Class Act

Timekeeping

May 16, 2014

By Nancy Hernandez

 

I did not know you until that time,

We scurried into your room

And found you pulseless, breathless, lifeless.

I was asked to keep

Time.

 

Fumbling for paper, I resorted to skin,

Marking the time we started to

Restore your blood flow.

Pumping in air,

Compressing your chest,

As you were infused with epinephrine,

I kept time.

 

Your story started pouring in,

You were post-op for an

Incision and drainage

Of your limb amputation site –

A diabetic’s fight.

Nonresponsive when a nurse returned

With the bedpan you had last requested.

 

Two minutes in,

With no palpable pulse.

Second epinephrine push,

 

 

I looked on as the team battled for your revival,

Their efforts visible by pearls of sweat

Dripping down their foreheads.

Their quick glances to me inquired if it was yet time,

With the mutual feeling that,

Every second felt longer than the one before.

With the mutual feeling that,

We wish we could do more.

 

Third epinephrine dose,

I kept time.

 

Seventeen minutes total,

The amount of time that we tried.

I wanted to hold your hand,

Your hand of already changed complexion,

From oxygen deprivation.

But what difference would it have made?

Was this desire for my own comfort, and nobody else’s?

 

Did you often wonder about this moment?

When would be your time?

This time unknown.

This time, your time.

This time I was honored to share with you.

This time that is now etched on my palm.

Nancy Hernandez is a 3rd year medical student at NYU School of Medicine

 

 

 

 

 

 

Lung Cancer Screening with Low-Dose CT Scans

May 9, 2014

By Susanna Jeurling

Peer Reviewed

The U.S. Preventive Services Task Force (USPSTF) recently finalized its position regarding annual low-dose computed tomography (LDCT) scanning for early detection of lung cancer. The grade B recommendation states that individuals between the ages of 55 and 80 with a 30 pack-year history or more of smoking who are current smokers or who have quit within the last 15 years should undergo annual LDCT screening, based on the results of the National Lung Screening Trial [1]. Lung cancer is the leading cause of cancer deaths in the United States and accounts for as many cancer deaths as breast, prostate, colon, and pancreatic cancer combined. Every year, 160,000 patients will die from lung cancer [2]. Nearly 60% of patients will have metastatic disease at the time of diagnosis and the combined 5-year survival rate for all types of lung cancer is only 17% [3]. An effective screening test for lung cancer could significantly improve survival rates. Randomized controlled studies of screening patients at high risk of lung cancer based on age and smoking history with chest X-rays and sputum samples did result in earlier detection of more lung cancers but unfortunately failed to demonstrate improvement in mortality rates [4]. The advent of dose-modulated CT scanning has allowed for a more sensitive and specific method of examining the lung parenchyma and opened up the possibility of truly effective lung cancer screening. In 2012, the National Lung Screening Trial (NLST), the largest and most expensive randomized controlled trial of a screening test ever undertaken, was completed. The trial enrolled over 50,000 current and former smokers aged 55 to 74 with a 30 pack-year or greater history at 33 centers nationwide and is the basis for the recent USPSTF recommendation [5]. The subjects were randomly assigned to either low dose LDCT or chest X-ray for 3 consecutive years. Positive screening results were then followed up with diagnostic procedures. Overall, the study found a 20% reduction in lung cancer mortality in the LDCT group, with 247 deaths from lung cancer per 100,000 person-years in the LDCT group vs 309 deaths per 100,000 person-years in the X-ray group. Estimates done by Ma and colleagues at the American Cancer Society predict that 5.2 million men and 3.4 million women in the United States would meet criteria for screening defined by the National Lung Screening Trial based on data from the 2010 National Health Interview Survey. Given the rate of lung cancer mortality within this population, derived from the National Health and Nutrition Examination Survey (NHANES-III), the authors estimate 12,000 deaths from lung cancer would be prevented annually if wide-scale LDCT screening were implemented across the United States [6]. Using modeling studies based on data from the NLST trial, the USPSTF concluded that screening up to age 80 could extend survival in the absence of serious medical co-morbidities and that only an estimated 10-12% of screen-detected cancers were “overdiagnosed,” meaning they would not have been detected in the patient’s lifetime without screening.

While a 20% reduction in mortality and the potential to avert 12,000 deaths from lung cancer annually are impressive results, screening and subsequent diagnostic and therapeutic interventions are not risk-free. The main drawbacks of screening to the individual patient are radiation exposure, poor specificity (73.4% in NLST), and potential complications of follow-up diagnostic procedures. Overall, the NLST found that LDCT scanning has a positive predictive value of 3.8%, meaning that over 96% of people with a positive scan who potentially undergo further diagnostic workup with additional imaging or biopsy will not have lung cancer. (The USPSTF model estimates a positive predictive value of 5%.) Ultimately, 7% of subjects in the NLST group with a positive scan underwent a biopsy procedure, of whom only 53% had confirmed disease. Given that the average case of lung cancer is diagnosed at age 70, are we willing to subject asymptomatic 55 year olds to additional radiation and potential biopsies as part of the diagnostic workup of a positive scan that is misleadingly worrisome in over 96% of people?

For a certain subset of patients, that risk may be worth it. Kovalchik and colleagues at the National Cancer Institute re-examined the data from the NLST and stratified the subjects in both arms into quintiles based on 5-year risk of death from lung cancer. Stratification was based on a risk-prediction model that weighed mortality from lung cancer vs death from other causes and incorporated validated risk factors for the development of lung cancer including age, body-mass index, family history of lung cancer, pack-years of smoking, years since smoking cessation, and pre-existing pulmonary conditions. Overall, 60% of patients with the highest risk of death accounted for over 88% of preventable lung cancer deaths from screening. They calculated the number needed to screen to prevent one lung cancer death to be 5276 in the lowest quintile vs 161 in the highest quintile [7]. A clinically useful risk stratification tool that further refined selection criteria among heavy smokers aged 55 to 74 to target those at greatest risk would maximize the benefits of LDCT scanning by boosting pretest probability and positive predictive value.

Although formal analysis of the cost effectiveness of widespread screening and subsequent treatment using final data from the NLST has not yet been generated, researchers at Harvard Medical School used preliminary data from the trial released in 2010 to generate estimates of the cost-effectiveness of screening. They found that annual screening of current and former smokers aged 50–74 would cost between $126,000– $169,000 per quality adjusted life year (QALY). By comparison, the authors estimate that smoking cessation therapy costs approximately $17,000 per QALY, given the current quit rates [8]. Additionally, the authors of the NLST point out that screening and subsequent diagnostic workup, including additional radiographic imaging, were done at advanced tertiary care facilities with dedicated chest radiologists and thoracic surgeons, and these necessary conditions may not generalize across the country. The cost and accessibility considerations may be especially relevant, given that the rate of smoking is over 60% higher among individuals below the poverty line (29%) than those above (17.9%) [9]. In an increasingly cost-conscious age of medicine, these estimates make it difficult to imagine that large-scale screening efforts would be economically feasible.

The National Lung Screening Trial clearly demonstrates that annual low dose CT screening of high-risk individuals results in earlier detection and reduced mortality from lung cancer. Yet the high false-positive rate coupled with the additional radiation exposure and the potentially risky follow-up procedures resulting from a positive scan complicate the decision for patients and their doctors on whether to screen. From a societal perspective, it is unlikely that widespread screening of at-risk individuals is cost-effective or even feasible. The National Lung Screening Trial represents real progress in developing an effective screening test for lung cancer, but without further refinement in the selection criteria and development of cheaper, less invasive diagnostic follow-up, widespread LDCT scanning does not yet constitute a viable screening test for lung cancer.

Susanna Jeurling is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Michael Tanner, MD, Executive Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1. Moyer VA on behalf of U.S. Preventive Task Force. Screening for lung cancer: USPTF recommendation statement.” Ann Intern Med. 2013 Dec 31. doi:10.7326/M13-2771. Link to USPSTF home page: http://www.uspreventiveservicestaskforce.org/uspstf13/lungcan/lungcanfinalrs.htm

2. American Cancer Society. Cancer Facts and Figures 2012. Atlanta, GA: American Cancer Society; 2012.

3. Howlader N, Noone AM, Krapcho M, (eds) et al. SEER cancer statistics review, 1975-2010. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2010

4. Henschke CI, Shaham D, Yankelevitz DF, Altorki NK. CT screening for lung cancer: past and ongoing studies. Semin Thorac Cardiovasc Surg. 2005; 17(2):99-106. http://www.ncbi.nlm.nih.gov/pubmed/16087075

5. National Lung Screening Trial Research Team, Church TR, Black WC, Aberle DR, et al. Results of initial low-dose computed tomographic screening for lung cancer. N Engl J Med. 2013;368(21):1980-1991. http://www.ncbi.nlm.nih.gov/pubmed/23697514

6. Ma J, Ward EM, Smith R, Jemal A. Annual number of lung cancer deaths potentially avertable by screening in the United States. Cancer. 2013 Apr 1;119(7):1381-1385. http://www.ncbi.nlm.nih.gov/pubmed/23440730

7. Kovalchik SA, Tammemagi M, Berg CD, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med. 2013;369(3):245-254. http://www.ncbi.nlm.nih.gov/pubmed/23863051

8. McMahon PM, Kong CY, Bouzan C, et al. Cost-effectiveness of computed tomography screening for lung cancer in the United States. J Thorac Oncol. 2011(11):1841-1848. http://www.ncbi.nlm.nih.gov/pubmed/21892105

9. Centers for Disease Control and Prevention. Current cigarette smoking among adults—United States, 2011.” Morbidity and Mortality Weekly Report. 2012;61(44):889–894. http://www.cdc.gov/vitalsigns/AdultSmoking/

Infection Transmission During Air Travel

May 7, 2014

By Aaron Smith, MD

Peer Reviewed

It’s become a familiar site to travelers: airline passengers wearing respiratory masks to filter pathogens from the cabin air. To those not wearing masks, the fashion trend can be discomfiting. Are the mask-wearers paranoid or prudent? What is the probability of contracting an illness on an airplane? And how unique is the aircraft environment when it comes to disease transmission?

