tbuckley/cabot-search huggingface dataset:
Acquiescence is Not Agreement: The Problem of Marginalization in Pediatric Decision Making
Authors: Amy E. Caruso Brown
Journal: The American Journal of Bioethics (2021)

Although parents are the default legal surrogate decision-makers for minor children in the U.S., shared decision making in a pluralistic society is often much more complicated, involving not just parents and pediatricians, but also grandparents, other relatives, and even community or religious elders. Parents may not only choose to involve others in their children's healthcare decisions but choose to defer to another; such deference does not imply agreement with the decision being made and adds complexity when disagreements arise between surrogate decision-makers for minor children and their physicians. I argue that clinicians and ethicists have a duty to consider voices marginalized by hierarchical structures, including but not limited to gender-based inequalities. This approach involves negotiating potential conflicts: between respecting differences of culture and religion, on one hand, and assuring that the wishes of those who are most invested in children's lives are considered, on the other.
The effect of extreme weather on mortality in Cyprus: High temperatures vs. synoptic air mass types
Authors: Haritini Tsangari, Anastasia Paschalidou, Pavlos Kassomenos, Zoi Konsoula, Stephanie Christou, E. Georgiou Kyriakos, Theodoulos Mesimeris, Sotiris Vardoulakis, H. Heaviside Clare, Edna N. Yamasaki
Journal: Environmental Health Perspectives (2013)
Tackling cancer cell dormancy: Insights from immune models, and transplantation
Authors: Alexandre Corthay, Tibor Bakacs, Govindarajan Thangavelu, Colin C. Anderson
Journal: Seminars in Cancer Biology (2021)

Disseminated non-dividing (dormant) cancer cells as well as those in equilibrium with the immune response remain the major challenge for successful treatment of cancer. The equilibrium between disseminated dormant cancer cells and the immune system is reminiscent of states that can occur during infection or allogeneic tissue and cell transplantation. We discuss here the major competing models of how the immune system achieves a self nonself discrimination (pathogen/danger patterns, quorum, and coinhibition/tuning models), and suggest that taking advantage of a combination of the proposed mechanisms in each model may lead to increased efficacy in tackling cancer cell dormancy.
Concepts and Applications of Information Theory to Immuno-Oncology
Authors: Aleksandra Karolak, Sergio Branciamore, Jeannine S. McCune, Peter P. Lee, Andrei S. Rodin, Russell C. Rockne
Journal: Trends in cancer (2021)

Recent successes of immune-modulating therapies for cancer have stimulated research on information flow within the immune system and, in turn, clinical applications of concepts from information theory. Through information theory, one can describe and formalize, in a mathematically rigorous fashion, the function of interconnected components of the immune system in health and disease. Specifically, using concepts including entropy, mutual information, and channel capacity, one can quantify the storage, transmission, encoding, and flow of information within and between cellular components of the immune system on multiple temporal and spatial scales. To understand, at the quantitative level, immune signaling function and dysfunction in cancer, we present a methodology-oriented review of information-theoretic treatment of biochemical signal transduction and transmission coupled with mathematical modeling.
Abstract PS10-30: An open label, pilot study of veliparib and lapatinib in patients with metastatic, triple negative breast cancer
Authors: Erica M Stringer-Reasor, Jori E May, Eva Olariu, Valeria Caterinicchia, Yufeng Li, Deborah Della Manna, Gabrielle B Rocque, Christos Vaklavas, Carla I Falkson, Lisle M Nabell, Edward P Acosta, Andres Forero-Torres, Eddy S Yang
Journal: Cancer Research (2021)

