Oncology Practice will be on site this coming week at the 2017 Genitourinary Cancers Symposium in Orlando with the latest on treatment of prostate, kidney, testicular, and urothelial cancers. Look for coverage of the best clinical presentations at the conference, hosted by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, including the following and more, beginning Thursday, Feb. 16:

• Outcomes of PD-1/PD-L1 responders who discontinued therapy for immune-related adverse events: Results of a cohort of patients with metastatic renal cell carcinoma. First author: Rana McKay, MD.
• Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. First author: Lisa Derosa, MD.
• Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy. First author: Guru Sonpavde, MD.
• Evolution of circulating tumor DNA profile from first-line to second-line therapy in metastatic renal cell carcinoma.
• First author: Sumanta Pal, MD.
• Clinical significance of AR mRNA quantification from circulating tumor cells in men with metastatic castration-resistant prostate cancer treated with abiraterone (Abi) or enzalutamide (Enza). First author: John Silberstein, MD.
• Adjuvant androgen deprivation versus mitoxantrone plus prednisone plus ADT in high-risk prostate cancer patients following radical prostatectomy: A phase III intergroup trial (SWOG S9921) NCT00004124. First author: L. Glode, MD.

Oncology Practice will be on site this coming week at the 2017 Genitourinary Cancers Symposium in Orlando with the latest on treatment of prostate, kidney, testicular, and urothelial cancers. Look for coverage of the best clinical presentations at the conference, hosted by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, including the following and more, beginning Thursday, Feb. 16:

• Outcomes of PD-1/PD-L1 responders who discontinued therapy for immune-related adverse events: Results of a cohort of patients with metastatic renal cell carcinoma. First author: Rana McKay, MD.
• Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. First author: Lisa Derosa, MD.
• Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy. First author: Guru Sonpavde, MD.
• Evolution of circulating tumor DNA profile from first-line to second-line therapy in metastatic renal cell carcinoma.
• First author: Sumanta Pal, MD.
• Clinical significance of AR mRNA quantification from circulating tumor cells in men with metastatic castration-resistant prostate cancer treated with abiraterone (Abi) or enzalutamide (Enza). First author: John Silberstein, MD.
• Adjuvant androgen deprivation versus mitoxantrone plus prednisone plus ADT in high-risk prostate cancer patients following radical prostatectomy: A phase III intergroup trial (SWOG S9921) NCT00004124. First author: L. Glode, MD.

Oncology Practice will be on site this coming week at the 2017 Genitourinary Cancers Symposium in Orlando with the latest on treatment of prostate, kidney, testicular, and urothelial cancers. Look for coverage of the best clinical presentations at the conference, hosted by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology, including the following and more, beginning Thursday, Feb. 16:

• Outcomes of PD-1/PD-L1 responders who discontinued therapy for immune-related adverse events: Results of a cohort of patients with metastatic renal cell carcinoma. First author: Rana McKay, MD.
• Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. First author: Lisa Derosa, MD.
• Circulating tumor (ct)-DNA alterations in metastatic castration-resistant prostate cancer (mCRPC): Association with outcomes and evolution with therapy. First author: Guru Sonpavde, MD.
• Evolution of circulating tumor DNA profile from first-line to second-line therapy in metastatic renal cell carcinoma.
• First author: Sumanta Pal, MD.
• Clinical significance of AR mRNA quantification from circulating tumor cells in men with metastatic castration-resistant prostate cancer treated with abiraterone (Abi) or enzalutamide (Enza). First author: John Silberstein, MD.
• Adjuvant androgen deprivation versus mitoxantrone plus prednisone plus ADT in high-risk prostate cancer patients following radical prostatectomy: A phase III intergroup trial (SWOG S9921) NCT00004124. First author: L. Glode, MD.

Controlling a Prosthesis With a Brain-Computer Interface

A brain-computer interface (BCI) that uses surface scalp electrodes can help a patient control a lower-extremity prosthesis and thus improve his or her daily life, researchers reported.  

A BCI allows a person to control a computer using his or her thoughts. The person is trained to use a specific thought such as flexing a knee for control. The thought generates electrical activity in the nerve cells and brainwaves. A chip can be implanted in the brain to monitor electrical activity, or electrodes can be placed on the scalp to monitor brainwaves. In people with paralysis or amputation, a BCI can help control the movement of muscles, limbs, and prosthetics.

"In general, using a prosthesis is an unnatural act that requires training [and] extra effort and can have a certain amount of awkwardness to it," said Douglas P. Murphy, MD, Associate Professor of Physical Medicine and Rehabilitation at Virginia Commonwealth University in Richmond. Dr. Murphy and colleagues sought to establish the feasibility of manipulating a prosthetic knee with a BCI. The use of a prosthesis can be difficult when climbing stairs or ramps, for example. The goal of all prosthetic research is to establish the same ease, comfort, and ability that the patient had with his or her natural leg, and controlling a prosthesis with thought is a big step in that direction, said Dr. Murphy.

Dr. Murphy's team worked with a person whose leg had been amputated above the knee (ie, a transfemoral amputee). Using surface scalp electrodes to transmit brainwave data to a computer software program, the participant learned how to activate a knee-unlocking switch through mental imaging. Surface scalp electrodes transmitted brainwave data to a software program that was keyed to activate the switch when the event-related desynchronization (ERD) in the EEG recording reached a certain threshold.  

"In our first attempt at using BCI with a lower extremity prosthesis, we wanted to test a simple system before moving on to more complicated ones to test the feasibility of the concept," said Dr. Murphy. "Thus, we chose control of the simplest prosthetic knee, which is the manual locking knee. When locked, the knee is rigid and straight, and when unlocked, the knee swings freely. Someone with an above-knee amputation would have to physically unlock the knee to sit and could lock or unlock in standing or walking, depending on his or her needs. We were interested to see if our participant could literally think his way to unlocking his prosthetic."

The participant learned to activate the knee-unlocking switch on his prosthesis that turned on a motor and unlocked his prosthetic knee. He walked up and down parallel bars while demonstrating his ability to unlock the knee to swing his leg and to sit down. Throughout the study, the participant was able to successfully unlock his knee between 50% and 100% of the time, and he responded to a questionnaire about his reactions to using the BCI with his prosthesis.

"The ultimate goal of this research is to provide the individual with a prosthesis that more easily and more successfully meets his or her needs for movement and walking," said Dr. Murphy. "The system should be comfortable [and] easy to use and serve useful purposes. The patient's subjective experience should reflect these goals. Our subject gave a good example of how this system could help him. He likes to hike with his children. Sometimes he is carrying his daughter and coming down a hill. With BCI control, he could adjust his prosthesis for descending the hill easily. This is the type of daily life activity we believe can be improved with BCI."

Based on this study, the BCI-controlled prosthesis would give patients a hands-free system of control, as well as a prosthesis that is responsive to more of their needs and takes less energy to use in complex environments. This system is in the early stages of development, and research is continuing.  

College Students Take Longer to Recover From a Concussion

College students take significantly more time to recover from a concussion than the general national average of seven to 14 days, investigators reported.

