Specific genes associated with marijuana addiction

“A genetic factor in cannabis dependence severity is important for the public to know. Look into the paragraph of Design, Setting, and Participants to appreciate the quality of this research. A 90% association of this genetic factor with another psychiatric condition or addiction is stunning.

The first paragraph is an announcement in the popular media. I looked up the original article and publish that article’s abstract below the horizontal line.”  Bill Chesnut, MD

To go back to New Health News: https://billchesnutmd.com/new-health-news

Researchers identify specific genes associated with marijuana addiction

TIME (3/30, Szalavitz) reports that “specific genes associated with marijuana addiction have been identified – and some of them are also linked to increased risk for depression and schizophrenia.” Researchers arrived at this conclusion after studying “the genes of nearly 15,000 people from three different groups.” The study’s findings may “help explain why 90% of people with marijuana addictions also suffer from another psychiatric condition or addiction.” The study was published online in JAMA Psychiatry.


Below is the abstract of that original research publication March 30, 2016.

Online First >

Original Investigation | March 30, 2016

Genome-wide Association Study of Cannabis Dependence Severity, Novel Risk Variants, and Shared Genetic Risks ONLINE FIRST

Richard Sherva, PhD1; Qian Wang, MS2; Henry Kranzler, MD3,4; Hongyu Zhao, PhD2,5,6,7; Ryan Koesterer, MS1; Aryeh Herman, PsyD8; Lindsay A. Farrer, PhD1,9,10,11,12; Joel Gelernter, MD7,8,13,14

JAMA Psychiatry. Published online March 30, 2016. doi:10.1001/jamapsychiatry.2016.0036



Importance  Cannabis dependence (CAD) is a serious problem worldwide and is of growing importance in the United States because cannabis is increasingly available legally. Although genetic factors contribute substantially to CAD risk, at present no well-established specific genetic risk factors for CAD have been elucidated.

Objective  To report findings for DSM-IV CAD criteria from association analyses performed in large cohorts of African American and European American participants from 3 studies of substance use disorder genetics.

Design, Setting, and Participants  This genome-wide association study for DSM-IV CAD criterion count was performed in 3 independent substance dependence cohorts (the Yale-Penn Study, Study of Addiction: Genetics and Environment [SAGE], and International Consortium on the Genetics of Heroin Dependence [ICGHD]). A referral sample and volunteers recruited in the community and from substance abuse treatment centers included 6000 African American and 8754 European American participants, including some from small families. Participants from the Yale-Penn Study were recruited from 2000 to 2013. Data were collected for the SAGE trial from 1990 to 2007 and for the ICGHD from 2004 to 2009. Data were analyzed from January 2, 2013, to November 9, 2015.

Main Outcomes and Measures  Criterion count for DSM-IV CAD.

Results  Among the 14 754 participants, 7879 were male, 6875 were female, and the mean (SD) age was 39.2 (10.2) years. Three independent regions with genome-wide significant single-nucleotide polymorphism associations were identified, considering the largest possible sample. These included rs143244591 (β = 0.54,P = 4.32 × 10−10 for the meta-analysis) in novel antisense transcript RP11-206M11.7;rs146091982 (β = 0.54,P = 1.33 × 10−9 for the meta-analysis) in the solute carrier family 35 member G1 gene (SLC35G1); andrs77378271 (β = 0.29, P = 2.13 × 10−8 for the meta-analysis) in the CUB and Sushi multiple domains 1 gene (CSMD1). Also noted was evidence of genome-level pleiotropy between CAD and major depressive disorder and for an association with single-nucleotide polymorphisms in genes associated with schizophrenia risk. Several of the genes identified have functions related to neuronal calcium homeostasis or central nervous system development.

Conclusions and Relevance  These results are the first, to our knowledge, to identify specific CAD risk alleles and potential genetic factors contributing to the comorbidity of CAD with major depression and schizophrenia.


Heavy marijuana use in late adolescence may put men at higher risk for death

“More long term effects of regular marijuana use continue to arrive. The plant bud is an anxiolytic drug. There are better and safer drugs for anxiety, including a daily workout.” Bill Chesnut, MD

To go back to New Health News: https://billchesnutmd.com/new-health-news

Heavy marijuana use in late adolescence may put men at higher risk for death by age 60, study finds

The CBS News (4/22, Marcus) website reported, “Heavy marijuana use in the late teen years puts men at a higher risk for death by age 60,” the findings of a study published online in the American Journal of Psychiatry suggest.

