tbuckley/cabot-search huggingface dataset:
Supporting Value-Based Health Care — Aligning Financial and Legal Accountability
Authors: Mark M. Zaki, Anupam B. Jena, Amitabh Chandra
Journal: New England Journal of Medicine (2021)

Under value-based payment models, there is a misalignment between organizations' incentives to spend wisely and individual physicians' incentives to reduce malpractice liability risk. One idea that has been proposed to correct this mismatch is enterprise liability.
薬剤溶出性ステント(DES)留置2年後に再狭窄を来たした1例
Authors: 笠原明子, 瀬川潤, 冬野隆一, 佐野哲朗, 三浦靖史, 縄田義夫, 冬野喜郎, 兼行雅司
Journal: Circulation (2008)
Covid-19: Vaccine passports approved in Scotland despite criticism
Authors: Bryan Christie
Journal: BMJ (2021)

Vaccine passports will be required for entry to nightclubs and other “high risk” venues in Scotland despite complaints there is no evidence the measure will reduce transmission of covid-19.

The Scottish parliament voted to introduce the scheme from 1 October when entry to such venues will be restricted to people who can prove they have been fully vaccinated. It comes as infection rates have soared in recent weeks in Scotland with the World Health Organization finding the country has some of the highest rates in Europe.1

The Scottish health secretary Humza Yousaf said, …
Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis
Authors: Raj Vuppalanchi, Stephen H. Caldwell, Nikolaos Pyrsopoulos, Andrew S. deLemos, Simona Rossi, Cynthia Levy, David S. Goldberg, Edward A. Mena, Aasim Sheikh, Ravi Ravinuthala, Farheen Shaikh, James D. Bainbridge, Deven V. Parmar, Naga P. Chalasani
Journal: Journal of Hepatology (2021)
The novel bronchodilator navafenterol: a phase 2a, multicentre, randomised, double-blind, placebo-controlled crossover trial in COPD
Authors: Dave Singh, Jutta Beier, Carol Astbury, Maria G. Belvisi, Carla A. Da Silva, Alexandra Jauhiainen, Eulalia Jimenez, Alejhandra Lei, Sofia Necander, Jaclyn A. Smith, Ulrika Wählby Hamrén, Wenjing Xin, Ioannis Psallidas
Journal: European Respiratory Journal (2021)

Background Navafenterol (AZD8871) belongs to a new class of bronchodilator, the single-molecule muscarinic antagonist and β-agonist, developed for the treatment of COPD. This study aimed to evaluate the efficacy, pharmacokinetics and safety of navafenterol versus placebo and an active comparator treatment for moderate-to-severe COPD. Methods This phase 2a, randomised, multicentre (Germany and UK), double-blind, double-dummy, three-way complete crossover study (ClinicalTrials.gov identifier: NCT03645434 ) compared 2 weeks’ treatment of once-daily navafenterol 600 µg via inhalation with placebo and a fixed-dose combination bronchodilator (umeclidinium/vilanterol (UMEC/VI); 62.5 µg/25 µg) in participants with moderate-to-severe COPD. The primary outcome was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) on day 15. Secondary end-points included change from baseline in peak FEV 1 ; change from baseline in Breathlessness, Cough and Sputum Scale (BCSS); change from baseline in COPD Assessment Tool (CAT); adverse events; and pharmacokinetics. Results 73 participants were randomised. After 14 days, trough FEV 1 was significantly improved with navafenterol compared with placebo (least-squares (LS) mean difference 0.202 L; p&lt;0.0001). There was no significant difference in FEV 1 between navafenterol and UMEC/VI (LS mean difference −0.046 L; p=0.075). COPD symptoms (CAT and BCSS) showed significantly greater improvements with both active treatments versus placebo (all p&lt;0.005). Novel objective monitoring (VitaloJAK) showed that cough was reduced with both active treatments compared with placebo. Safety profiles were similar across the treatment groups and no serious adverse events were reported in the navafenterol treatment period. Conclusion Once-daily navafenterol was well tolerated, improved lung function and reduced COPD-related symptoms, similar to an established once-daily fixed-dose combination bronchodilator.
Wild-type FUS corrects ALS-like disease induced by cytoplasmic mutant FUS through autoregulation
Authors: Inmaculada Sanjuan-Ruiz, Noé Govea-Perez, Melissa McAlonis-Downes, Stéphane Dieterle, Salim Megat, Sylvie Dirrig-Grosch, Gina Picchiarelli, Diana Piol, Qiang Zhu, Brian Myers, Chao-Zong Lee, Don W Cleveland, Clotilde Lagier-Tourenne, Sandrine Da Cruz, Luc Dupuis
Journal: Molecular Neurodegeneration (2021)

