Elephants can recognise the gender and ethnicity of human voices


Wild elephants can recognise the gender and ethnicity of a person just by listening to the sound of their voice, a new study has found.

A study conducted by researchers at the University of Sussex found the animals demonstrated more fear when they heard the voices of adult Masai men, compared to Kamba men.

Karen McComb, a professor of animal behaviour and cognition at the University of Sussex, and her colleagues at the University went to Amboseli National Park in Kenya, where hundreds of wild elephants live among humans.

“Basically they have developed this very rich knowledge of the humans that they share their habitat with,” Prof McComb explained.

The scientists used voice recordings of Maasai men, who on occasion come into conflict with elephants, and Kamba men, who are less of a threat to the animals.

The recordings contained the same phrase in two different languages: “Look over there. A group of elephants is coming.”

The elephants reacted more defensively by retreating and gathering in a bunch to the Maasai language recording because it was associated with the more threatening human tribe, according to the study co-author Graeme Shannon, of Colorado State University.

“They are making such a fine-level discrimination using human language skills,” Mr Shannon said. “They’re able to acquire quite detailed knowledge. The only way of doing this is with an exceptionally large brain.”

They repeated the experiment with recordings of Maasai men and women. Since women rarely spear elephants, the animals reacted less to the women’s voices. The same thing happened when they substituted their voices with the voices of young boys.

“Making this kind of fine distinctions in human voice patterns is quite remarkable,” said Emory University animal cognition expert Frans de Waal, who was not part of the study.

The study was published on Monday in the Proceedings of the National Academy of Sciences.

Light drinking ‘is preterm risk’


Even moderate drinking during the earliest months of pregnancy may be damaging, say researchers in Leeds.

Their study is the latest in a long debate over whether it is safe to drink at all during pregnancy.

Pregnancy

The findings, published in the Journal of Epidemiology and Community Health, suggest the chances of premature birth increased.

The NHS recommends people avoid alcohol during pregnancy or when trying to conceive.

But says if people choose to drink, then they should not have more than two units of alcohol (about one pint) twice a week.

Heavy drinking in pregnancy is known to be damaging as it can affect the baby’s development. But there is far more debate about drinking at the upper limit of the NHS guidelines.

Around seven in every 100 births in the UK is premature.

The study on 1,264 women in Leeds showed drinking more than the two units limit doubled the risk of premature birth, but even drinking at the limit increased the risk.

Camilla Nykjaer, one of the researchers at the University of Leeds, told the BBC: “This is a very sensitive issue, we don’t want women who are pregnant now to panic, the individual risk is actually low.

“They shouldn’t drink, they should stop drinking if they have been drinking during the pregnancy.”

A woman drinking (posed by model)

However, a study of more than 11,000 five-year-olds, conducted by University College London, showed drinking one or two units of alcohol a week during pregnancy did not raise the risk of developmental problems in the child.

Prof Yvonne Kelly who conducted that research told the BBC: “Heavy drinking is really very, very bad, but at low levels, in the work we’ve done we haven’t found any negative effects in childhood.

“It’s a massively charged area, getting the tone of this right is quite difficult.

“The guidelines are there, women are sentient beings and can choose – it’s hugely politically charged all of this, I guess people will make their own judgements.”

Dr Patrick O’Brien, a spokesperson for the Royal College of Obstetricians and Gynaecologists, said: “While the safest approach would be to choose not to drink at all, small amounts of alcohol, not more than one to two units once or twice a week, have not been shown to be harmful after 12 weeks of pregnancy.

“Pregnant women should always consult their midwives or doctors if they have any concerns about their alcohol intake.”

Five million Syrian children in need.


The number of Syrian children in need has more than doubled in the past year to 5.5 million, the United Nations Children’s Fund (Unicef) says.

Up to a million are living under siege and in areas that the agency and other humanitarian organisations cannot access, according to a new report.

Young Palestinian refugees, who fled the Yarmouk refugee camp in Syria, peer through holes made in their tent as they prepare to move to new houses built by the United Nations Development Programme at the Palestinian refugee camp of Ain El-Helweh, near the southern Lebanese coastal city of Sidon

Children in Syria have lost “lives and limbs, along with virtually every aspect of their childhood”, it warns.

UN figures say more than 10,000 have been killed in three years of conflict.

However, the report notes that real number is probably higher.

“Start Quote

This third devastating year for Syrian children must be the last”

Anthony LakeExecutive Director, Unicef

The statistics presented in Unicef’s report, Under Siege – the devastating impact on children of three years of conflict in Syria, are daunting.

Up to a million children live in areas which are either under siege or very hard for relief agencies to reach, while around three million have had their education completely disrupted.

More than three million been displaced inside Syria – a threefold increase in the space of a year – and 1.2 million – more than half the total number – have become refugees abroad, up from 260,000. Some 425,000 refugees are under five.

