tbuckley/cabot-search huggingface dataset:
End-of-life care among patients with schizophrenia and cancer: a population-based cohort study from the French national hospital database
Authors: Guillaume Fond, Sebastien Salas, Vanessa Pauly, Karine Baumstarck, Cecile Bernard, Veronica Orleans, Pierre-Michel Llorca, Christophe Lancon, Pascal Auquier, Laurent Boyer
Journal: The Lancet Public Health (2019)

BackgroundPatients with schizophrenia represent a vulnerable, underserved, and undertreated population who have been neglected in health disparities work. Understanding of end-of-life care in patients with schizophrenia and cancer is poor. We aimed to establish whether end-of-life care delivered to patients with schizophrenia and cancer differed from that delivered to patients with cancer who do not have diagnosed mental illness.MethodsWe did a population-based cohort study of all patients older than 15 years who had a diagnosis of advanced cancer and who died in hospital in France between Jan 1, 2013, and Dec 31, 2016. We divided this population into cases (ie, patients with schizophrenia) and controls (ie, patients without a diagnosis of mental illness) and compared access to palliative care and indicators of high-intensity end-of-life care between groups. In addition to unmatched analyses, we also did matched analyses (matched in terms of age at death, sex, and site of primary cancer) between patients with schizophrenia and matched controls (1:4). Multivariable generalised linear models were done with adjustment for social deprivation, year of death, time from cancer diagnosis to death, metastases, comorbidity, and hospital type (ie, specialist cancer centre vs non-specialist centre).FindingsThe main analysis included 2481 patients with schizophrenia and 222 477 controls. The matched analyses included 2477 patients with schizophrenia and 9896 controls. Patients with schizophrenia were more likely to receive palliative care in the last 31 days of life (adjusted odds ratio 1·61 [95% CI 1·45–1·80]; p<0·0001) and less likely to receive high-intensity end-of-life care—such as chemotherapy and surgery—than were matched controls without a diagnosis of mental illness. Patients with schizophrenia were also more likely to die younger, had a shorter duration between cancer diagnosis and death, and were more likely to have thoracic cancers and comorbidities than were controls.InterpretationOur findings suggest the existence of disparities in health and health care between patients with schizophrenia and patients without a diagnosis of mental illness. These findings underscore the need for better understanding of health inequalities so that effective interventions can be developed for this vulnerable population.FundingAssistance Publique des Hôpitaux de Marseille and Aix-Marseille University.
Single enzyme loaded nanoparticles for combinational ultrasound-guided focused ultrasound ablation and hypoxia-relieved chemotherapy
Authors: Jianzhi Zhu, Zhicong Li, Changchang Zhang, Lizhou Lin, Shoupeng Cao, Hailong Che, Xiangyang Shi, Han Wang, Jan C. M. van Hest
Journal: Theranostics (2019)

Constructing nanosystems that synergistically combine therapeutic and diagnostic features is of great interest to the nanomedicine community but also remains a tremendous challenge. Methods: In this work, we report novel catalytic nanoparticles composed of the enzyme catalase, encapsulated in a polymer shell and surface decorated with pH-sensitive poly(ethylene glycol) (PEGylated nCAT). These nanoparticles were used as a promoter for ultrasound (US)-guided focused ultrasound (FUS) ablation and hypoxia alleviation for application in Doxorubicin-based chemotherapy. Results: The PEGylated nCAT produced highly effectively O2 from endogenous H2O2 to ameliorate the hypoxic and therefore poor-acoustic tumor environment. The generated O2 was utilized as 1) a contrast agent for US imaging; 2) strengthening agent for FUS ablation and 3) normoxia inducer to enhance chemotherapeutic efficacy. The PEGylated nCAT exhibited favorable enzyme activity after long-term storage, and after exposure to proteolytic conditions and elevated temperatures. The pH-responsive PEGylation contributed on the one hand to an extended in vivo circulation time over 48 h and on the other hand enabled PEG cleavage in the vicinity of cancer cells to facilitate cellular uptake. Conclusion: The developed PEGylated nCAT can therefore effectively combine US-guided FUS and chemotherapy and can be regarded as a highly promising theranostic platform.
Insulin Sensitivity and Renal Hemodynamic Function in Metformin-Treated Adults With Type 2 Diabetes and Preserved Renal Function
Authors: Erik J.M. van Bommel, Danique Ruiter, Marcel H.A. Muskiet, Michaël J.B. van Baar, Mark H.H. Kramer, Max Nieuwdorp, Jaap A. Joles, Petter Bjornstad, Daniël H. van Raalte
Journal: Diabetes Care (2019)

