tbuckley/cabot-search huggingface dataset:
Heart Failure End Points in Cardiovascular Outcome Trials of Sodium Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus
Authors: Javed Butler, Milton Packer, Stephen J. Greene, Mona Fiuzat, Stefan D. Anker, Kevin J. Anstrom, Peter E. Carson, Lauren B. Cooper, Gregg C. Fonarow, Adrian F. Hernandez, James L. Januzzi, Mariell Jessup, Rita R. Kalyani, Sanjay Kaul, Mikhail Kosiborod, JoAnn Lindenfeld, Darren K. McGuire, Marc S. Sabatine, Scott D. Solomon, John R. Teerlink, Muthiah Vaduganathan, Clyde W. Yancy, Norman Stockbridge, Christopher M. O’Connor
Journal: Circulation (2019)

Following regulatory guidance set forth in 2008 by the US Food and Drug Administration for new drugs for type 2 diabetes mellitus, many large randomized, controlled trials have been conducted with the primary goal of assessing the safety of antihyperglycemic medications on the primary end point of major adverse cardiovascular events, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Heart failure (HF) was not specifically mentioned in the US Food and Drug Administration guidance and therefore it was not a focus of these studies when planned. Several trials subsequently showed the impact of antihyperglycemic drugs on HF outcomes, which were not originally specified as the primary end point of the trials. The most impressive finding has been the substantial and consistent risk reduction in HF hospitalization seen across 4 trials of sodium glucose cotransporter 2 inhibitors. However, to date, these results have not led to regulatory approval of any of these drugs for a HF indication or a recommendation for use by US HF guidelines. It is therefore important to explore to what extent persuasive treatment effects on nonprimary end points can be used to support regulatory claims and guideline recommendations. This topic was discussed by researchers, clinicians, industry sponsors, regulators, and representatives from professional societies, who convened on the US Food and Drug Administration campus on March 6, 2019. This report summarizes these discussions and the key takeaway messages from this meeting.
Antivaccination movement exploits public’s distrust in scientific authority
Authors: Maya J Goldenberg
Journal: BMJ (2019)

Perera and colleagues urge us to learn from the surge of self-organising networks that are driving the rapid spread of antivaccination messages.1 Better than adopting the social media techniques of this so-called new power, the case for vaccination could get a needed boost by tackling the conditions that precipitated this challenge to the old knowledge order. 

There is …
Evaluating Improvements and Shortcomings in Clinician Satisfaction With Electronic Health Record Usability
Authors: Kylie M. Gomes, Raj M. Ratwani
Journal: JAMA Network Open (2019)

With the widespread adoption of electronic health records (EHRs), there is increased focus on addressing the challenges of EHR usability, ie, the extent to which the technology enables users to achieve their goals effectively, efficiently, and satisfactorily.1 Poor usability is associated with clinician job dissatisfaction and burnout and could have patient safety consequences.2,3,4

The US Department of Health and Human Services Office of the National Coordinator for Health Information Technology established safety-enhanced design certification requirements for EHRs to promote usability. These requirements stipulate that vendors must conduct and report results of formal usability testing, including measuring satisfaction with the EHR system.5 Results are publicly available. While some vendors use a 5-point, ease-of-use rating scale, most vendors use the system usability scale (SUS), which is a validated posttest questionnaire that measures user satisfaction with product usability.6 The questionnaire provides a score (range, 0-100) based on a participant’s rating of 10 statements regarding a product’s usability.6 Higher scores indicate greater satisfaction with usability.6 Based on an analysis of more than 200 studies of various products in various industries, an SUS score of 68 is considered the average benchmark, and an SUS of 80 is considered the above-average benchmark.6 Recognizing the importance of satisfaction with EHR usability to clinician burnout and patient safety, reported product 2015 SUS scores for EHR systems were compared with 2014 SUS scores and with benchmarks to evaluate whether satisfaction is improving.2,3,4
Pilot Study on the Feasibility, Safety and Immunogenicity of a Personalized Neoantigen-Targeted Immunotherapy (NeoPepVac) in Combination with Anti-PD-1 or Anti-PD-L1 in Advanced Solid Tumors
Authors: S.K. Moerk, M. Donia, J.V. Kringelum, T. Bogenrieder, B. Rønø, A.B. Sorensen, A. Draghi, K.F. Bol, N.V. Petersen, M. Kadivar, S.S. Hernandez, S. Reker Hadrup, L.V. Andreasen, D. Christensen, P.L. Andersen, I.M. Svane
Journal: Annals of Oncology (2019)
Abstract B31: Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis
Authors: Jeffrey H. Lin, Austin P. Huffman, Emma E. Furth, Robert H. Vonderheide
Journal: Cancer Research (2019)

