Patient receiving chemotherapy

Credit: Rhoda Baer

Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.

Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.

The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.

“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.

“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”

Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.

So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.

The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.

Effects of palliative chemo

In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.

Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.

However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.

Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).

They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).

“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”

“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”

Explaining the negative effects

Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.

In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).

“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.

“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”

Moving forward

The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.

“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”

The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.

In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.

He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.

Patient receiving chemotherapy

Credit: Rhoda Baer

Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.

Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.

The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.

“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.

“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”

Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.

So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.

The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.

Effects of palliative chemo

In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.

Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.

However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.

Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).

They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).

“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”

“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”

Explaining the negative effects

Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.

In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).

“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.

“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”

Moving forward

The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.

“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”

The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.

In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.

He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.

Patient receiving chemotherapy

Credit: Rhoda Baer

Palliative chemotherapy can negatively impact the end of life for terminally ill cancer patients, according to a paper published in BMJ.

Investigators found that patients who received palliative chemotherapy in their last months of life had an increased risk of requiring intensive medical care, such as resuscitation, and dying in a place they did not choose, such as an intensive care unit.

The researchers therefore suggested that end-of-life discussions may be particularly important for patients who want to receive palliative chemotherapy.

“The results highlight the need for more effective communication by doctors of terminal prognoses and the likely outcomes of chemotherapy for these patients,” said study author Holly Prigerson, PhD, of Weill Cornell Medical College in New York.

“For patients to make informed choices about their care, they need to know if they are incurable and understand what their life expectancy is, that palliative chemotherapy is not intended to cure them, that it may not appreciably prolong their life, and that it may result in the receipt of very aggressive, life-prolonging care at the expense of their quality of life.”

Data have suggested that between 20% and 50% of patients with incurable cancers undergo palliative chemotherapy within 30 days of death. But it has not been clear whether the use of chemotherapy in a patient’s last months is associated with the need for intensive medical care in the last week of life or with the patient’s death.

So Dr Prigerson and her colleagues decided to study the use of palliative chemotherapy in patients with 6 or fewer months to live. The researchers used data from “Coping with Cancer,” a 6-year study of 386 terminally ill patients.

The patients were interviewed around the time of their decision regarding palliative chemotherapy. In the month after each patient died, caregivers were asked to rate their loved ones’ care, quality of life, and place of death as being where the patient would have wanted to die. The investigators then reviewed patients’ medical charts to determine the type of care they actually received in their last week.

Effects of palliative chemo

In all, 56% of patients opted to receive palliative chemotherapy. They were more likely to be younger, married, and better educated than patients not on the treatment.

Patients on chemotherapy also had better performance status, overall quality of life, physical functioning, and psychological well-being at study enrollment.

However, patients who received palliative chemotherapy had a greater risk of requiring cardiopulmonary resuscitation and/or mechanical ventilation (14% vs 2%), and they were more likely to need a feeding tube (11% vs 5%) in their last weeks of life.

Patients on chemotherapy had a greater risk of being admitted to an intensive care unit (14% vs 8%) and of having a late hospice referral (54% vs 37%).

They were also less likely to die where they wanted to (65% vs 80%). They had a greater risk of dying in an intensive care unit (11% vs 2%) and were less likely than their peers to die at home (47% vs 66%).

“It’s hard to see in these data much of a silver lining to palliative chemotherapy for patients in the terminal stage of their cancer,” Dr Prigerson said. “Until now, there hasn’t been evidence of harmful effects of palliative chemotherapy in the last few months of life.”

“This study is a first step in providing evidence that specifically demonstrates what negative outcomes may result. Additional studies are needed to confirm these troubling findings.”

Explaining the negative effects

Dr Prigerson said the harmful effects of palliative chemotherapy may be a result of misunderstanding, a lack of communication, and denial. Patients may not comprehend the purpose and likely consequences of palliative chemotherapy, and they may not fully acknowledge their own prognoses.

In the study, patients receiving palliative chemotherapy were less likely than their peers to talk to their oncologists about end-of-life care (37% vs 48%), to complete Do-Not-Resuscitate orders (36% vs 49%), or to acknowledge that they were terminally ill (35% vs 47%).

“Our finding that patients with terminal cancers were at higher risk of receiving intensive end-of-life care if they were treated with palliative chemotherapy months earlier underscores the importance of oncologists asking patients about their end-of-life wishes,” said Alexi Wright, MD, of the Dana-Farber Cancer Institute in Boston.

“We often wait until patients stop chemotherapy before asking them about where and how they want to die, but this study shows we need to ask patients about their preferences while they are receiving chemotherapy to ensure they receive the kind of care they want near death.”

Moving forward

The investigators stressed that the study results do not suggest patients should be denied palliative chemotherapy.

“The vast majority of patients in this study wanted palliative chemotherapy if it might increase their survival by as little as a week,” Dr Wright said. “This study is a step towards understanding some of the human costs and benefits of palliative chemotherapy.”

The researchers said additional studies should examine whether patients who are aware that chemotherapy is not intended to cure them still want to receive the treatment, confirm the negative outcomes of palliative chemotherapy, and determine if end-of-life discussions promote more informed decision-making and receipt of value-consistent care.

In a related editorial, Mike Rabow, MD, of the University of California, San Francisco, noted that although most patients with metastatic cancer choose to receive chemotherapy, evidence suggests most do not understand its intent.

He said Dr Prigerson’s study suggests the need to “better identify patients who are likely to benefit from chemotherapy near the end of life.” And he encouraged oncologists to discuss with patients the broader implications of chemotherapy when making decisions about treatment.

DNA coiled around histones

Credit: Eric Smith

Researchers say they’ve discovered how histones control PARP1’s ability to activate genes and repair DNA damage.

Their findings, published in Molecular Cell, appear to have implications for cancer treatment.

Specifically, the investigators found that chemical modification of the histone H2Av leads to substantial changes in nucleosome shape.

As a consequence, a previously hidden portion of the nucleosome becomes exposed and activates PARP1.

Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of PARP1 activation, thereby exposing specific genes for activation.

“[T]he nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” said study author Alexei V. Tulin, PhD, of Fox Chase Cancer Center in Philadelphia.

“We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”

In addition to revealing new information about how histones control gene activation, Dr Tulin’s research elucidated a new mechanism of PARP1 regulation.

“This mechanism of PARP1 regulation by histones is still very new,” Dr Tulin said. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.”

Previous research suggested that combining standard anticancer agents with drugs that inhibit PARP1 can more effectively kill cancer cells. But clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing results.

“I believe that, to a large extent, the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Dr Tulin said. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”

Dr Tulin and his colleagues are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials.

DNA coiled around histones

Credit: Eric Smith

Researchers say they’ve discovered how histones control PARP1’s ability to activate genes and repair DNA damage.

Their findings, published in Molecular Cell, appear to have implications for cancer treatment.

Specifically, the investigators found that chemical modification of the histone H2Av leads to substantial changes in nucleosome shape.

As a consequence, a previously hidden portion of the nucleosome becomes exposed and activates PARP1.

Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of PARP1 activation, thereby exposing specific genes for activation.

“[T]he nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” said study author Alexei V. Tulin, PhD, of Fox Chase Cancer Center in Philadelphia.

“We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”

In addition to revealing new information about how histones control gene activation, Dr Tulin’s research elucidated a new mechanism of PARP1 regulation.

“This mechanism of PARP1 regulation by histones is still very new,” Dr Tulin said. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.”

Previous research suggested that combining standard anticancer agents with drugs that inhibit PARP1 can more effectively kill cancer cells. But clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing results.

“I believe that, to a large extent, the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Dr Tulin said. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”

Dr Tulin and his colleagues are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials.

DNA coiled around histones

Credit: Eric Smith

Researchers say they’ve discovered how histones control PARP1’s ability to activate genes and repair DNA damage.

Their findings, published in Molecular Cell, appear to have implications for cancer treatment.

Specifically, the investigators found that chemical modification of the histone H2Av leads to substantial changes in nucleosome shape.

As a consequence, a previously hidden portion of the nucleosome becomes exposed and activates PARP1.

Upon activation, PARP1 assembles long branching molecules of Poly(ADP-ribose), which appear to open the DNA packaging around the site of PARP1 activation, thereby exposing specific genes for activation.

“[T]he nucleosome is often portrayed as a stable, inert structure, or a tiny ball,” said study author Alexei V. Tulin, PhD, of Fox Chase Cancer Center in Philadelphia.

“We found that the nucleosome is actually a quite dynamic structure. When we modified one histone, we changed the whole nucleosome.”

In addition to revealing new information about how histones control gene activation, Dr Tulin’s research elucidated a new mechanism of PARP1 regulation.

“This mechanism of PARP1 regulation by histones is still very new,” Dr Tulin said. “People believe that PARP1 is mainly activated through interactions with DNA, but we have found that the main pathway of PARP1 activation is through interactions with the nucleosome.”

Previous research suggested that combining standard anticancer agents with drugs that inhibit PARP1 can more effectively kill cancer cells. But clinical trials testing PARP1 inhibitors in cancer patients have produced disappointing results.

“I believe that, to a large extent, the previous setbacks were caused by a general misconception of the role of PARP1 in living cells and the mechanisms of PARP1 regulation,” Dr Tulin said. “Now that we know this mechanism of PARP1 regulation, we can design approaches to inhibit this protein in an effective way to better treat cancer.”

Dr Tulin and his colleagues are now developing the next generation of PARP1 inhibitors. Designed to block the newly identified mechanism of PARP1 activation, these inhibitors will specifically target PARP1, in contrast to the PARP1 inhibitors currently being tested in clinical trials.

Two-thirds of U.S. adults currently consume alcohol, according to the National Health Interview Survey. While most are infrequent or light drinkers, 8% are problem drinkers (more than 14 drinks per week for men and more than 7 drinks per week for women).

Alcohol consumption is the second-leading cause of preventable death and disability in the United States. Annually, excessive alcohol consumption costs us almost a quarter of a trillion dollars in lost productivity, health care, law enforcement, and motor vehicle collisions.

Alcoholism is a relapsing and remitting disease characterized by psychosocial impairment and drug craving and withdrawal. Challenged by access inequalities to formal treatment services, few alcoholics, when interacting with the medical setting for other reasons, are offered or receive treatment. Some patients may be open to receiving treatment by primary care providers, but few drugs are available (naltrexone, acamprosate, and disulfiram). Clinicians may be unconvinced of their efficacy or uncomfortable with their use.

Gabapentin is an antiepileptic used commonly in primary care settings, mostly for neuropathic pain. Gabapentin is well tolerated, with a favorable pharmacokinetic profile and a broad therapeutic index. Preclinical data suggest that gabapentin normalizes stress-induced GABA (gamma-aminobutyric acid) activation associated with alcohol use disorder. Human data suggest that gabapentin reduces alcohol craving and alcohol-associated sleep and mood problems.