In addition, many children have had to start working early and very young girls have been forced to marry for financial reasons. Boys as young as 12 have been recruited to support the fighting.

Around two million children are said to need counselling for trauma.

The Unicef report warns the situation is likely to get worse.

Children sit with their belongings as they wait to be evacuated from the Old City of Homs (12 February 2014)
Concerns about the loss of childhood take second place to the need to survive
Syrian refugee girls sit at the UNICEF "Child Friendly Spaces" in the Zaatari refugee camp, near the Jordanian border with Syria
Unicef has made “child-friendly spaces” in refugee camps to minimise disruption to children’s lives

“Cut off from aid, living in rubble and struggling to find food, many Syrian children have been left without protection, medical care or psychological support, and have little or no access to education,” it says.

“In the very worst cases children and pregnant women have been deliberately wounded or killed by snipers.”

Unicef says it has only been able to raise 8% of the funding it says it needs to do its job properly.

“This war has to end so that children can return to their homes to rebuild their lives in safety with their family and friends. This third devastating year for Syrian children must be the last,” said Unicef’s executive director, Anthony Lake.

Mass production of placenta stem cells gets FDA approval.


The US Food and Drug Administration has granted approval to Pluristem Therapeutics to mass produce therapeutic human-placenta-derived stem cell products within its commercial-scale manufacturing facility in Haifa, Israel.

Pluristem’s Placental Expanded (PLX) products are mesenchymal-like adherent stromal cells – connective tissue cells in an organ – from human placentas, which are lush with hormones and proteins. The FDA has cleared PLX for use in studies on treating injuries, one step closer to full approval of PLX cells in treatments.

Reuters/Wolfgang Rattay

PLX products are made via Pluristem’s “automated 3D cell expansion manufacturing platform that uses its patented high-throughput culturing technologies, 3D bioreactors, and downstream equipment.”

“The PLX cells are grown using the company’s proprietary 3D micro-environmental technology and are an ‘off-the-shelf’ product that requires no tissue matching prior to administration,” according to Pluristem.

Pluristem operates out of a high-output facility in northern Israel that can produce about 150,000 doses of PLX products a year.

“We believe we have the largest, scalable, most efficient, most consistent and controlled process for manufacturing cell therapies,” Zami Aberman, chairman and CEO of Pluristem, said in a statement.“Knowing that the ‘Process is the Product’ in cell therapy, we have established our leadership position in the industry by focusing on our 3D commercial scale cell manufacturing processes.”

Pluristem’s use of human placenta to boost cell repair involves “a drug delivery platform that releases a cocktail of therapeutic proteins in response to a host of local and systemic inflammatory and ischemic diseases.”

Though animal placenta, especially from horses, has been a popular form of treatment for cell repair, human placenta offers a naturally compatible genome.

Pluristem’s technology was cleared by the FDA to treat several conditions, The Times of Israel reported, including Buerger’s disease and aplastic anemia – both of which have no other treatment options.

The FDA’s move follows the January approval of the process from Germany’s top medical treatment regulator, the Paul Ehrlich Institute.

The clearance also follows positive results of a PLX study in which two patients with muscular injuries were treated with Pluristem cells. Specifically, the test patients suffered gluteal muscle injury as a result of hip replacement surgery associated with osteoporosis.

The results were “a very important study not only for Pluristem but for the cell therapy industry in general,” said Aberman. “Based on the results, we intend to move forward with implementing our strategy towards using PLX cells in orthopedic indications and muscle trauma.”

About 332,000 hip replacements occur each year in the US alone, according to the Centers for Disease Control and Prevention.

Woman Believes Her Willful ‘Out-Of-Body’ Experiences Are Totally Normal: Are They?


Many of us have sat around a camp fire and heard the stories and legends of astral projection, or out-of-body experiences. The idea of floating and rotating horizontally in the air above your physical body seems unreal and straight out an episode of the Twilight Zone, but current research suggests it may be more common than previously thought. According to a study in the journalFrontiers in Human Neuroscience, scientists described a case of a 24-year-old psychology student at the University of Ottawa who allegedly can have out-of-body experiences at will since childhood.

Woman is waking up again on bed as soul leaves body

“I feel myself moving, or, more accurately, can make myself feel as if I am moving. I know perfectly well that I am not actually moving,” the student told the researchers. “In fact, I am hyper-sensitive to my body at that point, because I am concentrating so hard on the sensation of moving. … For example, if I ‘spin’ for long enough, I get dizzy.” Moreover, the 24-year-old admitted the thought of being able to float outside her body was normal since her days at preschool — where it was used as a distraction when she was asked to nap.

