The Role of Tranexamic Acid in EMS & Preoperative Trauma Management.


You’re responding to a reported 25-year-old male with gunshot wounds. After your scene safety check, you make contact with a young adult male who admits to being in an altercation just minutes before your arrival. He is your only patient. He states he heard a gun fire twice and believes it was a 9mm caliber handgun.

You note that the patient is diaphoretic and pale while confirming an intact airway, assessing increased respirations, and palpating a rapid, thready radial pulse. When you expose the patient, you find a single gunshot wound in the mid-abdomen. You see no exit wound on your rapid head-to-toe scan, which is done while your colleagues ready the stretcher for a rapid “load and go” transport to the designated trauma center.

You’ve already ”pre-alerted” the trauma team before you ever left the scene, and your partner is one of the best emergency vehicle operators in the system, but factoring distance and traffic, you’re still 20 minutes out. The patient’s blood pressure is now 80/40 mmHg, heart rate remains at 134 beats per minute, respirations are 22 per minute and his mental status indicates he’s “hanging on the cliff.” You understand the benefits of permissive hypotension in hemorrhagic shock and are titrating IV fluids to keep the systolic pressure from getting too high, concerned about “blowing out the clots” that this seriously traumatized patient is hopefully forming on his own.

Despite expert assessment, timely decisions and care, and your desire to save his life, this patient may not survive, even to arrival at the trauma center. You continue to think of what else can be done to promote hemostasis. Direct pressure? On what? Pressure points? Where? Elevation? Of the abdomen? Suddenly, all the “basics” of bleeding control you learned seem useless—and they functionally are, for this patient.

What about a topical hemostatic dressing? Not for this patient; his brisk and ongoing bleeding is all internal. What about a hemostatic powder? The single gunshot wound is small and essentially already sealed. Besides, his vascular wounds are most likely deep and inaccessible without exploratory surgery. What about a tourniquet? You have read about a promising clamp type tourniquet for some lower truncal wounds, but this is not one of them. Clearly, your extremity tourniquets won’t work either. Frustration mounts as the patient’s blood pressure continues to drop.

If only there was something more we could do in the field for patients like this. There is. Read on.

A Difference-Maker
Difference-makers: We like to be them and we like to use them in our practice of EMS medicine. We clearly can make meaningful impact through “difference-makers” for airway obstructions (Heimlich maneuver, foreign body airway removal), cardiac arrest (timely defibrillation, high-quality CPR), ST-segment acute myocardial infarctions (early recognition by 12-lead ECG and pre-arrival activation of the cardiac cath lab team), and even extremity arterial bleeding from trauma (tourniquets—once eschewed as instruments of the devil and now being added on all emergency apparatus).

Is there a difference-maker for the kind of patient described in our scenario? One besides the current trauma life support care and rapid, safe transport? We believe there is, and it’s a chemical that has been around for decades: tranexamic acid, or TXA.

You don’t have to spend much time studying acute myocardial infarctions or strokes to become aware of medications that work to break down clots, known as fibrinolytics—fibrin being a substance that forms the matrix of a clot and lysis or lytic being to break apart. TXA works in the opposite direction. TXA is an “antifibrinolytic,” an anti-clot buster. Another way to think of how TXA works is to picture it as a medication given to help stabilize the clots patients are trying to form on their own as it works to inhibit natural clot breakdown.

It sounds promising, but can, and should, EMS administer TXA? Like most considerations in medicine, the answer depends on many variables. In this article, we present some background information on TXA and discuss recent studies that promote EMS use of TXA for certain patients in systems in which TXA treatment can continue in the hospital setting.

Old Drug, New Studies
TXA has existed for decades. It was historically used in cardiovascular surgery and has been in the medical literature for more than 40 years. We shouldn’t be surprised that we’re finding new applications for older care capabilities—your supply list likely includes intraosseous access equipment and tourniquets.

The Federal Drug Administration has long approved TXA to decrease bleeding in hemophilia and prolonged uterine bleeding.

When summarizing the prior surgical literature of TXA, we can contemplate how the trauma wounds we work to stabilize are similar to some extent to wounds created by surgery. With surgical wounds, we heal through a process of hemostasis as well. Any blood loss can challenge coagulation and stimulate clot breakdown (fibrinolysis). Not surprisingly, hyperfibrinolysis is associated with very poor survival.

In more than 50 studies of TXA in the setting of elective surgery, although there was not a significant change in overall survival, the need for resuscitative blood transfusion was reduced by approximately 33%. Those studies are a helpful foundation, but two recent studies help us far better evaluate the role for TXA in EMS.

The Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 (CRASH-2) study (published online at www.crash2.lshtm.ac.uk) is a landmark study for our consideration of TXA as an EMS difference-maker. This is a remarkably large study that enrolled more than 20,000 adult trauma patients at 274 hospitals in 40 countries (outside the US). Patients were identified as having significant bleeding, or at least at clinical risk for serious bleeding.

Significant bleeding was defined by tachycardia greater than 110 beats per minute, systolic blood pressure of less than 90 mmHg, or both. Patients were divided into the active treatment group and the placebo (no TXA) group within eight hours of injury. The active treatment group received TXA 1 g IV piggyback over 10 minutes, followed by a second dose of 1 g IV piggyback over eight hours.

