tbuckley/cabot-search huggingface dataset:
Speed of updating online evidence based point of care summaries: prospective cohort analysis
Authors: R. Banzi, M. Cinquini, A. Liberati, I. Moschetti, V. Pecoraro, L. Tagliabue, L. Moja
Journal: BMJ (2011)

To evaluate the ability of international point of care information summaries to update evidence relevant to medical practice.Prospective cohort bibliometric analysis.Top five point of care information summaries (Clinical Evidence, EBMGuidelines, eMedicine, Dynamed, UpToDate) ranked for coverage of medical conditions, editorial quality, and evidence based methodology.From June 2009 to May 2010 we measured the incidence of research findings relating to potentially eligible newsworthy evidence. As samples, we chose systematic reviews rated as relevant by international research networks (such as, Evidence-Based Medicine, ACP Journal Club, and the Cochrane Collaboration). Every month we assessed whether each sampled review was cited in at least one chapter of the five summaries. The cumulative updating rate was analysed with Kaplan-Meier curves. Results From April to December 2009, 128 reviews were retrieved; 53% (68) from the literature surveillance journals and 47% (60) from the Cochrane Library. At nine months, Dynamed had cited 87% of the sampled reviews, while the other summaries had cited less than 50%. The updating speed of Dynamed clearly led the others. For instance, the hazard ratios for citations in EBM Guidelines and Clinical Evidence versus the top performer were 0.22 (95% confidence interval 0.17 to 0.29) and 0.03 (0.01 to 0.05). Conclusions Point of care information summaries include evidence relevant to practice at different speeds. A qualitative analysis of updating mechanisms is needed to determine whether greater speed corresponds to more appropriate incorporation of new information.
Definition of a Functional Single Nucleotide Polymorphism in the Cell Migration Inhibitory Gene <i>MIIP</i> That Affects the Risk of Breast Cancer
Authors: Fangfang Song, Ping Ji, Hong Zheng, Fengju Song, Yingmei Wang, Xishan Hao, Qingyi Wei, Wei Zhang, Kexin Chen
Journal: Cancer Research (2010)

Abstract The migration and invasion inhibitory protein MIIP is an inhibitor of cancer cell migration and invasion that inhibits breast tumorigenesis. In this case-control study, we evaluated the MIIP single nucleotide polymorphism (SNP) rs2295283 (codon 167, A&amp;gt;G, K&amp;gt;E) from 1,524 breast cancer patients and 1,592 age-matched controls for its association with breast cancer risk. SNP analysis included a validation set of 736 cases and 760 controls. Colony formation and cell migration assays were then conducted to functionally interrogate the genotype difference. When compared with the AA genotype, the combined AG + GG genotypes (167E) were associated with a significantly lower risk of breast cancer. In the test set, the protective effects of the AG + GG genotypes were more evident among participants with a family history of cancer. Further case series analysis revealed that the GG genotype was associated with reduced breast cancer susceptibility in cases of tumor size &amp;gt;2 cm and late clinical stage (II + III + IV). Colony formation assays showed that MIIP 167E (the G variant) was a more potent inhibitor of colony formation but not cell migration. These results suggest MIIP K167E as a functional genetic marker of breast cancer development and prognosis. Cancer Res; 70(3); 1024–32
Myosin Drives Retrograde F-Actin Flow in Neuronal Growth Cones
Authors: C.H Lin, E.M Espreafico, M.S Mooseker, P Forscher
Journal: Neuron (1996)

Actin filaments assembled at the leading edge of neuronal growth cones are centripetally transported via retrograde F-actin flow, a process fundamental to growth cone guidance and other forms of directed cell motility. Here we investigated the role of myosins in retrograde flow, using two distinct modes of myosin inhibition: microinjection of NEM inactivated myosin S1 fragments, or treatment with 2,3-butanedione-2-monoxime, and inhibitor of myosin ATPase. Both treatments resulted in dose-dependent attenuation of retrograde F-actin flow and growth of filopodia. Growth was cytochalasin sensitive and directly proportional to the degree of myosin inhibition, suggesting that retrograde flow results from superimposition of two independent processes: actin assembly and myosin-based filament retraction. These results provide the first direct evidence for myosin involvement in neuronal growth cone function.
Allergy to Local Anesthetics
Authors: J. Antonio Aldrete
Journal: JAMA (1969)

