PrimeCuts

Primecuts – This Week In The Journals

June 17, 2015

By Arvind Reddy Devanabanda, MD

Peer Reviewed

Americans are anxiously awaiting a Supreme Court ruling in King v. Burwell. In this case, the existence of federal subsidies for health insurance coverage in 34 states is at risk. If the Supreme Court rules against the administration, average premiums in some states could double and this may lead to thousands dropping out of their health plans, which would hurt both Democrats and Republicans, and more importantly, American health care in general [1]. This week, we also look at other American public health challenges, including improving outcomes from out-of-hospital cardiac arrests.

Can early bystander CPR increase survival in out-of-hospital cardiac arrests?

A recent Swedish study published in the NEJM examined the impact of cardiopulmonary resuscitation (CPR) performed in out-of-hospital settings prior to arrival of emergency medical services (EMS) [2]. This remains a significant public health challenge as there are 420,000 deaths every year in the United States from out-of-hospital cardiac arrests. While international guidelines have established the benefit of CPR overall, one criticism has been the lack of randomized clinical trials to show that bystander CPR is beneficial. This recent study evaluated if CPR initiated before arrival of EMS was associated with an increase in 30-day survival compared to delayed CPR, after accounting for confounding variables such as age, sex, location of cardiac arrest, cause of cardiac arrest, initial cardiac rhythm, EMS response time from collapse to call for EMS, and year of the event.

The study included all cases of EMS-treated and bystander-witnessed out-of-hospital cardiac arrests in the Swedish Cardiac Arrest Registry from 1990 to 2011. Cases witnessed only by EMS and non-witnessed cases were excluded. CPR was performed before the arrival of EMS in 15,512 (51%) of cases and was not performed in 14,869 (48.9%) of cases. The 30-day survival rate was 10.5%, with an odds ratio of 2.15 (95% confidence interval, 1.88 to 2.45) when CPR was performed before EMS arrival. This compared to a 30-day survival rate of 4.0% when CPR was not performed before EMS arrival. Also of interest, telephone -based CPR instructions were associated with increased 30-day survival rates. The results of this study suggest that bystander CPR does indeed save lives. It was also noted that patients who underwent CPR before EMS arrival were likely in settings outside of the home. It is possible that many in-home cardiac arrests are witnessed by persons not trained in CPR, such as the elderly or children. It is estimated that approximately 3 million out of 9 million Swedes are trained in CPR. The question that now remains is how we as a nation can educate more people on basic life support and CPR. Should it be part of the mandatory educational curriculum of high schools and work places?

How can pharmacists help physicians control blood pressure?

The scope of the practice of pharmacists continues to evolve, particularly in the management of medications related to blood pressure control [3]. Prior systematic reviews and meta-analyses have shown that with interventions by pharmacists, systolic blood pressures can decrease by as much as 7.6 points (95% confidence interval -9.5 to 6.3) [4]. Importantly, this effect was limited by the extent of physician follow-up [5]. A recent randomized controlled trial conduced in Alberta, Canada hypothesized that by allowing pharmacists to independently prescribe drug therapy, hypertension can be better controlled. This study enrolled 248 adults with high blood pressure as defined by Canadian guidelines through community pharmacies, hospitals, or primary care centers in 23 communities in Alberta [3]. Patients in the intervention group received an assessment of blood pressure and cardiac risk factors from their pharmacists, including education on hypertension, laboratory monitoring, and follow-up visits, while the control group received usual care from their pharmacist or primary care physician. The primary outcome was change in systolic blood pressure (SBP) at 6 months. Overall, the intervention group had a mean reduction in SBP of 18.3 points compared with 11.8 points in the standard treatment group, with an odds ratio in favor of achieving BP target of 2.32 (95% confidence interval 1.17 – 4.15). There were, however, several limitations to the study. Neither the patients nor the pharmacists were blinded to the intervention, the sample size was small, and the pharmacists received remuneration for their participation, whereas the physicians did not. Finally, the study does not report adverse outcomes from medication management either from pharmacist or physician prescriptions. Despite these limitations, this study does provide evidence that the use of interdisciplinary teams that includes pharmacists is useful in achieving blood pressure targets.

Cinacalcet and cardiovascular disease in hemodialysis.

A disruption in bone metabolism is a common complication of chronic kidney disease (CKD). Fibroblast growth factor 23 (FGF-23), a hormone secreted by osteocytes and osteoblasts, has been shown to be elevated in patients with CKD and is associated with adverse cardiovascular outcomes. In animal models, FGF 23 has been shown to induce cardiac muscle hypertrophy as well as fatal cardiac arrhythmia [6]. Among patients receiving hemodialysis (HD), the serum concentrations of FGF-23 are two to three times the normal limits [6]. However, until the current EVOLVE trial (The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events), it was unknown whether reductions of FGF-23 can lead to improvement in cardiovascular and mortality outcomes [6]. In this study, the authors performed a secondary analysis of the EVOLVE trial comparing cinacalcet to conventional therapy to lower calcium levels in patients on HD with secondary hyperparathyroidism. Patients randomized to cinacalcet had a greater than 30% reduction in FGF-23 at week 20. This reduction in FGF-23 was associated with a nominally significant reduction in the death (HR 0.82, 95% CI 0.69-0.98), CV mortality (HR 0.66, 95% CI 0.50-0.87) and heart failure (HR 0.69, 95% CI 0.48-0.99). Overall, the study showed a nominal reduction in mortality associated with reductions of FGF23 levels and cinacalcet use and may suggest additional benefits of cinacalcet as well. However, association does not necessarily imply causation.

Other news in the journals:

Gastroenterology this week published a summary of recent advancements in the treatment of patients with co-infection of HIV and hepatitis C [7]. Also included in that same journal was an article describing how to achieve the fellowship of your choice, written from the perspective of several fellowship program directors [8].

Dr. Arvind Reddy Devanabanda is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Dr. Karin Katz, Chief Resident, Internal  Medicine at the VA Medical Center

Image courtesy of Wikimedia Commons

References:

1. The Health Care Supreme Court Case: Who would be Affected? New York Times. June 2, 2015. http://www.nytimes.com/interactive/2015/03/03/us/potential-impact-of-the-supreme-courts-decision-on-health-care-subsidies.html?_r=0

2. Hasselqvist. I, Riva G, Herlitz J et al. Early Cardiopulmonary Resuscitation in Out-of-Hospital Cardiac Arrest. New England Journal of Medicine. June 11, 2015. 372:2307-2315 http://www.nejm.org/doi/full/10.1056/NEJMoa1405796

3. Tsuyuki R, Houle S, Charrois T et al. A Randomized Trial of the Effect of Pharmacist Prescribing on Improving Blood Pressure in the Community: The Alberta Clinical Trial in Optimizing Hypertension (RxACTION). Circulation. Published Before Print. http://circ.ahajournals.org/content/early/2015/06/10/CIRCULATIONAHA.115.015464.abstract

4. Santashi V et al., Improving Blood Pressure Control Through Pharmacist Intervention: A meta-analysis of randomized control trials. Journal of American Heart Assoication. 2014 http://jaha.ahajournals.org/content/3/2/e000718.abstract

5. Altowaijri A et al., A systematic review of the clinical and economic effectiveness of clinical pharmacist intervention in secondary prevention of cardiovascular disease. Journal of Management Care Pharmacology. 2013 http://www.ncbi.nlm.nih.gov/pubmed/23697478

6. Moe et al. Cinacalcet, FGF23 and Cardiovascular disease in hemodialysis: The EVOLVE Trial. Circulation. Published before Print.  http://circ.ahajournals.org/content/early/2015/06/09/CIRCULATIONAHA.114.013876.abstract

7. Paul Y Kwo, Saurabh Agrawal. HCV/ HIV coinfection: A new treatment paradigm. Gastroenterology. Published online April 29, 2015 http://www.ncbi.nlm.nih.gov/pubmed/25935524

8. Andrew Chan, Kathyrn Peterson. How to position for the gastroenterology fellowship of your choice: The Program director perspective http://www.gastrojournal.org/article/S0016-5085(15)00578-8/abstract

 

 

Primecuts – This Week In The Journals

June 9, 2015

By: Karin Katz, MD

This past week, American Pharoah won Belmont and was the first Triple Crown winner in 37 years. “The Curious Incident of the Dog in the Night-Time” won best play at the 69th annual Tony Awards. Caitlyn Jenner made her debut on the cover of Vanity Fair. Now let’s turn our attention away from the Kardashians and back to the latest in medical news.

Not all 30-day readmissions are created equally

The Annals of Internal Medicine published a study evaluating differences between early and late hospital readmissions (1). Readmission rates are important quality metrics for hospitals, especially during the 30-days following discharge. However, a variety of both patient and provider factors can affect readmission rates. Do these factors have different impacts during different periods of this 30-day window? In a retrospective cohort analysis, Graham et al. evaluated factors contributing to readmission rates early (0 to 7 days) and late (8 to 30 days) after discharge. The study included a cohort of 13,355 admissions (representing 8,078 internal medicine patients) at a large urban teaching hospital over 2 years. Patients excluded were those who were sent to long-term acute care hospitals, as well as admissions followed by death within 30 days. The primary outcomes were early readmission and late readmission. The overall 30-day readmission rate was 19.7%, with 39.7% of readmissions occurring in the early period, and 60.3% of readmissions occurring in the late period. Not surprisingly, the sickest patients were readmitted the earliest. Early readmissions were associated with markers of the acute illness managed during a patient’s initial hospitalization. These markers included length of index hospital stay (OR for each day, 1.02, [95% CI, 1.00 to 1.03]), and whether the patient had a rapid response during the index hospitalization (OR, 1.48 [CI, 1.15 to 1.89]).

On the other hand, markers of chronic illness were associated with late readmissions. For example, being on hemodialysis was only associated with late readmissions (OR, 1.61 [1.19 to 2.17]). The authors hypothesized that readmissions in the first week after discharge were more associated with hospital care, and late readmissions were more associated with patient-specific factors. Therefore, they propose that quality metrics should reflect the heterogeneity between these two windows.

Long-term diabetes outcomes in veterans

Shifting gears from the acute inpatient setting to long-term care of patients with diabetes, the NEJM published a study evaluating intensive versus standard glycemic control on macrovascular disease in patients with type 2 diabetes (2). The Veteran Affairs Diabetes Trial (VADT) is a multisite, randomized, controlled trial of intensive compared to standard glucose control in veterans with type 2 diabetes. In both study groups, patients with a BMI of 27 kg/m2 or more were started on two oral agents, metformin plus rosiglitazone. Those with a BMI of less than 27 kg/m2 were started on glimepiride plus rosiglitazone. Patients in the intensive-therapy group were started on maximal doses, and those in the standard-therapy group were started on half of the maximal doses. For patients in the intensive-therapy group who did not achieve a glycated hemoglobin level of less than 6%, and for those in the standard-therapy group with a level of less than 9%, insulin was added.

In 2010, a study was published that reported no statistically significant differences in major cardiovascular events in patients treated with intensive-therapy compared to standard-therapy. The more recent trial in the NEJM includes 5 additional years of observational follow-up of the same study cohort. The study included 1,791 veterans with diabetes who were randomly assigned to receive either intensive or standard glucose control (3). Patients excluded from the study included those with a glycated hemoglobin level of less than 7.5%, a cardiovascular event in the last 6 months, advanced congestive heart failure, severe angina, life expectancy of less than 7 years, a body mass index (BMI) of more than 40, a serum creatinine more than 1.6 mg/dL, or an ALT more than three times the upper limit of normal.

Participants from the original study were followed through a national data registry. The primary outcome was the time to the first major cardiovascular event. The patients had a mean age of 60 years, and had diabetes for a mean of 11.5 years. More than 40% of patients had a previous cardiovascular event. The differences in the glycated hemoglobin between the intensive and standard-therapy group averaged 1.5 percentage points during the trial, and then decreased to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over about 10 years, the intensive-therapy group had a significantly lower risk of a major cardiovascular event than the standard-therapy group (hazard ratio, 0.83; 95% CI, 0.70 to 0.99, p=0.04), with an absolute reduction in risk of 8.6 major CV events per 1000 person-years. However, the intensive-therapy group did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; p=0.42).

Most randomized clinical trials to date have not shown a benefit of intensive therapy on macrovascular outcomes in patients with type 2 diabetes. In extrapolating the data of this study to patients, it is important to consider the homogeneity of the patient population, mostly older men with chronic and not newly diagnosed diabetes. In addition, the use of drugs in the thiazolidinedione class would not likely be used in a similar study started today, and novel therapeutic approaches to diabetes management could impact cardiovascular morbidity and mortality in the long-term.

Lipid-lowering therapy in acute coronary syndromes

Also in the NEJM this week, a new study evaluated different approaches to lipid-lowering therapy in the management of acute coronary syndrome (ACS). Cannon et al. evaluated the effect of ezetimibe combined with simvastatin, compared to simvastatin alone, in patients with ACS (4). Patients included men and women, at least 50 years of age, with an LDL level of 50 mg/dL or higher who were hospitalized for ACS in the last 10 days. The study included 18,144 patients followed over a median of 6 years. Those patients on long-term lipid-lowering therapy could have a maximum LDL level of 125 mg/dL prior to enrollment in the study. For patients not on lipid-lowering therapy, the maximum LDL level for eligibility in the study was 100 mg/dL. Patients were randomly assigned to receive simvastatin 40mg plus ezetimibe 10mg daily, or simvastatin monotherapy. Of note, for patients in either study group with an LDL level greater than 79 mg/dL on two consecutive measurements, the simvastatin dose was increased to 80mg in a double-blind fashion. Then, in 2011, when the FDA limited the use of this high dose of simvastatin, many patients had their dose reduced. The primary efficacy end point was a composite of death from cardiovascular disease, a major coronary event, or nonfatal stroke. The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group. This was compared to a Kaplan-Meier event rate of 34.7% in the simvastatin monotherapy group (hazard ratio, 0.936; 95% CI, 0.89 to 0.99, p=0.016). No major differences in adverse events between the two groups were reported. There were many limitations to this study. This trial was conducted based on the now outdated practice guidelines of using lipid-lowering therapy to target LDL goals. Is the study still applicable? The number needed to treat in the simvastatin-ezetimibe group to achieve the primary end point was 50. However, many patients were on a dose of simvastatin no longer used. Also of note, 42% of patients discontinued the study medication prematurely (equally in both groups). Although this study, supported by Merck, suggests a possible benefit of using both statin and nonstatin therapy adjunctively in the treatment of the acute coronary syndrome, more research is needed. The study does not discuss the cost of including ezetimibe in the treatment of acute coronary syndrome. This study also did not demonstrate differences in the rates of death from cardiovascular causes and from any cause in the two groups.

