tbuckley/cabot-search huggingface dataset:
Inferring the causal effect of work zones on crashes: Methodology and a case study
Authors: Zhuoran Zhang, Burcu Akinci, Sean Qian
Journal: Analytic Methods in Accident Research (2021)

The increasing number of crashes occurring in work zones has received considerable attention in recent years. Previous studies have mainly focused on associations between work zone configurations and crash occurrence. Although identification of associational relations helps us understand how work zones co-exist with crashes, it does not provide interventional guidelines necessary to improve safety of work zone operations. In this paper, a causal inference model based on the potential outcome framework is proposed to rigorously infer the causal effects of work zone presence on crash risks under various work zone configurations, along with robustness tests. In developing such a causal model, three research gaps are identified and addressed: (1) potential confounding bias due to unobservable roadway characteristics; (2) potential bias caused by unobserved variables in multisource data; and (3) lack of actually observed traffic data and weather information at the exact time when a crash occurred and lack of large-scale high-granular data. The proposed methodology is applied to 5,006 work zones in Pennsylvania from 2015 to 2017, and the results are validated via a series of robustness tests. The results show that the causal effect of a work zone on crash occurrence is significantly positive, especially on roadways with high traffic volumes, on long-distance work zones, and work zones conducted during daytime. It appears that conducting work zones during nighttime with the current deployment strategies on Pennsylvania state roads does not necessarily increase crash risks, but a work zone significantly increases crash risks during day time.
Abstract 9774: Shockable Rhythms Are Common First Rhythms in Cardiac Arrests Involving Patient with Heart Failure with Preserved Ejection Fraction
Authors: Matthew Hooks, Stephanie Joppa, Albertine Beard, Selcuk Adabag
Journal: Circulation (2021)

Introduction: Sudden cardiac death (SCD) is responsible from 25% of the total mortality in patients with heart failure with preserved ejection fraction (HFpEF). Whether SCD in HFpEF is due to shockable or unshockable rhythms is unknown. Hypothesis: Cardiac arrests in HFpEF are due to ventricular tachycardia/ventricular fibrillation (VT/VF). Methods: We determined the initial rhythm in 286 consecutive in-hospital cardiac arrests at the Minneapolis VA Health Care system from 2011 through 2020. Clinical and survival information were obtained from electronic health records. According to their heart failure history, we categorized the patients as HFpEF, heart failure with reduced ejection fraction (HFrEF) or no heart failure (NoHF). Results: Of the 286 patients (mean age 70.2±9.0 years old and 97.5% male), 51 (17.8%) had HFpEF, 77 (26.9%) had HFrEF and 158 (55.2%) had NoHF. The initial rhythm was VT/VF in 47.1%, 39.0% and 22.2% of patients with HFpEF, HFrEF and NoHF respectively (p&lt;0.001) (Figure). Return of spontaneous circulation (ROSC) after VT/VF arrest was similar amongst the three groups (66.7%, 73.3% and 74.3%, respectively; p=0.8) but the 30-day survival trended higher in HFpEF (54.2%) and NoHF (48.6%) when compared with HFrEF (26.7%) (p=0.08)(Figure). Among patients with HFpEF, 30-day survival was lower after cardiac arrests due to PEA/Asystole when compared to those due to VT/VF (18.5% vs. 54.2%, respectively, p=0.03). Conclusion: VT/VF was the initial rhythm in 47% of patients with HFpEF who had in-hospital cardiac arrest. The proportion of VT/VF and ROSC after in-hospital cardiac arrest was similar in HFpEF and HFrEF. These data provide one more piece of evidence that SCD could be a therapeutic target in HFpEF.