Mason and colleagues published the results from a randomized controlled clinical trial evaluating the efficacy and safety of different doses of gabapentin for increasing alcohol abstinence and reducing heavy drinking, insomnia, dysphoria, and craving. Potential participants were eligible for enrollment if they were aged 18 years or older, met criteria for alcohol dependence, and were recently abstinent from alcohol (at least 3 days). Participants were randomized to gabapentin 900 mg/day, gabapentin 1,800 mg/day, or placebo. Treatment was received for 12 weeks with titration and tapering (JAMA Intern. Med. 2014;174:70-7).

A total of 150 patients were randomized, and the groups were similar at baseline. Abstinence rates were 17%, 11.1%, and 4.1% in the 1,800-mg, 900-mg, and placebo groups (P = .04 for linear dose effect), respectively. The no-heavy-drinking rates were 44.7%, 29.6%, and 22.5% (P = .02 for linear dose effect). A dose effect was also observed for reductions in mood disturbance, sleep problems, and craving. No serious adverse events were reported.

We need to try to meet patients where they are. Patients should be directed to alcohol treatment services if they are willing to go. In my experience, many of them are not. In these cases, recommending an Alcoholics Anonymous group, trying gabapentin, and following them up in a clinic is a harm-reduction strategy worth trying.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. He reports no conflicts of interest.

Two-thirds of U.S. adults currently consume alcohol, according to the National Health Interview Survey. While most are infrequent or light drinkers, 8% are problem drinkers (more than 14 drinks per week for men and more than 7 drinks per week for women).

Alcohol consumption is the second-leading cause of preventable death and disability in the United States. Annually, excessive alcohol consumption costs us almost a quarter of a trillion dollars in lost productivity, health care, law enforcement, and motor vehicle collisions.

Alcoholism is a relapsing and remitting disease characterized by psychosocial impairment and drug craving and withdrawal. Challenged by access inequalities to formal treatment services, few alcoholics, when interacting with the medical setting for other reasons, are offered or receive treatment. Some patients may be open to receiving treatment by primary care providers, but few drugs are available (naltrexone, acamprosate, and disulfiram). Clinicians may be unconvinced of their efficacy or uncomfortable with their use.

Gabapentin is an antiepileptic used commonly in primary care settings, mostly for neuropathic pain. Gabapentin is well tolerated, with a favorable pharmacokinetic profile and a broad therapeutic index. Preclinical data suggest that gabapentin normalizes stress-induced GABA (gamma-aminobutyric acid) activation associated with alcohol use disorder. Human data suggest that gabapentin reduces alcohol craving and alcohol-associated sleep and mood problems.

Mason and colleagues published the results from a randomized controlled clinical trial evaluating the efficacy and safety of different doses of gabapentin for increasing alcohol abstinence and reducing heavy drinking, insomnia, dysphoria, and craving. Potential participants were eligible for enrollment if they were aged 18 years or older, met criteria for alcohol dependence, and were recently abstinent from alcohol (at least 3 days). Participants were randomized to gabapentin 900 mg/day, gabapentin 1,800 mg/day, or placebo. Treatment was received for 12 weeks with titration and tapering (JAMA Intern. Med. 2014;174:70-7).

A total of 150 patients were randomized, and the groups were similar at baseline. Abstinence rates were 17%, 11.1%, and 4.1% in the 1,800-mg, 900-mg, and placebo groups (P = .04 for linear dose effect), respectively. The no-heavy-drinking rates were 44.7%, 29.6%, and 22.5% (P = .02 for linear dose effect). A dose effect was also observed for reductions in mood disturbance, sleep problems, and craving. No serious adverse events were reported.

We need to try to meet patients where they are. Patients should be directed to alcohol treatment services if they are willing to go. In my experience, many of them are not. In these cases, recommending an Alcoholics Anonymous group, trying gabapentin, and following them up in a clinic is a harm-reduction strategy worth trying.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. He reports no conflicts of interest.

Two-thirds of U.S. adults currently consume alcohol, according to the National Health Interview Survey. While most are infrequent or light drinkers, 8% are problem drinkers (more than 14 drinks per week for men and more than 7 drinks per week for women).

Alcohol consumption is the second-leading cause of preventable death and disability in the United States. Annually, excessive alcohol consumption costs us almost a quarter of a trillion dollars in lost productivity, health care, law enforcement, and motor vehicle collisions.

Alcoholism is a relapsing and remitting disease characterized by psychosocial impairment and drug craving and withdrawal. Challenged by access inequalities to formal treatment services, few alcoholics, when interacting with the medical setting for other reasons, are offered or receive treatment. Some patients may be open to receiving treatment by primary care providers, but few drugs are available (naltrexone, acamprosate, and disulfiram). Clinicians may be unconvinced of their efficacy or uncomfortable with their use.

Gabapentin is an antiepileptic used commonly in primary care settings, mostly for neuropathic pain. Gabapentin is well tolerated, with a favorable pharmacokinetic profile and a broad therapeutic index. Preclinical data suggest that gabapentin normalizes stress-induced GABA (gamma-aminobutyric acid) activation associated with alcohol use disorder. Human data suggest that gabapentin reduces alcohol craving and alcohol-associated sleep and mood problems.

Mason and colleagues published the results from a randomized controlled clinical trial evaluating the efficacy and safety of different doses of gabapentin for increasing alcohol abstinence and reducing heavy drinking, insomnia, dysphoria, and craving. Potential participants were eligible for enrollment if they were aged 18 years or older, met criteria for alcohol dependence, and were recently abstinent from alcohol (at least 3 days). Participants were randomized to gabapentin 900 mg/day, gabapentin 1,800 mg/day, or placebo. Treatment was received for 12 weeks with titration and tapering (JAMA Intern. Med. 2014;174:70-7).

A total of 150 patients were randomized, and the groups were similar at baseline. Abstinence rates were 17%, 11.1%, and 4.1% in the 1,800-mg, 900-mg, and placebo groups (P = .04 for linear dose effect), respectively. The no-heavy-drinking rates were 44.7%, 29.6%, and 22.5% (P = .02 for linear dose effect). A dose effect was also observed for reductions in mood disturbance, sleep problems, and craving. No serious adverse events were reported.

We need to try to meet patients where they are. Patients should be directed to alcohol treatment services if they are willing to go. In my experience, many of them are not. In these cases, recommending an Alcoholics Anonymous group, trying gabapentin, and following them up in a clinic is a harm-reduction strategy worth trying.

Dr. Ebbert is professor of medicine, a general internist at the Mayo Clinic in Rochester, Minn., and a diplomate of the American Board of Addiction Medicine. The opinions expressed are those of the author. He reports no conflicts of interest.

Febrile neonates represent a challenge to clinicians as the risk for serious bacterial infections is highest at this age, the presence of discriminating clinical signs are often absent, and outcomes can be poor in the absence of early treatment. For this reason, most experts recommend that all neonates with a rectal temperature 38°C or higher have blood, urine, and cerebrospinal fluid cultures regardless of clinical appearance (Ann. Emerg. Med. 1993;22:1198-1210). Such neonates should be admitted to the hospital and treated with empiric antibiotics.

In a study of 41,890 neonates (up to 28 days of age) evaluated in 36 pediatric emergency departments, 2,253 (5.4%) were febrile. Three hundred sixty-nine (16%) infants were seen, then discharged from the ED; the remaining 1,884 (84%) were seen and admitted.

As with prior studies, a high rate of serious infection (12%) was documented; urinary tract infection (27%), meningitis (19%), bacteremia and sepsis (14%), cellulitis and soft tissue infections (6%), and pneumonia (3%) were most common. Of the 369 infants discharged, 3 (1%) had serious infection; of the 1,884 admitted, 266 (14%) did.

The study demonstrated significant variability in the approach used to evaluate and treat febrile neonates, with 16% of infants being discharged from the emergency department, the majority of whom (97%) did not get antimicrobial therapy. Sixty-four (3%) of all febrile infants were discharged without any laboratory evaluation or treatment. Eighty-four percent of febrile infants were admitted to the hospital, and 96% of those admitted received antimicrobial treatment (Pediatrics 2014;133:187).

Prior studies reported that serious bacterial infection was uncommon in febrile neonates who met the following six low-risk criteria: 1. an unremarkable medical history, 2. a healthy, nontoxic appearance, 3. no focal signs of infection, 4. an erythrocyte sedimentation rate less than 30 mm at the end of the first hour, 5. a white blood cell count of 5,000-15,000/mcL, and 6. a normal urine analysis (Arch. Dis. Child Fetal Neonatal Ed. 2007;92:F15-8).

Although it is unclear what criteria were used to discharge febrile neonates from the pediatric ED in the current study, only 1 of the 369 neonates discharged from the pediatric ED subsequently returned to the same pediatric ED and was diagnosed with serious infection; however, only 10 in total returned for evaluation. How many subsequently were diagnosed with serious infection at a different facility is unknown. These results were consistent with the initial studies of the "low-risk criteria," which indicates these criteria are not sufficiently reliable to exclude the presence of serious infection.

The study demonstrates that there remains disagreement about how febrile neonates should be evaluated and managed in the ED setting, and how much reliance should be placed on clinical and laboratory parameters. Unlike children older than 3 months of age, in whom immunization with Haemophilus influenzae type b and 13-valent pneumococcal conjugate vaccines has dramatically reduced the incidence of invasive disease, serious infection in febrile neonates up to 28 days of age remains common.

The current spectrum of pathogens and disease – gram-negative uropathogens, staphylococcal and streptococcal skin and soft tissue infections, group B Streptococcus and Staphylococcus aureus bacteremia, and CNS infection – have not been significantly impacted by efforts to prevent "early-onset" neonatal sepsis and by vaccine strategies that target primarily older children. Age remains a risk, with a decreasing incidence of serious bacterial infection as each week of life passes. However, in another study, the rate of serious bacterial infection in febrile neonates 15-21 days of age was found to be sufficiently high to warrant comparable management to that given younger neonates (Pediatr. Inf. Dis. J. 2012;31:455-8).

Thus, currently there seem to be few strategies that would protect febrile neonates from delays in therapy and preventable outcomes, other than the traditional practice of thorough medical evaluation, laboratory testing to include blood, urine, and cerebrospinal fluid cultures, chest x-ray when respiratory tract signs/symptoms are present, and presumptive treatment with parenteral antibiotic therapy.

Office-based studies report greater reliance on clinical judgment with the belief that reliance on clinical guidelines would have only a small benefit, if any, but would result in greater hospitalization and laboratory testing (JAMA 2004;291:1203-12). Still the high rate of disease (14%) in those admitted to the hospital underscore the vulnerability of this age group, the significance of fever, and the potential for a poor outcome without thorough evaluation of each child and presumptive treatment for serious bacterial infection.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. Dr. Pelton said he had no relevant financial disclosures. E-mail him at [email protected].

Febrile neonates represent a challenge to clinicians as the risk for serious bacterial infections is highest at this age, the presence of discriminating clinical signs are often absent, and outcomes can be poor in the absence of early treatment. For this reason, most experts recommend that all neonates with a rectal temperature 38°C or higher have blood, urine, and cerebrospinal fluid cultures regardless of clinical appearance (Ann. Emerg. Med. 1993;22:1198-1210). Such neonates should be admitted to the hospital and treated with empiric antibiotics.