The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur in the United States each year. On average, a person takes seven to 14 days to recover from a concussion. "This duration is in the pediatric and sports-specific populations, however. No prior study has evaluated the outcome of concussions in a collegiate student population," said Prakash Jayabalan, MD, PhD, Assistant Professor of Physical Medicine and Rehabilitation at Northwestern University Feinberg School of Medicine in Chicago. "This population is unique in that it is heterogeneous in individual sporting activity (varsity vs club sports vs recreational activity), and students can have relatively high academic demands placed on them.  

"The pivotal consensus statement on concussion in sport from the Fourth International Conference on Concussions advocates for cognitive rest. Yet maintaining a period of cognitive rest in collegiate students is particularly challenging due to the academic rigors of their schooling. Therefore, our research team wanted to determine if recovery time for patients in a college setting is different from those people outside of that setting," said Dr. Jayabalan.

To answer this question, Dr. Jayabalan and colleagues reviewed the medical charts of 128 students who were seen for concussion during the 2014-2015 academic year. They included subjects aged 18 or older at evaluation and enrolled as full-time students. Subjects were diagnosed with a concussion using the consensus statement on Concussion in Sport from the Zurich Guidelines. The investigators excluded subjects not examined within the first seven days after injury, those who did not complain of concussion-related symptoms on initial examination, those who did not complete the Standardized Concussion Assessment Tool, and those who did not provide a specific date of injury or date of symptom resolution.

On average, the students were age 20, and the population was 53.1% female. Forty-four students were varsity athletes, 33 played club sports, 34 played recreational sports, and 17 did not engage in regular physical activity or did not report their activity level.

The average duration of concussion symptoms for all subjects was 17.89 days. Dr. Jayabalan's team found that varsity athletes experienced a shorter duration of concussion symptoms (mean, 11.5 days), compared with club athletes (mean, 18.61 days) and recreational athletes (mean, 22.59 days). This difference could result from the higher amount of medical support student athletes receive, said Dr. Jayabalan. Concussions that were related to sports were shorter in duration (mean, 14.96 days), compared with those that were sustained during nonsporting activity (mean, 21.75 days).  

Female students took longer to recover, compared with men (20.79 days vs 14.60 days). People with seizure disorders or prior concussions were more likely to have symptoms that lasted longer than 28 days. Finally, graduate students took two weeks longer to recover, compared with undergraduates (31 days vs 16 days), although the number of graduate students with concussion was relatively small in this study.

"This is the first cross-sectional study reporting the outcome of concussions at a collegiate institution," said Dr. Jayabalan. University students who sustain a concussion need improved resources, he added. "The findings in our study highlight the difficulty in treating collegiate students with concussions, due to both the academic rigors of institutions and the differing needs of student populations. The study also provides insight into at-risk subsets of the student population. Factors such as level of sport, year in school, athlete versus nonathlete, premorbid conditions, and gender may affect outcome, and this needs to be an important consideration for the physician managing concussed college students."

As a next step, the research team plans to implement resources for students with concussion and assess their effect on recovery.

Day of Hospital Admission May Affect Outcome of Head Trauma

Older adults who are admitted to the hospital with head trauma during the weekend have a 14% increased risk of dying, compared with those admitted on a weekday, according to researchers.

Weekend hospital admission is associated with higher instances of death in cardiovascular emergencies and stroke, but the effect of weekend admissions on patients with head trauma is not well defined. Researchers from the University of Texas Southwestern Medical School, Johns Hopkins University School of Medicine, and the Johns Hopkins Bloomberg School of Public Health used data from the 2006, 2007, and 2008 Nationwide Inpatient Sample—a large, publicly available dataset that contains a sampling of data for seven million hospital stays each year—to determine whether older adults admitted to the hospital for head trauma during the weekend were at a higher mortality risk than those admitted during the week.

"Older adults are some of the most vulnerable members of our society, and multiple studies point to differences in outcomes for older adult patients. After seeing the weekend trend in other areas, we wanted to see if a similar pattern existed for older adult patients suffering traumatic head injuries," said Salman Hirani, MD, a second-year resident in the department of rehabilitation medicine at Icahn School of Medicine at Mount Sinai in New York City.

The team identified 38,675 patients with head injury in the sample who met their criteria, which included serious and severe head injuries, based on the Abbreviated Injury Scale (AIS). Individuals between ages 65 and 89 with head AIS equal to 3 or 4 and no other region score less than 3 were included. The researchers calculated Individual Charlson comorbidity scores and excluded individuals with missing mortality, sex, or insurance data. Dr. Hirani and colleagues used Wilcoxon rank sum and Student t-tests to compare demographics, length of stay, and total charges for weekday versus weekend admissions. The χ² tests compared sex and head injury severity. The investigators used logistic regression to model mortality, adjusting for age, sex, injury severity, comorbidity, and insurance status.

From the initial group, the researchers identified 9,937 patients (25.6%) who were admitted during the weekend. The average age of patients admitted during the weekend and those admitted on weekdays was 78. Weekend patients had fewer additional injuries and coexisting diseases outside of head trauma, compared with those admitted during the week (mean Charlson, 1.07 vs 1.14). Weekend patients also had lower head injury severity (58.3% vs 60.8% of weekday patients had an AIS of 4). Weekend patients were also predominantly female, when compared with weekday patients (52% vs 50%).

The median length of stay in the hospital was one day shorter for weekend patients (four days vs five days), said Dr. Hirani. In addition, the investigators found no significant differences in the charges incurred during each patient's stay. The average charge for weekend patients was $27,128 per patient per stay, compared with $27,703 per patient per stay for weekday patients.  

Where the groups differed was in the percentage of patients who did not survive their injuries. Proportional mortality was higher among weekend patients (9.3% vs 8.4%). After the researchers adjusted the data, weekend patients had a 14% increased risk of death, compared with weekday patients. For patients that survive their hospital stay, long term morbidity and functional capacity is not noted in the literature, said Dr. Hirani. Early rehabilitation intervention has been shown to reduce morbidity in such patients and could be critical for patients' long-term survival, he added.  

"Overall, weekend patients were less severely injured, had fewer coexisting diseases and conditions, and generated the same amount of charges for their care as weekday patients, yet they experienced a greater likelihood of death," says Dr. Hirani. "While we are not sure of the exact reason for this [result], we can continue to investigate and encourage hospitals to take a look at their own outcomes in order to put into place policies that would improve survival for older adults with traumatic brain injuries. Ultimately, we know that Level I trauma centers do not exhibit this weekend effect. It may then be important for an older adult with a traumatic brain injury, especially those occurring over the weekend, to be admitted to or transferred to a Level I trauma center or a facility with full-time staffing around the clock, as these patients may require closer observation."

What Are the Long-Term Effects of Traumatic Brain Injury?

Many parents whose children have had a traumatic brain injury (TBI) want to know what their children will be like 10 years after the injury. Research is beginning to indicate answers to this question.

Investigators from Cincinnati Children's Hospital have conducted research on the long-term effects of TBI. They currently have data for an average of seven years after injury. Patients with mild to moderate brain injuries are two times more likely to have developed attention problems, and those with severe injuries are five times more likely to develop secondary ADHD. These researchers are also finding that the family environment influences the development of these attention problems.

