tbuckley/cabot-search huggingface dataset:
Effectiveness of rivastigmine in Alzheimer's disease
Authors: Roger Bullock, Peter Passmore, David Wilkinson, Robert Howard, Roy Jones
Journal: BMJ (2000)

Editor—The clinical relevance of new drugs in Alzheimer's disease has been much debated, and there is little dispute that we need improved trials in the disease.1 Enrolment into trials, however, should be governed by clinical uncertainty.2

Bentham et al criticise recently published studies of rivastigmine and advocate support for studies such as the AD2000 donepezil trial.3 We are concerned that some health authorities in the United Kingdom have stated that reimbursement for donepezil would be made only if patients were randomised into this trial. Presumably, following the lack of participation in the trial by many clinicians in the United Kingdom, the threat of non-reimbursement is an attempt to aid flagging recruitment.

Many clinicians have chosen not to be involved for good reasons. Part of the trial's complicated design seems to attempt to replicate the studies that formed the basis of regulatory approval. The manufacturers already have over 3000 patients with detailed controlled data over six months. The first three months of the trial, before rerandomisation, will not add to this assessment and may confuse rather than enlighten, especially given the use of only the lower, 5 mg dose. The Bristol activities of daily living scale may not have been the optimum choice of primary outcome measure4: we are not aware that it has been shown to be a reliable measure of change over time. Other instruments have been validated longitudinally and used in several hundred patients.

We believe that the Birmingham study is considerably underpowered. On the basis of the dependency scale, we calculate that 4000 patients treated for two years are needed to show with 90% power, and allowing for drop outs, a moderate difference of 20% in dependency for patients with mild to moderate Alzheimer's disease.5 Extending the indications for which donepezil is approved by including vascular dementia is not a problem, but lack of characterisation of the disease at entry to the trial, especially without computerised scanning, is. A negative result is likely and could jeopardise the interpretation of existing data on the beneficial effects of donepezil, and other cholinesterase inhibitors, in Alzheimer's disease. We also query why free drug will not be provided.

The success of large simple trials has been built on the principle of uncertainty by consenting clinicians, not enforcement. Perhaps the authors could address some of these concerns; collectively we could turn this into a valid and relevant study. At present, the situation represents a threat to clinical freedom for many of us who are advocates of large simple trials; we are concerned that undue heed will be taken of the outcome.
An Introduction to General Physiology, with Practical Exercises.
Authors: William Maddock Bayliss
Journal: JAMA (1920)

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Abstract MP53: The Impact of the Obesity Epidemic on Atherosclerotic Cardiovascular Disease Risk Scores: The CARDIA Study
Authors: Duke Appiah, Pamela J Schreiner, Raegan W Durant, Sharina D Person, Catarina I Kiefe, Cora E Lewis, Catherine Loria, Stephen Sidney, O. Dale Williams
Journal: Circulation (2015)

Introduction: Cardiovascular disease (CVD) mortality has decreased over recent decades, in part, due to changes in the prevalence of risk factors. However, few studies have explored the impact of the obesity epidemic on CVD risk prediction in young adults. Hypothesis: We assessed the hypothesis that BMI trends are positively associated with changes in 10-year AHA/ACC atherosclerotic cardiovascular disease (ASCVD) risk scores from young adulthood to middle age beyond the effect of other CVD risk factors included in the scores (age, sex, race, lipids, blood pressure, hypertension medication, diabetes, smoking). METHODS: Data were obtained from 2437 black and white men and women aged 18-30 years at baseline (1985-1986) enrolled in the Coronary Artery Risk Development in Young Adults (CARDIA) study with follow-up exams at year 0, 5, 10, 15, 20 and 25 (ages 43-55 years). Repeated-measures regression was used to model the association between ASCVD risk scores and time-varying BMI measures. RESULTS: The average 10-year ASCVD risk increased from 0.6% at baseline (mean age: 25.3) to 3.9% at year 25 (mean age: 50.3) with the change higher for men (blacks: 1.0 to 8.2%, whites: 0.3 to 4.6%) than women (blacks: 0.5 to 3.6%, whites: 1.2 to 1.4%). The overall prevalence of obesity at baseline and year 25 was 10% and 42% respectively. BMI trends were positively associated with 10-year change in ASCVD risk scores (0.12% per 1 kg/m2 increase, p&lt;0.001). BMI adjustment minimally reduced risk scores trends with the greatest change between unadjusted and adjusted risk scores observed among black women (0.1 to 3.0%) (Figures A and B). CONCLUSION: In young adults, BMI trends are associated positively with 10-year changes in ASCVD risk independent of other risk factors. This adds to the evidence that weight control in early adulthood is an important predictor of lower future CVD risk.
A compliment: Having your research ideas stolen
Authors: L. C Rodrigues
Journal: BMJ (1998)

