tbuckley/cabot-search huggingface dataset:
A first-in-human phase I study of VGX-100, a selective anti-VEGF-C antibody, alone and in combination with bevacizumab in patients with advanced solid tumors.
Authors: Gerald Steven Falchook, Jonathan Wade Goldman, Jayesh Desai, Ian Leitch, David S. Hong, Vivek Subbiah, Razelle Kurzrock, Lee S. Rosen
Journal: Journal of Clinical Oncology (2014)

2524 Background: Tumoral escape following VEGF-A inhibition may be due to increased VEGF-C.VGX-100 is a novel fully human IgG1λ neutralizing monoclonal antibody targeting VEGF-C, inhibiting its activation of VEGFR-2 & VEGFR-3 receptors. Combination of VGX-100 with bevacizumab may result in synergistic effects by targeting multiple VEGF signalling pathways that mediate angiogenesis and lymphangiogenesis. Methods: An open label phase 1 study(NCT01514123) using a 3+3 design was initiated in patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function. Pts were treated with escalating doses of intravenous VGX-100 monotherapy or combination VGX-100 + bevacizumab in sequential cohorts of 3-6 pts for assessment of safety, maximum tolerated dose (MTD), PK, anti-VGX-100 antibodies, angiogenic biomarkers, and tumor response. Results: 43 pts were enrolled and treated; 19 pts with single agent VGX-100 (1-30 mg/kg, QW) and 24 pts with combination VGX-100 (2.5-20 mg/kg, QW) and bevacizumab (5 or 10 mg/kg, Q2W). Overall, the most common grade 1-2 toxicities were fatigue, rash, nausea, anorexia and hypertension. One dose-limiting toxicity of grade 3 hypertension occurred during cycle 1 in a pt at the lowest combination dose level VGX-100 (2.5 mg/kg) and bevacizumab (5 mg/kg); a grade 3 worsening congestive heart failure in another pt was also reported in cycle 3 at dose level VGX-100 2.5 (mg/kg) and bevacizumab (10 mg/kg). At steady state, weekly doses ≥20 mg/kg of VGX-100 exceeded predicted human circulating VEGF-C levels and efficacy exposures in xenograft models. No binding antibodies to VGX-100 were seen. Infusion related reactions grade 1-2 at VGX-100 doses ≥10 mg/kg were controlled by routine premedication allowing escalation to the maximum planned dose of 30 mg/kg weekly; thus a MTD was not reached. A total of 5 of 42 evaluable pts (12%), achieved a best response of durable stable disease ≥4 months. Conclusions: VGX-100 alone and in combination with bevacizumab was well tolerated. PK data support weekly dosing. Further clinical evaluation of VGX-100 in combination with chemotherapy and other targeted agents is warranted. Clinical trial information: NCT01514123.
Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project
Authors: Humberto Parada, Marilie D. Gammon, Jia Chen, Antonia M. Calafat, Alfred I. Neugut, Regina M. Santella, Mary S. Wolff, Susan L. Teitelbaum
Journal: Environmental Health Perspectives (2018)

Background: Phthalates, known endocrine disruptors, may play a role in breast carcinogenesis. Few studies have examined phthalates in relation to breast cancer (BC), and, to our knowledge, none have considered survival following BC. Objectives: We examined 11 urinary phthalate metabolites, individually and as molar sum groupings, in association with BC incidence and subsequent survival. Methods: Our study includes 710 women diagnosed with first primary BC in 1996–1997 and 598 women without BC from Long Island, New York. Within 3 mo of diagnosis, participants provided spot urine samples. Nine phthalate metabolites were measured in all women; two [monocarboxyoctyl phthalate (MCOP) and monocarboxy-isononyl phthalate (MCNP)] were measured in 320 women with and 205 without BC. Women with BC were followed since diagnosis using the National Death Index; during follow-up (median=17.6y), we identified 271 deaths (98 BC related). We examined creatinine-corrected metabolite concentrations in association with: BC, using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and all-cause/BC-specific mortality, using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We also examined effect modification by body mass index (BMI) and estrogen receptor (ER) status. Results: The highest (vs. lowest) quintiles of mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), MCNP, and MCOP were associated with BC ORs ranging from 0.71–0.73. The highest (vs. lowest) quintiles of mono(2-ethylhexyl) phthalate (MEHP) and MCOP were associated with BC-specific mortality HRs of 0.54 (95% CI: 0.28, 1.04) and 0.55 (95% CI: 0.23, 1.35), respectively. For BC-specific mortality, interactions were significant between BMI and mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP), with positive associations among women with BMI<25 and inverse associations among women with BMI≥25.0 kg/m2. Conclusions: Consistent with laboratory evidence, we observed inverse associations between urinary concentrations of several phthalate metabolites and BC and subsequent survival; however, these results should be interpreted with caution given that biospecimen collection among women with BC occurred after diagnosis, which may be of particular concern for our case–control findings. https://doi.org/10.1289/EHP2083
Abstract 16818: Circulating Cardiac Troponin I as Detected By a High-Sensitivity Assay among Patients Hospitalized with Acute Decompensated Heart Failure
Authors: Robb D Kociol, Steven E McNulty, Kerry L Lee, Fred S Apple, Russell P Tracy, Adrian F Hernandez, Robert J Mentz, Eugene Braunwald, Christopher M O'Connor, G. Michael Felker
Journal: Circulation (2011)