CRASH-2 investigators evaluated patients for the following three outcomes:
1. Death in hospital within four weeks of injury (e.g., bleeding, vascular occlusion of myocardial infarct/stroke/
pulmonary embolism, multi-organ failure, head injury, etc.);
2. Vascular occlusive events; and
3. The need for blood transfusion or surgery.

All-cause mortality in CRASH-2 was 14.5% with TXA and 16.0% without TXA—a statistically significant reduction in mortality with TXA. In death due to bleeding, there was also a statistically significant reduction (a relative 15% reduction), with 4.9% mortality with TXA and 5.7% without TXA. TXA did not reduce the need for blood or surgery.

When all factors in this study are considered, the number of patients needed to treat (NNT) with TXA to save one life is 67 patients. We certainly do many things in medicine in which the NNT is far greater than 67. This is a promising study for TXA use, even started as early as in the field.

As discerning as you are, you’re likely thinking this all sounds great, but could an antifibrinolytic, TXA specifically, cause harm? Does it increase bad clotting, the kind in myocardial infarcts, strokes, deep venous thrombosis or pulmonary embolism? Theoretically, it could. However, in the CRASH-2 trial, there were no increases in any of these events when comparing the active treatment group and the placebo group.

The second major study that compels our discussion of TXA in EMS is the “Military Application of Tranexamic Acid in Trauma Emergency Resuscitation Study (MATTERs),” published in Archives of Surgery in 2012. This study was done by British physicians, treating casualties in military combat theater helicopters in southern Afghanistan. MATTERs investigators were aware of the CRASH-2 trial being simultaneously conducted, but they used a slightly different treatment protocol for TXA administration, with 1 g being given slow IV push and repeated in the same format if felt clinically indicated.

All patients in the study were identified by receiving a transfusion of at least one unit of packed red blood cells. A further subgroup comparison was conducted in patients requiring a massive transfusion, defined as at least 10 units of packed red blood cells and other blood products.

Nearly 900 patients were in the MATTERs study. This is an important point to consider in both CRASH-2 and MATTERs. Large numbers of study patients promote more reliable results when the research is done correctly. Both studies were carefully conducted.

In MATTERs, the three primary TXA effect study points were:
1. Total blood product use required;
2. Thromboembolic complications; and
3. Mortality at 24 hours, 48 hours and 30 days.

What we’re all most concerned with is meaningful survival in our patients, so let’s primarily discuss the mortality outcomes in MATTERs. Overall, mortality in the TXA group was lower than the placebo (no TXA) group, 17.4% as compared to 23.9%. These are not just impressive in raw numbers, but statistically significant as well. Particularly in the massive transfusion subgroup, the results with TXA were remarkable, with 14.4% mortality vs. 28.1% mortality without TXA, nearly a 50% reduction in mortality with TXA.

These results are statistically significant and the survival odds ratio (how much more likely to survive with TXA) was more than seven.

The NNT for MATTERs was seven patients. Very few things we do in medicine require such a low NNT. For comparison, to date, the NNT is six for post-cardiac arrest therapeutic hypothermia. When we consider how prevalent that is becoming in EMS, we should give serious thought to the role of TXA in the EMS drug box.

A Note of Caution
Before you talk with your medical director and trauma surgeons and order a batch of TXA, you should be aware of the thromboembolic complications seen in MATTERs and at least how some are interpreting those results.

Overall, there were statistically significant increases in deep venous thrombosis and pulmonary embolism (DVT/PE) with TXA, and here’s where statistics must be interpreted very carefully. The absolute number of patients affected was very small; thus, a statistical significance can be easily reached. One important factor to consider is that the patients treated with TXA in MATTERs actually had higher injury burdens and therefore had higher likelihood of DVT/PE in the first place.

The bottom line: Before TXA in instituted in your system, it is imperative that all involved EMS administrative and clinical leaders understand and discuss the evidence-based literature supporting TXA. Resources can be found at the end of this article.

A final interesting summary point of MATTERs is that the mortality benefit was not clearly seen until 48 hours, meaning that TXA is likely not just a clot-forming drug alone. There likely is some still-to-be-better-understood anti-inflammatory component of TXA as well. While these large trials are unlikely to be replicated, there still exists need for better clarifying the benefits of TXA in future investigations.

Considerations for Use in EMS
TXA is now a Class I recommendation in the U.S. military’s Tactical Combat Casualty Care guidelines. Few medical interventions warrant this strength of support, again speaking to how well CRASH-2 and MATTERs have been conducted and reported in peer-reviewed medical literature.

So where does an EMS leader go from here? The cost of TXA is not everything, but it must be considered. Current cost estimates of 1 g of TXA, typically supplied in a 10 mL ampule or vial, is between $45 and $55. Using the NNTs from MATTERs and CRASH-2, this would translate from $350 to $3,550 per life saved. The reality is likely not that isolated, but it gives a starting point for discussion in your EMS budget.

Another consideration: Clinically, TXA use in the field is a lot like prehospital therapeutic hypothermia—it doesn’t make sense for EMS to start a treatment that isn’t going to be continued in the hospital. You must ensure your trauma surgery community is on board and supportive of TXA. You may be surprised to find your hospital is already stocking TXA for use in its massive transfusion protocols. We found this to be true in both Oklahoma City and Tulsa.

