tbuckley/cabot-search huggingface dataset:
Association Between Achieved Low-Density Lipoprotein Levels and Major Adverse Cardiac Events in Patients With Stable Ischemic Heart Disease Taking Statin Treatment
Authors: Morton Leibowitz, Tomas Karpati, Chandra J. Cohen-Stavi, Becca S. Feldman, Moshe Hoshen, Haim Bitterman, Samy Suissa, Ran D. Balicer
Journal: JAMA Internal Medicine (2016)

International guidelines recommend treatment with statins for patients with preexisting ischemic heart disease to prevent additional cardiovascular events but differ regarding target levels of low-density lipoprotein cholesterol (LDL-C). Trial data on this question are inconclusive and observational data are lacking.To assess the relationship between levels of LDL-C achieved with statin treatment and cardiovascular events in adherent patients with preexisting ischemic heart disease.Population-based observational cohort study from 2009 to 2013 using data from a health care organization in Israel covering more than 4.3 million members. Included patients had ischemic heart disease, were aged 30 to 84 years, were treated with statins, and were at least 80% adherent to treatment or, in a sensitivity analysis, at least 50% adherent. Patients with active cancer or metabolic abnormalities were excluded.Index LDL-C was defined as the first achieved serum LDL-C measure after at least 1 year of statin treatment, grouped as low (≤70.0 mg/dL), moderate (70.1-100.0 mg/dL), or high (100.1-130.0 mg/dL).Major adverse cardiac events included acute myocardial infarction, unstable angina, stroke, angioplasty, bypass surgery, or all-cause mortality. The hazard ratio of adverse outcomes was estimated using 2 Cox proportional hazards models with low vs moderate and moderate vs high LDL-C, adjusted for confounders and further tested using propensity score matching analysis.The cohort with at least 80% adherence included 31 619 patients, for whom the mean (SD) age was 67.3 (9.8) years. Of this population, 27% were female and 29% had low, 53% moderate, and 18% high LDL-C when taking statin treatment. Overall, there were 9035 patients who had an adverse outcome during a mean 1.6 years of follow-up (6.7 per 1000 persons per year). The adjusted incidence of adverse outcomes was not different between low and moderate LDL-C (hazard ratio [HR], 1.02; 95% CI, 0.97-1.07; P = .54), but it was lower with moderate vs high LDL-C (HR, 0.89; 95% CI, 0.84-0.94; P < .001). Among 54 884 patients with at least 50% statin adherence, the adjusted HR was 1.06 (95% CI, 1.02-1.10; P = .001) in the low vs moderate groups and 0.87 (95% CI, 0.84-0.91; P = .001) in the moderate vs high groups.Patients with LDL-C levels of 70 to 100 mg/dL taking statins had lower risk of adverse cardiac outcomes compared with those with LDL-C levels between 100 and 130 mg/dL, but no additional benefit was gained by achieving LDL-C of 70 mg/dL or less. These population-based data do not support treatment guidelines recommending very low target LDL-C levels for all patients with preexisting heart disease.
First-line nivolumab (anti-PD-1; BMS-936558, ONO-4538) monotherapy in advanced NSCLC: Safety, efficacy, and correlation of outcomes with PD-L1 status.
Authors: Scott N. Gettinger, Frances A. Shepherd, Scott Joseph Antonia, Julie R. Brahmer, Laura Quan Man Chow, Rosalyn A. Juergens, Hossein Borghaei, Yun Shen, Christopher Harbison, Suresh Alaparthy, Allen C. Chen, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2014)

