tbuckley/cabot-search huggingface dataset:
Targeting the CXCR4 pathway using a novel anti-CXCR4 IgG1 antibody (PF-06747143) in chronic lymphocytic leukemia
Authors: Manoj K. Kashyap, Carlos I. Amaya-Chanaga, Deepak Kumar, Brett Simmons, Nanni Huser, Yin Gu, Max Hallin, Kevin Lindquist, Rolla Yafawi, Michael Y. Choi, Ale-Ali Amine, Laura Z. Rassenti, Cathy Zhang, Shu-Hui Liu, Tod Smeal, Valeria R. Fantin, Thomas J. Kipps, Flavia Pernasetti, Januario E. Castro
Journal: Journal of Hematology & Oncology (2017)

The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL.Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model.PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine.We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.
Bariatric surgery improved HbA<sub>1c</sub> at 5 y more than intensive medical care alone in obese patients with T2DM
Authors: Clare J. Lee, Lawrence J. Cheskin
Journal: Annals of Internal Medicine (2017)

ACP Journal Club16 May 2017Bariatric surgery improved HbA1c at 5 y more than intensive medical care alone in obese patients with T2DMClare J. Lee, MD, MHS, Lawrence J. Cheskin, MD, FACP, FTOSClare J. Lee, MD, MHSJohns Hopkins School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland, USA (C.J.L., L.J.C.)Search for more papers by this author, Lawrence J. Cheskin, MD, FACP, FTOSJohns Hopkins School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland, USA (C.J.L., L.J.C.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/ACPJC-2017-166-10-057 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationSchauer PR, Bhatt DL, Kirwan JP, et al; STAMPEDE Investigators. Bariatric surgery versus intensive medical therapy for diabetes—5-year outcomes. N Engl J Med. 2017;376:641-51. https://pubmed.ncbi.nlm.nih.gov/28199805Clinical Impact RatingsGIM/FP/GP: Endocrinology: References1 Sjöström L, Peltonen M, Jacobson P, et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014;311:2297-304. [PMID: 24915261] Google Scholar2 Ikramuddin S, Korner J, Lee WJ, et al. Durability of addition of Roux-en-Y gastric bypass to lifestyle intervention and medical management in achieving primary treatment goals for uncontrolled type 2 diabetes in mild to moderate obesity: a randomized control trial. Diabetes Care. 2016;39:1510-8. [PMID: 27311493] Google Scholar3 Kumar AA, Palamaner Subash Shantha G, Kahan S, et al. Intentional weight loss and dose reductions of anti-diabetic medications—a retrospective cohort study. PLoS One. 2012;7:e32395. [PMID: 22384240] Google Scholar Author, Article, and Disclosure InformationAffiliations: Johns Hopkins School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland, USA (C.J.L., L.J.C.)This article was published at Annals.org on 2 May 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byWeight Loss and Changes in Adipose Tissue and Skeletal Muscle Volume after Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass: a Prospective Study with 12-Month Follow-Up 16 May 2017Volume 166, Issue 10Page: JC57KeywordsAbdominal surgeryBariatric surgeryGastrectomyHbA1cOverweightSafetySurgeryThoracic surgeryType 2 diabetes ePublished: 16 May 2017 Issue Published: 16 May 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Incidence-based analysis of lethal prostate cancer in Swedish counties with high versus low incidence of prostate cancer in nationwide, population-based registries.
Authors: Pär Stattin, Benny Holmström, David Robinson, Andrew J. Vickers, Hans Lilja, Jonas Hugosson, Håkan Jonsson
Journal: Journal of Clinical Oncology (2012)

4668 Background: Current data from randomized trials differ in the ratio of benefit to harms from screening for prostate cancer (PC) using prostate specific antigen (PSA) testing and it is further unclear if decreases in PC mortality in the US can be attributed to introduction of screening or to changes in treatment. The aim of this study was to investigate if rapidly increased incidence of PC diagnosis due to early and rapidly increased rate of PSA testing, is associated with decreased incidence of lethal PC. Methods: In this incidence-based study using highly representative data from nation-wide population-based registries we analysed the incidence of lethal prostate cancer in eight Swedish counties with the most rapid and largest increased incidence of PC diagnosis (high incidence counties) from 1995 through 2002, and six counties with the smallest increased PC incidence (low incidence counties). We analysed the rate ratio (RR) in high vs. low incidence counties of cases with metastatic PC at diagnosis, (positive bone scan or PSA above 100 ng/ml), PC-specific mortality, and excess mortality (death among PC cases regardless of cause). Participants were men aged 50-74 years during 2000 to 2009 in the high versus low incidence counties contributing 4,528,134 versus 2,471,373 person-years at risk, respectively. There were 33,780 incident PC diagnoses and 1,577 PC deaths in high incidence counties and 16,377 PC cases and 985 PC deaths in low incidence counties. Results: In high vs. low incidence counties, RR of metastatic PC was 0.85 (95% confidence interval [CI] = 0.79 to 0.92), RR of PC-specific mortality was 0.87 (95% CI = 0.81 to 0.95) and RR of excess mortality in men with PC was 0.75 (95 %CI = 0.66 to 0.86). Conclusions: Our study provides data on a population-level indicating a decreased incidence of lethal PC in areas with rapid and large increase in incident PC diagnosis due to increased rates of PSA testing, early diagnosis, and treatment with curative intent.
Predicting human adiposity – sometimes – with food insecurity: Broaden the model for better accuracy
Authors: Sarah E Hill, Randi P Proffitt Leyva, Danielle J DelPriore
Journal: Behavioral and Brain Sciences (2017)