Intrigued by the psychology student’s claims, a team of researchers at the University of Ottawa decided to have her undergo functional magnetic resonance imaging (fMRI) to see if her brain activity could provide a clue to her unusual ability. The researchers asked the student to respond to four questionnaires: the Pittsburgh Sleep Quality Index, used to detect sleep disturbances associated with altered somatosensory or vestibular perceptions; the 8-item Movement Imagery Questionnaire-Revised; the 20-item Kinesthetic and Visual Imagery Questionnaire, used to estimate visual and kinesthetic imagery; and the PAS perceptual aberration scale, to study the reliability and validity of the psychosis-proneness. All of the data was collected during one imaging session.

The findings revealed the participant’s extra-corporeal experience involved a “strong deactivation of the visual cortex,” Popular Science reported. Her out-of-body experience also activated the left side of several areas of the brain associated with kinesthetic imagery. Andra M. Smith and Claude Messier, researchers of the study, believe this is what may cause mental representations of bodily movement. “It is interesting that the development of the participant’s ability was associated with delayed sleep onset in childhood (which persisted in adulthood) because the occurrence of out-of-body experiences has been frequently associated with hypnagogic phenomena” — a peculiar sensory experience that marks the onset of sleep, they wrote.

This specific case raised a question among the scientists of whether these experiences could be more common than thought, or if people can only have the ability if they practice this during childhood. This case study may add credibility to the estimated 10 percent of 300 million Americans who have lived a true out-of-body experience, the study reports. Currently there are two explanations to these personal experiences: The human consciousness is separating from the human body and traveling in a discorporate form in the physical world, or that they are hallucinations, according to The Lucidity Institute.

 Interestingly, throughout the report, the word “hallucination” was used to describe the participant’s claims. However, there has yet to be an explanation as to why so many people have the same delusion if out-of-body experiences are considered to be a hallucination. In addition, the psychology student’s degree of detail is arguably very descriptive, which could put it outside the realm of fictional creation, says Rebecca Watson in a Popular Science blog post.

Whether out-of-body experiences are fact or fiction, or, normal or a hallucination, remains unknown. However, if studies, unlike the fMRI paper are done — as an experiment with a hypothesis — perhaps this could hold the answer to the phenomenon. Until then, skeptics will hold on to a lack of sufficient data, while believers will hold on to the small available data — such as this study.

Lipitor Without a Rx? Pfizer Pushes Ahead With OTC Plans.


Pfizer, the maker of Lipitor, is pushing forward with efforts to sell its drug to patients without a doctor’s prescription, according to the Wall Street Journal.

The company recently launched a 1200-patient study to investigate whether patients could successfully take over-the-counter (OTC)atorvastatin to lower their LDL-cholesterol levels. Patients in the trial, which is currently recruiting at 35 US pharmacies, would get their own blood tests and would make decisions based on those results.

A positive study would determine whether Pfizer will file for regulatory approval of its OTC medication, according to the Journal.

Simvastatin has been available OTC at the 10-mg dose in the UK for nearly 10 years. Merck has gone before the US Food and Drug Administration three times since 2000, but the agency has turned away its drug, lovastatin (Mevacor) 20 mg, each and every time. Merck sought approval of OTC lovastatin in moderate-risk patients and aimed to market its drug to the “motivated health-conscious consumer.”

Like Merck, Pfizer says an OTC Lipitor would close the gap for people at risk of cardiovascular disease but who are not currently taking the lipid-lowering therapy.

Dr Neil Stone (Northwestern University Feinberg School of Medicine, Chicago, IL), the chair of the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the treatment of cholesterol, told the Journal the new guidelines do not support OTC use of statins. In fact, the new guidelines don’t recommend treating to LDL targets any longer but instead recommend a moderate- or high-potency statin based on patient’s 10-year risk of cardiovascular disease.

Given that Pfizer is investigating the feasibility of just a 10-mg dose of Lipitor, undertreatment is a concern. “There’s a chance that a lot of people would take less than needed,” Dr Steven Nissen (Cleveland Clinic, OH) told the Journal.

At one stage, Lipitor was the world’s biggest-selling drug, with sales peaking at $13 billion in 2006, but since the patent expired sales have declined to $2.3 billion in 2012, reports the Journal.

Phase II Trial Offers ‘Proof of Concept’ for Therapeutic HIV Vaccine.


A peptide-based vaccine against HIV-1 reduces viral load set-point after combination antiretroviral therapy (cART), a new phase II trial demonstrates.

However, there was no difference between the vaccine and placebo groups in the study’s two primary endpoints, the proportion of patients who resumed treatment after cART interruption or CD4 cell count.

“We believe the study reported here provides initial proof of concept to support a role for therapeutic HIV vaccines, since the finding that Vacc-4x is immunogenic and capable of changing plasma viral load setpoint after an analytical treatment interruption of cART,” Dr. Richard Pollard of U.C. Davis Medical Center in Sacramento and colleagues stated in The Lancet Infectious Disease, in a paper online February 11.

