tbuckley/cabot-search huggingface dataset:
Association between mobility patterns and COVID-19 transmission in the USA: a mathematical modelling study
Authors: Hamada S Badr, Hongru Du, Maximilian Marshall, Ensheng Dong, Marietta M Squire, Lauren M Gardner
Journal: The Lancet Infectious Diseases (2020)

Within 4 months of COVID-19 first being reported in the USA, it spread to every state and to more than 90% of all counties. During this period, the US COVID-19 response was highly decentralised, with stay-at-home directives issued by state and local officials, subject to varying levels of enforcement. The absence of a centralised policy and timeline combined with the complex dynamics of human mobility and the variable intensity of local outbreaks makes assessing the effect of large-scale social distancing on COVID-19 transmission in the USA a challenge.We used daily mobility data derived from aggregated and anonymised cell (mobile) phone data, provided by Teralytics (Zürich, Switzerland) from Jan 1 to April 20, 2020, to capture real-time trends in movement patterns for each US county, and used these data to generate a social distancing metric. We used epidemiological data to compute the COVID-19 growth rate ratio for a given county on a given day. Using these metrics, we evaluated how social distancing, measured by the relative change in mobility, affected the rate of new infections in the 25 counties in the USA with the highest number of confirmed cases on April 16, 2020, by fitting a statistical model for each county.Our analysis revealed that mobility patterns are strongly correlated with decreased COVID-19 case growth rates for the most affected counties in the USA, with Pearson correlation coefficients above 0·7 for 20 of the 25 counties evaluated. Additionally, the effect of changes in mobility patterns, which dropped by 35-63% relative to the normal conditions, on COVID-19 transmission are not likely to be perceptible for 9-12 days, and potentially up to 3 weeks, which is consistent with the incubation time of severe acute respiratory syndrome coronavirus 2 plus additional time for reporting. We also show evidence that behavioural changes were already underway in many US counties days to weeks before state-level or local-level stay-at-home policies were implemented, implying that individuals anticipated public health directives where social distancing was adopted, despite a mixed political message.This study strongly supports a role of social distancing as an effective way to mitigate COVID-19 transmission in the USA. Until a COVID-19 vaccine is widely available, social distancing will remain one of the primary measures to combat disease spread, and these findings should serve to support more timely policy making around social distancing in the USA in the future.None.
Peptide Receptor Radionuclide Therapy as First-Line Systemic Treatment in Advanced Inoperable/Metastatic Neuroendocrine Tumors
Authors: Swayamjeet Satapathy, Bhagwant Rai Mittal, Ashwani Sood, Apurva Sood, Rakesh Kapoor, Rajesh Gupta
Journal: Clinical Nuclear Medicine (2020)

Purpose Advanced inoperable/metastatic neuroendocrine tumors (NETs) pose a therapeutic challenge with limited treatment options. Peptide receptor radionuclide therapy (PRRT), being specific in targeting the somatostatin receptors, is a promising and viable option in this setting. In this study, we intended to evaluate the role of PRRT as the first-line systemic therapy in advanced inoperable/metastatic NETs. Methods Data of consecutive patients of advanced inoperable/metastatic NETs treated with first-line 177 Lu-DOTATATE at our center, from September 2012 to August 2019, were collected and analyzed. Results Forty-five patients (median age, 50 years; range, 14–72 years) with treatment-naive advanced NETs received a median cumulative dose of 27 GBq (range, 13.3–41.3 GBq; over 2–7 cycles) 177 Lu-DOTATATE and 1250 mg/m 2 capecitabine from days 0 to 14 of each PRRT cycle. Three patients were lost to follow-up, 2 had nonmeasurable lesions on CT, and hence, radiological response using Response Evaluation Criteria in Solid Tumors version 1.1 could be assessed in 40 patients. Twelve of 40 patients (30%) showed a partial response, whereas stable disease was observed in 22 of 40 patients (55%). Disease progression was limited to 6 of 40 patients (15%). Treatment-related adverse effects were minimal with grade 3/4 anemia, leukopenia, neutropenia, and hepatotoxicity observed in 2%, 2%, 4%, and 4% of the patients, respectively. Median progression-free survival was 48 months (95% confidence interval, 34.7–61.3 months). Conclusions Our results indicate the efficacy and safety of first-line PRRT in advanced NETs. Future randomized trials, comparing PRRT and somatostatin analogs in treatment-naive patients, are required to identify the definite sequence of treatment options for these patients.
Plasma Tumor Mutation Burden and Response to Pembrolizumab—Letter
Authors: Xiaoyan Li, Yu Xu, Guoqiang Wang, Lin Li
Journal: Clinical Cancer Research (2020)

