risk of MRI in patients with abandoned CIED leads was low in this large observational study, including patients who underwent examination of the thorax. The growing aggregate of data questions the absolute contraindication for MRI in patients with abandoned CIED leads.
Megabase-scale methylation phasing using nanopore long reads and NanoMethPhase
Authors: Vahid Akbari, Jean-Michel Garant, Kieran O’Neill, Pawan Pandoh, Richard Moore, Marco A. Marra, Martin Hirst, Steven J. M. Jones
Journal: Genome biology (2021)

Abstract The ability of nanopore sequencing to simultaneously detect modified nucleotides while producing long reads makes it ideal for detecting and phasing allele-specific methylation. However, there is currently no complete software for detecting SNPs, phasing haplotypes, and mapping methylation to these from nanopore sequence data. Here, we present NanoMethPhase, a software tool to phase 5-methylcytosine from nanopore sequencing. We also present SNVoter, which can post-process nanopore SNV calls to improve accuracy in low coverage regions. Together, these tools can accurately detect allele-specific methylation genome-wide using nanopore sequence data with low coverage of about ten-fold redundancy.
Association of Obesity With Breast Cancer Outcome in Relation to Cancer Subtypes: A Meta-Analysis
Authors: Ana Elisa Lohmann, Sara V Soldera, Isabel Pimentel, Domen Ribnikar, Marguerite Ennis, Eitan Amir, Pamela J Goodwin
Journal: JNCI Journal of the National Cancer Institute (2021)

Abstract Background Obesity at breast cancer (BC) diagnosis has been associated with poor outcome, although the magnitude of effect in different BC subtypes is uncertain. We report on the association of obesity or overweight at diagnosis of nonmetastatic BC with disease-free (DFS) and overall survival (OS) in the following defined subtypes: hormone receptor positive/HER2 negative (HR+HER2−), HER2 positive (HER2+), and triple negative (TNBC). Methods We searched MEDLINE, EMBASE, and COCHRANE databases up to January 1, 2019. Study eligibility was performed independently by 2 authors. Studies reporting hazard ratios (HRs) of OS and/or DFS for obesity or overweight in BC subtypes were included. The pooled hazard ratio was computed and weighted using generic inverse variance and random effects models. Results Twenty-seven studies were included. Obese compared with nonobese women had worse DFS in all subtypes: the hazard ratios were 1.26 (95% confidence interval [CI] = 1.13 to 1.41, P &amp;lt; .001) for HR+HER2− BC, 1.16 (95% CI = 1.06 to 1.26, P &amp;lt; .001) for HER2+ BC, and 1.17 (95% CI = 1.06 to 1.29, P = .001) for TNBC. OS was also worse in obese vs nonobese women (HR+HER2− BC HR = 1.39, 95% CI = 1.20 to 1.62, P &amp;lt; .001; HER2+ BC HR = 1.18, 95% CI = 1.05 to 1.33, P = .006; and TNBC HR = 1.32, 95% CI = 1.13 to 1.53, P &amp;lt; .001). As opposed to obesity, overweight was not associated with either DFS or OS in HER2+ BC (HR = 1.02, 95% CI = 0.81 to 1.28, P = .85; and HR = 0.96, 95% CI = 0.76 to 1.21, P = .99, respectively) or TNBC (HR = 1.04, 95% CI = 0.93 to 1.18, P = .49; and HR = 1.08, 95% CI = 0.81 to 1.44, P = .17), respectively. In HR+HER2− BC, being overweight was associated with worse OS (HR = 1.14, 95% CI = 1.07 to 1.22, P &amp;lt; .001). Conclusions Obesity was associated with modestly worse DFS and OS in all BC subtypes.
Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy
Authors: Ayman Al-Hendy, Andrea S. Lukes, Alfred N. Poindexter, Roberta Venturella, Claudio Villarroel, Hilary O.D. Critchley, Yulan Li, Laura McKain, Juan C. Arjona Ferreira, Andria G.M. Langenberg, Rachel B. Wagman, Elizabeth A. Stewart
Journal: New England Journal of Medicine (2021)

Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects.
A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a Pediatric Brain Tumor Consortium study
Authors: Jason Fangusaro, Arzu Onar-Thomas, Tina Young Poussaint, Shengjie Wu, Azra H Ligon, Neal Lindeman, Olivia Campagne, Anu Banerjee, Sridharan Gururangan, Lindsay B Kilburn, Stewart Goldman, Ibrahim Qaddoumi, Patricia Baxter, Gilbert Vezina, Corey Bregman, Zoltan Patay, Jeremy Y Jones, Clinton F Stewart, Michael J Fisher, Laurence Austin Doyle, Malcolm Smith, Ira J Dunkel, Maryam Fouladi
Journal: Neuro-Oncology (2021)

Abstract Background Pediatric low-grade gliomas (pLGGs) are the most common childhood brain tumor. Progression-free survival (PFS) is much lower than overall survival, emphasizing the need for alternative treatments. Sporadic (without neurofibromatosis type 1) optic pathway and hypothalamic gliomas (OPHGs) are often multiply recurrent and cause significant visual deficits. Recently, there has been a prioritization of functional outcomes. Methods We present results from children with recurrent/progressive OPHGs treated on a PBTC (Pediatric Brain Tumor Consortium) phase II trial evaluating efficacy of selumetinib (AZD6244, ARRY-142886) a MEK-1/2 inhibitor. Stratum 4 of PBTC-029 included patients with sporadic recurrent/progressive OPHGs treated with selumetinib at the recommended phase II dose (25mg/m2/dose BID) for a maximum of 26 courses. Results Twenty-five eligible and evaluable patients were enrolled with a median of 4 (1-11) previous therapies. Six of 25 (24%) had partial response, 14/25 (56%) had stable disease, and 5 (20%) had progressive disease while on treatment. The median treatment courses were 26 (2-26); 14/25 patients completed all 26 courses. Two-year PFS was 78 ± 8.5%. Nineteen of 25 patients were evaluable for visual acuity which improved in 4/19 patients (21%), was stable in 13/19 (68%), and worsened in 2/19 (11%). Five of 19 patients (26%) had improved visual fields and 14/19 (74%) were stable. The most common toxicities were grade 1/2 CPK elevation, anemia, diarrhea, headache, nausea/emesis, fatigue, AST and ALT increase, hypoalbuminemia, and rash. Conclusions Selumetinib was tolerable and led to responses and prolonged disease stability in children with recurrent/progressive OPHGs based upon radiographic response, PFS, and visual outcomes.
Paraventricular thalamic nucleus plays a critical role in consolation and anxious behaviors of familiar observers exposed to surgery mice
Authors: Qiuting Zeng, Weiran Shan, Hui Zhang, Jianjun Yang, Zhiyi Zuo
Journal: Theranostics (2021)

Background: Consolation behaviors toward the sick are common in humans. Anxiety in the relatives of the sick is also common. Anxiety can cause detrimental effects on multiple systems. However, our understanding on the neural mechanisms of these behaviors is limited because of the lack of small animal models. Methods: Five of 6- to 8-week-old CD-1 male mice were housed in a cage. Among them, 2 mice had right common artery exposure (surgery) and the rest were without surgery. Allo-grooming and performance in light and dark box and elevated plus maze tests of the mice were determined. Results: Mice without surgery had increased allo-grooming toward mice with surgery but decreased allo-grooming toward non-surgery intruders. This increased allo-grooming toward surgery mice was higher in familiar observers of surgery mice than that of mice that were not cage-mates of surgery mice before the surgery. Familiar observers developed anxious behavior after being with surgery mice. Surgery mice with familiar observers had less anxious behavior than surgery mice without interacting with familiar observers. Multiple brain regions including paraventricular thalamic nucleus (PVT) were activated in familiar observers. The activated cells in PVT contained orexin receptors. Injuring the neurons with ibotenic acid, antagonizing orexin signaling with an anti-orexin antibody or inhibiting neurons by chemogenetic approach in PVT abolished the consolation and anxious behaviors of familiar observers. Conclusions: Mice show consolation behavior toward the sick. This behavior attenuates the anxious behavior of surgery mice. The orexin signaling in the PVT neurons play a critical role in the consolation of familiar observers toward surgery mice and their anxious behavior. Considering that about 50 million patients have surgery annually in the United States, our study represents the initial attempt to understand neural mechanisms for consolation and anxiety of a large number of people.
Correction to: Outcomes with sequential FLT3-inhibitor-based therapies in patients with AML
Authors: Musa Yilmaz, Mansour Alfayez, Courtney D. DiNardo, Gautam Borthakur, Tapan M. Kadia, Marina Y. Konopleva, Sanam Loghavi, Rashmi Kanagal-Shamanna, Keyur P. Patel, Elias J. Jabbour, Guillermo Garcia‑Manero, Naveen Pemmaraju, Sherry A. Pierce, Issa Ghayas, Nicholas J. Short, Guillermo Montalban-Bravo, Koichi Takahashi, Rita Assi, Ahmad S. Alotaibi, Maro Ohanian, Michael Andreeff, Jorge E. Cortes, Hagop M. Kantarjian, Farhad Ravandi, Naval G. Daver
Journal: Journal of Hematology & Oncology (2021)

