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http://www.eurekalert.org/pub_releases/2014-06/uops-pai061314.php

Penn anesthesiologists identify top 5 practices that could be avoided

Study supports 'choosing wisely' campaign to eliminate wasteful health care practices

PHILADELPHIA – A team of researchers led by Penn Medicine anesthesiologists have pinpointed the "top five" most common perioperative procedures that are supported by the least amount of clinical evidence, in an effort to direct providers to make more cost-effective treatment decisions. Their findings are published in the current issue of JAMA Internal Medicine.

The team surveyed anesthesiologists, many of them in academic practice, to identify the most common activities that should be questioned in the field, using practice parameters developed by the American Society of Anesthesiology (ASA) and other perioperative guidelines. Criteria for inclusion were common clinical practices that may be tied to poorer quality of care or increased costs, those for which there is little or no benefit to patients and that could easily be ceased in practice. Items were restricted to common preoperative and intraoperative practices, with the exclusion of postoperative and pain services.

The "Choosing Wisely" campaign is an ongoing effort by the American Board of Internal Medicine Foundation to help physicians become better stewards of health care resources. The Physician's Charter, a similar initiative, was issued in 2002 and outlined the physician's responsibilities to ensure access to high quality care by practicing evidence-based medicine, cost-effectively, and maintaining trust by minimizing conflicts of interest. This initiative was adopted by the ASA and more than 130 other organizations.

"The elimination of low-value services in low-risk patients represents a substantial savings, but we needed some consensus from our peers as to what the top least-valued services and procedures were," said the study's lead author, Onyi C. Onuoha, MD, MPH, assistant professor of Anesthesiology and Critical Care.

The researchers surveyed their peers on 18 items. First, practicing academic anesthesiologists affiliated with the Society of Academic Anesthesiology Associations responded, narrowing the list to 11 items. The list was then disseminated to the Association of University Anesthesiologists and to a subset of ASA members.

Respondents were overwhelmingly male, from academic practice settings, in practice for more than 20 years and working with the leadership of the ASA.

Survey respondents were asked to report their feedback on each clinical item across five domains, including frequency in practice, impact on quality of care, impact on cost of care, evidence supporting the activity, and the ease in implementation of avoidance.

The resulting top five activities the authors recommend questioning included:

Baseline laboratory studies in healthy patients without significant systemic disease when blood loss during surgery is expected to be minimal

Baseline cardiac testing or cardiac stress test in asymptomatic stable patients with known cardiac disease undergoing low-risk or moderate-risk noncardiac surgery

Routine use of PAC (pulmonary artery catheter) for cardiac surgery in patients with a low risk of blood pressure complications, especially if other diagnostic tools like an echocardiogram are being used during the procedure

Administration of blood in young healthy patients without ongoing blood loss and with a low-normal hemoglobin concentration, unless they show symptoms or blood pressure problems

Routine administration of specific types of intravenous fluids for replacement of blood or other fluids without appropriate indications.

These recommendations were then submitted to the Choosing Wisely campaign.

"We need buy-in from the other disciplines we work with, including the patient, primary care physician and surgeon, to implement many of these changes and still provide optimal preoperative and perioperative care. There is a lot of concern among those surveyed about attempting to implement these changes in isolation," says the study's senior author, Lee Fleisher, MD, chair of the Department of Anesthesiology and Critical Care. "Still, we believe that spreading awareness and encouraging physicians of varying disciplines to 'Choose Wisely' in delivering care is the first step in instituting change."

http://www.eurekalert.org/pub_releases/2014-06/waeh-gr061614.php

Gene 'switch' reverses cancer in common childhood leukaemia

Melbourne researchers have shown a type of leukaemia can be successfully 'reversed' by coaxing the cancer cells back into normal development.

The discovery was made using a model of B-progenitor acute lymphoblastic leukaemia (B-ALL), the most common cancer affecting children.

Researchers from the Walter and Eliza Hall Institute showed that switching off a gene called Pax5 could cause cancer in a model of B-ALL, while restoring its function could 'cure' the disease.

Institute researchers Dr Ross Dickins and Ms Grace Liu led the study with institute colleagues and collaborators in Vienna. The study was published today in the journal Genes & Development.

Ms Liu said the team used a newly developed 'genetic switch' technology to inhibit then reactivate Pax5 in the leukaemia model.

