tbuckley/cabot-search huggingface dataset:
Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients
Authors: Angélica Jayk Bernal, Monica M. Gomes da Silva, Dany B. Musungaie, Evgeniy Kovalchuk, Antonio Gonzalez, Virginia Delos Reyes, Alejandro Martín-Quirós, Yoseph Caraco, Angela Williams-Diaz, Michelle L. Brown, Jiejun Du, Alison Pedley, Christopher Assaid, Julie Strizki, Jay A. Grobler, Hala H. Shamsuddin, Robert Tipping, Hong Wan, Amanda Paschke, Joan R. Butterton, Matthew G. Johnson, Carisa De Anda
Journal: New England Journal of Medicine (2021)

New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
17. Diabetes Advocacy: <i>Standards of Medical Care in Diabetes—2022</i>
Journal: Diabetes Care (2021)

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes” includes the ADA’s current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA’s clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
75P Impact of axitinib therapy management on adverse event (AE) resolution/improvement (Res/Imp) among advanced renal cell carcinoma (aRCC) patients (Pts) receiving first-line (1L) axitinib + checkpoint inhibitor (CPI) therapy
Authors: L. Huynh, S.S. Du, R. Chang, S. Pi, S. Sundaresan, M.S. Duh, D. Thomaidou, G. Zanotti, Y. Zakharia
Journal: Annals of Oncology (2021)
Loss of bile salt export pump aggravates lipopolysaccharide‐induced liver injury in mice due to impaired hepatic endotoxin clearance
Authors: Jelena Remetic, Ahmed Ghallab, Zaynab Hobloss, Lisa Brackhagen, Reham Hassan, Maiju Myllys, Richard Radun, Veronika Mlitz, Ci Zhu, Maximilian Baumgartner, Waltraud C. Schrottmaier, Marion Mussbacher, Gerald Timelthaler, Hubert Scharnagl, Tatjana Stojakovic, Alice Assinger, Claudia D. Fuchs, Jan G. Hengstler, Michael Trauner
Journal: Hepatology (2021)

Abstract Background and Aims Lipopolysaccharide (LPS) clearance is delayed in cholestatic liver diseases. While compromised clearance by Kupffer cells (KCs) is involved, the role of LPS uptake into hepatocytes and canalicular excretion remains unclear. Approach and Results Wild‐type (WT) and bile salt export pump (Bsep) knockout (KO) mice were challenged i.p. with LPS. Liver injury was assessed by serum biochemistry, histology, molecular inflammation markers, and immune cell infiltration. LPS concentrations were determined in liver tissue and bile. Subcellular kinetics of fluorescently labeled LPS was visualized by intravital two‐photon microscopy, and the findings in Bsep KO mice were compared to common bile duct–ligated (BDL) and multidrug resistance protein 2 (Mdr2) KO mice. Changes in gut microbiota composition were evaluated by 16S ribosomal RNA gene amplicon sequencing analysis. Bsep KO mice developed more pronounced LPS‐induced liver injury and inflammatory signaling, with subsequently enhanced production of proinflammatory cytokines and aggravated hepatic immune cell infiltration. After LPS administration, its concentrations were higher in liver but lower in bile of Bsep KO compared to WT mice. Intravital imaging of LPS showed a delayed clearance from sinusoidal blood with a basolateral uptake block into hepatocytes and reduced canalicular secretion. Moreover, LPS uptake into KCs was reduced. Similar findings with respect to hepatic LPS clearance were obtained in BDL and Mdr2 KO mice. Pretreatment with the microtubule inhibitor colchicine inhibited biliary excretion of LPS in WT mice, indicating that LPS clearance is microtubule‐dependent. Microbiota analysis showed no change of the gut microbiome between WT and Bsep KO mice at baseline but major changes upon LPS challenge in WT mice. Conclusions Absence of Bsep and cholestasis in general impair LPS clearance by a basolateral uptake block into hepatocytes and consequently less secretion into canaliculi. Impaired LPS removal aggravates hepatic inflammation in cholestasis.
Silk‐Based Bioengineered Diaphyseal Cortical Bone Unit Enclosing an Implantable Bone Marrow toward Atrophic Nonunion Grafting
Authors: Joseph Christakiran Moses, Souradeep Dey, Ashutosh Bandyopadhyay, Manoj Agarwala, Biman B. Mandal
Journal: Advanced Healthcare Materials (2021)