Vacc-4x (Bachem AG, Bubendorf, Switzerland) targets domains on the HIV-1 core protein, p24Gag. The study, at 18 sites in the U.S. and Europe, enrolled 137 patients who were virologically controlled on cART, with data available for 135 patients.

Patients were given a dose of the vaccine weekly for the first four weeks of the study, and then booster immunizations at week 16 and week 18. Patients continued on cART for an additional 10 weeks, and then cART was stopped in individuals with a CD4 count above 350 x 1,000,000/L who were under virologic control. Patients resumed cART if their CD4 counts dropped below this level or fell to more than half of their levels at week 28; if their viral load went above 300,000 copies per mL on two consecutive measurements; or if they developed HIV- or AIDS-related events. The study ended at week 52, and patients were followed to week 104.

Thirty patients (34%) given Vacc-4x began taking cART again between week 28 and week 52, versus 11 patients (29%) on placebo (p=0.89). Time to resuming cART was a median 198 days in the vaccine group and 175 days in the placebo group (p=0.77).

At week 48, patients in the vaccine group had a viral load of 23,100 copies per mL, vs 71,800 copies per mL in the patients on placebo (p=0.025).

At week 52, median viral load was 19,550 in the vaccine group and 51,000 in the placebo group (p=0.041).

The vaccine was well tolerated, with most adverse events involving injection site reactions. Nine patients, including five in the vaccine group, had serious events.

“It is recognized that because of the smaller number of recruited participants than originally planned (137 vs. 345) and the use of additional analyses, done on a subgroup of participants who achieved a 52 week off-ART period, these data need to be considered as exploratory,” Dr. Pollard and colleagues write.

“It’s an encouraging first step,” Dr. Merlin Robb, of the US Military HIV Research Program at the Walter Reed Army Institute of Research in Silver Spring, Maryland, told Reuters Health. Dr. Robb co-wrote an editorial on the new study. “If we could arm the immune system to better control the virus after a period of suppression under drugs, then we might have an important avenue to improve treatment outcomes and possibly achieve a cure.”

He and his colleagues are currently conducting clinical trials of HIV vaccine in individuals in the acute phase of HIV infection, when it may be easier to reduce the reservoir of infected T cells, he added.

The SMART trial, which looked at the effect of interrupting cART in HIV patients, found that patients who interrupted cART therapy were actually at greater risk of side effects than those who continued on cART, Dr. Robb noted. Dr. Pollard and his colleagues attributed the difficulty they had recruiting patients to the current trial to the “climate after the release of the SMART data.”

But studies like the current investigation, which are seeking curative treatments, are different from SMART, which looked at management of HIV, Dr. Robb said. “We need to brace ourselves to do these treatment interruptions safely and carefully, because we don’t want to do any harm, but we also want to see if these interventions have any impact.”

Model Predicts Survival in Intrahepatic Cholangiocarcinoma.


A statistical model, or nomogram, has been developed to predict long-term survival of patients following resection for intrahepatic cholangiocarcinoma (ICC), based on data from an international multicenter study.

Although the tool is still investigational, the developers report that patients in the top quartile of predicted survival had a median survival of 80.2 months, compared with 14.8 months for those in the lowest quartile (P = .01).

The authors identified 6 variables that were the most closely associated with survival.

The findings were published online March 5 in JAMA Surgery by Omar Hyder, MD, from Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues.

Intrahepatic cholangiocarcinoma is the second most common primary liver malignant tumor, after hepatocellular carcinoma (HCC), and represents 10% to 20% of all primary liver malignant tumors, or about 3100 new cases every year in the US.

Yet the disease was only recently recognized as an entity distinct from HCC and provided its own unique staging system in the 7th edition of the American Joint Committee on Cancer (AJCC) Staging Manual. The previous 6 editions failed to make that distinction, said study coauthor Timothy M. Pawlik, MD, MPH, PhD, Director of the Johns Hopkins Medicine Liver Tumor Center Multi-Disciplinary Clinic, Johns Hopkins Hospital, told Medscape Medical News.

Although tumor staging is helpful, disease-specific nomograms also take into account clinical factors beyond pathology. “The nomogram will provide clinicians with a patient-specific way to predict survival following resection of ICC,” said Dr. Pawlik, who is also the John L. Cameron MD Professor of Alimentary Tract Diseases at Johns Hopkins.

Asked to comment on the study, David A. Geller, MD, Director of the UPMC Liver Cancer Center, University of Pittsburgh, in Pennsylvania, told Medscape Medical News, “developing a nomogram to predict survival after liver resection is very important,” noting that ICC incidence is increasing and overall prognosis is poor.

