tbuckley/cabot-search huggingface dataset:
Integrative Network Analysis of Newly Diagnosed Multiple Myeloma Identifies a Novel RNA-Seq Based High Riskgene Signature
Authors: Alessandro Lagana, Deepak Perumal, David Melnekoff, Ben Readhead, Brian Kidd, Violetta V Leshchenko, Pei-Yu Kuo, Jonathan J Keats, Mary Derome, Jennifer Yesil, Daniel Auclair, Deepu Madduri, Ajai Chari, Hearn Jay Cho, Bart Barlogie, Sundar Jagannath, Joel Dudley, Samir Parekh
Journal: Blood (2016)
Capitation based funding of general practice is not fit for purpose
Authors: David Shepherd
Journal: BMJ (2017)

I disagree with Majeed’s call for activity based funding for primary care, which would be a backwards step, ditching an important driver of cost effectiveness.1

He rightly says that this would be more expensive, but there are more fundamental problems. The current capitation based funding is not fit for purpose, for two reasons—the level of funding is inadequate, as many have …
Cardiac Manifestation of Fabry Disease in Jikei Registry
Authors: Hongo Kenichi, Ito Keiichi, Anan Ikuko, Inoue Yasunori, Tokuda Michifumi, Morimoto Satoshi, Tanaka Toshikazu, Ogawa Kazuo, Minai Kosuke, Kawai Makoto, Yoshimura Michihiro
Journal: Circulation (2016)
Preparing for what the reporting checklists will not tell you: the PREPARE Trial guide for planning clinical research to avoid research waste
Authors: Thomas Bandholm, Robin Christensen, Kristian Thorborg, Shaun Treweek, Marius Henriksen
Journal: British Journal of Sports Medicine (2017)

For the early career researcher or PhD student about to have a leading role in a clinical trial, it would be a tremendous help to have a ‘How to’ guide, consisting of advice and key literature to help the researcher move successfully along the initial trial pathway from research question to protocol completion. While the ideal trial team should include experienced trialists, who participate in the preparatory research meetings, this support is not always available. The PREPARE Trial guide is intended to assist the early career researcher in this situation, but not replace an experienced trial team and regular research meetings. The guide may also serve as preparation for research meetings, or part of curricula for courses on research methodology, to be used by experienced PhD supervisor, trialist or lecturer.

Evidence from randomised controlled trials (RCTs) is often wasted1 2 (for a collection of papers relating to this issue, please see http://researchwaste.net/). Many trials are not published, and hence the results are not reported, which is indeed a waste. There are many reasons for this waste, but we believe that at least some trials are discontinued because of poor trial planning. Similarly, many completed and published trials suffer from fundamental flaws or poor conduct due to lack of preparation and careful planning. Some flaws in the conception or planning phase prior to the finalised trial protocol and registration are difficult to rectify once the trial starts. For example, patients may decline participation if the study involves delaying or withholding treatment, or if the experimental condition is deemed unfeasible by patients. This can be avoided, for example, by involving patients in the planning of the trial or by conducting pilot or feasibility studies prior to the full-scale trial. In many cases, the planning of a trial is as least as important as …
The HITECH Era and the Path Forward
Authors: Vindell Washington, Karen DeSalvo, Farzad Mostashari, David Blumenthal
Journal: New England Journal of Medicine (2017)

Eight years ago, the HITECH Act launched an ambitious effort to modernize the U.S. health IT infrastructure. But the culture surrounding access to and sharing of information still needs to change to promote the seamless and secure flow of electronic information.
Pharmacogenetic variants associated with differential sirolimus clearance in pediatric patients.
Authors: Jordan Wright, Rebekah Karns, Tomoyuki Mizuno, Mitali Basu, Brian D. Weiss, Denise Adams, A.a. Vinks, Bruce Aronow, John Peter Perentesis
Journal: Journal of Clinical Oncology (2015)