Parenting and the home environment exert a powerful influence on recovery. Children with severe TBI in optimal environments may show few effects of their injuries, while children with milder injuries from disadvantaged or chaotic homes often demonstrate persistent problems, according to the data.

Early family response may be particularly important for long-term outcomes, suggesting that working to promote effective parenting may be an important early intervention. Certain skills that can affect social functioning, such as speed of information processing, inhibition, and reasoning, show greater long-term effects. Many children do well in the long term after brain injury, and most do not have across-the-board deficits.

More than 630,000 children and teenagers in the United States are treated in emergency rooms for TBI each year. But predictors of recovery following TBI are unclear. These environmental factors include family functioning, parenting practices, home environment, and socioeconomic status. Researchers at Cincinnati Children's hospital are working to identify genes that affect recovery after TBI and to understand how these genes may interact with environmental factors to influence recovery.

The investigators will be collecting salivary DNA samples from more than 330 children participating in the Approaches and Decisions in Acute Pediatric TBI Trial. The primary outcome will be global functioning at 3, 6, and 12 months post injury, and secondary outcomes will include a comprehensive assessment of cognitive and behavioral functioning at 12 months post injury. This project will provide information to inform individualized prognosis and treatment plans.

Controlling a Prosthesis With a Brain-Computer Interface

A brain-computer interface (BCI) that uses surface scalp electrodes can help a patient control a lower-extremity prosthesis and thus improve his or her daily life, researchers reported.  

A BCI allows a person to control a computer using his or her thoughts. The person is trained to use a specific thought such as flexing a knee for control. The thought generates electrical activity in the nerve cells and brainwaves. A chip can be implanted in the brain to monitor electrical activity, or electrodes can be placed on the scalp to monitor brainwaves. In people with paralysis or amputation, a BCI can help control the movement of muscles, limbs, and prosthetics.

"In general, using a prosthesis is an unnatural act that requires training [and] extra effort and can have a certain amount of awkwardness to it," said Douglas P. Murphy, MD, Associate Professor of Physical Medicine and Rehabilitation at Virginia Commonwealth University in Richmond. Dr. Murphy and colleagues sought to establish the feasibility of manipulating a prosthetic knee with a BCI. The use of a prosthesis can be difficult when climbing stairs or ramps, for example. The goal of all prosthetic research is to establish the same ease, comfort, and ability that the patient had with his or her natural leg, and controlling a prosthesis with thought is a big step in that direction, said Dr. Murphy.

Dr. Murphy's team worked with a person whose leg had been amputated above the knee (ie, a transfemoral amputee). Using surface scalp electrodes to transmit brainwave data to a computer software program, the participant learned how to activate a knee-unlocking switch through mental imaging. Surface scalp electrodes transmitted brainwave data to a software program that was keyed to activate the switch when the event-related desynchronization (ERD) in the EEG recording reached a certain threshold.  

"In our first attempt at using BCI with a lower extremity prosthesis, we wanted to test a simple system before moving on to more complicated ones to test the feasibility of the concept," said Dr. Murphy. "Thus, we chose control of the simplest prosthetic knee, which is the manual locking knee. When locked, the knee is rigid and straight, and when unlocked, the knee swings freely. Someone with an above-knee amputation would have to physically unlock the knee to sit and could lock or unlock in standing or walking, depending on his or her needs. We were interested to see if our participant could literally think his way to unlocking his prosthetic."

The participant learned to activate the knee-unlocking switch on his prosthesis that turned on a motor and unlocked his prosthetic knee. He walked up and down parallel bars while demonstrating his ability to unlock the knee to swing his leg and to sit down. Throughout the study, the participant was able to successfully unlock his knee between 50% and 100% of the time, and he responded to a questionnaire about his reactions to using the BCI with his prosthesis.

"The ultimate goal of this research is to provide the individual with a prosthesis that more easily and more successfully meets his or her needs for movement and walking," said Dr. Murphy. "The system should be comfortable [and] easy to use and serve useful purposes. The patient's subjective experience should reflect these goals. Our subject gave a good example of how this system could help him. He likes to hike with his children. Sometimes he is carrying his daughter and coming down a hill. With BCI control, he could adjust his prosthesis for descending the hill easily. This is the type of daily life activity we believe can be improved with BCI."

Based on this study, the BCI-controlled prosthesis would give patients a hands-free system of control, as well as a prosthesis that is responsive to more of their needs and takes less energy to use in complex environments. This system is in the early stages of development, and research is continuing.  

College Students Take Longer to Recover From a Concussion

College students take significantly more time to recover from a concussion than the general national average of seven to 14 days, investigators reported.

The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur in the United States each year. On average, a person takes seven to 14 days to recover from a concussion. "This duration is in the pediatric and sports-specific populations, however. No prior study has evaluated the outcome of concussions in a collegiate student population," said Prakash Jayabalan, MD, PhD, Assistant Professor of Physical Medicine and Rehabilitation at Northwestern University Feinberg School of Medicine in Chicago. "This population is unique in that it is heterogeneous in individual sporting activity (varsity vs club sports vs recreational activity), and students can have relatively high academic demands placed on them.  

"The pivotal consensus statement on concussion in sport from the Fourth International Conference on Concussions advocates for cognitive rest. Yet maintaining a period of cognitive rest in collegiate students is particularly challenging due to the academic rigors of their schooling. Therefore, our research team wanted to determine if recovery time for patients in a college setting is different from those people outside of that setting," said Dr. Jayabalan.

To answer this question, Dr. Jayabalan and colleagues reviewed the medical charts of 128 students who were seen for concussion during the 2014-2015 academic year. They included subjects aged 18 or older at evaluation and enrolled as full-time students. Subjects were diagnosed with a concussion using the consensus statement on Concussion in Sport from the Zurich Guidelines. The investigators excluded subjects not examined within the first seven days after injury, those who did not complain of concussion-related symptoms on initial examination, those who did not complete the Standardized Concussion Assessment Tool, and those who did not provide a specific date of injury or date of symptom resolution.

On average, the students were age 20, and the population was 53.1% female. Forty-four students were varsity athletes, 33 played club sports, 34 played recreational sports, and 17 did not engage in regular physical activity or did not report their activity level.

The average duration of concussion symptoms for all subjects was 17.89 days. Dr. Jayabalan's team found that varsity athletes experienced a shorter duration of concussion symptoms (mean, 11.5 days), compared with club athletes (mean, 18.61 days) and recreational athletes (mean, 22.59 days). This difference could result from the higher amount of medical support student athletes receive, said Dr. Jayabalan. Concussions that were related to sports were shorter in duration (mean, 14.96 days), compared with those that were sustained during nonsporting activity (mean, 21.75 days).  

Female students took longer to recover, compared with men (20.79 days vs 14.60 days). People with seizure disorders or prior concussions were more likely to have symptoms that lasted longer than 28 days. Finally, graduate students took two weeks longer to recover, compared with undergraduates (31 days vs 16 days), although the number of graduate students with concussion was relatively small in this study.