Abstract Purpose: Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2(gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple negative breast cancer (TNBC) with intact DNA repair, we previously showed an induced synthetic lethality with combined EGFR inhibition and PARPi. We report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Experimental Design: A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline and taxane therapy. Patients with gBRCA1/2 mutations were excluded. Results: Twenty patients were enrolled of which 17 were evaluable for response. Median number of prior therapies in the metastatic setting was 1 (range 0-2). Fifty percent of patients were Caucasian, 45% African-American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug-drug interactions noted. Gene expression analysis suggest baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions: Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Citation Format: Erica M Stringer-Reasor, Jori E May, Eva Olariu, Valeria Caterinicchia, Yufeng Li, Deborah Della Manna, Gabrielle B Rocque, Christos Vaklavas, Carla I Falkson, Lisle M Nabell, Edward P Acosta, Andres Forero-Torres, Eddy S Yang. An open label, pilot study of veliparib and lapatinib in patients with metastatic, triple negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-30.
Troponin Testing in the Emergency Department—When 2 Become 1
Authors: Barbra Eva Backus, Richard Body, Michael Barnett Weinstock
Journal: JAMA Network Open (2021)

Maereg Wassie, MD; Ming-Sum Lee, MD, PhD; Benjamin C. Sun, MD, MPH; Yi-Lin Wu, MS; Aileen S. Baecker, PhD; Rita F. Redberg, MD; Maros Ferencik, MD, PhD, MCR; Ernest Shen, PhD; Visanee Musigdilok, MPH; Adam L. Sharp, MD, MSc
Recovery of kidney function after dialysis initiation in children and adults in the US: A retrospective study of United States Renal Data System data
Authors: Elaine Ku, Raymond K. Hsu, Kirsten L. Johansen, Charles E. McCulloch, Mark Mitsnefes, Barbara A. Grimes, Kathleen D. Liu
Journal: PLoS Medicine (2021)

Background Little is known about factors associated with recovery of kidney function—and return to dialysis independence—or temporal trends in recovery after starting outpatient dialysis in the United States. Understanding the characteristics of individuals who may have the potential to recover kidney function may promote better recognition of such events. The goal of this study was to determine factors associated with recovery of kidney function in children compared with adults starting dialysis in the US. Methods and findings We determined factors associated with recovery of kidney function—defined as survival and discontinuation of dialysis for ≥90-day period—in children versus adults who started maintenance dialysis between 1996 and 2015 according to the United States Renal Data System (USRDS) followed through 2016 in a retrospective cohort study. We also examined temporal trends in recovery rates over the last 2 decades in this cohort. Among 1,968,253 individuals included for study, the mean age was 62.6 ± 15.8 years, and 44% were female. Overall, 4% of adults (83,302/1,953,881) and 4% of children (547/14,372) starting dialysis in the outpatient setting recovered kidney function within 1 year. Among those who recovered, the median time to recovery was 73 days (interquartile range [IQR] 43–131) in adults and 100 days (IQR 56–189) in children. Accounting for the competing risk of death, children were less likely to recover kidney function compared with adults (sub-hazard ratio [sub-HR] 0.81; 95% CI 0.74–0.89, p -value &lt;0.001; point estimates &lt;1 indicating increased risk for a negative outcome). Non-Hispanic black (NHB) adults were less likely to recover compared with non-Hispanic white (NHW) adults, but these racial differences were not observed in children. Of note, a steady increase in the incidence of recovery of kidney function was noted initially in adults and children between 1996 and 2010, but this trend declined thereafter. The diagnoses associated with the highest recovery rates of recovery were acute tubular necrosis (ATN) and acute interstitial nephritis (AIN) in both adults and children, where 25%–40% of patients recovered kidney function depending on the calendar year of dialysis initiation. Limitations to our study include the potential for residual confounding to be present given the observational nature of our data. Conclusions In this study, we observed that discontinuation of outpatient dialysis due to recovery occurred in 4% of patients with end-stage kidney disease (ESKD) and was more common among those with ATN or AIN as the cause of their kidney disease. While recovery rates rose initially, they declined starting in 2010. Additional studies are needed to understand how to best recognize and promote recovery in patients whose potential to discontinue dialysis is high in the outpatient setting.
A retrospective multicenter analysis of candidaemia among COVID-19 patients during the first UK pandemic wave
Authors: Sarah Denny, Alireza Abdolrasouli, Tamador Elamin, Ximena Gonzalo, Esmita Charani, Aatish Patel, Hugo Donaldson, Stephen Hughes, Darius Armstrong-James, Luke SP Moore, Nabeela Mughal
Journal: Journal of Infection (2021)
Comment on: Bronchoalveolar lavage fluid lymphocytosis in chronic hypersensitivity pneumonitis: a systematic review and meta-analysis
Authors: Onofre Moran-Mendoza, Mohamed Khalil
Journal: European Respiratory Journal (2021)

