tbuckley/cabot-search huggingface dataset:
Mechanistic studies of PEG-asparaginase-induced liver injury and hepatic steatosis in mice
Authors: Gundala Venkata Naveen Kumar, Keito Hoshitsuki, Sanjay Rathod, Manda J. Ramsey, Lauren Kokai, Erin E. Kershaw, Wen Xie, Christian A. Fernandez
Journal: Acta Pharmaceutica Sinica B (2021)

PEGylated-l-asparaginase (PEG-ASNase) is a chemotherapeutic agent used to treat pediatric acute lymphoblastic leukemia (ALL). Its use is avoided in adults due to its high risk of liver injury including hepatic steatosis, with obesity and older age considered risk factors of the injury. Our study aims to elucidate the mechanism of PEG-ASNase-induced liver injury. Mice received 1500 U/kg of PEG-ASNase and were sacrificed 1, 3, 5, and 7 days after drug administration. Liver triglycerides were quantified, and plasma bilirubin, ALT, AST, and non-esterified fatty acids (NEFA) were measured. The mRNA and protein levels of genes involved in hepatic fatty acid synthesis, β-oxidation, very low-density lipoprotein (VLDL) secretion, and white adipose tissue (WAT) lipolysis were determined. Mice developed hepatic steatosis after PEG-ASNase, which associated with increases in bilirubin, ALT, and AST. The hepatic genes Ppara, Lcad/Mcad, Hadhb, Apob100, and Mttp were upregulated, and Srebp-1c and Fas were downregulated after PEG-ASNase. Increased plasma NEFA, WAT loss, and adipose tissue lipolysis were also observed after PEG-ASNase. Furthermore, we found that PEG-ASNase-induced liver injury was exacerbated in obese and aged mice, consistent with clinical studies of ASNase-induced liver injury. Our data suggest that PEG-ASNase-induced liver injury is due to drug-induced lipolysis and lipid redistribution to the liver.
Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results
Authors: Nitin Jain, Michael J. Keating, Philip A. Thompson, Alessandra Ferrajoli, Jan A. Burger, Gautam Borthakur, Koichi Takahashi, Zeev E. Estrov, Koji Sasaki, Tapan M. Kadia, Marina Konopleva, Yesid Alvarado, Musa Yilmaz, Courtney D. DiNardo, Prithviraj Bose, Maro Ohanian, Naveen Pemmaraju, Elias J. Jabbour, Rashmi Kanagal-Shamanna, Keyur Patel, Wei Wang, Jeffrey L. Jorgensen, Sa A Wang, Naveen Garg, Xuemei Wang, Chongjuan Wei, Nichole Cruz, Ana Ayala, William Plunkett, Hagop Kantarjian, Varsha Gandhi, William G. Wierda
Journal: Blood (2021)
When I use a word . . . . The Precautionary Principle: a brief history
Authors: Jeffrey K Aronson
Journal: BMJ (2021)

When I use word . . . .The Precautionary Principle: a brief history Two ideas precede the modern Precautionary Principle.First, that prevention is better than cure, exemplified by an aphorism in an early 13th century book of Jewish aphorisms, the Sefer Hasidim: "Who is a skilled physician?He who can prevent sickness."Secondly, Thomas Sydenham's 17th century assertion that in healthcare it is important above all not to do harm, "primum est ut non nocere."These two ideas come together in the Vorsorgeprinzip, which was incorporated into German legislation for maintaining clean air in the 1960s and 1970s, and first appeared in English-language documents in 1982, which referred to taking a precautionary approach or precautionary measures, or more formally as the Precautionary Principle.The principle features in international documents such as the Rio Declaration and in many pieces of EU legislation relating to topics as diverse as genetically modified organisms, food safety, the safety of toys, and invasion of alien species of animals, plants, fungi, or microorganisms.
Abstract 12052: A Comprehensive Simulation-Based Training for E-CPR Improves the Neurological Outcome of Patients With Refractory Cardiac Arrest
Authors: Takaaki Toyofuku, Takashi Unoki, Junya Matsuura, Yutaka Konami, Hiroto Suzuyama, Masayuki Inoue, Eiji Horio, Tetsuo Yufu, Kazuhisa Kodama, Megumi Yamamuro, Eiji Taguchi, Tadashi Sawamura, Koichi Nakao, Tomohiro Sakamoto
Journal: Circulation (2021)