Background: Detectable circulating cardiac troponin (cTn) has been associated with increased risk of death or rehospitalization in patients hospitalized with acute decompensated heart failure (ADHF). Little is known about the association between cTn levels measured using high-sensitivity assays (hsTn) and outcomes. Methods: We analyzed hsTnI data from patients enrolled in DOSE - a randomized controlled trial of diuretic strategies in ADHF. hsTnI was measured at baseline at a central academic core laboratory using a high-sensitivity assay (Beckman Coulter hs-cTnI) with a lower limit of detection of 2.06 pg/mL and a 99 th percentile upper reference limit (URL) of 8.6 pg/mL. We used the Cox regression model to look for an association between baseline hsTnI (log transformed) and 60-day clinical outcomes (death, rehospitalization, or emergency department [ED] visit). Results: Among 308 patients in the trial, 290 had baseline cTnI values available for analysis. All patients had detectable hsTnI levels at baseline, and 92% had hsTnI levels above the 99 th percentile URL. The median (IQR) hsTnI was 21.8 pg/mL (13.1, 42.9). Median hsTnI stratified by gender, left ventricular ejection fraction, HF etiology and serum creatinine (Cr) are reported in the Table. Women and those with Cr &gt; 1.5 had higher median hsTnI values. The observed event rate was 46.2% within 60 days. We found no association between hsTnI and days free of death, rehospitalization, or ED visit after univariate analysis (P=0.11), or after adjustment for covariates (P=0.35). Conclusion: Using a high sensitivity hsTnI assay, 100% of ADHF had detectable circulating hsTnI and over 92% of patients had a hsTnI level above the 99 th percentile URL. These data suggest that such a cut point may have little relevance in the ADHF population when using high sensitivity assays. We found no association between hsTnI levels and clinical outcomes at 60 days.
The triglycerides and glucose (TyG) index: a new marker associated with Non Alcoholic Steatohepatitis (NASH) and fibrosis in obese patients?
Authors: S. Faure, R. Benjamin, J. Ramos, S. Medhi, N. David, L. Anne, F. Galtier, G.-P. Pageaux
Journal: Journal of Hepatology (2018)
Bitcoin technology could take a bite out of NHS data problem
Authors: Stephen Armstrong
Journal: BMJ (2018)

Blockchain recording of digital transactions could have many healthcare applications—from patient records to tracing pills—reports Stephen Armstrong , but is its potential overhyped? The cryptocurrency boom may be over, according to recent reports,1 but interest in its underlying technology, the blockchain, is far from it. Digital health experts are starting to wonder if blockchain could solve NHS data problems, and the UK's first trial of blockchain technology to create and support electronic health records will begin in July at a southwest London general practice group (box 1).8 Box 1 ### Blockchain examples in health #### Countering counterfeits "The blockchain provides a granular trail of a product's journey," explains Peter Bryant, chief operating officer of UK based global drug tracking system FarmaTrust. With the Drug Supply Chain Security Act in the US rolling out between 2015 and 2023,2 and the equivalent Falsified Medicines Directive in the EU coming into force next spring,3 all pharmaceutical products will require a label with a unique serial number, name, lot number, batch number, and expiry date. FarmaTrust is talking to 13 manufacturers as well as the Mongolian government to offer a blockchain tracking system that can link with existing databases. The company is also working with medicinal poppy and marijuana growers and the government in Thailand to ensure that products are traceable and the farmers are taxed on profits. #### Patient records Technology company Medicalchain is partnering with southwest London general practice group, The Groves, in the UK's first trial of blockchain to create and support electronic health records.4 It offers registered patients a free digital wallet to hold and manage access to their health records. The platform includes a cryptocurrency—Medicalchain's MedTokens—to encourage patients to participate, which they can use as private patients to pay for telemedicine services. Elsewhere, MIT research project MedRec is trialling a health records system that leaves patient … RETURN TO TEXT
Optimizing Bleeding Control Training for the Public
Authors: Eileen M. Bulger, Mark L. Gestring, Lenworth M. Jacobs
Journal: JAMA Surgery (2018)