Patients frequently relate a history suggesting allergy to local anesthetic drugs which have been commonly recognized as causing dermatitis and systemic reactions.<sup>1</sup>However, there appears to be a wide discrepancy between the actual incidence and the emphasis placed on them by textbooks and lectures. Patients who have such a suggestive history are often denied the benefits of local or regional anesthesia. Anesthetists and surgeons have been in somewhat of a dilemma because most reactions to local anesthetics are the result of overdosage, concomitant medication, or apprehension. Intracutaneous testing has been considered of little, if any, value in investigation of the suspected allergies.<sup>2</sup>We have instituted a reinvestigation of this method and believe it may be of clinical importance. The following case report is presented as an example. <h3>Report of a Case</h3> A 40-year-old woman was admitted to Colorado General Hospital for diagnosis and evaluation of an enlarged osteoblastic
COX-2: A Molecular Target for Colorectal Cancer Prevention
Authors: Joanne R. Brown, Raymond N. DuBois
Journal: Journal of Clinical Oncology (2005)

Cyclooxygenase (COX), a key enzyme in the prostanoid biosynthetic pathway, has received considerable attention due to its role in human cancers. Observational and randomized controlled studies in many different population cohorts and settings have demonstrated protective effects of nonsteroidal anti-inflammatory drugs (NSAIDs; the inhibitors of COX activity) for colorectal cancers (CRCs). COX-2, the inducible isoform of cyclooxygenase, is overexpressed in early and advanced CRC tissues, which portends a poor prognosis. Experimental studies have thus identified important mechanisms and pathways by which COX-2 plays an important role in carcinogenesis. Selective COX-2 inhibitors have been approved for use as adjunctive therapy for patients with familial polyposis. The role of COX-2 inhibitors is currently being evaluated for use in wider populations.
Anticoagulant therapy during primary percutaneous coronary intervention for acute myocardial infarction: a meta-analysis of randomized trials in the era of stents and P2Y12 inhibitors
Authors: S. Bangalore, B. Toklu, A. Kotwal, A. Volodarskiy, S. Sharma, A. J. Kirtane, F. Feit
Journal: BMJ (2014)

<b>Objectives</b> To investigate the relative benefits of unfractionated heparin, low molecular weight heparin(LMWH), fondaparinux, and bivalirudin as treatment options for patients with ST segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). <b>Design</b> Mixed treatment comparison and direct comparison meta-analysis of randomized trials in the era of stents and P2Y<sub>12</sub> inhibitors. <b>Data sources and study selection</b> A search of Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) for randomized trials comparing unfractionated heparin plus glycoprotein IIb/IIIa inhibitor(GpIIb/IIIa inhibitor), unfractionated heparin, bivalirudin, fondaparinux, or LMWH plus GpIIb/IIIa inhibitor for patients undergoing primary PCI. <b>Outcomes</b> The primary efficacy outcome was short term (in hospital or within 30 days) major adverse cardiovascular event; the primary safety outcome was short term major bleeding. <b>Results</b> We identified 22 randomized trials that enrolled 22 434 patients. In the mixed treatment comparison models, when compared with unfractionated heparin plus GpIIb/IIIa inhibitor, unfractionated heparin was associated with a higher risk of major adverse cardiovascular events (relative risk 1.49 (95% confidence interval 1.21 to 1.84), as were bivalirudin (relative risk 1.34 (1.01 to 1.78)) and fondaparinux (1.78 (1.01 to 3.14)). LMWH plus GpIIb/IIIa inhibitor showed highest treatment efficacy, followed (in order) by unfractionated heparin plus GpIIb/IIIa inhibitor, bivalirudin, unfractionated heparin, and fondaparinux. Bivalirudin was associated with lower major bleeding risk compared with unfractionated heparin plus GpIIb/IIIa inhibitor (relative risk 0.47 (0.30 to 0.74)) or unfractionated heparin (0.58 (0.37 to 0.90)). Bivalirudin, followed by unfractionated heparin, LMWH plus GpIIb/IIIa inhibitor, unfractionated heparin plus GpIIb/IIIa inhibitor, and fondaparinux were the hierarchy for treatment safety. Results were similar in direct comparison meta-analyses: bivalirudin was associated with a 39%, 44%, and 65% higher risk of myocardial infarction, urgent revascularization, and stent thrombosis respectively when compared with unfractionated heparin with or without GpIIb/IIIa inhibitor. However, bivalirudin was associated with a 48% lower risk of major bleeding compared with unfractionated heparin plus GpIIb/IIIa inhibitor and 32% lower compared with unfractionated heparin alone. <b>Conclusions</b> In patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding. These relationships should be considered in selecting anticoagulant therapies in patients undergoing primary PCI.
Predicting the Cumulative Risk of False-Positive Mammograms
Authors: C. L. Christiansen
Journal: JNCI Journal of the National Cancer Institute (2000)