It is clear that due to lower air exchange rates and decreased sunlight, enclosed spaces such as buildings and transport vehicles are more susceptible to the transmission of infectious particles than are the outdoors.[1] Aircraft cabins are particularly worrisome due to high occupant densities and long exposure times. Well-documented outbreaks of tuberculosis, influenza, severe acute respiratory syndrome (SARS), and norovirus are alleged to have occurred during air travel.[2][3][4][5] All of these diseases are transmitted via either large droplets or aerosolization.[6]

Large droplet transmission is a form of contact transmission in which contaminated large droplets (>5 units of measurement), generated when an infected person sneezes, coughs, or talks, are propelled short distances (<1m) and deposited on a susceptible host’s conjunctiva or mucosa. Aerosolization, or airborne transmission, occurs when residual large droplets evaporate to <5 units of measurement in size. These droplets are then dispersed widely and remain suspended in the air indefinitely. Other modes of disease transmission include common vehicle transmission (food- and water-spread illnesses) and vector-borne transmission (via insects). All of these forms of transmission can occur during air travel, but the large droplet and airborne mechanisms probably represent the greatest risk to passengers.[6]

Quantifying the risk of disease transmission for a particular contagion in an aircraft cabin has proven difficult. In a 2005 review published in the Lancet, Mangili et al. argued that there is insufficient data to perform a proper meta-analysis on the risk of transmitting any particular disease.[6] Furthermore, they noted that many of the available epidemiological studies are compromised by reporting bias secondary to incomplete passenger manifests, complicating risk assessment.

In 2012 Gupta et al. performed the most recent in a series of computational fluid dynamics (CFD) simulations to quantify the rate of influenza transmission in an aircraft cabin.[7] A CFD is a computer algorithm that analyzes fluid flow (in this case, airflow within a simulated aircraft cabin). CFD models are very complex, and the aircraft simulation mentioned above took four weeks of computational time over eight parallel processers to simulate just four minutes of airflow. The authors looked at what would happen if one subject infected with influenza coughed, exhaled, and talked on a plane. Using a code called FLUENT, the authors analyzed the dispersion pattern of exhaled droplets emitted from the infected passenger. By inserting this data into a mathematical equation, they attempted to estimate the relative probability of any given passenger on the aircraft becoming infected, accounting for both temporal and spatial variations in the transmission of particles.

To decipher the results of the simulation, it is helpful to understand some basic characteristics of aircraft ventilation. First, air circulation on airplanes is not random or uniform. On most commercial aircrafts, systems are designed so that air circulates in a side-to-side (laminar) pattern, with very little front-to-back or back-to-front (longitudinal) airflow.[8] This means that two passengers breathe the same air if they sit in the same row or in adjacent rows, but not if they sit several rows apart.

Second, the air on airplanes is actively ventilated and filtered. A typical commercial aircraft recirculates 50% of the air delivered to passengers, and this air passes through a high efficiency particle air filter (HEPA) before reentering the cabin.[6] HEPA filters are 99.97% effective at removing particles greater than 0.3 units of measurement in size from the air.[9] These filters effectively remove dust, vapors, bacteria, fungi, and the droplets via which most viruses are spread. The air on a typical aircraft is recirculated more often and filtered more often than the air in a typical office building.[6]

So, what were the results of the CFD simulation? The infected (index) passenger was sitting in seat 4D. When the index passenger coughed, the infected droplets moved backwards to row 5 and then towards the windows. The passengers with the highest risk of exposure were those sitting directly adjacent to the index passenger, and those sitting towards the windows in row 4 (the index row) and row 5. This pattern is consistent with previously described models of airflow in aircraft cabins, in which air is directed from the center towards the sides of the plane.[6]

Respirator masks reduced the probability of a given passenger becoming infected during the simulation. N95 respirators, commonly utilized by health professionals and increasingly worn by the general public, have been shown to be effective barriers to the transmission of airborne and large droplet-borne infections.[10] Gupta et al. calculated the decrease in exposure risk that a respirator would provide by estimating the number of infectious particles in a typical droplet and combining that data with the filtration efficiency of common respirator masks.[1] They estimated that in their simulation, the number of secondary infections would be reduced from three to zero if all of the passengers wore respiratory masks.

Of course, the ubiquity of contemporary air travel poses additional global health challenges. Someone infected with a disease endemic to a particular region, say polio in India, can easily hop on a plane and transmit the disease to a non-endemic region. A well-publicized example of this is alleged to have taken place in the early 1980s, when Gaetan Dugas, a flight attendant and one of the first documented cases of HIV, helped spread the virus throughout North America and Europe.[11] Airplanes can also harbor unwanted, non-human passengers, such as insects and other disease vectors. Cases have been documented of people from Florida and Virginia, without any history of foreign travel, contracting malaria.[12] “Airport malaria,” in which infected mosquitoes hitch a ride on an airplane and infect people in non-endemic countries, usually within the vicinity of an airport, is a real, albeit rare occurrence.

So should you wear a mask on your next flight? Nothing suggests that you are more likely to catch an illness on an airplane than in any other enclosed space. An aircraft cabin actually may even be safer than the average office building because its air is filtrated so frequently. Perhaps the reason people feel vulnerable to infections on airplanes is the same reason people feel vulnerable on airplanes in general: there can be something unnerving about moving five hundred miles per hour, forty thousand feet above the ground. Still, unless you are ready to start wearing an N95 respirator mask in all enclosed spaces, it probably does not make much sense to wear one specifically on an airplane.

Dr. Aaron Smith is a former medical student and now a  1st year  transitional medicine resident at Harbor-UCLA

Peer reviewed by Melanie Maslow, section editor, pharmacology,  Clinical Correlations

Image courtesy of Wikimedia Commons

References:

[1] Gupta JK, Lin C-H, Chen Q. Risk assessment of airborne infectious diseases in aircraft cabins. Indoor Air. 2012;22(5):388–395. doi:10.1111/j.1600-0668.2012.00773.x. http://www.ncbi.nlm.nih.gov/pubmed/22313168

[2] Kenyon TA, Valway SE, Ihle WW, Onorato IM, Castro KG. Transmission of multidrug-resistant Mycobacterium tuberculosis during a long airplane flight. N. Engl. J. Med. 1996;334(15):933–938. doi:10.1056/NEJM199604113341501  http://www.ncbi.nlm.nih.gov/pubmed/8596593

[3] Moser MR, Bender TR, Margolis HS, Noble GR, Kendal AP, Ritter DG. An outbreak of influenza aboard a commercial airliner. Am. J. Epidemiol. 1979;110(1):1–6. http://www.ncbi.nlm.nih.gov/pubmed/463858

[4] Olsen SJ, Chang H-L, Cheung TY-Y, et al. Transmission of the severe acute respiratory syndrome on aircraft. N. Engl. J. Med. 2003;349(25):2416–2422. doi:10.1056/NEJMoa031349  http://www.ncbi.nlm.nih.gov/pubmed/14681507

[5] Kirking HL, Cortes J, Burrer S, et al. Likely transmission of norovirus on an airplane, October 2008. Clin. Infect. Dis. 2010;50(9):1216–1221. doi:10.1086/651597 http://www.ncbi.nlm.nih.gov/pubmed/20353365

[6] Mangili A, Gendreau MA. Transmission of infectious diseases during commercial air travel. Lancet. 2005;365(9463):989–996. doi:10.1016/S0140-6736(05)71089-8  http://www.ncbi.nlm.nih.gov/pubmed/15767002

[7] Gupta JK, Lin C-H, Chen Q. Inhalation of expiratory droplets in aircraft cabins. Indoor Air. 2011;21(4):341–350. doi:10.1111/j.1600-0668.2011.00709.x.  http://www.ncbi.nlm.nih.gov/pubmed/21272076

[8] Gerencher CL. TRB Conference Proceedings: Research on the Transmission of Disease in Airports and on Aircraft: Summary of a Symposium. TR News. 2011.  http://trid.trb.org/view.aspx?id=934654

[9] Bull K. Cabin air filtration: helping to protect occupants from infectious diseases. Travel Med Infect Dis. 2008;6(3):142–144. doi:10.1016/j.tmaid.2007.08.004.  http://www.ncbi.nlm.nih.gov/pubmed/18486070

[10] Grinshpun SA, Haruta H, Eninger RM, Reponen T, McKay RT, Lee S-A. Performance of an N95 filtering facepiece particulate respirator and a surgical mask during human breathing: two pathways for particle penetration. J Occup Environ Hyg. 2009;6(10):593–603. doi:10.1080/15459620903120086.  http://www.ncbi.nlm.nih.gov/pubmed/?term=Grinshpun+SA%2C+Haruta+H%2C+Eninger+RM%2C+Reponen+T%2C+McKay+RT%2C+Lee+S-A.+Performance+of+an+N95+filtering+facepiece+particulate+respirator+and+a+surgical+mask+during+human+breathing%3A+two+pathways+for+particle+penetration

[11] Shilts, R. And the Band Played On. London: St. Martin’s Press, 1987.