It was my first research project after completing my PhD, and it required the collaboration of one large and 20 small centres. My professor and I had contacted the large centre, which will remain nameless. The director expressed interest in the study and invited us to visit and present our proposal. The potential local collaborators were eager for information: we discussed in great detail the hypothesis, the design, the sample size estimate, the questionnaires, the methods for data collection, the …
The New Face of Medical EducationON THE COVERMedicare Antifraud Initiatives: Effects on Resident EducationMedicare's Role in Financing Graduate Medical EducationAn Apology for Those Who Leave MedicineHistorical Perspective of Medical Residency Training: 50 Years of Changes
Authors: J D Robinson, S Gottlieb
Journal: JAMA (1999)

ALTHOUGH A MOMENT OF CALM HAS DESCENDED ON FEDERAL LEGISLAtive efforts to overhaul our national health care system, a quiet revolution is still at work. The driving force of that change will be US business interests. Under a system pioneered by health maintenance organizations, doctors are now asked to deliver adequate care, instead of care that maximizes the use of advanced medical resources. Residency education has been caught in the crosshairs of this new paradigm. Cost consciousness in medicine was barely on the horizon 30 years ago. Residents were trained to recognize and treat improbable and rare diseases. Today, the medical case that does not fit a neat algorithm quickly comes to the attention of a small battalion of case managers. It is not unheard of for discharge planning to begin even before the patient enters the hospital. Perhaps more than anything, the hurried pace of health care delivery has changed the resident’s appreciation of the course of illness. An increasing proportion of resident training now takes place in the outpatient setting. Diagnosis is quicker, and more time is spent with healthier patients. While these changes are not without benefit to patients, for medical trainees educational opportunities are lost by not being able to follow a particular illness until it is resolved. Today’s decisions are made farther from the bedside and according to algorithms established by statisticians. While this reduces idiosyncrasies in treatment, it also tends to shortcut the process of thinking through complex problems and all their alternative solutions. At the same time, as Lloyd Krieger points out in this issue of MSJAMA, the increased supervision of residents demanded by third-party payers and government regulators has reduced the responsibility and autonomy of trainees. Funding for residency training is itself constrained and, as Bobby Jindal discusses, this leaves medical educators with little wiggle room from which to escape the intentions of those who would place profits ahead of sound medical education. As in any struggle, these changes lack moral certainty and immediacy of effect. Subtle effects lie hidden and sometimes unfold in further doubts. In this issue, Ivan Oransky discusses concerns over the number of residents leaving medicine. Perhaps this is one early indicator that something is amiss. The final outcome of current changes in residency training will not arrive soon. It will be heralded by neither a new, sweeping legislative bill nor another corporate initiative to trim spending on health care services. The final analysis will be made in another time, when today’s medical trainees take the helm and exercise the knowledge, skills, and virtues that they are learning now.
Does the β <sub>2</sub> -Agonist Clenbuterol Help to Maintain Myocardial Potential to Recover During Mechanical Unloading?
Authors: Hiroshi Tsuneyoshi, Wnimunk Oriyanhan, Hideo Kanemitsu, Reiko Shiina, Takeshi Nishina, Satoshi Matsuoka, Tadashi Ikeda, Masashi Komeda
Journal: Circulation (2005)

