tbuckley/cabot-search huggingface dataset:
Zika Virus Disease and Pregnancy Outcomes in Colombia
Authors: Martha L. Ospina, Van T. Tong, Maritza Gonzalez, Diana Valencia, Marcela Mercado, Suzanne M. Gilboa, Andrea J. Rodriguez, Sarah C. Tinker, Angelica Rico, Christina M. Winfield, Lissethe Pardo, Jennifer D. Thomas, Greace Avila, Julie M. Villanueva, Sara Gomez, Denise J. Jamieson, Franklyn Prieto, Dana Meaney-Delman, Oscar Pacheco, Margaret A. Honein
Journal: New England Journal of Medicine (2020)

In 2015 and 2016, Colombia had a widespread outbreak of Zika virus. Data from two national population-based surveillance systems for symptomatic Zika virus disease (ZVD) and birth defects provided complementary information on the effect of the Zika virus outbreak on pregnancies and infant outcomes.We collected national surveillance data regarding cases of pregnant women with ZVD that were reported during the period from June 2015 through July 2016. The presence of Zika virus RNA was identified in a subgroup of these women on real-time reverse-transcriptase-polymerase-chain-reaction (rRT-PCR) assay. Brain or eye defects in infants and fetuses and other adverse pregnancy outcomes were identified among the women who had laboratory-confirmed ZVD and for whom data were available regarding pregnancy outcomes. We compared the nationwide prevalence of brain and eye defects during the outbreak with the prevalence both before and after the outbreak period.Of 18,117 pregnant women with ZVD, the presence of Zika virus was confirmed in 5926 (33%) on rRT-PCR. Of the 5673 pregnancies with laboratory-confirmed ZVD for which outcomes had been reported, 93 infants or fetuses (2%) had brain or eye defects. The incidence of brain or eye defects was higher among pregnancies in which the mother had an onset of ZVD symptoms in the first trimester than in those with an onset during the second or third trimester (3% vs. 1%). A total of 172 of 5673 pregnancies (3%) resulted in pregnancy loss; after the exclusion of pregnancies affected by birth defects, 409 of 5426 (8%) resulted in preterm birth and 333 of 5426 (6%) in low birth weight. The prevalence of brain or eye defects during the outbreak was 13 per 10,000 live births, as compared with a prevalence of 8 per 10,000 live births before the outbreak and 11 per 10,000 live births after the outbreak.In pregnant women with laboratory-confirmed ZVD, brain or eye defects in infants or fetuses were more common during the Zika virus outbreak than during the periods immediately before and after the outbreak. The frequency of such defects was increased among women with a symptom onset early in pregnancy. (Funded by the Colombian Instituto Nacional de Salud and the Centers for Disease Control and Prevention.).
A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study
Authors: Stephen A Harrison, Vlad Ratziu, Jérôme Boursier, Sven Francque, Pierre Bedossa, Zouher Majd, Geneviève Cordonnier, Fouad Ben Sudrik, Raphael Darteil, Roman Liebe, Jérémy Magnanensi, Yacine Hajji, John Brozek, Alice Roudot, Bart Staels, Dean W Hum, Sophie Jeannin Megnien, Suneil Hosmane, Noémie Dam, Pierre Chaumat, Rémy Hanf, Quentin M Anstee, Arun J Sanyal
Journal: The Lancet. Gastroenterology & hepatology (2020)
Abstract B76: Characterizing vascular invasion in hepatoblastoma
Authors: Sarah E. Woodfield, Roma H. Patel, Aryana M. Ibarra, Barry Zorman, Andrew Badachhape, Ketan B. Ghaghada, Dolores Lopez-Terrada, Pavel Sumazin, Sanjeev A. Vasudevan
Journal: Cancer Research (2020)