[12] Huang Z, Tatem AJ. Global malaria connectivity through air travel. Malar J. 2013;12(1):269. doi:10.1186/1475-2875-12-269.  http://www.ncbi.nlm.nih.gov/pubmed/23914776

 

 

Is the Funduscopic Exam Worthwhile For the General Practitioner?

May 2, 2014

By Emily Fisher

Peer Reviewed

Some have said that physical examination is a dying art and the nondilated funduscopic exam may be one of the best examples of this. With the increasing perception that the use of imaging and labs allows physicians to diagnose diseases with more confidence than a history and physical exam alone [1], the days when an ophthalmoscope was almost as important as the white coat or the stethoscope and was part of a “bag of tools,” are quickly becoming a distant memory [2]. One study found that the nondilated funduscopic examination using the ophthalmoscope to assess retinal vasculature was one of the physical exam skills that medical students, residents, and internists felt the least confident performing [3]. Furthermore, the study found that the same internists felt that it was the physical exam skill with the lowest perceived utility score [3]. A study in the United Kingdom found that only 56% of practitioners felt comfortable using an ophthalmoscope [4]. Therefore, with both the low perceived utility of the nondilated funduscopic exam and the lack of confidence that practitioners feel in their ability to accurately perform it, is the nondilated funduscopic exam worthwhile?

The funduscopic exam is the only part of the physical exam that offers a direct view of blood vessels as well as the central nervous system. It is also an exam of an organ that often has pathology in the general population. One study found that in a screening of a primary care population, 50% of 405 patients had ocular pathology [1]. Furthermore, some of the most common conditions such as diabetes and hypertension are associated with retinal pathology [1]. The funduscopic exam has the ability to reveal a broad range of systemic diseases, including accelerated hypertension, raised intracranial pressure, miliary tuberculosis, and cytomegalovirus [5].

The funduscopic exam can reveal pathology in a wide variety of patients:

1. Evaluating neurologic structures such as the optic disc is useful, for example in patients with headaches, evolving neurologic status, or head trauma. Papilledema or a swollen optic nerve head indicates elevated intracranial pressure. Elevated intracranial pressure is not ruled out by an absence of papilledema, as it does not occur immediately, but is less likely if retinal venous pulsations are seen on exam [6].

2. The retina may reveal proliferative changes such as those seen in immunocompromised patients. For example, Candida can cause endophthalmitis and exudates. Cytomegalovirus often leads to mixed hemorrhages and yellow granular exudates and appears like “crumbled cheese and ketchup.” Miliary tuberculosis appears with choroidal tubercles.

3. The retina can also demonstrate hemorrhages or Roth spots in patients with suspected endocarditis, pernicious anemia, leukemia, subarachnoid hemorrhage and disseminated intravascular coagulation [6]. In patients with severe hypertension, retinal hemorrhages are considered a marker of accelerated hypertension [6].

4. Pathology of vascular structures can be useful in evaluating patients with diabetes and hypertension, as diabetic retinopathy is one of the leading causes of blindness that can be contained with laser photocoagulation. Diabetic retinopathy appears as pre-proliferative lesions or frank neovascularization that leads to retinal and vitreous hemorrhage. Eventually, patients will become permanently blind if they are not treated. Furthermore, as diabetic nephropathy rarely occurs without diabetic retinopathy, the presence of proteinuria without retinopathy can indicate another underlying etiology and the need for kidney biopsy [6]. Retinal hypertension can be seen in mild systemic hypertension by generalized arteriolar narrowing and arteriovenous nicking and opacity of arteriolar walls and has been shown to predict the risk of hypertension in normotensive patients. More severe signs of hypertension, including microaneurysms, cottonwool spots, or hard exudates, are associated with a higher risk of stroke and death from cardiovascular causes [10].

5. Evidence of atheromas in peripheral blood vessels in patients with cerebrovascular disease indicates that there was a thrombotic event, as atherosclerotic plaques do not form in vessels as small as the retinal arterioles [6, 9].

Therefore, many patients with common diseases may have findings on the funduscopic examination that provide insight into their disease. While papilledema is an acute finding that is important for emergency medicine physicians to be able to assess, other pathology, like diabetic retinopathy, may be an indication for a more comprehensive exam by an ophthalmologist. Studies have shown that education can significantly improve the ability of non-ophthalmologists to detect and make appropriate referrals. One study found that after a 4-hour course, the likelihood of failing to detect and appropriately refer patients decreased from 60% to 15% in patients with preproliferative or proliferative retinopathy and decreased from 83% to 15.6% in patients with maculopathy [7]. Other studies indicate that adding retinal photographs, which allows for review by an ophthalmologist, improves the sensitivity of screening for diabetic retinopathy [8]. Furthermore, implementing retinal photographs at rural health care clinics was found to lead to an increased rate of laser therapy in diabetic patients [9].

Considering the wide range of pathology that a funduscopic examination can reveal, it is an important skill that should not be lost. Similar to other findings in the physical exam, the ophthalmologic exam should be used to obtain more information and assist the physician in forming a complete clinical picture. It should not replace the comprehensive exam by an ophthalmologist or stand in the way of digital retinal photographs, but instead should be added to the armamentarium of physical exam skills, that, combined with modern use of technology, will produce powerful and accurate physicians.

Emily Fisher is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Beno Oppenheimer, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Wang F, Ford D, Tielsch MJ, Quigley HA, Whelton PK. Undetected eye disease in a primary care clinic population. Arch Intern Med. 1994;154(16):1821-1828.

[2] Herbert F. Little black bags, ophthalmoscopy, and the Roth spot. Tex Heart Inst J. 2013; 40(2):115-116.

[3] Wu EH, Fagan MJ, Reinert SE, Diaz JA. Self-confidence in and perceived utility of the physical examination: a comparison of medical students, residents, and faculty internists. J Gen Intern Med. 2007;22(12):1725-1730.

[4] Chung KD, Wtatzke RC. A simple device for teaching direct ophthalmoscopy to primary care practitioners. Am J Ophthalmol. 2004;138(3):501-502.  http://www.ncbi.nlm.nih.gov/pubmed/15364247

[5] Robertsa E, Morgana R, Kinga D, Clerkin L. Funduscopy: a forgotten art? Postgrad Med J. 1999;75:282-284.

[6] Schneiderman H. The funduscopic examination. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 117. Available from: http://www.ncbi.nlm.nih.gov/books/NBK221/

[7] Awh CC, Cupples HP, Javitt JC. Improved detection and referral of patients with diabetic retinopathy by primary care physicians. Effectiveness of education. Arch Intern Med. 1991;151(7):1405-1408.  http://www.ncbi.nlm.nih.gov/pubmed/2064492

[8] O’Hare JP, Hopper A, Madhaven C, et al. Adding retinal photography to screening for diabetic retinopathy: a prospective study in primary care. BMJ. 1996;312(7032):679-682.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2350501/

[9] Orient JM, Sapira JD. The eye. In: Sapira’s Art & Science of Bedside Diagnosis. Philadelphia, Pa: Lippincott Williams & Wilkins; 2005:206-207.

[10] Grosso A, Veglio F, Wong TY, et al. Hypertensive retinopathy revisited: some answers, more questions. Br J Opthalmol. 2005:89(12):1646-1654.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1772998/

 

Direct-to-Consumer Genetic Testing: Impact on Patients and Preventive Medicine

April 25, 2014

By Neelesh Rastogi

Peer Reviewed

In reference to the $100,000 he spent to research the genetic basis of the pancreatic cancer that ultimately killed him, Steve Jobs famously said, “I’m either going to be the first to be able to outrun a cancer like this, or I’m going to be one of the last to die from it” [1]. Mr. Jobs was interested in finding the specific genetic mutations his tumor contained so as to allow doctors to optimize his drug therapy. Now other genetic tests that purport to tell patients their risk of certain diseases are becoming increasingly prevalent. With the rapidly decreasing cost of at-home genetic testing, what once seemed like technology reserved only for science-fiction movies like Gattaca may soon be a typical purchase for people eager to learn more about their genetic risk factors. A company called 23andMe recently made genetic testing available directly to consumers for a mere $99 [2]. Consumers submit a saliva test to the company to have their DNA analyzed for the million most important single nucleotide polymorphisms (SNPs) regarding ancestry, genealogy, and inherited traits [3]. Some might consider this a small price to pay to have this kind of knowledge; others may not want to know this information for fear of finding out they are at increased risk for a significant disease. Nevertheless, direct-to-consumer (DTC) genetic testing is now at a price affordable to many Americans and could have significant implications for preventive medicine in the near future.

23andMe is just one of several companies offering direct-to-consumer genetic testing. iGENEA, DNA Tribes, FamilyBuilder, deCODEme, Navigenics and others are also in the business [4]. When Angelina Jolie learned that she tested positive for the BRCA1 and BRCA2 gene mutations, putting her at increased risk of breast and ovarian cancers, she underwent prophylactic bilateral mastectomy, prompting a national dialogue on genetic testing and preventive care [2]. Will this type of genetically informed decision-making become more common as these tests become more widely available? If so, are certain segments of the population more likely to use these genetic tests? What will be the impact of the results of these genetic tests on patient behavior? At present, very little empirical evidence is available to answer these questions and explain how these tests will affect healthcare use and behaviors.

