Day: 03/26/2011

Complementary and Alternative Medicine and Multiple Sclerosis

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Complementary and alternative medicine (CAM) is used by one-half to three-fourths of multiple sclerosis (MS) patients. Although it is used widely, CAM may not be discussed during a conventional medical visit. In MS, CAM therapies exhibit a broad range of risk-benefit profiles; some of these therapies are low risk and possibly beneficial, whereas others are ineffective, dangerous, or unstudied. Health professionals who provide objective and practical information about the risks and benefits of CAM therapies may improve the quality of care for those with MS.

source: science direct

Clinical Value of Decompressive Craniectomy

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Patients with a variety of intracranial disorders — including traumatic brain injury, stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and brain tumors — often present with a progressive increase in intracranial pressure, leading to clinical deterioration and ultimately to death. Medical therapy1 can help to mitigate such increases in pressure, but despite the use of the best available measures, intracranial hypertension becomes life-threatening in some patients. More than a century ago, it was suggested that it might be beneficial to “decompress the brain by widely opening the skull to decrease the pressure”2 in patients with severe traumatic brain injury. This procedure, called decompressive craniectomy, has been shown to decrease intracranial pressure, but since there is no evidence of an association with a better clinical outcome, the procedure is considered optional.3

In the past 15 years, the use of decompressive craniectomy has increased substantially. There has also been a tremendous increase in the number of articles that have been published on the subject, mainly retrospective reviews of a limited number of cases. A PubMed search identified 143 articles that were published on this topic for a variety of intracranial disorders in 2009 and 2010.

The list of publications is much shorter, however, when only randomized, controlled trials are considered. In the field of traumatic brain injury, the results of only one small, prospective, randomized trial have been published.4 This trial involving 27 children showed promising results in favor of decompressive craniectomy. However, the surgical procedure that was used (bitemporal decompression without opening of the dura) is not the standard approach.

In this issue of the Journal, Cooper et al. report the results of the Decompressive Craniectomy (DECRA) trial,5 which investigated the role of early decompressive craniectomy in adults with severe head injury (Glasgow Coma Scale score of 3 to 8). Patients with refractory intracranial hypertension (defined as an intracranial pressure higher than 20 mm Hg for more than 15 minutes despite medical therapy) were randomly assigned either to receive standard care or to undergo standard care plus bifrontotemporoparietal decompression craniectomy. The study showed a significant decrease in intracranial pressure in patients in the surgical group, as was expected. However, clinical outcomes, as assessed by scores on the Extended Glasgow Outcome Scale, were worse in the surgical group than in the standard-care group, a finding that went against expectations.

There are a couple of important concerns regarding this otherwise valuable study. First, most neurosurgeons and intensivists dealing with traumatic brain injury will not consider decompressive craniectomy in patients who have an intracranial pressure of around 20 mm Hg for such a short time. This aggressive approach may be justified in order to decompress the brain as soon as possible, but in patients with diffuse injury without mass lesions, physicians in many centers would use medical therapy for a longer period, leaving decompressive craniectomy as a last resort.

Second, the screening of 3478 patients over a 7-year period to enroll only 155 study patients indicates that the results of this study are limited to a restricted subpopulation of patients with traumatic brain injury. Most of the patients who were excluded from this trial either had mass lesions (for which a different surgical approach might be appropriate) or had successful control of intracranial hypertension with medical management (thus not requiring surgical intervention at all).

An important question arising from the DECRA study is whether it is now appropriate to continue an ongoing trial of craniectomy, called the Randomized Evaluation of Surgery with Craniectomy for Uncontrollable Elevation of Intracranial Pressure (RESCUEicp; Current Controlled Trials number, ISRCTN66202560).6 As of March 16, 2011, a total of 294 patients had been enrolled in this trial, with an enrollment goal of 400 patients. However, the design of RESCUEicp differs from that of the DECRA study in some important ways. In RESCUEicp, patients are randomly assigned either to undergo craniectomy or to receive standard care (including the use of barbiturates) when maximal medical therapy cannot control intracranial pressure, with a threshold of 25 mm Hg (rather than 20 mm Hg) for more than 1 to 12 hours (rather than 15 minutes) at any time after injury. In addition, in RESCUEicp, as compared with the DECRA study, previous evacuation of a hematoma is allowed before randomization, and the permitted surgical techniques include both bifrontal decompression and unilateral wide decompression. The primary end point is the assessment of outcome at discharge and at 6 months. Thus, because of such differences in trial design, it seems that RESCUEicp should continue.