Predictive biomarkers are critical for patient selection in immune checkpoint inhibitor (ICI) therapy. However, the term “predictive” are often confused with “prognostic,” leading to inappropriate treatment choice in clinical practice and research.

We read with great interest the article by
Bayesian Evaluation of Temporal Signal in Measurably Evolving Populations
Authors: Sebastian Duchene, Philippe Lemey, Tanja Stadler, Simon Y W Ho, David A Duchene, Vijaykrishna Dhanasekaran, Guy Baele
Journal: Molecular Biology and Evolution (2020)

Phylogenetic methods can use the sampling times of molecular sequence data to calibrate the molecular clock, enabling the estimation of evolutionary rates and timescales for rapidly evolving pathogens and data sets containing ancient DNA samples. A key aspect of such calibrations is whether a sufficient amount of molecular evolution has occurred over the sampling time window, that is, whether the data can be treated as having come from a measurably evolving population. Here, we investigate the performance of a fully Bayesian evaluation of temporal signal (BETS) in sequence data. The method involves comparing the fit to the data of two models: a model in which the data are accompanied by the actual (heterochronous) sampling times, and a model in which the samples are constrained to be contemporaneous (isochronous). We conducted simulations under a wide range of conditions to demonstrate that BETS accurately classifies data sets according to whether they contain temporal signal or not, even when there is substantial among-lineage rate variation. We explore the behavior of this classification in analyses of five empirical data sets: modern samples of A/H1N1 influenza virus, the bacterium Bordetella pertussis, coronaviruses from mammalian hosts, ancient DNA from Hepatitis B virus, and mitochondrial genomes of dog species. Our results indicate that BETS is an effective alternative to other tests of temporal signal. In particular, this method has the key advantage of allowing a coherent assessment of the entire model, including the molecular clock and tree prior which are essential aspects of Bayesian phylodynamic analyses.
Tissue Doppler Imaging of the Diaphragm in Healthy Subjects and Critically Ill Patients
Authors: Eleni Soilemezi, Savvoula Savvidou, Panagiota Sotiriou, Dimitrios Smyrniotis, Matthew Tsagourias, Dimitrios Matamis
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Tissue Doppler imaging (TDI) is an echocardiographic method that measures the velocity of moving tissue.Objectives: We applied this technique to the diaphragm to assess the velocity of diaphragmatic muscle motion during contraction and relaxation.Methods: In 20 healthy volunteers, diaphragmatic TDI was performed to assess the pattern of diaphragmatic motion velocity, measure its normal values, and determine the intra- and interobserver variability of measurements. In 116 consecutive ICU patients, diaphragmatic excursion, thickening, and TDI parameters of peak contraction velocity, peak relaxation velocity, velocity–time integral, and TDI-derived maximal relaxation rate were assessed during weaning. In a subgroup of 18 patients, transdiaphragmatic pressure (Pdi)-derived parameters (peak Pdi, pressure–time product, and diaphragmatic maximal relaxation rate) were recorded simultaneously with TDI.Measurements and Main Results: In terms of reproducibility, the intercorrelation coefficients were >0.89 for all TDI parameters (P < 0.001). Healthy volunteers and weaning success patients exhibited lower values for all TDI parameters compared with weaning failure patients, except for velocity–time integral, as follows: peak contraction velocity, 1.35 ± 0.34 versus 1.50 ± 0.59 versus 2.66 ± 2.14 cm/s (P < 0.001); peak relaxation velocity, 1.19 ± 0.39 versus 1.53 ± 0.73 versus 3.36 ± 2.40 cm/s (P < 0.001); and TDI-maximal relaxation rate, 3.64 ± 2.02 versus 10.25 ± 5.88 versus 29.47 ± 23.95 cm/s2 (P < 0.001), respectively. Peak contraction velocity was strongly correlated with peak transdiaphragmatic pressure and pressure–time product, whereas Pdi-maximal relaxation rate was significantly correlated with TDI-maximal relaxation rate.Conclusions: Diaphragmatic tissue Doppler allows real-time assessment of the diaphragmatic tissue motion velocity. Diaphragmatic TDI-derived parameters differentiate patients who fail a weaning trial from those who succeed and correlate well with Pdi-derived parameters.