"This is the first cross-sectional study reporting the outcome of concussions at a collegiate institution," said Dr. Jayabalan. University students who sustain a concussion need improved resources, he added. "The findings in our study highlight the difficulty in treating collegiate students with concussions, due to both the academic rigors of institutions and the differing needs of student populations. The study also provides insight into at-risk subsets of the student population. Factors such as level of sport, year in school, athlete versus nonathlete, premorbid conditions, and gender may affect outcome, and this needs to be an important consideration for the physician managing concussed college students."

As a next step, the research team plans to implement resources for students with concussion and assess their effect on recovery.

Day of Hospital Admission May Affect Outcome of Head Trauma

Older adults who are admitted to the hospital with head trauma during the weekend have a 14% increased risk of dying, compared with those admitted on a weekday, according to researchers.

Weekend hospital admission is associated with higher instances of death in cardiovascular emergencies and stroke, but the effect of weekend admissions on patients with head trauma is not well defined. Researchers from the University of Texas Southwestern Medical School, Johns Hopkins University School of Medicine, and the Johns Hopkins Bloomberg School of Public Health used data from the 2006, 2007, and 2008 Nationwide Inpatient Sample—a large, publicly available dataset that contains a sampling of data for seven million hospital stays each year—to determine whether older adults admitted to the hospital for head trauma during the weekend were at a higher mortality risk than those admitted during the week.

"Older adults are some of the most vulnerable members of our society, and multiple studies point to differences in outcomes for older adult patients. After seeing the weekend trend in other areas, we wanted to see if a similar pattern existed for older adult patients suffering traumatic head injuries," said Salman Hirani, MD, a second-year resident in the department of rehabilitation medicine at Icahn School of Medicine at Mount Sinai in New York City.

The team identified 38,675 patients with head injury in the sample who met their criteria, which included serious and severe head injuries, based on the Abbreviated Injury Scale (AIS). Individuals between ages 65 and 89 with head AIS equal to 3 or 4 and no other region score less than 3 were included. The researchers calculated Individual Charlson comorbidity scores and excluded individuals with missing mortality, sex, or insurance data. Dr. Hirani and colleagues used Wilcoxon rank sum and Student t-tests to compare demographics, length of stay, and total charges for weekday versus weekend admissions. The χ² tests compared sex and head injury severity. The investigators used logistic regression to model mortality, adjusting for age, sex, injury severity, comorbidity, and insurance status.

From the initial group, the researchers identified 9,937 patients (25.6%) who were admitted during the weekend. The average age of patients admitted during the weekend and those admitted on weekdays was 78. Weekend patients had fewer additional injuries and coexisting diseases outside of head trauma, compared with those admitted during the week (mean Charlson, 1.07 vs 1.14). Weekend patients also had lower head injury severity (58.3% vs 60.8% of weekday patients had an AIS of 4). Weekend patients were also predominantly female, when compared with weekday patients (52% vs 50%).

The median length of stay in the hospital was one day shorter for weekend patients (four days vs five days), said Dr. Hirani. In addition, the investigators found no significant differences in the charges incurred during each patient's stay. The average charge for weekend patients was $27,128 per patient per stay, compared with $27,703 per patient per stay for weekday patients.  

Where the groups differed was in the percentage of patients who did not survive their injuries. Proportional mortality was higher among weekend patients (9.3% vs 8.4%). After the researchers adjusted the data, weekend patients had a 14% increased risk of death, compared with weekday patients. For patients that survive their hospital stay, long term morbidity and functional capacity is not noted in the literature, said Dr. Hirani. Early rehabilitation intervention has been shown to reduce morbidity in such patients and could be critical for patients' long-term survival, he added.  

"Overall, weekend patients were less severely injured, had fewer coexisting diseases and conditions, and generated the same amount of charges for their care as weekday patients, yet they experienced a greater likelihood of death," says Dr. Hirani. "While we are not sure of the exact reason for this [result], we can continue to investigate and encourage hospitals to take a look at their own outcomes in order to put into place policies that would improve survival for older adults with traumatic brain injuries. Ultimately, we know that Level I trauma centers do not exhibit this weekend effect. It may then be important for an older adult with a traumatic brain injury, especially those occurring over the weekend, to be admitted to or transferred to a Level I trauma center or a facility with full-time staffing around the clock, as these patients may require closer observation."

What Are the Long-Term Effects of Traumatic Brain Injury?

Many parents whose children have had a traumatic brain injury (TBI) want to know what their children will be like 10 years after the injury. Research is beginning to indicate answers to this question.

Investigators from Cincinnati Children's Hospital have conducted research on the long-term effects of TBI. They currently have data for an average of seven years after injury. Patients with mild to moderate brain injuries are two times more likely to have developed attention problems, and those with severe injuries are five times more likely to develop secondary ADHD. These researchers are also finding that the family environment influences the development of these attention problems.

Parenting and the home environment exert a powerful influence on recovery. Children with severe TBI in optimal environments may show few effects of their injuries, while children with milder injuries from disadvantaged or chaotic homes often demonstrate persistent problems, according to the data.

Early family response may be particularly important for long-term outcomes, suggesting that working to promote effective parenting may be an important early intervention. Certain skills that can affect social functioning, such as speed of information processing, inhibition, and reasoning, show greater long-term effects. Many children do well in the long term after brain injury, and most do not have across-the-board deficits.

More than 630,000 children and teenagers in the United States are treated in emergency rooms for TBI each year. But predictors of recovery following TBI are unclear. These environmental factors include family functioning, parenting practices, home environment, and socioeconomic status. Researchers at Cincinnati Children's hospital are working to identify genes that affect recovery after TBI and to understand how these genes may interact with environmental factors to influence recovery.

The investigators will be collecting salivary DNA samples from more than 330 children participating in the Approaches and Decisions in Acute Pediatric TBI Trial. The primary outcome will be global functioning at 3, 6, and 12 months post injury, and secondary outcomes will include a comprehensive assessment of cognitive and behavioral functioning at 12 months post injury. This project will provide information to inform individualized prognosis and treatment plans.

Controlling a Prosthesis With a Brain-Computer Interface

A brain-computer interface (BCI) that uses surface scalp electrodes can help a patient control a lower-extremity prosthesis and thus improve his or her daily life, researchers reported.  

A BCI allows a person to control a computer using his or her thoughts. The person is trained to use a specific thought such as flexing a knee for control. The thought generates electrical activity in the nerve cells and brainwaves. A chip can be implanted in the brain to monitor electrical activity, or electrodes can be placed on the scalp to monitor brainwaves. In people with paralysis or amputation, a BCI can help control the movement of muscles, limbs, and prosthetics.

"In general, using a prosthesis is an unnatural act that requires training [and] extra effort and can have a certain amount of awkwardness to it," said Douglas P. Murphy, MD, Associate Professor of Physical Medicine and Rehabilitation at Virginia Commonwealth University in Richmond. Dr. Murphy and colleagues sought to establish the feasibility of manipulating a prosthetic knee with a BCI. The use of a prosthesis can be difficult when climbing stairs or ramps, for example. The goal of all prosthetic research is to establish the same ease, comfort, and ability that the patient had with his or her natural leg, and controlling a prosthesis with thought is a big step in that direction, said Dr. Murphy.