An amendment to this paper has been published and can be accessed via the original article.
Mitochondria-Rich Extracellular Vesicles From Autologous Stem Cell–Derived Cardiomyocytes Restore Energetics of Ischemic Myocardium
Authors: Gentaro Ikeda, Michelle R. Santoso, Yuko Tada, Albert M. Li, Evgeniya Vaskova, Ji-Hye Jung, Connor O’Brien, Elizabeth Egan, Jiangbin Ye, Phillip C. Yang
Journal: Journal of the American College of Cardiology (2021)
Smartphone-based symbol-digit modalities test reliably captures brain damage in multiple sclerosis
Authors: Linh Pham, Thomas Harris, Mihael Varosanec, Vanessa Morgan, Peter Kosa, Bibiana Bielekova
Journal: npj Digital Medicine (2021)

Abstract As the burden of neurodegenerative diseases increases, time-limited clinic encounters do not allow quantification of complex neurological functions. Patient-collected digital biomarkers may remedy this, if they provide reliable information. However, psychometric properties of digital tools remain largely un-assessed. We developed a smartphone adaptation of the cognitive test, the Symbol-Digit Modalities Test (SDMT) by randomizing the test’s symbol-number codes and testing sequences. The smartphone SDMT showed comparable psychometric properties in 154 multiple sclerosis (MS) patients and 39 healthy volunteers (HV). E.g., smartphone SDMT achieved slightly higher correlations with cognitive subscores of neurological examinations and with brain injury measured by MRI ( R 2 = 0.75, Rho = 0.83, p &lt; 0.0001) than traditional SDMT. Mathematical adjustment for motoric disability of the dominant hand, measured by another smartphone test, compensates for the disadvantage of touch-based test. Averaging granular home measurements of the digital biomarker also increases accuracy of identifying true neurological decline.
Abstract 16467: A Novel CT-derived Radiotranscriptomic Signature of Perivascular Adipose Tissue Stratifies COVID-19 Vascular Cytokine Burst and Predicts in Hospital Outcomes
Authors: Christos P Kotanidis, Cheng Xie, Rafail Kotronias, Muhammad Siddique, Sheena Thomas, David Schottlander, Keith Channon, Stefan Neubauer, John Deanfield, Charalambos Antoniades
Journal: Circulation (2020)