Abstract Mutations in FUS, an RNA-binding protein involved in multiple steps of RNA metabolism, are associated with the most severe forms of amyotrophic lateral sclerosis (ALS). Accumulation of cytoplasmic FUS is likely to be a major culprit in the toxicity of FUS mutations. Thus, preventing cytoplasmic mislocalization of the FUS protein may represent a valuable therapeutic strategy. FUS binds to its own pre-mRNA creating an autoregulatory loop efficiently buffering FUS excess through multiple proposed mechanisms including retention of introns 6 and/or 7. Here, we introduced a wild-type FUS gene allele, retaining all intronic sequences, in mice whose heterozygous or homozygous expression of a cytoplasmically retained FUS protein ( Fus ∆NLS ) was previously shown to provoke ALS-like disease or postnatal lethality, respectively. Wild-type FUS completely rescued the early lethality caused by the two Fus ∆NLS alleles, and improved the age-dependent motor deficits and reduced lifespan caused by heterozygous expression of mutant FUS ∆NLS . Mechanistically, wild-type FUS decreased the load of cytoplasmic FUS, increased retention of introns 6 and 7 in the endogenous mouse Fus mRNA, and decreased expression of the mutant mRNA. Thus, the wild-type FUS allele activates the homeostatic autoregulatory loop, maintaining constant FUS levels and decreasing the mutant protein in the cytoplasm. These results provide proof of concept that an autoregulatory competent wild-type FUS expression could protect against this devastating, currently intractable, neurodegenerative disease.
An in vitro platform supports generation of human innate lymphoid cells from CD34+ hematopoietic progenitors that recapitulate ex vivo identity
Authors: Daniela Carolina Hernández, Kerstin Juelke, Nils Christian Müller, Pawel Durek, Bilge Ugursu, Mir-Farzin Mashreghi, Timo Rückert, Chiara Romagnani
Journal: Immunity (2021)
Patient-Based Prediction Algorithm of Relapse after Allo-HSCT for Acute Leukemia Using Machine Learning Approach
Authors: Kyoko Fuse, Shun Uemura, Tatsuya Suwabe, Takayuki Katagiri, Tomoyuki Tanaka, Takashi Ushiki, Yasuhiko Shibasaki, Naoko Sato, Toshio Yano, Takashi Kuroha, Shigeo Hashimoto, Tastuo Furukawa, Miwako Narita, Hirohito Sone, Masayoshi Masuko
Journal: Blood (2017)
The endoscopic ultrasound features of pancreatic fluid collections and their impact on therapeutic decisions: an interobserver agreement study
Authors: Carlo Fabbri, Todd H. Baron, Giulia Gibiino, Paolo Giorgio Arcidiacono, Cecilia Binda, Andrea Anderloni, Gianenrico Rizzatti, Manuel Pérez-Miranda, Andrea Lisotti, Loredana Correale, Joan B. Gornals, Ilaria Tarantino, Maria Chiara Petrone, Paolo Cecinato, Pietro Fusaroli, Alberto Larghi
Journal: Endoscopy (2021)