HealthDay (4/22, Preidt) reported that men “who were heavy marijuana users in their late teens were 40 percent more likely to die by age 60 than those who never used the drug, the investigators found.”

AMA News _ April 25, 2016.

The Accidental Deadly Drug Prescription

“There are many publications the medical world about opioid medications. Managing chronic pain without risking accidental death is hard. This article looks at anther much less known risk of opioid medications. The grave risk for some is combining an opioid with a benzodiazepine drug such as Xanax. This is a commentary in the Wall Street Journal. Dr. Wen shows you the difficulty in practicing the best medicine, being effective and keeps risks as low as possible. If you friends who take pain pills, tell them about the benzodiazepine class of drugs, all of their brand names. ” Bill Chesnut, MD

To go back to New Health News: https://billchesnutmd.com/new-health-news     

The Accidental Deadly Drug Prescription.   Many doctors are unaware that a drug like Valium or Xanax, taken with an opioid, could be fatal. By LEANA S. WEN,MD_______March 30, 2016

My patient was a college student brought into the emergency room after a minor car accident. Although CT scans showed no spinal fractures, he had severe neck pain and spasms. Instinctively, I prescribed Percocet for pain and Valium for muscle spasms. But I didn’t know then what I know now: These two drugs, when taken together, could interact and cost him his life.

Opioids—including prescriptions such as Percocet and OxyContin, as well as the illicit form, heroin—are under increased scrutiny. The number of Americans dying from an opioid overdose has quadrupled over the past decade, according to the Centers for Disease Control and Prevention. This week President Obama joined health officials and advocates to raise awareness of this growing epidemic. Clinicians and the public, however, are often unaware of the threat posed by opioid interaction with another frequently prescribed drug.

Benzodiazepines, known to most Americans as Xanax or Valium, typically treat anxiety or insomnia. But when combined with opioids, as they often are, they can suppress the instinct to breathe, increase sleepiness and cause death. In 2010, one in three unintentional overdose deaths in the U.S. from prescription opioids also involved benzodiazepines, according to the National Vital Statistics System. Maryland Department of Health data show more than 70% of deaths in the state associated with benzodiazepines also involved prescription opioids.

Despite this danger, doctors prescribe both drugs at increasing rates. The CDC reported that in 2012 there were over 259 million prescriptions of opioids in the U.S.—more than one for every adult. That year there were nearly 40 benzodiazepine prescriptions for every 100 Americans. Hospital admissions for patients with combined addiction to opioids and benzodiazepines have increased by 569% over 10 years, according to anotherfederal study.

Why do doctors continue to prescribe this deadly combination? In part, because that is what they are taught. When I was in medical school in the early 2000s, I learned to treat muscle pain and spasms with both opioids and benzodiazepines, so I routinely prescribed them together. A 2015 study published in the journal Pain Medicine found that one in three patients with chronic pain on opioids was also on benzodiazepines. Just as I acted on instinct with my ER patient, doctors prescribe medications based on habit.

Most overdose-education campaigns focus exclusively on the opioid epidemic, in part because there is an easy-to-use antidote available, naloxone. In Baltimore, we have increased its availability by allowing all 620,000 residents to obtain a naloxone prescription—no questions asked. Last year, we conducted over 8,000 targeted trainings, going to high-risk areas like jails, bus shelters and public markets to demonstrate use of this lifesaving medication.

Likewise, education for physicians has focused on increasing monitoring of opioid prescriptions, rather than on decreasing their use with benzodiazepines. But with mounting scientific and epidemiological evidence about this deadly combination, doctors must adjust their patterns. Shouldn’t they already know that combining these drugs is dangerous? Unfortunately, the figures suggest they don’t.

Last month, I co-led a coalition of over 40 city health-commissioners and state health-directors who sent a petition urging the Food and Drug Administration to require a “black-box warning”—the FDA’s strongest risk communication—any time that opioids and benzodiazepines are prescribed together. Such a warning would sound the alarm about the danger of taking these drugs at the same time. Thousands of health officials, academics, researchers, physicians and citizens signed our petition.