Introduction: COVID-19 is characterised by severe vascular inflammation. Perivascular adipose tissue (PVAT) has the ability to change its texture in response to vascular inflammation. Hypothesis: Computed Tomography Angiography (CTA)-based radiotranscriptomic phenotyping of PVAT may quantify COVID-19-induced vascular inflammation, predicting clinical outcomes. Methods: In Study 1, RNA sequencing of 60 internal mammary artery (IMA) biopsies from patients undergoing coronary bypass surgery was performed to build a transcriptomic fingerprint similar to that observed in COVID-19. This fingerprint was used to train an extreme gradient boosting algorithm, C19-RS, using CTA-derived radiomic features of PVAT around the IMA and descending thoracic aorta. In Study 2, C19-RS was validated in pulmonary artery CTAs from an independent cohort of 201 patients for COVID-19 detection and test its prognostic value in COVID-19. Results: Unsupervised hierarchical clustering of RNASeq data in Study 1 identified 2 clusters of vascular inflammation ( A ). Machine learning was used to train C19-RS to detect vascular inflammation based on 31 radiomic features. In study 2, 22 deaths and 32 ICU admissions were recorded. Patients with high C19-RS had an OR=3.11[95%CI:1.06-9.85] for COVID-19 adjusted for age, sex, risk factors, hsCRP, WBCC, COPD and CT tube voltage. C19-RS significantly improved the discrimination of a baseline model containing the above variables, for COVID-19 detection (delta[AUC]=0.03, p=0.008, B ). C19-RS was significantly associated with in-hospital death ( C ), and a composite endpoint of in-hospital death and ICU admission, with adjusted HR: 4.29 (95% CI: 1.48-13.52, p=0.009). Conclusion: COVID-19-induced vascular inflammation can be quantified by a radiotranscriptomic signature (C19-RS) derived from CT analysis of PVAT. C19-RS stratifies vascular inflammatory burden in COVID-19, and has striking prognostic value for in-hospital outcomes.
The NCI Genomic Data Commons
Authors: Allison P. Heath, Vincent Ferretti, Stuti Agrawal, Maksim An, James C. Angelakos, Renuka Arya, Rosita Bajari, Bilal Baqar, Justin H. B. Barnowski, Jeffrey Burt, Ann Catton, Brandon F. Chan, Fay Chu, Kim Cullion, Tanja Davidsen, Phuong-My Do, Christian Dompierre, Martin L. Ferguson, Michael S. Fitzsimons, Michael Ford, Miyuki Fukuma, Sharon Gaheen, Gajanan L. Ganji, Tzintzuni I. Garcia, Sameera S. George, Daniela S. Gerhard, Francois Gerthoffert, Fauzi Gomez, Kang Han, Kyle M. Hernandez, Biju Issac, Richard Jackson, Mark A. Jensen, Sid Joshi, Ajinkya Kadam, Aishmit Khurana, Kyle M. J. Kim, Victoria E. Kraft, Shenglai Li, Tara M. Lichtenberg, Janice Lodato, Laxmi Lolla, Plamen Martinov, Jeffrey A. Mazzone, Daniel P. Miller, Ian Miller, Joshua S. Miller, Koji Miyauchi, Mark W. Murphy, Thomas Nullet, Rowland O. Ogwara, Francisco M. Ortuño, Jesús Pedrosa, Phuong L. Pham, Maxim Y. Popov, James J. Porter, Raymond Powell, Karl Rademacher, Colin P. Reid, Samantha Rich, Bessie Rogel, Himanso Sahni, Jeremiah H. Savage, Kyle A. Schmitt, Trevar J. Simmons, Joseph Sislow, Jonathan Spring, Lincoln Stein, Sean Sullivan, Yajing Tang, Mathangi Thiagarajan, Heather D. Troyer, Chang Wang, Zhining Wang, Bedford L. West, Alex Wilmer, Shane Wilson, Kaman Wu, William P. Wysocki, Linda Xiang, Joseph T. Yamada, Liming Yang, Christine Yu, Christina K. Yung, Jean Claude Zenklusen, Junjun Zhang, Zhenyu Zhang, Yuanheng Zhao, Ariz Zubair, Louis M. Staudt, Robert L. Grossman
Journal: Nature Genetics (2021)
Covid-19: One in seven people in England have antibodies from infection or vaccination, finds study
Authors: Jacqui Wise
Journal: BMJ (2021)

Covid-19: One in seven people in England have antibodies from infection or vaccination, finds study Jacqui WiseAlmost 14% of people in England now have evidence of antibodies against SARS-CoV-2, according to the fifth round of the Real-time assessment of community transmission (React-2) study. 1 Office for National Statistics.Coronavirus (covid-19) infection survey, UK. 19 February 2021.
Prevalence of Prenatal Opioid Exposure in Ontario, Canada, 2014-2019
Authors: Andi Camden, Joel G. Ray, Teresa To, Tara Gomes, Li Bai, Astrid Guttmann
Journal: JAMA Network Open (2021)