Our discussions with our trauma surgeon leaders in both cities were surprisingly short. We anticipated a long review of the literature and having to assure our surgery community that our EMS clinicians were capable of identifying the right patients and administering TXA in the field. However, all our surgery partners were immediately supportive and congratulated us for keeping abreast of the surgery literature.

The Medical Control Board, which provides physician oversight to the EMS System for Metropolitan Oklahoma City and Tulsa, unanimously approved TXA for EMS use on Jan. 16, 2013, with implementation on April 1, 2013. We’ll watch these patients and their outcomes carefully and report back. For now, we encourage you to read the referenced studies (on TXA and other helpful hemostatic agents) and start similar discussions in your communities.

You already are the difference-maker in so many ways. Maybe TXA can help you do the same for certain patients that currently prove challenging and without a ready answer on the way to more definitive care.

Resources
1. Roberts I, Perel P, Prieto-Merino D, et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ. 2012;345:e5839.
2. Morrison JJ, Dubose JJ, Rasmussen TE, et al. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113–119.
3. Schwartz RB, Reynolds BZ, Shiver SA, et al. Comparison of two packable hemostatic Gauze dressings in a porcine hemorrhage model. Prehosp Emerg Care. 2011;15(4):477–482.
4. Littlejohn LF, Devlin JJ, Kircher SS, et al. Comparison of Celox-A, ChitoFlex, WoundStat, and combat gauze hemostatic agents versus standard gauze dressing in control of hemorrhage in a swine model of penetrating trauma. Acad Emerg Med. 2011;18(4):340–350.
5. Granville-Chapman J, Jacobs N, Midwinter MJ. Pre-hospital haemostatic dressings: a systematic review. Injury. 2011;42(5):447–459.
6. Shakur H, Roberts I, Bautista R, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet. 2010;376(9734):23–32.
7. Achneck HE, Sileshi B, Jamiolkowski RM, et al. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use. Ann Surg. 2010;251(2):217–228.
8. Cox ED, Schreiber MA, McManus J,  et al. New hemostatic agents in the combat setting. Transfusion. 2009;49Suppl5:248S–255S.
9. Kheirabadi BS, Scherer MR, Estep JS, et al. Determination of efficacy of new hemostatic dressings in a model of extremity arterial hemorrhage in swine. J Trauma. 2009;67(3):450–459; discussion 459–460.
10. Sohn VY, Eckert MJ, Martin MJ, et al. Efficacy of three topical hemostatic agents applied by medics in a lethal groin injury model. J Surg Res. 2009;154(2):258–261.
11. Mabry R, McManus JG. Prehospital advances in the management of severe penetrating trauma. J Spec Oper Med. 2009;9(2):93–101.
12. Kheirabadi BS, Edens JW, Terrazas IB, et al. Comparison of new hemostatic granules/powders with currently deployed hemostatic products in a lethal model of extremity arterial hemorrhage in swine. J Trauma. 2009;66(2):316–326; discussion 327–328.

A noble gas cage


When nuclear fuel gets recycled, the process releases radioactive krypton and xenon gases. Naturally occurring uranium in rock contaminates basements with the related gas radon. A new porous material called CC3 effectively traps these gases, and research appearing July 20 in Nature Materials shows how: by breathing enough to let the gases in but not out.

The CC3 material could be helpful in removing unwanted or hazardous radioactive elements from nuclear fuel or air in buildings and also in recycling useful elements from the nuclear fuel cycle. CC3 is much more selective in trapping these gases compared to other experimental materials. Also, CC3 will likely use less energy to recover elements than conventional treatments, according to the authors.

CC3

The team made up of scientists at the University of Liverpool in the U.K., the Department of Energy’s Pacific Northwest National Laboratory, Newcastle University in the U.K., and Aix-Marseille Universite in France performed simulations and laboratory experiments to determine how — and how well — CC3 might separate these gases from exhaust or waste.

“Xenon, krypton and radon are noble gases, which are chemically inert. That makes it difficult to find materials that can trap them,” said coauthor Praveen Thallapally of PNNL. “So we were happily surprised at how easily CC3 removed them from the gas stream.”

Noble gases are rare in the atmosphere but some such as radon come in radioactive forms and can contribute to cancer. Others such as xenon are useful industrial gases in commercial lighting, medical imaging and anesthesia.

The conventional way to remove xenon from the air or recover it from nuclear fuel involves cooling the air far below where water freezes. Such cryogenic separations are energy intensive and expensive. Researchers have been exploring materials called metal-organic frameworks, also known as MOFs, that could potentially trap xenon and krypton without having to use cryogenics. Although a leading MOF could remove xenon at very low concentrations and at ambient temperatures admirably, researchers wanted to find a material that performed better.

Thallapally’s collaborator Andrew Cooper at the University of Liverpool and others had been researching materials called porous organic cages, whose molecular structures are made up of repeating units that form 3-D cages. Cages built from a molecule called CC3 are the right size to hold about three atoms of xenon, krypton or radon.

To test whether CC3 might be useful here, the team simulated on a computer CC3 interacting with atoms of xenon and other noble gases. The molecular structure of CC3 naturally expands and contracts. The researchers found this breathing created a hole in the cage that grew to 4.5 angstroms wide and shrunk to 3.6 angstroms. One atom of xenon is 4.1 angstroms wide, suggesting it could fit within the window if the cage opens long enough. (Krypton and radon are 3.69 angstroms and 4.17 angstroms wide, respectively, and it takes 10 million angstroms to span a millimeter.)