Abstract Dendritic cell (DC) dysregulation in cancer has long been hypothesized to be a tumor-associated phenomenon. Using the KPC autochthonous mouse model of pancreatic ductal adenocarcinoma, we reveal that dysfunction of type 1 conventional DCs (cDC1s)—critical mediators of antitumor T-cell immunity—instead develops in the preinvasive stage of carcinogenesis and impacts the host systemically prior to malignancy. Both cDC1 survival and function are impacted, with cDC1s suspended in a state of semi-maturation in which genes involved in response to inflammation and proteasomal degradation are successfully upregulated while genes encoding T cell-polarizing cytokines necessary for T-cell activation fail to be induced. cDC1 dysfunction subsequently impairs CD8+ T-cell activation in vivo. However, this defect remains reversible even following progression to invasive cancer. CD40 activation induces an IFNg response signature that drives cDC1 maturation and migration to draining lymph nodes, restoring CD8+ T-cell activation to normal levels. This study therefore reveals the unexpected depths of cDC1 dysregulation in carcinogenesis but nevertheless elaborates therapeutically tractable strategies towards cDC1 repair. Citation Format: Jeffrey H. Lin, Austin P. Huffman, Emma E. Furth, Robert H. Vonderheide. Type 1 conventional dendritic cells are progressively and systemically dysregulated early in pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B31.
Abstract A48: Genetic ablation of microRNA-21 profoundly remodels stroma and shortens survival of K-Ras-driven pancreatic cancer mouse models
Authors: Josh Schipper, Ian Beddows, Matti Kiupel, Jose Conejo-Garcia, Lorenzo Sempere
Journal: Cancer Research (2019)

Abstract The tumor microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor-restraining and tumor-promoting fibroblast subpopulations. Re-education rather than indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied global loss of profibrotic noncoding regulatory microRNA-21 (miR-21) in K-Ras-driven genetically engineered mouse models of PDAC. We generated mouse strains carrying wild-type or knockout alleles of Mir-21 in a well-characterized K-Ras-driven, p53-deleted PDAC model (LSL-KrasG12D; p53lox/+;Pdx1-Cre, KPC). Even though miR-21 expression was upregulated in cancer cells and cancer-associated fibroblasts in KPC tumors, global loss of miR-21 activity did not inhibit tumor growth. Strikingly, loss of miR-21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. We uncovered a cell-autonomous requirement of miR-21 activity for induction of tumor-restraining myofibroblasts, whose absence led to a profound remodeling of the stroma and massive infiltrate of tumor-permissive immune cells. Low miR-21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in TCGA PDAC data set (n = 156) mirroring findings in genetic models. In vitro and in vivo isograft experiments showed that miR-21 activity was dispensable for cancer cell growth but required for complete execution of TGF-b-mediated programs. Our results suggest that modulation of miR-21 activity may provide a novel therapeutic opportunity to affect the composition of fibroblast subpopulations and enhance current chemotherapy and/or immunotherapy treatments. Citation Format: Josh Schipper, Ian Beddows, Matti Kiupel, Jose Conejo-Garcia, Lorenzo Sempere. Genetic ablation of microRNA-21 profoundly remodels stroma and shortens survival of K-Ras-driven pancreatic cancer mouse models [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A48.
Biocompatible near-infrared quantum dots delivered to the skin by microneedle patches record vaccination
Authors: Kevin J. McHugh, Lihong Jing, Sean Y. Severt, Mache Cruz, Morteza Sarmadi, Hapuarachchige Surangi N. Jayawardena, Collin F. Perkinson, Fridrik Larusson, Sviatlana Rose, Stephanie Tomasic, Tyler Graf, Stephany Y. Tzeng, James L. Sugarman, Daniel Vlasic, Matthew Peters, Nels Peterson, Lowell Wood, Wen Tang, Jihyeon Yeom, Joe Collins, Philip A. Welkhoff, Ari Karchin, Megan Tse, Mingyuan Gao, Moungi G. Bawendi, Robert Langer, Ana Jaklenec
Journal: Science Translational Medicine (2019)