<b>Bronchoalveolar lavage fluid lymphocytosis may be useful in the diagnosis of chronic hypersensitivity pneumonitis. However, reanalysis after eliminating studies that used bronchoalveolar lavage lymphocytosis as part of the diagnostic criteria is needed.</b>https://bit.ly/34AmHmm
The construction, expression, and enhanced anti-tumor activity of YM101: a bispecific antibody simultaneously targeting TGF-β and PD-L1
Authors: Ming Yi, Jing Zhang, Anping Li, Mengke Niu, Yongxiang Yan, Ying Jiao, Suxia Luo, Pengfei Zhou, Kongming Wu
Journal: Journal of Hematology & Oncology (2021)

Abstract Background Therapeutic antibodies targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis induce potent and durable anti-tumor responses in multiple types of cancers. However, only a subset of patients benefits from anti-PD-1/PD-L1 therapies. As a negative regulator of anti-tumor immunity, TGF-β impairs the efficacy of anti-PD-1/PD-L1 and induces drug resistance. Developing a novel treatment strategy to simultaneously block PD-1/PD-L1 and TGF-β would be valuable to enhance the effect of anti-PD-1/PD-L1 and relieve drug resistance. Methods Based on the Check-BODY™ technology platform, we developed an anti-TGF-β/PD-L1 bispecific antibody YM101. The bioactivity of the anti-TGF-β moiety was determined by Smad-luciferase reporter assay, transwell assay, western blotting, CCK-8, and flow cytometry. The bioactivity of the anti-PD-L1 moiety was measured by T cell activation assays. EMT-6, CT26, and 3LL tumor models were used to investigate the anti-tumor activity of YM101 in vivo. RNA-seq, immunohistochemical staining, and flow cytometry were utilized to analyze the effect of YM101 on the tumor microenvironment. Results YM101 could bind to TGF-β and PD-L1 specifically. In vitro experiments showed that YM101 effectively counteracted the biological effects of TGF-β and PD-1/PD-L1 pathway, including activating Smad signaling, inducing epithelial-mesenchymal transition, and immunosuppression. Besides, in vivo experiments indicated the anti-tumor activity of YM101 was superior to anti-TGF-β and anti-PD-L1 monotherapies. Mechanistically, YM101 promoted the formation of ‘hot tumor’: increasing the numbers of tumor infiltrating lymphocytes and dendritic cells, elevating the ratio of M1/M2, and enhancing cytokine production in T cells. This normalized tumor immune microenvironment and enhanced anti-tumor immune response might contribute to the robust anti-tumor effect of YM101. Conclusion Our results demonstrated that YM101 could simultaneously block TGF-β and PD-L1 pathways and had a superior anti-tumor effect compared to the monotherapies.
Vitamin D levels and risk of type 1 diabetes: A Mendelian randomization study
Authors: Despoina Manousaki, Adil Harroud, Ruth E. Mitchell, Stephanie Ross, Vince Forgetta, Nicholas J. Timpson, George Davey Smith, Constantin Polychronakos, J Brent Richards
Journal: PLoS Medicine (2021)