Postnatal fracture healing of atrophic long bone diaphyseal nonunions remains a challenge for orthopedic surgeons. Paucity of autologous spongiosa has potentiated the use of tissue engineered bone grafts to improve success rates of bone marrow engraftment used in plate reosteosynthesis. Herein, the development and in vitro validation of a "sandwich-type" biofabricated diaphyseal cross-sectional unit, with an outer mechanically robust bioprinted cortical bone shell, encompassing an engineered bone marrow, are reported. Channelized silk fibroin blend sponges derived from Bombyx mori and Antheraea assama help in developing compartmentalized endosteum, exhibiting specialized osteoblasts (endosteal niche) and discontinuous endothelium (vascular niche). The cellular cross-talk between these two niches triggered via integrin-mediated cell adhesion, enables in preserving quiescence state of CD34+ /CD38- hematopoietic stem cells and their recycling in the engineered marrow. The outer cortical bone strut is developed through multimaterial microextrusion bioprinting strategy. Osteogenically primed mesenchymal stem cells-laden silk fibroin-nano-hydroxyapatite bioink is bioprinted alongside paramagnetic Fe-doped bioactive glass-polycaprolactone blend thermoplastic ink, reinforcing it for mechanical stability. Pulsed magnetic field actuation positively influences the osteogenic commitment and maturation of the bioprinted constructs via mechanotransductory route. Therefore, the assembled engineered marrow and bioprinted cortical shell hold promise as potential orthobiologic substitutes toward atrophic nonunion repairs.
A Multi-Institution Analysis of Relapsed Lymphoma Occurring during Pregnancy Including Pharmacokinetics with Antenatal Checkpoint Inhibitor Therapy
Authors: Faheem Farooq, Elyce Cardonick, Evgenia Polushkina, Sairah Ahmed, Praveen Ramakrishnan, Adam J. Olszewski, Hesham Yasin, Nada Hamad, Yong Lin, Jennifer Edmonds, Laura Ciavolino, Charlotte Maggen, Robert Fruscio, Mina Mhallem Gziri, Karina Dahl Steffensen, Umar Farooq, Frédéric Amant, Elad Sharon, Tyler Yin, William D. Figg, Justin Brandt, Cody Peer, Julie M. Vose, Andrew Matthew Evens
Journal: Blood (2021)
Evaluation of dose, volume, and outcome in children with localized, intracranial ependymoma treated with proton therapy within the prospective KiProReg Study
Authors: Sarah Peters, Julien Merta, Laura Schmidt, Danny Jazmati, Paul-Heinz Kramer, Cristoph Blase, Stephan Tippelt, Gudrun Fleischhack, Annika Stock, Brigitte Bison, Stefan Rutkowski, Torsten Pietsch, Rolf-Dieter Kortmann, Beate Timmermann
Journal: Neuro-Oncology (2021)

Radiotherapy (RT) of ependymoma in children is an important part of the interdisciplinary treatment concept. However, feasibility and dose concepts are still under investigation, particularly in very young children. The aim of this study was to evaluate the standard dose and volume of proton therapy (PT) in children with ependymoma.In this analysis, 105 patients with localized, intracranial ependymoma under the age of 18 years treated with PT between 2013 and 2018 were included. Patient characteristics, treatment, outcome, and follow-up data were analyzed using descriptive statistics, Kaplan-Meier, and Cox regression analysis.The median age of patients at PT was 2.8 years (0.9-17.0 years). The molecular subgroup analysis was performed in a subset of 50 patients (37 EP-PFA, 2 EP-PFB, 7 EP-RELA, 2 EP-YAP, 2 NEC [not elsewhere classified]). The median total dose was 59.4 Gy (54.0-62.0 Gy). The median follow-up time was 1.9 years. The estimated 3-year overall survival (OS), local control (LC), and progression-free survival (PFS) rates were 93.7%, 74.1%, and 55.6%, respectively. Within univariable analysis, female gender and lower dose had a positive impact on OS, whereas age ≥4 years had a negative impact on OS and PT given after progression had a negative impact on PFS. In the multivariable analysis, multiple tumor surgeries were associated with lower PFS. New ≥3° late toxicities occurred in 11 patients.For children with localized ependymoma, PT was effective and well tolerable. Multiple surgeries showed a negative impact on PFS.
2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
Authors: Martha Gulati, Phillip D. Levy, Debabrata Mukherjee, Ezra Amsterdam, Deepak L. Bhatt, Kim K. Birtcher, Ron Blankstein, Jack Boyd, Renee P. Bullock-Palmer, Theresa Conejo, Deborah B. Diercks, Federico Gentile, John P. Greenwood, Erik P. Hess, Steven M. Hollenberg, Wael A. Jaber, Hani Jneid, José A. Joglar, David A. Morrow, Robert E. O’Connor, Michael A. Ross, Leslee J. Shaw
Journal: Circulation (2021)

