tbuckley/cabot-search huggingface dataset:
First-in-Human Experience of an Antidote-Controlled Anticoagulant Using RNA Aptamer Technology
Authors: Christopher K. Dyke, Steven R. Steinhubl, Neal S. Kleiman, Richard O. Cannon, Laura G. Aberle, Min Lin, Shelley K. Myles, Chiara Melloni, Robert A. Harrington, John H. Alexander, Richard C. Becker, Christopher P. Rusconi
Journal: Circulation (2006)

Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study.Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline.These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.
Apple crumble or a selection from the sweet trolley?
Authors: A. Panja
Journal: BMJ (2004)

In the first month of my GP registrar year, I remember sitting in on a soporific meeting with the accountants who looked after the practice's books. It was over lunch, and, just as I had begun to drift into the first of many microsleeps of the afternoon, one of the two money men thought he'd try to make polite conversation with me: “So, you're learning the ropes of general practice are you? How are you finding it?”

I gave him a stock answer, hoping he would leave me alone. “Yeah, it's great actually… really enjoying it, thanks,” I replied unoriginally. I was too jaded to ask him anything in return, like who or what “Super-Ann” was or why they kept referring to “drawings” when there wasn't an architect in sight.

Not comfortable …
Reviews and Notes: Why Psychiatry Is a Branch of Medicine
Authors: Gladys S. Fenichel
Journal: Annals of Internal Medicine (1993)

Literature of Medicine15 October 1993Reviews and Notes: Why Psychiatry Is a Branch of MedicineGladys S. Fenichel, MDGladys S. Fenichel, MDUniversity of Pennsylvania, Philadelphia, PA 19104Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-119-8-199310150-00029 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Why Psychiatry Is a Branch of MedicineSamuel B. Guze. 147 pages. New York: Oxford University Press; 1992. $24.95.In 1979 I decided to leave internal medicine and begin a residency program in psychiatry. I was confronted by colleagues who asked how I could leave internal medicine to enter a field without white coats, without discipline, and without a coherent model of disease. Most of my medical colleagues believed that psychiatry was certainly not a branch of medicine. Fortunately, Samuel Guze had already started writing his thoughts about the field of psychiatry. Now we have the monograph Why Psychiatry Is a Branch ... Author, Article, and Disclosure InformationAffiliations: University of Pennsylvania, Philadelphia, PA 19104 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 October 1993Volume 119, Issue 8Page: 864KeywordsBiologicsEpidemiologyPathogenesisResidency ePublished: 15 August 2000 Issue Published: 15 October 1993 Copyright & PermissionsCopyright © 1993 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
How do consumers search for and appraise health information on the world wide web? Qualitative study using focus groups, usability tests, and in-depth interviews
Authors: G. Eysenbach
Journal: BMJ (2002)

<h3>Abstract</h3> <b>Objectives:</b> To describe techniques for retrieval and appraisal used by consumers when they search for health information on the internet. <b>Design:</b> Qualitative study using focus groups, naturalistic observation of consumers searching the world wide web in a usability laboratory, and in-depth interviews. <b>Participants:</b> A total of 21 users of the internet participated in three focus group sessions. 17 participants were given a series of health questions and observed in a usability laboratory setting while retrieving health information from the web; this was followed by in-depth interviews. <b>Setting:</b> Heidelberg, Germany. <b>Results:</b> Although their search technique was often suboptimal, internet users successfully found health information to answer questions in an average of 5 minutes 42 seconds (median 4 minutes 18 seconds) per question. Participants in focus groups said that when assessing the credibility of a website they primarily looked for the source, a professional design, a scientific or official touch, language, and ease of use. However, in the observational study, no participants checked any "about us" sections of websites, disclaimers, or disclosure statements. In the post-search interviews, it emerged that very few participants had noticed and remembered which websites they had retrieved information from. <b>Conclusions:</b> Further observational studies are needed to design and evaluate educational and technological innovations for guiding consumers to high quality health information on the web. <h3>What is already known on this topic</h3> Little is known about how consumers retrieve and assess the quality of health information on the internet Qualitative data are needed to design educational and technological innovations to guide consumers to high quality health information <h3>What this study adds</h3> Users of the internet explore only the first few links on general search engines when seeking health information Consumers say that when assessing the credibility of a site they primarily look for the source, a professional design, and a variety of other criteria In practice, internet users do not check the "about us" sections of websites, try to find out who authors or owners of the site are, or read disclaimers or disclosure statements Very few internet users later remember from which websites they retrieved information or who stood behind the sites
Oxygen Tension of Tissues by the Polarographic Method
Authors: HUGH MONTGOMERY, HARRY F. ZINSSER, ORVILLE HORWITZ
Journal: Circulation (1950)