Background: Extracorporeal cardiopulmonary resuscitation (E-CPR) has been utilized as a rescue strategy for patients with refractory cardiac arrest (CA). To improve the outcome of E-CPR, we developed a comprehensive simulation-based E-CPR training program. In the present study we assessed whether the E-CPR training improved the mortality and the neurological outcome. Methods: We have implemented the comprehensive E-CPR simulation training program twice a year to the medical team, which consists of emergency physicians, cardiologists, nurses, clinical engineers, and radiographers using a mock vascular model for E-CPR (ECMO cannulation). We assessed collapse to ECMO time, cumulative 30-day survival and good neurological outcome at hospital discharge defined as the cerebral performance categories (CPC) of 1 or 2. Results: Fifty-three consecutive patients received E-CPR for OHCA from January 2012 to December 2020 in which 31 patients were prior to (until September 2017) and 22 were after (from October 2017) the initiation of the E-CPR training. No differences were found in age, rates of witnessed and bystander-CPR, shockable rhythms, or acute coronary syndrome (ACS). Intra-aortic balloon pump was used in 87% patients prior to and 27% patients after the training (p&lt;0.001), and a microaxial Impella pump was used in 55% after the training. Collapse to ECMO time was significantly shorter after the training (p&lt;0.001). Cumulative 30-day survival and the rate of favorable neurological outcome were significantly higher after the training (p&lt;0.05). Multivariate cox proportional hazard analysis revealed that age (hazard ratio [HR], 1.38 (10 years increase), 95% confidence interval [CI], 1.12-1.73, p=0.002), Collapse to ECMO time (HR, 1.14, 95%CI, 1.04-1.23, p=0.006), and additional Impella use (HR, 0.23, 95% CI, 0.08-0.69, p=0.0009) were significantly associated with the 30-day survival. Conclusions: The E-CPR training significantly improved the collapse to ECMO time. The faster deployment of ECMO improves the neurological outcome and 30-day survival in patients with refractory CA. Additional use of Impella may improve the survival.
Vaccine effectiveness against SARS-CoV-2 infection, hospitalization, and death when combining a first dose ChAdOx1 vaccine with a subsequent mRNA vaccine in Denmark: A nationwide population-based cohort study
Authors: Mie Agermose Gram, Jens Nielsen, Astrid Blicher Schelde, Katrine Finderup Nielsen, Ida Rask Moustsen-Helms, Anne Katrine Bjørkholt Sørensen, Palle Valentiner-Branth, Hanne-Dorthe Emborg
Journal: PLoS Medicine (2021)

The recommendations in several countries to stop using the ChAdOx1 vaccine has led to vaccine programs combining different Coronavirus Disease 2019 (COVID-19) vaccine types, which necessitates knowledge on vaccine effectiveness (VE) of heterologous vaccine schedules. The aim of this Danish nationwide population-based cohort study was therefore to estimate the VE against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death following the first dose of the ChAdOx1 vaccine and the combination of the ChAdOx1/mRNA vaccines.All individuals alive in or immigrating to Denmark from 9 February 2021 to 23 June 2021 were identified in the Danish Civil Registration System. Information on exposure, outcomes, and covariates was obtained from Danish national registries. Poisson and Cox regression models were used to calculate crude and adjusted VE, respectively, along with 95% confidence intervals (CIs) against SARS-CoV-2 infection and COVID-19-related hospitalization or death comparing vaccinated versus unvaccinated individuals. The VE estimates were adjusted for calendar time as underlying time and for sex, age, comorbidity, country of origin, and hospital admission. The analyses included 5,542,079 individuals (97.6% of the total Danish population). A total of 144,360 individuals were vaccinated with the ChAdOx1 vaccine as the first dose, and of these, 136,551 individuals received an mRNA vaccine as the second dose. A total of 1,691,464 person-years and 83,034 SARS-CoV-2 infections were included. The individuals vaccinated with the first dose of the ChAdOx1 vaccine dose had a median age of 45 years. The study population was characterized by an equal distribution of males and females; 6.7% and 9.2% originated from high-income and other countries, respectively. The VE against SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine was 88% (95% CI: 83; 92) 14 days after the second dose and onwards. There were no COVID-19-related hospitalizations or deaths among the individuals vaccinated with the combined vaccine schedule during the study period. Study limitations including unmeasured confounders such as risk behavior and increasing overall vaccine coverage in the general population creating herd immunity are important to take into consideration when interpreting the results.In this study, we observed a large reduction in the risk of SARS-CoV-2 infection when combining the ChAdOx1 and an mRNA vaccine, compared with unvaccinated individuals.
Abstract 11045: Pre-Hospital Airway for Out-of-Hospital Cardiac Arrest: A Nationwide Multicenter Study
Authors: Hansol Chang, Jin Ho Choi, DAUN JEONG
Journal: Circulation (2021)