"Along with other genetic changes, deactivating Pax5 drives normal blood cells to turn into leukaemia cells, which has been shown before," Ms Liu said. "However we showed for the first time that reactivating Pax5 enabled the cells to resume their normal development and lose their cancer-like qualities, effectively curing the leukaemia. What was intriguing for us was that simply restoring Pax5 was enough to normalise these cancer cells, despite the other genetic changes."

In leukaemia, immature white blood cells replicate abnormally and build up in the bone marrow, interfering with production of normal blood cells.

Ms Liu said Pax5 was a gene frequently 'lost' in childhood B-ALL. "Pax5 is essential for normal development of a type of white blood cells called B cells," she said. "When Pax5 function is compromised, developing B cells can get trapped in an immature state and become cancerous. We have shown that restoring Pax5 function, even in cells that have already become cancerous, removes this 'block', and enables the cells to develop into normal white blood cells."

Dr Dickins said the research shed light on the function of Pax5, which was one of about 100 genes known to 'suppress' human tumours. "When these tumour suppressor genes are inactivated by changes to the DNA, cancers start to develop," Dr Dickins said.

"This work shows how inactivating the tumour suppressor gene Pax5 contributes to B-ALL development and how leukaemia cells become 'addicted' to low Pax5 levels to continue proliferating. Even though the B-ALL cells have multiple genetic mutations, simply reactivating Pax5 causes tumour cells to resume normal development and lose their cancerous properties."

Dr Dickins said forcing B-ALL cells to resume their normal development could provide a new strategy for treating leukaemia. "While B-ALL has a relatively good prognosis compared with other cancers, current treatments can last years and have major side-effects. By understanding how specific genetic changes drive B-ALL, it may be possible to develop more specific treatments that act faster with fewer side-effects."

However Dr Dickins said that genes that are lost in tumour cells are not traditionally drug targets. "It is very difficult to develop drugs that restore the function of genes that are lost during cancer development," Dr Dickins said. "However by understanding the mechanisms by which Pax5 loss causes leukaemia, we can begin to look at ways of developing drugs that could have the same effect as restoring Pax5 function."

The genetic switch technology used to study Pax5 could also be used to understand 'tumour suppressor' genes in other cancers, he said.

The work was supported by the Australian National Health and Medical Research Council, the Leukaemia Foundation of Australia, the Sylvia and Charles Viertel Charitable Foundation, VESKI and the Victorian Government. The Walter and Eliza Hall Institute is a partner in the Victorian Comprehensive Cancer Centre.

http://www.eurekalert.org/pub_releases/2014-06/uom-vad061614.php

Vitamin A derivative potentially treats type 2 diabetes and prevents its complications

Potential of retinoic acid demonstrated in treating obesity and type 2 diabetes and preventing their cardiovascular complications

At a time when obesity, type 2 diabetes, and their complications are a veritable epidemic worldwide, researchers at the University of Montreal and CHUM Research Centre (CRCHUM) recently demonstrated the potential of retinoic acid (RA), a derivative of Vitamin A, in treating obesity and type 2 diabetes and preventing their cardiovascular complications. The findings were presented June 6, 2014 at the Annual Conference of the Canadian Nutrition Society in Saint John's, Newfoundland.

"In obese and insulin resistant mice, retinoic acid reduces the risk of cardiac apoptosis, stimulates the expression of cardio-protective genes reduced by the disease, and protects against the accumulation of collagen in the cardiac muscle, thus avoiding the occurrence of fibrosis and possible associated future complications," says the first author of the study, Daniel-Constantin Manolescu. Apoptosis is the process of programmed cell death. The discovery follows other research conducted by his team on the effects of RA on insulin resistance, diabetes, and obesity. "Blood glucose, insulin resistance, body weight, and adipocyte size were significantly decreased in treated animals, including abdominal fat, while dietary intake and physical activity were similar for treated or non-treated animals. This suggests an increase in basal energy expenditure," says Manolescu.

White fat is an energy reserve formed by the accumulation of fat in the form of triglycerides to meet unexpected increases in energy costs, but it is also a hormonal tissue with a delicate balance. Overall, if energy intake is greater than expenditures over an extended period, obesity increases, while hormonal balance and energy metabolism are disturbed. In this context, resistance to type 2 diabetes develops over time.