The majority of patients are inoperable at diagnosis, and in those who are able to undergo hepatic resection — the only chance for cure — overall 5-year survival is only 25% to 35%, added Dr. Geller, who was not involved in the study and is also the Richard L. Simmons Professor of Surgery at UPMC.

According to Dr. Geller, “This is a well-done multi-center, international study from leading centers around the world.” Once validated in external cohorts, “[the nomogram] potentially could be used to counsel patients and families about risk of recurrence, and could be one of several factors used by medical oncologists to discuss risks/benefits of adjuvant therapies.”

Dr. Pawlik said that the tool can be employed now. “Although the nomogram can be used now to help shape the discussion around patient prognosis, future validation should be performed.”

Six Variables Used to Predict Survival

Hyder and colleagues used data from a study of 514 patients who underwent resection for ICC at 13 major hepatobiliary centers in the United States, Europe, and Asia from 1990 through 2011. Approximately half (53%) of the patients were male and nearly two thirds (61%) were white. They had a mean age of 59 years.

Extended hepatectomy was performed in 39%, hemihepatectomy in 35%, and minor live resection in 26%. Median tumor size was 6.0 cm, with 56% having tumors of 5 cm or larger. Most of the patients (88%) had R0 surgical margins. Lymphadenectomy was performed in 49%, and 24% received adjuvant therapy.

Mean survival postsurgery was 39 months, with survival rates at 1, 3, and 5 years of 81%, 52%, and 40%, respectively.

From an initially selected 15 clinically relevant candidate variables, the authors identified 6 that were the most closely associated with survival. Of the 6 variables, 5 had statistically significant associations with P values < .05: age (hazard ratio [HR], 1.31); presence of multiple tumors (HR, 1.58); tumor size (HR, 1.50); lymph node metastasis (HR, 1.78); and macroscopic vascular invasion (HR, 2.1). The other variable, the presence of cirrhosis, carried a P value of .08 (HR, 1.51).

Further statistical examination of the effect of the 2 continuous variables — age and tumor size — revealed that both had a nonlinear effect on the risk for mortality. Specifically, the effect of tumor size was linear below a threshold of 7 cm, but was constant above that. Similarly, the highest risk for mortality was seen at extremes of age in both directions.

Based on the 6 variables, a nomogram was constructed with points assigned to indicate a survival prognosis. For example, lymph node metastasis was associated with 11 points, while the presence of macroscopic vascular invasion was given 15 points. Higher scores indicate worse prognosis.

The nomogram has a 69% probability of accurately predicting survival, say the study authors, referring to a calculation of the “Harrell’s C-index.”

In comparison, the probable accuracy for predicting survival in all cancer with the 7th edition of the AJCC Cancer Staging Manual is just 59%. For the 6th edition, which had staged ICC the same as HCC, the prognostic ability for ICC was 54%, the authors note.

Role of Tumor Size Reassessed

Dr. Pawlik told Medscape Medical News that his group had previously published findings showing no effect on tumor size. As a result, that variable is not included in the current AJCC ICC staging system.

The reason for the discrepancy with the current data may relate to the nonlinearity of the relationship between tumor size and prognosis, whereby it ceases to be significant above an approximate 7-cm diameter threshold. Previous studies may not have included enough patients with smaller tumors to have influenced the findings, the authors point out in their discussion.

This means that the AJCC staging will likely need to be revised to take tumor size into account as a predictor of survival, Dr. Pawlik told Medscape Medical News.

“Since the ICC staging in the current AJCC manual is the first version ever to be published, future refinements are to be expected. The nomogram is an important next step,” he said.

The authors point out that 1previous nomogram for ICC has been published, but it was based on data from just 1 center in China and evaluated age and tumor size as strictly linear variables.

Teen Publishes Groundbreaking Paper on Her Own Rare Cancer.


A New York City high school senior, Elana Simon, has identified a genetic alteration that may drive the development of a rare liver tumor, fibrolamellar hepatocellular carcinoma, which usually occurs in teens and young adults.

Simon, 18, was diagnosed with the disease at age 12.

Working with a set of professionals from New York institutions, she identified a lone genetic alteration in 100% of the tumors tested in the study (15/15). Notably, the alteration was not detected in matched normal tissue samples from study patients.

The evidence “suggests that this genetic alteration contributes to tumor pathogenesis,” write the authors, led by Simon and co-first author Joshua Honeyman, MD, of the department of surgery of Memorial Sloan Kettering Cancer Center in New York City.

Their new finding, which was published in the February 28th issue of Science , is a ground-breaking discovery.

“Little is known of [fibrolamellar hepatocellular carcinoma’s] molecular pathogenesis,” the authors write.

Or as Simon said in a video posted online: “Until now no one understood what causes this.”

The newly described genetic alteration, known as DNAJB1-PRKACA chimeric transcript, has not been reported in the literature and is not found in the COSMIC (Catalogue of Somatic Mutations in Cancer) database.