Rhabdoid Tumors Are Sensitive to the Protein-Translation Inhibitor Homoharringtonine
Authors: Thomas P. Howard, Elaine M. Oberlick, Matthew G. Rees, Taylor E. Arnoff, Minh-Tam Pham, Lisa Brenan, Mariana DoCarmo, Andrew L. Hong, Guillaume Kugener, Hsien-Chao Chou, Yiannis Drosos, Kaeli M. Mathias, Pilar Ramos, Brinton Seashore-Ludlow, Andrew O. Giacomelli, Xiaofeng Wang, Burgess B. Freeman, Kaley Blankenship, Lauren Hoffmann, Hong L. Tiv, Prafulla C. Gokhale, Cory M. Johannessen, Elizabeth A. Stewart, Stuart L. Schreiber, William C. Hahn, Charles W.M. Roberts
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Rhabdoid tumors are devastating pediatric cancers in need of improved therapies. We sought to identify small molecules that exhibit in vitro and in vivo efficacy against preclinical models of rhabdoid tumor. Experimental Design: We screened eight rhabdoid tumor cell lines with 481 small molecules and compared their sensitivity with that of 879 other cancer cell lines. Genome-scale CRISPR–Cas9 inactivation screens in rhabdoid tumors were analyzed to confirm target vulnerabilities. Gene expression and CRISPR–Cas9 data were queried across cell lines and primary rhabdoid tumors to discover biomarkers of small-molecule sensitivity. Molecular correlates were validated by manipulating gene expression. Subcutaneous rhabdoid tumor xenografts were treated with the most effective drug to confirm in vitro results. Results: Small-molecule screening identified the protein-translation inhibitor homoharringtonine (HHT), an FDA-approved treatment for chronic myelogenous leukemia (CML), as the sole drug to which all rhabdoid tumor cell lines were selectively sensitive. Validation studies confirmed the sensitivity of rhabdoid tumor to HHT was comparable with that of CML cell lines. Low expression of the antiapoptotic gene BCL2L1, which encodes Bcl-XL, was the strongest predictor of HHT sensitivity, and HHT treatment consistently depleted Mcl-1, the synthetic-lethal antiapoptotic partner of Bcl-XL. Rhabdoid tumor cell lines and primary-tumor samples expressed low BCL2L1, and overexpression of BCL2L1 induced resistance to HHT in rhabdoid tumor cells. Furthermore, HHT treatment inhibited rhabdoid tumor cell line and patient-derived xenograft growth in vivo. Conclusions: Rhabdoid tumor cell lines and xenografts are highly sensitive to HHT, at least partially due to their low expression of BCL2L1. HHT may have therapeutic potential against rhabdoid tumors.
Phase 0 and window of opportunity clinical trial design in neuro-oncology: a RANO review
Authors: Michael A Vogelbaum, Daria Krivosheya, Hamid Borghei-Razavi, Nader Sanai, Michael Weller, Wolfgang Wick, Riccardo Soffietti, David A Reardon, Manish K Aghi, Evanthia Galanis, Patrick Y Wen, Martin van den Bent, Susan Chang
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been expended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients who receive subtherapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements and determining intratumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood–brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this paper, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0–like (“window of opportunity”) studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include (i) only patients in whom a resection of the tumor is planned, (ii) use of clinical doses of an investigational agent, (iii) tissue sampling from enhancing and non-enhancing portions of the tumor, and (iv) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma.
Risk of Ischemic Stroke in Patients With Coronavirus Disease 2019 (COVID-19) vs Patients With Influenza
Authors: Alexander E. Merkler, Neal S. Parikh, Saad Mir, Ajay Gupta, Hooman Kamel, Eaton Lin, Joshua Lantos, Edward J. Schenck, Parag Goyal, Samuel S. Bruce, Joshua Kahan, Kelsey N. Lansdale, Natalie M. LeMoss, Santosh B. Murthy, Philip E. Stieg, Matthew E. Fink, Costantino Iadecola, Alan Z. Segal, Marika Cusick, Thomas R. Campion, Ivan Diaz, Cenai Zhang, Babak B. Navi
Journal: JAMA Neurology (2020)