2562 Background: Sirolimus inhibits the mammalian Target of Rapamycin pathway and is widely used in organ transplantation and treatment of malignancy. CYP3A5*3 polymorphisms have been shown to influence sirolimus clearance in solid organ transplant patients, but effects of other drug metabolism enzyme and transporter (DMET) gene polymorphisms have not been investigated thoroughly. We hypothesized that additional variants, alone or in combination, would better predict sirolimus clearance in pediatric and young adult patients with neurofibromatosis type 1 (NF1) associated plexiform neurofibromas and complex vascular malformations (CVM). Methods: Patients treated with single agent sirolimus (N = 74) had pharmacokinetic parameters including clearance measured in two studies of NF1 and CVM. Patients were genotyped for 1,931 known polymorphisms using the DMET Microarray (Affymetrix). Initial statistical analysis included univariate linear regression on SNPs with a minor allele frequency of > 0.05 for each of the clinical trials. Subsequently, the datasets were combined and a univariate regression analysis was obtained on the combined data. SNPs for which the association was strengthened in the combined dataset were then placed in a final multivariate regression model. Results: The final multiple regression analysis included five SNPs that were significant at p < 0.05: rs776746 (CYP3A5*3 6986 A > G), rs909530 (FMO3 855 C > T), rs1339067 (SLC15A1 1347 T > C), rs2276299 (SLC22A8 723 T > A), and rs6774801 (CYP8B1 6468 A > C). The model had an overall F-value of 7.83, p-value < 0.0001, and R-square of 0.38. Conclusions: Our analysis identified a multivariate model with five SNPs, of which four are novel and not previously described in the literature. The CYP3A5*3 allele, which has been identified in other studies, was significant in our analysis, offering additional support for the role of this SNP in sirolimus metabolism. Future studies in larger populations are needed to confirm this model, and will lead to potential pharmacogenetically-guided dosing for the safe and effective use of sirolimus.
Urinary Concentrations of Organophosphate Flame Retardant Metabolites and Pregnancy Outcomes among Women Undergoing <i>in Vitro</i> Fertilization
Authors: Courtney C. Carignan, Lidia Mínguez-Alarcón, Craig M. Butt, Paige L. Williams, John D. Meeker, Heather M. Stapleton, Thomas L. Toth, Jennifer B. Ford, Russ Hauser
Journal: Environmental Health Perspectives (2017)

Background: Evidence from animal studies suggests that exposure to organophosphate flame retardants (PFRs) can disrupt endocrine function and impair embryo development. However, no epidemiologic studies have been conducted to evaluate effects on fertility and pregnancy outcomes. Objectives: We evaluated associations between urinary concentrations of PFR metabolites and outcomes of in vitro fertilization (IVF) treatment among couples recruited from an academic fertility clinic. Methods: This analysis included 211 women enrolled in the Environment And Reproductive Health (EARTH) prospective cohort study (2005–2015) who provided one or two urine samples per IVF cycle. We measured five urinary PFR metabolites [bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropylphenyl phenyl phosphate (ip-PPP), tert-butylphenyl phenyl phosphate (tb-PPP), and bis(1-chloro-2-propyl) phosphate (BCIPP)] using negative electrospray ionization liquid chromatography tandem mass spectrometry (LC-MS/MS). Molar concentrations of the urinary PFR metabolites were summed. We used multivariable generalized linear mixed models to evaluate the association of the PFR metabolites with IVF outcomes, accounting for multiple IVF cycles per woman. Results: Detection frequencies were high for BDCIPP (87%), DPHP (94%), and ip-PPP (80%), but low for tb-PPP (14%) and BCIPP (0%). We observed decreased success for several IVF outcomes across increasing quartiles of both summed and individual PFR metabolites (DPHP and ip-PPP) in our adjusted multivariable models. Significant declines in adjusted means from the lowest to highest quartile of ΣPFR were observed for the proportion of cycles resulting in successful fertilization (10% decrease), implantation (31%), clinical pregnancy (41%), and live birth (38%). Conclusions: Using IVF to investigate human reproduction and pregnancy outcomes, we found that concentrations of some urinary PFR metabolites were negatively associated with proportions of successful fertilization, implantation, clinical pregnancy, and live birth. https://doi.org/10.1289/EHP1021
虚血性脳卒中と神経変性疾患における神経血管単位の機能障害:エージング効果【Powered by NICT】
Authors: Cai Wei, Zhang Kai, Li Peiying, Zhu Ling, Xu Jing, Yang Boyu, Hu Xiaoming, Lu Zhengqi, Chen Jun
Journal: Ageing Research Reviews (2017)
空間的に制御された多蛋白質ディスプレイのための担体としてのクラスリントリスケリオンの利用【Powered by NICT】
Authors: B Deci Michael, W Ferguson Scott, Liu Maixian, C Peterson Damian, P Koduvayur Sujatha, Nguyen Juliane
Journal: Biomaterials (2016)
Sixty seconds on . . . the private finance initiative
Authors: Anne Gulland
Journal: BMJ (2017)