Abstract The target article explores the role of food insecurity as a contemporary risk factor for human overweight and obesity. The authors provide conditional support for the insurance hypothesis among adult women from high-income countries. We consider the potential contribution of additional factors in producing variation in adiposity patterns between species and across human contexts.
PTU-159 Comparison of three commercially available point of care tests for coeliac disease: Abstract PTU-159 Table 1
Authors: PD Mooney, S Wong, M Burden, M Kurien, M Hadjivassiliou, DS Sanders
Journal: Gut (2015)

<h3>Introduction</h3> Coeliac disease (CD) remains underdiagnosed. A rapid point of care test (POCT) may increase uptake of serological testing in appropriate patient groups. 3 POCTs are commercially available in the UK and in continental European pharmacy outlets: Biocard an IgA tissue tranglutaminase (tTG) test (BHR pharmaceuticals); Celiac Quick Test (Biohit Healthcare) detecting IgA, IgG and IgM tTG and Simtomax (Tillotts Pharma) which detects IgA and IgG antibodies against deamidated gliadin peptides (DGP). A fourth POCT has also been developed but not marketed (Xeliac Test Pro, Personal Diagnostics), with availability being solely from the manufacturer and no published data existing supporting its validity. Of the 3 commercially available POCTs, there is a limited evidence base with significant ascertainment bias. For this reason we decided to compare 3 commercially available tests in an endoscopic setting. <h3>Method</h3> Patients referred with a positive endomysial antibody (EMA) for duodenal biopsy to confirm CD were recruited. All patients had repeat serum EMA, tTG and immunoglobulins and were tested simultaneously with the 3 POCTs as per the manufacturers’ instructions. All patients had quadrantic duodenal biopsies from the second part of the duodenum as well as a duodenal bulb biopsy. Demonstration of villous atrophy (VA) was required to diagnose CD. <h3>Results</h3> 82 patients (51.2% female, mean age 41.0) have been recruited. In 10 patients the EMA had normalised on repeat testing. None of these patients had VA on duodenal biopsy. 9 of these patients were referred with a weak EMA and had a negative tTG. One patient had a tTG of 10 times the upper limit of normal, and subsequent gluten challenge revealed a positive EMA and VA. Of the remaining 72 patients 59 new cases of CD were confirmed with the presence of villous atrophy, of the 13 EMA positive patients without VA 8 had Marsh 1 or 2 changes present with the remaining 5 patients having normal histology. Full sensitivity, specificity PPV and NPV for all of the tests compared to VA on duodenal biopsy are shown in Table 1. <h3>Conclusion</h3> In this pilot data set Simtomax appears to be the most sensitive of the POCTs when compared to histology with similar results to serum tTG as screening test. Further work is required in larger cohorts and lower prevalence populations to confirm the utility of these tests in adult CD. <h3>Disclosure of interest</h3> P. Mooney: None Declared, S. Wong: None Declared, M. Burden: None Declared, M. Kurien: None Declared, M. Hadjivassiliou: None Declared, D. Sanders Grant/ Research Support from: BHR pharmaceuticals; Tillotts Pharma for investigator led studies.
Republished research: Implementation research: what it is and how to do it
Authors: David H Peters, Taghreed Adam, Olakunle Alonge, Irene Akua Agyepong, Nhan Tran
Journal: British Journal of Sports Medicine (2013)

The field of implementation research is growing, but it is not well understood despite the need for better research to inform decisions about health policies, programmes, and practices. This article focuses on the context and factors affecting implementation, the key audiences for the research, implementation outcome variables that describe various aspects of how implementation occurs, and the study of implementation strategies that support the delivery of health services, programmes, and policies. We provide a framework for using the research question as the basis for selecting among the wide range of qualitative, quantitative, and mixed methods that can be applied in implementation research, along with brief descriptions of methods specifically suitable for implementation research. Expanding the use of well designed implementation research should contribute to more effective public health and clinical policies and programmes.