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Clearance of intracellular Klebsiella pneumoniae infection using gentamicin-loaded nanoparticles
Authors: Lai Jiang, Michelle K. Greene, Jose Luis Insua, Joana Sa Pessoa, Donna M. Small, Peter Smyth, Aidan P. McCann, Francesco Cogo, Jose A. Bengoechea, Clifford C. Taggart, Christopher J. Scott
Journal: Journal of Controlled Release (2018)
Abstract 17220: Treatment Persistence and Discontinuation With Rivaroxaban, Dabigatran and Warfarin for Stroke Prevention in Patients With Non-valvular Atrial Fibrillation
Authors: Craig Coleman, Muralikrishna Tangirala, Thomas Evers
Journal: Circulation (2015)

Introduction: Continuous use of oral anticoagulant (OAC) therapy is essential for reducing the risk of stroke in patients with non-valvular atrial fibrillation. To date, no single study has compared persistence and discontinuation rates between rivaroxaban, dabigatran and warfarin users. Hypothesis: To compare persistence and discontinuation rates between rivaroxaban, dabigatran and warfarin users with non-valvular atrial fibrillation. Methods: A retrospective cohort analysis of the United States MarketScan claims databases was performed. This included adult patients newly initiated on rivaroxaban, dabigatran or warfarin between 1 November 2011 and 31 December 2013 with a baseline CHA2DS2-VASc score ≥2, ≥2 atrial fibrillation diagnosis codes (427.31) and ≥6 months of continuous medical and pharmacy benefits prior to OAC initiation (index date). Propensity score matching was performed in a two-step process to match patients on rivaroxaban with dabigatran 1:1 and with warfarin 1:1. Patients were followed until the earliest of in-hospital death, end of continuous enrolment or end of study period. Persistence was defined as absence of refill gap of &gt;60 days. Discontinuation was defined as no additional refill for &gt;90 days and through end of follow-up. Cox proportional hazards models were estimated to examine hazard ratios (HRs) of OAC non-persistence and discontinuation. Results: A total of 32,634 patients were included (N=10,878/OAC group). At 3 months’ follow-up, treatment persistence was 79.2%, 69.6% and 70.9% for rivaroxaban, dabigatran and warfarin users, respectively, dropping to 70.2%, 57.8% and 58.8% after 6 months, 60.1%, 44.7% and 42.0% after 1 year and 50.4%, 30.6% and 26.5% after 2 years. On regression, rivaroxaban use was associated with a decreased hazard of non-persistence compared with dabigatran (HR=0.64; 95% confidence interval [CI] 0.62-0.67) and warfarin (HR=0.62; 95% CI 0.59-0.64), and a decreased rate of discontinuation versus dabigatran (HR=0.61; 95% CI 0.58-0.64) and warfarin (HR=0.65; 95% CI 0.62-0.68). Conclusions: This matched patient analysis indicated significantly higher persistence and lower discontinuation rates with rivaroxaban compared with dabigatran and warfarin.
Abstract 18720: HDL Particle Subclasses, Rosuvastatin Therapy, and Risk of Vascular Events: An Analysis From the JUPITER Trial
Authors: Akintunde O Akinkuolie, Patrick R Lawler, Robert J Glynn, Paul M Ridker, Samia Mora
Journal: Circulation (2015)