It’s definitely “still a thing,” to use a catchphrase that probably didn’t exist when Tony Blair lived at Downing Street. A report from the Centre for Health and the Public Interest says that the NHS and local authorities in England are still in hock to the private companies running the initiative, with taxpayer funds “leaking out of the NHS” into their coffers.1 …
Earmarking for global health: benefits and perils of the World Bank’s trust fund model
Authors: Janelle Winters, Devi Sridhar
Journal: BMJ (2017)

In the third article in this series, <b>Janelle Winters</b> and <b>Devi Sridhar</b> review different types of trust funds and how they fit within the bank’s lending mechanism, and discuss the major benefits and risks of the bank’s use of the trust fund model for health
The Blebbishield Emergency Program Overrides Chromosomal Instability and Phagocytosis Checkpoints in Cancer Stem Cells
Authors: Goodwin G. Jinesh, Ashish M. Kamat
Journal: Cancer Research (2017)

Genomic instability and immune evasion are hallmarks of cancer. Apoptotic cancer stem cells can evade cell death by undergoing cellular transformation by constructing "blebbishields" from apoptotic bodies. In this study, we report a novel linkage between genomic instability and phagocytosis evasion that is coordinated by the blebbishield emergency program. Blebbishield emergency program evaded genomic instability checkpoint, expressed genomic instability-associated genes at distinct phases of cellular transformation, exhibited chromosomal instability, and promoted increase in nuclear size. Blebbishields fused with immune cells to evade phagocytosis, and the resultant hybrid cells exhibited increased migration, tumorigenesis, metastasis, red blood cell recruitment to tumors, and induced hepatosplenomegaly with signatures of genomic instability, blebbishield emergency program, and phagocytosis evasion to offer poor prognosis. Overall, our data demonstrate that the blebbishield emergency program drives evasion of chromosomal instability and phagocytosis checkpoints by apoptotic cancer stem cells. Cancer Res; 77(22); 6144-56. ©2017 AACR.
From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely
Authors: Daphne Day, Arta M. Monjazeb, Elad Sharon, S. Percy Ivy, Eric H. Rubin, Gary L. Rosner, Marcus O. Butler
Journal: Clinical Cancer Research (2017)

Abstract Not until the turn of this century has immunotherapy become a fundamental component of cancer treatment. While monotherapy with immune modulators, such as immune checkpoint inhibitors, provides a subset of patients with durable clinical benefit and possible cure, combination therapy offers the potential for antitumor activity in a greater number of patients. The field of immunology has provided us with a plethora of potential molecules and pathways to target. This abundance makes it impractical to empirically test all possible combinations efficiently. We recommend that potential immunotherapy combinations be chosen based on sound rationale and available data to address the mechanisms of primary and acquired immune resistance. Novel trial designs may increase the proportion of patients receiving potentially efficacious treatments and, at the same time, better define the balance of clinical activity and safety. We believe that implementing a strategic approach in the early development of immunotherapy combinations will expedite the delivery of more effective therapies with improved safety and durable outcomes. Clin Cancer Res; 23(17); 4980–91. ©2017 AACR. See all articles in this CCR Focus section, “Clinical Trial Design Considerations in the Immuno-oncology Era.”
Antimicrobial policy interventions in food animal production in South East Asia
Authors: Flavie Luce Goutard, Marion Bordier, Clémentine Calba, Elisabeth Erlacher-Vindel, Delfy Góchez, Katinka de Balogh, Carolyn Benigno, Wantanee Kalpravidh, Francois Roger, Sirenda Vong
Journal: BMJ (2017)