Introduction: This study investigated whether use of pre-hospital advanced airway management (AAM) is associated with improved survival of adults with out-of hospital cardiac arrest (OHCA) compared to conventional bag-valve-mask ventilation (BVM). Method: The study subjects were derived from Korean Cardiac Arrest Research Consortium (KoCARC), a multi-center OHCA registry of Korea. Patients who underwent AAM or BVM using supraglottic airway, oropharyngeal airway, or endotracheal intubation were compared. The differences in baseline clinical characteristics were adjusted using propensity scoring matching (PSM) or inverse probability of treatment weighting (IPTW). The primary outcome was 30-day survival with neurologically favorable status of cerebral performance category ≤2. The outcome was also compared according to the duration of low-flow time. Results: Of 9,616 patients enrolled, (median age = 71, male sex = 65%) there were 7,583 AAM and 2,033 BVM patients. The unadjusted survival to with neurologically favorable status was lower in AAM compared to BVM (HR = 1.27, 95% confidence interval (CI) = 1.20 - 1.34, p&lt;0.001). However, there was no significant difference of survival to with neurologically favorable status between AAM and BVM after PSM or ITPW-adjusted comparisons (p&gt;0.05, all). This finding was consistent irrespective of duration of low-flow time. Conclusion: In this nationwide real-world data of out-of hospital cardiac arrest study, prehospital advanced airway management compared to bag-and-mask ventilation did not result in an improved clinical outcome at 30 days.
Abstract 12173: Out-of-Hospital Cardiac Arrest and Community First Response: Identifying Data Collection and Analysis Priorities via the Nominal Group Technique
Authors: Eithne Heffernan, Dylan Keegan, Jenny Mc Sharry, Tomas Barry, Andrew Murphy, David Menzies, Cathal O'Donnell, Siobhan Masterson
Journal: Circulation (2021)

Introduction: Community First Response (CFR) is an important intervention for out-of-hospital cardiac arrest (OHCA) in many countries. CFR entails the mobilization of volunteers by the Emergency Medical Services (EMS) to respond to OHCAs in their vicinity. These volunteers include lay-people and professionals (e.g. physicians, fire-fighters). CFR can increase rates of cardiopulmonary resuscitation (CPR) or defibrillation performed prior to EMS arrival. However, its impact on additional outcomes (e.g. survival, cognitive function) requires further study. This research aimed to identify the most important CFR data to collect and analyze, as well as the most important uses of CFR data. Methods: This study used the Nominal Group Technique: a structured consensus process where key stakeholders develop a set of prioritized recommendations. There were 16 participants, including CFR volunteers, an OHCA survivor, researchers, clinicians, EMS personnel, and policy-makers. They completed an online survey to generate lists of the most important (1) CFR data to collect and analyze and (2) uses of CFR data. They then attended a virtual meeting where they discussed the survey results in groups before voting for their top ten priorities from each list. They also identified barriers to CFR data collection. Results: The top ten CFR data to collect and analyze included volunteer response time, interventions performed by volunteers, time of emergency, time of CPR initiation, individuals who performed CPR, and the mental and physical effects of being a volunteer. The top ten uses of CFR data included providing feedback to volunteers, increasing bystander participation in resuscitation, improving volunteer training, measuring CFR effectiveness, and encouraging inter-operability with the EMS. Barriers to data collection included time constraints, prioritization of patient care, and limited training. Conclusions: This study established priorities for the collection, analysis, and use of CFR data in consultation with key stakeholders. These findings have important implications for both CFR research and practice. In particular, they can be used to improve the efficiency, consistency, and utility of CFR data collection and to build evidence for this intervention.
Abstract 9180: Importance of Preventing Decreased Levels of Lysophosphatidylcholine—DHA in Brain and Plasma for Attenuating Brain Injury After Cardiac Arrest
Authors: Mitsuaki Nishikimi, Muhammad Shoaib, Tomoaki Aoki, Rishabh Choudhary, Santiago J Miyara, Tsukasa Yagi, Tai Yin, Lance B Becker, Junhwan Kim
Journal: Circulation (2021)