This executive summary of the clinical practice guideline for the evaluation and diagnosis of chest pain provides recommendations and algorithms for clinicians to assess and diagnose chest pain in adult patients.A comprehensive literature search was conducted from November 11, 2017, to May 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Collaboration, Agency for Healthcare Research and Quality reports, and other relevant databases. Additional relevant studies, published through April 2021, were also considered. Structure: Chest pain is a frequent cause for emergency department visits in the United States. The "2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR Guideline for the Evaluation and Diagnosis of Chest Pain" provides recommendations based on contemporary evidence on the assessment and evaluation of chest pain. These guidelines present an evidence-based approach to risk stratification and the diagnostic workup for the evaluation of chest pain. Cost-value considerations in diagnostic testing have been incorporated and shared decision-making with patients is recommended.
miR-181a is a novel player in the STAT3-mediated survival network of TCRαβ+ CD8+ T large granular lymphocyte leukemia
Authors: Jorn L. J. C. Assmann, Leticia G. Leon, Christiaan J. Stavast, Sanne E. van den Bogaerdt, Joyce Schilperoord-Vermeulen, Yorick Sandberg, Mar Bellido, Stefan J. Erkeland, David J. Feith, Thomas P. Loughran Jr, Anton W. Langerak
Journal: Leukemia (2021)

T-LGL cells arise as a consequence of chronic antigenic stimulation and inflammation and thrive because of constitutive activation of the STAT3 and ERK pathway. Notably, in 40% of patients, constitutive STAT3 activation is due to STAT3 activating mutations, whereas in 60% this is unknown. As miRNAs are amongst the most potent regulators in health and disease, we hypothesized that aberrant miRNA expression could contribute to dysregulation of these pathways. miRNA sequencing in T-LGL leukemia cases and aged-matched healthy control TEMRA cells revealed overexpression of miR-181a. Furthermore, geneset enrichment analysis (GSEA) of downregulated targets of miR-181a implicated involvement in regulating STAT3 and ERK1/2 pathways. Flow cytometric analyses showed increased SOCS3+ and DUSP6+ T-LGL cells upon miR-181a inhibition. In addition, miR-181a-transfected human CD8+ T cells showed increased basal STAT3 and ERK1/2 phosphorylation. By using TL1, a human T-LGL cell line, we could show that miR-181a is an actor in T-LGL leukemia, driving STAT3 activation by SOCS3 inhibition and ERK1/2 phosphorylation by DUSP6 inhibition and verified this mechanism in an independent cell line. In addition, miR-181a inhibition resulted in a higher sensitivity to FAS-mediated apoptosis. Collectively, our data show that miR-181a could be the missing link to explain why STAT3-unmutated patients show hyperactive STAT3.
COVID-19 mRNA booster vaccines elicit strong protection against SARS-CoV-2 Omicron variant in patients with cancer
Authors: Cong Zeng, John P. Evans, Karthik Chakravarthy, Panke Qu, Sarah Reisinger, No-Joon Song, Mark P. Rubinstein, Peter G. Shields, Zihai Li, Shan-Lu Liu
Journal: Cancer Cell (2021)
<i>Erratum</i>: Vol. 69, No. SS-7
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

In the Surveillance Summary "Abortion Surveillance -United States, 2018," on page 5, the last sentence of the second paragraph should have read, "Overall, 0.9% of abortions were reported to CDC with unknown residence."On page 9, the fourth sentence of the first paragraph should have read, "Findings in this report on demographic characteristics of women seeking abortions were generally similar to previously published data from Guttmacher Institute's national survey of abortion patients in 2014, although the percentage of abortions accounted for by non-Hispanic Black women was lower and by Hispanic women was higher as compared with data provided to CDC (25)."
B cell–intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice
Authors: Michelle S.J. Lee, Takeshi Inoue, Wataru Ise, Julia Matsuo-Dapaah, James B. Wing, Burcu Temizoz, Kouji Kobiyama, Tomoya Hayashi, Ashwini Patil, Shimon Sakaguchi, A. Katharina Simon, Jelena S. Bezbradica, Satoru Nagatoishi, Kouhei Tsumoto, Jun-Ichiro Inoue, Shizuo Akira, Tomohiro Kurosaki, Ken J. Ishii, Cevayir Coban
Journal: The Journal of Experimental Medicine (2021)