Another important question is, How do the DECRA and RESCUEicp studies relate to the real practice of decompression in patients with traumatic brain injury? As noted above, the exclusion criteria for the DECRA study were such that the data do not apply to the majority of patients. In a multicenter study involving 729 patients with intradural mass lesions after traumatic injury,7 we found that about one third of patients undergoing surgery for an intracranial hematoma also required a decompressive procedure. In most of these cases, the decompression was unilateral and associated with hematoma evacuation. Such patients are not considered at all in the DECRA study and are only partially included in the RESCUEicp study. We therefore probably need another study of early decompression associated with hematoma evacuation, as has been suggested previously,8 since this procedure is a common one.

The main lesson from the DECRA study is that surgical reduction of intracranial pressure by the technique that was used by the investigators does not necessarily result in better outcomes for patients and indeed appears to worsen them in at least some circumstances. However, it is important that the procedure not be simply abandoned on the basis of these data. Rather, we must think more carefully about the risks and benefits of the decompressive craniectomy before performing the procedure and must work to define appropriate clinical settings for this procedure.

source: NEJM

Mutations block lung-cancer treatment

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Revealing the genetic changes that let tumours escape drugs offers hope for combination therapies.


Lung cancers can resist drugs from the outset, or develop resistance over time.

Tumours have many ways to dodge drug therapies, even those that are genetically targeted to attack them, two studies published today reveal. By uncovering these escape routes, researchers hope that therapies can be tailored to cut them off.

Both studies focus on lung cancers with genetic mutations that activate a protein called epidermal growth factor receptor (EGFR). Improper activation of this protein can lead to uncontrolled cell division, a hallmark of cancer. Two drugs — gefitinib (Iressa) and erlotinib (Tarceva) — block EGFR in tumours with activating mutations to prevent tumour growth.

These drugs help most patients: about three quarters of those with EGFR-activating mutations respond well to gefitinib, for example. But the rest respond poorly, if at all, and no one knows why.

“There is tremendous variation in response in patients with what look to be the same lesions,” says Charles Sawyers, a cancer researcher at the Memorial Sloan-Kettering Cancer Center in New York and lead author of one of the studies.

Resisting arrest

One cause of this variation, Sawyers reasoned, could be that other genes modify a patient’s response to the drugs. To test this, he and his colleagues ran experiments on a line of cultured cancer cells with EGFR-activating mutations that respond poorly to EGFR inhibitors.

The researchers used RNA interference to reduce the activity of cancer-related genes, and then tested the cells to determine whether this made them more sensitive to drug treatment. The findings are published in Nature1.

Of more than 2,000 genes screened by the team, 36 affected sensitivity to EGFR inhibitors. Half of those are linked to cellular signalling pathways involving a single protein called NF-κB, which governs many stress responses, and has been targeted by some pharmaceutical companies looking to develop anti-inflammatory drugs.

Sawyers’s results suggest that NF-κB inhibitors, used in combination with EGFR blockers, could fight recalcitrant tumours. The team found clinical evidence to back this up: in a trial of 52 people with lung cancer, those with high levels of a protein that inhibits NF-κB responded better to erlotinib than those with low levels.

The team is now testing the combination therapy in animal models.

The results are exciting and could lead to new cancer therapies, says William Pao, a cancer researcher at Vanderbilt University in Nashville, Tennessee.

The method could also be used to find genes that modify drug responses in other tumours, he says. For example, drugs called B-RAF inhibitors have shown promise in patients with advanced melanoma who carry a mutation that activates the protein B-RAF. But once again, the drug fails about 20% of these patients. Combination therapy could help that 20%.

Workarounds

Cancer therapies have another problem: even if a patient responds well at first, the drugs eventually fail. “The tumour melts away, and then it comes back,” says Daniel Haber, director of the Massachusetts General Hospital Cancer Center in Charlestown.