Most of the data regarding DTC genetic testing come from surveys; randomized-controlled trials are difficult to apply to this setting. Much of future research will come from cohort studies to determine outcomes and preventive measures taken by patients who underwent DTC genetic testing [5]. One survey of 1048 people who completed DTC genetic testing showed that 43% of the respondents sought additional information about a health condition screened for in the genetic test. Twenty-eight per cent discussed their results with a healthcare professional, and 9% underwent additional lab tests. To better understand the survey participants’ risk tolerance, their answers were stratified based upon their perceived colon cancer risk (low, medium, or high). Those who identified as “high risk” were significantly more likely to have sought information about a disease, discussed results with a physician, changed their diet, or started exercising more [4].

Another study of 2240 participants in the Scripps Genomic Health Initiative, a prospective longitudinal cohort study of adults who purchased the Navigenics Health Compass—a commercially available genomic test—showed that over a third of the test recipients shared their results with their physicians. Interestingly, the study also found that screening tests were not associated with long-term psychological risks. Most participants reported that they perceived the tests to be of high personal utility. Also, while this survey showed that the participants had no increase in anxiety after finding out the results, they did not consistently make lifestyle changes in terms of fat intake or exercise [5].

Genetic tests alone may not be enough to convince patients to make healthy lifestyle changes. The results of these two surveys indicate that different people have different perceptions of good health and health risk. Moreover, the data suggest that these differences in patient-perceived health risk and disease susceptibility lie at the root of health-related behavioral change. Those who felt that they were at low risk for a particular condition were less likely to seek out more information or to discuss their genetic test results with a healthcare professional. Personal and family histories of disease were positively associated with lifestyle changes after testing. Understanding the interplay between an individual’s perceived risk (through a combination of personal and family medical histories) and results of DTC genetic testing may offer primary care clinicians a new tool to prevent or better manage chronic disease and promote preventive health behavior.

The promise of direct-to-consumer genetic testing comes with a caveat, however. Through testing, patients can directly access very specific and complicated health information without a physician present to provide much-needed context. The legal and ethical implications of this information have yet to be defined [5]. For instance, who is responsible for following up an abnormal test result? Is there an obligation to share information about genetic risk with other family members who may potentially benefit from that information?

Researchers have attempted to examine the consistency of the results among the tests offered by different companies. A group of epidemiologists simulated genotype data using the methods of 23andMe, deCODEme, and Navigenics for 100,000 individuals and 6 diseases: age-related macular degeneration, atrial fibrillation, celiac disease, Crohn’s disease, prostate cancer, and type 2 diabetes. All of these diseases are known to have various SNPs with different effect sizes that contribute to the disease phenotype. Their analysis ultimately found that predicted risks differed substantially between the companies based on differences in the choice of SNP studied, average population risk estimates, and their individual formulas to calculate risks [7]. The data indicate that there may be strengths and weaknesses to each company’s approach, but ultimately the best algorithm will not be known until a longitudinal study is done on the actual predictive capacity of each test in real patients.

DTC genetic testing is a new frontier in medicine. Despite the promise of new information that could guide preventive care, doctors may be hesitant to recommend these commercial tests for fear that the results may be inaccurate or inconsistent. Furthermore, these tests are not supported by significant long-term research nor do they have the blessing of the FDA. The medico-legal questions that will inevitably arise from the disclosure of genetic information to insurance companies and the financial risks to individual policyholders will also need to be thoroughly considered. Direct-to-consumer genetic testing may have come a long way in the last decade due to scientific advancements, but it still has a long way to go before it becomes a routine part of everyday healthcare.

Commentary by Dr. Ishmeal Bradley

The author introduces us to an increasingly popular and heavily promoted area of healthcare: personalized medicine. Companies offering the consumer the ability to map his or her genome and to assess individual risk to specific diseases have proliferated. However, they have done so without significant evidence of consistency of results, benefit to patients, or cost-effectiveness. In November 2013 the FDA’s division on medical devices issued a cease-and-desist warning to the 23andMe. In its letter to the company, the FDA voiced significant concern that the testing offered by this company failed to demonstrate reliability and effectiveness [8]. 23andMe now offers “ancestry-related” rather than “health-related” genetic reports.

Of even more concern are the ethical considerations with DTC testing. Although many common diseases are due to a combination of genetic and environmental factors, testing oneself for genetic abnormalities inevitably provides information on other family members who share significant amounts of genetic material. This could result in a loss of privacy by inferring one’s genetic risk from the test results of one’s family members. There are other ethical and legal issues that are too numerous to discuss here.

As practicing clinicians, when we order a test for a patient, we should always ask ourselves how the result will affect our management. As with any new diagnostic modality, there comes the ability to learn ever more information, but is that newly acquired information worthwhile? The Roberts study showed that people who were more risk-averse and felt themselves to be at higher risk of poor health outcomes were more likely to act upon the results of their genetic testing [5]. Would these same health-conscious patients behave in the same manner without testing?

DTC genetic testing, with its shotgun approach for looking for complex diseases and reductionist attempts to quantify risk, is indeed a new frontier. Its promise of personalized medicine has yet to be realized. Consequently, both the clinical and public health communities should be wary.

Neelesh Rastogi is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Ishmeal Bradley, MD, Section Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

[1] Isaacson W. Steve Jobs. New York: Simon & Schuster; 2011.

[2] Su P. Direct-to-consumer genetic testing: a comprehensive view. Yale J Biol Med. 2013;86(3):359-365. http://www.ncbi.nlm.nih.gov/pubmed/24058310.

[3] 23andMe website. http://www.23andme.com Accessed March 1, 2014.

[4] Kaufman DJ, Bollinger JM, Dvoskin RL, Scott JA. Risky business: risk perception and the use of medical services among customers of DTC personal genetic testing. J Genet Couns. 2012;21(3):413-422. http://www.ncbi.nlm.nih.gov/pubmed/22278220.

[5] Roberts JS, Ostergren J. Direct-to-consumer genetic testing and personal genomics services: A review of recent empirical studies. Curr Genet Med Rep. 2013;1(3):182-200. http://www.ncbi.nlm.nih.gov/pubmed/24058877

[6] Bloss CS, Wineinger NE, Darst BF, Schork NJ, Topol EJ. Impact of direct-to-consumer genomic testing at long term follow-up. J Med Genet. 2013;50(6):393-400 http://www.ncbi.nlm.nih.gov/pubmed/23559530.

[7] Kalf RR, Mihaescu R, Kundu S, de Knijff P, Green RC, Janssens AC. Variations in predicted risks in personal genome testing for common complex diseases. Genet Med. 2014;16(1):85-91.

[8] U.S. Food and Drug Administration. Warning letter to 23andMe, Inc. Document number: GEN1300666. November 22, 2013. http://www.fda.gov/iceci/enforcementactions/warningletters/2013/ucm376296.htm

 

Should Physicians Ask Patients about Guns?

April 11, 2014

By Jennifer Zhu

Peer Reviewed

After the elementary school shooting in Newtown, CT in December 2012 that left 20 children and 6 adults dead, the country reacted as it had following the July 2012 movie theatre shooting in Aurora, CO, and the public meeting shooting involving Representative Gabrielle Giffords on January 11, 2011 in Tucson, AZ. Some called for tighter firearm safety laws, while others stood by the adage that “Guns don’t kill people,” and that this was no time to politicize a tragedy. The issue of mental health soon followed, with calls for greater awareness and resources directed toward mental health services.  While these important issues draw together the realms of healthcare, policy, and legislation, there is another related matter seldom discussed. What role, if any, do physicians play in asking patients about firearms?

According to the Centers for Disease Control and Prevention (CDC), there were 31,347 deaths due to firearms in 2009 [1]. Approximately 60% were suicides, 37% were homicides, and the remainder were accidental shootings.

There were 32,886 deaths due to motor vehicle accidents in 2010, the lowest ever. In fact, motor vehicle fatalities have steadily declined throughout the years. Much of this progress has been accomplished through traffic safety research. As a result, airbags and seatbelts are now required in all vehicles. Data, often collected by physicians at medical visits, spurred educational campaigns and harsher penalties for drunk driving [2]. When it comes to firearms, it’s a different story. National organizations such as the CDC do not analyze gun violence data, since they cannot use federal money to advocate for gun safety and control [3].

Many are familiar with the saying “An ounce of prevention is worth a pound of cure.” In medicine, we screen for all sorts of conditions in the hope of preventing or ameliorating diseases ranging from hypertension to cancer. We ask personal questions about alcohol and drug use, sexual health and mental health, domestic violence and abuse, suicidal and homicidal behavior. Gun use is a part of that conversation, since suicidal or homicidal individuals with access to guns are more likely to take action [4]. Essentially, we make inquiries about anything and everything that could be health-related.

Physicians have been making recommendations about firearm safety at least as long as an editorial titled “The Indiscriminate Sale of Revolvers,” appeared in the Lancet in 1893 [5]. Presently, the American Academy of Pediatrics and the American Medical Association recommend that physicians inquire about firearms and counsel patients on safety precautions, with individual doctors advocating for discussion as well [6,7]. However, the evidence regarding the efficacy of counseling–mostly conducted in the outpatient pediatric setting–is mixed, with 4 out of 7 trials demonstrating improved storage of firearms [8].

Efficacy aside, what has become a larger barrier and point of controversy is whether or not physicians even have a right to broach the subject. In 2011, a pediatrician in Florida asked one of her patients to find a new physician when the patient refused to answer questions about whether or not she owned firearms. This culminated with Governor Rick Scott signing into law “An Act Relating to Privacy of Firearms Owners.” The bill essentially stated that licensed health care workers were not legally allowed to ask about firearms unless they believed that guns were directly related to the medical issue at hand [9]. A few months later, a U.S. District Court judge granted a preliminary injunction, saying it violated the First Amendment. The state is in the process of appealing the ruling.