Dr. Murphy's team worked with a person whose leg had been amputated above the knee (ie, a transfemoral amputee). Using surface scalp electrodes to transmit brainwave data to a computer software program, the participant learned how to activate a knee-unlocking switch through mental imaging. Surface scalp electrodes transmitted brainwave data to a software program that was keyed to activate the switch when the event-related desynchronization (ERD) in the EEG recording reached a certain threshold.  

"In our first attempt at using BCI with a lower extremity prosthesis, we wanted to test a simple system before moving on to more complicated ones to test the feasibility of the concept," said Dr. Murphy. "Thus, we chose control of the simplest prosthetic knee, which is the manual locking knee. When locked, the knee is rigid and straight, and when unlocked, the knee swings freely. Someone with an above-knee amputation would have to physically unlock the knee to sit and could lock or unlock in standing or walking, depending on his or her needs. We were interested to see if our participant could literally think his way to unlocking his prosthetic."

The participant learned to activate the knee-unlocking switch on his prosthesis that turned on a motor and unlocked his prosthetic knee. He walked up and down parallel bars while demonstrating his ability to unlock the knee to swing his leg and to sit down. Throughout the study, the participant was able to successfully unlock his knee between 50% and 100% of the time, and he responded to a questionnaire about his reactions to using the BCI with his prosthesis.

"The ultimate goal of this research is to provide the individual with a prosthesis that more easily and more successfully meets his or her needs for movement and walking," said Dr. Murphy. "The system should be comfortable [and] easy to use and serve useful purposes. The patient's subjective experience should reflect these goals. Our subject gave a good example of how this system could help him. He likes to hike with his children. Sometimes he is carrying his daughter and coming down a hill. With BCI control, he could adjust his prosthesis for descending the hill easily. This is the type of daily life activity we believe can be improved with BCI."

Based on this study, the BCI-controlled prosthesis would give patients a hands-free system of control, as well as a prosthesis that is responsive to more of their needs and takes less energy to use in complex environments. This system is in the early stages of development, and research is continuing.  

College Students Take Longer to Recover From a Concussion

College students take significantly more time to recover from a concussion than the general national average of seven to 14 days, investigators reported.

The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur in the United States each year. On average, a person takes seven to 14 days to recover from a concussion. "This duration is in the pediatric and sports-specific populations, however. No prior study has evaluated the outcome of concussions in a collegiate student population," said Prakash Jayabalan, MD, PhD, Assistant Professor of Physical Medicine and Rehabilitation at Northwestern University Feinberg School of Medicine in Chicago. "This population is unique in that it is heterogeneous in individual sporting activity (varsity vs club sports vs recreational activity), and students can have relatively high academic demands placed on them.  

"The pivotal consensus statement on concussion in sport from the Fourth International Conference on Concussions advocates for cognitive rest. Yet maintaining a period of cognitive rest in collegiate students is particularly challenging due to the academic rigors of their schooling. Therefore, our research team wanted to determine if recovery time for patients in a college setting is different from those people outside of that setting," said Dr. Jayabalan.

To answer this question, Dr. Jayabalan and colleagues reviewed the medical charts of 128 students who were seen for concussion during the 2014-2015 academic year. They included subjects aged 18 or older at evaluation and enrolled as full-time students. Subjects were diagnosed with a concussion using the consensus statement on Concussion in Sport from the Zurich Guidelines. The investigators excluded subjects not examined within the first seven days after injury, those who did not complain of concussion-related symptoms on initial examination, those who did not complete the Standardized Concussion Assessment Tool, and those who did not provide a specific date of injury or date of symptom resolution.

On average, the students were age 20, and the population was 53.1% female. Forty-four students were varsity athletes, 33 played club sports, 34 played recreational sports, and 17 did not engage in regular physical activity or did not report their activity level.

The average duration of concussion symptoms for all subjects was 17.89 days. Dr. Jayabalan's team found that varsity athletes experienced a shorter duration of concussion symptoms (mean, 11.5 days), compared with club athletes (mean, 18.61 days) and recreational athletes (mean, 22.59 days). This difference could result from the higher amount of medical support student athletes receive, said Dr. Jayabalan. Concussions that were related to sports were shorter in duration (mean, 14.96 days), compared with those that were sustained during nonsporting activity (mean, 21.75 days).  

Female students took longer to recover, compared with men (20.79 days vs 14.60 days). People with seizure disorders or prior concussions were more likely to have symptoms that lasted longer than 28 days. Finally, graduate students took two weeks longer to recover, compared with undergraduates (31 days vs 16 days), although the number of graduate students with concussion was relatively small in this study.

"This is the first cross-sectional study reporting the outcome of concussions at a collegiate institution," said Dr. Jayabalan. University students who sustain a concussion need improved resources, he added. "The findings in our study highlight the difficulty in treating collegiate students with concussions, due to both the academic rigors of institutions and the differing needs of student populations. The study also provides insight into at-risk subsets of the student population. Factors such as level of sport, year in school, athlete versus nonathlete, premorbid conditions, and gender may affect outcome, and this needs to be an important consideration for the physician managing concussed college students."

As a next step, the research team plans to implement resources for students with concussion and assess their effect on recovery.

Day of Hospital Admission May Affect Outcome of Head Trauma

Older adults who are admitted to the hospital with head trauma during the weekend have a 14% increased risk of dying, compared with those admitted on a weekday, according to researchers.

Weekend hospital admission is associated with higher instances of death in cardiovascular emergencies and stroke, but the effect of weekend admissions on patients with head trauma is not well defined. Researchers from the University of Texas Southwestern Medical School, Johns Hopkins University School of Medicine, and the Johns Hopkins Bloomberg School of Public Health used data from the 2006, 2007, and 2008 Nationwide Inpatient Sample—a large, publicly available dataset that contains a sampling of data for seven million hospital stays each year—to determine whether older adults admitted to the hospital for head trauma during the weekend were at a higher mortality risk than those admitted during the week.

"Older adults are some of the most vulnerable members of our society, and multiple studies point to differences in outcomes for older adult patients. After seeing the weekend trend in other areas, we wanted to see if a similar pattern existed for older adult patients suffering traumatic head injuries," said Salman Hirani, MD, a second-year resident in the department of rehabilitation medicine at Icahn School of Medicine at Mount Sinai in New York City.

The team identified 38,675 patients with head injury in the sample who met their criteria, which included serious and severe head injuries, based on the Abbreviated Injury Scale (AIS). Individuals between ages 65 and 89 with head AIS equal to 3 or 4 and no other region score less than 3 were included. The researchers calculated Individual Charlson comorbidity scores and excluded individuals with missing mortality, sex, or insurance data. Dr. Hirani and colleagues used Wilcoxon rank sum and Student t-tests to compare demographics, length of stay, and total charges for weekday versus weekend admissions. The χ² tests compared sex and head injury severity. The investigators used logistic regression to model mortality, adjusting for age, sex, injury severity, comorbidity, and insurance status.