Impaired insulin sensitivity is associated with hyperfiltration (i.e., elevated glomerular filtration rate [GFR]) in adolescents with type 2 diabetes (T2D) and adults with prediabetes. Yet, these relationships are based on studies that relied on estimated GFR (eGFR), estimates of insulin sensitivity, or both. We aimed to verify the relationship between insulin sensitivity and renal hemodynamic function by gold standard methods in adults with T2D.Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp (M value) (glucose infusion rate in mg/kglean/min) and renal hemodynamic function by urinary inulin (GFR) and para-aminohippuric acid (effective renal plasma flow [ERPF]) clearances in participants with T2D without overt kidney disease. Filtration fraction (FF) (GFR/ERPF) was calculated. Relationships between insulin sensitivity and renal hemodynamic parameters were examined by multivariable linear regression. Renal hemodynamic parameters were examined across tertiles of M values.We tested 44 adults with T2D, of whom 77% were male, with mean ± SD age 63 ± 7 years, BMI 31.2 ± 4.0 kg/m2, and HbA1c 7.4 ± 0.6%. Average GFR was 110 ± 26 mL/min, with an FF of 22.1 ± 2.8% and median 24-h urinary albumin excretion of 11.3 mg (interquartile range 5.8-17.0). Average M value was 5.6 ± 2.9 mg/kglean/min. Insulin sensitivity inversely correlated with GFR (r = -0.44, P < 0.01) and FF (r = -0.40, P < 0.01), and these associations remained significant after multivariable adjustments for age, sex, renin-angiotensin system inhibitor use, and HbA1c. In addition, GFR, FF, and urinary albumin excretion were highest in the participants in the lowest M value tertile.For the first time, we demonstrate that impaired insulin sensitivity is associated with intrarenal hemodynamic dysfunction by gold standard techniques in adults with T2D treated with metformin monotherapy.
Improving Pulmonary Immunity to Bacterial Pathogens through <i>Streptococcus pneumoniae</i> Colonization of the Nasopharynx
Authors: Jeremy S. Brown
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

improved mucociliary clearance and mucous viscosity induced by losartan will enhance infection resolution.The question remains: is blocking CFTR function the perfect setting for the preclinical development of losartan?If not, what model really reproduces a reasonable, cost-effective means by which to explore specific therapies in the context of consistent and reproducible complexities of CF lung disease?Kim and colleagues' manuscript introduces the potential of losartan as a CF therapeutic and also highlights innovations in model development used for open-minded investigations and for the systematic development of novel therapeutics for CF.Innovation here is the key.
The Oncology Care Model—Why It Works and Why It Could Work Better
Authors: Aaron J. Lyss, Susanna N. Supalla, Stephen M. Schleicher
Journal: JAMA Oncology (2019)