Abstract Hepatoblastoma (HB) is the most common pediatric liver malignancy, and patients with high-risk, metastatic disease have a five-year overall survival (OS) of only about 40%. Of note, HB patients with vascular invasion (VI) have a much worse OS. Our hypothesis is that HB tumors with VI possess unique clones that invade the vasculature, resulting in dissemination of disease. We injected the aggressive HepT1 cell line with confirmed CTNNB1 and NFE2L2 mutations in the livers of immunocompromised NSG mice to generate intrahepatic tumors. After 4 weeks, we had 100% take of tumors in animals. Serum human α-fetoprotein (AFP) increased with the growth of tumors. At time of death, we saw clear presence of intrahepatic VI, vena caval tumor thrombus, extrahepatic disease including within periportal lymph nodes, and lung metastasis in animals with tumors. We grew adherent and nonadherent cell lines from tumor samples, including one cell line from intrahepatic VI and one from vena caval tumor thrombus. Cells derived from VI areas had obvious differences in phenotype from cells from the primary tumor (PT). To further pursue these provocative changes between PT and VI areas, we generated two unique patient-derived xenograft (PDX) models of HB with intrahepatic implantation of PT and VI tumor samples from a nonmetastatic pretreatment extent of disease (PRETEXT) stage 4 patient. Mice harboring the VI PDX showed serum elevation of human AFP and obvious tumor with MRI. PT and VI PDX tissues expressed established HB markers nuclear Beta-catenin, Glypican-3, and AFP, resembling the primary patient sample. We also developed a novel cell line with growth of cells from a VI tumor in vitro. With both the HepT1 and PDX models, gene set enrichment transcriptomic analyses of RNA sequencing data showed clear changes in expression in aggressive tissues that invaded vessels, including significant (p&amp;lt;0.05) changes in pathways associated with liver damage, inflammation, and metabolism. Further exploration of these pathways and agents that target these pathways could improve outcomes for HB patients with invasive disease. Citation Format: Sarah E. Woodfield, Roma H. Patel, Aryana M. Ibarra, Barry Zorman, Andrew Badachhape, Ketan B. Ghaghada, Dolores Lopez-Terrada, Pavel Sumazin, Sanjeev A. Vasudevan. Characterizing vascular invasion in hepatoblastoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B76.
Applying Lessons Learned From Low-Resource Settings to Prioritize Cancer Care in a Pandemic
Authors: Rebecca J. DeBoer, Temidayo A. Fadelu, Lawrence N. Shulman, Katherine Van Loon
Journal: JAMA Oncology (2020)

The coronavirus disease 2019 (COVID-19) pandemic has forced oncology clinicians and administrators in the United States to set priorities for cancer care owing to resource constraints. As oncology practices adapt to a contracted health care system, expertise gained from partnerships in low-resource settings can be used for guidance. This article provides a primer on priority setting in oncology and ethical guidance based on lessons learned from experience with cancer care priority setting in low-resource settings.Lessons learned from real-world experiences are myriad. First, in the setting of limited resources, a utilitarian approach to maximizing survival benefit should guide decision-making. Second, conflicting principles will often arise among stakeholders and decision makers. Third, fair decision-making procedures should be established to ensure moral legitimacy and accountability. Fourth, proactive safeguards must be implemented to protect vulnerable individuals, or disparities in cancer treatment and outcomes will only widen further. Fifth, communication with patients and families about priority setting decisions should be intentional and standardized. Sixth, moral distress among clinicians must be addressed to avoid burnout during a time when resilience is critical.Although the need to triage cancer care may be new to those who underwent training and now practice oncology in high-resource settings, it is familiar for those who practice in low- and middle-income countries. Oncologists in the United States facing unprecedented decisions about prioritization can draw on ethical frameworks and lessons learned from real-world cancer care priority setting in resource-constrained environments.
MICAL1 constrains cardiac stress responses and protects against disease by oxidizing CaMKII
Authors: Klitos Konstantinidis, Vassilios J. Bezzerides, Lo Lai, Holly M. Isbell, An-Chi Wei, Yuejin Wu, Meera C. Viswanathan, Ian D. Blum, Jonathan M. Granger, Danielle Heims-Waldron, Donghui Zhang, Elizabeth D. Luczak, Kevin R. Murphy, Fujian Lu, Daniel H. Gratz, Bruno Manta, Qiang Wang, Qinchuan Wang, Alex L. Kolodkin, Vadim N. Gladyshev, Thomas J. Hund, William T. Pu, Mark N. Wu, Anthony Cammarato, Mario A. Bianchet, Madeline A. Shea, Rodney L. Levine, Mark E. Anderson
Journal: Journal of Clinical Investigation (2020)