Background A validated classification of endoscopic ultrasound (EUS) morphological characteristics and consequent therapeutic intervention(s) in pancreatic and peripancreatic fluid collections (PFCs) is lacking. We performed an interobserver agreement study among expert endosonographers assessing EUS-related PFC features and the therapeutic approaches used. Methods 50 EUS videos of PFCs were independently reviewed by 12 experts and evaluated for PFC type, percentage solid component, presence of infection, recognition of and communication with the main pancreatic duct (MPD), stent choice for drainage, and direct endoscopic necrosectomy (DEN) performance and timing. The Gwet’s AC1 coefficient was used to assess interobserver agreement. Results A moderate agreement was found for lesion type (AC1, 0.59), presence of infection (AC1, 0.41), and need for DEN (AC1, 0.50), while fair or poor agreements were stated for percentage solid component (AC1, 0.15) and MPD recognition (AC1, 0.31). Substantial agreement was rated for ability to assess PFC–MPD communication (AC1, 0.69), decision between placing a plastic versus lumen-apposing metal stent (AC1, 0.62), and timing of DEN (AC1, 0.75). Conclusions Interobserver agreement between expert endosonographers regarding morphological features of PFCs appeared suboptimal, while decisions on therapeutic approaches seemed more homogeneous. Studies to achieve standardization of the diagnostic endosonographic criteria and therapeutic approaches to PFCs are warranted.
An “eat me” combinatory nano-formulation for systemic immunotherapy of solid tumors
Authors: Hend Mohamed Abdel-Bar, Adam A Walters, Yau Lim, Nadia Rouatbi, Yue Qin, Fatemeh Gheidari, Shunping Han, Rihab Osman, Julie Tzu-Wen Wang, Khuloud T Al-Jamal
Journal: Theranostics (2021)

Rational: Tumor immunogenic cell death (ICD), induced by certain chemotherapeutic drugs such as doxorubicin (Dox), is a form of apoptosis potentiating a protective immune response. One of the hallmarks of ICD is the translocation of calreticulin to the cell surface acting as an 'eat me' signal. This manuscript describes the development of a stable nucleic acid-lipid particles (SNALPs) formulation for the simultaneous delivery of ICD inducing drug (Dox) with small interfering RNA (siRNA) knocking down CD47 (siCD47), the dominant 'don't eat me' marker, for synergistic enhancement of ICD. Methods: SNALPs loaded with Dox or siCD47 either mono or combinatory platforms were prepared by ethanol injection method. The proposed systems were characterized for particle size, surface charge, entrapment efficiency and in vitro drug release. The ability of the SNALPs to preserve the siRNA integrity in presence of serum and RNAse were assessed over 48 h. The in vitro cellular uptake and gene silencing of the prepared SNALPs was assessed in CT26 cells. The immunological responses of the SNALPs were defined in vitro in terms of surface calreticulin expression and macrophage-mediated phagocytosis induction. In vivo therapeutic studies were performed in CT26 bearing mice where the therapeutic outcomes were expressed as tumor volume, expression of CD4 and CD8 as well as in vivo silencing. Results: The optimized SNALPs had a particle size 122 ±6 nm and an entrapment efficiency > 65% for both siRNA and Dox with improved serum stability. SNALPs were able to improve siRNA and Dox uptake in CT26 cells with enhanced cytotoxicity. siCD47 SNALPs were able to knockdown CD47 by approximately 70% with no interference from the presence of Dox. The siCD47 and Dox combination SNALPs were able to induce surface calreticulin expression leading to a synergistic effect on macrophage-mediated phagocytosis of treated cells. In a tumor challenge model, 50% of mice receiving siCD47 and Dox containing SNALPs were able to clear the tumor, while the remaining animals showed significantly lower tumor burden as compared to either monotreatment. Conclusion: Therefore, the combination of siCD47 and Dox in a particulate system showed potent anti-tumor activity which merits further investigation in future clinical studies.
Extracorporeal cardiopulmonary resuscitation in adults: evidence and implications
Authors: Darryl Abrams, Graeme MacLaren, Roberto Lorusso, Susanna Price, Demetris Yannopoulos, Leen Vercaemst, Jan Bělohlávek, Fabio S. Taccone, Nadia Aissaoui, Kiran Shekar, A. Reshad Garan, Nir Uriel, Joseph E. Tonna, Jae Seung Jung, Koji Takeda, Yih-Sharng Chen, Arthur S. Slutsky, Alain Combes, Daniel Brodie
Journal: Intensive Care Medicine (2021)
Does My District Need a Mobile Stroke Unit?
Authors: Kennedy R. Lees
Journal: New England Journal of Medicine (2021)