Studies show that black-box warnings change how physicians prescribe potentially dangerous medications. In the mid-2000s, a black-box warning was issued for an antidepressant associated with suicide in youth. This resulted in a 22% drop in prescriptions, according to a study in the American Journal of Psychiatry. Physicians listened to the warning and changed their practices.

The FDA recently proposed a black-box warning on opioids. It is a welcome move: 44 Americans die every day from prescription opioid overdose. Yet, while one-third of those deaths were associated with an unintentional combination with benzodiazepines, the FDA’s new warning doesn’t mention the dangers of combining the drugs.

When I look back at my practice, I wonder how many deaths my colleagues and I might have caused inadvertently—and how many we could have prevented if we had known the potential dangers sooner. It’s a harrowing thought that should spur physicians to change their prescribing practices and patients to look inside their medicine cabinets.

Dr. Wen is an emergency physician and the health commissioner for the city of Baltimore.


Warnings about concurrent use of opioids, benzodiazepines.

“This is an important health fact that is not broadly known. This is not research. It is a petition asking for warning labels. A combination of benzodiazepines and opioid pain medications is common. Benzodiazepines are a class of psychoactive drugs used to treat anxiety, insomnia, and a range of other conditions. They are one of the most widely prescribed medications in the U.S., particularly among elderly patients. Benzodiazepines possess sedative, hypnotic, anti-anxiety, anticonvulsant, and muscle relaxant properties.” Bill Chesnut, MD.

Public health officials petition FDA to add boxed warnings about concurrent use of opioids, benzodiazepines.

The Washington Post (2/22, Dennis) reports in “To Your Health” that “dozens of public health officials and academics across the country are pushing the Food and Drug Administration to warn people about the potential dangers of taking” opioid pain medications along with benzodiazepines. In a petition, officials from 41 state and municipal health departments, as well as some universities, “urged the agency” to add boxed warnings to both medications, “given evidence that using them together increases the chance of deadly overdoses.”


FDA postpones decision on opioid addiction implant_ Probuphine

“This is a policy report in the media referring to research that developed an implant to decrease opioid crave for six months. The medical issues are complicated. I don’t have the original report. Deciding on approval of this implant has more considerations than a short-lived oral medication. Let’s hope there is found to be a safe way to use this breakthrough.” Bill Chesnut, MD

 FDA postpones decision on opioid addiction implant_ Probuphine

 The Boston Herald (2/20, Kalter) reported that the Food and Drug Administration “postponed its decision on a matchstick-sized implant that would reduce cravings for people battling opioid addiction.” An advisory committee had recommended the approval of Probuphine in January. The device releases a steady dose of buprenorphine over a six-month period.

In a related story, according to STAT (2/19, Scott), a report issued by Senator Ed Markey (D-MA) accused the Food and Drug Administration of “failing to properly consult with its advisory committees to vet the approval of certain opioid drugs.” In the report, Markey said he “would continue to oppose the nomination of Dr. Robert Califf” until “the FDA changed its procedures.”

AMA News February 21, 2016.__WASHINGTON — The Food and Drug Administration is failing to properly consult with its advisory committees to vet the approval of certain opioid drugs, Massachusetts Senator Ed Markey alleges in a new report and letter obtained by STAT.

Markey, in a Feb. 19 letter to Health and Human Services Secretary Sylvia Mathews Burwell, said that until the FDA changed its procedures, he would continue to oppose the nomination of Dr. Robert Califf, President Obama’s choice to be the agency’s next commissioner. The first Senate floor vote, a procedural vote, on Califf’s nomination will be held Monday evening.

The report produced by Markey’s office laid out three problems from his point of view: First was that so-called “abuse-deterrent” opioids can still be abused. Second, since 2010, the FDA has not always consulted advisory committees when approving abuse-deterrent opioids.

“[The] FDA needs outside expert advice on all opioid approval decisions,” Markey wrote. “Whether an opioid is abuse deterrent or not hasn’t prevented tens of thousands of people who have had their wisdom teeth removed or experienced lower back pain from getting addicted to these painkillers.”

Markey and other lawmakers, including Senator Joe Manchin of West Virginia, have used Califf’s nomination to urge changes at the FDA that would address the opioid crisis, which is killing nearly 30,000 Americans a year.

The report underlines problems with the FDA’s approval process, said Andrew Kolodny, chief medical officer at Phoenix House, which runs dozens of addiction centers in the United States.