The effects of EGFR inhibitors typically last a year before the tumours, now drug-resistant, return. Combination therapies could also help in this case, but it is first necessary to characterize the many ways that a tumour can shield itself from the drugs.

In the second study, Jeffrey Engelman, a cancer researcher at the Massachusetts General Hospital, and his team characterized resistant tumours in 37 patients.

Many had additional EGFR-related mutations, which allowed the protein to dodge inhibitors. Others had extra copies of the MET gene, which spurs cancer growth. Both of these mutations had already been identified in drug-resistant tumours.

But some tumours behaved unexpectedly, by amplifying the gene for EGFR or picking up mutations in another cancer-promoting gene, called PIK3CA. The results are published in Science Translational Medicine2.

Five tumours had transformed from non-small-cell lung cancer to small-cell lung cancer, which is responsive to different kinds of chemotherapy. And in three patients, repeated biopsies showed that, over time, drug-resistant cells had once again become vulnerable to the inhibitors.

On target

The results highlight the importance of monitoring tumours throughout treatment, says Paul Workman, a molecular pharmacologist at the Institute of Cancer Research in Sutton, UK. Traditionally, cancer treatment is based on the results of a single biopsy during initial diagnosis. Sampling tumours is invasive, and repeated biopsies can be difficult to justify — particularly in lung cancer, when each biopsy carries a small risk of lung collapse, says Haber.

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But Engelman points out that serial biopsies paid off for some patients. Those who developed small-cell lung cancer could receive chemotherapy that would not have been tried in a non-small-cell lung cancer. Some of those patients, he notes, had “remarkable” responses to the treatment.

Nevertheless, finding so many paths to drug resistance means that patients will need an arsenal of possible drug combinations to conquer the disease. “It is humbling to see the many resistance mechanisms that can occur,” says Engelman. “It underscores the challenges ahead.”

source: nature

The Endocannabinoid 2-Arachidonoyl-Glycerol Activates Human Neutrophils: Critical Role of Its Hydrolysis and De Novo Leukotriene B4 Biosynthesis

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Although endocannabinoids are important players in nociception and obesity, their roles as immunomodulators remain elusive. The main endocannabinoids described to date, namely 2-arachidonoyl-glycerol (2-AG) and arachidonyl-ethanolamide (AEA), induce an intriguing profile of pro- and anti-inflammatory effects. This could relate to cell-specific cannabinoid receptor expression and/or the action of endocannabinoid-derived metabolites. Importantly, 2-AG and AEA comprise a molecule of arachidonic acid (AA) in their structure and are hydrolyzed rapidly. We postulated the following: 1) the released AA from endocannabinoid hydrolysis would be metabolized into eicosanoids; and 2) these eicosanoids would mediate some of the effects of endocannabinoids. To confirm these hypotheses, experiments were performed in which freshly isolated human neutrophils were treated with endocannabinoids. Unlike AEA, 2-AG stimulated myeloperoxidase release, kinase activation, and calcium mobilization by neutrophils. Although 2-AG did not induce the migration of neutrophils, it induced the release of a migrating activity for neutrophils. 2-AG also rapidly (1 min) induced a robust biosynthesis of leukotrienes, similar to that observed with AA. The effects of 2-AG were not mimicked nor prevented by cannabinoid receptor agonists or antagonists, respectively. Finally, the blockade of either 2-AG hydrolysis, leukotriene (LT) B4 biosynthesis, or LTB4 receptor 1 activation prevented all the effects of 2-AG on neutrophil functions. In conclusion, we demonstrated that 2-AG potently activates human neutrophils. This is the consequence of 2-AG hydrolysis, de novo LTB4 biosynthesis, and an autocrine activation loop involving LTB4 receptor.

source: american journal of immunology

Female hormone could be key to male contraceptive

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Progesterone-sensing molecule that guides sperm to egg offers fertility solution.


sperm and egg
Sperm are given and extra boost towards the egg by the hormone progesterone.René Pascal/Center of Advanced European Study and Research, Bonn

A sperm’s path to an egg is more a deadly obstacle course than a track sprint. The one ejaculated sperm cell in a million that is lucky enough to reach the fallopian tubes, where eggs await fertilization, must conquer thick, gelatinous layers of mucus and cells surrounding the egg to reach its prize.