In their article in this issue of the Journal on emergency medical response in cases of stroke, Grotta and colleagues1 report several positive findings for mobile stroke units in comparison with conventional medical service ambulances. These include 22% greater access to intravenous thrombolysis treatment with mobile stroke units (97.1% of eligible patients vs. 79.5%), a 36-minute shorter median time from stroke onset to initiation of treatment (72 minutes vs. 108 minutes), and a 24% larger percentage of patients returning to normal activities 3 months after stroke (55.0% vs. 44.4%). Specialist stroke care saves lives and reduces disability,2 and evidence supports . . .
Study that finds good sex clears a stuffed nose as well as a decongestant wins Ig Nobel prize for medicine
Authors: Janice Hopkins Tanne
Journal: BMJ (2021)

Good sex cures a stuffy nose, fear is in the air at a scary movie, beards protect against broken jaws, fat politicians are a sign of national corruption, and upside down flying rhinoceroses were among this year’s Ig Nobel prize winners.

The Ig Nobel prizes for research that “first make people laugh and then make people think” are given annually by the science humour magazine, Annals of Improbable Research , the Harvard-Radcliffe Science Fiction Association, and the Harvard-Radcliffe Society of Physics students. The awards were handed out on 9 September by actual Nobel prize winners at a virtual ceremony led by Annals editor Marc Abrahams.

18 orgasmic heterosexual couples in Heidelberg showed that good sex is a quick fix for a stuffy nose in a study by Olcay Cem Bulut of the University Hospital in Heidelberg and colleagues in Heilbronn, Germany, and York, England. The study won the medicine prize, perhaps confirming Freud’s thought that the nose and the genitals are connected.

The couples were professional healthcare workers and their partners, one or both suffering from nasal congestion. The …
Shigella ubiquitin ligase IpaH7.8 targets gasdermin D for degradation to prevent pyroptosis and enable infection
Authors: Giovanni Luchetti, Justin L. Roncaioli, Roberto A. Chavez, Alexander F. Schubert, Eric M. Kofoed, Rohit Reja, Tommy K. Cheung, Yuxin Liang, Joshua D. Webster, Isabelle Lehoux, Elizabeth Skippington, Janina Reeder, Benjamin Haley, Man Wah Tan, Christopher M. Rose, Kim Newton, Nobuhiko Kayagaki, Russell E. Vance, Vishva M. Dixit
Journal: Cell Host & Microbe (2021)

The pore-forming protein gasdermin D (GSDMD) executes lytic cell death called pyroptosis to eliminate the replicative niche of intracellular pathogens. Evolution favors pathogens that circumvent this host defense mechanism. Here, we show that the Shigella ubiquitin ligase IpaH7.8 functions as an inhibitor of GSDMD. Shigella is an enteroinvasive bacterium that causes hemorrhagic gastroenteritis in primates, but not rodents. IpaH7.8 contributes to species specificity by ubiquitinating human, but not mouse, GSDMD and targeting it for proteasomal degradation. Accordingly, infection of human epithelial cells with IpaH7.8-deficient Shigella flexneri results in increased GSDMD-dependent cell death compared with wild type. Consistent with pyroptosis contributing to murine disease resistance, eliminating GSDMD from NLRC4-deficient mice, which are already sensitized to oral infection with Shigella flexneri, leads to further enhanced bacterial replication and increased disease severity. This work highlights a species-specific pathogen arms race focused on maintenance of host cell viability.
Thirty Years of Neuroscientific Investigation of Placebo and Nocebo: The Interesting, the Good, and the Bad
Authors: Fabrizio Benedetti, Elisa Frisaldi, Aziz Shaibani
Journal: The Annual Review of Pharmacology and Toxicology (2021)