In a study of 41,890 neonates (up to 28 days of age) evaluated in 36 pediatric emergency departments, 2,253 (5.4%) were febrile. Three hundred sixty-nine (16%) infants were seen, then discharged from the ED; the remaining 1,884 (84%) were seen and admitted.

As with prior studies, a high rate of serious infection (12%) was documented; urinary tract infection (27%), meningitis (19%), bacteremia and sepsis (14%), cellulitis and soft tissue infections (6%), and pneumonia (3%) were most common. Of the 369 infants discharged, 3 (1%) had serious infection; of the 1,884 admitted, 266 (14%) did.

The study demonstrated significant variability in the approach used to evaluate and treat febrile neonates, with 16% of infants being discharged from the emergency department, the majority of whom (97%) did not get antimicrobial therapy. Sixty-four (3%) of all febrile infants were discharged without any laboratory evaluation or treatment. Eighty-four percent of febrile infants were admitted to the hospital, and 96% of those admitted received antimicrobial treatment (Pediatrics 2014;133:187).

Prior studies reported that serious bacterial infection was uncommon in febrile neonates who met the following six low-risk criteria: 1. an unremarkable medical history, 2. a healthy, nontoxic appearance, 3. no focal signs of infection, 4. an erythrocyte sedimentation rate less than 30 mm at the end of the first hour, 5. a white blood cell count of 5,000-15,000/mcL, and 6. a normal urine analysis (Arch. Dis. Child Fetal Neonatal Ed. 2007;92:F15-8).

Although it is unclear what criteria were used to discharge febrile neonates from the pediatric ED in the current study, only 1 of the 369 neonates discharged from the pediatric ED subsequently returned to the same pediatric ED and was diagnosed with serious infection; however, only 10 in total returned for evaluation. How many subsequently were diagnosed with serious infection at a different facility is unknown. These results were consistent with the initial studies of the "low-risk criteria," which indicates these criteria are not sufficiently reliable to exclude the presence of serious infection.

The study demonstrates that there remains disagreement about how febrile neonates should be evaluated and managed in the ED setting, and how much reliance should be placed on clinical and laboratory parameters. Unlike children older than 3 months of age, in whom immunization with Haemophilus influenzae type b and 13-valent pneumococcal conjugate vaccines has dramatically reduced the incidence of invasive disease, serious infection in febrile neonates up to 28 days of age remains common.

The current spectrum of pathogens and disease – gram-negative uropathogens, staphylococcal and streptococcal skin and soft tissue infections, group B Streptococcus and Staphylococcus aureus bacteremia, and CNS infection – have not been significantly impacted by efforts to prevent "early-onset" neonatal sepsis and by vaccine strategies that target primarily older children. Age remains a risk, with a decreasing incidence of serious bacterial infection as each week of life passes. However, in another study, the rate of serious bacterial infection in febrile neonates 15-21 days of age was found to be sufficiently high to warrant comparable management to that given younger neonates (Pediatr. Inf. Dis. J. 2012;31:455-8).

Thus, currently there seem to be few strategies that would protect febrile neonates from delays in therapy and preventable outcomes, other than the traditional practice of thorough medical evaluation, laboratory testing to include blood, urine, and cerebrospinal fluid cultures, chest x-ray when respiratory tract signs/symptoms are present, and presumptive treatment with parenteral antibiotic therapy.

Office-based studies report greater reliance on clinical judgment with the belief that reliance on clinical guidelines would have only a small benefit, if any, but would result in greater hospitalization and laboratory testing (JAMA 2004;291:1203-12). Still the high rate of disease (14%) in those admitted to the hospital underscore the vulnerability of this age group, the significance of fever, and the potential for a poor outcome without thorough evaluation of each child and presumptive treatment for serious bacterial infection.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. Dr. Pelton said he had no relevant financial disclosures. E-mail him at [email protected].

Febrile neonates represent a challenge to clinicians as the risk for serious bacterial infections is highest at this age, the presence of discriminating clinical signs are often absent, and outcomes can be poor in the absence of early treatment. For this reason, most experts recommend that all neonates with a rectal temperature 38°C or higher have blood, urine, and cerebrospinal fluid cultures regardless of clinical appearance (Ann. Emerg. Med. 1993;22:1198-1210). Such neonates should be admitted to the hospital and treated with empiric antibiotics.

In a study of 41,890 neonates (up to 28 days of age) evaluated in 36 pediatric emergency departments, 2,253 (5.4%) were febrile. Three hundred sixty-nine (16%) infants were seen, then discharged from the ED; the remaining 1,884 (84%) were seen and admitted.

As with prior studies, a high rate of serious infection (12%) was documented; urinary tract infection (27%), meningitis (19%), bacteremia and sepsis (14%), cellulitis and soft tissue infections (6%), and pneumonia (3%) were most common. Of the 369 infants discharged, 3 (1%) had serious infection; of the 1,884 admitted, 266 (14%) did.

The study demonstrated significant variability in the approach used to evaluate and treat febrile neonates, with 16% of infants being discharged from the emergency department, the majority of whom (97%) did not get antimicrobial therapy. Sixty-four (3%) of all febrile infants were discharged without any laboratory evaluation or treatment. Eighty-four percent of febrile infants were admitted to the hospital, and 96% of those admitted received antimicrobial treatment (Pediatrics 2014;133:187).

Prior studies reported that serious bacterial infection was uncommon in febrile neonates who met the following six low-risk criteria: 1. an unremarkable medical history, 2. a healthy, nontoxic appearance, 3. no focal signs of infection, 4. an erythrocyte sedimentation rate less than 30 mm at the end of the first hour, 5. a white blood cell count of 5,000-15,000/mcL, and 6. a normal urine analysis (Arch. Dis. Child Fetal Neonatal Ed. 2007;92:F15-8).

Although it is unclear what criteria were used to discharge febrile neonates from the pediatric ED in the current study, only 1 of the 369 neonates discharged from the pediatric ED subsequently returned to the same pediatric ED and was diagnosed with serious infection; however, only 10 in total returned for evaluation. How many subsequently were diagnosed with serious infection at a different facility is unknown. These results were consistent with the initial studies of the "low-risk criteria," which indicates these criteria are not sufficiently reliable to exclude the presence of serious infection.

The study demonstrates that there remains disagreement about how febrile neonates should be evaluated and managed in the ED setting, and how much reliance should be placed on clinical and laboratory parameters. Unlike children older than 3 months of age, in whom immunization with Haemophilus influenzae type b and 13-valent pneumococcal conjugate vaccines has dramatically reduced the incidence of invasive disease, serious infection in febrile neonates up to 28 days of age remains common.

The current spectrum of pathogens and disease – gram-negative uropathogens, staphylococcal and streptococcal skin and soft tissue infections, group B Streptococcus and Staphylococcus aureus bacteremia, and CNS infection – have not been significantly impacted by efforts to prevent "early-onset" neonatal sepsis and by vaccine strategies that target primarily older children. Age remains a risk, with a decreasing incidence of serious bacterial infection as each week of life passes. However, in another study, the rate of serious bacterial infection in febrile neonates 15-21 days of age was found to be sufficiently high to warrant comparable management to that given younger neonates (Pediatr. Inf. Dis. J. 2012;31:455-8).

Thus, currently there seem to be few strategies that would protect febrile neonates from delays in therapy and preventable outcomes, other than the traditional practice of thorough medical evaluation, laboratory testing to include blood, urine, and cerebrospinal fluid cultures, chest x-ray when respiratory tract signs/symptoms are present, and presumptive treatment with parenteral antibiotic therapy.

Office-based studies report greater reliance on clinical judgment with the belief that reliance on clinical guidelines would have only a small benefit, if any, but would result in greater hospitalization and laboratory testing (JAMA 2004;291:1203-12). Still the high rate of disease (14%) in those admitted to the hospital underscore the vulnerability of this age group, the significance of fever, and the potential for a poor outcome without thorough evaluation of each child and presumptive treatment for serious bacterial infection.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. Dr. Pelton said he had no relevant financial disclosures. E-mail him at [email protected].

Patients who are dementia-free but have two parents with late-onset Alzheimer’s disease may show signs of the disease during brain imaging decades before symptoms appear, researchers reported online ahead of print February 12 in Neurology. A total of 52 persons with normal cognition—including four demographically balanced groups with maternal, paternal, and maternal and paternal family history of late-onset Alzheimer’s disease, as well as those with a negative family history—underwent MRI, ¹¹C-Pittsburgh compound B (PiB) PET, and ¹⁸F-fluoro-2-deoxyglucose PET. Subjects with both parents with a history of Alzheimer’s disease had more severe abnormalities in all three biomarkers, compared with the other groups, regarding the number of regions affected and magnitude of impairment. PiB retention and hypometabolism were most pronounced in participants with a maternal and paternal history of Alzheimer’s disease, according to the investigators.

Patients with nonvalvular atrial fibrillation are encouraged to take oral anticoagulants to prevent stroke, according to an updated guideline published in the February 25, 2014, issue of Neurology. Treatment with anticoagulants is especially important for people who have already had a stroke or a transient ischemic attack, according to the authors. The current guideline concludes that new anticoagulants such as dabigatran, rivaroxaban, and apixaban are at least as effective as, if not more effective than, warfarin and entail a lower risk of bleeding in the brain. An advantage of the new drugs is that they do not require frequent blood testing as warfarin does. The guideline also recommends new anticoagulants for the elderly, people with mild dementia, and people at moderate risk of falls.

Giving patients medications to lower blood pressure during the first 48 hours after a stroke may not reduce the likelihood of death or major disability, according to research published February 5 in JAMA. Within 48 hours of onset, 4,071 patients with nonthrombolysed ischemic stroke and elevated systolic blood pressure were randomized to receive antihypertensive treatment or to discontinuation of antihypertensive medications. Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg in the control group within 24 hours after randomization. At 14 days or hospital discharge, researchers recorded 683 incidences of death or major disability in the antihypertensive treatment group and 681 incidences in the control group.

The FDA has granted accelerated approval for Northera (droxidopa) capsules for the treatment of neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure (eg, Parkinson’s disease or multiple system atrophy). Accelerated approval is granted to medicines that fill a serious unmet medical need. The capsules have a boxed warning to alert health care professionals and patients about the risk of supine hypertension, which can cause stroke. Two clinical trials involving people with NOH demonstrated droxidopa’s effectiveness over a period of two weeks. The drug, which is manufactured by Chelsea Therapeutics in Charlotte, North Carolina, has not been demonstrated to provide improvement in patient symptoms beyond two weeks. The most common adverse events reported by clinical trial participants taking droxidopa were headache, dizziness, nausea, high blood pressure, and fatigue.

Earlier treatment with an antiepileptic drug (AED) results in a shorter total seizure duration among children with febrile status epilepticus, according to a study published online ahead of print February 6 in Epilepsia. A total of 199 children (ages 1 month to 6 years), were included in the prospective, multicenter study. The median time from seizure onset to first administration of an AED by EMS or emergency department personnel was 30 minutes. The mean seizure duration for children who were given medication before admission to the emergency department was 81 minutes, compared with 95 minutes for those who were not treated beforehand. The median time from first dose of an AED to the end of a seizure was 38 minutes. “Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration,” the investigators concluded.