Flavie Goutard and colleagues  call for concerted multisectoral measures through stronger policies to combat antimicrobial resistance
Effect of Physician Notification Regarding Nonadherence to Colorectal Cancer Screening on Patient Participation in Fecal Immunochemical Test Cancer Screening
Authors: Cédric Rat, Corinne Pogu, Delphine Le Donné, Chloé Latour, Gaelle Bianco, France Nanin, Anne Cowppli-Bony, Aurélie Gaultier, Jean-Michel Nguyen
Journal: JAMA (2017)

<h3>Importance</h3> Increasing participation in fecal screening tests is a major challenge in countries that have implemented colorectal cancer (CRC) screening programs. <h3>Objective</h3> To determine whether providing general practitioners (GPs) a list of patients who are nonadherent to CRC screening enhances patient participation in fecal immunochemical testing (FIT). <h3>Design, Setting, and Participants</h3> A 3-group, cluster-randomized study was conducted from July 14, 2015, to July 14, 2016, on the west coast of France, with GPs in 801 practices participating and involving adult patients (50-74 years) who were at average risk of CRC and not up-to-date with CRC screening. The final follow-up date was July 14, 2016. <h3>Interventions</h3> General practitioners were randomly assigned to 1 of 3 groups: 496 received a list of patients who had not undergone CRC screening (patient-specific reminders group, 10 476 patients), 495 received a letter describing region-specific CRC screening adherence rates (generic reminders group, 10 606 patients), and 455 did not receive any reminders (usual care group, 10 147 patients). <h3>Main Outcomes and Measures</h3> The primary end point was patient participation in CRC screening 1 year after the intervention. <h3>Results</h3> Among 1482 randomized GPs (mean age, 53.4 years; 576 women [38.9%]), 1446 participated; of the 33 044 patients of these GPs (mean age, 59.7 years; 17 949 women [54.3%]), follow-up at 1 year was available for 31 229 (94.5%). At 1 year, 24.8% (95% CI, 23.4%-26.2%) of patients in the specific reminders group, 21.7% (95% CI, 20.5%-22.8%) in the generic reminders group, and 20.6% (95% CI, 19.3%-21.8%) in the usual care group participated in the FIT screening. The between-group differences were 3.1% (95% CI, 1.3%-5.0%) for the patient-specific reminders group vs the generic reminders group, 4.2% (95% CI, 2.3%-6.2%) for the patient-specific reminders group vs the usual care group, and 1.1% (95% CI, −0.6% to 2.8%) for generic reminders group vs the usual care group. <h3>Conclusions and Relevance</h3> Providing French GPs caring for adults at average risk of CRC with a list of their patients who were not up-to-date with their CRC screening resulted in a small but significant increase in patient participation in FIT screening at 1 year compared with patients who received usual care. Providing GPs with generic reminders about regional rates of CRC screening did not increase screening rates compared with usual care. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT02515344
Long-term exposure to ambient air pollution and incidence of brain tumor: the European Study of Cohorts for Air Pollution Effects (ESCAPE)
Authors: Zorana J Andersen, Marie Pedersen, Gudrun Weinmayr, Massimo Stafoggia, Claudia Galassi, Jeanette T Jørgensen, Johan N Sommar, Bertil Forsberg, David Olsson, Bente Oftedal, Gunn Marit Aasvang, Per Schwarze, Andrei Pyko, Göran Pershagen, Michal Korek, Ulf De Faire, Claes-Göran Östenson, Laura Fratiglioni, Kirsten T Eriksen, Aslak H Poulsen, Anne Tjønneland, Elvira Vaclavik Bräuner, Petra H Peeters, Bas Bueno-de-Mesquita, Andrea Jaensch, Gabriele Nagel, Alois Lang, Meng Wang, Ming-Yi Tsai, Sara Grioni, Alessandro Marcon, Vittorio Krogh, Fulvio Ricceri, Carlotta Sacerdote, Enrica Migliore, Roel Vermeulen, Ranjeet Sokhi, Menno Keuken, Kees de Hoogh, Rob Beelen, Paolo Vineis, Giulia Cesaroni, Bert Brunekreef, Gerard Hoek, Ole Raaschou-Nielsen
Journal: Neuro-Oncology (2017)