8024 Background: The fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody nivolumab has demonstrated durable responses and tolerability in patients (pts) with previously treated advanced NSCLC. Tumor PD-1 ligand (PD-L1) expression is being studied as a potential biomarker for nivolumab. We report interim phase I results of first-line nivolumab in chemotherapy-naïve advanced NSCLC pts. Methods: Pts with squamous (sq) or non-sq advanced NSCLC received nivolumab 3 mg/kg IV Q2W until progression or unacceptable toxicity (post-progression treatment allowed based on protocol-defined criteria). Responses (RECIST 1.1) were evaluated overall and according to tumor PD-L1 status (PD-L1+ = ≥5% tumor cells expressing PD-L1 [Dako immunohistochemistry assay]). Results on the first 20 pts are included. Results: After ≥6 months follow up, 17 pts (85%) experienced any-grade treatment-related adverse events (AEs), managed with standard algorithms. Treatment-related grade 3-4 AEs (3 pts, 15%) were AST or ALT elevations, hyperglycemia, and rash (n=1 each). No pneumonitis (any grade) was observed. Objective response rate (ORR) was 30% (Table); 5/6 responders (83%) achieved response by first scan (wk 11). Two pts had >80% target lesion reduction at 18 wks. Of 15 evaluable tumor samples, 9 were PD-L1+. ORR was 67% in PD-L1+ pts; no responses were observed in the 6 PD-L1- pts. Responses were durable (median duration of response [mDOR] not reached [NR]; 5 ongoing responses). Conclusions: In this phase I study, nivolumab led to early, durable responses in advanced NSCLC pts, with a tolerable safety profile. PD-L1 status appeared to correlate with ORR/progression-free survival (PFS). Follow up and responses of 30 additional treated pts will be reported. These data support further studies of first-line nivolumab monotherapy in advanced NSCLC. Clinical trial information: NCT01454102. ORR mDOR Median PFS n/N (%) wk (range) All pts 6/20 (30) NR (11.1+, 37.7+) 29.6 (5.9, 47.6+) Non-sq 4/11 (36) NR (36.1, 37.7+) 45.6 (9.6, 47.6+) Sq 2/9 (22) NR (11.1+, 27.9+) 15.1 (5.9, 37.9+) PD-L1+ 6/9 (67) NR (11.1+, 37.7+) NR (8, 47.6+) PD-L1- 0/6 n/a 23.1 (9.6, 47.3+) PD-L1 unknown 0/5 n/a 15.1 (5.9, 35.7+)
Abstract AS03: Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer
Authors: VY Chung, M Tan, TZ Tan, KT Kuay, J Ye, JP Thiery, RY Huang
Journal: Clinical Cancer Research (2015)

Abstract Epithelial ovarian cancer (EOC) is highly heterogeneous with five molecular subgroups, Epi-A, Epi-B, Mes, Stem-A and Stem-B, being identified. The mechanisms behind the clonal evolution and intertumoral molecular heterogeneity are not fully elucidated. Previously, we performed EOC profiling meta-analysis to identify epithelial-mesenchymal transition (EMT) as the crucial mechanism for molecular heterogeneity. Transcription factors SNAI1, SNAI2, ZEB1, ZEB1, TWIST1, and GRHL2 were identified as crucial regulators for the Mes subtype which has undergone EMT. Here, we utilized three in-vitro EOC cell lines, PEO1, OVCA420, and OVCA429, to model the EMT-driven clonal evolution by manipulating the expression levels of these EMT transcriptional regulators. We analysed the molecular subtypes of matched primary tumor versus peritoneal metastases. Six out of 11 pairs showed concordant molecular subtypes. We also analysed a dataset of matched primary tumor versus omental metastases. Four out of 9 pairs showed concordant molecular subtypes. Among the 10 pairs showing a shift of molecular subtypes, 5 out of 5 omental metastases were designated as Mes. The variation in the evolution of molecular heterogeneity can be explained by the differences in the EMT transcriptional cross-regulation of the in-vitro models. Manipulating EMT regulators in PEO1 did not induce any transcriptional cross-regulation with no molecular subtype switching observed. However, manipulating EMT regulators in OVCA420 and OVCA429 caused hierarchical transcriptional control and feedback loop regulation, respectively. The OVCA429 model showed molecular subtype switch from Epi-A to Mes. In conclusion, the heterogeneity caused by EMT-driven clonal evolution is the consequence of transcriptional feedback loops of EMT regulators. Citation Format: Chung VY, Tan M, Tan TZ, Kuay KT, Ye J, Thiery JP &amp; Huang RY. Epithelial-mesenchymal transition driven by transcriptional feedback loops contributes to intertumoral molecular heterogeneity in the metastasis and relapse of epithelial ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS03.
Case 19-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Herbert L. Abrams, Eugene J. Mark
Journal: New England Journal of Medicine (1985)