Accurate medical recordkeeping is a major challenge in many low-resource settings where well-maintained centralized databases do not exist, contributing to 1.5 million vaccine-preventable deaths annually. Here, we present an approach to encode medical history on a patient using the spatial distribution of biocompatible, near-infrared quantum dots (NIR QDs) in the dermis. QDs are invisible to the naked eye yet detectable when exposed to NIR light. QDs with a copper indium selenide core and aluminum-doped zinc sulfide shell were tuned to emit in the NIR spectrum by controlling stoichiometry and shelling time. The formulation showing the greatest resistance to photobleaching after simulated sunlight exposure (5-year equivalence) through pigmented human skin was encapsulated in microparticles for use in vivo. In parallel, microneedle geometry was optimized in silico and validated ex vivo using porcine and synthetic human skin. QD-containing microparticles were then embedded in dissolvable microneedles and administered to rats with or without a vaccine. Longitudinal in vivo imaging using a smartphone adapted to detect NIR light demonstrated that microneedle-delivered QD patterns remained bright and could be accurately identified using a machine learning algorithm 9 months after application. In addition, codelivery with inactivated poliovirus vaccine produced neutralizing antibody titers above the threshold considered protective. These findings suggest that intradermal QDs can be used to reliably encode information and can be delivered with a vaccine, which may be particularly valuable in the developing world and open up new avenues for decentralized data storage and biosensing.
Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia
Authors: Adrian C. Newland, Blanca Sánchez‐González, László Rejtő, Miklos Egyed, Nataliya Romanyuk, Marie Godar, Katrien Verschueren, Domenica Gandini, Peter Ulrichts, Jon Beauchamp, Torsten Dreier, E. Sally Ward, Marc Michel, Howard A. Liebman, Hans de Haard, Nicolas Leupin, David J. Kuter
Journal: American Journal of Hematology (2019)

Abstract Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder, characterized by a low platelet count (&lt;100 × 10 9 /L) in the absence of other causes associated with thrombocytopenia. In most patients, IgG autoantibodies directed against platelet receptors can be detected. They accelerate platelet clearance and destruction, inhibit platelet production, and impair platelet function, resulting in increased risk of bleeding and impaired quality of life. Efgartigimod is a human IgG1 antibody Fc‐fragment, a natural ligand of the neonatal Fc receptor (FcRn), engineered for increased affinity to FcRn, while preserving its characteristic pH‐dependent binding. Efgartigimod blocks FcRn, preventing IgG recycling, and causing targeted IgG degradation. In this Phase 2 study, 38 patients were randomized 1:1:1 to receive four weekly intravenous infusions of either placebo (N = 12) or efgartigimod at a dose of 5 mg/kg (N = 13) or 10 mg/kg (N = 13). This short treatment cycle of efgartigimod in patients with ITP, predominantly refractory to previous lines of therapy, was shown to be well tolerated, and demonstrated a favorable safety profile consistent with Phase 1 data. Efgartigimod induced a rapid reduction of total IgG levels (up to 63.7% mean change from baseline), which was associated with clinically relevant increases in platelet counts (46% patients on efgartigimod vs 25% on placebo achieved a platelet count of ≥50 × 10 9 /L on at least two occasions, and 38% vs 0% achieved ≥50 × 10 9 /L for at least 10 cumulative days), and a reduced proportion of patients with bleeding. Taken together, these data warrant further evaluation of FcRn antagonism as a novel therapeutic approach in ITP.
Abstract A16: A novel therapeutic approach to inhibit the bidirectional oncogenic crosstalk between pancreatic cancer cells and the surrounding stroma
Authors: Bekesho Geleta, Kyung Chan Park, Patric J. Jansson, Minoti Apte, Des R. Richardson, Zaklina Kovacevic
Journal: Cancer Research (2019)