Epidemiological evidence on the association between ambient air pollution and brain tumor risk is sparse and inconsistent.In 12 cohorts from 6 European countries, individual estimates of annual mean air pollution levels at the baseline residence were estimated by standardized land-use regression models developed within the ESCAPE and TRANSPHORM projects: particulate matter (PM) ≤2.5, ≤10, and 2.5-10 μm in diameter (PM2.5, PM10, and PMcoarse), PM2.5 absorbance, nitrogen oxides (NO2 and NOx) and elemental composition of PM. We estimated cohort-specific associations of air pollutant concentrations and traffic intensity with total, malignant, and nonmalignant brain tumor, in separate Cox regression models, adjusting for risk factors, and pooled cohort-specific estimates using random-effects meta-analyses.Of 282194 subjects from 12 cohorts, 466 developed malignant brain tumors during 12 years of follow-up. Six of the cohorts also had data on nonmalignant brain tumor, where among 106786 subjects, 366 developed brain tumor: 176 nonmalignant and 190 malignant. We found a positive, statistically nonsignificant association between malignant brain tumor and PM2.5 absorbance (hazard ratio and 95% CI: 1.67; 0.89-3.14 per 10-5/m3), and weak positive or null associations with the other pollutants. Hazard ratio for PM2.5 absorbance (1.01; 0.38-2.71 per 10-5/m3) and all other pollutants were lower for nonmalignant than for malignant brain tumors.We found suggestive evidence of an association between long-term exposure to PM2.5 absorbance indicating traffic-related air pollution and malignant brain tumors, and no association with overall or nonmalignant brain tumors.
Viral based vaccine TG4010 induces broadening of specific immune response and improves outcome in advanced NSCLC
Authors: Caroline Tosch, Bérangère Bastien, Luc Barraud, Benoit Grellier, Virginie Nourtier, Murielle Gantzer, Jean Marc Limacher, Eric Quemeneur, Kaïdre Bendjama, Xavier Préville
Journal: Journal for ImmunoTherapy of Cancer (2017)