Presentation of CaseA 46-year-old woman was admitted to the hospital because of cough, dyspnea, and obstruction of the right pulmonary artery.She was well until six months earlier, when she began to have a hacking cough, which was briefly productive and then became dry. Soon thereafter she began to experience exertional dyspnea, without fever. X-ray films of the chest, obtained elsewhere, showed an elevated right hemidiaphragm but were otherwise normal. Erythromycin was prescribed, with temporary improvement, but the cough worsened when the medication was discontinued. The hematocrit was 40 per cent, and the white-cell count 9100. Five weeks later . . .
Neural mechanisms of benzodiazepine actions
Authors: F E Bloom
Journal: American Journal of Psychiatry (1977)

Current experimental paradigms emphasize neurotransmitter-specific interactions to explain the behavioral effects of benzodiazepines. According to this approach the broad range of effects observed suggests the involvement of several transmitter systems without rigorously establishing that any single transmitter system or physiological synaptic function is either necessary or sufficient to express all benzodiazepine actions. Among the effects that occur, potentiation of amino acid-mediated presynaptic inhibition in the spinal cord and postsynaptic inhibitions elsewhere in the brain are attractive testable hypotheses. However, direct physiological evidence that benzodiazepines stimulate gamma-aminobutyric acid (GABA) or other amino acids specifically and exclusively is needed to corroborate this view.
Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series
Authors: Sudha S. Shankar, Adrian Vella, Ralph H. Raymond, Myrlene A. Staten, Roberto A. Calle, Richard N. Bergman, Charlie Cao, Danny Chen, Claudio Cobelli, Chiara Dalla Man, Mark Deeg, Jennifer Q. Dong, Douglas S. Lee, David Polidori, R. Paul Robertson, Hartmut Ruetten, Darko Stefanovski, Maria T. Vassileva, Gordon C. Weir, David A. Fryburg
Journal: Diabetes Care (2016)

Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states.Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT).From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations.Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.
Detecting Arrhythmias
Authors: ISRAEL M. STEIN
Journal: Annals of Internal Medicine (1974)

Comments and Correction1 October 1974Detecting ArrhythmiasISRAEL M. STEIN, M.D.ISRAEL M. STEIN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-81-4-564_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: In the article "Plasma Concentration of Procainamide and Prevalence of Exertional Arrhythmias" (Ann Intern Med 80:718-722, 1974), Gey and associates noted that "portable tape recorders . . . do not help to forecast exertional arrhythmias nor do they foretell the therapeutic potential of any drug under conditions of exercise stress." Several recent papers seriously question this judgment and the conclusions drawn by these authors.Crawford and associates (1), who studied 50 patients after myocardial infarction, noted that both treadmill testing and Holter monitoring (portable tape recording) are required for complete arrhythmia detection and that Holter monitoring often...References1. CRAWFORDO'ROURKERAMAKRISHNA MRN: Comparative effectiveness of exercise testing and Holter monitoring for detecting arrhythmia in patients with previous myocardial infarction (abstract). Am J Cardiol 33:132, 1974. CrossrefGoogle Scholar2. JELINEKLOHRBAUERLOWN MLB: Anti-arrhythmic drug therapy for sporadic ventricular ectopic arrhythmias. Circulation 49:659-666, 1974 CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Clinical Data Services Inc. 1622a Beacon St. Brookline, Massachusetts 02146 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 1 October 1974Volume 81, Issue 4Page: 564-564KeywordsArrhythmiaAttentionBlood plasmaDrugsExerciseExercise therapyMyocardial infarction Issue Published: 1 October 1974 PDF DownloadLoading ...
Effect of elevated BMI on radiation toxicity in early stage breast cancer patients.
Authors: Jordan Silberg, Kamila Nowak, Meredith Larose, Christopher Wright, Nicole Lynn Simone
Journal: Journal of Clinical Oncology (2016)