The computer simulations revealed that CC3 opens its windows big enough for xenon about 7 percent of the time, but that is enough for xenon to hop in. In addition, xenon has a higher likelihood of hopping in than hopping out, essentially trapping the noble gas inside.

The team then tested how well CC3 could pull low concentrations of xenon and krypton out of air, a mix of gases that included oxygen, argon, carbon dioxide and nitrogen. With xenon at 400 parts per million and krypton at 40 parts per million, the researchers sent the mix through a sample of CC3 and measured how long it took for the gases to come out the other side.

Oxygen, nitrogen, argon and carbon dioxide — abundant components of air — traveled through the CC3 and continued to be measured for the experiment’s full 45 minute span. Xenon however stayed within the CC3 for 15 minutes, showing that CC3 could separate xenon from air.

In addition, CC3 trapped twice as much xenon as the leading MOF material. It also caught xenon 20 times more often than it caught krypton, a characteristic known as selectivity. The leading MOF only preferred xenon 7 times as much. These experiments indicated improved performance in two important characteristics of such a material, capacity and selectivity.

“We know that CC3 does this but we’re not sure why. Once we understand why CC3 traps the noble gases so easily, we can improve on it,” said Thallapally.

To explore whether MOFs and porous organic cages offer economic advantages, the researchers estimated the cost compared to cryogenic separations and determined they would likely be less expensive.

“Because these materials function well at ambient or close to ambient temperatures, the processes based on them are less energy intensive to use,” said PNNL’s Denis Strachan.

The material might also find use in pharmaceuticals. Most molecules come in right- and left-handed forms and often only one form works in people. In additional experiments, Cooper and colleagues in the U.K. tested CC3’s ability to distinguish and separate left- and right-handed versions of an alcohol. After separating left- and right-handed forms of CC3, the team showed in biochemical experiments that each form selectively trapped only one form of the alcohol.

Antioxidant Supplements Don’t Fight Cancer, Research Suggests


Chemicals found natural foods and man-made pills that may prevent certain types of cell damage — have been touted for their supposed anti-cancer properties, but some research suggests these substances may not lower cancer risk and, in some cases, may even increase it.

In a new paper, published July 10 in the New England Journal of Medicine, researchers analyzed previous studies on antioxidants and cancer, trying to determine why taking antioxidants hasn’t seemed to reduce people’s cancer risk. The authors of the paper did not conduct their own study, but rather they analyzed previous research on cancer and antioxidants. Experts who were not involved in the paper told Live Science that people should continue to consume natural sources of antioxidants, such as fruits and vegetables, but they said to be cautious about taking dietary supplements of antioxidants.

“We completely got ahead of ourselves” regarding the possible benefits of antioxidants in lowering cancer risk, said Dr. Pieter Cohen, an assistant professor of medicine at Cambridge Health Alliance in Somerville, Massachusetts, who was not involved in the new paper.

Early studies suggested that an increased intake of antioxidants could counteract the damaging effect of molecules called “reactive oxygen species” (ROS). This early research proposed that, because ROS can damage cells and lead to cancer, antioxidants could thwart this process. [9 Healthy Habits You Can Do in 1 Minute (Or Less)]

However, “although some early preclinical studies supported this concept [that antioxidants can help combat cancer], dietary antioxidants have consistently failed to reduce the incidence of carcinoma [cancerous tumors] in prospective human clinical trials,” the authors of the new paper wrote in the study. “Rather, some studies have even suggested a harmful effect of antioxidants in persons at risk for cancer.”

For instance, the researchers pointed to the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Trial, which was conducted by the U.S. National Cancer Institute and the National Public Health Institute of Finland between 1985 and 1993. In the study, researchers found that male smokers who took of 20-milligram supplements of beta-carotene (an antioxidant) daily for five to eight years had an 18 percent increased rate of lung cancer, and an 8 percent increased mortality rate, compared with male smokers who did not take the supplements.

The authors of the new paper also referred to a recent animal study, published this January in the journal Science Translational Medicine, in which researchers found that two antioxidants — vitamin E and N-acetylcysteine (NAC) — accelerated the progression of lung cancer in mice.

And another study (not cited by the authors of the new paper), published in 2005 in The Journal of the American Medical Association, showed that taking vitamin E, an antioxidant, did not help prevent cancer in patients with vascular disease or diabetes. Moreover, the patients who took the vitamin had a higher risk of heart failure over a seven-year period than the patients who took a placebo.

In the new paper, the researchers said that one of the possible reasons why antioxidants may not be effective in combating cancer is that in living human cells, antioxidants may not reach the sites in cells where ROS are produced, and therefore cannot stop the cellular damage, the researchers said.

“We think that antioxidants are not getting to the right site of the cell,” and therefore, they cannot stop the cellular damage, said study co-author Dr. David Tuveson, a professor at Cold Spring Harbor Laboratory.

Or, it could be that antioxidants do actually stop the damage caused by ROS, but for cancer cells, this only makes them stronger and stimulates their growth, Tuveson said.

Future studies should examine the exact pathways of antioxidants within cancer cells, to find more effective ways to prevent and treat cancer, the researchers said.