Over the past 30 years there has been a surge of research on the placebo effect using a neuroscientific approach. The interesting aspects of this effort are related to the identification of several biological mechanisms of both the placebo and nocebo effects, the latter of which is defined as a negative placebo effect. Some important translational implications have emerged both in the setting of clinical trials and in routine medical practice. One of the principal contributions of neuroscience has been to draw the attention of the scientific and medical communities to the important role of psychobiological factors in therapeutic outcomes, be they drug related or not. Indeed, many biological mechanisms triggered by placebos and nocebos resemble those modulated by drugs, suggesting a possible interaction between psychological factors and drug action. Unfortunately, this new knowledge regarding placebos has the potential of being dangerously exploited by pseudoscience.
Alternative treatments for type 2 diabetes and associated metabolic diseases: medical therapy or endoscopic duodenal mucosal remodelling?
Authors: Annieke C G van Baar, Suzanne Meiring, Frits Holleman, David Hopkins, Geltrude Mingrone, Jacques Devière, Max Nieuwdorp, Jacques J G H M Bergman
Journal: Gut (2021)

### Key messages



The number of patients with type 2 diabetes (T2D) worldwide is expected to increase from 463 million in 2019 to 700 million in 2045, with a prevalence of more than 10% in Europe. Besides a role for genetics, causative factors include obesity, diet high in refined sugar and fat, and sedentary lifestyle. These factors may contribute to increased hepatic and peripheral insulin resistance, and thereafter pancreatic beta cells increase their insulin production to facilitate glucose uptake. …
Phenotyping heart failure patients for iron deficiency and use of intravenous iron therapy: data from the <scp>S</scp>wedish <scp>H</scp>eart <scp>F</scp>ailure <scp>R</scp>egistry
Authors: Peter Moritz Becher, Benedikt Schrage, Lina Benson, Marat Fudim, Carin Corovic Cabrera, Ulf Dahlström, Giuseppe M.C. Rosano, Ewa A. Jankowska, Stefan D. Anker, Lars H. Lund, Gianluigi Savarese
Journal: European Journal of Heart Failure (2021)
The deubiquitinase USP15 modulates cellular redox and is a therapeutic target in acute myeloid leukemia
Authors: Madeline Niederkorn, Chiharu Ishikawa, Kathleen M. Hueneman, James Bartram, Emily Stepanchick, Joshua R. Bennett, Ashley E. Culver-Cochran, Lyndsey C. Bolanos, Emma Uible, Kwangmin Choi, Mark Wunderlich, John P. Perentesis, Timothy M. Chlon, Marie-Dominique Filippi, Daniel T. Starczynowski
Journal: Leukemia (2021)

Abstract Ubiquitin-specific peptidase 15 (USP15) is a deubiquitinating enzyme implicated in critical cellular and oncogenic processes. We report that USP15 mRNA and protein are overexpressed in human acute myeloid leukemia (AML) as compared to normal hematopoietic progenitor cells. This high expression of USP15 in AML correlates with KEAP1 protein and suppression of NRF2. Knockdown or deletion of USP15 in human and mouse AML models significantly impairs leukemic progenitor function and viability and de-represses an antioxidant response through the KEAP1-NRF2 axis. Inhibition of USP15 and subsequent activation of NRF2 leads to redox perturbations in AML cells, coincident with impaired leukemic cell function. In contrast, USP15 is dispensable for human and mouse normal hematopoietic cells in vitro and in vivo. A preclinical small-molecule inhibitor of USP15 induced the KEAP1-NRF2 axis and impaired AML cell function, suggesting that targeting USP15 catalytic function can suppress AML. Based on these findings, we report that USP15 drives AML cell function, in part, by suppressing a critical oxidative stress sensor mechanism and permitting an aberrant redox state. Furthermore, we postulate that inhibition of USP15 activity with small molecule inhibitors will selectively impair leukemic progenitor cells by re-engaging homeostatic redox responses while sparing normal hematopoiesis.
Red Cell Distribution Width (RDW) As Prognostic Factor in Acute Leukemia Patients Undergoing Allogeneic Hematopoietic Transplantation
Authors: Giuseppe Milone, Annalia DiMarco, Giuseppe Sapienza, Salvatore Leotta, Luca Scalise, Carla Consoli, Maria Cristina Pirosa, Alessandra Cupri, Gaetano Moschetti, Maria Grazia Camuglia, Maria Sciacca, AnnaElisa Marchese
Journal: Blood (2017)
NMDAR-dependent somatic potentiation of synaptic inputs is correlated with β amyloid-mediated neuronal hyperactivity
Authors: Yifei Bao, Xin Yang, Yi Fu, Zhengyan Li, Ru Gong, Wei Lu
Journal: Translational Neurodegeneration (2021)