Preventing acute kidney injury during cardiac surgery

Acute kidney injury after cardiac surgery is associated with morbidity and mortality, and is quite common. Up to 30% of patients may develop acute kidney injury after cardiac surgery. In a multicenter, double blind, randomized trial, 240 patients enrolled between August 2013 and June 2014 at hospitals in Germany were randomized to receive remote ischemic preconditioning, or a sham procedure, prior to cardiac surgery (5). In remote ischemic preconditioning, brief episodes of ischemia and reperfusion are applied to distant tissues, in order to protect the myocardium from a lethal episode of ischemia and reperfusion, although the mechanisms of this are not completely understood. Several trials have provided evidence that remote ischemic preconditioning can reduce myocardial injury during coronary bypass surgery. This study evaluated whether or not ischemic preconditioning can also prevent acute kidney injury during surgery. Patients were followed up to 30 days post-operatively. Patients in the intervention group had remote ischemic preconditioning, which consisted of 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mm Hg (or at least 50 mm Hg higher than the systolic arterial pressure) to one upper arm after anesthesia induction. Then, patients had a 5-minute reperfusion with the cuff deflated. Patients in the control group had a sham remote ischemic preconditioning. This included 3 cycles of low pressure, 5-minute blood pressure cuff inflation and a 5-minute cuff deflation. The primary outcome of this study was the rate of acute kidney injury within the first 72 hours after cardiac surgery. In an intention-to-treat analysis, acute kidney injury was significantly reduced with remote ischemic preconditioning (45 of 120 patients [37.5%] compared with control (63 of 120 patients [52.5%]; absolute risk reduction, 15%; 95% CI, 2.56% to 27.44%; p=0.02). This corresponds to a NNT of 7. Interestingly, fewer patients receiving remote ischemic preconditioning received renal replacement therapy (7 [5.8%] versus 19 [15.8%]; absolute risk reduction, 10%; 95% CI, 2.25% to 17.75%; p=0.01). The mechanisms of ischemic preconditioning, and its pathophysiologic relationship to acute kidney injury, are incompletely understood. One hypothesis is that damage-associated molecules released from ischemic tissue during this process provoke self-protective mechanisms in the kidney. Ischemic preconditioning also decreased the post-cardiopulmonary bypass expression of biomarkers of acute kidney injury which were measured in the study, such as HMGB-1. There were no significant effects of this intervention on myocardial infarction, stroke or mortality. Even though there was no mortality benefit, the prospect of saving patients from needing hemodialysis is enticing. On the other hand, this is a small study, and it is important to consider other factors in the operating room that may affect the results. This includes estimated blood loss during surgery, as well as the type of anesthetic used. The benefit of this intervention is that it is low cost and easily applicable.

Also in the news…

A phase 1 trial was published on the safety and immunogenicity of a low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine on healthy adults in China. (6)

A review of alternative therapies marketed to treat Lyme disease was published in Clinical Infectious Diseases. More than 30 alternative treatments were found, including oxygen therapy, nutritional therapy, chelation, and even stem cell transplantation. Review of the medical literature did not substantiate these treatments (7).

Dr. Karin Katz is Chief Resident, Internal  Medicine at the VA Medical Center

Peer reviewed by Matthew Dallos, MD, a 3rd year resident at NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Graham KL, Wilker EH, Howell MD, Davis RB, Marcantonio ER. Differences between early and late readmissions among patients: a cohort study. Ann Intern Med 2015;162:741-749. http://annals.org.ezproxy.med.nyu.edu/article.aspx?articleid=2299852

2. Hayward RA, Reaven PD, Wiitala WL, Bahn GD, Reda DJ, Ge L, McCarren M, et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;372:2197-2206. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa1414266#t=articleDiscussion

3. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-139. http://www.nejm.org.ezproxy.med.nyu.edu/doi/full/10.1056/NEJMoa0808431#t=articleDiscussion

4. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1410489

5. Zarbock A, Schmidt C, Van Aken H, Wempe C, Martens S, Zahn PK, Wolf B, et al. Effect of remote ischemic preconditioning on kidney injury among high-risk patients undergoing cardiac surgery: a randomized clinical trial. JAMA 2015;313:2133-2141. http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2299339

6. Zhu FC, Hou LH, Li JX, Wu SP, Liu P, Zhang GR, Hu YM, et al. Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial. Lancet 2015. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60553-0/abstract

7. Lantos PM, Shapiro ED, Auwaerter PG, Baker PJ, Halperin JJ, McSweegan E, Wormser GP. Unorthodox alternative therapies marketed to treat lyme disease. Clin Infect Dis 2015;60:1776-1782. http://cid.oxfordjournals.org/content/60/12/1776

 

 

 

 

Primecuts – This Week In The Journals

June 1, 2015

By Samir Bhalla, MD

Peer Reviewed

Earlier this week, 14 individuals with ties to FIFA were indicted by US attorney general Loretta Lynch on charges of racketeering, corruption and conspiracy. A collaborative Swiss investigation remains underway to assess for corruption with regards to the 2018 and 2022 World Cup bids. These indictments raise questions into the integrity of FIFA, however will hopefully lead to significant improvements within the organization governing the world’s most popular sport.

Efficacy and Safety of a Recombinant Herpes Zoster Vaccine [1]

Speaking of improvements, the NEJM this week published the results of a landmark phase 3 clinical trial regarding the safety and efficacy of a recombinant varicella zoster virus (VZV) vaccine. Zostavax, the currently used live attenuated vaccine is estimated to be 51.3% efficacious for prevention of herpes zoster and 66.5% for post-herpetic neuralgia. These efficacy rates for the vaccine have been noted to decline with advancing patient age. Combined with inability to utilize the vaccine in immunocompromised patients, efforts have been made to create an improved and recombinant VZV vaccine.

HZ/su, produced by GlaxoSmithKline is a recombinant vaccine comprised of a VZV glycoprotein and a supplemental antigen which serves to enhance T cell response. This phase 3 large, multi-national, randomized clinical trial of over 15 thousand patients assessed the efficacy and safety of the vaccine compared to placebo. Enrolled patients over the age of 50 with no prior history of shingles or prior VZV vaccination were randomized and stratified by age to receive two doses of the vaccine or placebo. Following administration of the vaccine or placebo, patients were followed for nearly 30 months for development of herpes zoster, with cases confirmed by PCR testing of three skin lesions. Additionally, subgroups of each treatment arm were monitored for development of adverse reactions, titled the reactogenicity subgroup. The treatment arms were balanced with regards to age and sex of participants, however of note, the majority of patients were female and of Caucasian ethnicity.

The incidence of herpes zoster (HZ) was significantly decreased among all age groups in the vaccinated group as compared to placebo group, with an overall efficacy rate of 97.2%. This corresponds to a NNT of 36 and absolute risk reduction of 2.8%. Analysis of the reactogenicity subgroups revealed an increase in both local and systemic reactions within 7 days of administration of the vaccine compared to placebo. There was no significant difference in adverse effects beyond 30 days from administration.

Thus, the HZ/su recombinant vaccine decreased the incidence of herpes zoster with no significant change in efficacy with advancing age compared to placebo. This data shows enhanced efficacy compared to the published efficacy rates of Zostavax, however the two vaccines were not directly compared in this study.

Non-Invasive Ventilation for Hypoxemic Respiratory Failure [2]:

The use of non-invasive positive pressure ventilation (NIPPV) has become commonplace in inpatient medicine and has proven benefits for the management of acute respiratory failure secondary to COPD exacerbations and cardiogenic pulmonary edema. In patients with acute hypoxic respiratory failure, however, the best method of non-invasive ventilation is less well characterized.

In this week’s NEJM, Frat et al. published the results of their randomized clinical trial evaluating the relative efficacy of high flow nasal cannula versus standard nasal cannula and NIPPV in the management of acute hypoxic respiratory failure.

In the study, 310 patients with acute hypoxic respiratory failure, defined by PaO2/FiO2 ratio less than 300 and PCO2 no greater than 45 who did not require emergent intubation, were enrolled. Patients were randomized to three subgroups on admission; standard oxygen therapy, high flow nasal cannula for at least 2 days, or NIPPV for at least eight hours a day for 2 days. The patients were subsequently followed to assess for need for intubation within 28 days as the primary outcome and secondary outcomes of mortality in the ICU and within 90 days, and the number of ventilator free days.

Analysis of the results showed no significant difference in the need for intubation within 28 days of admission between the three groups. When focusing on severely hypoxemic patients with PaO2/FiO2 less than 200, however, high flow nasal cannula did produce a lower rate of intubation as compared to standard oxygen therapy and NIPPV. Additionally, patients in the high flow nasal cannula treatment group had a statistically significant increase in ventilator free days and reduction in 90 day mortality. This study, therefore, provides further generalizable evidence for the growing use of high flow nasal cannula in patients with acute hypoxemic respiratory failure.

Evidence for non-operative management for appendicitis? [3]

Although acute appendicitis is not a frequently encountered diagnosis in internal medicine, the dogma of early surgical intervention is engrained into the minds of nearly all physicians. This is a point that is heavily emphasized in medical school and board examinations. In this week’s New England Journal of Medicine, however, Flum provides a comprehensive review of the management of acute appendicitis and details evidence behind an “antibiotics-first” approach.

Interestingly, the first data on the so-called “antibiotics-first” strategy came from Naval officers who developed acute appendicitis while on active duty. Since this time, many randomized trials have investigated urgent appendectomy versus initiation of antibiotics for 48 hours, and delayed appendectomy if deemed necessary. It is difficult to produce a meta-analysis of the outcomes of these studies due to the large variability in treatment protocols and outcomes measured. As described by Flum, clinical outcomes were generally favorable for patients assigned to an antibiotic-first strategy. When compared to early appendectomy, patient’s who received antibiotic based treatment did not have a statistically significant higher risk of perforation, had decreased reported pain scores, and returned to work sooner. The frequency with which patients assigned to antibiotic treatment needed to be converted to urgent surgery ranged from 0-53%. This wide range of conversion to surgery has been attributed to use of different levels of adherence to antibiotic approach and varying criteria to assess need for surgery.

Questions still remain regarding the antibiotic regimen of choice, risk of recurrence, and the eventual need for appendectomy in patients managed acutely with antibiotics. Further standardized clinical trials will be needed to address these questions, and therefore the current recommendations still favor urgent appendectomy for acute uncomplicated appendicitis. There clearly is growing evidence, however, that non-operative antibiotic treatment is a reasonable strategy, especially in patients with contraindications to surgery.

Oral Steroids for Acute Radiculopathy Due to a Lumbar Herniated Disc [4]

Acute radiculopathy is a common presenting complaint in outpatient medicine, with estimates reporting a lifetime prevalence of nearly 10%. For the majority of patients, the likelihood of spontaneous resolution is high, and therefore management is geared towards symptomatic treatment only. For patients with persistent symptoms, however, the role of epidural spinal injections (ESI) and surgical interventions has been growing. Systemic glucocorticoids are often used by outpatient physicians, but the efficacy has not been investigated thoroughly, prompting the study published by Goldberg et al. in this week’s JAMA.

Patients presenting with radicular pain and MRI imaging confirming lumbar disc herniation as the etiology were randomized to receive a 15 day taper of prednisone or placebo. The Oswestry Disability Index (OSI) and Numerical Rating Scale (NRS) were used as markers for the patient’s degree of symptoms and pain. Analysis of the data showed that patients in the steroid arm of the trial had a statistically significant greater reduction in OSI than compared to placebo group at both 3 weeks and 52 weeks after treatment initiation. There was no significant reduction in reported pain measured by NRS at 3 or 52 weeks of follow up. The use of steroids was associated with a statistically significant higher rate of adverse effects including insomnia, nervousness, and appetite increase within 3 weeks, but no significant difference in long term adverse effects. Most importantly, there was no significant difference in the need for eventual spinal surgery between the groups at 1 year of follow up.

Thus, while often used for the management of acute radiculopathy, this study shows that oral steroids provide a decrease in disability and activity restriction, but without any significant change in pain or eventual need for surgery.

Also in the journals this week:

What is the evidence and guidelines regarding the use of beta blockers peri-operatively for both cardiac and non-cardiac surgeries? http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2297147

Should supplemental oxygen be given to all patients presenting with STEMI? This article published in Circulation reveals increased mortality associated with providing supplemental oxygen to patients with STEMI but without hypoxia. http://circ.ahajournals.org.ezproxy.med.nyu.edu/content/early/2015/05/22/CIRCULATIONAHA.114.014494.abstract

An update on the development of an Ebola vaccine: http://jama.jamanetwork.com.ezproxy.med.nyu.edu/article.aspx?articleid=2297164

Dr. Samir Bhalla is a 1st year resident, Internal Medicine, at NYU Langone Medical Center

Peer reviewed by Gregory Schrank, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References:

1) Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015;372:2087-2096  http://www.nejm.org/doi/full/10.1056/NEJMoa1501184

2) Frat JP, Thille AW, Mercat A, et al. High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure. N Engl J Med. 2015; DOI: 10.1056/NEJMoa1503326 http://www.nejm.org/doi/full/10.1056/NEJMoa1503326

3) Flum DR. Clinical practice. Acute appendicitis–appendectomy or the “antibiotics first” strategy. N Engl J Med. 2015;372(20):1937-43. DOI:+10.1056/NEJMcp1215006 http://www.ncbi.nlm.nih.gov/pubmed/25970051

4) Goldberg H, Firtch W, Tyburski M, et al. Oral Steroids for Acute Radiculopathy Due to a Herniated Lumbar Disk: A Randomized Clinical Trial. JAMA. 2015;313(19):1915-1923. doi:10.1001/jama.2015.4468. http://jama.jamanetwork.com/article.aspx?articleid=2293294

 

 

 

 

 

Primecuts-This Week in the Journals

May 19, 2015

By: Arvind Reddy Devanabanda, MD

This week we are reminded of the costs of over-testing and over-diagnosis in Dr. Atul Gawande’s article “Overkill” published in the New Yorker. Six years later Dr. Gawande revisits the health care costs in the city of McAllen, Texas, which was introduced in his prior article “Cost Conundrum”. Since the inception of the Affordable Care Act, cities across America, like McAlllen, have begun to see the cost of a Medicare patient flatten out. In addition, the United States’ health care inflation is at its lowest in fifteen years per Dartmouth Institute of Health Policy and Clinical Practice. [1]

What is the accuracy of a capsule colonoscopy (PillCam) testing and which patients is it appropriate for? [2]

Adaptation of the capsule endoscopy has been challenging as the first generation capsules captured photos at only 4 frames per second. The second generation capsules now capture at 35 frames per second with motion and 4 frames per second at rest, and the angle view increased from 156 degrees to 172 degrees. In a study published in Gastroenterology, second generation capsule endoscopy was used to identify polyps at least 6mm or bigger at 16 medical centers in the US and Israel

The primary endpoint of this prospective study was the diagnostic accuracy  of the capsule for detecting patients with polyps 6 mm or larger compared with conventional colonoscopy. Capsule endoscopy identified 1 or more polyps 6 mm or larger with 81% sensitivity (95% CI, 77-84%) and 93% specificity (95% CI, 91-95%) and polyps 10 mm or larger with 80% sensitivity (95% CI 74-86%) and 97% specificity (95% CI 96-98%). The study also found identification of adenomas 6 mm or larger with capsule endoscopy with 88% sensitivity (95% CI 82-93%) and 82% specificity (95% CI, 80-83%).