Implementation research attempts to solve a wide range of implementation problems; it has its origins in several disciplines and research traditions (supplementary table A). Although progress has been made in conceptualising implementation research over the past decade,1 considerable confusion persists about its terminology and scope.2–,4 The word “implement” comes from the Latin “implere,” meaning to fulfil or to carry into effect.5 This provides a basis for a broad definition of implementation research that can be used across research traditions and has meaning for practitioners, policy makers, and the interested public: “Implementation research is the scientific inquiry into questions concerning implementation—the act of carrying an intention into effect, which in health research can be policies, programmes, or individual practices (collectively called interventions).”

Implementation research can consider any aspect of implementation, including the factors affecting implementation, the processes of implementation, and the results of implementation, including how to introduce potential solutions into a health system or how to promote their large scale use and …
n–3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors
Authors: Maria Carla Roncaglioni, Massimo Tombesi, Fausto Avanzini, Simona Barlera, Vittorio Caimi, Paolo Longoni, Irene Marzona, Valentina Milani, Maria Giuseppina Silletta, Gianni Tognoni, Roberto Marchioli
Journal: New England Journal of Medicine (2013)

Trials have shown a beneficial effect of n-3 polyunsaturated fatty acids in patients with a previous myocardial infarction or heart failure. We evaluated the potential benefit of such therapy in patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction.In this double-blind, placebo-controlled clinical trial, we enrolled a cohort of patients who were followed by a network of 860 general practitioners in Italy. Eligible patients were men and women with multiple cardiovascular risk factors or atherosclerotic vascular disease but not myocardial infarction. Patients were randomly assigned to n-3 fatty acids (1 g daily) or placebo (olive oil). The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes.Of the 12,513 patients enrolled, 6244 were randomly assigned to n-3 fatty acids and 6269 to placebo. With a median of 5 years of follow-up, the primary end point occurred in 1478 of 12,505 patients included in the analysis (11.8%), of whom 733 of 6239 (11.7%) had received n-3 fatty acids and 745 of 6266 (11.9%) had received placebo (adjusted hazard ratio with n-3 fatty acids, 0.97; 95% confidence interval, 0.88 to 1.08; P=0.58). The same null results were observed for all the secondary end points.In a large general-practice cohort of patients with multiple cardiovascular risk factors, daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity. (Funded by Società Prodotti Antibiotici and others; ClinicalTrials.gov number, NCT00317707.).
ACUTE HEPATITIS ASSOCIATED WITH MOUSE LEUKEMIA
Authors: John B. Nelson
Journal: The Journal of Experimental Medicine (1955)

Observations on the behavior of MHV (Pr) in the cerebral tissue of Princeton and Swiss weanling mice indicated a limited neurotropism. The virus migrated to the brain on intraperitoneal injection and was established there by cranial passage, though with difficulty in Swiss mice. Intracerebral multiplication was rarely followed by outward signs of nervous disorder. A slight pathologic reaction occurred in the brains of intracerebrally injected Princeton mice, but it was negligible compared with that of the ensuing hepatitis. In Swiss mice, injected intracerebrally with a mixture of MHV (Pr) and Eperythrozoon coccoides, a related virus with restricted pathogenicity and host range, possibly a mutant, was isolated from the liver and brain. MHV (C), an actively hepatotropic virus recovered from leukemic Balb C mice, was much more neurotropic than MHV (Pr). Intracerebral injection of Balb C and Swiss weanling mice was attended by marked leptomeningeal and encephalitic lesions. Paralysis of the extremities occurred in some of the animals. The virus was essentially inactive in Princeton mice. During the intracerebral passage of MHV (C) in Swiss mice a pleuropneumonia-like organism was isolated from the brain. In conjunction with the virus this organism produced a vigorous leukocytic reaction.
High-dose gemcitabine, busulfan, and melphalan for autologous stem-cell transplant in patients with relapsed or refractory myeloma: a phase 2 trial and matched-pair comparison with melphalan
Authors: Yago Nieto, Benigno C Valdez, Sai R Pingali, Roland Bassett, Ruby Delgado, John Nguyen, Nina Shah, Uday Popat, Roy B Jones, Borje S Andersson, Alison Gulbis, Sairah Ahmed, Qaiser Bashir, Simrit Parmar, Krina Patel, Alan Myers, Gabriela Rondon, Robert Z Orlowski, Richard Champlin, Muzaffar Qazilbash
Journal: The Lancet Haematology (2017)
Encouraging activity for R-CHOP in advanced stage nodular lymphocyte–predominant Hodgkin lymphoma
Authors: Michelle A. Fanale, Chan Yoon Cheah, Amy Rich, L. Jeffrey Medeiros, Chao-Ming Lai, Yasuhiro Oki, Jorge E. Romaguera, Luis E. Fayad, F. B. Hagemeister, Felipe Samaniego, Maria A. Rodriguez, Sattva S. Neelapu, Hun J. Lee, Loretta Nastoupil, Nathan H. Fowler, Francesco Turturro, Jason R. Westin, Michael L. Wang, Peter McLaughlin, Chelsea C. Pinnix, Sarah A. Milgrom, Bouthaina Dabaja, Sandra B. Horowitz, Anas Younes
Journal: Blood (2017)
The long and winding road of chest radiography for tuberculosis detection
Authors: Cecily Miller, Knut Lonnroth, Giovanni Sotgiu, Giovanni Battista Migliori
Journal: European Respiratory Journal (2017)