Background: In the JUPITER trial, total HDL particle concentration (HDL-P) performed better that HDL-cholesterol (HDL-C) in predicting residual vascular risk. It is uncertain whether biological heterogeneity of HDL particle subclasses relates to differential vascular risk in the setting of statin therapy. Methods: We analyzed data from JUPITER (NCT00239681) in which participants with LDL-C &lt;130 mg/dL and hsCRP ≥2 mg/L were randomized to 20mg/day of rosuvastatin vs placebo. HDL subclass concentrations were measured and categorized into 5 groups (very large, large, medium, small, and very small) by NMR spectroscopy (LipoScience, NC [now LapCorp]) in 12,487 participants before and 1 year after randomization. Results: A total of 308 first vascular events (MI, stroke, revascularization, unstable angina, CVD death) occurred during maximum follow-up of 5.0 (median, 1.9) years. For baseline risk, multivariable adjusted Cox regression models demonstrated that the baseline concentrations of all HDL subclasses were inversely associated with incident vascular events (Table), with statistically significant associations for large HDL (adjusted HR per SD: 0.85, 95% CI, 0.76-0.95) and medium HDL (HR 0.89, 95% CI 0.80-0.98) even after mutually adjusting for the other HDL subclasses. By contrast, among rosuvastatin-allocated participants, on-treatment concentrations of very large HDL subclasses were associated with an increased risk of residual risk of vascular events (adjusted HR per SD: 1.65, 95% CI, 1.02-2.66). Conclusion: In JUPITER participants, baseline levels of HDL subclasses were inversely associated with the risk of incident vascular events with significant associations for the large and medium particles. However, on-statin levels of very large HDL particles were significantly associated with an increased risk of vascular events.
Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled phase IIIb study of patients with moderate-to-severe genital psoriasis
Authors: C. Ryan, A. Menter, L. Guenther, A. Blauvelt, R. Bissonnette, K. Meeuwis, J. Sullivan, J.C. Cather, G. Yosipovitch, A.B. Gottlieb, J.F. Merola, K. Callis Duffin, S. Fretzin, O.O. Osuntokun, R. Burge, A.N. Naegeli, F.E. Yang, C.-Y. Lin, K. Todd, A. Potts Bleakman
Journal: British Journal of Dermatology (2018)

Genital psoriasis (GenPs) is a common, debilitating and difficult-to-treat manifestation of plaque psoriasis. However, few controlled, interventional studies of GenPs exist.To determine the efficacy of ixekizumab vs. placebo in patients with moderate-to-severe GenPs with ≥ 1% involved body surface area (BSA).Patients with moderate-to-severe GenPs, defined as a baseline static Physician's Global Assessment of Genitalia (sPGA-G) score of ≥ 3, with BSA ≥ 1% were randomized 1 : 1 to receive placebo (n = 74) or the recommended dosing of ixekizumab (n = 75). Major outcomes included the percentage of patients achieving 0 or 1 scores on the sPGA-G (primary end point), overall sPGA, GenPs Sexual Frequency Questionnaire (GenPs-SFQ) item 2, and ≥ 3-point improvement from baseline on the GenPs itch numerical rating scale.At week 12, ixekizumab was superior to placebo for sPGA-G 0/1 (73% vs. 8%, P < 0·001), overall sPGA 0/1 (73% vs. 3%, P < 0·001), GenPs-SFQ item 2 score of 0 or 1 (78% vs. 21%, P < 0·001) and genital itch (60% vs. 8%, P < 0·001). No candidiasis was reported, no deaths occurred and one (1%) serious adverse event was reported in a patient receiving placebo.Ixekizumab was superior to placebo for the treatment of moderate-to-severe GenPs with BSA ≥ 1%. The safety profile of ixekizumab was consistent with previous studies in moderate-to-severe plaque psoriasis.
Health-Related Quality of Life in patients with autoimmune hepatitis
Authors: A. Takahashi, K. Moriya, H. Ohira, T. Arinaga-Hino, T. Torimura, M. Zeniya, M. Abe, A. Takaki, J.-H. Kang, A. Inui, T. Fujisawa, K. Yoshizawa, Y. Suzuki, N. Nakamoto, K. Koike, H. Yoshiji, A. Goto, A. Tanaka, Z.M. Younossi, H. Takikawa
Journal: Journal of Hepatology (2018)
Risk for thrombosis in patients with myeloproliferative neoplasms was highest near the time of diagnosis
Authors: Ian Rabinowitz
Journal: Annals of Internal Medicine (2018)

Source Citation Hultcrantz M, Bjorkholm M, Dickman PW, et al. Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms: a population-based cohort study. Ann Intern Med. 2018;168:317-25. 29335713
Abstract 18813: Microvascular Complications Predict Cardiovascular Disease In Type 2 Diabetes: A Population Study
Authors: Jack Brownrigg, Hughes Cian, Kausik Ray, Robert Hinchliffe
Journal: Circulation (2016)