Background: The cumulative risk of a false-positive mammogram can be substantial. We studied which variables affect the chance of a false-positive mammogram and estimated cumulative risks over nine sequential mammograms. Methods: We used medical records of 2227 randomly selected women who were 40–69 years of age on July 1, 1983, and had at least one screening mammogram. We used a Bayesian discrete hazard regression model developed for this study to test the effect of patient and radiologic variables on a first false-positive screening and to calculate cumulative risks of a false-positive mammogram. Results: Of 9747 screening mammograms, 6.5% were false-positive; 23.8% of women experienced at least one false-positive result. After nine mammograms, the risk of a false-positive mammogram was 43.1% (95% confidence interval [CI] = 36.6%–53.6%). Risk ratios decreased with increasing age and increased with number of breast biopsies, family history of breast cancer, estrogen use, time between screenings, no comparison with previous mammograms, and the radiologist's tendency to call mammograms abnormal. For a woman with highest-risk variables, the estimated risk for a false-positive mammogram at the first and by the ninth mammogram was 98.1% (95% CI = 69.3%–100%) and 100% (95% CI = 99.9%–100%), respectively. A woman with lowest-risk variables had estimated risks of 0.7% (95% CI = 0.2%–1.9%) and 4.6% (95% CI = 1.1%–12.5%), respectively. Conclusions: The cumulative risk of a false-positive mammogram over time varies substantially, depending on a woman's own risk profile and on several factors related to radiologic screening. By the ninth mammogram, the risk can be as low as 5% for women with low-risk variables and as high as 100% for women with multiple high-risk factors.
CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis
Authors: Isabelle A. Leclercq, Geoffrey C. Farrell, Jaqueline Field, David R. Bell, Frank J. Gonzalez, Graham R. Robertson
Journal: Journal of Clinical Investigation (2000)

Nonalcoholic steatohepatitis (NASH) and alcoholic liver disease have similar pathological features. Because CYP2E1 plays a key role in alcoholic liver disease with its ability to stimulate lipid peroxidation, we tested the proposal that CYP2E1 could also be a factor in the development of NASH. In a dietary model — mice fed a methionine- and choline-deficient (MCD) diet — liver injury was associated with both induction of CYP2E1 and a 100-fold increase in hepatic content of lipid peroxides. Microsomal NADPH-dependent lipid oxidases contributed to the formation of these lipid peroxides, and in vitro inhibition studies demonstrated that CYP2E1 was the major catalyst. To further define the role of CYP2E1 as an initiator of oxidative stress in NASH, Cyp2e1–/–mice were administered the MCD diet. CYP2E1 deficiency neither prevented the development of NASH nor abrogated the increased microsomal NADPH-dependent lipid peroxidation, indicating the operation of a non-CYP2E1 peroxidase pathway. In Cyp2e1–/– mice with NASH (but not in wild-type mice), CYP4A10 and CYP4A14 were upregulated. Furthermore, hepatic microsomal lipid peroxidation was substantially inhibited by anti-mouse CYP4A10 antibody in vitro. These results show that experimental NASH is strongly associated with hepatic microsomal lipid peroxidation. CYP2E1, the main enzyme associated with that process in wild-type mice, is not unique among P450 proteins in catalyzing peroxidation of endogenous lipids. We have now identified CYP4A enzymes as alternative initiators of oxidative stress in the liver.
A systematic review of psychosocial factors associated with emotional adjustment in in vitro fertilization patients
Authors: Helen E. Rockliff, Stafford L. Lightman, Emily Rhidian, Heather Buchanan, Uma Gordon, Kavita Vedhara
Journal: Human Reproduction Update (2014)