Abstract Background: Pancreatic cancer (PaCa) is a leading cause of cancer-related deaths and is projected to be the second most common cancer in a decade. It is characterized by a dense stroma surrounding tumor cells, known as desmoplasia that is stimulated by Sonic Hedgehog (SHH) released by PaCa cells. Stromal cells, in turn, release mitogenic substances such as hepatocyte growth factor (HGF) and Insulin-like growth factor receptor (IGF-1) by glioma-associated oncogene homolog 1 (GLI1) transcription factor that stimulate tumor growth, invasion, and resistance to therapy. We investigated the potential of targeting the metastasis suppressor gene N-myc downstream regulated gene 1 (NDRG1) to interrupt the oncogenic crosstalk between cancer associated human pancreatic stellate cells (PSCs) and PaCa cells. Methods: We assessed novel thiosemicarbazone anti-cancer agents, Dp44mT and DpC, that upregulate NDRG1 and their effects on: (i) SHH production by PaCa cells and also HGF and IGF-1 production by PSCs; (ii) HGF and IGF-1 receptors and their downstream signaling in indirect 2D and direct 3D co-culture of PSCs and PaCa cells; (iii) GLI1 and its upstream mediators in PSCs; and (iv) proliferative and metastatic properties of PaCa cells co-cultured with PSCs. Results: Dp44mT and DpC upregulated NDRG1 and reduced SHH production by PaCa. These agents also inhibited downstream HGF and IGF-1 signaling pathways in PaCa cells, leading to reduced metastatic potential in co-culture 2D and 3D models. Further, these agents also inhibited GLI1 levels and activation in PSCs, leading to reduced HGF and IGF-1 production by these stromal cells. NDRG1 overexpression alone had similar effects, while silencing NDRG1 further potentiated the oncogenic crosstalk between PaCa and PSC cells. Conclusions: Novel agents targeting NDRG1 have the unique ability to block the oncogenic crosstalk between PaCa cells and the surrounding stroma. This presents a novel approach to PaCa treatment that can potentially overcome the major problems attributed to desmoplasia, including therapeutic resistance and metastasis. Citation Format: Bekesho Geleta, Kyung Chan Park, Patric J. Jansson, Minoti Apte, Des R. Richardson, Zaklina Kovacevic. A novel therapeutic approach to inhibit the bidirectional oncogenic crosstalk between pancreatic cancer cells and the surrounding stroma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A16.
Effectiveness of management strategies for uninvestigated dyspepsia: systematic review and network meta-analysis
Authors: Leonardo H Eusebi, Christopher J Black, Colin W Howden, Alexander C Ford
Journal: BMJ (2019)