From the initial group, the researchers identified 9,937 patients (25.6%) who were admitted during the weekend. The average age of patients admitted during the weekend and those admitted on weekdays was 78. Weekend patients had fewer additional injuries and coexisting diseases outside of head trauma, compared with those admitted during the week (mean Charlson, 1.07 vs 1.14). Weekend patients also had lower head injury severity (58.3% vs 60.8% of weekday patients had an AIS of 4). Weekend patients were also predominantly female, when compared with weekday patients (52% vs 50%).

The median length of stay in the hospital was one day shorter for weekend patients (four days vs five days), said Dr. Hirani. In addition, the investigators found no significant differences in the charges incurred during each patient's stay. The average charge for weekend patients was $27,128 per patient per stay, compared with $27,703 per patient per stay for weekday patients.  

Where the groups differed was in the percentage of patients who did not survive their injuries. Proportional mortality was higher among weekend patients (9.3% vs 8.4%). After the researchers adjusted the data, weekend patients had a 14% increased risk of death, compared with weekday patients. For patients that survive their hospital stay, long term morbidity and functional capacity is not noted in the literature, said Dr. Hirani. Early rehabilitation intervention has been shown to reduce morbidity in such patients and could be critical for patients' long-term survival, he added.  

"Overall, weekend patients were less severely injured, had fewer coexisting diseases and conditions, and generated the same amount of charges for their care as weekday patients, yet they experienced a greater likelihood of death," says Dr. Hirani. "While we are not sure of the exact reason for this [result], we can continue to investigate and encourage hospitals to take a look at their own outcomes in order to put into place policies that would improve survival for older adults with traumatic brain injuries. Ultimately, we know that Level I trauma centers do not exhibit this weekend effect. It may then be important for an older adult with a traumatic brain injury, especially those occurring over the weekend, to be admitted to or transferred to a Level I trauma center or a facility with full-time staffing around the clock, as these patients may require closer observation."

What Are the Long-Term Effects of Traumatic Brain Injury?

Many parents whose children have had a traumatic brain injury (TBI) want to know what their children will be like 10 years after the injury. Research is beginning to indicate answers to this question.

Investigators from Cincinnati Children's Hospital have conducted research on the long-term effects of TBI. They currently have data for an average of seven years after injury. Patients with mild to moderate brain injuries are two times more likely to have developed attention problems, and those with severe injuries are five times more likely to develop secondary ADHD. These researchers are also finding that the family environment influences the development of these attention problems.

Parenting and the home environment exert a powerful influence on recovery. Children with severe TBI in optimal environments may show few effects of their injuries, while children with milder injuries from disadvantaged or chaotic homes often demonstrate persistent problems, according to the data.

Early family response may be particularly important for long-term outcomes, suggesting that working to promote effective parenting may be an important early intervention. Certain skills that can affect social functioning, such as speed of information processing, inhibition, and reasoning, show greater long-term effects. Many children do well in the long term after brain injury, and most do not have across-the-board deficits.

More than 630,000 children and teenagers in the United States are treated in emergency rooms for TBI each year. But predictors of recovery following TBI are unclear. These environmental factors include family functioning, parenting practices, home environment, and socioeconomic status. Researchers at Cincinnati Children's hospital are working to identify genes that affect recovery after TBI and to understand how these genes may interact with environmental factors to influence recovery.

The investigators will be collecting salivary DNA samples from more than 330 children participating in the Approaches and Decisions in Acute Pediatric TBI Trial. The primary outcome will be global functioning at 3, 6, and 12 months post injury, and secondary outcomes will include a comprehensive assessment of cognitive and behavioral functioning at 12 months post injury. This project will provide information to inform individualized prognosis and treatment plans.

Serum levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were unable to distinguish between patients with mild traumatic brain injury (mTBI) and patients with orthopedic trauma, according to a study published online ahead of print January 27 in the Journal of Neurotrauma. The results cast doubt on the value of these proposed biomarkers in diagnosing mTBI, the researchers said. Serum UCH-L1 and GFAP were longitudinally measured in 73 patients with acute orthopedic injury and in 93 patients with CT-negative mTBI when they arrived at the hospital and one, two, three, and seven days after admission, as well as at a follow-up visit between three and 10 months after injury. Levels of GFAP were higher in patients with orthopedic trauma than in patients with mTBI on arrival, but subsequent levels did not differ between groups. Levels of UCH-L1 did not significantly differ between the groups.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation without maintenance therapy is effective for inducing long-term sustained remission of active relapsing-remitting multiple sclerosis at five years, according to a study published online ahead of print February 1 in Neurology. Twenty-five participants were evaluated for transplant, and 24 participants underwent high-dose immunosuppressive therapy and hematopoietic cell transplantation. Median follow-up was 62 months. Event-free survival (ie, survival without disability progression, relapse, or new lesions on MRI) was 69.2%. Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3%, 86.9%, and 86.3%, respectively. Adverse events were consistent with toxic effects associated with high-dose immunosuppressive therapy and hematopoietic cell transplantation, including cytopenia and infection. Neurologic disability improved among participants who survived and completed the study, with a median change in Expanded Disability Status Scale score of -0.5.

Estimated glomerular filtration rate on admission is an important predictor of poststroke short-term outcomes, according to a cohort study published in the February issue of Stroke. Investigators analyzed data from 232,236 patients with ischemic stroke in Get With The Guidelines-Stroke. Patients were age 65 or older. In all, 11.8% of patients died during hospitalization or were discharged to hospice, and 38.6% were discharged home. Renal dysfunction was independently associated with an increased risk of in-hospital mortality that was highest among those with an estimated glomerular filtration rate of less than 15 mL/min/1.73 m2 without dialysis (odds ratio, 2.52). In addition, receiving dialysis and having an estimated glomerular filtration rate of less than 29 mL/min/1.73 m2 were associated with lower odds of being discharged home.

Habitual sleep duration in monozygotic twins may be associated with distinct patterns of differential gene expression and pathway enrichment that affect immune response, according to a study published in the January issue of Sleep. Investigators selected 11 healthy monozygotic twin pairs (82% female; mean age, 42.7) based on subjective sleep duration discordance and then monitored participants' habitual sleep duration with two weeks of wrist actigraphy. Peripheral blood leukocyte RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. The mean 24-hour sleep duration of the total sample was 439.2 minutes. Mean within-pair sleep duration difference per 24 hours was 64.4 minutes. The researchers observed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with upregulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Genes that were downregulated with short sleep were highly enriched in immunoinfammatory pathways, as well as developmental programs, coagulation cascade, and cell adhesion.

A brain-computer interface that can decipher the thoughts of people who are unable to communicate may help people with completely locked-in syndrome, according to a study published January 31 in PLOS Biology. Researchers studied a brain-computer interface in four patients with advanced amyotrophic lateral sclerosis and completely locked-in syndrome. Patients responded to "yes" or "no" questions by thinking their answers. The noninvasive brain-computer interface assessed changes in frontocentral cortical oxygenation, measured using functional near-infrared spectroscopy, to determine patients' answers. Patients communicated with an above-chance-level correct response rate over 70%. EEG oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication.  