Normal individuals breathing pure oxygen obtain full saturation of their hemoglobin, whereas those with right to left shunts do not. Oxygen hemoglobin dissociation curves indicate that increases to full oxygen saturation of hemoglobin are accompanied by marked increases of the oxygen tension. When breathing oxygen fails to produce full saturation, relatively little change in oxygen tension occurs. When the cutaneous circulation is rapid, changes in skin oxygen tension have been shown to vary directly with changes in blood oxygen tension. Taking advantage of these facts the authors have described a method of detecting significant right to left shunts by polarographic measurements of skin oxygen tension.
High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG
Authors: E Lengfelder, C Haferlach, S Saussele, T Haferlach, B Schultheis, S Schnittger, W-D Ludwig, P Staib, C Aul, A Grüneisen, W Kern, A Reichle, H Serve, W E Berdel, J Braess, K Spiekermann, B Wörmann, M-C Sauerland, A Heinecke, W Hiddemann, R Hehlmann, T Büchner
Journal: Leukemia (2009)
GEOMETRIC DIFFERENCES IN MITRAL APPARATUS BETWEEN DIFFERENT TYPES OF ISCHEMIC MITRAL REGURGITANT JET: A COLOR DOPPLER REAL–TIME 3D TRANSESOPHAGEAL ECHOCARDIOGRAPHY STUDY
Authors: Masaki Izumo, Eiji Kuwahara, Takeji Saitoh, Jun Tanaka, Yoko Fukuoka, Swaminatha V. Gurudevan, Robert J. Siegel, Takahiro Shiota
Journal: Journal of the American College of Cardiology (2013)
Asthma Attacks with Eosinophilia Predict Mortality from Chronic Obstructive Pulmonary Disease in a General Population Sample
Authors: JEANNETTE J. HOSPERS, JAN P. SCHOUTEN, SCOTT T. WEISS, BERT RIJCKEN, DIRKJE S. POSTMA
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We studied the association between allergy defined as eosinophilia (>/= 275 cells/mm(3)) and/or positive skin tests (sum score >/= 3) and mortality from chronic obstructive pulmonary disease (COPD) after adjustment for major risk factors. In addition, we investigated this association in subgroups of respiratory symptoms and lung function. We used data from 7,556 participants of the respiratory surveys in 1964 -1972 in the general populations of Vlagtwedde, Vlaardingen, and Meppel (The Netherlands; mean age +/- SD: 39.3 yr +/- 14 in the 1960s). In 1995, the vital status was available (5,135 alive, 106 lost to follow-up, 121 primary deaths from COPD, and 2,194 other primary causes of which 137 had a secondary death cause from COPD. Positive skin tests were not associated with increased COPD mortality. The association between eosinophilia and COPD mortality was restricted to those who had reported asthma attacks and was present for both COPD as a primary cause (relative risk [RR] = 4.80; 95% confidence interval [CI] 1.9 to 11.9) and combined primary and secondary causes of death (RR = 3. 90; 95% CI 2.05 to 7.40). We conclude that eosinophilia with asthma attacks is a risk factor for COPD mortality in addition to known risk factors also found in our study such as male gender, older age, current smoking, low lung function, underweight, and dyspnea.
Transcriptional regulation of IFN-λ genes in Hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-κB complex
Authors: Hai-Chon Lee, Je-In Youn, Kyungwha Lee, Hwanyul Yong, Seung-Yong Seong
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Hepatitis C virus (HCV) infection in hepatocytes stimulates innate antiviral responses including the production of type III interferons (IFN-λ), including IL-28A, IL-28B, and IL-29 (Figure [1][1]). However, the molecular mechanism(s) regulating the expression of IFN- λ genes in
Effect of Hormonal Therapy on Plasma Testosterone Levels in Prostatic Carcinoma
Authors: M. R. G. Robinson, B. S. Thomas
Journal: BMJ (1971)