Introduction:  Diabetes confers a 2-fold excess risk of cardiovascular disease (CVD), yet predicting individual risk remains challenging. The effect of total microvascular disease burden on CVD risk among individuals with diabetes is unknown.   Hypothesis:  Microvascular disease states alone or in unison are independently associated with CVD.   Methods:  A population-based cohort of patients with type 2 diabetes from the UK Clinical Practice Research Datalink was studied (n=49 027). We used multivariable Cox models to estimate hazard ratios for the primary outcome (cardiovascular death, non-fatal myocardial infarction or non-fatal ischemic stroke) associated with cumulative burden of retinopathy, nephropathy and peripheral neuropathy among individuals with no history of cardiovascular disease at baseline.   Results:  During a median follow-up of 5·5 years, 2822 (5·8%) individuals experienced a primary outcome. Significant associations were observed for the primary outcome individually for retinopathy, peripheral neuropathy, and nephropathy after adjustment for established risk factors. The hazard ratios (with 95% confidence intervals) were 1·39 (1·09-1·76), 1·40 (1·19-1·66), and 1·35 (1·15-1·58), respectively. For individuals with one, two or three microvascular disease states versus none, the multivariable-adjusted hazard ratios for the primary outcome were 1·32 (1·16-1·50), 1·62 (1·42-1·85) and 1.99 (1·70-2.34), respectively. Similar trends were observed for cardiovascular death, all cause mortality and for hospitalization for heart failure. Across the two AHA/ACC categories of cardiovascular risk (   Conclusions:  The cumulative burden of microvascular disease significantly impacts the risk of future CVD among individuals with type 2 diabetes. Improvements in reclassification potentially offer correct intensity of statin therapy and the best net benefit, avoiding exposure of lower CVD risk patients to potentially unnecessary dose-dependent side-effects on higher intensity statins, which might affect compliance and patient engagement.
A Disintegrin and Metalloproteinase Domain-8: A Novel Protective Proteinase in Chronic Obstructive Pulmonary Disease
Authors: Francesca Polverino, Joselyn Rojas-Quintero, Xiaoyun Wang, Hans Petersen, Li Zhang, Xiaoyan Gai, Andrew Higham, Duo Zhang, Kushagra Gupta, Amit Rout, Ilyas Yambayev, Victor Pinto-Plata, Lynette M. Sholl, Danen Cunoosamy, Bartolomé R. Celli, James Goldring, Dave Singh, Yohannes Tesfaigzi, Jadwiga Wedzicha, Henric Olsson, Caroline A. Owen
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: ADAM8 (a disintegrin and metalloproteinase domain-8) is expressed by leukocytes and epithelial cells in health, but its contribution to the pathogenesis of chronic obstructive pulmonary disease (COPD) is unknown.Objectives: To determine whether the expression of ADAM8 is increased in the lungs of patients with COPD and cigarette smoke (CS)-exposed mice, and whether ADAM8 promotes the development of COPD.Methods: ADAM8 levels were measured in lung, sputum, plasma, and/or BAL fluid samples from patients with COPD, smokers, and nonsmokers, and wild-type (WT) mice exposed to CS versus air. COPD-like lung pathologies were compared in CS-exposed WT versus Adam8−/− mice.Measurements and Main Results: ADAM8 immunostaining was reduced in macrophages, and alveolar and bronchial epithelial cells in the lungs of patients with COPD versus control subjects, and CS- versus air-exposed WT mice. ADAM8 levels were similar in plasma, sputum, and BAL fluid samples from patients with COPD and control subjects. CS-exposed Adam8−/− mice had greater airspace enlargement and airway mucus cell metaplasia than WT mice, but similar small airway fibrosis. CS-exposed Adam8−/− mice had higher lung macrophage counts, oxidative stress levels, and alveolar septal cell death rates, but lower alveolar septal cell proliferation rates and soluble epidermal growth factor receptor BAL fluid levels than WT mice. Adam8 deficiency increased lung inflammation by reducing CS-induced activation of the intrinsic apoptosis pathway in macrophages. Human ADAM8 proteolytically shed the epidermal growth factor receptor from bronchial epithelial cells to reduce mucin expression in vitro. Adam8 bone marrow chimera studies revealed that Adam8 deficiency in leukocytes and lung parenchymal cells contributed to the exaggerated COPD-like disease in Adam8−/− mice.Conclusions: Adam8 deficiency increases CS-induced lung inflammation, emphysema, and airway mucus cell metaplasia. Strategies that increase or prolong ADAM8's expression in the lung may have therapeutic efficacy in COPD.
Well-Founded Recommendations for Radioactive Iodine Treatment of Differentiated Thyroid Cancer Require Balanced Study of Benefits and Harms
Authors: Mark Tulchinsky, Richard P. Baum, K.G. Bennet, Leonard M. Freeman, Ian Jong, Kalevi Kairemo, Carol S. Marcus, Renee M. Moadel, Paritosh Suman
Journal: Journal of Clinical Oncology (2018)