Oxidant stress can contribute to health and disease. Here we show that invertebrates and vertebrates share a common stereospecific redox pathway that protects against pathological responses to stress, at the cost of reduced physiological performance, by constraining Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity. MICAL1, a methionine monooxygenase thought to exclusively target actin, and MSRB, a methionine reductase, control the stereospecific redox status of M308, a highly conserved residue in the calmodulin-binding (CaM-binding) domain of CaMKII. Oxidized or mutant M308 (M308V) decreased CaM binding and CaMKII activity, while absence of MICAL1 in mice caused cardiac arrhythmias and premature death due to CaMKII hyperactivation. Mimicking the effects of M308 oxidation decreased fight-or-flight responses in mice, strikingly impaired heart function in Drosophila melanogaster, and caused disease protection in human induced pluripotent stem cell-derived cardiomyocytes with catecholaminergic polymorphic ventricular tachycardia, a CaMKII-sensitive genetic arrhythmia syndrome. Our studies identify a stereospecific redox pathway that regulates cardiac physiological and pathological responses to stress across species.
Abstract B08: Beyond synthetic lethality: Multiple mechanisms can explain genetic interactions within childhood cancer
Authors: Josephine T. Daub, Saman Amini, Frank C.P. Holstege, Patrick Kemmeren
Journal: Cancer Research (2020)

Abstract Even though the survival rate of childhood cancer has increased in the last decades to around 80% today, it is still a leading cause of death for children in developed countries. Cancer develops through the acquisition of multiple mutations, and it is assumed that genetic interactions between mutated genes play an important role in cancer onset and progression. One approach to find genetic interactions in cancer is to search for pairs of mutated genes that occur more (or less) often than expected given the frequency of the individual mutated genes. Highly co-occurring mutated genes suggest a cooperative role of these altered genes in cancer development. Mutually exclusive gene pairs can be a signal of synthetic lethality, where the combination of the two mutations is lethal for the cancer cells, and could therefore point to possible cancer treatments. We developed a statistical pipeline, based on two genetic interaction tests, to detect significant cases of co-occurrence and mutual exclusivity in two pediatric cancer data sets, comprising over 2,500 tumors from 23 cancer types. In total we detect 15 co-occurring and 26 mutually exclusive candidate genetic interactions. Nearly all candidate gene pairs are uniquely found in one cancer type, supporting earlier findings that genetic interactions are often cell or cancer type specific. Interestingly, we find that synthetic lethality is not the main cause of the mutual exclusivity patterns in our data set. The majority of these patterns can be attributed to cancer subtypes and within pathway relationships, where the effect of a mutated gene is similar to mutating a (downstream) gene in the same pathway. This initial map of genetic interactions in childhood cancer provides a solid starting point to select suitable candidates for experimental validation as well as extending the analyses to investigate the contribution of genetic interactions towards structural variants, genetic predisposition, and cellular pathways. Citation Format: Josephine T. Daub, Saman Amini, Frank C.P. Holstege, Patrick Kemmeren. Beyond synthetic lethality: Multiple mechanisms can explain genetic interactions within childhood cancer [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B08.
Abstract 12586: Posttraumatic Stress Disorder & Prevalence of Cardiovascular Risk Factors Among Women Veterans
Authors: Ramin Ebrahimi, Jennifer Sumner, Kristine Lynch, Benjamin Viernes, Gregorio Coronado, Aria Naeim, Chi-Hong Tseng, Paul Dennis, Jean Beckham
Journal: Circulation (2019)