Plasma concentrations of testosterone were estimated in normal men, in patients before treatment for prostatic cancer, and in patients who had had various forms of endocrine treatment for prostatic carcinoma. There was no decline in plasma testosterone levels with age. Patients with non-metastatic disease had levels similar to those of normal controls, but in advanced metastatic disease the levels were low. After orchidectomy the plasma testosterone level fell to that found in normal women. In every patient stilboestrol in doses as small as 1 mg three times a day suppressed plasma testosterone at first to negligible amounts, irrespective of the clinical response. Subsequently a small but significant rise in the concentration was always observed over a period of six months9 oestrogen therapy. Pituitary ablation with yttrium-90 lowered the plasma testosterone concentration again to negligible amounts in patients who had been on stilboestrol. In advanced metastatic disease this was often associated with relief of pain. Preliminary studies with aminoglutethimide indicate that it can produce biochemical and clinical effects similar to those of pituitary ablation.
Africans are dying of AIDS without pain relief
Authors: D. Carlisle
Journal: BMJ (2003)

Millions of people in Africa are dying of AIDS without any pain relief, despite oral morphine being one of the cheapest drugs in the world, a conference was told this week.

The conference, organised by the Diana Princess of Wales Memorial Fund and Help the Hospices and held in London this week, heard how legal obstacles made morphine hard to get, while lack of training of health professionals prevented prescribing of the drug at the level of the community.

The demand for oral morphine and other drugs to manage pain and to control …
Effect of DNA topology on the transfection efficiency of poly((2-dimethylamino)ethyl methacrylate)–plasmid complexes
Authors: J.-Y. Cherng, N.M.E. Schuurmans-Nieuwenbroek, W. Jiskoot, H. Talsma, N.J. Zuidam, W.E. Hennink, D.J.A. Crommelin
Journal: Journal of Controlled Release (1999)
Injury from lightning strike while using mobile phone
Authors: Swinda Esprit, Prasad Kothari, Ram Dhillon
Journal: BMJ (2006)

Contraction and convergence: myth and realityEditor-The review of climate change issues in the BMJ of 10 June was comprehensive.On grounds of morality, the principle of contraction and convergence is unassailable. 1 In the real world, it is a pipe dream.It would work only by being enforcible, which implies an international policing authority with real teeth.Can we seriously believe that the United States, China, or Russia would submit to such an authority?Sadly there is no mileage in morality when affluent lifestyles are threatened.It is right to plead for changes in individual behaviour, but only the de-carbonising of energy at source will make a predictable and sustained impact on carbon dioxide emissions.The only long term route to this goal will be through the adoption of renewable energy technologies on two levels.Firstly, small scale to micro-generation systems are rapidly approaching market viability.Within five to 10 years, millions of homes could become cost effective mini-power stations linked to a local mini-grid under the umbrella of distributed generation.The Energy Saving Trust estimates that this sector could meet 40% of UK electricity demand. 2 Secondly, base load electricity could be provided by gigawatt scale technologies mostly drawing energy from wind, rivers, and seas.Tidal stream, tidal estuary, tidal impoundment, wave power, and offshore wind could more than match the output of today's nuclear power. 3 In the short term, "balancing power" to compensate for intermittency would be provided by combined cycle gas power plants.In the longer term, surplus electricity, which is an intrinsic problem with renewables, will be directed to producing hydrogen for grid connected gigawatt scale fuel cells in a symbiotic coupling with high energy density renewables installations.All this will, of course, depend on massive government investment, but so would nuclear energy.On the demand side, buildings are the biggest carbon culprits.The only effective answer, embracing both new and existing buildings, is the concept of the carbon budget, enforcible by law.This could also be adapted for transport.These have complex implications, perhaps for another time.
Abstract 964: Gefitinib resistance due to STAT3-mediated Akt activation in lung cancer cells.
Authors: Kai Wu, Yongju Lu, Bailing Chen, Qingshan Chang, Ping Qiu, Miaomiao Yu
Journal: Cancer Research (2013)