Abstract 13347: Oxygen Metabolism After Cardiac Arrest: Patterns and Association With Survival
Authors: Katherine M Berg, Lakshman Balaji, Mahmoud S Issa, Michael W Donnino, Anne V Grossestreuer
Journal: Circulation (2021)

Introduction: How mitochondrial damage from cardiac arrest (CA) and resuscitation affects oxygen metabolism, and whether changes in metabolism are associated with outcome, is not well understood. We previously reported an association between higher oxygen consumption (VO2) in the first 12 hours after return of spontaneous circulation (ROSC) and survival in 17 post-arrest (PA) patients. The present study was conducted to investigate the association of VO2, VCO2 and RQ with survival in a larger PA cohort. Methods: From adult patients enrolled in several CA trials at our center, we selected those receiving targeted temperature management with ≥60 minutes of post-ROSC metabolic data collected in the first 24 hours after ROSC, using a gas exchange monitor that measures continuous VO2, VCO2 and RQ.The area under the curve (AUC) for VO2, VCO2 and RQ was calculated using all available values in the first 12 and 24 hours after ROSC. For both time periods, logistic regression was used to describe the relationship between survival and each AUC. We adjusted for temperature, sedation, and vasopressor s. Hourly medians were plotted by survival. Results: Of 64 patients included, 32 (50%) survived. There was no significant association between survival and AUC-VO2 or AUC-VCO2 in the first 12 (n=43) or 24 (n=64) hours after ROSC. 21 (49%) had a median RQ &lt;0.7 in the first 12 hours, and there was an association between survival and AUC-RQ in this time period (see table). Conclusion: There were no significant associations between VO2, VCO2 and survival in the first 12 and 24 hours after ROSC. RQ was abnormally low in many patients, and higher RQ in the first 12 hours after ROSC was associated with survival.
Data Errors in Results
Journal: JAMA Psychiatry (2021)

Ryan J. Van Lieshout, MD, PhD; Haley Layton, MPH; Calan D. Savoy, MSc; June S. L. Brown, PhD; Mark A. Ferro, PhD; David L. Streiner, PhD; Peter J. Bieling, PhD; Andrea Feller, MD; Steven Hanna, PhD
156P Safety/tolerability and antitumor activity of sitravatinib plus tislelizumab in patients with PD-(L)1-refractory/resistant unresectable or metastatic melanoma from a phase Ib study
Authors: C. Cui, H. Pan, M.S. Carlino, J. Cui, X. Wang, X. Li, J. Sun, L. Yang, J. Guo
Journal: Annals of Oncology (2021)
Abacavir dosing in neonates from birth to 3 months of life: a population pharmacokinetic modelling and simulation study
Authors: Adrie Bekker, Edmund V Capparelli, Avy Violari, Mark F Cotton, Mae Cababasay, Jiajia Wang, Ruth Mathiba, Lubbe Wiesner, Andrew Wiznia, Pearl Samson, Renee Browning, Jack Moye, Firdose L Nakwa, Eric Decloedt, Helena Rabie, Mark Mirochnick, Tim R Cressey
Journal: The Lancet HIV (2021)
INNV-14. PREDICTIVE UTILITY OF TEMOZOLOMIDE RESPONSE AS DETERMINED BY 3D EX-VIVO CELL CULTURE ASSAYS IN NEWLY DIAGNOSED GLIOBLASTOMA: A SINGLE INSTITUTION CASE SERIES EVALUATING PROGRESSION FREE SURVIVAL
Authors: Lindsay J Lipinski, Ajay Abad, Robert A Fenstermaker, Andrew J Fabiano, Dheerendra Prasad, Ashley M Smith, Matthew Gevaert, Teresa M DesRochers, Cecile Rose T Vibat
Journal: Neuro-Oncology (2021)

Abstract Glioblastoma is an aggressive tumor that is clinically and pathologically heterogeneous, and as such, remains challenging to treat. Response to initial standard treatment is widely variable and patient specific. We describe a cohort of 11 newly diagnosed patients enrolled in the 3D-PREDICT study at a single institution who underwent maximal safe surgical resection with tumor tissue collected prospectively for ex vivo cell culture assays against a panel of commonly used agents, including temozolomide. Nine of eleven patients received concurrent radiation + temozolomide followed by adjuvant temozolomide as per current standard of care. Two patients progressed immediately following concurrent chemoradiation; pseudoprogression was ruled out with short interval repeat imaging and clinical deterioration with pathology confirming recurrent tumor on re-resection in one patient. Median follow-up was 10 months (range 2-18). Outcomes were assessed retrospectively using Kaplan-Meier time-to-event curves, separating into two groups the temozolomide responders (n=4) and temozolomide nonresponders (n=7), as defined by the previously validated assay. The event was reached when radiographic tumor recurrence/progression occurred. Due to limited sample size, statistical significance was not reached, but a trend toward longer time to recurrence was noted among the temozolomide responder group. Continued experience with this tool may help clinicians predict which patients with newly diagnosed glioblastoma will respond well to initial treatment with temozolomide and those that may be more appropriate for clinical trial enrollment, independent of MGMT promoter methylation status. Longer term studies with a larger number of patients will help to determine the true significance of this drug response prediction assay.