Thus, in an average risk screening population, capsule performance is a relatively sensitive and specific method of cancer screening for patients who cannot undergo colonoscopy or had incomplete colonoscopies.  Colonoscopy however, should still be the preferred method of detection.

A new approach to allergenic asthma presented at the meeting of the American Thoracic Society. [3]

Asthma is a chronic inflammatory and obstructive airway disease that has several clinical phenotypes and pathophysiological mechanisms. A particular mechanism seen predominantly in allergic asthma is driven by helper T cells (Th2).   In asthma,  the activation of Th2 cells leads to the production of cytokines IL- 4,5, and 13. The expression and production of these cytokines is regulated by transcriptional factor GATA-3. It has been previously shown that GATA3 overexpression is seen in lung biopsies of patients with severe asthma. This study developed a GATA3 specific DNA enzyme SB010 that has the ability to cleave GATA3.

This drug was then used in a randomized, double blinded, placebo-controlled, multicenter clinical trial in which 21 patients were assigned to receive 10 mg of SB010 and 19 received placebo. Each drug was administered by inhalation once daily for 28 days. The primary end point was late asthmatic response quantified by the area under curve (AUC) of forced expiratory volume in 1 second (FEV1). Results showed that SB010 attenuated the early and late asthmatic response by 11% and 34% respectively , while the placebo increased the early and late asthmatic response by 1% and 111% respectively. Furthermore, IL-5 levels and sputum induced eosinophilia were also attenuated in the treatment group. This is an exciting new development in asthma therapy, especially after so many years of little innovation in asthma treamtent.  Further clinical studies are required to understand if these benefits translate to benefit from persistent symptomatic asthma

A Potential New Target in the Treament of Atrial Fibrillation [5]

As we all encounter in our clinical practice, successful treatment of atrial fibrillation (AF) is challenging and the arrhythmia remains a significant risk factor for stroke, heart failure and hospitalization. Pathophysiologically, the shortening of action potential duration (APD) that occurs in atrial fibrillation promotes reentry and supports the perpetuation of the arrhythmia. While increased K+ channel current (specifically cardiac K2P3.1 channel current) is implicated in shortening APD during AF, other ion channels are poorly understood.

In this study, atrial tissues were obtained from patients with paroxysmal (p) or chronic (c) atrial fibrillation and from sinus rhythm (SR) controls. Ion channel expression was analyzed by PCR and Western blot. K2P3.1 subunits exhibited predominant atrial expression with K2P3.1 mRNA levels increased in cAF. By contrast K2P3.1 mRNA levels were not significantly increased in pAF. Subsequent pharmacologic inhibition of K2P3.1 channel prolonged APD in atrial myocytes from cAF patients compared to SR. In summary, the K2P3.1 channel can be considered as a novel target for pharmacologic inhibition and treatment of atrial fibrillation.

Update on renal denervation therapy for the use of drug resistant hypertension. [6]

Despite the effectiveness of conventional antihypertensive agents, about 10% of patients continue to have arterial hypertension and remain at high cardiovascular and renal risk. Renal denervation therapy is a recent development in the treatment of drug resistant hypertension that acts by decreasing the sympathetic response in hypertension. A recent study, Simplicity HTN– 3, however, failed to show reduction in blood pressure in the renal denervation group. The study was limited by the variable experience of interventionalists, the variable drug regimens, and the patients’ poor adherence to therapy prior to enrollment. A new study published in the Lancet, DENERHTN, with the same catheter used in Simplicity HTN3 study, was able to meet its primary end point with reduction of systolic blood pressure by 5.9 points compared to drug treatment group.  While Simplicity HTN-3 was a negative study, Simplicity HTN-1, Simplicity HTN-2 and DENERHTN, showed a positive impact of renal denervation therapy in drug resistant hypertension. As hypertension continues to be a major challenge due to medication adherence we look forward to further trials to clarify the role of nonpharmacologic treatments.

Also in the journals this week…

This week the meeting of the American Thoracic Society published results that in patients with non-hypercapenic, acute hypoxemic respiratory failure, treatment with high flow oxygen, standard oxygen or noninvasive ventilation did not result in significantly different intubation rates.  There was however a significant difference in favor of high flow oxygen with 90 day mortality rates. [7]

It has been shown that psychological distress is a risk factor in cardiovascular mortality. A recent metanalysis in Gastroenterology journal, looked at psychological distress in liver disease mortality. The age and sex adjusted hazard ratio was 3.48 in patients with depression, and after adjusted for health behavior, socioeconomic status, BMI, and diabetes the hazard ratio decreased to 2.59. [8] URL:

Did you know that prolonged TV viewing is associated witha  modest increase in risk for colorectal adenoma independent of leisure time physical activity and obesity? [9]

References :

  1. Gawande. A. Overkill. New Yorker. May 11, 2015
  2. Rex KD., Adler S., Aisenberg ., et al. Accuracy of Capsule Colonoscopy in detecting colorectal polyps in a screening population. Gastroenterology. May 2015, Volume 148, Issue 5, Pages 948-957.
  3. Krug N., Hohlfeld J., Kirsten A., et al. Allergen Induced Asthmatic Responses Modified by GATA3- Specific DNAzyme. New England Journal of Medicine. May 17, 2015. DOI: 10.1056/NEJMoa1411776
  4. I Cheng Ho et al. GATA3 is required for both STAT6 dependent and STAT6 independent pathways for TH2 cell differentiation. Nature Reviews Immunology. February 2009.
  5. Schmidt et al. Upregulation of K2P3.1 K+ current causes action potential shortening in patients with chronic atrial fibrillation. Circulation, May 2015. Published ahead of print
  6. Dagmara Hering. Renal Denervation superior to drug therapy in hypertension. Lancet. Volume 385, Issue 9981, Pages 1917-2014, e47-e48 (16–22 May 2015)
  7. Fratt J., Thille A., Mercatt A., et al. High flow oxygen through nasal cannula in acute hypoxemic respiratory failure. New England Journal of Medicine. Epub ahead of print. May 24, 2015
  8. Russ et al. Association between psychological distress and Liver disease mortality: A meta analysis of individual study participants. Gastroenterology. May 2015. Volume 148, issue 5, pages 958-966.
  9. Cao Y et al. Television watching and risk of colorectal adenocarcinoma. British Journal of Cancer. January 2015.

Arvind Devanabanda, MD is a first year resident at NYU Langone Medical Center
Peer Reviewer : Greg Scrhank, MD, Associate Editor, Clinical Correlations

Primecuts – This Week In The Journals

May 11, 2015

By Jessica Taff, M.D.

Peer Reviewed

As the curfew in Baltimore was lifted, the excitement of the Mayweather-Pacquiao boxing match died down, and Nepal continued on its recovery after the recent earthquake, medical literature remained relatively subdued this week as well. That is, until The New England Journal of Medicine (NEJM) grabbed national headlines with its brief report of Ebola Virus RNA isolated from aqueous humor in the eye of Dr. Ian Crozier, who was successfully treated for Ebola Virus Disease in September 2014, and subsequently presented with uveitis[1]. This finding underscores the importance of continued monitoring and reminds the public that we still know little about the epidemic virus that ravaged West Africa.

Moving toward diseases more common in the United States, the NEJM also published a trial related to coronary artery disease, evaluating the efficacy of continued dual antiplatelet therapy with aspirin and ticagrelor, a P2Y12 receptor antagonist, more than 1 year following a Myocardial Infarction (MI)[2]. The study randomized nearly 21,000 patients, 1-3 years after MI, in a double-blind fashion, to receive either ticagrelor 90mg twice daily, ticagrelor 60mg twice daily, or placebo in addition to their low-dose aspirin. Patients were followed for 33 months on average. Those receiving ticagrelor 90mg and 60mg doses had a significantly reduced rate cardiovascular death, MI, or stroke at 3 years compared to aspirin alone, with a hazard ratio of 0.85 (95% CI .75-0.96, p=0.008) and 0.85 (95%CI, 0.74-0.94, p=0.004) respectively. Despite this reduction in composite end points, there was an increase in the rate of major bleeding (defined by TIMI bleeding criteria as intracranial bleeding, overt signs of hemorrhage associated with a hemoglobin drop of >5g/dL or >15% absolute decrease in hematocrit, or fatal bleeding that directly results in death within 7 days)[3] in both the 90mg ticagrelor group (2.60%) and the 60mg ticagrelor group (1.06%) (p<0.001). Interestingly, dyspnea may be a rate-limiting side effect of ticagrelor, with 3-year event rates of 18.93% in those receiving 90mg of ticagrelor twice daily and 15.84% in those receiving 60mg twice daily, compared to 6.38% in the placebo group (P<0.001). This study adds to the growing body of literature in the risk versus benefit debate, including that from the recent Dual Antiplatelet Therapy (DAPT) study that similarly concludes P2Y12 antagonists have clear benefits but at the expense of increased risk of bleeding.

Moving on to gastroenterology, JAMA reports the results of a phase 2, randomized, double-blind, placebo-controlled study to determine optimal dosing, fecal recolonization, recurrence rate, and safety of nontoxigenic C. difficile strain M3 (NTCD-M3) for gut colonization and prevention recurrent C. difficile infection (CDI)[4]. 173 adult patients with CDI treated with metronidazole, oral vancomycin, or both, received oral liquid formations of the M3 spores in varying amounts (104 spores/day for 7 days [n=43]; 107 spores/day for 7 days [n=44]; 107 spores/day for 14 days [n=42]; or placebo for 14 days [n=44]). Of the 93% of participants who completed treatment, fewer patients receiving NTCD-M3 reported diarrhea (46% vs 60% in the placebo group) and abdominal pain (17% vs 33% in the placebo group). Those receiving NTCD-M3 also reported fewer treatment-related adverse events, 3% (95% CI 1%-8%) vs. 7% (95% CI 2%-19%), than those receiving placebo. Recurrence of CDI was significantly decreased following administration of NTCD-M3 (Odds Ratio 0.28; 95% CI, 0.11-0.69, P=0.006), with the fewest cases recurring in patients who received 107 spores/day for 7 days (OR 0.1; 95% CI, 0.0-0.6; P=0.01 compared to placebo). This new data suggests that NTCD-M3 is generally safe and tolerated by patients and may offer a new approach to current treatment with either prolonged antimicrobial treatment or fecal microbiota transplantation.

Prolonged or recurrent illness, along with a multitude of stressors, can contribute to episodes of major depression (MD) in many patients. A causal relationship between early stressful life events and later MD is long established, laying the groundwork for current studies of stress’ molecular signature in patients with MD. A newly published study in Current Biology[5] recruited 5864 women with recurrent MD and 5783 matched controls, and measured their lifetime stressful events, sexual abuse in childhood, telomere length, and amounts of mitochondrial DNA (mtDNA). Analysis demonstrated a highly significant association between MD and the amount of mtDNA (OR 1.33, 95% CI= 1.29-1.37; P=9.00x 10-42) and telomere length (OR 0.85, 95% CI, 0.81-0.89; P=2.84×10-14). This difference was even more pronounced when participants were stratified by number of lifetime adverse events. Women with recurrent MD had shorter telomeres and more mtDNA than those without MD, a finding that supports the role of MD in altering these biologic markers. Additional experiments reported also suggest a causal role of glucocorticoids, which reproduced similar results when administered to mice.

Now to a lighter subject; Proceedings of the National Academy of Sciences of the United States of America[6] this week published the results of an experiment comparing fructose and glucose in dietary behaviors. Twenty-four volunteers were randomized in a double-blinded, random-order cross-over design to receive a cherry-flavored juice containing either fructose or glucose. The patients then underwent functional magnetic resonance imaging (fMRI) sessions, during which they viewed blocks of high-calorie food items or nonfood items and rated their hunger, desire for food, and willingness to give up delayed monetary compensation in exchange for immediate high-calorie foods. Patients reported greater hunger, desire for food, and willingness to give up monetary compensation (mean difference in willingness to pay +/- Standard Error: 1.45 +/- 0.45 dollars, Z = 2.305, P= 0.015) after ingesting the fructose drink compared to the glucose drink. More objectively, fMRI also showed greater activation of the brain to food cues in the visual cortex and left orbital cortex of patients receiving fructose. Measured levels of insulin showed smaller increases in response to fructose as well, while other hormones active in feeding behavior (leptin and grehlin) did not differ significantly between the two groups. This article raises concern that the ubiquity of high fructose additives suppresses appetite to a lesser degree than glucose and promotes obesity via increased feeding behavior.

Also in the news:

The CDC’s Morbidity and Mortality Weekly Report[7] shows that screening rates for colorectal, breast, and cervical cancers have not improved since 2010 and remain approximately 10% below the Healthy People 2020 targets[8]. Only 58% of people ages 50-75 reported recent colorectal cancer screening, 73% of women 50-74 reportedly received a mammography, and 81% of women ages 21-65 had a recent pap test.

A viewpoint piece in The Lancet discuses the promising future of personalized medicine[9]. Utilizing a health simulation model, the authors estimate billions of dollars of cost savings with improved screening for cancer, diabetes, heart disease, hypertension, lung disease, and stroke as a result of personalization.

Clinical Infectious Disease released a report of antibiotic overuse rates in the US in 2011, showing that 8 in 10 Americans received antibiotic prescriptions that year[10]. Highest rates were seen among infants, children to age 9, and adults over age 65, with more than one antibiotic prescribed per these individuals. Of these antibiotics, amoxicillin was the most commonly prescribed for children/teenagers and azithromycin was most common for adults.