Brown fat also stores triglycerides, but it has the ability to produce heat. Abundant in babies, brown fat does not disappear completely in adulthood. It is irrigated by blood vessels and has many mitochondria, the energy factories of cells. Vitamin A derivatives stimulate a mitochondrial uncoupling protein (UCP1) that allows uncoupling of the mitochondria pathway (oxidative phosphorylation ), which uses energy from the oxidation of nutrients for the production of adenosine triphosphate (ATP). For a period of time, they generate heat (thermogenesis) instead of ATP, which is traditionally the energy required for active metabolism. Exposure to cold leads to the stimulation of brown fat and white fat, promoting the conversion of triglycerides to free fatty acids and glycerol. However, in brown adipocytes, these fatty acids are rapidly oxidized in the mitochondria and produce heat (under the influence of the UCP1 protein). Brown fat thus helps to increase basal energy metabolism. As a result, hibernating mammals fatten in the fall without developing diabetes and lose weight without moving too much in the winter (while warming their den). They are also the animals that accumulate the most Vitamin A in their livers. Retinoic acid (a Vitamin A derivative) is recognized for its involvement in cell maturation and differentiation and may guide pre-adipocytes to become brown (or beige) instead of white. It is as if "boilers" were installed directly in reserves of white fat to melt it on the spot and prevent it from over-accumulating.

"Vitamine A is a bioactive nutrient. The originality of our project is in addressing obesity and type 2 diabetes through the involvement of retinoids. We have attracted international attention and were named among 12 teams in the world to bring conclusive data in this regard," says Dr. Pangala V. Bhat.

"Our studies on animals show that retinoic acid induces normalization of blood glucose and reduction of obesity. It is an important contribution to understanding RA action on the liver, fat, muscles, and the heart, and on retinoid metabolism, energy metabolism, fatty acid oxidation, and insulin resistance. Our research identifies new metabolic effects of retinoids and may lead to anti-obesity and anti-diabetic medicines," says Dr. Jean-Louis Chiasson.

1) "Natriuretic peptide and other cardio-protective genes are stimulated by Vitamin A (retinoid acid), preventing apoptosis and fibrosis in obese-diabetic mice heart" (Manolescu et al., 2014). Collaboration between the laboratoires of Dr. Jean-Louis Chiasson and Dr. Jolanta Gutkowska, CRCHUM.http://www.nrcresearchpress.com/doi/abs/10.1139/apnm-2014-0005

2) "All-trans retinoic acid lowers serum retinol-binding protein 4 concentrations and increases insulin sensitivity in diabetic mice" (Manolescu et al. 2010). http://www.ncbi.nlm.nih.gov/pubmed/20032483

http://www.eurekalert.org/pub_releases/2014-06/uoc--sfe061214.php

Survey finds e-cigarette online market on fire

First comprehensive survey of e-cigarettes underscores the complexity in regulating the rapidly growing market

Researchers at the University of California, San Diego School of Medicine have completed the first comprehensive survey of e-cigarettes for sale online and the results, they believe, underscore the complexity in regulating the rapidly growing market for the electronic nicotine delivery devices.

The survey, published in a June 16 special supplement of the journal Tobacco Control, found that 10 new e-cigarette brands entered the Internet marketplace every month, on average, from 2012 to 2014, and that there are currently 466 e-cigarette brands online, offering more than 7,700 flavors, including candy flavors such as gummy bear and marshmallow, that may appeal to children. In contrast, traditional cigarettes sold in the United States can be marketed in just two flavors: tobacco and menthol.

The scientists also documented a shift in the marketing of e-cigarettes, with newer brands selling customizable e-cigarettes that might look nothing like an old-fashioned tobacco cigarette. For example, some resemble pens, flashlights, even a violin.

The marketing messages also change with the products: Older brands were more likely to claim that e-cigarettes were healthier or cheaper than smoking, or that e-cigarettes could help people quit smoking. Newer brands are less inclined to making these claims. Instead, their marketing is focused on consumer choice, such as flavors or models.

"It almost seems that newer brands don't want to be compared to cigarettes, which are associated with the image of cancer" said lead author Shu-Hong Zhu, PhD, professor of Family and Preventive Medicine and director of the Center for Research and Interventions in Tobacco Control at UC San Diego.

Smoking-related diseases are the leading cause of preventable death worldwide, estimated to be responsible for 6 million deaths annually. Although smoking rates among American adults have declined by more than half, from 42 percent in 1965 to 18 percent in 2012, tobacco use in the United States is still responsible for nearly one in five deaths, according to the American Cancer Society. E-cigarettes vaporize nicotine, the addictive ingredient in tobacco products. They first became available in the U.S. in 2007 and have since stoked controversy about whether they improve or worsen public health by reducing tobacco cigarette consumption or provide an alternative way to consume nicotine.