The FDA has granted 510(k) clearance to the Reveal LINQ Insertable Cardiac Monitor (ICM) System. The device is indicated for patients who have symptoms such as dizziness, palpitation, syncope, and chest pain that may suggest a cardiac arrhythmia, and for patients at increased risk for cardiac arrhythmias. The Reveal LINQ ICM is part of a system that allows physicians to monitor a patient’s heart continuously and wirelessly for as long as three years. The system also provides remote monitoring through the Carelink Network, which allows physicians to request notifications to alert them if their patients have had cardiac events. The Reveal LINQ ICM is approximately one-third the size of an AAA battery. The device is manufactured by Medtronic, which is headquartered in Minneapolis.

The final stage of the normal inflammatory process may be disrupted in patients with Alzheimer’s disease, according to research published online ahead of print February 14 in Alzheimer’s and Dementia. Researchers analyzed specialized proresolving mediators (SPMs), receptors, a biosynthetic enzyme, and downstream effectors involved in inflammation resolution in postmortem hippocampal tissue from patients with and without Alzheimer’s disease. SPMs were analyzed in CSF. Levels of the SPM lipoxin A₄ (LXA₄) were reduced in patients with Alzheimer’s disease in the CSF and the hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in brains of patients with Alzheimer’s disease. LXA₄ and RvD1 levels in CSF correlated with Mini-Mental State Examination scores. Stimulation of inflammation resolution may reduce neuronal death in the brain, said the investigators.

Toxic chemicals may be triggering the recent increases in neurodevelopmental disabilities among children, according to a study published in the March issue of Lancet Neurology. In 2006, researchers identified five industrial chemicals as developmental neurotoxicants. The current study offers updated findings about those chemicals and adds information on six newly recognized ones, including manganese, fluoride, chlorpyrifos and DDT (ie, pesticides), tetrachloroethylene (a solvent), and the polybrominated diphenyl ethers (flame retardants). The study found that manganese is associated with diminished intellectual function and impaired motor skills, solvents are linked to hyperactivity and aggressive behavior, and certain pesticides may cause cognitive delays. More neurotoxicants may remain undiscovered, according to the investigators, who propose a global prevention strategy to control what they call a pandemic of developmental neurotoxicity.

For relatives of patients with multiple sclerosis (MS), the risk of developing the disease may be lower than previously assumed, according to a study published in the March issue of Brain. Researchers from Karolinska Institutet assessed the familial risks for MS using population registers and health care registries. They identified 28,396 patients with MS, along with first- and second-degree relatives and cousins. The investigators used matched population-based controls to calculate relative risks and found lower estimates of familial MS risks than previously reported. Despite a well-established lower prevalence of MS among males, the relative risks were equal among maternal and paternal relations. Using 74,757 twin pairs, the researchers estimated the disease’s heritability to be 0.64 and its shared environmental component to be 0.01.

Football helmets differ in their ability to reduce the risk of concussion, researchers reported online ahead of print January 31 in the Journal of Neurosurgery. The investigators conducted a retrospective analysis of head impact data from 1,833 collegiate football players from 2005 to 2010 who wore helmet-mounted accelerometer arrays for games and practices. The researchers compared concussion rates between players who wore the Riddell VSR4 and Riddell Revolution helmets. A total of 1,281,444 head impacts were recorded, and 64 concussions were diagnosed. The investigators found that the relative risk of sustaining a concussion in a Revolution helmet versus a VSR4 helmet was 46.1%. “Although helmet design may never prevent all concussions from occurring in football, evidence illustrates that it can reduce the incidence of this injury,” the researchers concluded.

Women have a worse quality of life, compared with men, for as long as 12 months after a stroke, even after adjustment for key sociodemographic variables, stroke severity, and disability, according to a study published online ahead of print February 7 in Neurology. Researchers assessed the quality of life in 1,370 patients (53.7% male; median age, 65) with ischemic stroke or transient ischemic attack (TIA) at three and 12 months postdischarge. Women had a significantly lower quality of life at three and 12 months poststroke. After multivariable adjustment for sociodemographic, clinical, and stroke-related factors, the investigators found that women continued to have a lower quality of life at three and 12 months. Women also had a poorer outcome in the dimensions of mobility, pain or discomfort, and anxiety or depression at three and 12 months.

High levels of high-density lipoprotein (HDL) cholesterol and low levels of low-density lipoprotein (LDL) cholesterol may be correlated with lower levels of amyloid plaque deposition in the brain, according to a study published in the February issue of JAMA Neurology. Investigators examined 74 individuals age 70 or older, including three participants with mild dementia, 33 cognitively normal participants, and 38 people with mild cognitive impairment. Cerebral amyloid-beta was measured with carbon C11–labeled Pittsburgh Compound B (PiB) PET. Statistical models that controlled for age and APOE ɛ4 revealed independent associations among the levels of LDL cholesterol, HDL cholesterol, and PiB index. Higher LDL cholesterol and lower HDL cholesterol levels were associated with a higher PiB index. The finding suggests an important role for cholesterol in amyloid-beta processing, said the researchers.

Patients with acute ischemic stroke who receive prompt treatment with t-PA may avoid a lengthy stay in an ICU, according to a study published February 12 in PLOS One. In a retrospective chart review of 153 patients who received IV t-PA for stroke, those with an NIH Stroke Scale (NIHSS) score of 10 or higher had a 7.7-times higher risk of requiring ICU resources, compared with patients who presented with an NIHSS score lower than 10. Eighty-one percent of patients with ICU needs developed them before the end of t-PA infusion, while 7% of those without ICU needs at the end of the t-PA infusion required ICU care later on. “We propose that patients without ICU needs by the end of the t-PA infusion might be safely monitored in a non-ICU setting if NIHSS at presentation is low,” the researchers advised.

—Erik Greb and Colby Stong

Patients who are dementia-free but have two parents with late-onset Alzheimer’s disease may show signs of the disease during brain imaging decades before symptoms appear, researchers reported online ahead of print February 12 in Neurology. A total of 52 persons with normal cognition—including four demographically balanced groups with maternal, paternal, and maternal and paternal family history of late-onset Alzheimer’s disease, as well as those with a negative family history—underwent MRI, ¹¹C-Pittsburgh compound B (PiB) PET, and ¹⁸F-fluoro-2-deoxyglucose PET. Subjects with both parents with a history of Alzheimer’s disease had more severe abnormalities in all three biomarkers, compared with the other groups, regarding the number of regions affected and magnitude of impairment. PiB retention and hypometabolism were most pronounced in participants with a maternal and paternal history of Alzheimer’s disease, according to the investigators.

Patients with nonvalvular atrial fibrillation are encouraged to take oral anticoagulants to prevent stroke, according to an updated guideline published in the February 25, 2014, issue of Neurology. Treatment with anticoagulants is especially important for people who have already had a stroke or a transient ischemic attack, according to the authors. The current guideline concludes that new anticoagulants such as dabigatran, rivaroxaban, and apixaban are at least as effective as, if not more effective than, warfarin and entail a lower risk of bleeding in the brain. An advantage of the new drugs is that they do not require frequent blood testing as warfarin does. The guideline also recommends new anticoagulants for the elderly, people with mild dementia, and people at moderate risk of falls.

Giving patients medications to lower blood pressure during the first 48 hours after a stroke may not reduce the likelihood of death or major disability, according to research published February 5 in JAMA. Within 48 hours of onset, 4,071 patients with nonthrombolysed ischemic stroke and elevated systolic blood pressure were randomized to receive antihypertensive treatment or to discontinuation of antihypertensive medications. Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg in the control group within 24 hours after randomization. At 14 days or hospital discharge, researchers recorded 683 incidences of death or major disability in the antihypertensive treatment group and 681 incidences in the control group.

The FDA has granted accelerated approval for Northera (droxidopa) capsules for the treatment of neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure (eg, Parkinson’s disease or multiple system atrophy). Accelerated approval is granted to medicines that fill a serious unmet medical need. The capsules have a boxed warning to alert health care professionals and patients about the risk of supine hypertension, which can cause stroke. Two clinical trials involving people with NOH demonstrated droxidopa’s effectiveness over a period of two weeks. The drug, which is manufactured by Chelsea Therapeutics in Charlotte, North Carolina, has not been demonstrated to provide improvement in patient symptoms beyond two weeks. The most common adverse events reported by clinical trial participants taking droxidopa were headache, dizziness, nausea, high blood pressure, and fatigue.

Earlier treatment with an antiepileptic drug (AED) results in a shorter total seizure duration among children with febrile status epilepticus, according to a study published online ahead of print February 6 in Epilepsia. A total of 199 children (ages 1 month to 6 years), were included in the prospective, multicenter study. The median time from seizure onset to first administration of an AED by EMS or emergency department personnel was 30 minutes. The mean seizure duration for children who were given medication before admission to the emergency department was 81 minutes, compared with 95 minutes for those who were not treated beforehand. The median time from first dose of an AED to the end of a seizure was 38 minutes. “Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration,” the investigators concluded.

The FDA has granted 510(k) clearance to the Reveal LINQ Insertable Cardiac Monitor (ICM) System. The device is indicated for patients who have symptoms such as dizziness, palpitation, syncope, and chest pain that may suggest a cardiac arrhythmia, and for patients at increased risk for cardiac arrhythmias. The Reveal LINQ ICM is part of a system that allows physicians to monitor a patient’s heart continuously and wirelessly for as long as three years. The system also provides remote monitoring through the Carelink Network, which allows physicians to request notifications to alert them if their patients have had cardiac events. The Reveal LINQ ICM is approximately one-third the size of an AAA battery. The device is manufactured by Medtronic, which is headquartered in Minneapolis.

The final stage of the normal inflammatory process may be disrupted in patients with Alzheimer’s disease, according to research published online ahead of print February 14 in Alzheimer’s and Dementia. Researchers analyzed specialized proresolving mediators (SPMs), receptors, a biosynthetic enzyme, and downstream effectors involved in inflammation resolution in postmortem hippocampal tissue from patients with and without Alzheimer’s disease. SPMs were analyzed in CSF. Levels of the SPM lipoxin A₄ (LXA₄) were reduced in patients with Alzheimer’s disease in the CSF and the hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in brains of patients with Alzheimer’s disease. LXA₄ and RvD1 levels in CSF correlated with Mini-Mental State Examination scores. Stimulation of inflammation resolution may reduce neuronal death in the brain, said the investigators.

Toxic chemicals may be triggering the recent increases in neurodevelopmental disabilities among children, according to a study published in the March issue of Lancet Neurology. In 2006, researchers identified five industrial chemicals as developmental neurotoxicants. The current study offers updated findings about those chemicals and adds information on six newly recognized ones, including manganese, fluoride, chlorpyrifos and DDT (ie, pesticides), tetrachloroethylene (a solvent), and the polybrominated diphenyl ethers (flame retardants). The study found that manganese is associated with diminished intellectual function and impaired motor skills, solvents are linked to hyperactivity and aggressive behavior, and certain pesticides may cause cognitive delays. More neurotoxicants may remain undiscovered, according to the investigators, who propose a global prevention strategy to control what they call a pandemic of developmental neurotoxicity.