 
Using a new noninvasive fMRI method, physicians may be able to predict who is more likely to continue experiencing symptoms months or years after concussion, according to a study published online ahead of print January 13 in the Journal of Neurotrauma. Investigators recruited 75 patients with mild traumatic brain injury (mTBI) and 47 healthy subjects as part of the prospective, multicenter Transforming Research and Clinical Knowledge in TBI pilot study. Researchers compared the functional connectivity of the resting-state networks between patients and controls, and group differences in the interactions between resting-state networks. They assessed patients' cognitive and behavioral performance at six months post injury. Spatial maps of resting-state networks involved in behavioral and cognitive processes differed between patients with mTBI and healthy controls, and these differences were predictive of patients' outcomes at six months post injury.

 
Among patients with Alzheimer's disease, lifelong bilingualism correlates with functional modulations in crucial neural networks, suggesting neural reserve and compensatory mechanisms, according to a study published online ahead of print January 30 in the Proceedings of the National Academy of Sciences. Eighty-five patients with Alzheimer's disease (45 German-Italian bilingual speakers and 40 monolingual speakers) matched for disease duration were included in this study. Bilingual individuals were on average five years older than people who did not speak another language. Consistent with models of cognitive reserve, cerebral hypometabolism was more severe in the group of bilingual individuals with Alzheimer's disease. Metabolic connectivity analyses supported a neuroprotective effect of bilingualism by showing increased connectivity in the executive control and the default mode networks in bilingual patients, compared with monolingual patients.

 
The Huntington's Disease Society of America (HDSA), in conjunction with the FDA, conducted two surveys to gather the perspectives of patients with Huntington's disease and juvenile Huntington's disease and their caregivers. Findings from the surveys were published online ahead of print January 24 in the Journal of Huntington's Disease. One survey covered disease symptoms that matter most to people with Huntington's disease, and the other covered current approaches to treatment. The surveys received a total of 3,631 responses. "The frequency and impact of symptoms appear to be felt more by caregivers than individuals with Huntington's Disease, especially when it comes to loss of abilities," said lead investigator George J. Yohrling, PhD, Senior Director of Mission and Scientific Affairs for the HDSA. "There was also a large difference in the perception of symptom frequency between caregivers and individuals with Huntington's disease."

 
Intentional and unintentional head impacts are independently associated with moderate to severe CNS symptoms in adult amateur soccer players, according to a study published online ahead of print February 1 in Neurology. Soccer players completed an online questionnaire about how often they played soccer during the previous two weeks, how many times they had unintentional head impacts, how many times they headed the ball, and the frequency and severity of CNS symptoms. A total of 222 players completed 470 questionnaires. Heading-related symptoms were reported in 20% of the questionnaires. Heading in the highest quartile was significantly associated with CNS symptoms when controlling for unintentional head impacts. People with unintentional head impacts were at increased risk for CNS symptoms when controlling for heading.

 
Meditation or music listening may significantly enhance subjective memory function and objective cognitive performance in adults with subjective cognitive decline, according to a study published February 3 in the Journal of Alzheimer's Disease. A total of 60 participants with subjective cognitive decline were randomized to a Kirtan Kriya meditation program or a music listening program. The researchers asked participants to practice 12 minutes each day for three months, then at their discretion for the ensuing three months. At baseline, three months, and six months, researchers measured memory and cognitive functioning. Fifty-three participants completed the study. Both groups showed marked and significant improvements at three months in memory and cognitive performance. At six months, overall gains were maintained or improved, with effect sizes ranging from medium to large.

 
Yoga and aerobic exercise interventions do not significantly reduce objectively measured sleep disturbances among midlife women who are experiencing hot flashes, according to a study published January 15 in the Journal of Clinical Sleep Medicine. Researchers conducted secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health network. In the trial, 186 late transition and postmenopausal women ages 40 to 62 with hot flashes were randomized to 12 weeks of yoga, supervised aerobic exercise, or usual activity. Changes in the actigraphic sleep outcomes from baseline to weeks 11 to 12 were small and did not differ between groups. An exploratory analysis suggested that women with poor self-reported sleep quality at baseline potentially had improved sleep stability following yoga.

 
Longitudinal data provide strong evidence of cognitive aging in midlife women, with substantial within-woman declines in processing speed and memory, according to a study published January 3 in PLoS One. Researchers used data from 2,124 participants from the Study of Women's Health Across the Nation. Participants completed annual tests of processing speed, verbal episodic memory, and working memory. Average age at baseline was 54. There were 7,185 cognitive assessments with a median follow-up time of 6.5 years. In mixed effects regression, adjusted for practice effects, retention, menopause symptoms, and covariates, scores on two of four cognition tests declined. Mean decline in cognitive speed was 0.28 per year or 4.9% in 10 years, and mean decline in verbal episodic memory (delayed testing) was 0.02 per year or 2% in 10 years.  

 
The FDA has approved Emflaza (deflazacort) for the treatment of Duchenne muscular dystrophy in patients age 5 and older. The corticosteroid is available in an immediate-release tablet formulation (6 mg, 18 mg, 30 mg, and 36 mg) as well as an oral suspension formulation (22.75 mg/mL). In a multicenter, randomized, double-blind, placebo-controlled study of 196 male pediatric patients, patients who received deflazacort had improved muscle strength at 12 weeks, compared with patients who received placebo. Through the 52-week study, an overall stability in average muscle strength was maintained in patients who received deflazacort. Results on several timed measures of patient function (eg, time to stand from supine, time to climb four stairs, and time to walk or run 30 feet) also numerically favored deflazacort 0.9 mg/kg/day at week 12. Marathon Pharmaceuticals, headquartered in Northbrook, Illinois, markets Emflaza.

—Kimberly Williams

Serum levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were unable to distinguish between patients with mild traumatic brain injury (mTBI) and patients with orthopedic trauma, according to a study published online ahead of print January 27 in the Journal of Neurotrauma. The results cast doubt on the value of these proposed biomarkers in diagnosing mTBI, the researchers said. Serum UCH-L1 and GFAP were longitudinally measured in 73 patients with acute orthopedic injury and in 93 patients with CT-negative mTBI when they arrived at the hospital and one, two, three, and seven days after admission, as well as at a follow-up visit between three and 10 months after injury. Levels of GFAP were higher in patients with orthopedic trauma than in patients with mTBI on arrival, but subsequent levels did not differ between groups. Levels of UCH-L1 did not significantly differ between the groups.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation without maintenance therapy is effective for inducing long-term sustained remission of active relapsing-remitting multiple sclerosis at five years, according to a study published online ahead of print February 1 in Neurology. Twenty-five participants were evaluated for transplant, and 24 participants underwent high-dose immunosuppressive therapy and hematopoietic cell transplantation. Median follow-up was 62 months. Event-free survival (ie, survival without disability progression, relapse, or new lesions on MRI) was 69.2%. Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3%, 86.9%, and 86.3%, respectively. Adverse events were consistent with toxic effects associated with high-dose immunosuppressive therapy and hematopoietic cell transplantation, including cytopenia and infection. Neurologic disability improved among participants who survived and completed the study, with a median change in Expanded Disability Status Scale score of -0.5.