IVF treatment is usually stressful for patients, but individual differences in emotional response do exist. Differences in the stress response may be related to reproductive outcomes as well as to the development of psychiatric problems. This review collates research exploring which psychosocial factors (e.g. personality traits and coping strategies) are associated with the emotional adjustment of IVF patients. The aim is to reveal what is currently known about risk and protective factors for coping with the stress of IVF treatment and where further enquiry would be most beneficial.The databases, MEDLINE/PUBMED (US National Library of Medicine), PsycINFO (American Psychological Association), Web of Science (Social Sciences Citation Index) and EMbase, were searched from 1978 to September 2012 using relevant key words. All published peer-reviewed studies exploring associations between psychosocial factors and emotional adjustment outcomes were considered for inclusion.There were 23 studies identified for review. One-third of the psychosocial factors explored were found to be significantly related to emotional adjustment outcome measures. Neuroticism and the use of escapist coping strategies were positively associated with distress by multiple studies. Social support was negatively associated with distress by several studies. A number of other psychosocial variables appear to be associated with distress, including self-criticism, dependency, situation appraisals and attachment style, but these have only been explored by one or two studies at most. There is a paucity of research using positive emotional outcome measures (e.g. well-being, positive affect, happiness or life satisfaction) to quantify emotional adjustment.Whilst some psychosocial variables appear to be consistently associated with distress for IVF patients, two-thirds of the variables tested to date do not appear to be associated with emotional adjustment. This review highlights key psychosocial factors to assist the identification of patients at high risk of psychological distress. These findings highlight at least two psychological factors that may be amenable to alteration with psychological or educational interventions. Future work should explore whether experimental manipulation of such psychosocial factors can provide effective stress reduction in this clinical context.
Sonic Hedgehog Signaling in Basal Cell Nevus Syndrome
Authors: Mohammad Athar, Changzhao Li, Arianna L. Kim, Vladimir S. Spiegelman, David R. Bickers
Journal: Cancer Research (2014)

The hedgehog (Hh) signaling pathway is considered to be a major signal transduction pathway during embryonic development, but it usually shuts down after birth. Aberrant Sonic hedgehog (Shh) activation during adulthood leads to neoplastic growth. Basal cell carcinoma (BCC) of the skin is driven by this pathway. Here, we summarize information related to the pathogenesis of this neoplasm, discuss pathways that crosstalk with Shh signaling, and the importance of the primary cilium in this neoplastic process. The identification of the basic/translational components of Shh signaling has led to the discovery of potential mechanism-driven druggable targets and subsequent clinical trials have confirmed their remarkable efficacy in treating BCCs, particularly in patients with nevoid BCC syndrome (NBCCS), an autosomal dominant disorder in which patients inherit a germline mutation in the tumor-suppressor gene Patched (Ptch). Patients with NBCCS develop dozens to hundreds of BCCs due to derepression of the downstream G-protein-coupled receptor Smoothened (SMO). Ptch mutations permit transposition of SMO to the primary cilium followed by enhanced expression of transcription factors Glis that drive cell proliferation and tumor growth. Clinical trials with the SMO inhibitor, vismodegib, showed remarkable efficacy in patients with NBCCS, which finally led to its FDA approval in 2012.
The Sertraline vs Electrical Current Therapy for Treating Depression Clinical Study
Authors: Andre R Brunoni, Leandro Valiengo, Alessandra Baccaro, Tamires A Zanão, Janaina F de Oliveira, Alessandra Goulart, Paulo S Boggio, Paulo A Lotufo, Isabela M Benseñor, Felipe Fregni
Journal: JAMA Psychiatry (2013)