Introduction: Posttraumatic stress disorder (PTSD) is associated with coronary artery disease (CAD). This association is mostly based on data from male veterans. Despite sex differences in the prev...
<i>Vital Signs:</i> Clinical Characteristics of Patients with Confirmed Acute Flaccid Myelitis, United States, 2018
Authors: Sarah Kidd, Adriana Lopez, W. Allan Nix, Gloria Anyalechi, Megumi Itoh, Eileen Yee, M. Steven Oberste, Janell Routh
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Acute flaccid myelitis (AFM) is a serious neurologic syndrome that affects mostly children and is characterized by the acute onset of limb weakness or paralysis. Since U.S. surveillance for AFM began in 2014, reported cases have peaked biennially. This report describes the clinical characteristics of AFM patients during 2018, the most recent peak year.Medical records from persons meeting AFM clinical criterion (acute onset of flaccid limb weakness) were submitted to CDC. Patients with confirmed AFM met the clinical criterion and had magnetic resonance imaging indicating spinal cord lesions largely restricted to gray matter and spanning one or more vertebral segments. Symptoms, physical findings, test and imaging results, and hospitalization data were abstracted and described.Among 238 patients with confirmed AFM during 2018, median age was 5.3 years. Among the 238 patients, 205 (86%) had onset during August-November. Most (92%) had prodromal fever, respiratory illness, or both beginning a median of 6 days before weakness onset. In addition to weakness, common symptoms at clinical evaluation were gait difficulty (52%), neck or back pain (47%), fever (35%), and limb pain (34%). Among 211 who were outpatients when weakness began, most (76%) sought medical care within 1 day, and 64% first sought treatment at an emergency department. Overall, 98% of patients were hospitalized, 54% were admitted to an intensive care unit, and 23% required endotracheal intubation and mechanical ventilation.Clinicians should suspect AFM in children with acute flaccid limb weakness, especially during August-November and when accompanied by neck or back pain and a recent history of febrile respiratory illness. Increasing awareness in frontline settings such as emergency departments should aid rapid recognition and hospitalization for AFM.
Marked reductions in outpatient antibiotic prescriptions for children and adolescents – a population-based study covering 83% of the paediatric population, Germany, 2010 to 2018
Authors: Jakob Holstiege, Maike Schulz, Manas K Akmatov, Annika Steffen, Jörg Bätzing
Journal: Eurosurveillance (2020)

Background Prescribing of systemic antibiotics in general and of cephalosporins in particular in German paediatric outpatients has previously been reported to be higher than in other European countries. Aim Our objective was to assess recent trends in antibiotic prescribing in German children. Methods This study was conducted as consecutive annual cross-sectional analyses and included all children aged 0–14 years (n = 9,389,183 in 2018) covered by statutory health insurance in Germany. Annual antibiotic prescription rates from 2010 to 2018 were calculated for the age groups 0–1, 2–5, 6–9 and 10–14 years. Poisson regression was used to estimate trends of prescription rates by age group and antibiotic subgroup. Results Overall, the age-standardised antibiotic prescription rate decreased significantly by 43% from 746 prescriptions per 1,000 persons in 2010 to 428 per 1,000 in 2018 (p &lt; 0.001). Reductions were most pronounced in the age groups 0–1 year (−50%) and 2–5 years (−44%). The age group 2–5 years exhibited the highest prescription rate with 683 per 1,000 in 2018 (0–1 year: 320/1,000; 6–9 years: 417/1,000; 10–14 years: 273/1,000). Cephalosporins (second and third generation) accounted for 32% of prescribed antibiotics. Conclusions Marked reductions in antibiotic prescribing during the last decade indicate a change towards more judicious paediatric prescribing habits. Compared with other European countries, however, prescribing of second- and third-generation cephalosporins remains high in Germany, suggesting frequent first-line use of these substances for common respiratory infections. Considerable regional variations underline the need for regionally targeted interventions.
Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection
Authors: Vijendra Ramlall, Phyllis M. Thangaraj, Cem Meydan, Jonathan Foox, Daniel Butler, Jacob Kim, Ben May, Jessica K. De Freitas, Benjamin S. Glicksberg, Christopher E. Mason, Nicholas P. Tatonetti, Sagi D. Shapira
Journal: Nature Medicine (2020)
Whole-genome sequencing of Mycobacterium tuberculosis directly from clinical samples for high-resolution genomic epidemiology and drug resistance surveillance: an observational study
Authors: Galo A Goig, Irving Cancino-Muñoz, Manuela Torres-Puente, Luis M Villamayor, David Navarro, Rafael Borrás, Iñaki Comas
Journal: The Lancet Microbe (2020)