Dr. Jessica Taff is an Associate Editor, Clinical Correlations

Peer reviewed by Mark H. Adelman, MD, Associate Editor, Clinical Correlations

Image courtesy of Wikimedia Commons

References

1. Varkey JB, Shantha JG, Crozier I, et al. Brief Report: Persistence of Ebola Virus in Ocular Fluid during Convalescence. N Engl J Med 2015; May 7 2015. Epub ahead of print. http://www.nejm.org/doi/full/10.1056/NEJMoa1500306

2. Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015;372:1791-1800. http://www.nejm.org/doi/full/10.1056/NEJMoa1500857

3. Mehran R, Rao SV, Bhatt DL, et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011;123:2736-47. http://circ.ahajournals.org/content/123/23/2736.full

4. Gerding DN et al. Administration of spores of nontoxigenic Clostridium difficile strain M3 for prevention of recurrent C difficile infection: A randomized clinical trial. JAMA 2015 May 5; 313:1719. http://jama.jamanetwork.com/article.aspx?articleid=2281703

See more at: http://www.jwatch.org/na37776/2015/05/05/treatment-with-nontoxigenic-c-difficile-prevent-cdi#sthash.nwRGerQ6.dpuf

5. Cai N et al. Molecular signatures of major depression. Curr Biol 2015 May 4; 25(9):1146. http://www.cell.com/current-biology/fulltext/S0960-9822(15)00322-X

See more at: http://www.jwatch.org/na37716/2015/05/07/biomarkers-major-depression#sthash.4Oi2BdfO.dpuf

6. Luo S, Monterosso JR, Sarpelleh K, Page KA. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. PNAS 2015; published ahead of print May 4, 2015. http://www.pnas.org/content/early/2015/04/29/1503358112

7. Sabatino SA, White MC, Thompson TD, Klabunde CN. Cancer Screening Test Use – United States, 2013. Morbidity and Mortality Weekly Report. Centers for Disease Control and Prevention. May 8 2015. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6417a4.htm?s_cid=mm6417a4_w

8. US Department of Health and Human Services Office of Disease Prevention and Health Promotion. Healthy people 2020. Available at http://www.healthypeople.gov/

9. Dzau V, Ginsburg G, Van Nuys K, et al. Viewpoint: Aligning incentives to fulfill the promise of personalized medicine. The Lancet. Published online May 6 2015. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)60722-X/fulltext

10. Hicks LA et al. US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. Clin Infect Dis 2015 May 1; 60:1308. http://cid.oxfordjournals.org/content/60/9/1308.full

See more at: http://www.jwatch.org/na37789/2015/05/05/numbers-behind-antibiotic-overuse#sthash.JlpYVUAk.dpuf

 

Primecuts – This Week In The Journals

April 22, 2015

By Luke O’Donnell, MD

Peer reviewed

This week , winter finally gives way to a suggestion of spring and as temperatures flirt with the non-frigid range of the thermostat, more people—including the older among us—are leaving their apartments to enjoy the outdoors. A study this week in Circulation looked at sports-related sudden cardiac arrest (SCA) in this age group [1].

SCA represents a major public health issue worldwide accounting for almost half of cardiovascular mortality [1]. Circulation this week published the first comprehensive epidemiological assessment of SCA in sports activity among middle-aged participants in the United States. The research analyzed data from the Oregon Sudden Unexpected Death Study (Oregon-SUDS) which is an ongoing community-based prospective study of out-of-hospital SCA in Portland. Since 2002, any case of SCA has undergone a comprehensive evaluation including investigation of the circumstances of the SCA, pre-arrest medication record, and available autopsy data [1].

Per this study, middle age (rather cruelly) begins at 35 years and continues to age 65. This age range included 1247 case of SCA of which only 5 percent (63 cases) where sports related. Further assessment showed that the mean age of sport-related SCA was 51.1 plus or minus 7.7 years. SCA was significantly higher in men—RR 18.68 (CI 2.12-139.56). While the reasons for this gender-gap are unclear, the researchers felt that it might be secondary to increased rates of intense sport activity in middle-aged man compared to women, as well as underlying gender-related pathophysiological differences, including discrepancies in electrical conduction and plaque formation/rupture [1].

The other big finding in this analysis was most sports-related SCA was in cardiovascular risk factors. 16 percent of cases had known pre-existing cardiac disease such as coronary artery disease (CAD), atrial fibrillation (AF), and heart failure. 56 percent of patients had greater than one cardiovascular risk factors including diabetes mellitus, dyslipidemia, systemic hypertension, and smoking disorder. Of all the sports-related SCA cases, 36 percent had reported typical cardiovascular symptoms in the week preceding the SCA, such as a recent chest pain or dyspnea presentation [1].

The conclusion drawn by the authors was that the media overblows the risks of sport-related SCA. This study supports that sport-related SCA in middle-aged individuals is a relatively small portion of the overall SCA burden, reinforcing that exercise is a high-benefit, low risk activity [1]. Targeted education to patients with cardiovascular risk factors should include education on the necessity for chest pain and dyspnea evaluations as this could represent possible cardiac compromise.

Published as well this week is literature that furthers the discussion on the appropriate treatment of extended-spectrum beta-lactamase (ESBL) bacteria.

ESBL is found chiefly in Escherichia coli, Klebsiella pneumonia, Klebsiella oxytoca, and Proteus species. The unifying characteristic among these bacteria is the ability to hydrolyze third-generation cephalosporins and aztreonam, but on a whole can be inhibited by commercially available beta-lactamases inhibitors—such as clavulanic acid, sulbactam, and tazobactam. The effectiveness of piperacillin-tazobactam (PTZ), however, for the treatment of extended-spectrum beta- lactamase (ESBL) bacteremia is controversial.

Since first discovered 30 years ago in Germany, ESBL bacteria have posed a serious therapeutic challenge. Although many of these organisms are inhibited by tazobactam, EBSL organisms also have additional resistance mechanism such as the presence of AmpC B-lactamase—an emerging beta-lactamase with resistant to current inhibitors. One controversy that has emerged is whether or not carbapenems should be the empiric treatment choice in suspected ESBL bacteremia. More liberal use of carbapenems could propagate resistance, however, it could be more effective than PTZ for treating the critically ill patient.

Researchers at John Hopkins investigate 14-day mortality in patients with proven ESBL bacteremia who were empirically treated with PTZ versus carbapenems [2]. After ESBL bacteremia was confirmed with culture, all studied patients were switch to carbapenems. This retrospective study included 331 unique patients from January 2007 to April 2014 with a definitive end point of death [2].

In the study, 48% (103) received PTZ empirically and 52% (110) received carbapenems empirically. There were 17 deaths (17%) in the PTZ group and 9 (8%) deaths in the carbapenem group within 14 days of positive blood cultures. The adjusted risk of death was 1.92 (95% CI, 1.73 to 3.45) times greater for patients receiving empiric PTZ compared to empiric carbapenems [2].

Based on this study, patients who have expected ESBL bacteremia—such as those with supporting previous culture data—should receive empiric carbapenems [2,3].

As noted in the Clinical Infectious Diseases editorial commentary that accompanies the study, carbapenems may be the best empiric therapy for patients with serious blood stream infectious caused by ESBL-producing bacteria [3]. Obviously this is a constantly changing frontier, one in with bacteria are continuously adapting and additional research is necessary. Investigation is now focusing on being able to determine the causative agent of bacteremia in a day or less. Novel beta-lactamase inhibitors such as avibactam and relebactam are in the advanced stages of clinical development. A novel cephalosporin, ceftolozane, combined with tazobactam, has accompanying data from in vitro studies to suggest extended activity over most ESBL producing bacteria, and could become an effective agent to reduce the necessity of carbapenem use [3].

Also new this week, The New England Journal of Medicine (NEJM) published an investigation into the effectiveness of aerosolized measles vaccination [4], which investigators to ease the injection-related concerns of many Southern California parents.

Aerosolized measles vaccination has been used in Mexico since the 1980; however, data investigating its effectiveness is inconsistent due to heterogeneous study design, biased reports, and small sample sizes [4].

The World Health Organization (WHO), Center for Disease Control (CDC), and American Red Cross recruited nearly 2500 children to receive their primary dose of measles vaccine either by subcutaneous injection or aerosolized formulation in an open label trial in Prune, India. The children were then tested at day 91 to determine seropositivity via an enzyme-linked immunosorbent assay (ELISA) against measles IgG antibodies or via plaque reduction neutralization test (PRNT). In the aerosolized vaccination group, 84.5% (95% CI 82.5 to 88) had seropositivity determined to be greater than 0.1 optical-density units on ELISA or more than 120mlU per ml via PRNT. The subcutaneous group has a 94.6% (95% CI, 92.7-96.1) show seropositive by these means [4].

The end conclusion was that aerosolized vaccine against measles was immunogenic, but inferior to the subcutaneous vaccine with respect to seropositivity [4]. The ease of administration and the lack of hypodermic needle use, however, could possibly make up for this shortcoming in resource-limited areas. Further investigation in seropositive after two administrations of aerosolized vaccination and age-specific response is necessary [4].

Other studies circulating in this week’s literature include:

The NEJM published an investigation of alirocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin-Kexin type 9 (PCSK9). Inhibition of PCSK9 allows for increased degradation of low-density lipoprotein (LDL). The study included 2341 patient at high risk for cardiovascular events who had LDL cholesterol levels of 70mg /dL or more on maximum tolerated statin therapy. Patient received alirocumab subcutaneous injection verse placebo injection every 2 weeks for 78 weeks. At 24 weeks, the mean percent change from baseline in calculated LDL cholesterol level was negative 62 percent (P< 0.001). The actual effects on mortality are unclear. In post-hoc analysis, there was a 42 percent reduction in fatal coronary artery disease, non-fatal stroke, fatal stroke, unstable angina. Only 1.7 percent in the alirocumab group experienced these events versus 3.7 percent in the placebo group. When coronary artery disease requiring revascularization and congestive heart failure exacerbation where included, however, the difference between the two groups was not significant. [5]

The Lancet published an article investigating the effectiveness of antidepressants for recurrent depression versus taping off antidepressants with emphasis on mindfulness-based cognitive therapy (MBCT)—a psychosocial intervention that teaches patients with depression some practical skills to stay well long-term. While MBCT was not superior to maintenance antidepressant treatment, both forms of treatment had positive outcomes in terms of recurrence, residual depressive symptoms, and quality of life. [6]

There was little evidence that nighttime physician staffing models affect patient outcome per an article published in Chest this week. ICUs without physician at night may exhibit reduced hospital mortality that is possibly attributed to differences in end-of-life care practices. [7]

Dr. Luke O’Donnell is a 2nd year resident at NYU Langone Medical Center and a hopeful rave club denizen

Peer reviewed by Greg Schrank, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

1, Marijon E, Uy-Evanado A et Al. Sudden Cardiac Arrest During Sports Activity in Middle Age. Circulation. 131. 1384-1391. 2015. http://circ.ahajournals.org/content/early/2015/03/17/CIRCULATIONAHA.114.011988.abstract

2, Tamma P, Han J et al. Carbapenem Therapy is Associated With Improbed Survival Compared With Pipercillin-Tazobactam for Patient With Extended-Spectrum Beta-Lactamase Bactermia. Clinical infectious Disease. 2015 (60), 1319-1325. http://cid.oxfordjournals.org.ezproxy.med.nyu.edu/content/60/9/1319.full.pdf+html

3, Perez F et Bonomo R. Bloodstream Infection Caused by Extended-Spectrum Beta-Lactamase-Producing Gram-Negative Bacteria: How to Define the Best Treatment Regiment? Clinical infectious Disease. 2015 (60), 1326-1329. http://cid.oxfordjournals.org.ezproxy.med.nyu.edu/content/60/9/1326.full.pdf+html

4, Low N, Bavdekar A et al. A Randomized Controlled Trail of an Aerosolized vaccine against Measles. New England Journal of Medicine. 372(16), 1519-1529, 2015. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1407417

5, Robinson J, Farnier M et al. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. New England Journal of Medicine. 372(16), 1489-1499, 2015. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1501031

6, Kuykenm W, Hayes R et al. Effectiveness and cost-effectiveness of mindful-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomized controlled trail. The Lancet Online. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62222-4/abstract

7, Kerlin M, Harhay M et al. Nighttime Intensivist Staffing, Mortality, and Limits on Life Support. Chest. 147(4), 951-958. 2015. http://journal.publications.chestnet.org/article.aspx?articleID=1918415

Primecuts – This Week In The Journals

April 13, 2015

By Arvind Devanabanda, MD

Peer Reviewed

Last week, the president stated:“No challenge poses more of a public threat than climate change” at a round table discussion at Howard University. We are now four years into California’s drought and Governor Jerry Brown announced mandatory water restrictions ordering urban water use to be decreased by 25 percent. Many parts of Texas and Oklahoma also continue to experience severe droughts. The issue is again making global headlines, with the Pope to join the battle against climate change. Pope Francis, in his papal letter, will reach out to the United Nations Climate Change conference meeting to reduce global warming in Paris. For now, San Diego and much of California has started to look toward the sea as it plans to build additional desalination plants[1].

Does red cell storage duration affect cardiac surgery outcomes? [2]

Staying on the topic of essential needs, this week, the New England Journal of Medicine (NEJM) published a prospective, multi-centered trial focused red blood cell storage-time in transfusion for patients undergoing cardiac surgery. In this trial, 1100 adults were randomized to receive blood that was stored either for 10 days or less or 21 days or more. Participants in both groups received a median of 3 units of blood by postoperative day 7. Survival was assessed via the multiple organ dysfunction score (MODS), a measure sensitive to minor changes in clinical status that also incorporates mortality, ranging from 0 to 24, with higher scores indicating more severe disease. No significant difference in the increase in MODS was found between the short-term storage and longer-term storage groups (8.5 vs. 8.7, 95%CI -0.6 to 0.3, p=0.44). All-cause mortality between the two groups was also similar at day 7 (2.8% and 2.0%) and 28 days (4.4% and 5.3%). Further, the only adverse event with notable difference was hyperbilirubinemia, occurring more frequently in the longer-term storage group (1.5 mg per deciliter vs 0.8 mg per deciliter). Thus, the trial provides reassurance that dispensing older red blood cells is not significantly more harmful to patients.

Is manual thrombectomy beneficial during a percutaneous coronary intervention (PCI)? [3]

To date, several small trials concluded that thrombectomy during PCI, prior to stent deployment, decreases distal embolization and improves microvascular perfusion. In fact, practice guidelines were even changed to recommend routine manual thrombectomy if indicated, although new evidence questions if this is indeed beneficial. The Trial of Routine Aspiration Thrombectomy with PCI versus PCI alone in patients with STEMI (TOTAL) was published this week in NEJM to assess composite death from cardiovascular causes, recurrent myocardial infarction, cardiogenic shock, or New York Heart Association class IV heart failure within 180 days of stent placement. The study randomized 10,732 patients with STEMI undergoing primary PCI to a strategy of upfront manual thrombectomy prior to PCI versus PCI alone. There was no significant difference in composite death (6.9% in thrombectomy group vs. 7% in PCI alone group, hazard ratio [HR], 0.99) or cardiovascular death between the two groups (3.1% with thrombectomy vs. 3.5% with PCI alone. HR 0.90). Despite lack of mortality difference, there was a notable increase in stroke within 30 days in the thrombectomy group (0.7% vs 0.3%. HR 2.06.) These findings caution against changing clinical practice prematurely and emphasize the importance of large multicenter trials to verify findings of smaller trials.

P53 induces cell cycle arrest, senescence and apoptosis and now also Ferroptosis. [4]

We already know that p53 is a binding transcription factor important in cell cycle mediated arrest, senescence and apoptosis. According to a study by Le Jiang, et al. now published in Nature, p53 also plays a significant role in ferroptosis, a non apoptotic and iron dependent form of oxidative cell death. New research shows that p53 inhibits cystine uptake and sensitizes cells to ferroptosis by repressing the expression of SLC7A11 a key component of the cystine/glutamate antiporter. This allows p53 to inhibit cystine uptake and sensitize the cell to death by ferroptosis, suggesting a novel p53 mediated mechanism of tumor suppression.