So does this mean that all antioxidants are useless or even harmful? No, said Dr. Dana Simpler, an internal medicine specialist at Mercy Medical Center in Baltimore, Maryland. Getting antioxidants from natural sources, such as fruits and vegetables, is still safe, Simpler said.

But caution is recommended when it comes to taking supplements, Cohen said.

In most large studies that found either no benefit of antioxidants or a harmful effect on people’s cancer risk, researchers were testing the effects of antioxidant supplements, and not natural foods with antioxidants, Cohen said.

“If you are not really careful how you intervene, then you could be doing more harm than good,” Cohen said, adding that it is important to first test the safety of any substances, including antioxidant supplements, in clinical trials, before people start consuming them.

“Every time antioxidant supplements have been tried in cancer, they actually make things worse,” Simpler said. “Healthful whole foods, however, are a different story.”

Another lesson to be learned from all this research is that antioxidants cannot be counted on to counteract the effects of behaviors that raise people’s risk of cancer, such as smoking, Dr. Eric Newman, a radiology resident at Jacobi Medical Center in New York, told Live Science.

“People should still eat healthy food,” but they need to be realistic about its benefits for health, and should not hope that consuming either natural food products or supplements will fix the damage that comes from unhealthy behaviors, he said.

 

Diagram of relationship of reduction of LDL and reduction in cardiovascular risk based on varioius lipid lowering trials – General Practice Notebook


  • A 1% decrease in LDL-C is associated with a 1% decrease in CHD risk (1)
    • this compares with the association that a 1% increase in HDL-C is associated with a 2-3% decrease in CHD risk

Relationship between LDL and event risk in trial data – there seems a linear reduction in risk with lowering LDL

Notes:

  • a meta-analysis concluded that statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about one fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics (2).

Reference:

  1. Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Programme (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol in Adults Adult Treatment Panel III). JAMA2001;285:2486-97.
  2. Baigent C et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005 Oct 8;366(9493):1267-78

45 YEARS AFTER APOLLO.


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The first humans who will step foot on Mars are walking the Earth today.

It was 45 years ago that Neil Armstrong took the small step onto the surface of the moon that changed the course of history. The years that followed saw a Space Age of scientific, technological and human research, on which we have built the modern era. We stand on a new horizon, poised to take the next giant leap—deeper into the solar system. The Apollo missions blazed a path for human exploration to the moon and today we are extending that path to near-Earth asteroids, Mars and beyond.

Technology drives exploration and we’re building on the Apollo program’s accomplishments to test and fly transformative, cutting-edge technologies today for tomorrow’s missions. As we develop and test the new tools of 21st century spaceflight on the human Path to Mars, we once again will change the course of history.

The Path to Mars begins with research on Earth and extends beyond its bounds, aboard the orbiting laboratory of the International Space Station, with our international partners. Some 250 miles above our heads, astronauts are conducting hundreds of experiments not possible on Earth, teaching us how humans can live, work and thrive for longer periods in space.

To help this nation send humans to deep space and return them to Earth safely, engineers across the country are developing a new space transportation capability, destined to travel far beyond our home planet. The Orion spacecraft and Space Launch System (SLS) heavy-lift rocket will be the most advanced space vehicles ever built. Together, they will take us farther into the solar system than humans have ever traveled. They are our spaceship to Mars and beyond.

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The neurochemistry of addiction.


We’ve all heard the term “addictive personality,” and many of us know individuals who are consistently more likely to take the extra drink or pill that puts them over the edge. But the specific balance of neurochemicals in the brain that spurs him or her to overdo it is still something of a mystery.

“There’s not really a lot we know about specific molecules that are linked to vulnerability to ,” said Tod Kippin, a neuroscientist at UC Santa Barbara who studies . In a general sense, it is understood that animals—humans included—take substances to derive that pleasurable rush of dopamine, the neurochemical linked with the reward centerof the brain. But, according to Kippin, that dopamine rush underlies virtually any type of reward animals seek, including the kinds of urges we need to have in order to survive or propagate, such as food, sex, or water. Therefore, therapies that deal with that reward system have not been particularly successful in treating addiction.

However, thanks to a collaboration between UCSB researchers Kippin; Tom Soh, professor of mechanical engineering and of materials; and Kevin Plaxco, professor of chemistry and biochemistry—and funding from a $1 million grant from the W. M. Keck Foundation—the neurochemistry of addiction could become a lot less mysterious and a lot more specific. Their study, “Continuous, Real-Time Measurement of Psychoactive Molecules in the Brain,” could, in time, lead to more effective therapies for those who are particularly inclined toward addictive behaviors.

“The main purpose is to try to identify individuals that would be vulnerable to based on their initial neurochemistry,” said Kippin. “The idea is that if we can identify phenotypes—observable characteristics—that are vulnerable to addiction and then understand how drugs change the neurochemistry related to that phenotype, we’ll be in a better position to develop therapeutics to help people with that addiction.”

To identify these addiction-prone neurochemical profiles, the researchers will rely on technology they recently developed, a biosensor that can track the concentration of specific molecules in vivo, in . One early incarnation of this device was called MEDIC (Microfluidic Electrochemical Detector for In vivo Concentrations). Through artificial DNA strands called aptamers, MEDIC could indicate the concentration of target molecules in the bloodstream.