Objective— Chronic mechanical unloading induces left ventricular (LV) atrophy, which may impair functional recovery during support with an LV-assist device. Clenbuterol, a β 2 -adrenergic receptor (AR) agonist, is known to induce myocardial hypertrophy and might prevent LV atrophy during LV unloading. Furthermore, β 2 -AR stimulation is reported to improve Ca 2+ handling and contribute to antiapoptosis. However, there is little information on the effects of clenbuterol during LV unloading. Methods and Results— We investigated LV atrophy and function after LV unloading produced by heterotopic heart transplantation in isogenic rats. After transplantation, rats were randomized to 1o f 2 groups (n=10 each). The clenbuterol group received 2 mg·kg −1 ·d −1 of the drug for 2 weeks; the control group received normal saline. The weight of unloaded control hearts was 48% less than that of host hearts after 2 weeks of unloading. Clenbuterol significantly increased the weight of the host hearts but did not prevent unloading-induced LV atrophy. Papillary muscles were isolated and stimulated, and there was no difference in developed tension between the 2 groups. However, the inotropic response to the β-AR agonist isoproterenol significantly improved in the clenbuterol group. The mRNA expression of myocardial sarco(endo)plasmic reticulum Ca 2+ -ATPase 2a (SERCA2a) and fetal gene shift (myosin heavy chain [MHC] mRNA isozyme) was also significantly improved by clenbuterol treatment. There was no difference in β 1 -AR mRNA expression between the 2 groups. In contrast, β 2 -AR mRNA was significantly decreased in the clenbuterol-treated, unloaded heart. This indicates that clenbuterol may downregulate β 2 -ARs. In the evaluation of apoptosis, mRNA expression of caspase-3, which is the central pathway for apoptosis, tended to be better in the clenbuterol group. Conclusions— During complete LV unloading, clenbuterol did not prevent myocardial atrophy but improved gene expression (SERCA2a, β-MHC) and β-adrenergic responsiveness and potentially prevented myocardial apoptosis. However, chronic administration of clenbuterol may be associated with downregulation of β 2 -ARs.
Abstract 5590: Molecular characterization of pancreatic tumors arising in the background of germline BRCA mutations
Authors: Susan Hsiao, Anne Koehne de Gonzalez, Mahesh M. Mansukhani, Robert L. Fine, Helen E. Remotti
Journal: Cancer Research (2014)

Abstract Background: BRCA1 and BRCA2 are tumor suppressor genes which play a role in the repair of DNA double stranded breaks and the maintenance of genomic stability. Inherited BRCA mutations increase the risk of development of pancreatic cancer. In sporadic tumors BRCA mutations occur late in pancreatic tumorigenesis. Few studies to date have examined molecular heterogeneity within pancreatic tumors with respect to founder and progressor mutations. This is the first study to examine heterogeneity of mutations in pancreatic carcinomas associated with germline BRCA mutations. Design: Cases of pancreatic tumors arising in four patients with previously confirmed germline BRCA1 or BRCA2 mutations were identified from our case files. Representative sections of formalin-fixed, paraffin embedded tissue from surgical resection specimens were reviewed and 3 sections of tumor from different geographic regions and 1 section of non-tumor tissue were selected for molecular analysis for each case. Samples were manually macrodissected and genomic DNA was isolated. Genomic DNA was used for target capture and amplification of 212 amplicons targeting mutational hotspots in 48 genes using the TruSeq Amplicon Cancer Panel. Next generation sequencing was performed on the MiSeq Benchtop Sequencer and analyzed with NextGENe software. Results: In all cases concordant results were observed in all three tumor samples, with no evidence of intratumoral heterogeneity for the genes tested. In one patient with a BRCA1 germline mutation, TP53 and SMAD4 mutations were identified. In two patients with germline BRCA2 mutations, two additional driver mutations were identified involving KRAS, TP53, or SMAD4. In one case with BRCA2 germline mutation, no additional mutations were identified. Conclusion: Pancreatic tumors arising in the background of germline BRCA mutations had between 1-3 driver mutations per tumor, which is consistent with the reported numbers of driver mutations in sporadically arising pancreatic tumors. No mutual exclusivity among the mutated genes was observed. Mutations observed include KRAS codon 12 mutation, TP53 mutation (within the DNA binding domain), and SMAD4 mutation. Taken together, these results suggest that pancreatic tumors occurring in BRCA patients show similar mutational profiles of key oncogenes and tumor suppressor genes as seen in sporadic tumors with little heterogeneity with respect to these driver mutations. Citation Format: Susan Hsiao, Anne Koehne de Gonzalez, Mahesh M. Mansukhani, Robert L. Fine, Helen E. Remotti. Molecular characterization of pancreatic tumors arising in the background of germline BRCA mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5590. doi:10.1158/1538-7445.AM2014-5590
Abstract 346: Passive Ventilation During Cardiopulmonary Resuscitation Inside the Emergency Department
Authors: Robyn McDannold, Tyler Bronnenkant, Christopher Crowe, Annemarie Silver, Frederick Geheb, Uli Herken, Daniel Spaite, Bentley Bobrow
Journal: Circulation (2014)