Firearm usage and safety are controversial topics in this country. For better or worse, physicians often find themselves injected into these conversations, since we have the ability to affect both individuals and populations with our actions. It’s a question worth discussing: should healthcare workers speak with patients about gun use and counsel them on safety? And, perhaps more importantly, would it have an impact?

Commentary by Antonella Surbone, MD, PhD, FACP, Ethics Editor, Clinical Correlations

Why should healthcare workers not speak with patients or parents about gun use and counsel them on safety? Unfortunately, the topic of gun control involves political and financial interests that seem to go beyond the traditional understanding of “safety” and the physician’s moral and professional duty to make reasonable inquiries on this account.

While our “ability to affect both individuals and populations with our actions” may not always reach as far as we would wish, commitment to life, rather than infliction of suffering or death in all forms, remains a keystone of the medical profession.

Jennifer Zhu is a 4th year medical student at NYU School of Medicine

Image courtesy of Wikimedia Commons

Peer Reviewed by Antonella Surbone, MD, PhD, FACP, Ethics Editor, Clinical Correlations

References

1. Kochanek KD, Xu J, Murphy SL, Miñino AM, Kung H-C. Deaths: final data for 2009. Natl Vital Stat Rep. 2011;60(3).

2. Bass JL, Christoffel KK, Widome M, et al. Childhood injury prevention counseling in primary care settings: a critical review of the literature. Pediatrics. 1993;92(4):544–550.

3. Centers for Disease Control and Prevention. Funding opportunity announcements; additional requirements. AR-13: Prohibition on use of CDC funds for certain gun control activities. www.cdc.gov/od/pgo/funding/grants/additional_req.shtm#ar13. Accessed December 19, 2012.

4. Dahlberg LL, Ikeda RM, Kresnow MJ. Guns in the home and risk of a violent death in the home: findings from a national study. Am J Epidemiol. 2004;160(10):929-936.

5. The indiscriminate sale of revolvers. Lancet. 1893;141(3626):428.

6. American Medical Association-Medical Student Section. Firearms: safety and regulation. Digest of policy actions: policy number 145.000. http://www.ama-assn.org/resources/doc/mss/digest_of_actions.pdf. Updated November 2010. Accessed December 19, 2012.

7. Fleegler EW, Monuteaux MC, Bauer SR, Lee LK. Attempts to silence firearm injury prevention. Am J Prev Med. 2012;42(1):99-102.

8. McGee KS, Coyne-Beasley T, Johnson RM. Review of evaluations of educational approaches to promote safe storage of firearms. Inj Prev. 2003;9(2):108–111.

9. Florida House of Representatives. CS/CS/HB 155: An act relating to the privacy of firearms owners. http://www.myfloridahouse.gov/sections/Bills/billsdetail.aspx?BillId=44993 Accessed December 19, 2012.

Orders Of Magnitude

March 21, 2014

By Olivia Richardson, MD

On the order of angstroms,

infinitesimally small

nucleotides pair off

and cling tightly to one another,

inseparable,

hundreds of kilojoules

binding them.

 

Like teenagers they dance,

entangled.

With arms entwined

they spin around one another-

spinning and twirling,

waltzing in neat lines

to the beat of their fate.

 

With endless energy,

they waltz-

in infinite numbers,

in trillions of cells,

with flawless precision,

never a step off beat.

 

On the order of angstroms,

a single nucleotide,

in an act

of unchecked rebellion,

with one missed step unnoticed,

topples this precarious perfection.

 

 

We measure a woman

on the order of inches,

by her strength of character,

quickness of wit,

her scent, her charm, her warmth.

 

This woman is a mother above all.

 

You can tell by her daughters,

who sit perched atop her bed,

one nuzzled at her side,

the other at her feet,

a barricade,

defending her with their barrage

of alternating facts and questions-

a fortress built from scraps of information,

of hope,

picked up along the way.

 

You can tell by the tangle

of neoprene balloons,

which float above her head,

red and silver and green,

tied to her bedpost,

filled to the brim with helium,

threatening to-

at any moment-

sweep up her small frame,

and whisk her away.

 

A loose fitting cuff hangs

from her wasted arm,

a limb unknown to her-

to a woman who once measured

one hundred and forty pounds,

whose curves stopped a man in his tracks,

and prompted him to give her his name.

Not only a mother-

also a lover,

a wife.

 

She lies very still,

and rests her left hand

over her ribs

just under her breast,

where it is tender from her fall.

 

What makes a woman?

Her scent, her warmth, her soul,

the trillions of waltzing cells,

the one misstep,

on the order of angstroms,

that leads to her fall.

This piece was inspired by Ms. A.P., a 70-year-old woman with locally advanced pancreatic cancer. Wife and mother of four.

 

The Blue Phone and the Bow-Tie

March 14, 2014

By Joseph Zakhar

Peer Reviewed

The Patient:

Fate is the sound of a ringing phone.

I, however, am growing to hate the sound.

I’m strangled by the words, by the rough sheets, the silence as a stranger far away connects us, sitting in some room. There’s a tension, an unsettling sense of doom as I count the doctors’ blinks and wait for the “bonjourno.” I hope the translator – the one who lets me and my doctors talk – is somewhere warm, like Texas.

The phone is a harbinger of straight facts, none too good as I sit here with my heart. It’s a necessary coldness. I always sit very, very still as they explain, so precisely, what’s happening. I sit still, afraid to shake the words out of my ears.

Repeat back that I’m agreeing to surgery tomorrow. Do I know what a cabbage procedure is? CABG? AVR? What’s my family’s medical history?

Yes.

I understand.

A nod can do as much. But only so much. And as an immigrant (and proud Italian), I’ve grown use to the basics: vague gesticulation and mangled speech. But what I’m agreeing to makes me scared for the first time in my many years.

After years in America I continue to wake up at dawn and almost expect to pull on my knee-high rubber boots I wore on the boats back home. My habits have changed now. I’m still waking up in the morning, only to hear the squeak of white Keds on the pristine floors and the gentle rumble of wheelchairs being pushed along, harmonized with the scrapes from the IV poles pushed around by emaciated men in cheap slippers. At night I like to watch the cars swing by the hospital, their headlights all yellow like lazy jaundiced eyes.

I miss the smell of fish from back home. Or maybe it’s that I hate the coldness leeching from the phone into the scent here. It’s like this new place where I can’t talk, can’t communicate, doesn’t want me or my smell here. As if the place is trying its best to ignore me.

Which is why I was so surprised when I heard Italian, not echoing out of the dark recesses of cold plastic, but from a young man. With a bow tie. Not a kid, really. He has a white coat.

So he walked in, the cold blue translator phone ignored in the corner as he sat at the edge of my bed, and just… talked. And in those halting phrases, horrible accents (on his part), wide smiles, and sweeping gestures I establish a new habit.

And as long as I’m here I will talk. To the phone, yes, but also in my rough English. And he’s shown me that he will listen and thinks that I am more than a badly worded turn of phrase. I will see him. I’ve asked him to say hello, or maybe it’s goodbye, before my surgery.

As long as I have breath and can joke and talk about my fish and my women, I will try to tell him. Tell the bow-tie kid.

I will show them all that I am alive.

The Student:

“Adriano and Joe,” he says, laughing and pointing at him, then me. I laugh. I laugh a lot when I spend time with him. And he laughs all the harder to see that a) what he’s said is recognizable and b) it’s funny.

And it means so much to him. He’s had one visitor. One time. In four weeks. No family to speak of. Four weeks of staring out the window. Which means he’s starved for company. And though I relish analyzing his daily lab values and talking to my team, discussing surgery options and catheterization results, there’s something to be said for actively ignoring the heart rate monitor dips, the IV’s swooping with the liquids dancing into his body.

And I live for it. These moments. It’s worth all the times I can almost feel my soul disengage from my body, passing through a bittersweet cloud of coffee stained breath and over my UpToDate printouts on its way out.

I’ve looked over his reports. Pored over his Echocardiogram. His illness isn’t messing around. But there he is. At first, he was all casual Friday. Don’t worry, be happy. A buddy cop movie. And underneath it all was a clawing, desperate sense of isolation. A prisoner of his broken body. A prisoner of his native tongue.

When I first met him, he seemed the embodiment of loneliness. And when I thought of him, he reminded me of the color yellow. A faint statement of a color that claims a small existence, but could be easily swept away by anything else – overwhelmed by other colors.

Or maybe like the letter Q. A broken circle. Rarely used – last pick of the hangman.

And then we talked. And after a week of daily visits, he told me that initially he didn’t want to disappoint me and wasn’t telling me when he was in pain or scared or confused. And then he asked me to talk to him before his procedure. And then asked me to call him when he went home to his one-room apartment. I realized I was no longer a translator or a messenger, by definition never telling my own story. In that brief time I was his confidant, his teacher, his friend.

There’s not much to life but timing. I was there, me with my 3rd generation broken-Italian, when he was there. And thanks to his surgeons, his medical team, and maybe even my friendly chats, he’s alive. In countless ways, in countless colors and letters that disregard language. Alive.

Joseph Zakhar is a 3rd year medical student at NYU School of Medicine

Image courtesy of Wikimedia Commons

From The Archives: Intercessory Prayer: What Do Sneezes and Prayers Have in Common?