EMG guided biofeedback mechanisms in treating functional abdominal distention. [5]

Functional bloating, irritable bowel syndrome and functional dyspepsia are often associated with sensation and visibility of abdominal bloating via a mechanism that remains poorly understood. A prospective study by Barba et al., published in Gastroenterolgy, seeks to clarify the muscular activity behind the morphological changes involved in abdominal distention. Forty-two patients with functional intestinal disorders (Irritable Bowel Syndrome or Functional Bloating) were assessed with CT and EMG of the abdominothoracic wall during basal states compared to episodes of severe abdominal distention. Episodes of abdominal distention were associated with diaphragmatic and intercostal contraction, increase in lung volume and anterior abdominal wall protrusion. The EMG guided biofeedback treatment arm showed a reduction in the activity of the intercostal and diaphragm muscles by 19% and 18% respectively, and a reduced abdominal girth by 2.5 cm. For patients with functional gut disorders, this article suggests that abdominal distension is a behavioral response that can be reduced with EMG-guided, respiratory targeted biofeedback therapy that potentially improves patient symptoms.

Other interesting questions answered in this week’s literature

What is the impact of antithrombotic therapy on stroke and bleeding risk for otherwise low risk patients with atrial fibrillation? The American Journal of Academic Cardiology published a study showing that antithrombotic therapy for low-risk patients [defined as CHADS2-VASc score less than 0 for men and 2 for women] with the presence of 1 additional stroke risk factor increased the stroke rate at 1 year to 1.55 per 100 people. Bleeding risk also increased by 2.35-fold, and death increased by 3.12-fold, bringing into question the risk-benefit analysis of therapeutic anticoagulation in low-risk patients with atrial fibrillation. [6] http://content.onlinejacc.org/article.aspx?articleID=2196166

Would you consider atrial fibrillation ablation and mitral valve surgery at the same time? NEJM published a study from Icahn School of Medicine suggesting an increased rate of freedom from persistent atrial fibrillation during concurrent ablation and valvular surgery, but higher risk for implantation of a permanent pacemaker.7 Ultimately, this remains a personal decision in which several factors, including this new data, should be considered.[7]  http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500528

And lastly, can dragons truly be dismissed as creatures of fantasy? If you too are wondering about this, be sure to check out this recent Nature article on how anthropogenic effects on the world’s climate may inadvertently pave the way for resurgence of these beasts. Or, if you are not in the mood for a good read, you can just enjoy dragons in the new season of Game of Thrones starting on HBO this week.[8] http://www.nature.com/nature/journal/v520/n7545/full/520042a.html

Dr. Arvind Devanabanda is a 1st year resident at NYU Langone Medical Center

Peer reviewed by Jessica Taff, MD, Chief Resident, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Gillis, J. “For Drinking Water in Drought, California Looks Warily to Sea” http://www.nytimes.com/2015/04/12/science/drinking-seawater-looks-ever-more-palatable-to-californians.html?hp&action=click&pgtype=Homepage&module=second-column-region&region=top-news&WT.nav=top-news.  Published April 11 , 2015

2. Steiner et al., “Effects of Red-Cell storage duration on Patients Undergoing Cardiac Surgery” New N Engl J Med 2015; 372:1419-1429 April 9, 2015 http://www.nejm.org/doi/full/10.1056/NEJMoa1414219

3. Jolly et al., “Randomized Trial of Primary PCI with or without routine manual thrombectomy” N Engl J Med 2015; 372:1389-1398 April 9, 2015 http://www.nejm.org/doi/full/10.1056/NEJMoa1415098

4. Le Jiang et al., “Ferroptosis as a p53-mediated activity during tumor suppression”. Nature 520,57–62, 02 April 2015  http://www.nature.com/nature/journal/v520/n7545/abs/nature14344.html

5. Barba et al., “Abdominothoracic mechanisms of functional abdominal distention and correction by biofeedback” Gastroenterology April 2015; Vol 148, issue 4, pages 732-739 http://www.sciencedirect.com/science/article/pii/S0016508514015315

6. Gregory Y.H. et al., “Oral anticoagulation , aspirin, or no therapy in patients with non valvular AF with 0 or 1 stroke risk factor based on the CHADS2-VASc score.” JACC . 2015; 65 (14): 1385- 1394. http://content.onlinejacc.org/article.aspx?articleID=2196166

7. Gillinov A et al., “ Surgical ablation of atrial fibrillation during Mitral valve surgery” N Engl J Med 2015; 372:1399-1409April 9, 2015 http://www.nejm.org/doi/pdf/10.1056/NEJMoa1500528

8. Hamilton A., et al., “ Zoology: Here be dragons” Nature 520 42-43 (02-April 2015) http://www.nature.com/nature/journal/v520/n7545/full/520042a.html

 

Primecuts – This Week In The Journals

April 8, 2015

By Jovan Begovic, MD

Peer Reviewed

On March 26th, a gas explosion on the Lower East Side of Manhattan caused a fire in three adjacent buildings, 25 injuries, and 2 recently confirmed deaths. Bellevue was readied for triage in case of an emergency rush of admissions from the accident, but luckily most victims were not severely injured and many did not require hospitalization. Several days later the 2 missing persons were discovered as search crews cleared out the wreckage from a sushi restaurant on the first floor. Now, most recently, a story has emerged regarding a possible cause of the gas explosion: there may have been an illegal gas siphoning operation underway to provide an adequate supply for the growing population of tenants [1]. This story continues to develop.

Are we overtreating pneumonia?

A study in the NEJM this week looked at the effects of different antibiotic treatment strategies for community-acquired pneumonia for non-ICU patients [2]. The strategies were beta-lactam monotherapy (BL), beta-lactam + macrolide (BLM), and fluoroquinolone monotherapy (FQ). The primary outcome measure was 90-day all-cause mortality, and secondary measures were length of stay and rate of complications. During the course of a year, over 2200 eligible patients in 7 hospitals in the Netherlands were treated using one of the three strategies during consecutive periods of 4 months, and each participating hospital was assigned a random order in which to implement the three separate strategies. The final results did not show a statistically significant difference in 90-day mortality between any of the strategies (9% BL vs. 11.1% BLM vs. 8.8% FQ), and no significant differences in length of hospital stay or rate of complications were observed. This large study attempted to minimize confounding factors by having each participating site rotate through periods of each treatment strategy. The results may have been affected by the characteristics and prevalence of the specific bacteria causing community-acquired pneumonia during different seasons and among different regions. If the results of the study are generalizable to other regions, it is reassuring to know that in case of limited resources we have a wide range of options for treating community-acquired pneumonia.

Should we leave intracranial stenosis be?

A neurointerventional study published in JAMA examined the long-term outcomes of intracranial stenting for patients with >70% intracranial arterial stenosis, a common precursor of ischemic stroke, compared to medical management alone [3]. Patients were randomized to receive balloon-expandable stent plus medical management, or medical management alone. The patients enrolled in this study had symptomatic intracranial stenosis as evidenced by TIA in the past 30 days. This trial was stopped early due to significant adverse events reported from a simultaneous trial (SAMMPRIS) involving intracranial stenting outcomes. The primary safety measure was any stroke, death, hemorrhage, within 30 days of randomization, and any TIA within 2 days to 30 days of randomization. The primary outcome measure was any stroke in the same territory within 12 months of randomization, or a TIA in the same territory day 2 through month 12 post-randomization. The primary outcome measure occurred more than twice as frequently in the intracranial stenting group (36.2%) compared to the medical management group (15.1%) (95% CI 6.7-27.6, p=0.02). Though many of the subgroup results were not statistically significant, this may have been a result of insufficient sample size due to premature termination of enrollment. Although in theory stenting should help alleviate symptomatic intracranial stenosis, the pathophysiology following intervention is in practice more complex and with present techniques leads to unfavorable outcomes when compared to traditional medical management.

Evaluating second-generation drug-eluting stents

A recent prospective cardiology trial published in the NEJM compared complication rates of percutaneous coronary intervention (PCI) using second-generation drug-eluting stents (Everolimus) versus coronary artery bypass grafting (CABG) [4]. The trial was conducted at 27 sites in Southeast Asia and included subjects 18 and older with >70% occlusion in at least 2 major vessels who were deemed acceptable surgical candidates. Over 5 years, 880 patients were enrolled in the study. Major adverse events, including death, myocardial infarction, or target-vessel revascularization), were higher in the PCI group (15.3%) compared to 10.6% of patients in the CABG group (hazard ratio, 1.47; 95% CI, 1.01 to 2.13, p=0.04). The rate of spontaneous MI was significantly higher in the PCI group (4.3% vs. 1.6%, p=0.02). In subgroup analyses, the rate of a major adverse event after PCI was particularly common in patients with diabetes (19.2 vs. 9.1%, p=0.007), suggesting, like several prior studies, that CABG may be more appropriate in the setting of advanced cardiovascular disease attributed to diabetes. While several prior studies have found PCI to be associated with increased risk of subsequent stroke, this trial showed similar risks of stroke in the two groups. Possible explanations proposed are differences in the CABG technique used and the underlying cardiovascular characteristics of the Asian population.

Going forward, larger prospective trials examining PCI versus CABG will aid us in better quantifying the risks and the benefits of the two procedures to our patients and their families, whom we must so often help make urgent, life-changing decisions at stressful times.

Postoperative transfusion goals

There are risks and benefits to consider when deciding on a transfusion strategy in the ICU. While a liberal transfusion strategy may decrease long-term complications by providing more oxygen to sensitive organs in times of bodily stress, the introduction of foreign blood product may also result in immune suppression that could subsequently lead to infection or malignancy. In The Lancet last week, a prospective study looked at the long-term survival of hip surgery patients aged 50 and older with cardiovascular risk factors that were randomized to liberal (Hb >10 mg/dL) versus restrictive (Hb>8mg/dL) blood transfusion strategies postoperatively. There was no significant difference in 3-year mortality between the two groups. In subgroup analyses, risk factors such age and various medical comorbidities did not correlate with a higher risk for either strategy. Likewise, stratified causes of death, including cardiovascular disease, cancer, and infection, contributed similar percentages to total mortality regardless of transfusion strategy. Prior transfusion goal studies have been largely observational and have rarely included follow-up times exceeding 180 days. This prospective trial, the largest of its kind with over 2000 participants enrolled, showed no differences in 3-year mortality even when stratified for causes of death, providing evidence in support of restrictive transfusion strategies that may conserve valuable hospital resources without detrimentally affecting patient outcomes [5].

Other tidbits…

Adverse effects of psychiatric medications

A JAMA paper analyzed the incidence of adverse drug events due to various psychiatric medications in patients admitted to the emergency department. Antipsychotics and lithium were the main players, though the remaining categories combined still made up a significant slice of the pie [6].

Putting Chagas on the radar screen

An impressive and growing number of Latin American immigrants develop heart failure as a sequelae of untreated Chagas disease. An excellent article in JAMA this week outlines the epidemiology as well as treatment strategies that can help control Chagas in the US [7].

Molecular physiology of water balance

Is your spiel on nephron channels getting rusty? Med students starting to give you quizzical looks? Check out this excellent review article in this week’s NEJM [8].

Dr. Jovan Begovic is a Resident at NYU Langone Medical Center

Peer reviewed by Karin Katz, MD, Internal Medicine, Resident, NYU Langone Medical Center

Image courtesy of Youtube

References

[1] http://www.nytimes.com/2015/04/01/nyregion/east-village-explosion-might-have-followed-attempt-to-hide-gas-siphoning.html?hp&action=click&pgtype=Homepage&module=photo-spot-region&region=top-news&WT.nav=top-news&_r=0

[2] Postma DF, Van werkhoven CH, Van elden LJ, et al. Antibiotic treatment strategies for community-acquired pneumonia in adults. N Engl J Med. 2015;372(14):1312-23. http://www.nejm.org/doi/full/10.1056/NEJMoa1406330?query=featured_home

[3] Zaidat OO, Fitzsimmons BF, Woodward BK, et al. Effect of a balloon-expandable intracranial stent vs medical therapy on risk of stroke in patients with symptomatic intracranial stenosis: the VISSIT randomized clinical trial. JAMA. 2015;313(12):1240-8. http://jama.jamanetwork.com/article.aspx?articleid=2208809

[4] Park SJ, Ahn JM, Kim YH, et al. Trial of everolimus-eluting stents or bypass surgery for coronary disease. N Engl J Med. 2015;372(13):1204-12. http://www.nejm.org/doi/full/10.1056/NEJMoa1415447

[5] Carson JL, Sieber F, Cook DR, et al. Liberal versus restrictive blood transfusion strategy: 3-year survival and cause of death results from the FOCUS randomised controlled trial. Lancet. 2014;9984(385):1183-89. http://www.sciencedirect.com/science/article/pii/S0140673614622868

[6] Olfson M. Surveillance of adverse psychiatric medication events. JAMA. 2015;313(12):1256-7. http://jama.jamanetwork.com/article.aspx?articleid=2208788

[7] Kuehn BM. Putting Chagas disease on the US radar screen. JAMA. 2015;313(12):1195-7. http://jama.jamanetwork.com/article.aspx?articleid=2208802

[8] Knepper MA, Kwon TH, Nielsen S. Molecular physiology of water balance. N Engl J Med. 2015;372(14):1349-58. http://www.nejm.org/doi/full/10.1056/NEJMra1404726

Primecuts – This Week In The Journals

March 23, 2015

By Ian Henderson, MD

Peer Reviewed

This past Tuesday The 2015 NCAA College Basketball tournament began. The yearly event, always filled with bracket busting upsets and edge-of-your-seat buzzer beaters, normally stars players and coaches. During the first round matchup between number 14 seed Georgia State and 3 seed Baylor, it was a seat that stole the show(1). This wasn’t a seat bolted to the floor in the stands but rather a stool with four wheels on it. Georgia State coach Ron Hunter, after an Achilles tendon injury he sustained while celebrating a previous victory, patrolled the sideline in his cast from the stool. Hunter and the seat became the center of attention when they went tumbling over on the court after Hunter’s son RJ Hunter hit a three to upset Baylor. The moment was more than another comical celebration and viral sensation. The moment beautiful summed up what is so special this time of the year, the excitement of watching and coaching your son hit an upset winning three point shot, is the staple of March Madness.

Revascularization Method in Multivessel CAD

The generally preferred revascularization method for patients with multivessel coronary artery disease (CAD) is coronary artery by-pass graft surgery (CABG) due it’s proven long term mortality benefit (2-5). This recommendation, however, is based on trials done before the advent of second generation drug eluting stents (DES). These newer stents not only contain different drugs but are also by nature of their design less thrombogenic and pro-inflammatory, leading to a lower rate of stent thrombosis, MI, and death compared to first generation DES.