The authors are hopeful that this newly found fusion gene “may represent a diagnostic marker” and a “therapeutic target” for fibrolamellar hepatocellular carcinoma. Currently, there are no molecular diagnostic tests for the disease.

“Now we actually have a potential diagnostic for this cancer, which is great because the key to surviving fibrolamellar is finding it early,” said Simon.

She speaks from experience. Her tumor was completely removed at MSKCC 6 years ago by a team led by Michael LaQuaglia, MD, also a coauthor of the study.

“I was very lucky…I have been fine ever since,” Simon said.

I was very lucky…I have been fine ever since.

Surgery is the mainstay of treatment for this liver tumor, which has a clinical phenotype distinct from conventional hepatocellular carcinoma. The tumors “do not respond well to chemotherapy,” the authors say.

Overall survival is 30%-45% at 5 years.

Simon explained that before undertaking the current study she was an intern at a New York City lab and worked on a genomic analysis of pancreatic cancer. So, she had already cut her teeth in genomics.

“I decided to sequence the genome of my own cancer,” she explained.

I decided to sequence the genome of my own cancer.

Simon has had the good fortune of being born into a scientific family. Her father, Sanford Simon, PhD, the senior author of the paper, is from the Laboratory of Cellular Biophysics at Rockefeller University in New York City.

The Simons and their team performed whole genome and transcriptome sequencing of paired tumor and adjacent normal liver samples. To determine whether there were tumor-specific fusion transcripts among the coding RNA, they used the FusionCatcher program on RNA data from the tumors, metastases, and recurrences of 11 patients. Four more patients’ tumors were tested later, for a total of 15 patients.

“We have found the same change in every patient tested, which strongly suggests that this could be the change that is driving this cancer,’ said the younger Simon in her video.

Simon, who attends The Dalton School in Manhattan, has also helped develop the Fibrolamellar Registry, a Web site for patients who can share their medical information with each other and interested researchers and clinicians, according to a profile in The New Yorker .

Clinicians, computer scientists, and the National Institutes of Health’s office of rare diseases have already agreed to join the project as collaborators.

Long-term Consequences of Chronic Proton Pump Inhibitor Use.


Proton pump inhibitors (PPIs), available with or without a prescription, are commonly used for the treatment of acid-related disorders. Despite their ease of availability and common use, PPIs can have severe side effects. The long-term consequences of chronic PPI use include the potential increased risk of hypocalcemia, hypomagnesemia, Clostridium difficile infections, and pneumonia. Community pharmacists are poised to provide evidence-based recommendations and educate patients about the benefits and risks associated with chronic PPI use.

Introduction

Proton pump inhibitor (PPIs) have been on the market since the late 1980s and have replaced the histamine2receptor-antagonists (H2RAs) as the most potent class of drugs for the treatment of acid-related diseases.[1]Anti-ulcer medications (therapeutic areas are based on proprietary IMS Health definitions) were the ninth largest class based on prescription volume in the United States in 2012 and the 11th in sales.[2,3]

Medications in the PPI class are widely available with or without a prescription. Currently, the U.S. market contains six PPIs, two of which are also available as OTC products (Table 1).[4–9] In the early 2000s, the FDA announced the availability of omeprazole (Prilosec OTC) as the first OTC PPI.[10] It was soon followed by the approval of OTC lansoprazole (Prevacid 24HR).[11]

PPIs are used for the treatment of many gastric conditions including peptic ulcer disease, eradication ofHelicobacter pylori infections, treatment and prevention of nonsteroidal anti-inflammatory drug (NSAID) gastroduodenal ulcer, Zollinger-Ellison syndrome, and gastroesophageal reflux disease (GERD).[1] Generally, these medications are prescribed because of the low incidence of side effects and superior efficacy compared to other drugs used to treat the same conditions.[1]

Long-term use of any medication raises safety concerns, especially if that product is available OTC. The American Gastroenterological Association (AGA) released guidelines on the management of GERD in 2008 that recommended against routine monitoring for PPIs due to insufficient evidence.[12] However, since then studies have continued to show long-term consequences from chronic PPI use including malabsorption consequences and infections. Subsequently, in March 2013, the American College of Gastroenterology (ACG) released guidelines for the diagnosis and treatment of GERD.[13] These guidelines do provide some insight into monitoring for long-term consequences of chronic PPI use. This article is a review of the recent literature and guideline recommendations regarding the possible long-term consequences of chronic PPI pharmacotherapy and opportunities to prevent these complications.