Introduction: Lysophosphatidylcholine (LPC) was found to be decreased in plasma in the early phase of resuscitation after cardiac arrest (CA), including a species containing docosahexaenoic acid (LPC-DHA). Supplementing this deficiency of plasma LPC-DHA post-CA significantly attenuated brain dysfunction implicating a causative role of plasma decreased LPC-DHA for brain injury. Previous studies showed the importance of LPC-DHA as a carrier of DHA to maintain proper brain function. However, the role of LPC-DHA for brain function has not been fully understood. Objective: This study is aimed at determining the importance of maintaining proper brain LPC-DHA level via plasma supplementation to prevent brain damage after CA using human patients, animal model, and in-vitro cell studies. Methods and Results: We first evaluated associations between the plasma LPC-DHA levels and neurological outcomes using 45 post-CA patients. We then measured LPC-DHA levels and histological, biochemical, metabolic alterations in the plasma and brain after 10 min CA rat model and examined how these alterations were attenuated by supplementing LPC-DHA. Finally, we further investigated the beneficial effect of LPC-DHA using cell cultures. We found that the decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased level of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized the brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocyte, and expression of various inflammatory and mitochondrial dysfunction genes. We also found normalized overall metabolic alterations from the untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. Conclusion: The attenuation of biochemical and physiologic alterations, and the normalization of decreased brain LPC-DHA post-CA with LPC-DHA supplementation demonstrate plasma LPC-DHA is important for the maintenance of proper brain LPC-DHA levels, which is essential for preventing brain damage post-CA.
Impaired Insulin Clearance as the Initial Regulator of Obesity-Associated Hyperinsulinemia: Novel Insight Into the Underlying Mechanism Based on Serum Bile Acid Profiles
Authors: Zhenzhen Fu, Qinyi Wu, Wen Guo, Jingyu Gu, Xuqin Zheng, Yingyun Gong, Chenyan Lu, Jingya Ye, Xuan Ye, Wanzi Jiang, Moran Hu, Baowen Yu, Qi Fu, Xiang Liu, Jianling Bai, John Zhong Li, Tao Yang, Hongwen Zhou
Journal: Diabetes Care (2021)