For relatives of patients with multiple sclerosis (MS), the risk of developing the disease may be lower than previously assumed, according to a study published in the March issue of Brain. Researchers from Karolinska Institutet assessed the familial risks for MS using population registers and health care registries. They identified 28,396 patients with MS, along with first- and second-degree relatives and cousins. The investigators used matched population-based controls to calculate relative risks and found lower estimates of familial MS risks than previously reported. Despite a well-established lower prevalence of MS among males, the relative risks were equal among maternal and paternal relations. Using 74,757 twin pairs, the researchers estimated the disease’s heritability to be 0.64 and its shared environmental component to be 0.01.

Football helmets differ in their ability to reduce the risk of concussion, researchers reported online ahead of print January 31 in the Journal of Neurosurgery. The investigators conducted a retrospective analysis of head impact data from 1,833 collegiate football players from 2005 to 2010 who wore helmet-mounted accelerometer arrays for games and practices. The researchers compared concussion rates between players who wore the Riddell VSR4 and Riddell Revolution helmets. A total of 1,281,444 head impacts were recorded, and 64 concussions were diagnosed. The investigators found that the relative risk of sustaining a concussion in a Revolution helmet versus a VSR4 helmet was 46.1%. “Although helmet design may never prevent all concussions from occurring in football, evidence illustrates that it can reduce the incidence of this injury,” the researchers concluded.

Women have a worse quality of life, compared with men, for as long as 12 months after a stroke, even after adjustment for key sociodemographic variables, stroke severity, and disability, according to a study published online ahead of print February 7 in Neurology. Researchers assessed the quality of life in 1,370 patients (53.7% male; median age, 65) with ischemic stroke or transient ischemic attack (TIA) at three and 12 months postdischarge. Women had a significantly lower quality of life at three and 12 months poststroke. After multivariable adjustment for sociodemographic, clinical, and stroke-related factors, the investigators found that women continued to have a lower quality of life at three and 12 months. Women also had a poorer outcome in the dimensions of mobility, pain or discomfort, and anxiety or depression at three and 12 months.

High levels of high-density lipoprotein (HDL) cholesterol and low levels of low-density lipoprotein (LDL) cholesterol may be correlated with lower levels of amyloid plaque deposition in the brain, according to a study published in the February issue of JAMA Neurology. Investigators examined 74 individuals age 70 or older, including three participants with mild dementia, 33 cognitively normal participants, and 38 people with mild cognitive impairment. Cerebral amyloid-beta was measured with carbon C11–labeled Pittsburgh Compound B (PiB) PET. Statistical models that controlled for age and APOE ɛ4 revealed independent associations among the levels of LDL cholesterol, HDL cholesterol, and PiB index. Higher LDL cholesterol and lower HDL cholesterol levels were associated with a higher PiB index. The finding suggests an important role for cholesterol in amyloid-beta processing, said the researchers.

Patients with acute ischemic stroke who receive prompt treatment with t-PA may avoid a lengthy stay in an ICU, according to a study published February 12 in PLOS One. In a retrospective chart review of 153 patients who received IV t-PA for stroke, those with an NIH Stroke Scale (NIHSS) score of 10 or higher had a 7.7-times higher risk of requiring ICU resources, compared with patients who presented with an NIHSS score lower than 10. Eighty-one percent of patients with ICU needs developed them before the end of t-PA infusion, while 7% of those without ICU needs at the end of the t-PA infusion required ICU care later on. “We propose that patients without ICU needs by the end of the t-PA infusion might be safely monitored in a non-ICU setting if NIHSS at presentation is low,” the researchers advised.

—Erik Greb and Colby Stong

Patients who are dementia-free but have two parents with late-onset Alzheimer’s disease may show signs of the disease during brain imaging decades before symptoms appear, researchers reported online ahead of print February 12 in Neurology. A total of 52 persons with normal cognition—including four demographically balanced groups with maternal, paternal, and maternal and paternal family history of late-onset Alzheimer’s disease, as well as those with a negative family history—underwent MRI, ¹¹C-Pittsburgh compound B (PiB) PET, and ¹⁸F-fluoro-2-deoxyglucose PET. Subjects with both parents with a history of Alzheimer’s disease had more severe abnormalities in all three biomarkers, compared with the other groups, regarding the number of regions affected and magnitude of impairment. PiB retention and hypometabolism were most pronounced in participants with a maternal and paternal history of Alzheimer’s disease, according to the investigators.

Patients with nonvalvular atrial fibrillation are encouraged to take oral anticoagulants to prevent stroke, according to an updated guideline published in the February 25, 2014, issue of Neurology. Treatment with anticoagulants is especially important for people who have already had a stroke or a transient ischemic attack, according to the authors. The current guideline concludes that new anticoagulants such as dabigatran, rivaroxaban, and apixaban are at least as effective as, if not more effective than, warfarin and entail a lower risk of bleeding in the brain. An advantage of the new drugs is that they do not require frequent blood testing as warfarin does. The guideline also recommends new anticoagulants for the elderly, people with mild dementia, and people at moderate risk of falls.

Giving patients medications to lower blood pressure during the first 48 hours after a stroke may not reduce the likelihood of death or major disability, according to research published February 5 in JAMA. Within 48 hours of onset, 4,071 patients with nonthrombolysed ischemic stroke and elevated systolic blood pressure were randomized to receive antihypertensive treatment or to discontinuation of antihypertensive medications. Mean systolic blood pressure was reduced from 166.7 mm Hg to 144.7 mm Hg within 24 hours in the antihypertensive treatment group and from 165.6 mm Hg to 152.9 mm Hg in the control group within 24 hours after randomization. At 14 days or hospital discharge, researchers recorded 683 incidences of death or major disability in the antihypertensive treatment group and 681 incidences in the control group.

The FDA has granted accelerated approval for Northera (droxidopa) capsules for the treatment of neurogenic orthostatic hypotension (NOH) caused by primary autonomic failure (eg, Parkinson’s disease or multiple system atrophy). Accelerated approval is granted to medicines that fill a serious unmet medical need. The capsules have a boxed warning to alert health care professionals and patients about the risk of supine hypertension, which can cause stroke. Two clinical trials involving people with NOH demonstrated droxidopa’s effectiveness over a period of two weeks. The drug, which is manufactured by Chelsea Therapeutics in Charlotte, North Carolina, has not been demonstrated to provide improvement in patient symptoms beyond two weeks. The most common adverse events reported by clinical trial participants taking droxidopa were headache, dizziness, nausea, high blood pressure, and fatigue.

Earlier treatment with an antiepileptic drug (AED) results in a shorter total seizure duration among children with febrile status epilepticus, according to a study published online ahead of print February 6 in Epilepsia. A total of 199 children (ages 1 month to 6 years), were included in the prospective, multicenter study. The median time from seizure onset to first administration of an AED by EMS or emergency department personnel was 30 minutes. The mean seizure duration for children who were given medication before admission to the emergency department was 81 minutes, compared with 95 minutes for those who were not treated beforehand. The median time from first dose of an AED to the end of a seizure was 38 minutes. “Reducing the time from seizure onset to AED initiation was significantly related to shorter seizure duration,” the investigators concluded.

The FDA has granted 510(k) clearance to the Reveal LINQ Insertable Cardiac Monitor (ICM) System. The device is indicated for patients who have symptoms such as dizziness, palpitation, syncope, and chest pain that may suggest a cardiac arrhythmia, and for patients at increased risk for cardiac arrhythmias. The Reveal LINQ ICM is part of a system that allows physicians to monitor a patient’s heart continuously and wirelessly for as long as three years. The system also provides remote monitoring through the Carelink Network, which allows physicians to request notifications to alert them if their patients have had cardiac events. The Reveal LINQ ICM is approximately one-third the size of an AAA battery. The device is manufactured by Medtronic, which is headquartered in Minneapolis.

The final stage of the normal inflammatory process may be disrupted in patients with Alzheimer’s disease, according to research published online ahead of print February 14 in Alzheimer’s and Dementia. Researchers analyzed specialized proresolving mediators (SPMs), receptors, a biosynthetic enzyme, and downstream effectors involved in inflammation resolution in postmortem hippocampal tissue from patients with and without Alzheimer’s disease. SPMs were analyzed in CSF. Levels of the SPM lipoxin A₄ (LXA₄) were reduced in patients with Alzheimer’s disease in the CSF and the hippocampus. An enzyme involved in LXA4 synthesis and two SPM receptors were elevated in brains of patients with Alzheimer’s disease. LXA₄ and RvD1 levels in CSF correlated with Mini-Mental State Examination scores. Stimulation of inflammation resolution may reduce neuronal death in the brain, said the investigators.

Toxic chemicals may be triggering the recent increases in neurodevelopmental disabilities among children, according to a study published in the March issue of Lancet Neurology. In 2006, researchers identified five industrial chemicals as developmental neurotoxicants. The current study offers updated findings about those chemicals and adds information on six newly recognized ones, including manganese, fluoride, chlorpyrifos and DDT (ie, pesticides), tetrachloroethylene (a solvent), and the polybrominated diphenyl ethers (flame retardants). The study found that manganese is associated with diminished intellectual function and impaired motor skills, solvents are linked to hyperactivity and aggressive behavior, and certain pesticides may cause cognitive delays. More neurotoxicants may remain undiscovered, according to the investigators, who propose a global prevention strategy to control what they call a pandemic of developmental neurotoxicity.

For relatives of patients with multiple sclerosis (MS), the risk of developing the disease may be lower than previously assumed, according to a study published in the March issue of Brain. Researchers from Karolinska Institutet assessed the familial risks for MS using population registers and health care registries. They identified 28,396 patients with MS, along with first- and second-degree relatives and cousins. The investigators used matched population-based controls to calculate relative risks and found lower estimates of familial MS risks than previously reported. Despite a well-established lower prevalence of MS among males, the relative risks were equal among maternal and paternal relations. Using 74,757 twin pairs, the researchers estimated the disease’s heritability to be 0.64 and its shared environmental component to be 0.01.

Football helmets differ in their ability to reduce the risk of concussion, researchers reported online ahead of print January 31 in the Journal of Neurosurgery. The investigators conducted a retrospective analysis of head impact data from 1,833 collegiate football players from 2005 to 2010 who wore helmet-mounted accelerometer arrays for games and practices. The researchers compared concussion rates between players who wore the Riddell VSR4 and Riddell Revolution helmets. A total of 1,281,444 head impacts were recorded, and 64 concussions were diagnosed. The investigators found that the relative risk of sustaining a concussion in a Revolution helmet versus a VSR4 helmet was 46.1%. “Although helmet design may never prevent all concussions from occurring in football, evidence illustrates that it can reduce the incidence of this injury,” the researchers concluded.