Background Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). Methods and findings For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D–insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. Conclusions Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.
In-depth genomic characterization of programmed cell death ligand 1 (PD-L1) expression in Chinese lung adenocarcinoma patients.
Authors: Li Kang, Jun Liu, Jia Li, Lin Wu, Yajie Xiao, Haijian Du, Zhikun Zhao, Xiaoting Li, Dongfang Wu, Zhuxiang Zhao, bolin chen
Journal: Journal of Clinical Oncology (2021)

e20500 Background: Immune checkpoint blockades have revolutionized anticancer treatments for lung cancers, and PD-L1 expression has been served as crucial predictive biomarkers for immunotherapies. However, PD-L1 expression has been found to be influenced by some extrinsic or intrinsic factors in vitro or to be associated with other biomarkers in vivo. Methods: An amount of tumor tissues was taken from a biopsy or surgery for PD-L1 expression assay and genomic profiling in Chinese lung adenocarcinoma patients using extend targeted sequencing panel. In-depth retrospective analyses of clinical features, gene alternations, singling pathways and immune signatures was conducted in negative group (TPS &lt; 1%), intermediate group (1% ≤ TPS &lt; 50%), and high group (TPS ≥ 50%). Clinical responses to selected mutation were also evaluated from public database such as TCGA and MSKCC. Results: A total of 248 Chinese patients with lung adenocarcinoma was retrospectively identified and included in this study, consisting of negative group (n = 124, 50%), intermediate group (n = 93, 38%), and high group (n = 38, 12%). High tumor mutation burden was significantly as associated with high PD-L1 expression. In addition, PD-L1 expression was highly related with gene alternations such as PRKDC, KMT2D, ERBB2 and SETD2. Moreover, signaling pathways of DDR, TP53, cell cycles and NOTCH also obviously related with PD-L1 expression. Besides, most of patients in high PD-L1 group were determined as high-grade immune subtypes (C2-C4), showing significant higher levels of IFN-gamma, CD8+ T-cells, NK cells, NK CD56 dim cells, Th1 cells, Th2 cells (P &lt; 0.0001). Moreover, the prognostic value of SETD2 mutation was slight positive with overall survival from MSKCC cohort (HR 1.92 [95%CI 0.90-4.10], P = 0.085), and the percentage of IFN-gamma was significantly higher in SETD2 mutant group than in wild-type subgroup ( P &lt; 0.01). Conclusions: This study illustrated in-depth genomic profiles and immune signatures of PD-L1 expression in Chinese lung adenocarcinoma patients, which might interpret more potential molecular mechanisms for anti-cancer immunotherapy in NSCLC. In addition, SETD2 may be potential biomarkers for predicting patients’ prognosis.
Sunitinib-induced cardiac hypertrophy and the endothelin axis
Authors: Joevin Sourdon, Caterina Facchin, Anaïs Certain, Thomas Viel, Blaise Robin, Franck Lager, Carmen Marchiol, Daniel Balvay, Thulaciga Yoganathan, Judith Favier, Pierre-Louis Tharaux, Neeraj Dhaun, Gilles Renault, Bertrand Tavitian
Journal: Theranostics (2021)