In a observational registry-based study, Bangalore, et al.(6) compared revascularization with an everolimus-eluting second generation DES (esDES) to CABG in patients with multivessel CAD, defined as > 70% in at least 2 epicardial coronary arteries. The study included a total of 18,446 patients with multivessel CAD who underwent revascularization and the primary outcome was all cause mortality. Secondary outcomes included MI, stroke, and repeat revascularization. After a mean follow-up of 2.9 years?, PCI with esDES was associated with a similar risk of death as CABG (HR 1.04, CI 0.93-1.17, P=0.5). In a subgroup analysis of diabetics, a group in which CABG is traditionally favored, the risk remained the same. Patient’s undergoing PCI had a higher risk of initial MI than CABG (HR 1.51, P<0.001), but had a lower risk of stroke (HR 0.62, P<0.001). When looked further, it was found that the increased risk of MI was only statically significant for patient who did not have complete revascularization with PCI.

This study, though observational in nature, suggests that PCI with esDES may be equivalent to CABG in terms of long term mortality. The increased risk of MI with PCI appears to only occur when complete revascularization is not achieved. When complete revascularization is possible with PCI, it may be an equivalent option to CABG and offers patients with multivessel CAD a less invasive, yet equally effective treatment. Given the observational nature of this study, further randomized data is needed to change guideline recommendations.

Treatment of Severe Sepsis: to follow protocol or not?

Mortality from severe sepsis and septic shock has significantly decreased over the past decade, from 46.5% in the control arm of the Rivers, et al. trial of 2001(7), to 28.3% in the 2012 Surviving Sepsis Campaign (SSC) study(8). The decrease in mortality may be from institution of the SSC guidelines, based on Rivers, et al.’s early goal directed therapy (EGDT) strategy. In the decade since River’s landmark study, there have been many changes to the management of sepsis. To address the question of whether a full EGDT protocol is still necessary, a group of investigators designed three studies comparing usual care in that region to an EGDT protocol based strategy.

In the third of these studies, which was completed in England, Mouncey et al.(9) enrolled 1260 patients with severe sepsis or septic shock, which defined as known or proven infection, two or more SIRS criteria, and refractory hypotension. The primary outcome of the study was all cause mortality at 90 days. The patients were randomized to the usual group received treatment at the discretion of the treating physician for the initial 6 hours whereas patient’s in the EGDT group received treatment per SSC guidelines for the initial 6 hours. Treatment after the initial 6 hours was at the discretion of the treating physician. Mortality at 90 days did not significantly differ amount the two treatment groups (RR 1.01, CI 0.85-1.2, P=0.90). In the EGDT group, patients received more central venous lines, more RBC transfusions, a larger median volume of intravenous fluids, as well as more frequent treatment with vasopressors or inotropic agents. The outcome of this study is in line with the outcomes of its two sister studies, done previously in America(10) and Australia(11).

In combination, these studies show that current usual care for the treatment of severe sepsis and septic shock is as effective as protocol based EGDT therapy. This is likely due to advancements in care adopted and learned over the last decade, including some from the Rivers, et al. trial. A strict EGDT based treatment protocol for sepsis may not be necessary and may lead to greater resource utilization, as well as potentially increased morbidity from invasive procedures and transfusions . A closer look at this data, however, reveals the patients in these three studies had an overall lower severity of illness as compared to those in the Rivers, et al. study. Patients in this current study and the Australian study had lower mean APACHE-II scores, 18 and 15 respectively, compared to 20 in the Rivers study. In patients with a greater severity of illness, there may still be benefit to following EGDT.

Folic Acid Supplementation for Stroke Prevention

Stroke is a major cause of morbidity and mortality both in American and worldwide. This is even more pronounced in countries without folate-enriched food, such as China, where stroke is the leading cause of death (12). Primary prevention of stroke is exceedingly important given that 77% of strokes are first events and are always potentially devastating(13). Many trials have previously studied the use of folate supplementation for the secondary prevention of cardiovascular disease, with inconsistent results.

In attempt to better understand the role of folate in primary prevention of stroke in a Chinese population, Huo et al.(14) designed a randomized control trial comparing treatment with folate supplementation plus enalapril to enalapril alone. A total of 20,702 hypertensive patients with average of 60 were enrolled. Patients with a history stroke, MI, heart failure, or coronary revascularization were excluded. The rates of hyperlipidemia, diabetes, antiplatelet drug use were low (<4%) in these patients. Patients in both groups were treated with 10mg of enalapril daily, and patients in the intervention arm were given 0.8 mg of folic acid daily. Baseline folate levels and MTHFR (the main enzyme in folate metabolism) polymorphisms were checked in all patients. The primary outcome was first stroke; hemorrhagic or ischemic, fatal or non-fatal. After a median treatment period of 4.5 years, treatment with folate and enalapril was associated with a statically significant reduced risk of first stroke when compared to treatment with enalapril alone(HR 0.79, 95% CI 0.68-0.93). The folic acid supplementation group also had reduced rates of first ischemic stroke and a composite cardiovascular events outcome consisting of MI, stroke, and cardiovascular death. When stratifying patients by baseline folate level, there was a statistically non-significant trend toward a greater beneficial effect of folate supplementation in the lowest quartile serum folate levels.

This study, though not applicable to the United States, is of importance to the management of non-communicable disease from a global health perspective. Many countries outside of North America do not have folate-enriched foods, and as such have lower serum folic acid levels. Huo, et al. clearly demonstrate a beneficial effect of folate supplementation in preventing a first stroke. Given the global disease burden of stroke, an argument can be made for enriching food with folate or providing supplemental folate to members of these countries. It is unknown what benefit folate supplementation would have in patients with multiple risk factors for stroke, including diabetics and those with hyperlipidemia, as there were so few included in the study.

Second line treatment options for Rheumatoid Arthitis:

The mainstay of treatment of Rheumatoid Arthritis (RA) is the first line disease-modifying antirheumatic drug (DMARD) methotrexate. Despite treatment with methotrexate, many patients will continue to have symptoms and disease progression. With the advent of the biologic class of tumor necrosis factor(TNF) inhibitors, rheumatologists gained a powerful new class of second line add-on treatments. These drugs do not come without risks and are a large financial burden on the health care system, with international spending on these drugs exceeding $23 billion(15).

In this week’s edition of the British Medical Journal, Scott, et al. (15) conducted an open label randomized non-inferiority study comparing treatment of RA patients who have failed methotrexate with the addition a TNF inhibitor or additional DMARDs. A total of 214 patients were randomized and were given treatment per study guideline. For those treated with TNF inhibitors, treatment was consistent with National Institute for Health and Care Excellence (NICE) guidance. For those treated in the DMARD group, medication choices were made at the discretion of the treating rheumatologist and were permitted to be on up to 5 DMARDs. The primary outcome of the study was the score on the health assessment questionnaire at 12 months. In previous studies of RA, this score has been shown to be sensitive to change and equal in performance to disease activity measures, such as joint count (16,17). Patients in both groups experienced statistically significant decreases in their scores on the health assessment questionnaire at 12 months, -0.30 (95% CI -0.42 to -0.19) for the TNF group compared to ?0.45 (95% CI ?0.55 to ?0.34) for the DMARD group. Both of these reductions represent a reduction in patient disability and symptoms. The mean difference between the scores, -0.14(95% CI ?0.29 to 0.01) was below the pre-specified non-inferiority margin of 0.22. When looked at over shorter time intervals, patients treated with TNF had great reduction in disease activity scores at 3 and 6 months, though the scores at 12 months became similar.

This study demonstrates that treatment with 2nd line disease modifying agents in addition to methotrexate is at least equally efficacious as current standard of care treatment with a TNF inhibitor and methotrexate. This provides patients and health care providers with a more economical option to biologic therapy and provides patients intolerant to TNF inhibitors with a non-inferior treatment option. A disadvantage of DMARD treatment is patients are likely to have to take many medications as 55.8% in the DMARD group took 3 or more medications. TNF inhibitors appear to have a faster onset of symptom reduction and should be considered in patients whom need rapid treatment. Weaknesses of this study include its unblinded design and the variability in treatment regimens given among the DMARD group. It is possible that one of these DMARD regimens drove the non-inferior findings of the group, and other regimens are not as efficacious, as the authors did not do a stratified analysis.

Now for some fresh takes:

An article in this week’s issue of Gastroenterology, quantified and detailed, the growing problem that Nonalcoholic Steatohepatits(NASH) has become in America. NASH is now the 2nd leading cause of cirrohosis among adults awaiting transplant with the number of adults awaiting transplants tripling since 2004(18).

Statins are one of the most frequently prescribed drugs by internist and are felt to be generally safe. Despite the teratogenic risk of statins in humans is not known. This week’s BMJ has a cohort study looking the safety of statins in pregnancy(19).

An article in these week’s edition of JAMA shows the benefits of aspirin prevention in colon cancer vary by genotype. In fact, there may be some in whom aspirin use increases colon cancer risk(20).

Dr. Ian Henderson is a 1st year resident at NYU Langone Medical Center

Peer reviewed by  Gregory Schrank, associate editor, Clinical Correlations

References:

1. SPOUSTA, TOM. “Georgia State’s Sixth Man Has Four Wheels and Countless Fans” New York Times. MARCH 20, 2015. http://www.nytimes.com/2015/03/21/sports/ncaabasketball/georgia-states-sixth-man-has-four-wheels-and-countless-fans.html?ref=sports&_r=0

2. Hannan EL, Racz MJ, Walford G, et al. Long-term outcomes of coronary-artery bypass grafting versus stent implantation. N Engl J Med 2005;352:2174-83. http://www.ncbi.nlm.nih.gov/pubmed/15917382

3. Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial. Lancet 2013;381:629-38.

4. Hannan EL, Racz MJ, McCallister BD, et al. A comparison of three-year survival after coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1999;33:63-72.

5. Hannan EL, Wu C, Walford G, et al. Drug-eluting stents vs. coronary-artery bypass grafting in multivessel coronary disease. N Engl J Med 2008;358:331-41.

6. Bangalore, et al. Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Disease. N Engl J Med Published online March2015. DOI: 10.1056/NEJMoa1412168 http://www.nejm.org/doi/full/10.1056/NEJMoa1412168

7. Rivers, et al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. N Engl J Med 2001; 345:1368-1377  http://www.nejm.org/doi/full/10.1056/NEJMoa010307

8. Levy MM, Artigas A, Phillips GS, et al. Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. Lancet Infect Dis2012;12:919-92

9. Mouncey, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med. Pubilished online March 17, 2015. DOI: 10.1056/NEJMoa1500896

10. The ProCESS Investigators. A randomized trial of protocol-based care for early septic shock.N Engl J Med 2014;370:1683-1693. http://www.nejm.org/doi/full/10.1056/NEJMoa1401602

11. The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014;371:1496-1506

12. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-2128.

13. Lloyd-Jones D, Adams RJ, Brown TM, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation. 2010; 121(7):e46-e215.

14. Huo Y, Li J, Qin X, et al. Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial. JAMA. Published online March 15, 2015. doi:10.1001/jama.2015.2274.  http://jama.jamanetwork.com/article.aspx?articleid=2205876

15. Scott David L, Ibrahim Fowzia, Farewell Vern, O’keffe Aidan G, Walker David, Kelly Clive et al. Tumor necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis” TACIT non-inferiority randomized controlled trial. BMJ 2015;350 :h1046

16. Scott DL, Strand V. The effects of disease-modifying anti-rheumatic drugs on the Health Assessment Questionnaire score. Lessons from the leflunomide clinical trials database. Rheumatology2002;41:899-909.  http://www.ncbi.nlm.nih.gov/pubmed/12154207

17. Her M, Kavanaugh A. Patient-reported outcomes in rheumatoid arthritis. Curr Opin Rheumatol2012;24:327-34.

18. Wong, et al. Nonalcoholic Steatohepatitis Is the Second Leading Etiology of Liver Disease Among Adults Awaiting Liver Transplantation in the United States. Gastroenterology. Published Online November 24, 2014. doi:10.1053/j.gastro.2014.11.039 http://www.mdlinx.com/gastroenterology/medical-news-article/2014/12/02/fatty-liver-unos-optn-waitlist-mortality/5757051/?

19. Nan H, Hutter CM, Lin Y, et al. Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants. JAMA. 2015;313(11):1133-1142. doi:10.1001/jama.2015.1815.

20. Bateman Brian T, Hernandez-Diaz Sonia, Fischer Michael A, Seely Ellen W, Ecker Jeffrey L, Franklin Jessica M et al. Statins and congenital malformations: cohort study BMJ 2015; 350: h1035 http://www.bmj.com/content/350/bmj.h1035

 

 

 

Primecuts – This Week In The Journals

March 9, 2015

By Anjali Mone, MD

Peer Reviewed

As the Northeast recovers from non-stop snowstorms and the frozen East River thaws, daylight savings time may finally mark the end of winter, except in Arizona and Hawaii who will not be “springing forward”. Arizona and Hawaii might be on the right track since “springing forward” and “falling back” have actually been associated with increased traffic accidents. While our nation debates whether losing an hour of sleep actually saves energy or increases productivity, one country in West Africa can finally say that it is Ebola free. However given that the disease remains prevalent there, much work is still needed, particularly in terms of developing a vaccine to combat this deadly epidemic.

Hepatitis C gets all the hype….

However another viral hepatitis has shown significant advancements in terms of vaccine development. Hepatitis E is thought to be a problem isolated only to pregnant women in resource-poor, underdeveloped countries, however it is also a significant cause of acute viral hepatitis in developed countries. In a rapidly globalizing world, with more and more travel and contact between distant nations and peoples, this disease is having an increasingly world-wide impact. Vaccines against Hepatitis E have been available for some time, however no studies had been conducted to demonstrate whether the vaccines are effective in the long-term. A recent study published in the NEJM confirms that the Hepatitis E vaccine has long-term efficacy and more importantly suggests that Hepatitis E is preventable with a vaccine. In a randomized, double-blinded, placebo-controlled trial conducted in China, Zhang et al. studied 112,604 healthy patients ages 16 to 65. Initially a phase 3 clinical trial was performed to demonstrate that the vaccine, commercially named Hecolin, was safe and 95% effective over a one year period after vaccination. [3] In the long-term follow-up study Zhang et al [4] demonstrate that the vaccine provides sustained protection against Hepatitis E for at least 54 months. Furthermore, no significant adverse events were noted. While it is true that this study is mainly relevant for the strain of Hepatitis E prevalent in China, it is promising research that suggests vaccines can now be developed to protect against all strains of Hepatitis E. This vaccine would effectively be able to eradicate a disease that was previously fatal among pregnant women, particularly those living in crowded, unsanitary conditions. Even though a Hepatitis E vaccine has been available for some time, limited data about disease burden in both developed and underdeveloped regions of the world have likely limited its availability. This is the first study in which Hepatitis E vaccines have progressed beyond a phase 2 clinical trial, and thus may have far-reaching impact in terms of preventing and controlling this disease.[5]

Ulcerative colitis and budesonide foam.