"Some consider them promising products to help smokers quit traditional cigarettes, while others believe they will re-normalize smoking, which will keep more people smoking," Zhu said.

Although the authors support the Food and Drug Administration's proposed rules that e-cigarette companies be required to list ingredients and nicotine strengths, follow good manufacturing practices to ensure product safety, require child proof e-liquid containers and ban sale to minors, they caution that overly stringent regulations could have unintended consequences. Regulations would likely favor brands with strong financial backing and most of these would be owned by tobacco companies.

"Obviously, tobacco companies would be more concerned with protecting cigarette market share than smaller e-cigarette companies," Zhu said.

Too many regulations run the risk of changing only the market share of different e-cigarette brands rather than reducing the prevalence of smoking, he said. The most important goal in e-cigarette regulation should be to reduce the number of people smoking cigarettes. Cigarettes are the most deadly tobacco product, killing half its users.

Co-authors include Jessica Sun, Erika Bonnevie, Sharon Cummins, Anthony Gamst, Lu Yin and Madeleine Lee, UC San Diego Moores Cancer Center.

Funding for the study came from the National Cancer Institute under the State and Community Tobacco Control Initiative (grant UO1-CA154280).
http://www.eurekalert.org/pub_releases/2014-06/ifor-efl061614.php

E-cigarettes far less harmful than cigarettes, says researcher at INFORMS Conference

Rates alcohol most dangerous drug to public, heroin worst for individuals

A London School of Economics researcher examining the public and private dangers of drugs argues against demonizing e-cigarettes in a presentation being given at a conference of the Institute for Operations Research and the Management Sciences (INFORMS). He also calls on public officials to recognize that alcohol causes greater harm than other recreational drugs and more public attention should be paid to controlling its harmful effects.

Lawrence D. Phillips, an emeritus professor at the London School of Economics, will present his research group's findings about the relative risks of different drugs at Advances in Decision Analysis, a conference sponsored by the INFORMS Decision Analysis Society (DAS). The conference takes place June 16-18 at Georgetown University in Washington, DC.

A recent workshop facilitated by Prof. Phillips led a group of researchers to write a letter to the World Health Organization advocating against the classification of e-cigarettes as tobacco. They argued that e-cigarettes should be classified as a device for fighting nicotine addiction. . " It is well known that 'people smoke for the nicotine, but die from the smoke'," he says.

In his upcoming presentation, Prof. Philips draws on a study about drugs in the United Kingdom he co-authored in 2010 that was published in The Lancet. "Drug Harms in the UK: A Multi-Criteria Analysis" has lessons that can be applied in the U.S. and across the world, he says. The 2010 results are based on an expert panel that was called upon to use participants' judgment to assess the relative harm of 20 different drugs. Because the drugs are illegal and data is extremely difficult to obtain, the participants relied on their collective knowledge and experience to score the drugs and a decision analysis model to aggregate the judgments.

Similar results were obtained in 2013 among a group assessing drug risk in Europe. A .993 correlation between the two panels, which contained different sets of experts, is considered extremely high.

A 2013 expert panel about the relative harm of 12 nicotine products named cigarettes the most harmful but ranked e-cigarettes near the bottom, in ninth place. Prof. Phillips explores its results in his presentation at Georgetown University.

The various panels used decision analysis to determine psychological, physical and social harm to users and to those around them. Members of the United Kingdom's Independent Scientific Committee on Drugs scored 20 drugs on 16 criteria.

Decision analysis of the UK panel ratings showed that heroin, crack cocaine, and methamphetamine were the most harmful drugs to individuals (scoring 34, 37, and 32, respectively). Alcohol, heroin, and crack cocaine were the most harmful to others (46, 21, and 17).

Overall, alcohol was the most harmful drug (overall harm score 72), with heroin (55) and crack cocaine (54) in second and third places. Similar results were found when analyzing the continental Europe panel.

Several experts from the drug harm workshop, including The Lancet study's co-author David Nutt, the Edmund J Safra Professor of Neuropsychopharmacology and Head of the Department of Neuropsychopharmacology and Molecular Imaging at Imperial College London, have called on British and international health organizations like WHO to adjust their guidelines about dangerous drugs based on the findings.

In the 2010 paper, they write, "the present drug classification systems have little relation to the evidence of harm. They also accord with the conclusions of previous expert reports that aggressively targeting alcohol harms is a valid and necessary public health strategy."