from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Potential impact of Helicobacter pylori-related metabolic syndrome and Galectin-3 on liver, chronic kidney and brain disorders
Authors: Marina Boziki, Stergios A. Polyzos, Apostolis Papaefthymiou, Michael Doulberis, Christos Bakirtzis, Styliani - Aggeliki Sintila, Maria Touloumtzi, Nikolaos Grigoriadis, Jannis Kountouras
Journal: Metabolism (2021)
Secondary Infections Are Common in Patients Hospitalized for COVID-19 and Are Associated With Severe Outcomes
Authors: E. R. Anderson, T. Azam, H. Shadid, M. Pan, H. Berlin, C. Meloche, R. Feroze, J. Leya, P. O'Hayer, R. Kaakati, A. Bitar, K. Padalia, D. Perry, P. Blakely, P. Y. Zhao, L. L. Zhao, S. Hayek
Journal: Circulation (2020)
[177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial
Authors: Michael S Hofman, Louise Emmett, Shahneen Sandhu, Amir Iravani, Anthony M Joshua, Jeffrey C Goh, David A Pattison, Thean Hsiang Tan, Ian D Kirkwood, Siobhan Ng, Roslyn J Francis, Craig Gedye, Natalie K Rutherford, Andrew Weickhardt, Andrew M Scott, Sze-Ting Lee, Edmond M Kwan, Arun A Azad, Shakher Ramdave, Andrew D Redfern, William Macdonald, Alex Guminski, Edward Hsiao, Wei Chua, Peter Lin, Alison Y Zhang, Margaret M McJannett, Martin R Stockler, John A Violet, Scott G Williams, Andrew J Martin, Ian D Davis, Arun A Azad, Wei Chua, Ian D Davis, Nattakorn Dhiantravan, Louise Emmett, Kate Ford, Michael S Hofman, Roslyn J Francis, Craig Gedye, Jeffrey C Goh, Alex Guminski, Edward Hsiao, Amir Iravani, Anthony M Joshua, Ian D Kirkwood, Ailsa Langford, Nicola Lawrence, Sze-Ting Lee, Peter Lin, Andrew J Martin, William McDonald, Margaret M McJannett, Siobhan Ng, David A Pattison, Shakher Ramdave, Nisha Rana, Andrew D Redfern, Natalie K Rutherford, Shahneen Sandhu, Andrew M Scott, Martin R Stockler, Shalini Subramaniam, Thean Hsiang Tan, John A Violet, Andrew Weickhardt, Scott G Williams, Sonia Yip, Alison Y Zhang
Journal: The Lancet (2021)
Do as AI say: susceptibility in deployment of clinical decision-aids
Authors: Susanne Gaube, Harini Suresh, Martina Raue, Alexander Merritt, Seth J. Berkowitz, Eva Lermer, Joseph F. Coughlin, John V. Guttag, Errol Colak, Marzyeh Ghassemi
Journal: npj Digital Medicine (2021)

Abstract Artificial intelligence (AI) models for decision support have been developed for clinical settings such as radiology, but little work evaluates the potential impact of such systems. In this study, physicians received chest X-rays and diagnostic advice, some of which was inaccurate, and were asked to evaluate advice quality and make diagnoses. All advice was generated by human experts, but some was labeled as coming from an AI system. As a group, radiologists rated advice as lower quality when it appeared to come from an AI system; physicians with less task-expertise did not. Diagnostic accuracy was significantly worse when participants received inaccurate advice, regardless of the purported source. This work raises important considerations for how advice, AI and non-AI, should be deployed in clinical environments.
Alwyn Lishman: the “father” of neuropsychiatry
Authors: John Illman
Journal: BMJ (2021)

Photo credit: UCL Institute of Neurology

In the early 20th century, psychiatry and neurology were considered to be a single discipline, but in the wake of eminent neurologists such as Freud and Charcot, much of psychiatry became more psychoanalytical, at the expense of neurology. Some psychiatrists thereafter reportedly received minimal neurological training and some neurologists minimal psychiatric training.

Alwyn Lishman bridged the divide, fostering the development of neuropsychiatry, most famously through his landmark textbook, Organic Psychiatry . Before its publication in 1978, many patients with complex and mysterious disorders of mind and body were denied expert psychiatric care.

The story behind the book—considering its profound influence on patient care and the training of thousands of clinicians—is barely credible, making it, arguably, one of psychiatry’s greatest stories. For three years Lishman resisted approaches from Blackwell’s, the publishers, who had been reliably told that he was the person to write a book “putting the brain back into psychiatry.”

Trained in physiology, psychiatry, and neurology, Lishman told The Psychiatrist in 2012, “The reason why I finally did it was quite ridiculous. I’m slightly ashamed of this, but I wanted a Bechstein grand piano and I saw one. I got the offer of a substantial advance for …