Women have a worse quality of life, compared with men, for as long as 12 months after a stroke, even after adjustment for key sociodemographic variables, stroke severity, and disability, according to a study published online ahead of print February 7 in Neurology. Researchers assessed the quality of life in 1,370 patients (53.7% male; median age, 65) with ischemic stroke or transient ischemic attack (TIA) at three and 12 months postdischarge. Women had a significantly lower quality of life at three and 12 months poststroke. After multivariable adjustment for sociodemographic, clinical, and stroke-related factors, the investigators found that women continued to have a lower quality of life at three and 12 months. Women also had a poorer outcome in the dimensions of mobility, pain or discomfort, and anxiety or depression at three and 12 months.

High levels of high-density lipoprotein (HDL) cholesterol and low levels of low-density lipoprotein (LDL) cholesterol may be correlated with lower levels of amyloid plaque deposition in the brain, according to a study published in the February issue of JAMA Neurology. Investigators examined 74 individuals age 70 or older, including three participants with mild dementia, 33 cognitively normal participants, and 38 people with mild cognitive impairment. Cerebral amyloid-beta was measured with carbon C11–labeled Pittsburgh Compound B (PiB) PET. Statistical models that controlled for age and APOE ɛ4 revealed independent associations among the levels of LDL cholesterol, HDL cholesterol, and PiB index. Higher LDL cholesterol and lower HDL cholesterol levels were associated with a higher PiB index. The finding suggests an important role for cholesterol in amyloid-beta processing, said the researchers.

Patients with acute ischemic stroke who receive prompt treatment with t-PA may avoid a lengthy stay in an ICU, according to a study published February 12 in PLOS One. In a retrospective chart review of 153 patients who received IV t-PA for stroke, those with an NIH Stroke Scale (NIHSS) score of 10 or higher had a 7.7-times higher risk of requiring ICU resources, compared with patients who presented with an NIHSS score lower than 10. Eighty-one percent of patients with ICU needs developed them before the end of t-PA infusion, while 7% of those without ICU needs at the end of the t-PA infusion required ICU care later on. “We propose that patients without ICU needs by the end of the t-PA infusion might be safely monitored in a non-ICU setting if NIHSS at presentation is low,” the researchers advised.

—Erik Greb and Colby Stong

As providers we are often questioned about healthy habits, working out, and diets, but in the pediatric population, what works for adults may be very harmful to the growing body. Many of the food products that are advertised as "healthy" are nowhere close to healthy.

With childhood obesity on the rise, many parents and teens are looking for ways to lose weight or maintain a healthy lifestyle to avoid obesity. But, many resort to restricted diets that lack important nutrients for proper growth.

Adolescents also are notorious for skipping meals, snacking, and late night eating. Teens in particular resort to starvation to lose weight quickly. This is usually ineffective because most will binge on unhealthy food when they become hungry, negating the effects of the decreased intake (J. Pediatr. Nurs. 2005;20:258-67). In terms of skipping breakfast in particular, a study of schools that participated in a breakfast program showed that there was an increase in math grades and physical performance in children who ate breakfast. Generally, teens who consistently ate breakfast had better nutrition than those who did not.

The use of diet aids and stimulants is another quick weight loss trick that has detrimental side effects. Hydroxycut, diuretics, and amphetamines are just a few of the many substances used. Hydroxycut use has been linked to elevated liver enzymes, jaundice, and seizures. The Food and Drug Administration has urged consumers to stop using this product. Improper use of diuretics can cause electrolyte imbalances, and improper use of some stimulants has been indicated as a cause of sudden death.

Fad diets come out weekly and usually include low-carbohydrate/low-fat or meatless diets. Vegetarian diets also are becoming more popular. The problem with any diet in the adolescent age group is that their bodies are growing, and they actually have a higher demand for certain nutrients, in particular iron, zinc, and calcium.

A typical adolescent diet is low in iron, calcium, folic acid, fiber, and zinc. Low iron intake has been shown to impair cognitive function and physical performance. Low calcium intake increases the risk of fractures and osteoporosis later in life.

Vegetarian diets, depending on how restricted they are, can leave children with significant deficiencies. Children with rapid growth have increased iron needs. Iron from meat sources are more readily absorbed than from plant sources, and iron absorption from plant sources is greatly affected by dietary components. Therefore, there is less absorption of iron if consumed with legumes, nuts, and soy protein. Supplementing the diet with consumption of vitamin C during a meal significantly increases the absorption of iron (Hum. Nutr. Appl. Nutr. 1986;40:97-113). Careful consideration of what food is eliminated in a diet and ensuring its replacement by food substitution or vitamin supplements can prevent deficiencies.

Exercise and weight training are another avenue for weight loss but unfortunately are not used as often because they require discipline and time. But exercising and weight lifting aren’t without risk either. The growing adolescent has open growth plates. Therefore, with intense resistance exercises, there is a risk of injuring the growth plate, which could negatively impact the growth of the affected bone. Encouraging teens to train with supervision and to get accurate instructions are crucial to avoiding injury.

The use of protein shakes is popular among male teens, who are often looking to bulk up. Whey protein is commonly used and is safe when taken in proper amounts and with good hydration. The average teen needs approximately 50 g of protein per day. Excessive protein has been thought to cause kidney disease, but the research does not support this claim. Although lowering protein intake can be beneficial for a person with kidney disease, that does not extrapolate to excessive protein leading to kidney disease. But adequate hydration should be encouraged.

It is always prudent to monitor for eating disorders and the use of illicit drugs to improve physique. In adolescents who seem to be overly competitive or overly obsessed with their appearance, addressing concerns directly, informing parents of your observations, and making the appropriate referrals can prevent significant injury and health consequences.

Here are some general recommendations to help you guide your patients:

• Visit choosemyplate.gov, a comprehensive site that reviews dietary guidelines and individualizes the guidelines based on age, sex, and activity level.

• Educate families on reading food labels so they can make good choices.

• Warn against following restricted diets that could lead to nutritional deficiencies resulting in illness.

• Educate about the danger of weight loss drugs and their risks.

• Advise families that strength training can be effective but only when well designed and supervised to avoid injury.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code to view similar columns.

As providers we are often questioned about healthy habits, working out, and diets, but in the pediatric population, what works for adults may be very harmful to the growing body. Many of the food products that are advertised as "healthy" are nowhere close to healthy.

With childhood obesity on the rise, many parents and teens are looking for ways to lose weight or maintain a healthy lifestyle to avoid obesity. But, many resort to restricted diets that lack important nutrients for proper growth.

Adolescents also are notorious for skipping meals, snacking, and late night eating. Teens in particular resort to starvation to lose weight quickly. This is usually ineffective because most will binge on unhealthy food when they become hungry, negating the effects of the decreased intake (J. Pediatr. Nurs. 2005;20:258-67). In terms of skipping breakfast in particular, a study of schools that participated in a breakfast program showed that there was an increase in math grades and physical performance in children who ate breakfast. Generally, teens who consistently ate breakfast had better nutrition than those who did not.

The use of diet aids and stimulants is another quick weight loss trick that has detrimental side effects. Hydroxycut, diuretics, and amphetamines are just a few of the many substances used. Hydroxycut use has been linked to elevated liver enzymes, jaundice, and seizures. The Food and Drug Administration has urged consumers to stop using this product. Improper use of diuretics can cause electrolyte imbalances, and improper use of some stimulants has been indicated as a cause of sudden death.

Fad diets come out weekly and usually include low-carbohydrate/low-fat or meatless diets. Vegetarian diets also are becoming more popular. The problem with any diet in the adolescent age group is that their bodies are growing, and they actually have a higher demand for certain nutrients, in particular iron, zinc, and calcium.

A typical adolescent diet is low in iron, calcium, folic acid, fiber, and zinc. Low iron intake has been shown to impair cognitive function and physical performance. Low calcium intake increases the risk of fractures and osteoporosis later in life.

Vegetarian diets, depending on how restricted they are, can leave children with significant deficiencies. Children with rapid growth have increased iron needs. Iron from meat sources are more readily absorbed than from plant sources, and iron absorption from plant sources is greatly affected by dietary components. Therefore, there is less absorption of iron if consumed with legumes, nuts, and soy protein. Supplementing the diet with consumption of vitamin C during a meal significantly increases the absorption of iron (Hum. Nutr. Appl. Nutr. 1986;40:97-113). Careful consideration of what food is eliminated in a diet and ensuring its replacement by food substitution or vitamin supplements can prevent deficiencies.

Exercise and weight training are another avenue for weight loss but unfortunately are not used as often because they require discipline and time. But exercising and weight lifting aren’t without risk either. The growing adolescent has open growth plates. Therefore, with intense resistance exercises, there is a risk of injuring the growth plate, which could negatively impact the growth of the affected bone. Encouraging teens to train with supervision and to get accurate instructions are crucial to avoiding injury.

The use of protein shakes is popular among male teens, who are often looking to bulk up. Whey protein is commonly used and is safe when taken in proper amounts and with good hydration. The average teen needs approximately 50 g of protein per day. Excessive protein has been thought to cause kidney disease, but the research does not support this claim. Although lowering protein intake can be beneficial for a person with kidney disease, that does not extrapolate to excessive protein leading to kidney disease. But adequate hydration should be encouraged.

It is always prudent to monitor for eating disorders and the use of illicit drugs to improve physique. In adolescents who seem to be overly competitive or overly obsessed with their appearance, addressing concerns directly, informing parents of your observations, and making the appropriate referrals can prevent significant injury and health consequences.

Here are some general recommendations to help you guide your patients:

• Visit choosemyplate.gov, a comprehensive site that reviews dietary guidelines and individualizes the guidelines based on age, sex, and activity level.

• Educate families on reading food labels so they can make good choices.

• Warn against following restricted diets that could lead to nutritional deficiencies resulting in illness.

• Educate about the danger of weight loss drugs and their risks.

• Advise families that strength training can be effective but only when well designed and supervised to avoid injury.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code to view similar columns.

As providers we are often questioned about healthy habits, working out, and diets, but in the pediatric population, what works for adults may be very harmful to the growing body. Many of the food products that are advertised as "healthy" are nowhere close to healthy.

With childhood obesity on the rise, many parents and teens are looking for ways to lose weight or maintain a healthy lifestyle to avoid obesity. But, many resort to restricted diets that lack important nutrients for proper growth.

Adolescents also are notorious for skipping meals, snacking, and late night eating. Teens in particular resort to starvation to lose weight quickly. This is usually ineffective because most will binge on unhealthy food when they become hungry, negating the effects of the decreased intake (J. Pediatr. Nurs. 2005;20:258-67). In terms of skipping breakfast in particular, a study of schools that participated in a breakfast program showed that there was an increase in math grades and physical performance in children who ate breakfast. Generally, teens who consistently ate breakfast had better nutrition than those who did not.

The use of diet aids and stimulants is another quick weight loss trick that has detrimental side effects. Hydroxycut, diuretics, and amphetamines are just a few of the many substances used. Hydroxycut use has been linked to elevated liver enzymes, jaundice, and seizures. The Food and Drug Administration has urged consumers to stop using this product. Improper use of diuretics can cause electrolyte imbalances, and improper use of some stimulants has been indicated as a cause of sudden death.