Kolodny emphasized that the abuse-deterrent drugs the FDA is approving can still be abused. Abuse-deterrent drugs are usually intended to only stop the pill from being crushed or injected, Kolodny said. Many people end up addicted to opioids by simply swallowing the pills.

“I have had very serious concerns about the FDA’s opioid decision-making for a long time,” he said. “I’m actually pleased that [Markey is] taking a stand on this.”

The agency has recently endured significant controversy for not consulting with advisory committees. The approval of Oxycontin for children saw backlash, including from Democratic presidential candidate Hillary Clinton. An advisory committee was not consulted on the approval, and those critical of the decision, including Kolodny, said they didn’t believe a committee would have favored it.

The episode was one of those highlighted by Markey’s report, which charged that the FDA “ignored its own guidance calling for an advisory committee when a question of ‘pediatric dosing’ is involved.”

Third, and the point that Markey focused on in his letter, the opioid action plan that the agency released earlier this month in response to the addiction crisis still allows some abuse-deterrent opioids to be approved without an advisory committee being consulted.


Solving America’s opioid crisis: Remember the patient

“Caring for patients with chronic pain is complicated. It requires close attention and frequent monitoring of the treatment response. “ Bill Chesnut, MD

 Solving America’s opioid crisis: Remember the patient  AMA News_1/25/2016, 3:43 PM

Physicians, medical organizations and public health experts around the nation all have shared reasons why the opioid overdose epidemic must be top of mind in the medical world, and it comes down to one focus—the patient. A panel of experts recently gave recommendations that lead the way to making patient-focused pain management possible.

Reducing the stigma of chronic pain

One important aspect of the efforts to combat the opioid epidemic is reducing stigma so that patients with chronic pain do not lose access to the care that they need.

“What is our role as physicians in this current problem?” asked John A. Renner, MD, president of the American Academy of Addiction Psychiatry and professor of psychiatry at Boston University School of Medicine, speaking to physician leaders at the AMA State Legislative Strategy Conference earlier this month during a session on the opioid crisis.

“This epidemic is not going to be contained until we change practice within medicine,” Dr. Renner said. “Medicine does not shrink from treating these chronic conditions.”

There are many things that physicians can do now to begin those changes, he added. “Before prescribing opiates for either acute or chronic pain, the clinician must screen every patient for a history of substance use disorders and for co-occurring psychiatric disorders. A review of the PDMP should be part of every routine assessment.”

“Recognize that patients with any history of alcoholism or substance use disorder are at higher risk for abuse, and they should be managed very carefully,” Dr. Renner said. “This means avoiding prescribing opiates if there are other medications that may be more effective, careful[ly] prescribing … opiates if that is necessary, [and] it means monitoring the patient carefully, to look at how the treatment is progressing.”

However, this does not mean withholding opiates from patients with acute pain, he said.

Dr. Renner cited a case where a patient with a history of addiction needed surgery. The surgeon gave the patient a four-day supply of opioids but also carefully monitored the patient during those four days and the time following to make sure the patient’s pain was managed sufficiently.

“Sometimes prescribing [opioid-based] medication is the best way to prevent relapse,” Dr. Renner said. In other cases, “we need to work with primary care physicians as well as pain management specialists to develop alternatives for handling chronic pain without relying on opiates.”

“There is a moral imperative to treat pain,” said Myra Christopher, the Kathleen M. Foley chair for pain and palliative care at the Center for Practical Bioethics. “Those who are in the healing professions have ethical and moral obligations to do so.”

“That does not mean that there is a moral imperative, an ethical duty or obligation to prescribe opioids,” she added. “It means there is a moral imperative to address this issue [of chronic pain].” One solution, Christopher suggested, is to increase training in pain management.

“If you ask any medical school applicant” why they want to go to medical school, “they will say ‘I want to alleviate, or I want to treat pain and suffering,’” Christopher said. “That notion is really the foundation of what it means to be a healing profession.” However, although comprehensive management for chronic pain is necessary for many patients, most physicians have inadequate training on this approach.

Actions physicians can take to end the overdose crisis

In conjunction with patient-focused chronic pain management, physicians also need to be vigilant in taking steps to prevent overdose and treat patients who are living with substance use disorder.