March 13, 2014

Please enjoy this post from the archives dated September 21, 2011

By Alon Mass

Faculty Peer Reviewed

The overlap between religion and medicine is ancient. On a recent medical volunteer trip to India I met a medical student who proudly wore a school sweatshirt with the saying: In God we trust. The rest we dominate.

This arrogant approach is probably uncommon, but praying to God for healing–self or intercessory–is not.

Intercessory prayer is a form of prayer conducted by a group or individual who petitions a god on behalf of another individual in need of assistance. Intercessory sessions often occur in highly-developed belief systems, but are also sporadically used by nonreligious people, not only as a tool for healing, but as a coping mechanism for those engaging in the prayer.[1] Occasionally, the affected individual may be included in the intercessory prayer session.

When working as an intern in a hospital, rabbi/physician Abraham Twersky was treating a man who suffered a severe iatrogenic complication during a routine procedure. When Dr. Twersky saw that the man was filled with anxiety and fear, he offered to pray with him. As a result of the prayer session, the man’s attitude changed, his fears diminished, and he was able to cope more positively with what had befallen him. In a remark to the doctor the following day, he said, “I am no longer afraid. The antibiotics worked, but the prayer worked better.”[2] In this story, we find an example of how a patient can perceive prayer to be as efficacious, if not more so, than medical intervention.

Many prospective studies have examined the use of prayer as a coping mechanism and its relationship with the healing process. One randomized, double-blinded, prospective study of coronary care unit (CCU) patients found that intercessory prayer was associated with less adverse health events during the CCU course, but had no affect on length of stay.[3] The 2006 Study of the Therapeutic Effects of Intercessory Prayer (STEP) trial was a multicenter randomized study that stratified patients due to undergo coronary artery bypass graft surgery (CABG) into 3 groups. The first 2 groups either received intercessory prayer or did not, but were blind to their grouping. A third group was aware of receiving prayer by another. Patients aware of receiving prayer had statistically more complications than the unaware groups.[4] While intercessory prayer seems to have little effect on health outcomes, one study found that private self-prayer did make a positive difference in mental optimism. Prayer was found to be associated with increased preoperative positive attitude,[5] which one study suggested leads to a better quality of life as well as faster rate of recovery after coronary artery bypass grafting.[6] Despite the limited and inconclusive evidence in favor of prayer, nationwide polls have shown that 80% of Americans commonly pray for healing.[7]

A fascinating early example of people evoking intercessory prayer in connection with health and illness is the phrase “God bless you,” a term that Kavka asserts is “inseparably [attached] to the sneeze.”[8] Religious or not, take a moment to ask yourself this question: how often do you say “Bless you!” or even “God bless you!” in response to hearing a friend or even stranger engage in sternutation (which Merriam-Webster defines as “the expulsion of air from the lungs through the nose and mouth, most commonly caused by the irritation of the nasal mucosa”). If your answer is not “never,” ask yourself why. Dr. Kavka adds, “No routine comment is invited by someone belching, coughing, groaning, hiccupping, retching, snoring, vomiting, wheezing, or breaking wind, even when these symptoms may portend trouble.”[8] So, why pray for another after they sneeze?

It seems like we humans are programmed to hope and pray for the well being of others after they sneeze. While it is well documented that humans are inherently altruistic–Fehrl & Fischbacher elegantly stated that “evidence indicates that human altruism is a powerful force and is unique in the animal world”[10]–it seems that little benefit would come from hoping for another to recover from a benign sneeze. In order to fully explain why we innately utter niceties after hearing a fellow human blast mucous and disease particles out of their nares, we must understand disease in the context of the past 2 millennia.

The act of sneezing was once considered sacred. The ancient Greeks, for example, thought that the sneeze was a heavenly sign from the Gods. The Greek physician Hippocrates knew the sneeze helped spread pulmonary pathogens, but otherwise thought it to be beneficial in the absence of ongoing disease. The Romans too considered the sneeze to be a sign of good health. Since it arose from the lungs, an organ they considered divine, Romans often greeted the sneeze with the phrase “Live long.”[9]

This all changed during the 14th century, when the bubonic plague killed one-third to one-half of Europe’s population. Plague is caused by Yersinia pestis, a gram-negative ovoid bacillus that is spread by fleas or rodents. Marked lymphadenopathy, often in the inguinal region, is the hallmark of plague. The last stage of disease, however, is characterized by respiratory distress, chest pain, and violent sneezing that causes patients to aerosolize and spread bacteria.[11] The association of the sneeze with death led Pope Gregory VII (reign 1073-85) to decree that the sentence “May God bless you” must be said as a short prayer after one sneezed. Over time, the sneeze was believed to be a way to expel demons from the body.[9]

Saying “God bless you” after one sneezes is now a common practice. In the Seinfeld episode “The Good Samaritan,” Jerry pokes fun at the “God bless you” reflex, and recommends that the compliment “You are so good looking!” would be more meaningful to the sneezer.[12] Jerry, it seems, took the secular approach to the sneeze.

Regardless of the ailment, treating the whole person and not just the disease is necessary for the healing process. The medical literature will continue to debate the objective implications of prayer on health and recovery. The use of intercessory prayer or spiritual intervention as an adjuvant therapy to medical intervention seems to contribute in many situations to the patient’s well being and should not be easily dismissed. So whether you find yourself standing next to a sneezing stranger or helping a loved one cope with a debilitating illness, do whatever you can to make them feel better. Your words may just make the extra difference.

Commentary by Dr. Michael Tanner

The Cochrane Database authors reviewed 10 studies of intercessionary prayer involving 7646 patients and wrote, “These findings are equivocal and, although some of the results of individual studies suggest a positive effect of individual prayer, the majority do not and the evidence does not support a recommendation either in favour or against the use of intercessory prayer.”[1] They conclude, somewhat contemptuously, “We are not convinced that further trials of this intervention should be undertaken and would prefer to see any resources available for such a trial used to investigate other questions in health care.” Yet, while walking the halls of Bellevue over the years I have overheard many group prayer sessions in full swing and been amazed by the energy emanating from the patient’s room. My first reaction: “Stay out of there: these people are taking a different approach to the case.” My second: “Might help, can’t hurt.”

Alon Mass is a 4th year medical student at NYU Langone Medical Center

Peer reviewed by Michael Tanner, MD, Executive Editor, Clinical Correlations

References

  1. Roberts L, Ahmed I, Hall S, Davison A. Intercessory prayer for the alleviation of ill health. Cochrane Database Syst Rev. 2009;(2):CD000368. http://www.ncbi.nlm.nih.gov/pubmed/19370557
  2. Twersky AJ. Do Unto Others: How Good Deeds Can Change Your Life. Kansas City, MO: Andrews Mcmeel Publishing; 1997:127.
  3. Harris WS, Gowda M, Kolb JW, et al. A randomized, controlled trial of the effects of remote, intercessory prayer on outcomes in patients admitted to the coronary care unit. Arch Intern Med. 1999;159(19):2273-8. http://www.ncbi.nlm.nih.gov/pubmed/10547166
  4. Benson H, Dusek JA, Sherwood JB, et al. Study of the Therapeutic Effects of Intercessory Prayer (STEP) in cardiac bypass patients: a multicenter randomized trial of uncertainty and certainty of receiving intercessory prayer. Am Heart J. 2006;151(4):934-942. http://www.ncbi.nlm.nih.gov/pubmed/16569567
  5. Ai AL, Peterson C, Bolling SF, Koenig H. Private prayer and optimism in middle-aged and older patients awaiting cardiac surgery. Gerontologist. 2002;42(1):70-81. http://www.ncbi.nlm.nih.gov/pubmed/11815701
  6. Scheier MF, Matthews KA, Owens JF, et al. Dispositional optimism and recovery from coronary artery bypass surgery: the beneficial effects on physical and psychological well-being. J Pers Soc Psychol. 1989;57(6):1024-1040.
  7. CBS poll: prayer can heal. CBS News website. February 11, 2009. Accessed September 23,2010. http://www.cbsnews.com/stories/1998/04/29/opinion/main8285.shtml.
  8. Kavka SJ. The sneeze—blissful or baneful? JAMA. 1983;249(17):2304-2305. http://jama.ama-assn.org/content/249/17/2304.refsassn.org/content/249/17/2304.refs
  9. Songu M, Cingi C. Sneeze reflex: facts and fiction. Ther Adv Respir Dis. 2009;3(3):131-141. http://www.medscape.com/viewarticle/714420
  10. Fehrl E, Fischbacher, U. The nature of human altruism. Nature. 2003;425:785-791. http://www.nature.com/nature/journal/v425/n6960/full/nature02043.html
  11. Cobbs CG, Chansolme DH. Plague. Dermatol Clin. 2004;22(3):303-312.
  12. “The Good Samaritan.” Seinfeld. NBC television. New York. March 4, 1992. http://www.youtube.com/watch?v=Oq-1CtCPUyo

The Sentinel

March 7, 2014

By Michael D. O’Donnell

The patient was a 60 year old female with a history heavy chain (AH) amyloidosis with renal and cardiac involvement, nephrotic syndrome, and hyperlipidemia who presented with progressive generalized weakness and fatigue for several weeks and nausea and vomiting for 5 days. The patient was seen in cardiology and hematology clinic one month prior to admission at which time chemotherapy was recommended for treatment of amyloidosis, but the patient needed time to confer with her family. After admission to medicine, the patient was severely hypotensive and had tachycardia, cold extremities, delayed capillary refill and minimal urine output. The patient became febrile and short of breath with a blood pressure at 60/30. After pan-culture, intravenous fluid resuscitation, and initiation of vancomycin and ceftriaxone, the patient was transferred to the medical ICU where she became progressively lethargic. Upon transfer to the MICU an airway was called and the patient was intubated after significant vomiting. During the airway, the patient’s pulse became non-palpable and compressions were begun for approximately 5 minutes. The patient was profoundly hypotensive without response to fluids or pressors and ultimately expired May 13th, 2013 at 3:50 AM, son at bedside.