A phase 1 trial of lipid-encapsulated mRNA encoding a monoclonal antibody with neutralizing activity against Chikungunya virus
Authors: Allison August, Husain Z. Attarwala, Sunny Himansu, Shiva Kalidindi, Sophia Lu, Rolando Pajon, Shu Han, Jean-Michel Lecerf, Joanne E. Tomassini, Marjie Hard, Leon M. Ptaszek, James E. Crowe, Tal Zaks
Journal: Nature Medicine (2021)

Abstract Chikungunya virus (CHIKV) infection causes acute disease characterized by fever, rash and arthralgia, which progresses to severe and chronic arthritis in up to 50% of patients. Moreover, CHIKV infection can be fatal in infants or immunocompromised individuals and has no approved therapy or prevention. This phase 1, first-in-human, randomized, placebo-controlled, proof-of-concept trial conducted from January 2019 to June 2020 evaluated the safety and pharmacology of mRNA-1944, a lipid nanoparticle-encapsulated messenger RNA encoding the heavy and light chains of a CHIKV-specific monoclonal neutralizing antibody, CHKV-24 ( NCT03829384 ). The primary outcome was to evaluate the safety and tolerability of escalating doses of mRNA-1944 administered via intravenous infusion in healthy participants aged 18–50 years. The secondary objectives included determination of the pharmacokinetics of mRNA encoding for CHKV-24 immunoglobulin heavy and light chains and ionizable amino lipid component and the pharmacodynamics of mRNA-1944 as assessed by serum concentrations of mRNA encoding for CHKV-24 immunoglobulin G (IgG), plasma concentrations of ionizable amino lipid and serum concentrations of CHKV-24 IgG. Here we report the results of a prespecified interim analysis of 38 healthy participants who received intravenous single doses of mRNA-1944 or placebo at 0.1, 0.3 and 0.6 mg kg −1 , or two weekly doses at 0.3 mg kg −1 . At 12, 24 and 48 h after single infusions, dose-dependent levels of CHKV-24 IgG with neutralizing activity were observed at titers predicted to be therapeutically relevant concentrations (≥1 µg ml −1 ) across doses that persisted for ≥16 weeks at 0.3 and 0.6 mg kg −1 (mean t 1/2 approximately 69 d). A second 0.3 mg kg −1 dose 1 week after the first increased CHKV-24 IgG levels 1.8-fold. Adverse effects were mild to moderate in severity, did not worsen with a second mRNA-1944 dose and none were serious. To our knowledge, mRNA-1944 is the first mRNA-encoded monoclonal antibody showing in vivo expression and detectable ex vivo neutralizing activity in a clinical trial and may offer a treatment option for CHIKV infection. Further evaluation of the potential therapeutic use of mRNA-1944 in clinical trials for the treatment of CHIKV infection is warranted.