<h3>Background</h3> Advanced non-small cell lung cancer patients receiving TG4010, a therapeutic viral vaccine encoding human Mucin 1 and interleukin-2 in addition to standard chemotherapy, displayed longer overall survival in comparison to that of patients treated with standard chemotherapy alone. Our study intended to establish the association between overall survival and vaccine-induced T cell responses against tumor associated antigens (TAA) targeted by the vaccine. <h3>Method</h3> The TIME trial was a placebo-controlled, randomized phase II study aimed at assessing efficacy of TG4010 with chemotherapy in NSCLC. 78 patients from the TIME study carrying the HLA-A02*01 haplotype were analyzed using combinatorial encoding of MHC multimers to detect low frequencies of cellular immune responses to TG4010 and other unrelated TAA. <h3>Results</h3> We report that improvement of survival under TG4010 treatment correlated with development of T cell responses against MUC1. Interestingly, responses against MUC1 were associated with broadening of CD8 responses against non-targeted TAA, thus demonstrating induction of epitope spreading. <h3>Conclusion</h3> Our results support the causality of specific T-cell response in improved survival in NSCLC. Additionally, vaccine induced epitope spreading to other TAA participates to the enrichment of the diversity of the anti-tumor response. Hence, TG4010 appears as a useful therapeutic option to maximize response rate and clinical benefit in association with other targeted immuno-modulators. <h3>Trial registration</h3> Registered on ClinicalTrials.gov under identifier NCT01383148 on June 23rd, 2011.
Hepatitis E virus-induced primary cutaneous CD30(+) T cell lymphoproliferative disorder
Authors: Vincent Mallet, Julie Bruneau, Julien Zuber, Cécile Alanio, Stéphanie Leclerc-Mercier, Anne-Marie Roque-Afonso, Anke R.M. Kraft, Lucile Couronné, Dominique Roulot, Heiner Wedemeyer, Matthew L. Albert, Patrick Hillon, Liliane Laroche, Stanislas Pol, Olivier Hermine
Journal: Journal of Hepatology (2017)
Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380–1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial
Authors: Paul E Sax, Anton Pozniak, M Luisa Montes, Ellen Koenig, Edwin DeJesus, Hans-Jürgen Stellbrink, Andrea Antinori, Kimberly Workowski, Jihad Slim, Jacques Reynes, Will Garner, Joseph Custodio, Kirsten White, Devi SenGupta, Andrew Cheng, Erin Quirk
Journal: The Lancet (2017)
Overall survival (OS) with CPX-351 versus 7+3 in older adults with newly diagnosed, therapy-related acute myeloid leukemia (tAML): Subgroup analysis of a phase III study.
Authors: Jeffrey E. Lancet, David Rizzieri, Gary J. Schiller, Robert K. Stuart, Jonathan E. Kolitz, Scott R. Solomon, Laura F. Newell, Harry Paul Erba, Geoffrey L. Uy, Robert Ryan, Michael Chiarella, Arthur Chin Louie, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2017)

7035 Background: tAML may occur as a late complication of cytotoxic therapy and is associated with a poor prognosis. CPX-351 is a liposomal formulation that delivers a synergistic 5:1 molar ratio of cytarabine (C) and daunorubicin (D). In a randomized, open-label, controlled phase III trial in patients (pts) aged 60-75 years with newly diagnosed, secondary AML (tAML or after MDS), CPX-351 significantly improved OS versus 7+3. The current analysis of this phase III study evaluated outcomes in the subgroup of pts with tAML. Methods: Pts were randomized 1:1 to induction with 1-2 cycles of CPX-351 (100 u/m 2 [C 100 mg/m 2 + D 44 mg/m 2 ] on Days 1, 3, and 5 [2nd induction: Days 1 and 3]) or 7+3 (C 100 mg/m 2 /day x 7 days [2nd induction: x 5 days] + D 60 mg/m 2 on Days 1, 2, and 3 [2nd induction: Days 1 and 2]). Pts with complete remission (CR) or CR with incomplete platelet or neutrophil recovery (CRi) could receive up to 2 cycles of consolidation therapy. The study was not powered for this subgroup analysis. Results: 304 pts were enrolled and received study treatment, including 62 (20%) pts with tAML; demographics of tAML pts were similar between study arms. Pts with tAML had typically received prior non-anthracycline chemotherapy alone (25%), radiation alone (25%), or non-anthracycline chemotherapy + radiation (32%). CPX-351 was associated with an OS benefit versus 7+3 in older tAML pts and numerically longer event-free survival (EFS) and remission duration (Table). A greater proportion of tAML pts achieved CR+CRi (47% vs 36%, respectively) and proceeded to stem cell transplantation (37% vs 27%) with CPX-351. The safety profile of CPX-351 was comparable to that of 7+3. Conclusions: CPX-351 is associated with improved outcomes in older pts with newly diagnosed tAML. Outcomes in the tAML subgroup mirrored the overall study population, indicating CPX-351 may represent a new therapeutic option for this difficult to treat population. Clinical trial information: NCT01696084. [Table: see text]