The aspiration to ensure early diagnosis for all people with tuberculosis (TB) [1], combined with recent advancements in digital technology, has brought chest radiography back to the forefront for TB detection. Once a mainstay for TB control in the community, but discouraged once bacteriology became the standard for TB diagnosis, chest radiography has recently come back into favour for its ability to detect TB early, often before the onset of clear symptoms. In addition, the advent of digital radiography has improved the quality and safety of the procedure and has led to possibilities such as telemedicine and computer-aided reading and detection. Chest radiography, an old tool for TB detection, is back at the forefront of the global effort to end TB <http://ow.ly/92wI30aCxpq>
Performance of a fully disposable, digital, single-operator cholangiopancreatoscope
Authors: Raj Shah, Isaac Raijman, Brian Brauer, Bora Gumustop, Douglas Pleskow
Journal: Endoscopy (2017)

Abstract Background and study aim Our aim was to evaluate the first use in humans of a new, single-use, digital, single-operator intraductal cholangiopancreatoscopy system (IDCP). Patients and methods Data were collected retrospectively from four US institutions between February 2015 and April 2015. The visual impression of neoplasia or benign findings with IDCP was determined by the performing endoscopist. High grade dysplasia, intraductal papillary mucinous neoplasm, neuroendocrine tumor, and malignancy were categorized as neoplasia. Benign disease was defined as the absence of neoplasia during ≥ 6 months of follow-up. Results Patients (n = 108) with indeterminate strictures, dilatation, or difficult stones underwent IDCP. Of 74 patients with indeterminate stricture or dilatation, 29 (39 %) had neoplasia, of which 25 were confirmed by miniature biopsy forceps, 2 by surgical pathology, and 2 by the presence of metastatic disease on follow-up imaging. In patients with benign disease, 15 had concentric stenosis or normal/erythematous changes, 5 had low papillary mucosal projections, 6 had coarse granular mucosa, and 4 had nodular mucosa. Findings in patients with neoplastic disease included dilated, tortuous vessels (“tumor vessels”; n = 13), irregular margins with partial occlusion of the lumen (infiltrative stricture, n = 12), villous or nodular mass (n = 9), and finger-like villiform projections (n = 5). Operating characteristics for indeterminate stricture or dilatation were: 97 % sensitivity, 93 % specificity, 90 % positive predictive value, 98 % negative predictive value. Targeted biopsy yielded 86 % sensitivity and 100 % specificity. Stone clearance was noted in all cases. Adverse events occurred in 3 %. Conclusion The new IDCP system provides enhanced image resolution, and may improve the ability to target difficult stones and diagnose indeterminate strictures.
Avoiding another cyberattack will take human and technical solutions, say experts
Authors: Nigel Hawkes
Journal: BMJ (2017)

Protecting against a cyberattack of the sort that paralysed at least 47 NHS trusts on 12 May123 will not be simple, experts have warned. Vulnerability is likely to increase rather than diminish as more and more IT systems are linked and patients’ access to them is made easier.

Bryan Hurcombe, of the accountancy and consulting company Deloitte, told a Westminster Forum meeting in London on 18 May that the problem was both human and technical. “Many NHS organisations have legacy IT systems that were never designed with cyber-risks in mind,” he said. “It’s very hard to get rid of these systems—they’re engrained in the DNA of organisations. It’s not just a case of lifting and shifting them.

“Today they would be built to be ‘secure by design,’ but that’s very challenging to do. Hundreds of articles have appeared asking, ‘Why haven’t we …
ACC/AHA 2008 Guidelines for the Management of Adults With Congenital Heart Disease: Executive Summary
Authors: Carole A. Warnes, Roberta G. Williams, Thomas M. Bashore, John S. Child, Heidi M. Connolly, Joseph A. Dearani, Pedro del Nido, James W. Fasules, Thomas P. Graham, Ziyad M. Hijazi, Sharon A. Hunt, Mary Etta King, Michael J. Landzberg, Pamela D. Miner, Martha J. Radford, Edward P. Walsh, Gary D. Webb
Journal: Circulation (2008)