Abstract 10907: Association of Intentional Cooling, Achieved Temperature, and Hypothermia Duration with Survival in Patients Treated with Extracorporeal Cardiopulmonary Resuscitation-An Exploratory Analysis of ELSO Registry
Authors: Takahiro Nakashima, Soshiro Ogata, Teruo Noguchi, Kunihiro Nishimura, Nana Sefa, Cindy H Hsu, Nathan L Haas, Jan Belohlavek, Vincent Pellegrino, Joseph Tonna, Jonathan Haft, Robert W Neumar
Journal: Circulation (2021)

Background: The efficacy of targeted temperature management remains unclear for patients treated with extracorporeal cardiopulmonary resuscitation (ECPR) due to refractory cardiac arrest. Methods: We analyzed the Extracorporeal Life Support Organization registry between 2010 and 2019. Patients 18-79 years old who received ECPR and had a reported temperature were included. First, we compared outcomes between patients who completed intentional cooling (IC) and those who did not complete intentional cooling (NIC). Among those who completed IC, we compared the outcomes between i) actual observed temperature &lt;34°C, 34 - 36°C, and ≥36°C, and ii) hypothermia duration below 36°C for &lt;12 hours, 12 - 48 hours, and &gt;48 hours. The primary outcome was in-hospital death within 90 days. Cox proportional hazard models were conducted with adjustment for covariates. Results: Among a total of 8,060 patients who received ECPR, 911 patients who had a record of actual temperature were identified. After multivariable adjustment, there was no significant difference in in-hospital mortality between patients treated with IC and NIC (Hazard ratio [HR] 1.13 [95% CI 0.93 - 1.39], p=0.2252). However, among patients treated with IC, recorded temperature at 34 - 36°C had a significantly lower adjusted HR for in-hospital mortality compared with ≥36°C (HR 0.73 [0.56 - 0.97], p=0.0274). Maintaining a temperature &lt;36°C for 12 - 48 hours had a significantly lower adjusted HR for in-hospital mortality compared with &lt;36°C for &lt;12 hours (HR 0.70 [0.53 - 0.91], p=0.0080). Conclusion: In this exploratory analysis, IC was not associated with lower in-hospital mortality in patients treated with ECPR. However, among those treated with IC, achieving a target temperature of 34 - 36°C and maintaining it for 12 - 48 hours were associated with lower in-hospital mortality.
CircIL4R activates the PI3K/AKT signaling pathway via the miR-761/TRIM29/PHLPP1 axis and promotes proliferation and metastasis in colorectal cancer
Authors: Tao Jiang, Hongyu Wang, Lianyu Liu, Hu Song, Yi Zhang, Jiaqi Wang, Lei Liu, Teng Xu, Ruizhi Fan, Yixin Xu, Shuai Wang, Linsen Shi, Li Zheng, Renhao Wang, Jun Song
Journal: Molecular Cancer (2021)

Accumulating studies have revealed that aberrant expression of circular RNAs (circRNAs) is widely involved in the tumorigenesis and progression of malignant cancers, including colorectal cancer (CRC). Nevertheless, the clinical significance, levels, features, biological function, and molecular mechanisms of novel circRNAs in CRC remain largely unexplored.CRC-related circRNAs were identified through bioinformatics analysis and verified in clinical specimens by qRT-PCR and in situ hybridization (ISH). Then, in vitro and in vivo experiments were performed to determine the clinical significance of, functional roles of, and clinical characteristics associated with circIL4R in CRC specimens and cells. Mechanistically, RNA pull-down, fluorescence in situ hybridization (FISH), luciferase reporter, and ubiquitination assays were performed to confirm the underlying mechanism of circIL4R.CircIL4R was upregulated in CRC cell lines and in sera and tissues from CRC patients and was positively correlated with advanced clinicopathological features and poor prognosis. Functional experiments demonstrated that circIL4R promotes CRC cell proliferation, migration, and invasion via the PI3K/AKT signaling pathway. Mechanistically, circIL4R was regulated by TFAP2C and competitively interacted with miR-761 to enhance the expression of TRIM29, thereby targeting PHLPP1 for ubiquitin-mediated degradation to activate the PI3K/AKT signaling pathway and consequently facilitate CRC progression.Our findings demonstrate that upregulation of circIL4R plays an oncogenic role in CRC progression and may serve as a promising diagnostic and prognostic biomarker for CRC detection and as a potential therapeutic target for CRC treatment.
Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma
Authors: Frederick L. Locke, David B. Miklos, Caron A. Jacobson, Miguel-Angel Perales, Marie-José Kersten, Olalekan O. Oluwole, Armin Ghobadi, Aaron P. Rapoport, Joseph McGuirk, John M. Pagel, Javier Muñoz, Umar Farooq, Tom van Meerten, Patrick M. Reagan, Anna Sureda, Ian W. Flinn, Peter Vandenberghe, Kevin W. Song, Michael Dickinson, Monique C. Minnema, Peter A. Riedell, Lori A. Leslie, Sridhar Chaganti, Yin Yang, Simone Filosto, Jina Shah, Marco Schupp, Christina To, Paul Cheng, Leo I. Gordon, Jason R. Westin
Journal: New England Journal of Medicine (2021)

The prognosis of patients with early relapsed or refractory large B-cell lymphoma after the receipt of first-line chemoimmunotherapy is poor.In this international, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with large B-cell lymphoma that was refractory to or had relapsed no more than 12 months after first-line chemoimmunotherapy to receive axicabtagene ciloleucel (axi-cel, an autologous anti-CD19 chimeric antigen receptor T-cell therapy) or standard care (two or three cycles of investigator-selected, protocol-defined chemoimmunotherapy, followed by high-dose chemotherapy with autologous stem-cell transplantation in patients with a response to the chemoimmunotherapy). The primary end point was event-free survival according to blinded central review. Key secondary end points were response and overall survival. Safety was also assessed.A total of 180 patients were randomly assigned to receive axi-cel and 179 to receive standard care. The primary end-point analysis of event-free survival showed that axi-cel therapy was superior to standard care. At a median follow-up of 24.9 months, the median event-free survival was 8.3 months in the axi-cel group and 2.0 months in the standard-care group, and the 24-month event-free survival was 41% and 16%, respectively (hazard ratio for event or death, 0.40; 95% confidence interval, 0.31 to 0.51; P<0.001). A response occurred in 83% of the patients in the axi-cel group and in 50% of those in the standard-care group (with a complete response in 65% and 32%, respectively). In an interim analysis, the estimated overall survival at 2 years was 61% in the axi-cel group and 52% in the standard-care group. Adverse events of grade 3 or higher occurred in 91% of the patients who received axi-cel and in 83% of those who received standard care. Among patients who received axi-cel, grade 3 or higher cytokine release syndrome occurred in 6% and grade 3 or higher neurologic events in 21%. No deaths related to cytokine release syndrome or neurologic events occurred.Axi-cel therapy led to significant improvements, as compared with standard care, in event-free survival and response, with the expected level of high-grade toxic effects. (Funded by Kite; ZUMA-7 ClinicalTrials.gov number, NCT03391466.).
68P A phase Ib study of lenvatinib + pembrolizumab (LEN + PEMBRO) in patients (pts) with unresectable hepatocellular carcinoma (uHCC): Study 116 follow-up analysis
Authors: M. Kudo, R. Finn, M. Ikeda, A. Zhu, M. Sung, A. Baron, T. Okusaka, M. Kobayashi, H. Kumada, S. Kaneko, M. Pracht, T. Meyer, S. Nagao, K. Saito, K. Mody, L. Dubrovsky, J. Llovet
Journal: Annals of Oncology (2021)
144P Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer (TD-NICE): A single arm, phase II study
Authors: X. Yan, J. Zhao, J. Lei, H. Duan, Y. Ni, Y. Zhou, X. Wang, H. Qi, H. Liu, F. Tian, Q. Lu, J. Sun, E. Yang, D. Zhong, T. Wang, L. Huang, J. Wang, T. Jiang
Journal: Annals of Oncology (2021)
Lin28b-<i>Let-7</i>-PRC1 Axis Guides Developmental Maturation of the Hematopoietic System
Authors: Mayuri Tanaka-Yano, Dahai Wang, Eleanor Meader, Melissa A. Kinney, Vivian Morris, Edroaldo Lummertz da Rocha, Nan Liu, Stuart H. Orkin, Trista E. North, George Q. Daley, Robert Grant Rowe
Journal: Blood (2021)
EXTH-32. NOVEL THIORIDAZINE DERIVATES: ANTIPROLIFERATIVE AND APOPTOSIS-INDUCING ACTIVITY ON GLIOBLASTOMA CELLS IN VITRO