Abstract Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, are effective drugs for a subset of non-small cell lung cancer. Gefitinib binds to the tyrosine kinase domain of EGFR and hence inactivates its downstream prosurvival signaling pathways, including PI3k/Akt and MAPK pathways. However, most patients received gefitinib eventually developed resistance to this drug. In this study, we demonstrated that in gefitinib-treated A549 cells (human lung cancer cell line), Akt activation undergoes a time-dependent recovery following an initial inhibition by gefitinib. Since constant activation of Akt has been associated with treatment failure of gefitinib in lung cancer cells, exploring the mechanisms that lead to Akt restoration should provide new insights into the drug resistance and therapeutic efficacy. For that purpose, alterations in Akt activation and other signaling pathways, including MAPK and STAT3, involved in EGFR-mediated cellular responses were determined in A549 cells treated with gefitinib. Among them, we found that activation of STAT3 was inhibited in the cells without gefitinib treatment. Gefitinib treatment inhibited EGFR phosphorylation on tyrosine 1086 (Y1086), which leads to STAT3 activation. Further studies showed that interruption of the STAT3 signaling by either chemical inhibitor or siRNA against STAT3 prevented fast recovery of Akt activation and enhanced gefitinib-induced suppression of cell proliferation. Taken together, these data suggest that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFR TKIs. Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs on lung cancer. Citation Format: Kai Wu, Yongju Lu, Bailing Chen, Qingshan Chang, Ping Qiu, Miaomiao Yu. Gefitinib resistance due to STAT3-mediated Akt activation in lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 964. doi:10.1158/1538-7445.AM2013-964
Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease
Authors: Sarah E Flanagan, Emma Haapaniemi, Mark A Russell, Richard Caswell, Hana Lango Allen, Elisa De Franco, Timothy J McDonald, Hanna Rajala, Anita Ramelius, John Barton, Kaarina Heiskanen, Tarja Heiskanen-Kosma, Merja Kajosaari, Nuala P Murphy, Tatjana Milenkovic, Mikko Seppänen, Åke Lernmark, Satu Mustjoki, Timo Otonkoski, Juha Kere, Noel G Morgan, Sian Ellard, Andrew T Hattersley
Journal: Nature Genetics (2014)
Political mindset needs to change
Authors: G. Winyard
Journal: BMJ (2013)