ResultsHospital births during the study period totaled 701 896, and 37 415 newborns (5.3%) had POE.Mothers were a mean (SD) age of 30.9 (5.3) years at current birth, 74.7% were Canadian-born, and 10.5% had pain-related hospital care 2 years before conception.The annual prevalence of POE decreased from 6.1% in 2014 to 4.5% in 2019 (P < .001).The highest rates of POE were among women aged 20 to 24 years (8.8% in 2014 to 7.1% in 2019), those living in rural areas (8.3% in 2014
Sarah Scott-Barrett
Authors: Will Scott-Barrett, Erika Denton
Journal: BMJ (2021)

Sarah Scott-Barrett was born in Birmingham, the daughter of a surgeon. She was educated at Edgbaston High School and trained at Guy’s Hospital Medical School. After graduating, she worked at Guy’s, the Whittington, St George’s, the Royal Marsden, the National Heart, and the Royal Brompton hospitals.

After a brief time in anaesthetics, she switched to radiology and was based …
Expanding evolutionary neuroscience: insights from comparing variation in behavior
Authors: Nicholas Jourjine, Hopi E. Hoekstra
Journal: Neuron (2021)

Neuroscientists have long studied species with convenient biological features to discover how behavior emerges from conserved molecular, neural, and circuit level processes. With the advent of new tools, from viral vectors and gene editing to automated behavioral analyses, there has been a recent wave of interest in developing new, "nontraditional" model species. Here, we advocate for a complementary approach to model species development, that is, model clade development, as a way to integrate an evolutionary comparative approach with neurobiological and behavioral experiments. Capitalizing on natural behavioral variation in and investing in experimental tools for model clades will be a valuable strategy for the next generation of neuroscience discovery.
Impairment of type H vessels by NOX2-mediated endothelial oxidative stress: critical mechanisms and therapeutic targets for bone fragility in streptozotocin-induced type 1 diabetic mice
Authors: Xiao-Fan Hu, Geng Xiang, Tian-Ji Wang, Yu-Bo Ma, Yang Zhang, Ya-Bo Yan, Xiong Zhao, Zi-Xiang Wu, Ya-Fei Feng, Wei Lei
Journal: Theranostics (2021)

Rationale: Mechanisms underlying the compromised bone formation in type 1 diabetes mellitus (T1DM), which causes bone fragility and frequent fractures, remain poorly understood. Recent advances in organ-specific vascular endothelial cells (ECs) identify type H blood vessel injury in the bone, which actively direct osteogenesis, as a possible player. Methods: T1DM was induced in mice by streptozotocin (STZ) injection in two severity degrees. Bony endothelium, the coupling of angiogenesis and osteogenesis, and bone mass quality were evaluated. Insulin, antioxidants, and NADPH oxidase (NOX) inhibitors were administered to diabetic animals to investigate possible mechanisms and design therapeutic strategies. Results: T1DM in mice led to the holistic abnormality of the vascular system in the bone, especially type H vessels, resulting in the uncoupling of angiogenesis and osteogenesis and inhibition of bone formation. The severity of osteopathy was positively related to glycemic levels. These pathological changes were attenuated by early-started, but not late-started, insulin therapy. ECs in diabetic bones showed significantly higher levels of reactive oxygen species (ROS) and NOX 1 and 2. Impairments of bone vessels and bone mass were effectively ameliorated by treatment with anti-oxidants or NOX2 inhibitors, but not by a NOX1/4 inhibitor. GSK2795039 (GSK), a NOX2 inhibitor, significantly supplemented the insulin effect on the diabetic bone. Conclusions: Diabetic osteopathy could be a chronic microvascular complication of T1DM. The impairment of type H vessels by NOX2-mediated endothelial oxidative stress might be an important contributor that can serve as a therapeutic target for T1DM-induced osteopathy.