“Specifically, the DNA molecules are modified so that when they bind their specific target molecule they begin to transfer electrons to an underlying electrode, producing an easily measurable current,” said Plaxco. Prior to the Keck award, the team had shown that this technology could be used to measure specific drugs continuously and in real time in blood drawn from a subject via a catheter. With Keck funding, “the team is hoping to make the leap to measurements performed directly in vivo. That is, directly in the brains of test subjects,” said Plaxco.

For this study, the technology would be modified for use in the brain tissue of awake, ambulatory animals, whose neurochemical profiles would be measured continuously and in real time. The subjects would then be allowed to self-dose with cocaine, while the levels of the drug in their brain are monitored. Also monitored are concomitant changes in the animal’s neurochemistry or drug-seeking (or other) behaviors.

“The key aspect of it is understanding the timing of the neurochemical release,” said Kippin. “What are the changes in neurochemistry that causes the animals to take the drug versus those that immediately follow consumption of the drug?”

Among techniques for achieving this goal, a single existing technology allows scientists to monitor more than one target molecule at a time (e.g., a drug, a metabolite, and a neurotransmitter). However, Kippin noted, it provides an average of one data pointabout every 20 minutes, which is far slower than the time course of drug-taking behaviors and much less than the sub-second timescale over which the brain responds to drugs. With the implantable biosensor the team has proposed, it would be possible not only to track how the concentration of neurochemicals shift in relation to addictive behavior in real time, but also to simultaneously monitor the concentrations of several different molecules.

“One of our hypotheses about what makes someone vulnerable to addiction is the metabolism of a drug to other active molecules so that they may end up with a more powerful, more rewarding pharmacological state than someone with a different metabolic profile,” Kippin said. “It’s not enough to understand the levels of the compound that is administered; we have to understand all the other compounds that are produced and how they’re working together.”

The implantable biosensor technology also has the potential to go beyond cocaine and shed light on addictions to other substances such as methamphetamines or alcohol. It also could explore behavioral impulses behind obesity, or investigate how memory works, which could lead to further understanding of diseases such as Alzheimers.

Nervous system may hold key to treating asthma attacks.


The wheezing, coughing, and gasping for breath that come with a sudden asthma attack aren’t just the fault of an overactive immune system. A particularly sensitive bundle of neurons stretching from the brain to the lungs might be to blame as well, researchers have found. Drugs that alter these neurons could provide a new way to treat some types of asthma.

“This is an exciting confirmation of an idea that’s been around for decades,” says Allison Fryer, a pulmonary pharmacology researcher at Oregon Health & Science University in Portland, who was not involved in the new study.

Breathe easy. Drugs targeting the neurons leading to the lungs and airways could ease asthma symptoms or prevent attacks.

An asthma attack can be brought on by a variety of triggers, including exercise, cold temperatures, pollen, and dust. During an attack, a person’s airways become inflamed, mucus clogs their lungs, and the muscles surrounding their airways tighten. Asthma is often considered a disease of the immune system because immune cells go into overdrive when they sense a trigger and cause inflammation. But a bundle of nerves that snakes through the neck and chest, the vagus nerve, has long been suspected to play a role; the cells it contains, after all, control the airway muscles. Studying which cell types and molecular pathways within the thick nerve bundle are involved, though, has been tough—the vagus contains a multitude of different cells that are physically intertwined.

Working together at the Howard Hughes Medical Institute’s Janelia Farm Research Campus in Ashburn, Virginia, neurobiologists Dimitri Tränkner, now at the University of Utah in Salt Lake City, and Charles Zuker of Columbia University turned to genetics to work out the players. They selectively shut off different sets of the neurons in mice based on which genes each neuron expressed, rather than their physical location. Then, through a series of injections, they gave the animals an egg white allergy that causes asthmalike symptoms.

After exposure to egg white protein, most mice suffered an immune reaction and a narrowing of their airways. But in rodents in which the researchers had genetically inactivated nerve cells expressing a receptor called transient receptor potential vanilloid 1 (TRPV1), egg white proteins failed to make the airways constrict, even when the immune system ramped up. And when the researchers next boosted the activity of the TRPV1-containing cells, symptoms of an asthma attack worsened in mice already prone to the attacks, they report online today in theProceedings of the National Academy of Sciences.

“These cells really tie everything together,” Tränkner says. The last piece of the puzzle, though, came when the group showed that the TRPV1-expressing nerve cells could be activated by a substance that’s known to be released by immune cells in the lungs of asthmatics, a molecule called sphingosine-1-phosphate. The observation suggests communication between the immune system and the neurons.

“If it were as simple as some people having different TRPV1 cells, researchers likely would have already found genetic mutations that cause asthma,” Tränkner says. “Our guess is that instead, the immune system can permanently change these neurons during some initial immune response.” As an allergy develops, he says, not only does the immune system become primed for an asthma attack, but immune molecules also likely interact with the neurons, altering their behavior and the receptors they express, and making them more likely to cause airway constriction.

“The technological approach used in this paper is really unprecedented in the field,” says neuroscientist Sven-Eric Jordt of Duke University School of Medicine in Durham, North Carolina. But more studies will be needed, he says, to show whether the same pathways are important in human asthma. The mouse egg white allergy isn’t a perfect model of the human disease, because mice don’t actually develop asthma, but instead show airway symptoms of an allergy.