1049 Background: Weight gain is associated with an increased risk of cancer and unfavorable outcomes after a cancer diagnosis. Women with an elevated body mass index (BMI) at diagnosis have worse quality of life after completing radiation therapy (RT) for breast cancer as well as increased recurrence rates and cancer-related death. In this retrospective study we investigated the impact of a patient’s BMI on RT acute toxicities and on recurrence rates in patients treated for early stage breast cancer. Methods: Charts of 397 consecutive patients with early stage breast cancer undergoing breast conservation treatment between 2008 and 2013 were retrospectively analyzed. Patients were divided into three groups, normal BMI, overweight (BMI 25-30 kg/m2) and obese (BMI > 30 kg/m2). Acute toxicities, including skin toxicity and fatigue, were scored using CTCAE version 4.0. Recurrence was assessed based on the patient’s last mammogram. The three patient groups were compared using ANOVA and a paired-test. Results: 42.3% of the patients were obese. 72.7% of the patients developed fatigue, 30.0% of the patients developed dry desquamation, and 24.7% of the patients developed moist desquamation. Obese women experienced significantly higher rates of dry skin desquamation (p = 0.000256) and moist skin desquamation (p = 5.86x10-9) as compared to patients with a normal BMI. There was no significant association between fatigue and increasing BMI. 5.2% of patients in the study recurred. Compared with women of normal weight, women with increased BMI were more likely to experience a tumor recurrence (p = 0.0468). Conclusions: Increased BMI is associated with increased risk of acute skin toxicities during radiation treatment for early stage breast cancer. In addition, elevated BMI is associated with a higher rate of tumor recurrence. Strategies to promote weight loss before and during cancer treatment should be offered to patients to decrease treatment-related toxicity and rate of recurrence.
A Population-Based Study of All-Cause Mortality and Cardiovascular Disease in Association With Prior History of Hypoglycemia Among Patients With Type 1 Diabetes
Authors: Chin-Li Lu, Hsiu-Nien Shen, Susan C. Hu, Jung-Der Wang, Chung-Yi Li
Journal: Diabetes Care (2016)

OBJECTIVE This study investigated the effects of severe hypoglycemia on risks of all-cause mortality and cardiovascular disease (CVD) incidence in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS Two nested case-control studies with age- and sex-matched control subjects and using the time-density sampling method were performed separately within a cohort of 10,411 patients with T1DM in Taiwan. The study enrolled 564 nonsurvivors and 1,615 control subjects as well as 743 CVD case subjects and 1,439 control subjects between 1997 and 2011. History of severe hypoglycemia was identified during 1 year, 1–3 years, and 3–5 years before the occurrence of the study outcomes. Conditional logistic regression analyses were performed to estimate the odds ratio (OR) and 95% CI of the study outcomes. RESULTS Prior severe hypoglycemic events within 1 year were associated with higher risks of all-cause mortality and CVD (adjusted OR 2.74 [95% CI 1.96–3.85] and 2.02 [1.35–3.01], respectively). Events occurring within 1–3 years and 3–5 years before death were also associated with adjusted ORs of 1.94 (95% CI 1.39–2.71) and 1.68 (1.15–2.44), respectively. Significant dose–gradient effects of severe hypoglycemia frequency on mortality and CVD were observed within 5 years. CONCLUSIONS Although the CVD incidence may be associated with severe hypoglycemic events occurring in the previous year, the risk of all-cause mortality was associated with severe hypoglycemic events occurring in the preceding 5 years. Exposure to repeated severe hypoglycemic events can lead to higher risks of mortality and CVD.
NUP98 Fusion Proteins Are Recurrent Aberrancies in Childhood Acute Myeloid Leukemia: A Report from the AIEOP AML-2001-02 Study Group
Authors: Valeria Bisio, Martina Pigazzi, Elena Manara, Riccardo Masetti, Marco Togni, Annalisa Astolfi, Cristina Mecucci, Vincenzo Zappavigna, Valentina Salsi, Pietro Merli, Carmelo Rizzari, Franca Fagioli, Franco Locatelli, Giuseppe Basso
Journal: Blood (2014)
European men who have sex with men still at risk of HIV infection despite three decades of prevention efforts
Authors: K Haar, A J Amato-Gauci
Journal: Eurosurveillance (2015)