Fad diets come out weekly and usually include low-carbohydrate/low-fat or meatless diets. Vegetarian diets also are becoming more popular. The problem with any diet in the adolescent age group is that their bodies are growing, and they actually have a higher demand for certain nutrients, in particular iron, zinc, and calcium.

A typical adolescent diet is low in iron, calcium, folic acid, fiber, and zinc. Low iron intake has been shown to impair cognitive function and physical performance. Low calcium intake increases the risk of fractures and osteoporosis later in life.

Vegetarian diets, depending on how restricted they are, can leave children with significant deficiencies. Children with rapid growth have increased iron needs. Iron from meat sources are more readily absorbed than from plant sources, and iron absorption from plant sources is greatly affected by dietary components. Therefore, there is less absorption of iron if consumed with legumes, nuts, and soy protein. Supplementing the diet with consumption of vitamin C during a meal significantly increases the absorption of iron (Hum. Nutr. Appl. Nutr. 1986;40:97-113). Careful consideration of what food is eliminated in a diet and ensuring its replacement by food substitution or vitamin supplements can prevent deficiencies.

Exercise and weight training are another avenue for weight loss but unfortunately are not used as often because they require discipline and time. But exercising and weight lifting aren’t without risk either. The growing adolescent has open growth plates. Therefore, with intense resistance exercises, there is a risk of injuring the growth plate, which could negatively impact the growth of the affected bone. Encouraging teens to train with supervision and to get accurate instructions are crucial to avoiding injury.

The use of protein shakes is popular among male teens, who are often looking to bulk up. Whey protein is commonly used and is safe when taken in proper amounts and with good hydration. The average teen needs approximately 50 g of protein per day. Excessive protein has been thought to cause kidney disease, but the research does not support this claim. Although lowering protein intake can be beneficial for a person with kidney disease, that does not extrapolate to excessive protein leading to kidney disease. But adequate hydration should be encouraged.

It is always prudent to monitor for eating disorders and the use of illicit drugs to improve physique. In adolescents who seem to be overly competitive or overly obsessed with their appearance, addressing concerns directly, informing parents of your observations, and making the appropriate referrals can prevent significant injury and health consequences.

Here are some general recommendations to help you guide your patients:

• Visit choosemyplate.gov, a comprehensive site that reviews dietary guidelines and individualizes the guidelines based on age, sex, and activity level.

• Educate families on reading food labels so they can make good choices.

• Warn against following restricted diets that could lead to nutritional deficiencies resulting in illness.

• Educate about the danger of weight loss drugs and their risks.

• Advise families that strength training can be effective but only when well designed and supervised to avoid injury.

Dr. Pearce is a pediatrician in Frankfort, Ill. E-mail her at [email protected]. Scan this QR code to view similar columns.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

New research suggests that older non-Hodgkin lymphoma patients are more likely than their younger counterparts to receive prophylaxis for neutropenia, but the older patients still have a higher incidence of severe neutropenia.

Most of the patients studied had received granulocyte colony-stimulating factor (G-CSF) as neutropenia prophylaxis, but more than half of patients in each age group developed grade 3/4 neutropenia.

And although patients aged 65 and older were more likely to receive G-CSF, they had a higher incidence of grade 3/4 neutropenia than patients who were younger than 65.

Lee S. Schwartzberg, MD, of The West Clinic in Memphis, Tennessee, and his colleagues reported these findings in Supportive Care in Cancer.

The researchers conducted a review of 1579 patients with non-Hodgkin lymphoma. Nearly 46% of patients were 65 years of age or older, and 54.1% were younger than 65.

Most patients had received treatment with R-CHOP every 3 weeks. And the dose levels were about the same in both groups of patients. The mean relative dose intensity was 80.4% among younger patients and 73.9% among the older patients.

The incidence of treatment delays was similar between the 2 groups—24.6% among the older patients and 26.5% among the younger patients.

But older patients were more likely to experience dose reductions—24.9% compared to 9.6% of younger patients.

A majority of all patients—86.9%—received G-CSF, but older patients were more likely to receive it upfront.

Among the older patients, 80.1% received G-CSF as primary prophylaxis, 11.6% received it as secondary prophylaxis, and 8.3% received it as treatment.

Among the younger patients, 71.9% received G-CSF as primary prophylaxis, 17.4% received it as secondary prophylaxis, and 10.7% received it as treatment.

The incidence of grade 3/4 neutropenia was 52.3% for the younger patients and 63.2% for the older patients.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

New research suggests that older non-Hodgkin lymphoma patients are more likely than their younger counterparts to receive prophylaxis for neutropenia, but the older patients still have a higher incidence of severe neutropenia.

Most of the patients studied had received granulocyte colony-stimulating factor (G-CSF) as neutropenia prophylaxis, but more than half of patients in each age group developed grade 3/4 neutropenia.

And although patients aged 65 and older were more likely to receive G-CSF, they had a higher incidence of grade 3/4 neutropenia than patients who were younger than 65.

Lee S. Schwartzberg, MD, of The West Clinic in Memphis, Tennessee, and his colleagues reported these findings in Supportive Care in Cancer.

The researchers conducted a review of 1579 patients with non-Hodgkin lymphoma. Nearly 46% of patients were 65 years of age or older, and 54.1% were younger than 65.

Most patients had received treatment with R-CHOP every 3 weeks. And the dose levels were about the same in both groups of patients. The mean relative dose intensity was 80.4% among younger patients and 73.9% among the older patients.

The incidence of treatment delays was similar between the 2 groups—24.6% among the older patients and 26.5% among the younger patients.

But older patients were more likely to experience dose reductions—24.9% compared to 9.6% of younger patients.

A majority of all patients—86.9%—received G-CSF, but older patients were more likely to receive it upfront.

Among the older patients, 80.1% received G-CSF as primary prophylaxis, 11.6% received it as secondary prophylaxis, and 8.3% received it as treatment.

Among the younger patients, 71.9% received G-CSF as primary prophylaxis, 17.4% received it as secondary prophylaxis, and 10.7% received it as treatment.

The incidence of grade 3/4 neutropenia was 52.3% for the younger patients and 63.2% for the older patients.

Neutrophil engulfing bacteria

Credit: Volker Brinkmann

New research suggests that older non-Hodgkin lymphoma patients are more likely than their younger counterparts to receive prophylaxis for neutropenia, but the older patients still have a higher incidence of severe neutropenia.

Most of the patients studied had received granulocyte colony-stimulating factor (G-CSF) as neutropenia prophylaxis, but more than half of patients in each age group developed grade 3/4 neutropenia.

And although patients aged 65 and older were more likely to receive G-CSF, they had a higher incidence of grade 3/4 neutropenia than patients who were younger than 65.

Lee S. Schwartzberg, MD, of The West Clinic in Memphis, Tennessee, and his colleagues reported these findings in Supportive Care in Cancer.

The researchers conducted a review of 1579 patients with non-Hodgkin lymphoma. Nearly 46% of patients were 65 years of age or older, and 54.1% were younger than 65.

Most patients had received treatment with R-CHOP every 3 weeks. And the dose levels were about the same in both groups of patients. The mean relative dose intensity was 80.4% among younger patients and 73.9% among the older patients.

The incidence of treatment delays was similar between the 2 groups—24.6% among the older patients and 26.5% among the younger patients.

But older patients were more likely to experience dose reductions—24.9% compared to 9.6% of younger patients.

A majority of all patients—86.9%—received G-CSF, but older patients were more likely to receive it upfront.

Among the older patients, 80.1% received G-CSF as primary prophylaxis, 11.6% received it as secondary prophylaxis, and 8.3% received it as treatment.

Among the younger patients, 71.9% received G-CSF as primary prophylaxis, 17.4% received it as secondary prophylaxis, and 10.7% received it as treatment.

The incidence of grade 3/4 neutropenia was 52.3% for the younger patients and 63.2% for the older patients.

GRAPEVINE, TEXAS—Intestinal bacteria can offer protection from death related to graft-vs-host disease (GVHD), according to research presented at the 2014 BMT Tandem Meetings.

Experiments showed that Blautia, commensal bacteria found in the intestinal tract, can protect against GVHD-related mortality in mice and in humans.

So efforts to support Blautia survival—such as restricting the use of antibiotics and promoting better nutrition—may

prevent GVHD-related death, according to researchers.

Robert Jenq, MD, of Memorial Sloan-Kettering Cancer Center in New York, discussed this possibility when presenting this research, which was designated one of the “Best Abstracts” at the meeting (abstract 1*).

Dr Jenq noted that researchers have been trying for decades to determine whether the intestinal flora impact GVHD. Clinical studies have suggested that prophylaxis against anaerobes and gram-positive bacteria can reduce GVHD.

And murine studies have indicated that prophylaxis against gram-negative bacteria can reduce GVHD, that Lactobacillus can reduce GVHD, and that donor microbiota do not impact GVHD.

“If you’re confused, so are we,” Dr Jenq said. “It seems like it’s a mixed picture.”

So he and his colleagues conducted a series of experiments in an attempt to determine if any bacterial subgroups impact the risk of gut GVHD in mice and humans.

Bacteria seem to impact GVHD

The researchers first studied 76 adult transplant patients, analyzing stool samples taken at roughly 10 days after transplant (+/- 4 days). The team performed 16S gene sequencing using the Roche 454 platform.

This revealed the presence of several types of bacteria, including 6 gram-positive Firmicutes, 2 gram-negative Proteobacteria, and 2 gram-negative Bacteroidetes.

The researchers then used a computational assay to determine which of these bacteria might be associated with protection from GVHD. And they identified 2 possibilities—Lactobacillus and Blautia.

Additional analyses revealed that Blautia and Lactobacillus were significantly associated with GVHD-related mortality at 1500 days after transplant (P=0.03 and 0.01, respectively). But there was no significant association with Bacteroides (P=0.6), Enterobacteriales (P=0.2), or Enterococcus (P=0.3).

Blautia appears to affect GVHD-related mortality

To confirm their initial findings, Dr Jenq and his colleagues analyzed a second cohort of 50 adult transplant patients. The team analyzed stool samples for the abundance of bacterial subgroups using a different sequencing platform, Illumina miseq.

This time, they found that Blautia abundance predicted GVHD-related mortality at more than 500 days after transplant, but the abundance of Lactobacillus did not (P=0.01 and 1, respectively).

“Not enough Blautia in your gut seems to lead to an increase in GVHD-related mortality,” Dr Jenq said. “So what does this do to overall survival? In the first cohort, there’s a big difference in overall survival between the ‘haves’ and ‘have nots’ with Blautia [P=0.0008]. And this also holds up in the second cohort [P=0.04].”

Further analyses of data from both cohorts suggested that Blautia abundance was associated with GVHD-related mortality (P=0.004) and relapse-related mortality (P=0.01) but not non-relapse- and non-GVHD-related mortality (P=0.4).

“I don’t have a good explanation for [the relationship between Blautia and relapse-related death],” Dr Jenq said. “This was a surprise finding.”

The researchers also looked at Blautia’s ability to predict GVHD-related mortality. They found that, around day 10 after transplant, Blautia abundance predicts “very strongly” for GVHD-related death.