If the findings hold true, Fryer says, they could lead to new classes of asthma drugs that not only treat symptoms, but also reverse the hypersensitivity that leads to attacks. Such drugs could target either the TRPV1 protein or the sphingosine-1-phosphate receptor, and they might work in patients who don’t respond to existing treatments, she says. “People have actually proposed both of those as drug targets before, but this really reinforces the rationale behind that idea.”

A Spotless Sun Baffles the Scientists.



“For the last few days, telescopes aimed at the sun have detected very few sunspots experiencing an unusual phenomenon dubbed a “Big Quiet”.

The event marks the absence of sunspots during what is supposed to be a heightened period of magnetic activity on our sun, which Swinburne University astrophysicist Dr Alan Duffy called a “very weird” development.

“Sunspots can change all the time, but when you should be seeing many dozens at any one point of time, it’s quite strange that we’re not seeing any at all,” Duffy told the Sydney Morning Herald. “We don’t have any idea why that is.”

Sunspots are temporary phenomena on the photosphere of the sun that appear visibly as dark spots, compared to surrounding regions.

They are the region of the sun where solar activity originates when material is ejected into space following solar flares, sudden flashes of brightness and coronal mass ejections (CMEs).

Sunspots appear darker to us as they are caused by highly concentrated magnetic fields that are slightly cooler than the surrounding surface of the sun. Solar flares and CMEs occur when built-up energy is released.

The spots are one gauge of a solar cycle, an approximately 11-year period of above average or below average magnetic activity. Currently, the sun is in a maximum period, so observations of sunspots and solar flares should be more common.

Yet an image taken by Nasa’s Solar Dynamics Observatory shows a distinct absence of sunspots, with just a small dot of brown just right of the centre where a small sunspot appears to be developing.

Speaking to the LA Times, physicist Tony Phillips, who writes about solar activity on his website Spaceweather.com, said it was not altogether that usual to have a Big Quiet event.

“It is weird, but it’s not super weird,” said Phillips. “To have a spotless day during solar maximum is odd, but then again, this solar maximum we are in has been very wimpy.”

Phillips explained that we were currently in the weakest solar maximum to have been observed in the space age, so a spotless sun was not all that uncommon.

“It all underlines that solar physicists really don’t know what the heck is happening on the sun,” Phillips said. “We just don’t know how to predict the sun, that is the take away message of this event.”

Comparative Outcomes of Catheter-Directed Thrombolysis Plus Anticoagulation vs Anticoagulation Alone to Treat Lower-Extremity Proximal Deep Vein Thrombosis.


Importance  The role of catheter-directed thrombolysis (CDT) in the treatment of acute proximal deep vein thrombosis (DVT) is controversial, and the nationwide safety outcomes are unknown.

Objectives  The primary objective was to compare in-hospital outcomes of CDT plus anticoagulation with those of anticoagulation alone. The secondary objective was to evaluate the temporal trends in the utilization and outcomes of CDT in the treatment of proximal DVT.

Design, Setting, and Participants  Observational study of patients with a principal discharge diagnosis of proximal or caval DVT from 2005 to 2010 in the Nationwide Inpatient Sample (NIS) database. We compared patients treated with CDT plus anticoagulation with the patients treated with anticoagulation alone. We used propensity scores to construct 2 matched groups of 3594 patients in each group for comparative outcomes analysis.

Main Outcomes and Measures  The primary study outcome was in-hospital mortality. The secondary outcomes included bleeding complications, length of stay, and hospital charges.

Results  Among a total of 90 618 patients hospitalized for DVT (national estimate of 449 200 hospitalizations), 3649 (4.1%) underwent CDT. The CDT utilization rates increased from 2.3% in 2005 to 5.9% in 2010. Based on the propensity-matched comparison, the in-hospital mortality was not significantly different between the CDT and the anticoagulation groups (1.2% vs 0.9%) (OR, 1.40 [95% CI, 0.88-2.25]) (P = .15). The rates of blood transfusion (11.1% vs 6.5%) (OR, 1.85 [95% CI, 1.57-2.20]) (P < .001), pulmonary embolism (17.9% vs 11.4%) (OR, 1.69 [95% CI, 1.49-1.94]) (P < .001), intracranial hemorrhage (0.9% vs 0.3%) (OR, 2.72 [95% CI, 1.40-5.30]) (P = .03), and vena cava filter placement (34.8% vs 15.6%) (OR, 2.89 [95% CI, 2.58-3.23]) (P < .001) were significantly higher in the CDT group. The CDT group had longer mean (SD) length of stay (7.2 [5.8] vs 5.0 [4.7] days) (OR, 2.27 [95% CI, 1.49-1.94]) (P < .001) and higher hospital charges ($85 094 [$69 121] vs $28 164 [$42 067]) (P < .001) compared with the anticoagulation group.

Conclusions and Relevance  In this study, we did not find any difference in the mortality between the CDT and the anticoagulation groups, but evidence of higher adverse events was noted in the CDT group. In the context of this observational data and continued improvements in technology, a randomized trial with outcomes such as mortality and postthrombotic syndrome is needed to definitively address this comparative effectiveness.

Uterine Pathology in Women Undergoing Minimally Invasive Hysterectomy Using Morcellation.