In animal studies, PPIs raised concerns about a potential for hypergastrinemia, but human studies failed to show an association.[1] Therefore, long-term consequences of chronic PPI use can be grouped into two main categories, malabsorption and infections.[1] Malabsorption secondary to PPI use affects calcium and magnesium, and the literature specifies two infections most often associated with PPI use, Clostridium difficileand pneumonia. Unfortunately, a definition in the literature for “long-term” is lacking; neither the AGA guidelines nor the ACG guidelines define what is considered long-term. For the rest of this article, the authors use long-term to designate therapy greater than 14 days, the maximum therapy for the OTC products.[10,11]

Malabsorption

The first potential long-term consequence of chronic PPI use is malabsorption of key minerals in the body, namely calcium and magnesium. The loss of these minerals could lead to bone fractures or cardiac abnormalities.

Decreased Calcium Absorption (Hypocalcemia)

Long-term PPI use has been associated with an increased risk of osteoporosis and decreased bone mineral density (BMD), with a 35% increased risk of fractures.[14] Calcium serves an important role in bone health and formation, as it is a key component of hydroxyapatite (the main structural element of bone). Bone material is a major reservoir for calcium and may contain greater than 99% of a body’s calcium.[15] The hypothesis for the mechanism of PPI-induced bone fractures is that dietary calcium absorption is dependent upon an acidic environment in the gastrointestinal (GI) tract. Due to the decrease in acidity from the pharmacologic effect of PPIs, a potential loss of calcium absorption occurs. This reduction in calcium absorption leads to decreased osteoclastic activity and thus decreases in BMD, thereby increasing fracture risk.[1]

The 2013 ACG guidelines on GERD state that existing osteoporosis is not a contraindication to PPI therapy.[13]Patients with osteoporosis may remain on PPI therapy unless another risk factor for hip fracture exists.[13]Furthermore, in March 2011, the FDA modified its osteoporosis and fracture warning. It was concluded that OTC products do not warrant label changes to include warnings of fracture risk.[16]

However, several studies have demonstrated an association between long-term PPI use and risk of fractures, but they contain numerous confounders. Common risk factors for fractures such as a sedentary lifestyle and concomitant use of certain medications (e.g., thiazide diuretics, hormone replacement therapy, corticosteroids) are often observed in patients who routinely take PPIs.[14] Additionally, patients who take high doses of PPIs are at higher fracture risk versus patients who take lower OTC doses.[17] Finally, patients who take PPIs for extended periods of time (>1 year) are more likely to experience a fracture.[18]

An analysis of the data obtained from the Canadian Multicentre Osteoporosis Study revealed that the use of PPIs was associated with lower BMD, particularly at the hip and femoral neck, when compared to non-PPI use.[19]However, long-term PPI use was not associated with an accelerated decline in BMD. Targownik et al reported that patients using PPIs did have lower BMD; however, these patients were significantly older (66.3 vs. 60.9 years; P <.001) and had a higher mean body mass index (BMI) (28.3 vs. 26.9; P <.001).[19]

Data remain relatively inconclusive and conflicting regarding the magnitude of the PPI and fracture association in the absence of additional risk factors. According to the 2013 ACG guidelines, there is insufficient evidence to warrant routine BMD tests, calcium supplementation, or other routine precautions because of PPI use.[13] In contrast, Health Canada issued an alert in April 2013 stating that patients with existing risk factors for osteoporosis should be monitored closely and should also receive short-term PPI therapy at the lowest effective dose.[20] This is parallel to current recommendations from the FDA despite the lack of recommendations from the ACG.[16] If calcium supplementation is indicated, use of calcium citrate is the preferred calcium supplement in patients taking PPIs, as it can be absorbed in the absence of an acidic environment.[1]

Decreased Magnesium Absorption (Hypomagnesemia)

In March 2011, the FDA released a warning regarding low serum magnesium levels associated with long-term use of PPIs.[21] An analysis of reports from the FDA’s Adverse Event Reporting System (AERS) states that approximately 1% of patients who experienced an adverse effect while on a PPI experienced hypomagnesemia.[21] The mechanism behind the changes in absorption is unknown. Symptoms of hypomagnesemia include seizures, arrhythmias, hypotension, and tetany. Hypomagnesemia is also potentially fatal.[22] Hypomagnesemia related to chronic PPI use was not addressed in the 2013 ACG guidelines.[13]

All PPIs are associated with decreased magnesium absorption.[21] Hypomagnesemia was more common in older patients taking a PPI (mean age 64.4 years).[21] Mean time to onset of hypomagnesemia was 5.5 years after initiation of therapy.[21] Similarly, a systematic review of case reports found that patients who presented with hypomagnesemia in association with PPI use also presented with other electrolyte disturbances, specifically hypokalemia and hypocalcemia.[23] Hypomagnesemia generally resolved with the discontinuation of the PPI and recurred soon after the PPI was rechallenged.[24]

Concurrent use of medications that also decrease magnesium increases the risk of significant hypomagnesemia. Danziger et al reported that patients who take a PPI with a diuretic have nearly a 55% greater risk of hypomagnesemia than patients who take only a PPI.[22]