“Where do we start when there are 44 people dying from opioid-related overdoses every day?” said Patrice A. Harris, MD, chair-elect of the AMA Board of Trustees, who also chairs the AMA Task Force to Reduce Prescription Opioid Abuse, during her opening remarks.

“This public health crisis related to opioid misuse and heroin addiction results in nearly 30,000 deaths annually and challenges us as physicians to amplify our current efforts and actions,” Dr. Harris said. “We use the word ‘actions’ deliberately [because] we must take concrete actions that will help end this crisis.”

The task force focuses on five recommendations for all physicians from “inside the profession,” Dr. Harris said. “These recommendations come from physicians who treat acute pain, chronic pain and patients who have substance use disorder. We must also look inwardly …. As physicians, we run toward the health crisis, not away from it.”

Action No. 1: Physicians should “voluntarily register for and use [their] state prescription drug monitoring programs (PDMP),” Dr. Harris said.

One example of a successful PDMP comes from the Ohio State Medical Association (OSMA). Also speaking on the panel with Christopher and Dr. Harris, Michael Bourn, DO, medical director of pain and palliative services at Doctor’s Hospital in Columbus, Ohio, described the success of his state’s PDMP for physician leaders.

The Ohio Automated Rx Reporting System (OARRS) is a tool to track the dispensing and personal furnishing of controlled prescription drugs to patients. OARRS is designed to monitor this information for suspected abuse or diversion and can give a prescriber or pharmacist critical information regarding a patient’s controlled substance prescription history to identify high-risk patients who could benefit from early intervention.

In 2010 there were about 5,000 Ohio prescribers with a voluntary OARRS account, but that number has increased to over 36,000 presently and counting. Between 2007 and 2014 the number of OARRS reports requested increased 5,900 percent, signifying its expanded use throughout the state in just seven years. In that same seven year period, Ohio experienced an approximately 50 percent decrease in “doctor shoppers” throughout the state and saw a significant drop in the number of patients seeking multiple prescriptions.

Action No. 2: “Focus on education,” Dr. Harris said. “Encourage yourselves and encourage your colleagues to ask themselves: When was the last time you took CME that was focused on opioid prescribing, to learn how to effectively use your state’s PDMP and to learn how to recognize the signs of abuse?”

Actions Nos. 3 and 4: “The third and fourth recommendations have to do with the stigma of pain,” Dr. Harris said. It’s important to reduce the stigma that surrounds pain patients in order for those with chronic pain to receive the care and the prescriptions they need to live happier, healthier lives, Dr. Harris said. It is also important to reduce the stigma of substance use disorder and increase access to treatment so patients feel comfortable in seeking that treatment.

Action No. 5: “Consider co-prescribing naloxone and support broad Good Samaritan protections,” Dr. Harris said. Last year access to naloxone—the life-saving medication that can reverse the effects of an opioid overdose by restoring breathing and preventing death—was increased substantially through new products and availability. “At the end of the day, remember what is most important—our patients.”

From JAMA Newsletter 1.26.16.                                 By AMA staff writer Troy Parks


You’ve got the power…to banish negative thoughts!

“Here is another plea for you to improve your mood, lower your stress and secondarily enjoy better health by actively using methods that are easy to learn and use. Elsewhere here I present articles of blood and saliva tests showing the change in levels of Interleukin 6, an inflammatory marker, by changing your thinking. Practice this daily. Give this information to young people as research shows we are most effective changing habits of thinking in young people.” Bill Chesnut, MD

You’ve got the power…to banish negative thoughts!  Cleveland Clinic Wellness newsletter.

Here’s a surprising fact: A typical person has about 60,000 thoughts every day. A whopping 95 percent of those are repeated daily. (It’s like Groundhog Day in your head!) Here’s the real surprise (not!): It turns out that many of those thoughts are negative. But habitual thought patterns, your mind’s way of dealing with life’s little annoyances and daily challenges, don’t have to define you. If you’re willing, you can actually change your thought patterns, which is really pretty cool. “When we meditate, we have the opportunity to experience our thoughts as passing events,” says Jennifer Hunter, LISW-S, Cleveland Clinic’s director of wellness, employer services. “We learn to distance ourselves from the content of the thought and simply observe it as it is happening, allowing it to pass,” she says. “This helps us to develop a vital skill — the ability to accept our thinking without judgment.”