<h3>Importance</h3> It is uncertain whether coronavirus disease 2019 (COVID-19) is associated with a higher risk of ischemic stroke than would be expected from a viral respiratory infection. <h3>Objective</h3> To compare the rate of ischemic stroke between patients with COVID-19 and patients with influenza, a respiratory viral illness previously associated with stroke. <h3>Design, Setting, and Participants</h3> This retrospective cohort study was conducted at 2 academic hospitals in New York City, New York, and included adult patients with emergency department visits or hospitalizations with COVID-19 from March 4, 2020, through May 2, 2020. The comparison cohort included adults with emergency department visits or hospitalizations with influenza A/B from January 1, 2016, through May 31, 2018 (spanning moderate and severe influenza seasons). <h3>Exposures</h3> COVID-19 infection confirmed by evidence of severe acute respiratory syndrome coronavirus 2 in the nasopharynx by polymerase chain reaction and laboratory-confirmed influenza A/B. <h3>Main Outcomes and Measures</h3> A panel of neurologists adjudicated the primary outcome of acute ischemic stroke and its clinical characteristics, mechanisms, and outcomes. We used logistic regression to compare the proportion of patients with COVID-19 with ischemic stroke vs the proportion among patients with influenza. <h3>Results</h3> Among 1916 patients with emergency department visits or hospitalizations with COVID-19, 31 (1.6%; 95% CI, 1.1%-2.3%) had an acute ischemic stroke. The median age of patients with stroke was 69 years (interquartile range, 66-78 years); 18 (58%) were men. Stroke was the reason for hospital presentation in 8 cases (26%). In comparison, 3 of 1486 patients with influenza (0.2%; 95% CI, 0.0%-0.6%) had an acute ischemic stroke. After adjustment for age, sex, and race, the likelihood of stroke was higher with COVID-19 infection than with influenza infection (odds ratio, 7.6; 95% CI, 2.3-25.2). The association persisted across sensitivity analyses adjusting for vascular risk factors, viral symptomatology, and intensive care unit admission. <h3>Conclusions and Relevance</h3> In this retrospective cohort study from 2 New York City academic hospitals, approximately 1.6% of adults with COVID-19 who visited the emergency department or were hospitalized experienced ischemic stroke, a higher rate of stroke compared with a cohort of patients with influenza. Additional studies are needed to confirm these findings and to investigate possible thrombotic mechanisms associated with COVID-19.
Multidrug-Resistant Infections in U.S. Hospitals
Authors: Rémi Le Guern, Caroline Loiez, Frederic Wallet
Journal: New England Journal of Medicine (2020)

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<i>CEACAM3</i>decreases asthma exacerbations and modulates respiratory syncytial virus latent infection in children
Authors: Ching-Hui Tsai, Ann Chen Wu, Bor-Luen Chiang, Yao-Hsu Yang, Shih-Pin Hung, Ming-Wei Su, Ya-Jen Chang, Yungling L Lee
Journal: Thorax (2020)