Authors: Stephanie Schwab, Katharina Sarnow, Eirin Alme, Roland Goldbrunner, Hans-René Bjørsvik, Rolf Bjerkvig
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Although withdrawn from the market due to cardiotoxicity, we showed that the antipsychotic drug Thioridazine shows chemosensitizing effects in combination with Temozolomide (TMZ) for the treatment of glioblastoma multiforme (GBM). Based on our prior observations, the aim of this study was through medicinal chemistry, to design and synthesize new compounds based on Thioridazines tricyclic structure, and to determine their therapeutic potential. METHODS Fourteen compounds were synthesized where variations were made within the tricyclic side chains. The newly synthesized compounds were screened for therapeutic efficacy with or without TMZ using a WST-1 cell viability assay and real-time imaging system (IncuCyte). Tests were performed on both monolayer cell cultures, as well as on glioma stem cell spheroids (GSC). The therapeutic effects were also studied on human astrocytes (NHA) as well as on rat brain organoids (BO). Annexin V/propidium iodide (PI) double staining followed by flow cytometric analysis was performed after 48 hours of treatment. RESULTS Following an extensive screening, we identified two novel compounds (EA01 and EA02) that at concentrations of 4 and 9.5 µM showed a strong cytotoxicity on GBM cell lines (U-87 MG p&amp;lt; 0,0001, U251 p&amp;lt; 0,0001, LN18 p= 0,0004) as well as on glioma stem cells (GSC) (P3 p&amp;lt; 0,0001) compared to NHA and BOs respectively. Also, when BOs were confronted with GSC spheres in an invasion assay, a selective cytotoxicity was observed in the GSCs. Mechanistically, we show that both compounds induce apoptosis in GBM cells. Moreover, intravenous delivery of increasing concentrations of EA01 and EA02 revealed no toxicity in animals at concentrations up to 21 mg/kg. CONCLUSION We developed two new tricyclic therapeutic compounds that show a strong selective cytotoxicity in GBM cells with limited systemic toxicity in animals. Ongoing studies are investigating the therapeutic potential of EA01 and EA02 in orthotopic xenografts in vivo.
Measurement-Based and Data-Informed Psychological Therapy
Authors: Wolfgang Lutz, Brian Schwartz, Jaime Delgadillo
Journal: Annual Review of Clinical Psychology (2021)

Outcome measurement in the field of psychotherapy has developed considerably in the last decade. This review discusses key issues related to outcome measurement, modeling, and implementation of data-informed and measurement-based psychological therapy. First, an overview is provided, covering the rationale of outcome measurement by acknowledging some of the limitations of clinical judgment. Second, different models of outcome measurement are discussed, including pre-post, session-by-session, and higher-resolution intensive outcome assessments. Third, important concepts related to modeling patterns of change are addressed, including early response, dose-response, and nonlinear change. Furthermore, rational and empirical decision tools are discussed as the foundation for measurement-based therapy. Fourth, examples of clinical applications are presented, which show great promise to support the personalization of therapy and to prevent treatment failure. Finally, we build on continuous outcome measurement as the basis for a broader understanding of clinical concepts and data-driven clinical practice in the future.
Current practice and evolving concepts in septic shock resuscitation
Authors: Jan Bakker, Eduardo Kattan, Djillali Annane, Ricardo Castro, Maurizio Cecconi, Daniel De Backer, Arnaldo Dubin, Laura Evans, Michelle Ng Gong, Olfa Hamzaoui, Can Ince, Bruno Levy, Xavier Monnet, Gustavo A. Ospina Tascón, Marlies Ostermann, Michael R. Pinsky, James A. Russell, Bernd Saugel, Thomas W. L. Scheeren, Jean-Louis Teboul, Antoine Vieillard Baron, Jean-Louis Vincent, Fernando G. Zampieri, Glenn Hernandez
Journal: Intensive Care Medicine (2021)