The Sentinel

He watched

as she lay in bed

delicately wrapped in

thin cotton, tucked and

folded lovingly

by her only visitor.

For days he would stand,

as motionless as the body

over which he kept vigil,

his dark eyes rising

just once each morning

to glean from us

what he knew himself.

 

And he watched

as sunlight danced across

the floor each day,

as six white coats entered

and six white coats exited,

brief witnesses

to the constant standoff

between a son – barely nineteen –

and the Disease

that had become his foe.

 

And he watched

as they moved her,

as hospitals do,

in the end,

for the final act of a drama

only he could know.

He watched

as they wheeled her bed

through fluorescent halls,

as they hooked her to screens,

as her breathing slowed,

as her heart stopped.

 

And we watched

as active players

and distant outsiders

– inextricably linked –

burdened and bound

by unyielding loss;

his eyes closed,

alone.

 

West Nile Virus: Just How Bad Is It?

March 5, 2014

By Julian Horwitz

Peer Reviewed

As of mid-August 2012, the CDC had reported 1118 cases of West Nile virus (WNV) infections and 41 related deaths, which, pro rata, made 2012 the most prolific year for WNV in the United States [1]. Although West Nile’s classification as a public health crisis remains debatable, the lack of treatment and vaccination options make associated severe infections a real threat.

West Nile virus, a single-stranded RNA virus of the Flavivirus family, was first isolated in Uganda in 1937 [2]. Since its emergence in the United States in 1999, there have been approximately 33,000 cases and 1,200 deaths. The virus is maintained in an enzootic cycle between over 300 avian species and Culex mosquitos, which act as the transmission vector. It is believed that only birds can maintain high enough viral loads to be infectious hosts, as humans and other mammals result in “dead-end” infections [2].

Upon viral inoculation via an infected mosquito, WNV initially infects local dendritic cells in the skin, followed by viral amplification in regional lymph nodes. Subsequently, a mild viremia, which is cleared in approximately 1 week by a rapid IgM response, results in a multi-organ infection as well as highly variable systemic symptoms [2]. Only 20-40% of individuals who are infected will become symptomatic after the virus’s 2-14 day incubation period. The majority of these individuals develop a mild, flu-like, self-limiting illness known as West Nile fever [3].

Less than 1% of infected patients, however, will develop severe neuroinvasive disease. The manifestations of these severe infections include meningitis, encephalitis, and acute flaccid paralysis. WNV infection of the central nervous system can be definitively diagnosed by the presence of West Nile IgM in the cerebrospinal fluid, detectable in greater than 90% of patients with neuroinvasive disease by day 8 of presentation [4]. Of clinical significance, serum WNV IgM false-positives are possible with recent yellow fever or Japanese encephalitis vaccination or a recent infection with a Flavivirus (St. Louis encephalitis or dengue). Supplemental testing with plaque-reduction neutralization testing and nucleic acid amplification testing can increase the specificity and accuracy, respectively, of serum IgM detection [4].

In neuroinvasive disease, viral entry into the CNS is likely mediated by both an increase in blood-brain barrier permeability, secondary to local TNF-alpha production, and by retrograde transmission via peripheral neurons [2]. West Nile meningitis, which represents 40% of West Nile neuroinvasive disease, is associated with a favorable prognosis with <1% mortality [5]. Approximately 50% of neuroinvasive infections, especially in the elderly and immunocompromised, are characterized as West Nile encephalitis. These infections result in a 20% in-hospital mortality rate as well as persistent Parkinsonian symptoms in up to 40% of survivors [5]. Finally, the most devastating disease variant is West Nile acute flaccid paralysis (WNP), which accounts for approximately 10% of neuroinvasive disease [5]. Interestingly, WNP is not a transient demyelinating process, as seen with infection-mediated Guillain-Barré syndrome; rather, the paralysis is due to irreversible anterior horn neuronal damage consistent with poliomyelitis [3]. The extent of paralysis can range form monoplegia to quadriplegia with neuromuscular respiratory failure, which results in mortality rates ranging from 10-50% [5]. In addition to short-term morbidity and mortality, neuroinvasive West Nile disease is associated with persistent fatigue, weakness, ataxia, and cognitive dysfunction in nearly 50% of survivors in long-term follow-up studies [5].

Although the probability of severe disease is <1% of the relatively small number of total West Nile infections, there is currently no specific approved therapy for WNV. Therapeutic candidates for WNV such as ribavirin, mycophenolic acid, and interferon-alpha have demonstrated efficacy in vitro, but they have failed to show a clinical benefit [6]. Passive immunity with anti-WNV antibodies has demonstrated reduction in mortality in animal models as well as improvement in neuroinvasive disease in small human trials, particularly among elderly and immunocompromised patients who have high viral titers [6]. This promising therapeutic option is currently undergoing phase 2 clinical trials. Another experimental treatment approach involves small-interfering RNA (siRNA) to target intracellular viral RNA, thus limiting viral translation and subsequent replication. While this form of treatment is efficacious in early-diagnosed infections, advances in the delivery system technology for siRNA will be a required next step before widespread clinical use [6].

Until the establishment of a WNV vaccine or effective treatment, the single most important (and least expensive) intervention is prevention, which is particularly important in the peak months of July through September [4]. The CDC recommends DEET-based insect repellents and mosquito nets for personal protection, especially at night and near sources of still water. At the community level, some areas are adopting strategically timed low-volume insecticide applications, which appear to effectively decrease WNV transmission [4]. The CDC also uses local authorities to track bird deaths in order to assess for avian WNV infections, thus better identifying high-risk locations [7].

While WNV may present as an incurable neuroinvasive disease (as is often portrayed by the media), statistically speaking, over 99% of infections range from asymptomatic to a self-limiting flu-like illness, especially in immunocompetent individuals. Regardless of the favorable probabilities, appropriate precautions and continued antiviral research will hopefully soon eliminate 100% of this annual viral threat.

Julian Horwitz is a 4th year medical student at NYU School of Medicine

Peer Reviewed by Harold Horowitz, MD, Medicine,  NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[1] Kaiser J. Public health. Outbreak pattern stymies vaccine work. Science. 2012:337(6098):1030.  http://www.sciencemag.org/content/337/6098/1030.short

[2] Ulbert S. West Nile virus: the complex biology of an emerging pathogen. Intervirology. 2011:54(4):171-184.  http://www.ncbi.nlm.nih.gov/pubmed/21576931

[3] Kramer LD, Li J, Shi PY. West Nile virus. Lancet Neurol. 2007:6(2):171-181.  http://www.ncbi.nlm.nih.gov/pubmed/17239804

[4] Peterson LR, Brault AC, Nasci RS. West Nile virus: review of the literature. JAMA. 2013:310(3):308-315.  http://www.ncbi.nlm.nih.gov/pubmed/23860989

[5] Sejvar JJ. The long-term outcomes of human West Nile virus infection. Clin Infect Dis. 2007:44(12):1617-1624.   http://cid.oxfordjournals.org/content/44/12/1617.full

[6] Diamond MS. Progress on the development of therapeutics against West Nile virus. Antiviral Res. 2009:83(3):214-227.  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2759769/

[7] Centers for Disease Control and Prevention. Epidemic/epizootic West Nile virus in the United States: guidelines for surveillance, prevention, and control. http://www.cdc.gov/westnile/resources/pdfs/wnvguidelines.pdf.  Revised June 14, 2013. Accessed February 19, 2014.

What Physicians Should Know About MDMA (Ecstasy)

February 20, 2014

By Loren Gorcey

Peer Reviewed

With the recent resurgence of techno music and raves in the United States, the drug MDMA, known worldwide by the name “ecstasy,” has experienced a comeback. In light of a New Year’s Eve rave in Los Angeles in 2010, where 18 MDMA-related emergency room visits and 1 death occurred, MDMA is once again becoming a problem [1]. Locally, 4 MDMA-related emergency room visits and 2 MDMA-related deaths occurred this past summer at Electric Zoo, an annual electronic music festival in New York City’s Randall’s Island. While common drugs such as alcohol, cocaine, and marijuana remain at the forefront of nightlife-related abuse, teenagers, college students, and post-graduate young adults have taken a particular liking to ecstasy. In 2010, a study showed that 10% of teens reported using ecstasy, up from 6% in 2008. Data from that study translate into approximately one million high school students using ecstasy in the past month [2]. In addition, ecstasy-related emergency department visits increased approximately 75% between 2004 and 2008 [1]. Users of MDMA describe drug-induced sensations such as increased mental stimulation, enhanced sensory perception, and increased emotional warmth and empathy towards others. Due to the drug’s stimulant properties, it also increases physical stamina and is popularly used for the purpose of extended physical exertion, such as dancing. However, as enticing as these qualities may sound to a growing number of individuals, the drug’s adverse events and possibility of death outweigh the perceived benefits. It is important for the clinician to understand the pharmacology and mechanism of MDMA in order to properly counsel and treat patients.