Prof. Phillips notes the important role of judgment in quantitative models, particularly when there is limited data available, as was the case for these panels. The 20 drugs rated in the studies were alcohol, amphetamines, anabolic steroids, benzodiazepines, buprenorphine, butane, cannabis, cocaine, crack, Ecstasy, GHB, heroin, ketamine, khat, LST, mephedrone, methadone, methamphetamine, mushrooms, and tobacco.

The combined research shows the important role for judgment in quantitative models, particularly when there is very little data available, as in research about illegal drugs. The decision science techniques provided new tools to reevaluate common perceptions and laws governing hazardous drugs.



This research was made public in conjunction with the INFORMS Decision Analysis Society (DAS).Formed in 1980 with a thousand current members, DAS promotes the development and use of logical methods for improving decision-making in public and private enterprise. For more information, visit http://www.informs.org/Community/DAS.

http://www.eurekalert.org/pub_releases/2014-06/uoc--hob061114.php

How our brains store recent memories, cell by single cell

Findings may shed light on how to treat neurological conditions like Alzheimer's and epilepsy

Confirming what neurocomputational theorists have long suspected, researchers at the Dignity Health Barrow Neurological Institute in Phoenix, Ariz. and University of California, San Diego School of Medicine report that the human brain locks down episodic memories in the hippocampus, committing each recollection to a distinct, distributed fraction of individual cells.



This is a human neuron showing actin formation in response to stimulation. Michael A. Colicos, UC San Diego

The findings, published in the June 16 Early Edition of PNAS, further illuminate the neural basis of human memory and may, ultimately, shed light on new treatments for diseases and conditions that adversely affect it, such as Alzheimer's disease and epilepsy.

"To really understand how the brain represents memory, we must understand how memory is represented by the fundamental computational units of the brain – single neurons – and their networks," said Peter N. Steinmetz, MD, PhD, program director of neuroengineering at Barrow and senior author of the study. "Knowing the mechanism of memory storage and retrieval is a critical step in understanding how to better treat the dementing illnesses affecting our growing elderly population."

Steinmetz, with first author John T. Wixted, PhD, Distinguished Professor of Psychology, Larry R. Squire, PhD, professor in the departments of neurosciences, psychiatry and psychology, both at UC San Diego, and colleagues, assessed nine patients with epilepsy whose brains had been implanted with electrodes to monitor seizures. The monitoring recorded activity at the level of single neurons.

The patients memorized a list of words on a computer screen, then viewed a second, longer list that contained those words and others. They were asked to identify words they had seen earlier, and to indicate how well they remembered them. The observed difference in the cell-firing activity between words seen on the first list and those not on the list clearly indicated that cells in the hippocampus were representing the patients' memories of the words.

The researchers found that recently viewed words were stored in a distributed fashion throughout the hippocampus, with a small fraction of cells, about 2 percent, responding to any one word and a small fraction of words, about 3 percent, producing a strong change in firing in these cells.

"Intuitively, one might expect to find that any neuron that responds to one item from the list would also respond to the other items from the list, but our results did not look anything like that. The amazing thing about these counterintuitive findings is that they could not be more in line with what influential neurocomputational theorists long ago predicted must be true," said Wixted.

Although only a small fraction of cells coded recent memory for any one word, the scientists said the absolute number of cells coding memory for each word was large nonetheless – on the order of hundreds of thousands at least. Thus, the loss of any one cell, they noted, would have a negligible impact on a person's ability to remember specific words recently seen.

Ultimately, the scientists said their goal is to fully understand how the human brain forms and represents memories of places and things in everyday life, which cells are involved and how those cells are affected by illness and disease. The researchers will next attempt to determine whether similar coding is involved in memories of pictures of people and landmarks and how hippocampal cells representing memory are impacted in patients with more severe forms of epilepsy.

Co-authors include Yoonhee Jang, University of Montana; Megan H. Papesh, Louisiana State University; Stephen D. Goldinger, Arizona State University; Joel Kuhn, UCSD; Kris A. Smith and David M. Treiman, Barrow Neurological Institute.

Funding for this research came, in part, from the Medical Research Service of the Department of Veterans Affairs, the National Institute of Mental Health (grant 24600), the National Institute for Deafness and Other Communications Disorders (grant 1R21DC009781), the Barrow Neurological Foundation, the Arizona Biomedical Research Council and the UC San Diego Kavli Institute for Brain and Mind.

http://www.eurekalert.org/pub_releases/2014-06/gsoa-doe061614.php

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