This Viewpoint argues that changing the Oncology Care Model to hold clinicians accountable for inappropriate drug utilization, not drug costs, could improve the model while preventing unintended disincentives to clinicians for using effective treatments.
Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study
Authors: Tanya Simuni, Liz Uribe, Hyunkeun Ryan Cho, Chelsea Caspell-Garcia, Christopher S Coffey, Andrew Siderowf, John Q Trojanowski, Leslie M Shaw, John Seibyl, Andrew Singleton, Arthur W Toga, Doug Galasko, Tatiana Foroud, Duygu Tosun, Kathleen Poston, Daniel Weintraub, Brit Mollenhauer, Caroline M Tanner, Karl Kieburtz, Lana M Chahine, Alyssa Reimer, Samantha J Hutten, Susan Bressman, Kenneth Marek, Vanessa Arnedo, Adrienne Clark, Mark Fraiser, Catherine Kopil, Sohini Chowdhury, Todd Sherer, Nichole Daegele, Cynthia Casaceli, Ray Dorsey, Renee Wilson, Sugi Mahes, Christina Salerno, Karen Crawford, Paola Casalin, Giulia Malferrari, Mali Gani Weisz, Avi Orr-Urtreger, Thomas Montine, Chris Baglieri, Amanda Christini, David Russell, Nabila Dahodwala, Nir Giladi, Stewart Factor, Penelope Hogarth, David Standaert, Robert Hauser, Joseph Jankovic, Marie Saint-Hilaire, Irene Richard, David Shprecher, Hubert Fernandez, Katrina Brockmann, Liana Rosenthal, Paolo Barone, Alberto Espay, Dominic Rowe, Karen Marder, Anthony Santiago, Shu-Ching Hu, Stuart Isaacson, Jean-Christophe Corvol, Javiar Ruiz Martinez, Eduardo Tolosa, Yen Tai, Marios Politis, Debra Smejdir, Linda Rees, Karen Williams, Farah Kausar, Karen Williams, Whitney Richardson, Diana Willeke, Shawnees Peacock, Barbara Sommerfeld, Alison Freed, Katrina Wakeman, Courtney Blair, Stephanie Guthrie, Leigh Harrell, Christine Hunter, Cathi-Ann Thomas, Raymond James, Grace Zimmerman, Victoria Brown, Jennifer Mule, Ella Hilt, Kori Ribb, Susan Ainscough, Misty Wethington, Madelaine Ranola, Helen Mejia Santana, Juliana Moreno, Deborah Raymond, Krista Speketer, Lisbeth Carvajal, Stephanie Carvalo, Ioana Croitoru, Alicia Garrido, Laura Marie Payne, Veena Viswanth, Lawrence Severt, Maurizio Facheris, Holly Soares, Mark A. Mintun, Jesse Cedarbaum, Peggy Taylor, Kevin Biglan, Emily Vandenbroucke, Zulfiqar Haider Sheikh, Baris Bingol, Tanya Fischer, Pablo Sardi, Remi Forrat, Alastair Reith, Jan Egebjerg, Gabrielle Ahlberg Hillert, Barbara Saba, Chris Min, Robert Umek, Joe Mather, Susan De Santi, Anke Post, Frank Boess, Kirsten Taylor, Igor Grachev, Andreja Avbersek, Pierandrea Muglia, Kaplana Merchant, Johannes Tauscher
Journal: The Lancet Neurology (2019)
A management algorithm for patients with intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
Authors: Gregory W. J. Hawryluk, Sergio Aguilera, Andras Buki, Eileen Bulger, Giuseppe Citerio, D. Jamie Cooper, Ramon Diaz Arrastia, Michael Diringer, Anthony Figaji, Guoyi Gao, Romergryko Geocadin, Jamshid Ghajar, Odette Harris, Alan Hoffer, Peter Hutchinson, Mathew Joseph, Ryan Kitagawa, Geoffrey Manley, Stephan Mayer, David K. Menon, Geert Meyfroidt, Daniel B. Michael, Mauro Oddo, David Okonkwo, Mayur Patel, Claudia Robertson, Jeffrey V. Rosenfeld, Andres M. Rubiano, Juan Sahuquillo, Franco Servadei, Lori Shutter, Deborah Stein, Nino Stocchetti, Fabio Silvio Taccone, Shelly Timmons, Eve Tsai, Jamie S. Ullman, Paul Vespa, Walter Videtta, David W. Wright, Christopher Zammit, Randall M. Chesnut
Journal: Intensive Care Medicine (2019)

Management algorithms for adult severe traumatic brain injury (sTBI) were omitted in later editions of the Brain Trauma Foundation's sTBI Management Guidelines, as they were not evidence-based.We used a Delphi-method-based consensus approach to address management of sTBI patients undergoing intracranial pressure (ICP) monitoring. Forty-two experienced, clinically active sTBI specialists from six continents comprised the panel. Eight surveys iterated queries and comments. An in-person meeting included whole- and small-group discussions and blinded voting. Consensus required 80% agreement. We developed heatmaps based on a traffic-light model where panelists' decision tendencies were the focus of recommendations.We provide comprehensive algorithms for ICP-monitor-based adult sTBI management. Consensus established 18 interventions as fundamental and ten treatments not to be used. We provide a three-tier algorithm for treating elevated ICP. Treatments within a tier are considered empirically equivalent. Higher tiers involve higher risk therapies. Tiers 1, 2, and 3 include 10, 4, and 3 interventions, respectively. We include inter-tier considerations, and recommendations for critical neuroworsening to assist the recognition and treatment of declining patients. Novel elements include guidance for autoregulation-based ICP treatment based on MAP Challenge results, and two heatmaps to guide (1) ICP-monitor removal and (2) consideration of sedation holidays for neurological examination.Our modern and comprehensive sTBI-management protocol is designed to assist clinicians managing sTBI patients monitored with ICP-monitors alone. Consensus-based (class III evidence), it provides management recommendations based on combined expert opinion. It reflects neither a standard-of-care nor a substitute for thoughtful individualized management.
Engineering Nanoparticles to Reprogram the Tumor Immune Microenvironment for Improved Cancer Immunotherapy
Authors: Madiha Saeed, Jing Gao, Yang Shi, Twan Lammers, Haijun Yu
Journal: Theranostics (2019)