Background: Continuing high quality chest compressions (CC) without interruption for active positive pressure ventilation (PPV) early in CPR has been demonstrated to improve patient outcomes in out-of-hospital cardiac arrest (OHCA). During the first minutes of CPR, passive oxygenation may be sufficient for oxygenating vital tissues. However, less is known about the later minutes of CPR. To evaluate this issue, in OHCA patients after hospital arrival, we quantified ventilation volumes during CCs in the ED. Methods: CPR quality metrics were obtained on patients who had CPR inside the ED with the E-Series defibrillator/monitor (Zoll Medical). Detailed ventilation data were obtained using a Non-Invasive Cardiac Output (NICO) Monitor (Philips/Respironics) with a CO2/flow sensor placed at the endotracheal tube. NICO waveform and breath-by-breath data were captured to measure ventilation volume associated with CCs. Results: Data files on 21 cardiac arrest patients who presented to the ED were included. [Male: 17, median age: 59 (IQR 47, 72)]. A total of 29,935 compressions (CCs) were analyzed [median depth 2.1 in (IQR=1.9, 2.5), median rate 126 CC/min (IQR=122-129). The median passive tidal volume during CCs was 5.8 mL, (IQR 3.4, 11.0). The highest volume was 124 mL, however 81% of the measured tidal volumes were &lt;20 mL. Conclusion: This quantified analysis of ventilation volumes during chest compressions in the ED suggests that significant passive ventilation volumes may not occur later in CPR. Even in patients who were receiving effective compressions, passive tidal volumes were extremely low overall, suggesting that the value of compression only CPR may, in part, be due to the avoidance of the harmful effects of hyperventilation rather than any potential effect of passive ventilation.
UNIVERSITY COLLEGE HOSPITAL.
Authors: J.B. Mills, Samuel Cooper, Robt. Liston, R. Quain, Thomas Graham, AnthonyTodd Thomson, W. Sharpey, John Taylor, Erasmus Wilson, Thomas Morton, Richard Quain, John Hall Davis, Marshall Hall, N. Arnott, Henry Bennet, William Coulson, Frederick Hale Thomson, William Marsden, John Gay, ThomasB. Peacock, George Borlase Childs, Auguste Berard, Auguste Berard, Jobert De Lamballe
Journal: The Lancet (1848)
Malignant Mesothelioma
Authors: Karen Hamm Antman
Journal: New England Journal of Medicine (1980)

DURING the two decades since the association of asbestos and mesothelioma became established, substantial progress has been made in the under-standing of the biology of this previously rare neoplasm. The causative role of asbestos exposure has been extensively investigated, and populations at increased risk have been identified.1 Observation of the natural history of mesothelioma reveals that in contrast to patients with the other sarcomas, who generally die of hematogenously disseminated metastases, patients with mesothelioma succumb to complications of their primary lesions.2 With more appropriate treatment regimens designed specifically for mesotheliomas, series in single institutions have established that mesotheliomas respond to . . .
Abstract 308: Metropolitan Police First-Responder Defibrillation Significantly Increases Survival Rates
Authors: Mario Krammel, Markus Winnisch, Thomas Hamp, Elisabeth Lobmeyr, Harald Herkner, Wolfgang Schreiber, Dieter Winnisch, Andreas Zajicek, Raphael van Tulder, Philip Datler, Markus Keferboeck, Michael Poppe, Sebastian Zeiner, Patrick Sulzgruber, Fritz Sterz
Journal: Circulation (2014)