<h2>Summary</h2><h3>Background</h3> Direct whole-genome sequencing of <i>Mycobacterium tuberculosis</i> from clinical specimens will be a major breakthrough in tuberculosis diagnosis and control. To date, direct whole-genome sequencing has never been used in genomic epidemiology, and its accuracy in transmission inference remains unknown. We investigated the technical challenges imposed by direct whole-genome sequencing, and used it to infer transmission clusters and predict drug resistance. <h3>Methods</h3> Using an optimised workflow, we did direct whole-genome sequencing for 37 clinical specimens from 23 tuberculosis patients. Nine sputum samples from nine patients who were infected with different non-tuberculous mycobacteria and culture-negative for tuberculosis were used as controls in the qPCR assays and pre-sequencing runs. Additionally, 780 clinical isolates in the region of Comunidad Valenciana (Spain) were whole-genome sequenced between Jan 1, 2014, and Dec 31, 2016. We analysed the genomic variants to build a tuberculosis transmission network for the region, including the clinical specimens, and to predict drug susceptibility profiles. <h3>Findings</h3> After sequencing 37 clinical specimens, 28 specimens (22 [85%] of 26 smear-positive and six [55%] of 11 smear-negative) met the quality criteria for downstream analysis. All 28 clinical specimens clustered with their matching culture isolates, with a median distance of 0 single nucleotide polymorphisms. Of the 28 clinical specimens, 16 (57%) were accurately assigned to ten transmission clusters in the region, and 12 (43%) were unique cases. Transmission inferences and drug-susceptibility predictions from direct whole-genome sequencing data were concordant with sequences from corresponding cultures and phenotypic drug-susceptibility testing. Complete genomic analysis, within a week of specimen receipt, cost €217 per sample (excluding personnel costs). <h3>Interpretation</h3> Direct whole-genome sequencing could be used to accurately delineate transmission clusters of tuberculosis and conduct culture-independent surveillance. Compared with conventional approaches, direct whole-genome sequencing allows researchers to do real-time genomic epidemiology and drug resistance surveillance in settings where culture and drug susceptibility testing are not available. <h3>Funding</h3> European Research Council; Ministerio de Ciencia, Innovación y Universidades (Spanish Government).
The NAM and the Quality of Health Care — Inflecting a Field
Authors: Donald M. Berwick, Christine K. Cassel
Journal: New England Journal of Medicine (2020)

Interview with Dr. Donald Berwick on the history and challenges of measuring and improving health care quality in the United States. (10:49)Download In 1999 and 2001, the Institute of Medicine published two landmark documents on health care quality and serious quality problems. Two decades later, focal progress in quality improvement is undeniable, but wholesale, systemic improvement has been hard to bring to scale.
CircRNAs: biogenesis, functions, and role in drug-resistant Tumours
Authors: Shuo Ma, Shan Kong, Feng Wang, Shaoqing Ju
Journal: Molecular Cancer (2020)

Abstract Targeted treatment, which can specifically kill tumour cells without affecting normal cells, is a new approach for tumour therapy. However, tumour cells tend to acquire resistance to targeted drugs during treatment. Circular RNAs (circRNAs) are single-stranded RNA molecules with unique structures and important functions. With the development of RNA sequencing technology, circRNAs have been found to be widespread in tumour-resistant cells and to play important regulatory roles. In this review, we present the latest advances in circRNA research and summarize the various mechanisms underlying their regulation. Moreover, we review the role of circRNAs in the chemotherapeutic resistance of tumours and explore the clinical value of circRNA regulation in treating tumour resistance.