Transcranial direct current stimulation (tDCS) trials for major depressive disorder (MDD) have shown positive but mixed results.To assess the combined safety and efficacy of tDCS vs a common pharmacological treatment (sertraline hydrochloride, 50 mg/d).Double-blind, controlled trial. Participants were randomized using a 2 × 2 factorial design to sertraline/placebo and active/sham tDCS.Outpatient, single-center academic setting in São Paulo, Brazil.One hundred twenty antidepressant-free patients with moderate to severe, nonpsychotic, unipolar MDD.Six-week treatment of 2-mA anodal left/cathodal right prefrontal tDCS (twelve 30-minute sessions: 10 consecutive sessions once daily from Monday to Friday plus 2 extra sessions every other week) and sertraline hydrochloride (50 mg/d). MAIN OUTCOME MEASURES In this intention-to-treat analysis, the primary outcome measure was the change in Montgomery-Asberg depression rating scale score at 6 weeks (end point). We considered a difference of at least 3 points to be clinically relevant. The analysis plan was previously published. Safety was measured with an adverse effects questionnaire, the young mania rating scale, and cognitive assessment. Secondary measures were rates of clinical response and remission and scores on other scales.At the main end point, there was a significant difference in Montgomery-Asberg depression rating scale scores when comparing the combined treatment group (sertraline/active tDCS) vs sertraline only (mean difference, 8.5 points; 95% CI, 2.96 to 14.03; P = .002), tDCS only (mean difference, 5.9 points; 95% CI, 0.36 to 11.43; P = .03), and placebo/sham tDCS (mean difference, 11.5 points; 95% CI, 6.03 to 17.10; P < .001). Analysis of tDCS only vs sertraline only presented comparable efficacies (mean difference, 2.6 points; 95% CI, -2.90 to 8.13; P = .35). Use of tDCS only (but not sertraline only) was superior to placebo/sham tDCS. Common adverse effects did not differ between interventions, except for skin redness on the scalp in active tDCS (P = .03). There were 7 episodes of treatment-emergent mania or hypomania, 5 occurring in the combined treatment group.In MDD, the combination of tDCS and sertraline increases the efficacy of each treatment. The efficacy and safety of tDCS and sertraline did not differ. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01033084.
Rheumatoid arthritis: GWAS or TMI?
Authors: Bruce N Cronstein
Journal: Genome Medicine (2009)

Genome-wide association studies are the most comprehensive and straightforward approach to teasing out the identity of genetic polymorphisms associated with any given disease or characteristic. With the availability of DNA banks from large cohorts of ethnically matched patients and healthy individuals it is now possible to define even marginal genetic associations between genetic polymorphisms and diseases. As increasing numbers of these studies are carried out and as associations with smaller and smaller risks are identified, there is the growing concern that the findings will be of increasingly marginal value. Thus, the glut of new genetic associations is rapidly overwhelming our interest in the results, a situation that could be described as TMI (too much information). Recent genetic association studies in rheumatoid arthritis suggest that we may be approaching the TMI stage of genome-wide association studies.
Response to MET Inhibitors in Patients with Stage IV Lung Adenocarcinomas Harboring <i>MET</i> Mutations Causing Exon 14 Skipping
Authors: Paul K. Paik, Alexander Drilon, Pang-Dian Fan, Helena Yu, Natasha Rekhtman, Michelle S. Ginsberg, Laetitia Borsu, Nikolaus Schultz, Michael F. Berger, Charles M. Rudin, Marc Ladanyi
Journal: Cancer Discovery (2015)

Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain containing the CBL E3-ubiquitin ligase-binding site, and decreased turnover of the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models. We now report responses to the MET inhibitors crizotinib and cabozantinib in four patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping, highlighting a new therapeutic strategy for the 4% of lung adenocarcinoma patients whose tumors harbor this previously underappreciated genetic alteration.