Immunotherapy is rapidly maturing towards extensive clinical use.However, it does not work well in large patient populations because of an immunosuppressed microenvironment and limited reinvigoration of antitumor immunity.The tumor microenvironment is a complex milieu in which the principles of physiology and anatomy are defied and which is considered an immune-privileged site promoting T cell exhaustion.Tremendous research interest exists in developing nanoparticle-based approaches to modulate antitumor immune responses.The increasing use of immunotherapies in the clinic requires robust programming of immune cells to boost antitumor immunity.This review summarizes recent advances in the engineering of nanoparticles for improved anticancer immunotherapy.It discusses emerging nanoparticle-based approaches for the modulation of tumor cells and immune cells, such as dendritic cells, T cells and tumor-associated macrophages, with the intention to overcome challenges currently faced in the clinic.Furthermore, this review describes potentially curative combination therapeutic approaches to provoke effective tumor antigen-specific immune responses.We foresee a future in which improvement in patient's surveillance will become a mainstream practice.
A DNAH17 missense variant causes flagella destabilization and asthenozoospermia
Authors: Beibei Zhang, Hui Ma, Teka Khan, Ao Ma, Tao Li, Huan Zhang, Jianing Gao, Jianteng Zhou, Yang Li, Changping Yu, Jianqiang Bao, Asim Ali, Ghulam Murtaza, Hao Yin, Qian Gao, Xiaohua Jiang, Feng Zhang, Chunyu Liu, Ihsan Khan, Muhammad Zubair, Hafiz Muhammad Jafar Hussain, Ranjha Khan, Ayesha Yousaf, Limin Yuan, Yan Lu, Xiaoling Xu, Yun Wang, Qizhao Tao, Qiaomei Hao, Hui Fang, Hongtao Cheng, Yuanwei Zhang, Qinghua Shi
Journal: The Journal of Experimental Medicine (2019)

Asthenozoospermia is a common cause of male infertility, but its etiology remains incompletely understood. We recruited three Pakistani infertile brothers, born to first-cousin parents, displaying idiopathic asthenozoospermia but no ciliary-related symptoms. Whole-exome sequencing identified a missense variant (c.G5408A, p.C1803Y) in DNAH17, a functionally uncharacterized gene, recessively cosegregating with asthenozoospermia in the family. DNAH17, specifically expressed in testes, was localized to sperm flagella, and the mutation did not alter its localization. However, spermatozoa of all three patients showed higher frequencies of microtubule doublet(s) 4–7 missing at principal piece and end piece than in controls. Mice carrying a homozygous mutation (Dnah17M/M) equivalent to that in patients recapitulated the defects in patients’ sperm tails. Further examinations revealed that the doublets 4–7 were destabilized largely due to the storage of sperm in epididymis. Altogether, we first report that a homozygous DNAH17 missense variant specifically induces doublets 4–7 destabilization and consequently causes asthenozoospermia, providing a novel marker for genetic counseling and diagnosis of male infertility.
Proliferative regulation of alveolar epithelial type 2 progenitor cells by human <i>Scnn1d</i> gene
Authors: Runzhen Zhao, Gibran Ali, Jianjun Chang, Satoshi Komatsu, Yoshikazu Tsukasaki, Hong-Guang Nie, Yongchang Chang, Mo Zhang, Yang Liu, Krishan Jain, Bock-Gie Jung, Buka Samten, Dianhua Jiang, Jiurong Liang, Mitsuo Ikebe, Michael A. Matthay, Hong-Long Ji
Journal: Theranostics (2019)