Background: Sudden cardiac arrest (SCA) is one of the most common causes of death in western, industrialized countries. The hospital discharge rate after Out-of-Hospital Cardiac Arrests (OHCA with cardiac etiology and first monitored rhythm shockable) was 2011 24.7% in Vienna (Austria). The overall bystander CPR rate was 42% and in only 4% of the cases an AED was used by laypeople. Therefore, we wanted to assess whether a police first responder program with immediately initiated resuscitation measures (chest compression and use of an AED within the first three minutes) may increase survival rates after SCA in the Austrian capital. Methods: The police forces in Vienna were provided with 112 AEDs (52 in police cars / 60 at police stations) and CPR plus AED training. Emergency dispatching was organized such as AED-equipped police (P-AED) and conventional emergency medical service (EMS) responders were simultaneously dispatched to patients with assumed cardiac arrest. One month survival states of cardiac arrest victims provided with P-AED were compared to patient outcomes when EMS was the sole responder. Results: From August 2013 to April 2014, a 50% hospital discharge rate was observed for victims with initial ventricular fibrillation (VF) in the P-AED group, compared to 26% for standard EMS treatment. However, the overall survival benefit was diluted by the fact - that 75% of the initial rhythms were non-shockable, reducing the absolute survival to 10%. There have been 701 OHCA in this time, but due to lack of information, only 654 were included in the study. Figure 1 shows the outcome in detail. Conclusion: Use of AEDs by police first responders significantly increases survival and hospital discharge in VF patients. There was no benefit for victims with non-shockable rhythms yet. Further campaigning will be necessary, to increase the number of police first responder commitments and to implement an Austria wide P-AED system.
Abstract MP76: The Impact of Low Consumption of Fruits and Vegetables on Mortality from Cardiovascular Diseases in 187 Countries
Authors: Shahab Khatibzadeh, Ashkan Afshin, Renata Micha, Peilin Shi, Mohammad Yawar Yakoob, Gitangali Maya Singh, Mayuree Rao, Saman Fahimi, Majid Ezzati, Dariush Mozaffarian
Journal: Circulation (2014)

Background: Consumption of fruits and of vegetables each influence CVD risk. Yet, the global CVD mortality attributable to low intakes of each, by country, age, and sex, are not established. Objectives: To quantify the burdens of CVD attributable to low fruit consumption and low vegetable consumption by age and sex in 187 countries in 2010. Methods: We characterized consumption of fruits and vegetables by age, sex, and country based on 204 national and subnational surveys from 109 countries representing 85.2% of the world’s adult population complemented by bayesian hierarchical imputation for missing data. Etiologic effects of fruit and vegetable intake on CHD and stroke were quantified based on meta-analyses of prospective observational studies, supported by effects on CVD risk factors in intervention studies. Cause-specific mortality rates were obtained from the 2010 Global Burden of Diseases Study. CHD and stroke mortality attributable to low intakes of fruits [&lt;300g/d] and vegetables (including legumes) [&lt;400g/d] were estimated using comparative risk assessment, by country, age, and sex. Results: In 2010, 2,814,850 CVD deaths [95%UI: 2,652,230-2,977,471] were attributable to low fruit intake [36% CHD, 17% ischemic stroke, 47% hemorrhagic and other nonischemic stroke] and 1,922,582 CVD deaths [1,839,270-2,005,894] were attributable to low vegetable intake [42% CHD, 21% ischemic stroke, 37% hemorrhagic other nonischemic stroke]. Burdens were similar by sex: 55% and 54% of these deaths, respectively, occurred in men. Nearly 1 in 2 CVD deaths attributable to fruits and 2 in 5 attributable to vegetables occurred prematurely, before age 70 y. Substantial heterogeneity was evident across nations (Figure). Conclusions: These results highlight the substantial burdens as well as disparities in CVD attributable to insufficient consumption of fruits and vegetables around the world, informing prevention strategies and priorities.
Kronik Myelositik Löseminin Blast Krizinde Tanısal İpucu Olarak Chilblain Benzeri Erüpsiyon
Authors: Hitoshi Yazawa, Kenji Saga, Fusayuki Omori, Kowichi Jimbow, Yutaka Sasagawa Sapporo, Japonya
Journal: Journal of the American Academy of Dermatology (2004)
Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury
Authors: Barbara S. Slusher, James J. Vornov, Ajit G. Thomas, Patricia D. Hurn, Izumi Harukuni, Anish Bhardwaj, Richard J. Traystman, Michael B. Robinson, Paul Britton, X.-C. May Lu, Frank C. Tortella, Krystyna M. Wozniak, Marc Yudkoff, Beth M. Potter, Paul F. Jackson
Journal: Nature Medicine (1999)