Patients with ulcerative proctitis and ulcerative proctosigmoiditis are traditionally limited to treatment with oral or rectal mesalamine along with suppositories and rectal enemas. However there are various limitations to this treatment modality including the fact that it is not only difficult to administer this therapy but also difficult for patients to retain. Although systemic steroids are effective against ulcerative colitis, targeted approaches are desired to avoid the side effects of systemic steroids including weight gain, decreased bone density, and adrenal abnormalities. A recent study with two randomized, double-blind, placebo-controlled phase 3 trials demonstrated that budesonide foam was a safe and effective method for delivery and retention of budesonide to induce remission in patients with ulcerative proctitis or ulcerative proctosigmoiditis. At 6 week follow-up, patients receiving budesonide foam achieved remission significantly more when compared with placebo (Study 1: 38.3% vs 25.8%; P =0.0324; Study 2: 44% vs 22.4%; P<0.0001). Furthermore, those using budesonide foam had significant improvement in rectal bleeding as well as endoscopic improvement. [6]

Could eating nuts be good for your heart?

The health benefits of a Mediterranean diet and more specifically consumption of peanuts and tree nuts has previously been demonstrated in various studies. Nut consumption has been linked to decreased risk of hypertension, diabetes mellitus, and coronary artery disease. [7] In fact, recent studies have shown that nut consumption was found to be inversely associated with total mortality and cause-specific mortality. However, studies looking at high intake of nuts and reduced mortality were primarily conducted in individuals of European descent and high socioeconomic status. A recent study published in JAMA addressed this disparity and demonstrated that eating nuts is associated with a lower risk of cardiovascular disease and death across many different ethnic and socioeconomic groups. This prospective study included 71,764 black and white Americans, primarily of lower socioeconomic status, as well as over 130,000 men and women living in Shanghai. Using well-validated food frequency questionnaires, researchers in this study gathered information about nut-consumption. After following participants for up to 12 years, and controlling for other confounding factors, they found that those with the highest nut consumption had a 21% lower risk of death in Americans of African and European descent and 17% lower risk among Asians. There was a similar association for lower risk of deaths from cardiovascular disease in all ethnicities, however decreased risk of ischemic and hemorrhagic stroke was only found to be significant in Asians. Overall this study suggests that nut consumption, which is fairly affordable for all socioeconomic classes, is a good intervention to prevent all cause mortality. [9]

Does intensity of exercise matter?

It is well established that regular exercise is essential for reducing obesity, diabetes, and heart disease. However until now it was unknown whether increased exercise intensity provided any additional health benefits. This single-center, parallel-group trial followed 300 patients with abdominal obesity over a 24 month period. The study had four trial arms: no exercise, low-amount, low-intensity exercise (LALI), high-amount, low-intensity exercise (HALI), or high-amount, high-intensity exercise (HAHI). In terms of their primary endpoints, waist circumference reduction was higher in the exercise groups than the control groups, but there were no significant differences among the exercise groups. The other primary endpoint, reduction in 2-hour glucose level, was greater in the HAHI group versus control, however did not differ between the LALI or HALI groups versus control group. As would be expected, overall weight loss was greater in all exercise groups compared with the control group. However weight loss did not differ among exercise groups, which suggests that higher exercise intensity provides no additional benefits in abdominal obesity reduction. Furthermore reductions in 2-hour glucose levels is best achieved by high amounts of high intensity exercise, however the benefit of reducing 2-hour glucose level in non-diabetic adults remains unclear. Either way these results do not provide any information that should affect current exercise guidelines. [10]

In other medical news…..

Twins and working out.

Researchers in Finland took advantage of the FinnTwin16 database and studied 10 pairs of adult identical twins in their early to mid twenties, particularly those whose exercise habits had become different since leaving their childhood homes. It was difficult to find these types of twins, because most had similar exercise habits. However in a few twin pairs, work or family pressures led one twin to work out less than the other. They measured body composition, insulin sensitivity, endurance capacity and also scanned each twin’s brain. The twin that worked out less had lower endurance, higher body fat percentage, and signs of insulin resistance, despite similar diets. Furthermore the active twin generally had more grey matter in the brain, particularly in motor control and coordination. This study only showed divergence over 3 years, which shows how quickly our bodies can change. [11]

Head transplant – Fantasy or reality?

In a provocative and controversial journal article, an Italian neuroscientist, Dr. Sergio Canavero outlines a possible technique to perform a human head transplant to help patients suffering from conditions such as muscular dystrophy or quadriplegia. Dr. Canavero suggests that the biggest obstacle to performing this procedure is reconnecting the donor and recipient spinal cords. However it remains unclear if this is just science fiction or a real possibility. [12]

Ebola vaccine on the horizon?

Now moving from fantasy to reality. In breaking news, the last Ebola patient in Liberia was recently discharged. However the disease remains a threat in neighboring countries including Sierra Leone and Guinea, and there is still a need for a vaccine. In a recent issue of JAMA, Lai et al report successful administration of postexposure experimental Ebola vaccination to a physician who had a needlestick while working in an Ebola treatment unit. While it is not possible to make any conclusions from one case report, it seems likely this intervention was helpful in controlling Ebola virus replication. There was a similar case in 2009 when a laboratory worker in Germany had a needlestick injury and also received the vaccine, with nearly identical results. These cases suggest that a much needed Ebola vaccine may become a reality in the near future. [13]

The first biosimilar drug – a step towards making medications more affordable.

On the subject of medications that need to be widely available, the US FDA took a major step towards making biotech drugs more affordable and approved Sandoz to make the first biosimilar cancer drug, Zarxio, which is almost identical to neupogen. Unlike generic drugs, biosimilar drugs are derived from living organisms.

Sleep and stroke.

Recently published in Neurology, researchers have found that people that sleep more may have higher risk for stroke. After controlling for multiple variables, the authors found that individuals that slept over 8 hours a day were at higher risk for stroke than those who slept 6-8 hours. Furthermore, the risk of stroke was higher among people who reported their sleep requirements increased over the study period. There is an important distinction to be made here and the authors caution the reader not to misinterpret the study as it is an association, not a causal relationship. Furthermore, their data was collected from surveys and self-reports which can be unreliable. However, this data suggests that there could be something happening in the brain preceding a stroke leading individuals to require more sleep, so maybe excessive sleep is an early sign of pending stroke. [14]

PPI use and CDI.

Although antibiotic use is the most well-established risk factor for infection with C. difficile (CDI) through its effect on the intestinal microbiota, there has been increasing literature suggesting a link between PPI use and CDI. Recently published in JAMA, a restrospective study shows that PPI use is associated with a higher risk of CDI recurrence. The authors suggest that unnecessary PPI use should be stopped at the time of CDI diagnosis. [15] This becomes more relevant in light of growing evidence of the increasing burden of CDI in the US- Lessa et al. recently published data in the NEJM that showed that CDI was responsible for almost ½ million infections. The need to reduce C. difficile risk factors is therefore more than evident. [16]

Dr. Anjali Mone is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References

1. Dalton HR, Hunter JG, Bendall R. Autochthonous hepatitis E in developed countries and HEV/HIV coinfection. Seminars in liver disease. Feb 2013;33(1):50-61. http://www.ncbi.nlm.nih.gov/pubmed/23564389

2. Dalton HR, Bendall R, Ijaz S, Banks M. Hepatitis E: an emerging infection in developed countries. The Lancet. Infectious diseases. Nov 2008;8(11):698-709.

3. Zhu FC, Zhang J, Zhang XF, et al. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet. Sep 11 2010;376(9744):895-902. http://www.ncbi.nlm.nih.gov/pubmed/20728932

4. Zhang J, Zhang XF, Huang SJ, et al. Long-term efficacy of a hepatitis E vaccine. The New England journal of medicine. Mar 5 2015;372(10):914-922.  http://www.nejm.org/doi/full/10.1056/NEJMoa1406011

5. Teshale E, Ward JW. Making hepatitis E a vaccine-preventable disease. The New England journal of medicine. Mar 5 2015;372(10):899-901.  http://www.nejm.org/doi/full/10.1056/NEJMp1415240

6. Sandborn WJ, Bosworth B, Zakko S, et al. Budesonide Foam Induces Remission in Patients With Mild to Moderate Ulcerative Proctitis and Ulcerative Proctosigmoiditis. Gastroenterology. Jan 30 2015. http://www.sciencedirect.com/science/article/pii/S0016508515001547

7. Luo C, Zhang Y, Ding Y, et al. Nut consumption and risk of type 2 diabetes, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis. The American journal of clinical nutrition. Jul 2014;100(1):256-269.

8. Afshin A, Micha R, Khatibzadeh S, Mozaffarian D. Consumption of nuts and legumes and risk of incident ischemic heart disease, stroke, and diabetes: a systematic review and meta-analysis. The American journal of clinical nutrition. Jul 2014;100(1):278-288. http://www.ncbi.nlm.nih.gov/pubmed/24898241

9. Luu HN, Blot WJ, Xiang YB, et al. Prospective Evaluation of the Association of Nut/Peanut Consumption With Total and Cause-Specific Mortality. JAMA internal medicine. Mar 2 2015.

10. Ross R, Hudson R, Stotz PJ, Lam M. Effects of exercise amount and intensity on abdominal obesity and glucose tolerance in obese adults: a randomized trial. Annals of internal medicine. Mar 3 2015;162(5):325-334.  http://www.ncbi.nlm.nih.gov/pubmed/25732273

11. Rottensteiner M, Leskinen T, Niskanen E, et al. Physical activity, fitness, glucose homeostasis, and brain morphology in twins. Medicine and science in sports and exercise. Mar 2015;47(3):509-518.  http://www.ncbi.nlm.nih.gov/pubmed/25003773

12. Canavero S. The “Gemini” spinal cord fusion protocol: Reloaded. Surgical neurology international. 2015;6:18.

13. Lai L, Davey R, Beck A, et al. Emergency Postexposure Vaccination With Vesicular Stomatitis Virus-Vectored Ebola Vaccine After Needlestick. JAMA : the journal of the American Medical Association. Mar 5 2015.  http://jama.jamanetwork.com/article.aspx?articleID=2195001

14. Leng Y, Cappuccio FP, Wainwright NW, et al. Sleep duration and risk of fatal and nonfatal stroke: A prospective study and meta-analysis. Neurology. Feb 25 2015.  http://m.amedeo.com/25716357

15. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection. JAMA internal medicine. Mar 2 2015.  http://www.ncbi.nlm.nih.gov/pubmed/25730198

16. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. The New England journal of medicine. Feb 26 2015;372(9):825-834.

 

 

 

Primecuts – This Week In The Journals

March 2, 2015

By Akansha Chhabra, MD

Peer Reviewed

Blue and black or white and gold? This seems to be the most popular question across social media platforms over the last few days. And what is this all about? A dress. It all started when guitarist Caitlin McNeill posted a picture of this perplexing two-tone dress on her tumblr last week. Not an hour later it stirred up a heated debate among the masses. [1] Neuroscientist Bevil Conway stepped forward to explain the “dress phenomenon.” He reports, “what’s happening here is your visual system is looking at this thing, and you’re trying to discount the chromatic bias of the daylight axis. So people either discount the blue side, in which case they end up seeing white and gold, or discount the gold side, in which case they end up with blue and black.” [2] Nonetheless, many people, including big name celebrities such as Mindy Kaling, Julianne Moore, and James Franco, continue to remain loyal to their respective views. Whether the truth lies behind a conspiracy theory, or a scientific explanation of rods and cones, the world may forever remain divided on this ever so important question.

Now in medical news…

The role of corticosteroids in severe community-acquired pneumonia.

A study published by the Journal of the American Medical Association last week looked at the effect of methylprednisolone on treatment failure in patients with severe community-acquired pneumonia. In this multicenter, randomized, double blind, placebo-controlled trial, 120 patients with severe community acquired pneumonia and a C-reactive protein level of greater than 150mg/L at admission were randomized to receive an intravenous bolus of methylprednisolone or placebo every 12 hours for 5 days. It is important to note that although antimicrobial treatment was similar in both study groups (combination of ceftriaxone with levofloxacin and azithromycin) they were not all completely identical. The primary outcome of the study was divided into early and late treatment failure. Early treatment failure included development of shock, need for invasive mechanical ventilation, or death within 72 hours of treatment whereas late treatment failure included radiographic progression, persistent severe respiratory failure, development of shock, need for invasive mechanical ventilation, or death between 72 and 120 hours after the initiation of treatment. Results of the study revealed that overall there was a 13% treatment failure in the methylprednisolone group compared to 31% in the placebo group (p= 0.02). The methylprednisolone group also had less radiographic progression than the placebo group (2% versus 15%, p =0.007). The two groups did not differ in rate of invasive mechanical ventilation, septic shock, and in-hospital mortality. Although these findings could alter the way in which physicians treat patients with severe community-acquired pneumonia, it is important to take into account the adverse effects of intravenous corticosteroids including hyperglycemia, gastrointestinal bleeding, and risk of infection, which were all reported in this study.

Direct oral anticoagulants in cancer-associated venous thromboembolism.

Although direct oral anticoagulants (DOAs) have been studied extensively in treatment and prevention of venous thromboembolism (VTE) [4], there have been limited trials in the use of DOAs in cancer-associated VTE. Last week, Chest published a meta-analysis illustrating the efficacy of DOAs in patients with VTE and malignancy. [5] The study authors completed a systematic review of several randomized controlled trials that compared DOAs with vitamin K antagonists in cancer patients with VTE. They selected six studies to include in their meta-analysis and looked at VTE recurrence and bleeding events in these patients. There was a 3.9% VTE recurrence rate in cancer patients being treated with a DOA in comparison to a 6% recurrence rate in those being treated with conventional treatment (heparin followed by a vitamin K antagonist), which was not statistically significant (OR 0.63; 95% CI, 0.37-1.10). Major bleeding occurred in 3.2% of the patients treated with DOAs and 4.2% of the patients treated with conventional anticoagulation (OR 0.77, 95% CI 0.41-1.44), which was also noted to be statistically insignificant. This trial shows that direct oral anticoagulants seem to be as effective as vitamin K antagonists in prevention of VTE in cancer patients, along with the same risk of bleeding. In current practice, low molecular weight heparin (LMWH) is the standard of care for VTE treatment in patients with cancer but with the growing use of DOAs, this meta-analysis will hopefully set the path for future research that compares the safety and efficacy of DOAs versus LMWH.

The benefits and costs of supplemental ultrasound screening in women with dense breasts.