Lung epithelial sodium channel (ENaC) encoded by Scnn1 genes is essential for maintaining transepithelial salt and fluid homeostasis in the airway and the lung. Compared to α, β, and γ subunits, the role of respiratory δ-ENaC has not been studied in vivo due to the lack of animal models. Methods: We characterized full-length human δ802-ENaC expressed in both Xenopus oocytes and humanized transgenic mice. AT2 proliferation and differentiation in 3D organoids were analysed with FACS and a confocal microscope. Both two-electrode voltage clamp and Ussing chamber systems were applied to digitize δ802-ENaC channel activity. Immunoblotting was utilized to analyse δ802-ENaC protein. Transcripts of individual ENaC subunits in human lung tissues were quantitated with qPCR. Results: The results indicate that δ802-ENaC functions as an amiloride-inhibitable Na+ channel. Inhibitory peptide α-13 distinguishes δ802- from α-type ENaC channels. Modified proteolysis of γ-ENaC by plasmin and aprotinin did not alter the inhibition of amiloride and α-13 peptide. Expression of δ802-ENaC at the apical membrane of respiratory epithelium was detected with biophysical features similar to those of heterologously expressed channels in oocytes. δ802-ENaC regulated alveologenesis through facilitating the proliferation of alveolar type 2 epithelial cells. Conclusion: The humanized mouse line conditionally expressing human δ802-ENaC is a novel model for studying the expression and function of this protein in vivo .
GDNF-expressing macrophages restore motor functions at a severe late-stage, and produce long-term neuroprotective effects at an early-stage of Parkinson’s disease in transgenic Parkin Q311X(A) mice
Authors: Yuling Zhao, Matthew J. Haney, Yeon S. Jin, Olga Uvarov, Natasha Vinod, Yueh Z. Lee, Benjamin Langworthy, Jason P. Fine, Myosotys Rodriguez, Nazira El-Hage, Alexander V. Kabanov, Elena V. Batrakova
Journal: Journal of Controlled Release (2019)
Where Were the Women? Gender Parity in Clinical Trials
Authors: Robert H. Goldstein, Rochelle P. Walensky
Journal: New England Journal of Medicine (2019)

On October 3, the FDA approved coformulated tenofovir alafenamide and emtricitabine (F/TAF) for HIV prevention in at-risk "adults and adolescents…excluding those who have receptive vaginal sex." F/TAF's story highlights numerous flaws in the drug-approval process.
Adhesion of T Cells to Endothelial Cells Facilitates Blinatumomab-Associated Neurologic Adverse Events
Authors: Matthias Klinger, Gerhard Zugmaier, Virginie Nägele, Maria-Elisabeth Goebeler, Christian Brandl, Matthias Stelljes, Hans Lassmann, Arend von Stackelberg, Ralf C. Bargou, Peter Kufer
Journal: Cancer Research (2019)

Blinatumomab, a CD19/CD3-bispecific T-cell engager (BiTE) immuno-oncology therapy for the treatment of B-cell malignancies, is associated with neurologic adverse events in a subgroup of patients. Here, we provide evidence for a two-step process for the development of neurologic adverse events in response to blinatumomab: (i) blinatumomab induced B-cell-independent redistribution of peripheral T cells, including T-cell adhesion to blood vessel endothelium, endothelial activation, and T-cell transmigration into the perivascular space, where (ii) blinatumomab induced B-cell-dependent T-cell activation and cytokine release to potentially trigger neurologic adverse events. Evidence for this process includes (i) the coincidence of T-cell redistribution and the early occurrence of most neurologic adverse events, (ii) T-cell transmigration through brain microvascular endothelium, (iii) detection of T cells, B cells, and blinatumomab in cerebrospinal fluid, (iv) blinatumomab-induced T-cell rolling and adhesion to vascular endothelial cells in vitro, and (v) the ability of antiadhesive agents to interfere with blinatumomab-induced interactions between T cells and vascular endothelial cells in vitro and in patients. On the basis of these observations, we propose a model that could be the basis of mitigation strategies for neurologic adverse events associated with blinatumomab treatment and other T-cell therapies. SIGNIFICANCE: This study proposes T-cell adhesion to endothelial cells as a necessary but insufficient first step for development of blinatumomab-associated neurologic adverse events and suggests interfering with adhesion as a mitigation approach.
Doctors need an environmental rating system for drugs
Authors: J M Tom Pierce, Laurence Bourton
Journal: BMJ (2019)

Van Hove and Leng raise some very valuable points on how the healthcare sector could reduce the environmental impact of metered dose inhaler propellants and anaesthetic gases.1

When buying lightbulbs, we look for A++ rating labels indicating low energy consumption. Drugs have no such rating. Although various matrices exist—such as the process mass intensity (the ratio of mass of raw materials to active pharmaceutical ingredient; typically 50-150)—they aren’t …