Background Respiratory syncytial virus (RSV) is associated with childhood asthma. Nevertheless, not all children exposed to RSV develop asthma symptoms, possibly because genes modulate the effects of RSV on asthma exacerbations. Objective The purpose of this study was to identify genes that modulate the effect of RSV latent infection on asthma exacerbations. Methods We performed a meta-analysis to investigate differentially expressed genes (DEGs) of RSV infection from Gene Expression Omnibus datasets. Expression quantitative trait loci (eQTL) methods were applied to select single nucleotide polymorphisms (SNPs) that were associated with DEGs. Gene-based analysis was used to identify SNPs that were significantly associated with asthma exacerbations in the Taiwanese Consortium of Childhood Asthma Study (TCCAS), and validation was attempted in an independent cohort, the Childhood Asthma Management Program (CAMP). Gene–RSV interaction analyses were performed to investigate the association between the interaction of SNPs and RSV latent infection on asthma exacerbations. Results A total of 352 significant DEGs were found by meta-analysis of RSV-related genes. We used 38 123 SNPs related to DEGs to investigate the genetic main effects on asthma exacerbations. We found that eight RSV-related genes ( GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3 ) were significantly associated with asthma exacerbations in TCCAS and also validated in CAMP. In TCCAS, rs7251960 ( CEACAM3 ) significantly modulated the effect of RSV latent infection on asthma exacerbations (false-discovery rate &lt;0.05). The rs7251960 variant was associated with CEACAM3 mRNA expression in lung tissue (p for trend=1.2×10 −7 ). CEACAM3 mRNA was reduced in nasal mucosa from subjects with asthma exacerbations in two independent datasets. Conclusions rs7251960 is an eQTL for CEACAM3 , and CEACAM3 mRNA expression is reduced in subjects experiencing asthma exacerbations. CEACAM3 may be a modulator of RSV latent infection on asthma exacerbations.
Crucial Role of AIM/CD5L in the Development of Glomerular Inflammation in IgA Nephropathy
Authors: Akiko Takahata, Satoko Arai, Emiri Hiramoto, Kento Kitada, Rina Kato, Yuko Makita, Hitoshi Suzuki, Junichiro Nakata, Kimi Araki, Toru Miyazaki, Yusuke Suzuki
Journal: Journal of the American Society of Nephrology (2020)

IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition.We established an AIM-deficient IgAN model (AIM-/- gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA-/- gddY) was also generated to further determine the role of AIM.In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM-/- gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA-/- gddY mice.AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.
Checklists for Tracheal Intubation of Critically Ill Adults
Authors: David R. Janz
Journal: JAMA Network Open (2020)

Joseph S. Turner, MD; Antonino W. Bucca, MD; Steven L. Propst, MD; Timothy J. Ellender, MD; Elisa J. Sarmiento, MSPH-EPAP; Laura M. Menard, MLS; Benton R. Hunter, MD
Health inequalities in ageing: towards a multidimensional lifecourse approach
Authors: Alessandra Marengoni, Amaia Calderon-Larrañaga
Journal: The Lancet Public Health (2020)

Since the late 1990s, considerable research has focused on better understanding the determinants of healthy ageing. However, the complexity of the ageing process requires an innovative research approach that shifts from the traditional focus on single diseases and specific time-windows towards multidimensional and longitudinal health trajectories. Awareness is increasing of the need to assess older people's health in a multidimensional way that comprises measures of functional ability reflecting people's capacity to meet their basic needs.
Robust expansion of HIV CAR T cells following antigen boosting in ART-suppressed nonhuman primates
Authors: Blake J. Rust, Leslie S. Kean, Lucrezia Colonna, Katherine E. Brandenstein, Nikhita H. Poole, Willimark Obenza, Mark R. Enstrom, Colby R. Maldini, Gavin I. Ellis, Christine M. Fennessey, Meei-Li Huang, Brandon F. Keele, Keith R. Jerome, James L. Riley, Hans-Peter Kiem, Christopher W. Peterson
Journal: Blood (2020)
Perivascular Fat Phenotyping Predicts Plaque Progression and Allows Detection of Unstable Plaque Using Coronary Computed Tomography Angiography
Authors: E K Oikonomou, S Thomas, S Kesavan, L M Fan, A S Antonopoulos, S Anthony, N Sabharwal, A Kelion, C Shirodaria, J P Langrish, A J Lucking, R K Kharbanda, S Neubauer, K M Channon, C Antoniades
Journal: Circulation (2018)