Here’s what to do: When you find yourself having a negative thought, step back and call the thought what it is: a thinking habit. Acknowledge that you’re feeling stressed, and allow the thought to pass. Then, take a deep breath and ask yourself, “I wonder what my next thought will be?” The break will give you a moment to slow down your thinking and create pauses between thoughts. The key is to get to know your negative thought patterns and work on developing more beneficial ones. “You must take a moment to pause, breathe and step back from the thoughts that feel emotionally charged,” says Hunter. “Then come back to what you’re doing and enjoy the present moment.”

Growing number of Americans taking prescription medications

“This unintended consequence of losing control of physical health is so important. It cannot be understated easily. The amount of orthopedic surgery that might be avoided by maintaining optimal physical condition can’t be estimated. This study uses   prescribing data from Medicare Part D, making it an excellent source for conclusions. A life lost to constant poor quality from years of obesity is a tragedy. We should feel empathy for those trapped and double our efforts to find an effective treatment.” Bill Chesnut, MD

Growing number of Americans taking prescription medications 

The Washington Post (11/4, Dennis) reports that research published in the Journal of the American Medical Association indicates that “nearly three in five American adults take a prescription” medication. That number “is up markedly since 2000 because of much higher use of almost every type of medication, from antidepressants to treatments for high cholesterol and diabetes.”

The Los Angeles Times (11/4, Kaplan) reports that “the graying of America and the advent of Medicare Part D contributed to the increase, but the nation’s obesity crisis was probably a bigger factor…wrote” the researchers. They found that “among the 10 drugs that were most widely used in 2011 and 2012, eight are prescribed to treat diabetes, high cholesterol,” hypertension, “or other conditions often related to being overweight or obese.”

NBC News (11/4, Fox) reports on its website that “more people are also taking antidepressants and proton pump inhibitors.”

The Milwaukee Journal Sentinel (11/4, Fauber) reports, however, that “some drug classes saw a decline in use including sex hormones for women…and antibiotics.”

Meanwhile, the NPR (11/4, Kodjak) “Shots” blog reports that the research “also shows a rising number of people are taking multiple meds.” The data indicated that “the share of people who took more than five prescription drugs in a month nearly doubled to 15 percent.”

AMA News, Wednesday, November 4, 2015

Four in ten Americans know someone addicted to opioids, survey finds

“Four in ten Americans know someone addicted to opioids, this survey finds. It is more prevalent than it is apparent. If someone’s behavior is off, and it wasn’t, suspect, they have a health problem that is being treated with opioids.” Bill Chesnut, MD

Four in ten Americans know someone addicted to opioids, survey finds

The Washington Post (11/24, Bernstein) reports that nearly four in 10 Americans “know someone who has been addicted to prescription” pain medications, “including 25 percent who say it was a close friend or family member and 2 percent who acknowledge their own addiction, according to a new poll” released today by the Kaiser Family Foundation. The survey also found that 16 percent of people say they know someone who has died from an opioid overdose. The Post adds that by “a margin of 77 percent to 58 percent, those polled say it is easy to get non-prescribed” pain medications “than say it is easy for people who medically need the drugs to get them.”

Bloomberg News (11/24, Tozzi) reports that the demographics of those “touched by the crisis skew white, higher-income, college-educated, younger, and male.” According to the article, drug overdoses “are eclipsing car crashes as a leading cause of accidental death for American adults.”

Drew Altman, president and CEO of the Kaiser Family Foundation, writes on the Wall Street Journal (11/24) “Washington Wire” blog that the broad impact of opioid addiction means the issue will likely gain more political traction.

Sen. Shaheen proposes $600 million in additional funding to fight opioid abuse TheAP (11/24, Ramer) reports that Sen. Jeanne Shaheen (D-NH) “is proposing $600 million in emergency funding to address” an opioid abuse “crisis that she says is spiraling out of control.” Shaheen, who announced her funding bill yesterday, said, “This should be an all-hands-on-deck moment, not just for New Hampshire but for our country.” According to the AP, most of the money in Shaheen’s proposal would go to HHS, including $250 million distributed to states as block grants for prevention and treatment programs. The CDC “would get $50 million to support work on prescription monitoring and other programs, and the National Institute on Drug Abuse would get $35 million for targeted research on drug addiction.”

AMA newsletter, November, 2015.