The germinal center (GC) is a site where somatic hypermutation and clonal selection are coupled for antibody affinity maturation against infections. However, how GCs are formed and regulated is incompletely understood. Here, we identified an unexpected role of Tank-binding kinase-1 (TBK1) as a crucial B cell–intrinsic factor for GC formation. Using immunization and malaria infection models, we show that TBK1-deficient B cells failed to form GC despite normal Tfh cell differentiation, although some malaria-infected B cell–specific TBK1-deficient mice could survive by GC-independent mechanisms. Mechanistically, TBK1 phosphorylation elevates in B cells during GC differentiation and regulates the balance of IRF4/BCL6 expression by limiting CD40 and BCR activation through noncanonical NF-κB and AKTT308 signaling. In the absence of TBK1, CD40 and BCR signaling synergistically enhanced IRF4 expression in Pre-GC, leading to BCL6 suppression, and therefore failed to form GCs. As a result, memory B cells generated from TBK1-deficient B cells fail to confer sterile immunity upon reinfection, suggesting that TBK1 determines B cell fate to promote long-lasting humoral immunity.
Outcomes of Laparoscopic Total Gastrectomy Combined With Spleen-Preserving Hilar Lymphadenectomy for Locally Advanced Proximal Gastric Cancer
Authors: Chaohui Zheng, Yanchang Xu, Gang Zhao, Lisheng Cai, Guoxin Li, Zekuan Xu, Su Yan, Zuguang Wu, Fangqin Xue, Yihong Sun, Dongbo Xu, Wenbin Zhang, Jin Wan, Peiwu Yu, Jiankun Hu, Xiangqian Su, Jiafu Ji, Ziyu Li, Jun You, Yong Li, Lin Fan, Junpeng Lin, Jianxian Lin, Ping Li, Changming Huang
Journal: JAMA Network Open (2021)

The long-term survival of patients with laparoscopic total gastrectomy combined with spleen-preserving splenic hilar lymphadenectomy (LSTG) for advanced upper-third gastric cancer (AUTGC) and the association of splenic hilar lymph node (LN-10) metastasis with survival remain controversial.To evaluate the long-term outcomes of LSTG and the value index of LN-10 metastasis for patients with AUTGC.The Chinese Laparoscopic Gastrointestinal Surgery Study 4 (CLASS-04) was a prospective, multicenter, single-arm trial that involved 19 centers in China. A total of 251 eligible patients with clinical stage T2, T3, or T4a upper-third gastric cancer without distant metastases were enrolled from September 1, 2016, to October 31, 2017. The final follow-up was on December 31, 2020.All patients were enrolled to undergo LSTG.The main outcomes were the 3-year overall survival (OS) and disease-free survival (DFS). Multivariate analyses were used to explore the association of LN-10 metastasis with survival.Among the 251 patients, 246 (98.0%; mean [SD] age, 60.1 [9.4] years; 197 [80.1%] male) underwent LSTG and completed the study. The 3-year OS was 79.1% (95% CI, 74.0%-84.2%), and the 3-year DFS was 73.1% (95% CI, 67.4%-78.8%). In addition, the 3-year therapeutic value index of LN-10 dissection was 4.5, exceeding the indexes for the partial D2 LN group (including LNs 5, 6, 11d, and 12a). Nineteen patients (7.7%) with LN-10 metastasis had significantly worse survival than the nonmetastasis group, and multivariate analysis revealed that splenic LN-10 metastasis was an independent risk factor (OS: hazard ratio [HR], 2.38; 95% CI, 1.08-5.26; P = .03; DFS: HR, 2.28; 95% CI, 1.12-4.63; P = .02). Moreover, patients with LN-10 metastasis were more likely to have recurrence (42.1% vs 20.7%, P = .03), especially when multiple site metastasis was present (21.1% vs 4.4%, P = .01). However, patients with LN-10 metastasis who received adjuvant chemotherapy had significantly better OS and DFS than those without adjuvant chemotherapy and achieved the same oncologic effect as those without LN-10 metastasis.This results of this study suggest that LSTG for AUTGC has feasible long-term outcomes. In addition, patients with LN-10 metastasis may have worse survival and may be more prone to recurrence.
Retraction
Authors: Lucrezia Raimondi, Laura Giaconi, Gian Spinelli, Rachele Lazzeroni, Laura Benedetto, Maria Filippo, Arianna Raimondi, Luigi Rocco
Journal: Journal of Clinical Oncology (2021)