Abstract Objective To determine the effectiveness of management strategies for uninvestigated dyspepsia. Design Systematic review and network meta-analysis. Data sources Medline, Embase, Embase Classic, the Cochrane Central Register of Controlled Trials, and clinicaltrials.gov from inception to September 2019, with no language restrictions. Conference proceedings between 2001 and 2019. Eligibility criteria for selecting studies Randomised controlled trials that assessed the effectiveness of management strategies for uninvestigated dyspepsia in adult participants (age ≥18 years). Strategies of interest were prompt endoscopy; test for Helicobacter pylori and perform endoscopy in participants who test positive; test for H pylori and eradication treatment in those who test positive (“test and treat”); empirical acid suppression; or symptom based management. Trials reported dichotomous assessment of symptom status at final follow-up (≥12 months). Results The review identified 15 eligible randomised controlled trials that comprised 6162 adult participants. Data were pooled using a random effects model. Strategies were ranked according to P score, which is the mean extent of certainty that one management strategy is better than another, averaged over all competing strategies. “Test and treat” ranked first (relative risk of remaining symptomatic 0.89, 95% confidence interval 0.78 to 1.02, P score 0.79) and prompt endoscopy ranked second, but performed similarly (0.90, 0.80 to 1.02, P score 0.71). However, no strategy was significantly less effective than “test and treat.” Participants assigned to “test and treat” were significantly less likely to receive endoscopy (relative risk v prompt endoscopy 0.23, 95% confidence interval 0.17 to 0.31, P score 0.98) than all other strategies, except symptom based management (relative risk v symptom based management 0.60, 0.30 to 1.18). Dissatisfaction with management was significantly lower with prompt endoscopy (P score 0.95) than with “test and treat” (relative risk v “test and treat” 0.67, 0.46 to 0.98), and empirical acid suppression (relative risk v empirical acid suppression 0.58, 0.37 to 0.91). Upper gastrointestinal cancer rates were low in all trials. Results remained stable in sensitivity analyses, with minimal inconsistencies between direct and indirect results. Risk of bias of individual trials was high; blinding was not possible because of the pragmatic trial design. Conclusions “Test and treat” was ranked first, although it performed similarly to prompt endoscopy and was not superior to any of the other strategies. “Test and treat” led to fewer endoscopies than all other approaches, except symptom based management. However, participants showed a preference for prompt endoscopy as a management strategy for their symptoms. Systematic review registration PROSPERO registration number CRD42019132528.
90TiP FRAIL-IMMUNE: A multicenter, prospective, single arm phase II of the combination of durvalumab with carboplatin and paclitaxel as first-line treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck not eligible to standard chemotherapy (GORTEC 2018-03)
Authors: J. Fayette
Journal: Annals of Oncology (2019)
Model for End‐Stage Liver Disease With Additional Criteria to Predict Short‐Term Mortality in Severe Flares of Chronic Hepatitis B
Authors: James Fung, Lung‐Yi Mak, Albert Chi‐Yan Chan, Kenneth Siu‐Ho Chok, Tiffany Cho‐Lam Wong, Tan‐To Cheung, Wing‐Chiu Dai, Sui‐Ling Sin, Wong‐Hoi She, Ka‐Wing Ma, Wai‐Kay Seto, Ching‐Lung Lai, Chung‐Mau Lo, Man‐Fung Yuen
Journal: Hepatology (2019)

Background and Aims The prognosis in severe acute flares of chronic hepatitis B (AFOCHB) is often unclear. The current study aimed to establish the predictive value using the Model for End‐Stage Liver Disease (MELD) score for short‐term mortality for severe AFOCHB. Approach and Results Patients with severe AFOCHB with bilirubin &gt; 50 µmol/L, alanine aminotransferase &gt; 10× upper limit of normal, and international normalized ratio &gt; 1.5 were included. All patients were commenced on entecavir and/or tenofovir. Laboratory results and MELD scores were pooled to calculate mortality at four time points (days 7, 14, 21, and 28). A total of 240 patients were included. Median hepatitis B virus DNA was 7.77 log IU/mL (range, 4.11‐10.06), and 49 (20.4%) were hepatitis B e antigen–positive. The 7, 14, 21, and 28‐day survival was 96.7%, 88.5%, 79.5%, and 72.8%, respectively. Using pooled results derived from 4,201 blood samples, the area under the receiver operating curve for the MELD score to predict day 7, 14, 21, and 28 mortality was 0.909, 0.892, 0.883, and 0.871, respectively. For MELD ≤ 28, mortality at day 28 was low (&lt;25%) compared with &gt; 50% mortality for MELD ≥ 32. For MELD = 28‐32, higher day‐28 mortality was observed for four criteria: age ≥52 years, alanine aminotransferase &gt; 217 U/L, platelets &lt; 127, and abnormal baseline imaging (all P &lt; 0.001). In this MELD bracket, the 28‐day mortality was 0%, 12.1%, 23.8%, 59.4%, and 78.8% for the presence of zero, one, two, three, and four criteria, respectively. Conclusions MELD score at any time points can accurately predict the short‐term mortality. Patients with MELD ≥ 28 should be worked up for liver transplantation, and those with MELD = 28‐32 with three to four at‐risk criteria, or MELD ≥ 32 should be listed.