MDMA, short for 3,4-methylenedioxymethamphetamine, is a Schedule I drug, also known by the names “XTC,” “Molly,” “Adam,” or “E.” To date, there have been over 16 ecstasy-related compounds identified [3]. First synthesized in 1912 as an appetite suppressant, ecstasy was later “rediscovered” and used as an adjunct to psychotherapy in the late 1970s until 1985 when it became designated as an illegal Schedule I drug due to its toxicity and high abuse potential [4]. Tablets sold as ecstasy usually contain a variety of other drugs and adulterants including amphetamine, methamphetamine, caffeine, ketamine, and acetaminophen, and tablets may not even contain MDMA at all [3]. MDMA causes the release of serotonin, dopamine, and norepinephrine from the central nervous system, in addition to inhibiting their reuptake (specifically serotonin’s) [5]. These neurotransmitters have important roles in mood control, thermoregulation, control of sleep, appetite, reward, and the autonomic nervous system. It has been shown that after administering MDMA, levels of cortisol, prolactin, antidiuretic hormone, and adrenocorticotropic hormone rise [6]. The rise in prolactin may be responsible for the emotional closeness ecstasy users experience, possibly mimicking a “post-orgasmic state” [7].

MDMA has a plasma half-life of 7.6 hours; users begin to experience desired effects within 1 hour of ingestion. It is primarily metabolized by the liver and excreted in the urine. Short-term adverse events frequently occur and include paranoia, anxiety, depression, pupil dilation, increased jaw tension and teeth grinding, loss of appetite, dry mouth, tachycardia, hot and cold flushes, and sweaty palms. Once the drug wears off (within 4-6 hours), users experience a “hangover” that can last up to 5 days, which includes anxiety, restlessness, irritability, sleep disturbances, and depression [8]. This hangover is likely due to the temporary reduction of serotonin, norepinephrine, and dopamine within the central nervous system. In addition to hangover, MDMA can produce other serious and potentially lethal side effects.

The risk of death for first-time users has been estimated to be between 1 in 2000 to 1 in 50,000 [9]. The most common causes of ecstasy-related death are hyperthermia, serotonin syndrome, and hyponatremia. Less frequent causes of death occur secondary to cardiac arrhythmias, disseminated intravascular coagulation, convulsions, and intracranial hemorrhage [4].

The syndrome of hyperthermia with rhabdomyolysis and multi-organ failure is well described in the literature. Both serotonin and dopamine are involved in central control of thermoregulation, and MDMA’s effects lead to the activation of mechanisms that conserve and produce heat. Many cases of hyperthermia do not result directly from toxic insult of MDMA and are instead associated with excessive exertion (such as dancing) combined with inadequate fluid replacement [10]. The users who dance all night in a warm environment (such as a crowded rave) predispose themselves to the development of exertional hyperthermia. Interestingly, the blood levels of MDMA found in those who suffer from hyperthermia vary drastically, leading to the notion that the hyperthermia-related effects of MDMA are not necessarily dose-dependent, but are more likely related to the circumstances in which the drug is taken.

Due to its mechanism of action, symptoms of MDMA toxicity overlap with those of serotonin syndrome, prompting the realization that serotonin syndrome itself is a manifestation of ecstasy toxicity. Ecstasy users commonly experience symptoms of mild serotonin syndrome (tachycardia, hyperthermia, agitation), which can quickly escalate to severe serotonin syndrome with high body fever and excessive muscle use [11]. As many users excessively exert themselves in crowded environments, the possibility of progression from mild to severe serotonin syndrome is alarming. Persons taking other medications, such as monoamine oxidase inhibitors or selective serotonin reuptake inhibitors (SSRIs), are most likely to develop severe serotonin syndrome in the absence of excessive physical exertion [12]. In light of a recent report by the CDC stating that 11% of Americans are prescribed an SSRI, a significant number of users and are at increased risk for developing severe serotonin syndrome. [13]

Many ecstasy users have learned that not drinking enough water while on ecstasy can lead to hyperthermia, and therefore drink excessively large volumes to prevent dehydration. Clubs have been known to encourage hydration, providing “chill-out” areas with free drinking water available. This education and encouragement has led to more ecstasy-related deaths due to dilutional hyponatremia and consequential cerebral edema [14]. In addition, MDMA has been shown to promote ADH release in humans, compounding the hyponatremia initiated by excessive water intake in the context of volume depletion caused by excessive exertion [6].

Liver failure has also been reported in association with MDMA use, but generally occurs in the picture of multi-organ failure caused by hyperthermia. However, episodes of isolated liver failure have occurred and histologically resemble acute cholestatic hepatitis. Studies have found eosinophils and histiocytes within the liver tissue, suggesting a hypersensitivity reaction [15].

Tolerance develops with chronic use of MDMA, where the positive effects diminish over time and the negative effects increase. Long-term use leads to memory and higher cognitive deficits, including problems with executive processing, logical reasoning, problem solving, and emotional intelligence. Chronic use of MDMA leads to significant serotonergic reductions in the cerebral cortex and, as a neuroadaptive response, higher receptor binding potential. Using electroencephalographic and neuroimaging studies, these serotonergic reductions have been associated with poor cognitive performance. It has even been suggested that light MDMA users may have dysfunctional inhibitory circuits in their hippocampus [16].

Overall, it is clear that serious acute illness and death are potential adverse events of MDMA. Some users will argue that they use MDMA because they believe it to be safer than other street drugs, such as heroin and cocaine. This is not the case. Despite the popular belief that certain forms of ecstasy such as “molly” (short for “molecule”) are purified and therefore safe, there is no formal regulation of the drug and users never know what exactly they are getting. In 2013 alone, 59% of pills sold as ecstasy, tested by the Ecstasy Data Project, did not even contain MDMA [17]. Although life-threatening adverse events are less frequent than with other street drugs, they still occur unpredictably. With 11% of the population on antidepressants, the concurrent use of MDMA in these patients can lead to severe and life-threatening serotonin syndrome. As clinicians, we have a responsibility to know this information and counsel our patients accordingly.

By Loren Gorcey is a 4th year medical student at NYU School of Medicine

Peer reviewed by Dr. Daniel Lugassy, Emergency Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

[1] Ecstasy overdoses at a New Year’s Eve rave–Los Angeles, California, 2010. MMWR Morb Mortal Wkly Rep, 2010. 59(22):677-681.

[2] Feliz J. Full report and key findings: the 2010 Partnership Attitude Tacking Study, sponsored by Met Life Foundation. The Partnership at Drugfree.org.  http://www.drugfree.org/newsroom/full-report-and-key-findings-2010 Published April 2011. Accessed October 2013.

[3] Wolff K, Hay AW, Sherlock K, Conner M. Contents of “ecstasy.” Lancet. 1995;346(8982):1100-1101.  http://www.ncbi.nlm.nih.gov/pubmed/7564809

[4] Kahn DE, Ferraro N, Benveniste RJ. 3 cases of primary intracranial hemorrhage associated with “Molly”, a purified form of 3,4-methylenedioxymethamphetamine (MDMA). J Neurol Sci. 2012;323(1-2): 257-260.   http://www.ncbi.nlm.nih.gov/pubmed/22998806

[5] Green AR, Mechan AO, Elliott JM, O’Shea E, Colado MI. The pharmacology and clinical pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”). Pharmacol Rev. 2003;55(3):463-508.   http://www.ncbi.nlm.nih.gov/pubmed/12869661

[6] Henry JA, Fallon JK, Kicman AT, Hutt AJ, Cowan DA, Forsling M. Low-dose MDMA (“ecstasy”) induces vasopressin secretion. Lancet. 1998;351(9118):1784.

[7] McElrath K. MDMA and sexual behavior: ecstasy users’ perceptions about sexuality and sexual risk. Subst Use Misuse, 2005;40(9-10):1461-1477.  http://www.ncbi.nlm.nih.gov/pubmed/16048828

[8] Curran HV, Travill RA. Mood and cognitive effects of +/-3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’): week-end ‘high’ followed by mid-week low. Addiction. 1997;92(7):821-831.

[9] Gore SM. Fatal uncertainty: death-rate from use of ecstasy or heroin. Lancet. 1999;354(9186):1265-1266.

[10] Henry JA. Ecstasy and the dance of death. BMJ. 1992;305(6844):5-6.

[11] Parrott AC. Recreational Ecstasy/MDMA, the serotonin syndrome, and serotonergic neurotoxicity. Pharmacol Biochem Behav. 2002;71(4):837-844.   http://www.ncbi.nlm.nih.gov/pubmed/11888574

[12] Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. Br J Anaesth. 2005;95(4):434-441.

[13] Pratt LA, Brady DJ, GuQ. Antidepressant use in persons aged 12 and over: United States, 2005-2008. Centers for Disease Control and Prevention. National Center for Health Statistics Data Brief No. 76. http://www.cdc.gov/nchs/data/databriefs/db76.pdf Published October 2011. Accessed January 2014.

[14] Maxwell DL, Polkey MI, Henry JA. Hyponatraemia and catatonic stupor after taking “ecstasy”. BMJ. 1993;307(6916):1399.

[15] Ellis AJ, Wendon JA, Portmann B, Williams R. Acute liver damage and ecstasy ingestion. Gut. 1996;38(3):454-458.   http://www.ncbi.nlm.nih.gov/pubmed/8675102

[16] Parrott AC. Human psychobiology of MDMA or ‘Ecstasy’: an overview of 25 years of empirical research. Hum Psychopharmacol. 2013;28(4):289-307.

[17] EcstasyData.org. Providing access to lab testing results for street ecstasy tablets. http://www.ecstasydata.org/results.php.  Updated January 2014. Accessed January 2014.