An FDA Drug Safety Communication warns of the risks of hypomagnesemia and recommends that providers monitor serum magnesium levels in patients taking PPIs.[21] The FDA suggests that providers obtain serum magnesium levels prior to initiation of therapy and periodically thereafter for patients who will continue prolonged treatment and for patients who take medications that also cause hypo-magnesemia. Patients who present with clinically significant hypomagnesemia may require discontinuation of PPI therapy, magnesium replacement via oral or IV methods, and treatment with an alternative class of drugs for GI conditions such as an H2RA.[1]

Infections

In addition to decreased magnesium and calcium absorption, patients on long-term PPIs may be at an increased risk of infection. The hypothesis for the mechanism of action is that the gastric acid secretions act as a defense mechanism against enteric bacteria, and the increased gastric pH during PPI use allows for colonization of opportunistic microbes.[1] The 2013 ACG guidelines warned about the risk of increased infections of C difficile and community-acquired pneumonia (CAP).[13]

Clostridium difficile

In a 2005 retrospective study, researchers found that patients who were taking PPIs had a hazard ratio (HR) of 2.9 (95% CI, 2.4–3.4); i.e., patients had a 2.9-fold increase in the risk of acquiring C difficile than patients who were not on a PPI.[25] Seventy-five percent of the patients with reported cases were over the age of 65 years. Not only does long-term use of PPIs cause an increased incidence of C difficile, but patients who received a PPI during treatment of C difficile were also 42% (95% CI, 1.11–1.82) more likely to have a recurrent infection after finishing therapy.[25]

A 2010 study by Linsky et al looked at the association of PPI use and recurrent C difficile. [26] The authors determined whether or not the patient had an infection with recurrent C difficile, 15 to 90 days after initial C difficile infection, if the patient received a PPI within 14 days of initial C difficle infection. The HR for patients exposed to PPIs during treatment was 1.42 (95% CI, 1.11–1.82). For patients over the age of 80 years, the HR increases from 1.42 to 1.86 (95% CI, 1.15–3.01).[26]

In 2012, the FDA issued a statement detailing the relationship between C difficile–associated diarrhea (CDAD) with the use of a PPI.[27] The FDA safety alert warns patients and healthcare professionals to consider CDAD if a patient takes a PPI and experiences persistent diarrhea.[27] The FDA also recommends that patients be on the lowest dose for the shortest period of time to treat their current condition.[27] The 2013 ACG guidelines recommend use of PPIs with caution in patients with a risk of C difficile infections.[13]

Community-Acquired Pneumonia

Patients taking PPIs may potentially be at an increased risk for CAP. However, the degree of association is unclear due to conflicting data.[28–30] The 2013 ACG guidelines state that short-term PPI use may increase the risk of CAP, but the risk does not seem to be elevated in long-term use.[13]

A 2012 cohort study by de Jagar et al showed that patients on PPIs were 2.23 times (95% CI, 1.28–3.75) more likely to develop a CAP infection compared to patients not on PPIs.[31] Unfortunately, the duration of time that patients were prescribed was not included in the study design.[31] In a meta-analysis completed in 2004, researchers discovered that patients who were on an acid-suppressing agent, either a PPI or an H2RA, were 4.5 (95% CI, 3.8–5.1) times more likely to develop pneumonia.[30] Mean duration of use for H2RAs was 2.8 months; for PPIs the mean duration was 5 months.[30]

Conversely, a 2008 study conducted by Sarkar et al showed that current PPI use was not associated with an increased risk of CAP (odds ratio [OR] 1.02, 95% CI 0.97–1.08).[29] However, the study did observe an increased risk of acquiring an infection in patients initiated on a PPI within the past 14 days (adjusted OR 3.21, 95% CI 2.46–4.18).[29]

The data support a short-term increase risk of pneumonia infections, but they are conflicting regarding long-term consequences. Despite the conflicting data, this risk is important to consider, especially because of the new Centers for Medicare & Medicaid (CMS) regulations on hospital readmissions.[32] Laheij et al determined that the incidence rate of pneumonia was 2.5 per 100 patient-years for patients on PPIs.[30] With 65.7 million prescriptions of omeprazole alone and an increased $15,682 cost to Medicare beneficiaries due to pneumonia hospitalizations, the risk of PPI use-associated infections warrants vigilance and evidence-based medicine on the part of the pharmacist.[33,34]

Conclusion

PPIs are an efficacious and safe drug class. They offer relief to patients in a patient-centered healthcare system. Unfortunately, these agents do potentially have some long-term consequences from continued use, including malabsorption issues and increased risk of infections. The pharmacist can be an advocate for the patient in the hospital system or in the community by understanding these risks and fostering patient-centered care by empowering a well-informed patient in healthcare decisions.