Another question was whether known GVHD risk factors—such as donor type, race, gender, and performance status—impact Blautia abundance. But an analysis revealed that Blautia is an independent risk factor for GVHD-related mortality.

A possible mechanism

To gain more insight into the association between Blautia and GVHD-related death, Dr Jenq and his colleagues decided to study it in mice.

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.

*Data in the abstract differ from data presented.

GRAPEVINE, TEXAS—Intestinal bacteria can offer protection from death related to graft-vs-host disease (GVHD), according to research presented at the 2014 BMT Tandem Meetings.

Experiments showed that Blautia, commensal bacteria found in the intestinal tract, can protect against GVHD-related mortality in mice and in humans.

So efforts to support Blautia survival—such as restricting the use of antibiotics and promoting better nutrition—may

prevent GVHD-related death, according to researchers.

Robert Jenq, MD, of Memorial Sloan-Kettering Cancer Center in New York, discussed this possibility when presenting this research, which was designated one of the “Best Abstracts” at the meeting (abstract 1*).

Dr Jenq noted that researchers have been trying for decades to determine whether the intestinal flora impact GVHD. Clinical studies have suggested that prophylaxis against anaerobes and gram-positive bacteria can reduce GVHD.

And murine studies have indicated that prophylaxis against gram-negative bacteria can reduce GVHD, that Lactobacillus can reduce GVHD, and that donor microbiota do not impact GVHD.

“If you’re confused, so are we,” Dr Jenq said. “It seems like it’s a mixed picture.”

So he and his colleagues conducted a series of experiments in an attempt to determine if any bacterial subgroups impact the risk of gut GVHD in mice and humans.

Bacteria seem to impact GVHD

The researchers first studied 76 adult transplant patients, analyzing stool samples taken at roughly 10 days after transplant (+/- 4 days). The team performed 16S gene sequencing using the Roche 454 platform.

This revealed the presence of several types of bacteria, including 6 gram-positive Firmicutes, 2 gram-negative Proteobacteria, and 2 gram-negative Bacteroidetes.

The researchers then used a computational assay to determine which of these bacteria might be associated with protection from GVHD. And they identified 2 possibilities—Lactobacillus and Blautia.

Additional analyses revealed that Blautia and Lactobacillus were significantly associated with GVHD-related mortality at 1500 days after transplant (P=0.03 and 0.01, respectively). But there was no significant association with Bacteroides (P=0.6), Enterobacteriales (P=0.2), or Enterococcus (P=0.3).

Blautia appears to affect GVHD-related mortality

To confirm their initial findings, Dr Jenq and his colleagues analyzed a second cohort of 50 adult transplant patients. The team analyzed stool samples for the abundance of bacterial subgroups using a different sequencing platform, Illumina miseq.

This time, they found that Blautia abundance predicted GVHD-related mortality at more than 500 days after transplant, but the abundance of Lactobacillus did not (P=0.01 and 1, respectively).

“Not enough Blautia in your gut seems to lead to an increase in GVHD-related mortality,” Dr Jenq said. “So what does this do to overall survival? In the first cohort, there’s a big difference in overall survival between the ‘haves’ and ‘have nots’ with Blautia [P=0.0008]. And this also holds up in the second cohort [P=0.04].”

Further analyses of data from both cohorts suggested that Blautia abundance was associated with GVHD-related mortality (P=0.004) and relapse-related mortality (P=0.01) but not non-relapse- and non-GVHD-related mortality (P=0.4).

“I don’t have a good explanation for [the relationship between Blautia and relapse-related death],” Dr Jenq said. “This was a surprise finding.”

The researchers also looked at Blautia’s ability to predict GVHD-related mortality. They found that, around day 10 after transplant, Blautia abundance predicts “very strongly” for GVHD-related death.

Another question was whether known GVHD risk factors—such as donor type, race, gender, and performance status—impact Blautia abundance. But an analysis revealed that Blautia is an independent risk factor for GVHD-related mortality.

A possible mechanism

To gain more insight into the association between Blautia and GVHD-related death, Dr Jenq and his colleagues decided to study it in mice.

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.

*Data in the abstract differ from data presented.

GRAPEVINE, TEXAS—Intestinal bacteria can offer protection from death related to graft-vs-host disease (GVHD), according to research presented at the 2014 BMT Tandem Meetings.

Experiments showed that Blautia, commensal bacteria found in the intestinal tract, can protect against GVHD-related mortality in mice and in humans.

So efforts to support Blautia survival—such as restricting the use of antibiotics and promoting better nutrition—may

prevent GVHD-related death, according to researchers.

Robert Jenq, MD, of Memorial Sloan-Kettering Cancer Center in New York, discussed this possibility when presenting this research, which was designated one of the “Best Abstracts” at the meeting (abstract 1*).

Dr Jenq noted that researchers have been trying for decades to determine whether the intestinal flora impact GVHD. Clinical studies have suggested that prophylaxis against anaerobes and gram-positive bacteria can reduce GVHD.

And murine studies have indicated that prophylaxis against gram-negative bacteria can reduce GVHD, that Lactobacillus can reduce GVHD, and that donor microbiota do not impact GVHD.

“If you’re confused, so are we,” Dr Jenq said. “It seems like it’s a mixed picture.”

So he and his colleagues conducted a series of experiments in an attempt to determine if any bacterial subgroups impact the risk of gut GVHD in mice and humans.

Bacteria seem to impact GVHD

The researchers first studied 76 adult transplant patients, analyzing stool samples taken at roughly 10 days after transplant (+/- 4 days). The team performed 16S gene sequencing using the Roche 454 platform.

This revealed the presence of several types of bacteria, including 6 gram-positive Firmicutes, 2 gram-negative Proteobacteria, and 2 gram-negative Bacteroidetes.

The researchers then used a computational assay to determine which of these bacteria might be associated with protection from GVHD. And they identified 2 possibilities—Lactobacillus and Blautia.

Additional analyses revealed that Blautia and Lactobacillus were significantly associated with GVHD-related mortality at 1500 days after transplant (P=0.03 and 0.01, respectively). But there was no significant association with Bacteroides (P=0.6), Enterobacteriales (P=0.2), or Enterococcus (P=0.3).

Blautia appears to affect GVHD-related mortality

To confirm their initial findings, Dr Jenq and his colleagues analyzed a second cohort of 50 adult transplant patients. The team analyzed stool samples for the abundance of bacterial subgroups using a different sequencing platform, Illumina miseq.

This time, they found that Blautia abundance predicted GVHD-related mortality at more than 500 days after transplant, but the abundance of Lactobacillus did not (P=0.01 and 1, respectively).

“Not enough Blautia in your gut seems to lead to an increase in GVHD-related mortality,” Dr Jenq said. “So what does this do to overall survival? In the first cohort, there’s a big difference in overall survival between the ‘haves’ and ‘have nots’ with Blautia [P=0.0008]. And this also holds up in the second cohort [P=0.04].”

Further analyses of data from both cohorts suggested that Blautia abundance was associated with GVHD-related mortality (P=0.004) and relapse-related mortality (P=0.01) but not non-relapse- and non-GVHD-related mortality (P=0.4).

“I don’t have a good explanation for [the relationship between Blautia and relapse-related death],” Dr Jenq said. “This was a surprise finding.”

The researchers also looked at Blautia’s ability to predict GVHD-related mortality. They found that, around day 10 after transplant, Blautia abundance predicts “very strongly” for GVHD-related death.

Another question was whether known GVHD risk factors—such as donor type, race, gender, and performance status—impact Blautia abundance. But an analysis revealed that Blautia is an independent risk factor for GVHD-related mortality.

A possible mechanism

To gain more insight into the association between Blautia and GVHD-related death, Dr Jenq and his colleagues decided to study it in mice.

The team killed off Blautia in mice using vancomycin and ampicillin, then introduced either murine Blautia or murine Enterococcus, transplanted the mice with MHC-disparate T cells, and monitored them for GVHD.

Mice that received Blautia had significantly better overall survival (at more than 80 days after transplant) than mice that received Enterococcus (P<0.001).

“So how is this happening?” Dr Jenq asked. “We think, potentially, it might be due to short-chain fatty acids . . . butyric acid, propionic acid, and acetic acid. These are metabolites that bacteria produce when they ferment glucose and other sugars.”

To test this theory, the researchers treated mice with antibiotics and introduced Blautia or Enterococcus.

Blautia increased the level of short-chain fatty acids (butyrate and propionate) when compared to Enterococcus, although levels were not as high as those observed in mice that did not receive antibiotics. Nevertheless, these results point to a possible mechanism, according to Dr Jenq.

Explaining Blautia reduction

Dr Jenq also noted that antibiotics may contribute to the decrease in Blautia observed in transplant patients. When patients come in for transplant, they often have more than 25% Blautia in their stool. But the bacteria decrease to negligible levels by day 2 after transplant.

To determine the role of antibiotics, the researchers treated mice with 4 different antibiotics and looked at the levels of different bacteria.

They found that aztreonam and cefepime increased the levels of Bacteroidales and Clostridiales (the family to which Blautia belongs), but imipenem and metronidazole decreased bacteria levels.

So antibiotics do affect Blautia levels, Dr Jenq said, but they’re only part of the problem. He noted that patients’ Blautia levels start to decrease before antibiotics are administered. So he and his colleagues believe nutrition might also play a part.

The team found a significant difference in Blautia abundance between patients who received total parenteral nutrition and those who did not (P<0.001).

The researchers also discovered that reduced caloric intake led to a loss of Blautia and other Clostridiales. They analyzed 50 samples from 5 patients and found that patients who consumed fewer than 500 calories had a marked reduction in Blautia (P<0.0001).

And experiments in mice confirmed this association. A week of calorie restriction significantly reduced the abundance of Blautia and other Clostridiales (P=0.0002).

“In GVHD, as we all know, patients and mice eat less because of the nausea,” Dr Jenq said. “And we found that GVHD itself can also lead to a reduction in Clostridiales, both in humans [P=0.02] and in mice [P=0.01].”

Protecting Blautia to prevent GVHD

Having confirmed the role of nutrition in Blautia reduction, the researchers set out to identify a nutrition-based intervention to support Blautia in transplant recipients.

They settled on a sugar called raffinose, which is found in beans, cruciferous vegetables, and whole grains. It passes undigested through the upper intestine but is fermented in the lower intestine and metabolized to produce short-chain fatty acids.

The team tested raffinose in mice by introducing it into their drinking water. At 100 days after transplant, mice that received raffinose had significantly better overall survival than controls (P<0.001).

Based on these results, Dr Jenq and his colleagues believe nutritional intervention can protect Blautia and, therefore, may prevent GVHD and related death. The team thinks encouraging eating, gastric nutritional supplementation, and flora-targeted nutritional supplements might all prove effective.

But other interventions might work as well, such as reintroducing endogenous flora (via autologous fecal microbiota transplant), reintroducing select bacteria with beneficial potential, selecting antibiotics that spare bacteria with beneficial potential, and identifying and introducing bacterial metabolites that mediate anti-inflammatory effects.

*Data in the abstract differ from data presented.