Fortunately for the sperm, there is help. Two studies published today in Nature1,2 show how sperm sense progesterone, a female sex hormone, that has been released by cells surrounding the egg. The hormone may guide the sperm towards the egg as well as giving it a final push to get there, the research suggests. The findings could be used to design a new class of contraceptive drug.

“It really is a significant step forward in terms of how we understand what regulates sperm,” says Steven Publicover, a reproductive biologist at the University of Birmingham, UK, who was not involved in either study.

In some previous experiments, ejaculated human sperm have been shown to swim towards areas with high levels of progesterone. The hormone also causes the cells to beat their whip-like tails more powerfully to make it through to the egg, a condition called hyperactivity. “We’ve got good reason to think that the response to progesterone matters, but it’s bloody difficult to pin it down,” says Publicover.

Changing channel

The latest studies, led by independent teams in Germany and the United States who agreed to publish their findings simultaneously, show that progesterone activates a molecular channel called CatSper, which floods sperm cells with calcium.

Mice without the channel are infertile, as are some men with mutations in the genes that make it, says Polina Lishko, a reproductive biologist at the University of California, San Francisco, who led one of the studies2. Sperm that don’t make CatSper cannot become hyperactive.

Lishko and Kirichok’s team developed a way of measuring the electrical currents within sperm that are created by ions like calcium, similar to how neuroscientists record the electrical activity of neurons. They found that adding progesterone to ejaculated human sperm boosts the current, and that treating sperm with drugs that block CatSper reduces it. Putting the cells into high-pH environments, like those found around the egg, also activated CatSper. A combination of high pH and high progesterone had an even stronger effect.

A second team, led by Benjamin Kaupp, a biophysicist at the Center of Advanced European Studies and Research in Bonn, Germany, came to the same conclusion in their own experiments1. They also measured calcium levels within human sperm, and found that the effects of administering progesterone are almost instantaneous. Kaupp says that this quick action leaves little time for traditional molecular-signalling pathways to act, and suggests that CatSper itself detects the sex hormone and causes calcium levels to rise.

Problems with progesterone sensing could explain some cases of infertility, says Kaupp. “It could be that some eggs do not produce enough progesterone, or that some sperm are not as sensitive to progesterone as others.”

Yet there would be little demand for infertility drugs that activate CatSper, says Kaupp, because infertility is already well-addressed by in vitro fertilization. More promising, say researchers, are drugs that stymie conception by hindering the channel’s ability to sense progesterone — or to work at all.

“The consequence for humans is that if you could block CatSper it would be an ideal contraceptive,” says David Clapham, a biochemist at Children’s Hospital Boston in Massachusetts, whose team discovered the channel and are looking for drugs that inhibit it. Sperm are the only cells known to make CatSper, so such a drug is unlikely to have many side effects. It would also, presumably, work regardless of whether it is men or women who take it because it could act on sperm regardless of their location, adds Lishko.

source: nature news

Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks

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Life diversity can now be clearly explored with the next-generation DNA sequencing technology, allowing the discovery of genetic variants among individuals, patients and tumors. However, beyond causal mutations catalog completion, systems medicine is essential to link genotype to phenotypic cancer diversity towards personalized medicine. Despite advances with traditional single genes molecular research, including rare mutations in BRCA1/2 and CDH1 for primary prevention and trastuzumab for treating HER2-overexpressing breast and gastric tumors, overall, treatment failure and death rates are still alarmingly high. Revolution in sequencing reveals that, now both a huge number and widespread variability of driver mutations, including single-nucleotide polymorphisms, genomic rearrangements and copy-number changes involved in breast cancer development. All these genetic alterations result in a heterogeneous deregulation of signaling pathways, including EGFR, HER2, VEGF, Wnt/Notch, TGF and others.Cancer initiation, progression and metastases are driven by complex molecular networks rather than linear genotype–phenotype relationship. Therefore, clinical expectations by traditional molecular research strategies targeting single genes and single signaling pathways are likely minimal. This review discusses the necessity of molecular networks modeling to understand complex gene–gene, protein–protein and gene–environment interactions. Moreover, the potential of systems clinico-biological approaches to predict intracellular signaling pathways components networks and cancer heterogeneous cells within an individual tumor is described. A flowchart specific for three steps in cancer evolution separately tumorigenesis, early-stage and advanced-stage breast cancer is presented. Using reverse engineering starting with the integration of available established clinical, environmental, treatment and oncological outcomes (survival and death) data and then the still incomplete but progressively accumulating genotypic data into computational networks modeling may lead to bionetworks-based discovery of robust biomarkers and highly effective cancer drugs targets.

source: the pharmagenomic journal

Test tube sperm successfully grown for the first time

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Scientists have taken cells from mouse testes and successfully produced sperm in a test tube (well, a dish actually) – an unprecedented feat for the field of male infertility.