Even though minimally invasive surgery has improved outcomes for hysterectomy, the procedure requires removal of the uterus through small incisions. Morcellation, or fragmentation of the uterus into smaller pieces, is one method to remove the uterus. Recently, concern has been raised that morcellation may result in the spread of undetected malignancies.1

Despite the commercial availability of electric power morcellators for 2 decades, accurate estimates of the prevalence of malignancy at the time of electric power morcellation (herein referred to as morcellation) are lacking,1,2 with single-center studies reporting prevalences from 9 to 100 in 10 000.3,4 We used a large insurance database to investigate the prevalence of underlying cancer in women who underwent uterine morcellation.

The Perspective database was used to identify women who underwent a minimally invasive hysterectomy from 2006-2012. Perspective is an all-payer database including more than 500 hospitals capturing 15% of hospitalizations. Hospitals within this database are more frequently urban teaching centers and located in the southern United States. Data undergo a rigorous quality control process. Use of commercially available morcellators was captured by identification of charge codes.5 The analysis was deemed exempt by the Columbia University institutional review board.

The primary outcome was identification of uterine corpus cancer (all histologies) based onInternational Classification of Diseases, Ninth Revision, coding at surgery. We also examined the occurrence of uterine neoplasms of uncertain malignant potential; malignancies of other parts of the uterus, including cervical cancer, and surrounding adnexal structures (other gynecologic cancer); and endometrial hyperplasia.

Multivariable mixed-effects log-linear models, including clinical and demographic covariates and a random-intercept for the procedural hospital, were developed for uterine cancer and endometrial hyperplasia. The other outcomes were rare and the models did not converge.

All statistical analyses were 2-sided and performed with SAS version 9.4 (SAS Institute Inc). A Pvalue of <.05 was considered statistically significant.

Within the cohort of 232 882 women who underwent minimally invasive hysterectomy from 2006-2012, morcellation was performed in 36 470 (15.7%). Women who underwent morcellation differed in clinical and demographic characteristics from women who did not (eTable in the Supplement). Among those who underwent morcellation, 99 cases of uterine cancer were identified, a prevalence of 27/10 000 (95% CI, 22-32/10 000). Twenty-six cases of other gynecologic malignancies were found (a prevalence of 7/10 000 [95% CI, 4-10/10 000]), 39 uterine neoplasms of uncertain malignant potential (11/10 000 [95% CI, 7-14/10 000]), and 368 cases of endometrial hyperplasia (101/10 000 [95% CI, 91-111 per 10 000]).

Among women who underwent morcellation, advanced age was associated with underlying cancer and endometrial hyperplasia (Table). Compared with women younger than 40 years, the prevalence ratio for a uterine malignancy increased with increasing age from 4.97 (95% CI, 1.91-12.93) in women aged 50 to 54 years, to 19.37 (95% CI, 7.66-48.95) in those aged 55 to 59 years, to 21.36 (95% CI, 7.22-63.21) in those aged 60 to 64 years, and to 35.97 (95% CI, 14.14-91.53) for women aged 65 years or older.
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Table.  Multivariable Models Among Women Who Underwent Morcellation

Image not available.

Our data demonstrate that uterine cancers occurred in 27 per 10 000 women undergoing morcellation. Other malignancies and precancerous abnormalities were also detected. Although morcellators have been in use since 1993, few studies have described the prevalence of unexpected pathology at the time of hysterectomy.2– 4 Prevalence information is the first step in determining the risk of spreading cancer with morcellation. Although data are limited, women with apparent uterine-confined neoplasms at the time of morcellation have been found to have intraperitoneal tumor dissemination at the time of reexploration.3,6

We recognize a number of limitations including the inability to verify pathological findings, possible misclassification of pathology, potential undercapture of morcellation, and the fact that our findings may not be generalizable to all hospitals. Last, we lack data on long-term follow-up, and the outcome of women with pathological abnormalities who underwent morcellation requires further study. Patients considering morcellation should be adequately counseled about the prevalence of cancerous and precancerous conditions prior to undergoing the procedure.

REFERENCES
1
 Patient safety must be a priority in all aspects of care. Lancet Oncol. 2014;15(2):123.
PubMed   |  Link to Article
2
Kho  KA, Nezhat  CH.  Evaluating the risks of electric uterine morcellation. JAMA. 2014;311(9):905-906.
PubMed   |  Link to Article
3
Seidman  MA, Oduyebo  T, Muto  MG, Crum  CP, Nucci  MR, Quade  BJ.  Peritoneal dissemination complicating morcellation of uterine mesenchymal neoplasms. PLoS One. 2012;7(11):e50058.
PubMed   |  Link to Article
4
Hagemann  IS, Hagemann  AR, LiVolsi  VA, Montone  KT, Chu  CS.  Risk of occult malignancy in morcellated hysterectomy: a case series. Int J Gynecol Pathol. 2011;30(5):476-483.
PubMed   |  Link to Article
5
Wright  JD, Ananth  CV, Lewin  SN,  et al.  Robotically assisted vs laparoscopic hysterectomy among women with benign gynecologic disease. JAMA. 2013;309(7):689-698.
PubMed   |  Link to Article
6
Oduyebo  T, Rauh-Hain  AJ, Meserve  EE,  et al.  The value of re-exploration in patients with inadvertently morcellated uterine sarcoma. Gynecol Oncol. 2014;132(2):360-365.
PubMed   |  Link to Article
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