Abstract Background β Amyloid (Aβ)-mediated neuronal hyperactivity, a key feature of the early stage of Alzheimer’s disease (AD), is recently proposed to be initiated by the suppression of glutamate reuptake. Nevertheless, the underlying mechanism by which the impaired glutamate reuptake causes neuronal hyperactivity remains unclear. Chronic suppression of the glutamate reuptake causes accumulation of ambient glutamate that could diffuse from synaptic sites at the dendrites to the soma to elevate the tonic activation of somatic N -methyl- D -aspartate receptors (NMDARs). However, less attention has been paid to the potential role of tonic activity change in extrasynaptic glutamate receptors (GluRs) located at the neuronal soma on generation of neuronal hyperactivity. Methods Whole-cell patch-clamp recordings were performed on CA1 pyramidal neurons in acute hippocampal slices exposed to TFB-threo-β-benzyloxyaspartic acid (TBOA) or human Aβ 1–42 peptide oligomer. A series of dendritic patch-clamp recordings were made at different distances from the soma to identify the location of the changes in synaptic inputs. Moreover, single-channel recording in the cell-attached mode was performed to investigate the activity changes of single NMDARs at the soma. Results Blocking glutamate uptake with either TBOA or the human Aβ 1–42 peptide oligomer elicited potentiation of synaptic inputs in CA1 hippocampal neurons. Strikingly, this potentiation specifically occurred at the soma, depending on the activation of somatic GluN2B-containing NMDARs (GluN2B-NMDARs) and accompanied by a substantial and persistent increment in the open probability of somatic NMDARs. Blocking the activity of GluN2B-NMDARs at the soma completely reversed both the TBOA-induced or the Aβ 1–42 -induced somatic potentiation and neuronal hyperactivity. Conclusions The somatic potentiation of synaptic inputs may represent a novel amplification mechanism that elevates cell excitability and thus contributes to neuronal hyperactivity initiated by impaired glutamate reuptake in AD.
Extracellular protein components of amyloid plaques and their roles in Alzheimer’s disease pathology
Authors: M. Mahafuzur Rahman, Christofer Lendel
Journal: Molecular Neurodegeneration (2021)

Abstract Alzheimer’s disease (AD) is pathologically defined by the presence of fibrillar amyloid β (Aβ) peptide in extracellular senile plaques and tau filaments in intracellular neurofibrillary tangles. Extensive research has focused on understanding the assembly mechanisms and neurotoxic effects of Aβ during the last decades but still we only have a brief understanding of the disease associated biological processes. This review highlights the many other constituents that, beside Aβ, are accumulated in the plaques, with the focus on extracellular proteins. All living organisms rely on a delicate network of protein functionality. Deposition of significant amounts of certain proteins in insoluble inclusions will unquestionably lead to disturbances in the network, which may contribute to AD and copathology. This paper provide a comprehensive overview of extracellular proteins that have been shown to interact with Aβ and a discussion of their potential roles in AD pathology. Methods that can expand the knowledge about how the proteins are incorporated in plaques are described. Top-down methods to analyze post-mortem tissue and bottom-up approaches with the potential to provide molecular insights on the organization of plaque-like particles are compared. Finally, a network analysis of Aβ-interacting partners with enriched functional and structural key words is presented.