Spermatogenesis – the creation of sperm – has been difficult to recreate outside of mammal testes. Biologists have tried in the lab and failed for centuries.

So a team of Japanese scientists led by Takehiko Ogawa of Yokohama City University designed a way to culture sperm and allow them to mature outside of the body.

  1. They took tissue fragments from newborn mouse testes. Since the mice were only 2 or 3 days old, they didn’t already have mature sperm.
  2. Then they soaked the testes tissue in a mixture called KnockOut Serum Replacement, often used to grow embryonic stem cells.
  3. After several weeks in the mix, the testes looked normal and were producing sperm. Nearly half of the samples contained cells with sperm-like tails (pictured).
  4. Finally, they took the resulting sperm, injected them into egg cells, and then artificially inseminated surrogate female mice.
  5. Those sperm ended up siring a dozen healthy and fertile mouse pups.

In fact, the testes continued to make sperm for two more months. And sperm was also produced from testicular tissue that was frozen in liquid nitrogen for several weeks.

Eventually, the researchers hope to culture pieces of testis removed in biopsies from humans and produce functional sperm that could be used for in vitro fertilization (IVF).

The technique holds significant promise for male infertility, which afflicts 2 million men in the US. As ScienceNOW explains, many infertile men who don’t produce sperm have normal reproductive stem cells, and with modifications to Ogawa’s technique, culture of testis biopsies from these men or men with testicular cancer could allow them to develop sperm.

By growing sperm cells that can be frozen, the technique could also aid prepubescent boys about to undergo cancer therapies that destroy fertility, Nature News reports. While men can have their sperm frozen before cancer treatment, this research suggests that boys could have testicular tissue removed before chemotherapy or radiation.

“It will be useful for diagnosis and treatment of infertility in future, for sure,” says Ogawa, who adds that the sperm-growing procedure shouldn’t be expensive.

source: Nature today.

Venous Thromboembolism and Inflammatory Bowel Disease

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Risk for VTE was two times higher in patients with IBD than in sex- and age-matched controls.

Patients with inflammatory bowel disease (IBD) have elevated risk for venous thromboembolism (VTE) — including deep venous thrombosis (DVT) and pulmonary embolism (PE) — and possibly arterial thrombosis.

To estimate the size of that risk, researchers in Denmark conducted a population-based study of 49,799 patients with IBD (14,211 with Crohn disease, 35,229 with ulcerative colitis, and 359 with unspecified IBD) and a non-IBD comparison group of 477,504 residents matched by age and sex.

Overall, patients with IBD had a two-fold increased risk for VTE compared with the non-IBD population. Although the overall incidence rates for DVT and PE increased with age, the relative risks for patients with IBD compared with residents without IBD were higher among younger patients. Patients 20 years old with IBD had a sixfold higher risk for DVT and PE than their non-IBD counterparts. Excess risk for VTE persisted after adjusting for comorbidities such as heart failure, diabetes, myocardial infarction, and stroke, and for use of medications associated with increased risk, including hormone replacement therapy.

Comment: The most notable observation of this large population-based study is that the relative risks for VTE, DVT, and PE among IBD patients are highest in the youngest age group (20). However, the absolute risk is still low in that group. Prophylactic anticoagulation should be considered in hospitalized patients with IBD, at least in older patients for whom the absolute risk is higher. Whether outpatients with active disease should be anticoagulated is still unclear. Obviously, anticoagulation could increase the risk for bleeding and iron-deficiency anemia in patients with active disease. Certainly, those patients with IBD who have experienced previous episodes of DVT or PE should be considered for lifelong anticoagulation therapy.