Preview this article: European men who have sex with men still at risk of HIV infection despite three decades of prevention efforts, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/20/14/art21087-en-1.gif
Use of Decision Models in the Development of Evidence-Based Clinical Preventive Services Recommendations: Methods of the U.S. Preventive Services Task Force
Authors: Douglas K. Owens, Evelyn P. Whitlock, Jillian Henderson, Michael P. Pignone, Alex H. Krist, Kirsten Bibbins-Domingo, Susan J. Curry, Karina W. Davidson, Mark Ebell, Matthew W. Gillman, David C. Grossman, Alex R. Kemper, Ann E. Kurth, Michael Maciosek, Albert L. Siu, Michael L. LeFevre
Journal: Annals of Internal Medicine (2016)

The U.S. Preventive Services Task Force (USPSTF) develops evidence-based recommendations about preventive care based on comprehensive systematic reviews of the best available evidence. Decision models provide a complementary, quantitative approach to support the USPSTF as it deliberates about the evidence and develops recommendations for clinical and policy use. This article describes the rationale for using modeling, an approach to selecting topics for modeling, and how modeling may inform recommendations about clinical preventive services. Decision modeling is useful when clinical questions remain about how to target an empirically established clinical preventive service at the individual or program level or when complex determinations of magnitude of net benefit, overall or among important subpopulations, are required. Before deciding whether to use decision modeling, the USPSTF assesses whether the benefits and harms of the preventive service have been established empirically, assesses whether there are key issues about applicability or implementation that modeling could address, and then defines the decision problem and key questions to address through modeling. Decision analyses conducted for the USPSTF are expected to follow best practices for modeling. For chosen topics, the USPSTF assesses the strengths and limitations of the systematically reviewed evidence and the modeling analyses and integrates the results of each to make preventive service recommendations.
Further evidence for genotype-phenotype disparity in Griscelli syndrome
Authors: J.Y.W. Lee, M.S. Eldeeb, C.-K. Hsu, R. Saito, S.A. Abouzeid, J.A. McGrath
Journal: British Journal of Dermatology (2016)

First described in 1978, Griscelli syndrome (GS) is a rare autosomal recessive disorder featuring pigmentary dilution of hair and skin.1 GS is caused by mutations in any of three genes encoding a tripartite protein complex essential for melanosome transport.2 GS1 (MIM214450) presents as hypomelanosis with primary neurological defects and is caused by mutations in MYO5A,3 and which also may be the same entity as Elejalde syndrome (MIM256710).4

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Mineralocorticoid Receptor Antagonists in the Management of Heart Failure and Resistant Hypertension
Authors: David M. Flatt, Michael C. Brown, Adam M. Mizeracki, Bryan J. King, Karl T. Weber
Journal: JAMA Cardiology (2016)

Heart failure (HF), with or without reduced ejection fraction, and multidrug-resistant hypertension (RHT) are major worldwide health problems of ever-increasing proportions. The mineralocorticoid receptor antagonists (MRAs) spironolactone and eplerenone have proved valuable additions to the overall management of these disorders in patients without significant renal dysfunction.Neurohormonal activation, including aldosteronism, in HF and RHT, has provided the pathophysiologic basis for the inclusion of MRA in the overall management of these disorders and the respective survival benefit and control of blood pressure. Furthermore, MRAs attenuate the appearance of secondary hyperparathyroidism that accompanies excretory Ca2+ losses induced by aldosteronism in which elevated parathyroid hormone levels raise the risk of adverse cardiovascular events and atraumatic bone fracture. Serial surveillance of serum electrolytes and creatinine levels is mandated to avoid serious hyperkalemia (potassium concentration >5.5 mEq/L) and its attendant risks in patients receiving MRAs.Mineralocorticoid receptor antagonists are a valuable addition to the practice of medicine. Their judicious use in patients with HF or RHT can improve treatment of these patients.