Breast cancer screening is a topic that has been long scrutinized in the medical literature with new and changing guidelines every few years. A recent study published by the Annals of Internal Medicine closely examined the costs and benefits of ultrasonography as a supplemental screening method. [6] The study population included women between ages 50 and 74 years undergoing biennial mammography screening- a secondary analysis was performed on a subset of women 40-84 years undergoing annual screening, which will not be discussed here. The subjects were further divided into 3 different screening strategies: those who received mammography alone, those who received mammography plus screening ultrasound after a negative mammogram result for women with extremely dense breast tissue, and mammography plus handheld screening ultrasound after a negative mammogram for women with extremely dense breast tissue. These groups were compared to no screening at all. The outcomes measured included averted breast cancer deaths, quality-adjusted life-years (QALYs) gained, cost, and biopsies recommended after a false positive ultrasound result. The study projected that for women aged 50-74 years with extremely dense breasts who were receiving supplemental ultrasound screening after negative mammography, there would be a gain of 1.7 QALYs per 1000 women with aversion of 0.36 breast cancer deaths. Ultrasonography in these patients also resulted in 354 biopsy recommendations per 1000 women secondary to a false-positive result on ultrasound compared to patients who received biennial mammography screening alone. Cost-effectiveness ratio was calculated to be $325,000 per QALY gained for supplemental ultrasonography relative to digital mammography screening alone. The authors of this study conclude that unless there is a more efficient and more economical way to incorporate supplemental ultrasonography with biennial mammography, the use of ultrasound in breast cancer screening may just not be worth the cost.

A little teaser for other interesting articles from the past week…

A study published in the Journal of the National Cancer Institute found that although women who had given birth had a 33% higher risk of estrogen receptor negative breast cancer and a 37% higher risk of triple-negative breast cancer than those who were nulliparous, these numbers were lower in women who had breastfed than those who had never breastfed. [7]

Lately, it seems that when at a loss, intravenous immunoglobulin (IVIG) use has been on the rise as a last resort of treatment in various diseases. Rheumatology briefs us on the multiple uses of IVIG in rheumatic diseases including Kawasaki’s disease, lupus, and ANCA-associated vasculitis. [8]

For most of us, melatonin is usually used to overcome jetlag or those long stretches of night shifts as a resident, but can it also have anti-malignant, anti-hyperglycemic, and cardioprotective effects? Take a look at this week’s Lancet for a brief correspondence on what may be the new partner to aspirin. [9]

We’ve always been told that exercise is a good thing, but is there such a thing as too much exercise? Circulation last week published a study on how much exercise is exactly needed to reduce vascular disease risk. [10]

Selective serotonin reuptake inhibitors have long been implicated in fracture risk and osteoporosis. Endocrine takes a look at exactly what dose, length of treatment, time of treatment, and sex/age leads to a fracture risk in patients taking SSRIs. [11]

Dr. Akansha Chhabra is a 2nd year medical resident at NYU Langone Medical Center

Peer reviewed by Anish B. Parikh, MD, 3rd year resident, Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

1. Mahler J. (2015, February 27). A White and Gold (No, Blue and Black!) Dress Melts the Internet. New York Times. Retrieved from http://www.nytimes.com/2015/02/28/business/a-simple-question-about-a-dress-and-the-world-weighs-in.html?_r=0.

2. Rogers A. (2015, February 26). The Science of Why No One Agrees on the Color of This Dress. Wired. Retrieved from http://www.wired.com/2015/02/science-one-agrees-color-dress/

3. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response. JAMA. 2015 Feb 17;313(7):677-86. http://jama.jamanetwork.com/article.aspx?articleid=2110967

4. Schulman S, Kearon C, Kakkar AK, et al. RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-2352. http://www.nejm.org/doi/full/10.1056/NEJMoa0906598

5. Vedovati MC, Germini F, Agnelli G et al. Direct oral anticoagulants in patients with VTE and cancer. Chest. 2015 Feb; 147 (2): 475-83. http://journal.publications.chestnet.org/article.aspx?articleid=1905082

6. Sprague BL, Stout NK, Schechter C, et al. Benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts. Annals of Internal Medicine. 2015; 162(3): 157-166. http://annals.org/article.aspx?articleid=2020458

7. Phipps AI, Li CI. Breastfeeding and triple-negative breast cancer: potential implications for racial/ethnic disparities. Journal of the National Cancer Institute. 2014; 106(10): 1-2. http://jnci.oxfordjournals.org/content/106/10/dju281.long

8. Mulhearn B, Bruce IN. Indications for IVIG in rheumatic diseases. Rheumatology. 2015 Mar; 54(3): 383-391. http://rheumatology.oxfordjournals.org.ezproxy.med.nyu.edu/content/54/3/383.full

9. Opie L, Lecour S. Melatonin, the new partner to aspirin? The Lancet. 2015; 385(9970): 774. http://www.sciencedirect.com.ezproxy.med.nyu.edu/science/article/pii/S014067361560438X#

10. Armstrong ME, Green J, Reeves GK et al. Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United Kingdom. Circulation. 2015; 131: 721-729. http://circ.ahajournals.org.ezproxy.med.nyu.edu/content/131/8/721.full

11. Bruyere O, Reginster J. Ostepoosis in patients taking selective serotonin reuptake inhibitos: a focus on fracture outcome. Endocrine. 2015; 48(1): 65-68. http://link.springer.com/article/10.1007/s12020-014-0357-0?wt_mc=Other.Other.10.CON871.ALMjournalmega_ment_408

Primecuts – This Week In The Journals

February 25, 2015

By Steven R. Liu, MD

Peer Reviewed

“And the award goes to…” – for those of you who watched the Academy Awards this week, you will have been an admirer of Neil Patrick Harris’ opening, his presence in the audience, and his underwear spoof of “Birdman”. The event made for glamorous viewing, and also included heartfelt speeches from winners about the lingering state of race relations, suicide, and equality for women among some of the topics.

In the journals this week…

Nitric oxide, antihypertensive treatment and acute stroke

From the world of neurology comes another attempt at deciphering the relationship between blood pressure and ischemic stroke. With the not too recent INTERACT2 trial fresh in our collective consciousness, we now have concluded that strict blood pressure control in hemorrhagic stroke improves clinical neurologic outcomes. However, though it has been well described that there is a U-shaped relationship between blood pressure and worsening outcomes post ischemic CVA [1], there has yet to be a definitive study suggesting that controlling that blood pressure in the post-stroke period has any significant changes in outcomes of stroke.

The ENOS Trial, published ahead of print last year, now in this month’s Lancet attempted to demonstrate improved outcomes in a randomized, multicenter, partial factorial, non-blinded trial [2]. The study included patients with either acute ischemic or hemorrhagic stroke with hypertension between SBPs of 140 to 220mmHg. Patients were randomized to be started on transdermal glyceryl trinitrate or nothing with the additional randomization of restarting their home medications to see if there was a difference in modified Rankin scores (assessing functional status post-CVA).

Investigators successfully demonstrated a reduction in blood pressures between the treatment and non-treatment groups of initially 7 mmHg SBP / 3.5 mmHg DBP which was maintained at 10 mmHg / 5 mmHg by the end of treatment phase (p<0.0001 for both). However, the study did not show any significance in modified Rankin score between the two groups (OR 1.01, 95% CI 0.91-1.13, p=0.83). Additionally, there was no difference between median hospital stay or death on discharge; nor was there a statistically significant difference between death or any of the additional functional tests performed (including mini-mental status exam, EuroQol Visual Analogue Score, Verbal Fluency, Health utility status, Zung depression scale, or modified telephone interview for cognitive status) at 90 days.

The authors suggest that this study may be interpreted as “it seems reasonable to withhold blood pressure-lowering drugs until patients with an acute stroke are medically and neurologically stable, and have suitable oral or enteral access to allow safe drug reintroduction”. It further adds, though, to the suggestion that efforts to normalize blood pressure in the setting of acute stroke likely does not change neurologic recovery outcomes.

Driving Pressure and Survival in the Acute Respiratory Distress Syndrome

Mechanical-ventilation strategies that use lower end-inspiratory (plateau) airway pressures, lower tidal volumes (VT), and higher positive end-expiratory pressures (PEEPs) (collectively termed lung-protective strategies) have been associated with survival benefits in randomized clinical trials involving patients with the acute respiratory distress syndrome (ARDS) [3]. In this month’s New England Journal of Medicine, Amato et al. provide us with the proposition that driving pressure (VT / compliance) would be an index more strongly associated with survival than VT or PEEP in patients with acute respiratory distress syndrome (ARDS) [4].

This group derived a survival-prediction model with the use of data from a cohort of 336 patients with ARDS from four early randomized clinical trials testing various strategies of volume-limited ventilation. They then tested and refined their model with data from a validation cohort of 861 patients from a large, randomized trial comparing lower versus higher VT values. Finally, they retested the model with data from a more recent validation cohort of 2365 patients with ARDS enrolled in four randomized trials comparing higher-PEEP versus lower-PEEP strategies. The primary outcome (the dependent variable) was survival in the hospital at 60 days.

In their results section, this group report a strong association between driving pressure and survival even though all the ventilator settings that were used were lung-protective (relative risk of death, 1.36; 95% confidence interval [CI], 1.17 to 1.58; P<0.001). In contrast, further reductions in plateau pressures or VT below these thresholds (plateau pressures ≤30 cm of water and VT ≤7 ml per kilogram of predicted body weight) had no effect on survival. This result stands, however only for ventilation in which the patient is not making respiratory efforts; it is difficult to interpret driving pressure in actively breathing patients.

This group highlights The Acute Respiratory Distress Syndrome Network (ARDSNet) trial, which shows that low VT values per se decrease mortality from ARDS. However, they postulate that the efficacy of this strategy is also critically dependent on other components of the lung-protective bundle (e.g. plateau-pressure limitation, respiratory-rate modification, and hypercapnia). For example, when low VT values were introduced into the lung, improved survival was observed only when large changes in driving pressure (the dependent variable during volume control) were avoided.

This fascinating article is not without drawbacks, however. Indeed, it is a post-hoc observational analysis. Going forward, trials need to be designed in which ventilator changes are linked to achieve changes in driving pressure, in order to determine whether this group’s observations can be translated into changes that may be implemented at the bedside.

High-dose versus Standard-dose Influenza Vaccines in US residents >65

Another research group published in the Lancet sought to establish whether high-dose inactivated influenza vaccine was more effective for prevention of influenza-related visits and hospital admissions in US Medicare beneficiaries than was standard-dose inactivated influenza vaccine [5].

In this retrospective cohort study, the authors identified Medicare beneficiaries aged 65 years and older who received high-dose or standard-dose inactivated influenza vaccines from community pharmacies that offered both vaccines during the 2012–13 influenza season. The primary outcome was probable influenza infection, defined by receipt of a rapid influenza test followed by dispensing of the neuraminidase inhibitor oseltamivir. The secondary outcome was a hospital or emergency department visit, listing a Medicare billing code for influenza. In total, 929 730 recipients of high-dose vaccine and 1 615 545 recipients of standard-dose vaccine were evaluated. Each group was matched well with regards to age and presence of underlying medical conditions.

Results from this study revealed that the high-dose vaccine (1•30 outcomes per 10 000 person-weeks) was 22% (95% CI 15–29) more effective than the standard-dose vaccine (1•01 outcomes per 10 000 person-weeks) for prevention of probable influenza infections (rapid influenza test followed by oseltamivir treatment) and 22% (95% CI 16–27%) more effective for prevention of influenza hospital admissions (0•86 outcomes per 10 000 person-weeks in the high-dose cohort vs 1•10 outcomes per 10 000 person-weeks in the standard-dose cohort). Given the large population in their study, this enabled toe group to show that there was a significant reduction in influenza-related hospital admissions in high-dose compared to standard-dose vaccine recipients – something for us all to perhaps ponder as we order our ‘flu vaccines in clinic.

In other news…

In early February, GlaxoSmithKline began Phase II trials for Ebola vaccination with the ChAd3-ZEBOV vaccine in West Africa in Cameroon, Ghana, Mali, Nigeria, and Senegal, with a plan to start Phase III trials in Guinea, Liberia, and Sierra Leone [6]. As previously reported, the number of Ebloa cases have decreased to 25 in January. Now, the WHO has approved use of ReEBOV Antigen Rapid Test, the first rapid blood test for Ebola, which reports a definitive answer in 12 to 24 hours [7].

In other virologic news, an article in Nature suggests that a new HIV drug, termed the AAV-delivered eCD4-Ig could function like an effective HIV-1 vaccine [8]. In the past, investigators have attempted to develop non-conventional vaccines by inducing immune responses which might prevent viral entry. This new product is a CD4-Ig w/ a small CCR5-mimetic zone which binds to the conserved region of the HIV-1 envelope glycoprotein, preventing viral entry and CD4 binding for more than 40 weeks.

Outbreak! Again, continuing our infectious disease trend. There was a carbapenem-resistant enterobacteriae outbreak at UCLA involving advanced endoscopy [9]. Despite adequate sterilization of the scopes per the manufacturer’s standards, over 100 patients were potentially exposed.

And finally, in a non-infectious update, it appears that drinking dark roast coffee may decrease spontaneous DNA breaks. The studies investigators concluded “that regular coffee consumption contributes to DNA integrity.” [10] Food for thought.

Dr.Steven R. Liu is a 3rd year resident at NYU Langone Medical Center.

Peer Reviewed by Cilian J. White, M.D., Internal Medicine Resident, NYU Langone Medical Center.

Image courtesy of Wikimedia Commons.

References

1. Bee J, Bath PMW, Phillips SJ, et al. Blood Pressure and Clinical Outcomes in the International Stroke Trial. Stroke. 2002;33:1315-1320.

2. The ENOS Trial Investigators. Efficacy of nitric oxide, with or without continuing antihypertensive treatment, for management of high blood pressure in acute stroke (ENOS): a partial-factorial randomized trial. The Lancet. 2015;385:617-628. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)61121-1/abstract

3. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med. 2000;342:1301-1308.

4. Marcelo BP, Amato MD, Meade M, et al. Driving Pressure and Survival in the Acute Respiratory Distress Syndrome. N Engl J Med. 2015;372:747-755. http://www.nejm.org/doi/full/10.1056/NEJMsa1410639#t=articleBackground

5. Izurieta H, Thadani N, Shay DK, et al. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet. 2015;15(3):293-300. http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(14)71087-4/abstract?showall=true

6. Doyle M. “Ebola crisis: First major vaccine trials in Liberia”. BBC News Africa, Feb 2nd, 2015. http://www.bbc.com/news/world-africa-31087727

7. Gallagher J. “Fifteen-minute Ebola test approved.” BBC News Health, Feb 20th 2015. http://www.bbc.com/news/health-31550815

8. Gardner MR, Mattenhorn LM, Kondur HR, et al. AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges. Nature. 2015. Published online. http://www.nature.com/nature/journal/vaop/ncurrent/full/nature14264.html

9. UCLA statement on notification of patients regarding endoscopic procedures. UCLA Newsroom, Feb 18th 2015. http://newsroom.ucla.edu/stories/ucla-statement-on-notification-of-patients-regarding-endoscopic-procedures

10. Bakuradze T, Lang R, Hofmann T, et al. Consumption of a dark roast coffee decreases the level of spontaneous DNA stard breaks: a randomized controlled trial. Eur J Nutr. 2015; 54:149-156. http://rd.springer.com/article/10.1007%2Fs00394-014-0696-x