Source:Journal Watch Gastroenterology

 

Development of Small-Animal PET Prototype Using Silicon Photomultiplier (SiPM): Initial Results of Phantom and Animal Imaging Studies

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Silicon photomultiplier (SiPM; also called a Geiger-mode avalanche photodiode) is a promising semiconductor photosensor in PET and PET/MRI because it is intrinsically MRI-compatible and has internal gain and timing properties comparable to those of a photomultiplier tube. In this study, we have developed a small-animal PET system using SiPMs and lutetium gadolinium oxyorthosilicate (LGSO) crystals and performed physical evaluation and animal imaging studies to show the feasibility of this system. Methods: The SiPM PET system consists of 8 detectors, each of which comprises 2 x 6 SiPMs and 4 x 13 LGSO crystals. Each crystal has dimensions of 1.5 x 1.5 x 7 mm. The crystal face-to-face diameter and axial field of view are 6.0 cm and 6.5 mm, respectively. Bias voltage is applied to each SiPM using a finely controlled voltage supply because the gain of the SiPM strongly depends on the supply voltage. The physical characteristics were studied by measuring energy resolution, sensitivity, and spatial resolution. Various mouse and rat images were obtained to study the feasibility of the SiPM PET system in in vivo animal studies. Reconstructed PET images using a maximum-likelihood expectation maximization algorithm were coregistered with animal CT images. Results: All individual LGSO crystals within the detectors were clearly distinguishable in flood images obtained by irradiating the detector using a 22Na point source. The energy resolution for individual crystals was 25.8% ± 2.6% on average for 511-keV photopeaks. The spatial resolution measured with the 22Na point source in a warm background was 1.0 mm (2 mm off-center) and 1.4 mm (16 mm off-center) when the maximum-likelihood expectation maximization algorithm was applied. A myocardial 18F-FDG study in mice and a skeletal 18F study in rats demonstrated the fine spatial resolution of the scanner. The feasibility of the SiPM PET system was also confirmed in the tumor images of mice using 18F-FDG and 68Ga-RGD and in the brain images of rats using 18F-FDG. Conclusion: These results indicate that it is possible to develop a PET system using a promising semiconductor photosensor, which yielded reasonable PET performance in phantom and animal studies.

source: Society of Nuclear Medicine

Highly Sensitive ED Protocol for Identifying Low-Risk Patients with Chest Pain

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Implementation of a new accelerated diagnostic protocol could reduce emergency department length of stay and hospitalization rate.

Protocols to facilitate safe early discharge from the emergency department (ED) for low-risk patients with chest pain have limitations, including lack of validation and variable sensitivity. The prospective, observational, multinational Asia-Pacific Evaluation of Chest Pain Trial assessed a new, accelerated diagnostic protocol in consecutive adult ED patients who had at least 5 minutes of chest, neck, jaw, or arm pain or discomfort without obvious noncardiac cause and who did not have ST-segment-elevation myocardial infarction (STEMI).

The protocol included Thrombolysis In Myocardial Infarction (TIMI) score (see the table), electrocardiogram (ECG), and point-of-care biomarker testing (within 2 hours after arrival) for troponin I, creatine kinase MB, and myoglobin. Patients with TIMI scores of 0, no new ischemic changes on initial ECG, and normal biomarker panels were classified as low risk.

Among 3582 patients who completed 30-day follow-up, 421 (11.8%) had major adverse cardiac events within 30 days, most often non-STEMI (10.1%). Of 352 patients (9.8%) who were classified as low risk, 3 (0.9%) had major adverse cardiac events. The protocol had a sensitivity of 99.3% for identifying low-risk patients, a specificity of 11.0%, and a negative predictive value (NPV) of 99.1%. Had TIMI score not been included, NPV would have been 96.7%, and an additional 44 patients with major adverse cardiac events would have been missed.

Comment: This study demonstrates that the combination of no new ischemic changes on initial ECG, normal point-of-care biomarker panel within 2 hours, and low pretest probability (TIMI score of 0) identifies patients who can safely be discharged from the ED. However, several issues about use of the protocol remain to be addressed, including performance relative to other protocols, whether use of laboratory biomarker testing improves accuracy, effect on patient care costs and hospit/al stay, and malpractice risk.

Source:Journal Watch Emergency Medicine