Clinical of Oncology (JCO).An Expression of Concern was previously issued by JCO on June 16, 2021.
Abstract 13658: Characterization of Acute Respiratory Distress Syndrome in Post-Cardiac Arrest Patients
Authors: Jenny A Shih, Mahmoud S Issa, Hannah Robertson, Anne V Grossestreuer, Michael Donnino, Katherine Berg, Ari Moskowitz
Journal: Circulation (2021)

Introduction: Acute respiratory distress syndrome (ARDS) may be precipitated by cardiac arrest, but the incidence and epidemiology of post-arrest ARDS is not well characterized in the in-hospital cardiac arrest (IHCA) setting. This study aimed to describe the incidence of ARDS after IHCA and ARDS-associated IHCA outcomes. Methods: This was a single-center retrospective study of adult patients admitted to the hospital between 2017-2018 who suffered IHCA, were resuscitated, and were intubated within 2 hours of arrest. Patients who died or were extubated on the day of resuscitation and those with pre-arrest ARDS were excluded. Post-IHCA ARDS was defined as meeting the Berlin criteria in the first 3 days after the cardiac arrest. Outcomes included hospital length-of-stay and hospital mortality. Results: Of the 105 patients included, 78 (74.3%) developed ARDS within 3 days of arrest. The mean PaO2:FiO2 ratio was 222 (SD 105). Of those with ARDS, most had mild (32%) or moderate (41%) disease. Patients with ARDS had a median hospital and ICU length of stay of 17 (IQR: 8, 31) and 7.5 (IQR: 3, 16) days compared to patients without ARDS, who had a median hospital and ICU length of stay of 10 (IQR: 7, 19) and 5 (IQR: 3, 11) days (p&gt;0.1 for both comparisons). There was a higher use of midazolam in patients with ARDS (18% vs 4%), but this was not statistically significant (p=0.1). Conclusion: There is a high incidence (74%) of post-arrest ARDS in IHCA patients. This compares to recent estimates suggesting a post-arrest ARDS incidence of approximately 50% in the out-of-hospital arrest population. While there was no statistically significant difference in outcomes, this study was limited by a small sample size. Future studies should further investigate these relationships in a larger cohort.
Reply to Jha: Addition of 5% CO<sub>2</sub> to Inspiratory Gas in Preventing Lung Injury Due to Pulmonary Artery Ligation
Authors: Elena Spinelli, Tommaso Mauri
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

dyne/s/cm 25 ).A higher trend in PVR was maintained through 48 hours compared with the ligation group alone.However, the rise in mean arterial pressure after double insults of hypercarbia and PA ligation appears clinically insignificant.This finding is indeed clinically promising for anesthesiologists and critical care physicians managing various cardiac surgeries, noncardiac surgeries, and acute respiratory distress syndrome.Considering the extent of the rise in PA pressure after ligation and hypercarbia in the 5% CO 2 group in this study, a ventilator strategy involving permissive hypercapnia and hypercarbia to avoid volutrauma in acute respiratory distress syndrome appears safe.Furthermore, 5% CO 2 may offer protection from lung damage during PA ligation (pneumonectomy or lobectomy), PA banding, and PA occlusion to facilitate Blalock-Taussig shunt and cavopulmonary anastomosis.PA ligation is akin to acute thromboembolism, which may lead to a rapid rise in right ventricular load, right ventricular dilatation, and reduction in cardiac output (5).Interestingly, cardiac output rose (4.4 L/min to 5.1 L/min) in the 5% CO 2 group, and therefore ligation and hypercarbia did not seem to produce right ventricular dysfunction until the end of the study.Thus, assessing change in systolic or diastolic right ventricular function compared with baseline after pulmonary artery ligation or hypercarbia could have further provided mechanistic insight.Finally, the authors have stressed that the diversion of minute ventilation instead of blood flow is responsible for pulmonary edema in the nonligated lung (right lung).Nevertheless, hypercarbia in the 5% CO 2 group produced pulmonary vasoconstriction (PVR = 360 and 352 dyne/s/cm 25 at 12 and 24 hours) during the initial phases, which could have prevented the development of pulmonary edema in the right lung.Moreover, in addition to excessive ventilation in producing lung injury, the role of toxic or inflammatory mediators from the ligated hypoxic, anoxic, or infarcted lung in inflicting lung damage to the nonligated lung needs to be investigated.