<h3>ABSTRACT</h3> <h3>Background</h3> Real-time prediction is key to prevention and control of healthcare-associated infections. Contacts between individuals drive infections, yet most prediction frameworks fail to capture the dynamics of contact. We develop a real-time machine learning framework that incorporates dynamic patient contact networks to predict patient-level hospital-onset COVID-19 infections (HOCIs), which we test and validate on international multi-site datasets spanning epidemic and endemic periods. <h3>Methods</h3> Our framework extracts dynamic contact networks from routinely collected hospital data and combines them with patient clinical attributes and background contextual hospital data to forecast the infection status of individual patients. We train and test the HOCI prediction framework using 51,157 hospital patients admitted to a UK (London) National Health Service (NHS) Trust from 01 April 2020 to 01 April 2021, spanning UK COVID-19 surges 1 and 2. We then validate the framework by applying it to data from a non-UK (Geneva) hospital site during an epidemic surge (40,057 total inpatients) and to data from the same London Trust from a subsequent period post surge 2, when COVID-19 had become endemic (43,375 total inpatients). <h3>Findings</h3> Based on the training data (London data spanning surges 1 and 2), the framework achieved high predictive performance using all variables (AUC-ROC 0·89 [0·88-0·90]) but was almost as predictive using only contact network variables (AUC-ROC 0·88 [0·86-0·90]), and more so than using only hospital contextual (AUC-ROC 0·82 [0·80-0·84]) or patient clinical (AUC-ROC 0·64 [0·62-0·66]) variables. The top three risk factors we identified consisted of one hospital contextual variable (background hospital COVID-19 prevalence) and two contact network variables (network closeness, and number of direct contacts to infectious patients), and together achieved AUC-ROC 0·85 [0·82-0·88]. Furthermore, the addition of contact network variables improved performance relative to hospital contextual variables on both the non-UK (AUC-ROC increased from 0·84 [0·82–0·86] to 0·88 [0·86–0·90]) and the UK validation datasets (AUC-ROC increased from 0·52 [0·49–0·53] to 0·68 [0·64-0·70]). <h3>Interpretation</h3> Our results suggest that dynamic patient contact networks can be a robust predictor of respiratory viral infections spreading in hospitals. Their integration in clinical care has the potential to enhance individualised infection prevention and early diagnosis. <h3>Funding</h3> Medical Research Foundation, World Health Organisation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Swiss National Science Foundation, German Research Foundation.
Retinopathy induced in mice by targeted disruption of the rhodopsin gene
Authors: Marian M. Humphries, Derrick Rancourt, G. Jane Farrar, Paul Kenna, Mark Hazel, Ronald A. Bush, Paul A. Sieving, Denise M. Sheils, Peter Creighton, Alexandra Erven, Andras Boros, Karoly Gulya, Mario R. Capecchi, Peter Humphries
Journal: Nature Genetics (1997)
The requirement for DNA synthesis and gene expression in the generation of cytotoxicity in vitro.
Authors: J Nedrud, M Touton, W R Clark
Journal: The Journal of Experimental Medicine (1975)

The requirement for cell division and expression of new genes was examined in the primary and secondary mouse mixed leukocyte culture (MLC). Hydroxyurea (HU) was used to block DNA synthesis and cell division, and 5-bromo-2'-deoxyuridine (BUdR) was used to probe for the expression of new cell-specific genes. In the primary MLC, inhibition of DNA synthesis and cell division by HU almost totally suppressed the generation of initial, target-specific cytotoxicity. When HU was washed out of the cultures, cytotoxicity was generated after a lag time approximately equal to the period of treatment with HU. The rate of development and maximal value of cytotoxicity in HU-reversed cultures was identical to untreated controls, suggesting that the inhibition was not due to a nonspecific lethal effect of the drug. Development of initial cytotoxicity in primary MLC was similarly suppressed by levels of BUdR 25 to 75-fold below the levels of this drug having nonspecific mutagenic effects in lymphocytes, indicating that development of cytotoxicity was also dependent on the expression of a new genetic program. In the secondary MLC, regeneration of both DNA synthesis and cytotoxicity was apparent 12-15 h after re-exposure to initial stimulating antigen. In this reaction, however, generation of cytotoxicity was insensitive to both HU and BUdR. Thus, the cytotoxic program developed in the primary MLC appears to be genetically stable through the production of effector memory cells, and into regeneration of fully cytotoxic memory cells in secondary MLC.