OBJECTIVE To investigate the roles of insulin clearance and insulin secretion in the development of hyperinsulinemia in obese subjects and to reveal the association between insulin clearance and bile acids (BAs). RESEARCH DESIGN AND METHODS In cohort 1, insulin secretion, sensitivity, and endogenous insulin clearance were evaluated with an oral glucose tolerance test in 460 recruited participants. In cohort 2, 81 participants underwent an intravenous glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess insulin secretion, endogenous and exogenous insulin clearance, and insulin sensitivity. Based on insulin resistance levels ranging from mild to severe, obese participants without diabetes were further divided into 10 quantiles in cohort 1 and into tertiles in cohort 2. Forty serum BAs were measured in cohort 2 to examine the association between BAs and insulin clearance. RESULTS All obese participants had impaired insulin clearance, and it worsened with additional insulin resistance in obese subjects without diabetes. However, insulin secretion was unchanged from quantile 1 to 3 in cohort 1, and no difference was found in cohort 2. After adjustments for all confounding factors, serum-conjugated BAs, especially glycodeoxycholic acid (GDCA; β = −0.335, P = 0.004) and taurodeoxycholic acid (TDCA; β = −0.333, P = 0.003), were negatively correlated with insulin clearance. The ratio of unconjugated to conjugated BAs (β = 0.335, P = 0.002) was positively correlated with insulin clearance. CONCLUSIONS Hyperinsulinemia in obese subjects might be primarily induced by decreased insulin clearance rather than increased insulin secretion. Changes in circulating conjugated BAs, especially GDCA and TDCA, might play an important role in regulating insulin clearance.
Identifying Brigham and Women's Hospital stage T2a cutaneous squamous cell carcinomas at risk of poor outcomes
Authors: Neha Gupta, Rachel E. Weitzman, Fadi Murad, Shlomo A. Koyfman, Timothy D. Smile, Michael S. Chang, Jacqueline M. Maher, Chrysalyne D. Schmults, Allison T. Vidimos, Emily S. Ruiz
Journal: Journal of the American Academy of Dermatology (2021)
84P Predicting longer-term progression-free survival (PFS) with durvalumab after chemoradiotherapy (CRT) in unresectable stage III NSCLC using a mixture cure model (MCM)
Authors: C. Faivre-Finn, D. Jackson, K.R. Abrams, N.S. Hawkins, P. Thiyagarajah, Y. Zhang, R. Hettle, W. Dunlop, D.R. Spigel
Journal: Annals of Oncology (2021)
Immunogenicity and safety of two doses of the CoronaVac SARS-CoV-2 vaccine in SARS-CoV-2 seropositive and seronegative patients with autoimmune rheumatic diseases in Brazil: a subgroup analysis of a phase 4 prospective study
Authors: Nadia E Aikawa, Leonard V K Kupa, Sandra G Pasoto, Ana C Medeiros-Ribeiro, Emily F N Yuki, Carla G S Saad, Tatiana Pedrosa, Ricardo Fuller, Samuel K Shinjo, Percival D Sampaio-Barros, Danieli C O Andrade, Rosa M R Pereira, Luciana P C Seguro, Juliana M L Valim, Filipe Waridel, Ana Marli C Sartori, Alberto J S Duarte, Leila Antonangelo, Ester C Sabino, Paulo Rossi Menezes, Esper G Kallas, Clovis A Silva, Eloisa Bonfa
Journal: The Lancet Rheumatology (2021)

We aimed to examine the immunogenicity pattern induced by the inactivated SARS-CoV-2 vaccine CoronaVac (Sinovac Life Sciences, Beijing, China) in SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases compared with seropositive controls, seronegative patients with autoimmune rheumatic diseases, and seronegative controls.
Abstract 10412: Duration of Interruptions in Chest Compressions Increases with Increasing Number of Interventions During Cardiac Arrest
Authors: Jennifer Larson, Casey Owens, Daniel Jafari, Timmy Li, Ghania Haddad, Lance Becker, Daniel Rolston
Journal: Circulation (2021)

Introduction: The American Heart Association recommends limiting chest compression interruptions to ≤10 seconds because prolonged interruptions are detrimental to survival in cardiac arrest. Determining the causes of interruptions is important to structure teams to minimize interruption time. This study sought to determine 1) whether performing more interventions during an interruption increases interruption time and 2) whether the time into the resuscitation in which the interruption occurs affects the duration of the interruption. Hypothesis: We hypothesize that the median duration of an interruption increases as the number of interventions increases and that the median duration of an interruption increases if it occurs later in the resuscitation. Methods: In January 2018 our Emergency Department (ED) began video recording all cardiac arrest resuscitations. These videos are reviewed by a committee of physicians, nurses, technicians, and research staff, and specific data points are confirmed by a physician. The duration of each interruption and cause of each intervention performed during each interruption was recorded. Results: A total of 122 patients with 798 chest compression interruptions from January 2018 to December 2020 were included in our analysis. Median age was 78 years and 44% were female. The median duration of interruptions was 13 seconds (interquartile range [IQR]: 10, 18) when no interventions were performed, 12 seconds (IQR: 8, 18) with 1 intervention, 17 seconds (IQR: 12, 26) with 2 interventions, and 19 seconds (IQR: 13, 24) with 3 or 4 interventions (p&lt;0.0001). The median duration of interruptions was 14 seconds (IQR: 10, 22) in the first quartile of resuscitation length, 14 seconds (IQR: 10, 20) in quartile 2, 14 seconds (IQR: 10, 24) in quartile 3, and 11 seconds (IQR: 8, 18) in quartile 4 (p=0.0058). Conclusions: Our findings demonstrate that the median duration of chest compression interruptions increases as the number of interventions performed during that interruption increases. Additionally, interruption duration was shortest when the interruption was performed later in the resuscitation. These findings suggest that interruptions in chest compressions can be minimized by performing fewer tasks during the interruption.