Estimated glomerular filtration rate on admission is an important predictor of poststroke short-term outcomes, according to a cohort study published in the February issue of Stroke. Investigators analyzed data from 232,236 patients with ischemic stroke in Get With The Guidelines-Stroke. Patients were age 65 or older. In all, 11.8% of patients died during hospitalization or were discharged to hospice, and 38.6% were discharged home. Renal dysfunction was independently associated with an increased risk of in-hospital mortality that was highest among those with an estimated glomerular filtration rate of less than 15 mL/min/1.73 m2 without dialysis (odds ratio, 2.52). In addition, receiving dialysis and having an estimated glomerular filtration rate of less than 29 mL/min/1.73 m2 were associated with lower odds of being discharged home.

Habitual sleep duration in monozygotic twins may be associated with distinct patterns of differential gene expression and pathway enrichment that affect immune response, according to a study published in the January issue of Sleep. Investigators selected 11 healthy monozygotic twin pairs (82% female; mean age, 42.7) based on subjective sleep duration discordance and then monitored participants' habitual sleep duration with two weeks of wrist actigraphy. Peripheral blood leukocyte RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. The mean 24-hour sleep duration of the total sample was 439.2 minutes. Mean within-pair sleep duration difference per 24 hours was 64.4 minutes. The researchers observed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with upregulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Genes that were downregulated with short sleep were highly enriched in immunoinfammatory pathways, as well as developmental programs, coagulation cascade, and cell adhesion.

A brain-computer interface that can decipher the thoughts of people who are unable to communicate may help people with completely locked-in syndrome, according to a study published January 31 in PLOS Biology. Researchers studied a brain-computer interface in four patients with advanced amyotrophic lateral sclerosis and completely locked-in syndrome. Patients responded to "yes" or "no" questions by thinking their answers. The noninvasive brain-computer interface assessed changes in frontocentral cortical oxygenation, measured using functional near-infrared spectroscopy, to determine patients' answers. Patients communicated with an above-chance-level correct response rate over 70%. EEG oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication.  

 
Using a new noninvasive fMRI method, physicians may be able to predict who is more likely to continue experiencing symptoms months or years after concussion, according to a study published online ahead of print January 13 in the Journal of Neurotrauma. Investigators recruited 75 patients with mild traumatic brain injury (mTBI) and 47 healthy subjects as part of the prospective, multicenter Transforming Research and Clinical Knowledge in TBI pilot study. Researchers compared the functional connectivity of the resting-state networks between patients and controls, and group differences in the interactions between resting-state networks. They assessed patients' cognitive and behavioral performance at six months post injury. Spatial maps of resting-state networks involved in behavioral and cognitive processes differed between patients with mTBI and healthy controls, and these differences were predictive of patients' outcomes at six months post injury.

 
Among patients with Alzheimer's disease, lifelong bilingualism correlates with functional modulations in crucial neural networks, suggesting neural reserve and compensatory mechanisms, according to a study published online ahead of print January 30 in the Proceedings of the National Academy of Sciences. Eighty-five patients with Alzheimer's disease (45 German-Italian bilingual speakers and 40 monolingual speakers) matched for disease duration were included in this study. Bilingual individuals were on average five years older than people who did not speak another language. Consistent with models of cognitive reserve, cerebral hypometabolism was more severe in the group of bilingual individuals with Alzheimer's disease. Metabolic connectivity analyses supported a neuroprotective effect of bilingualism by showing increased connectivity in the executive control and the default mode networks in bilingual patients, compared with monolingual patients.

 
The Huntington's Disease Society of America (HDSA), in conjunction with the FDA, conducted two surveys to gather the perspectives of patients with Huntington's disease and juvenile Huntington's disease and their caregivers. Findings from the surveys were published online ahead of print January 24 in the Journal of Huntington's Disease. One survey covered disease symptoms that matter most to people with Huntington's disease, and the other covered current approaches to treatment. The surveys received a total of 3,631 responses. "The frequency and impact of symptoms appear to be felt more by caregivers than individuals with Huntington's Disease, especially when it comes to loss of abilities," said lead investigator George J. Yohrling, PhD, Senior Director of Mission and Scientific Affairs for the HDSA. "There was also a large difference in the perception of symptom frequency between caregivers and individuals with Huntington's disease."

 
Intentional and unintentional head impacts are independently associated with moderate to severe CNS symptoms in adult amateur soccer players, according to a study published online ahead of print February 1 in Neurology. Soccer players completed an online questionnaire about how often they played soccer during the previous two weeks, how many times they had unintentional head impacts, how many times they headed the ball, and the frequency and severity of CNS symptoms. A total of 222 players completed 470 questionnaires. Heading-related symptoms were reported in 20% of the questionnaires. Heading in the highest quartile was significantly associated with CNS symptoms when controlling for unintentional head impacts. People with unintentional head impacts were at increased risk for CNS symptoms when controlling for heading.

 
Meditation or music listening may significantly enhance subjective memory function and objective cognitive performance in adults with subjective cognitive decline, according to a study published February 3 in the Journal of Alzheimer's Disease. A total of 60 participants with subjective cognitive decline were randomized to a Kirtan Kriya meditation program or a music listening program. The researchers asked participants to practice 12 minutes each day for three months, then at their discretion for the ensuing three months. At baseline, three months, and six months, researchers measured memory and cognitive functioning. Fifty-three participants completed the study. Both groups showed marked and significant improvements at three months in memory and cognitive performance. At six months, overall gains were maintained or improved, with effect sizes ranging from medium to large.

 
Yoga and aerobic exercise interventions do not significantly reduce objectively measured sleep disturbances among midlife women who are experiencing hot flashes, according to a study published January 15 in the Journal of Clinical Sleep Medicine. Researchers conducted secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health network. In the trial, 186 late transition and postmenopausal women ages 40 to 62 with hot flashes were randomized to 12 weeks of yoga, supervised aerobic exercise, or usual activity. Changes in the actigraphic sleep outcomes from baseline to weeks 11 to 12 were small and did not differ between groups. An exploratory analysis suggested that women with poor self-reported sleep quality at baseline potentially had improved sleep stability following yoga.

 
Longitudinal data provide strong evidence of cognitive aging in midlife women, with substantial within-woman declines in processing speed and memory, according to a study published January 3 in PLoS One. Researchers used data from 2,124 participants from the Study of Women's Health Across the Nation. Participants completed annual tests of processing speed, verbal episodic memory, and working memory. Average age at baseline was 54. There were 7,185 cognitive assessments with a median follow-up time of 6.5 years. In mixed effects regression, adjusted for practice effects, retention, menopause symptoms, and covariates, scores on two of four cognition tests declined. Mean decline in cognitive speed was 0.28 per year or 4.9% in 10 years, and mean decline in verbal episodic memory (delayed testing) was 0.02 per year or 2% in 10 years.  

 
The FDA has approved Emflaza (deflazacort) for the treatment of Duchenne muscular dystrophy in patients age 5 and older. The corticosteroid is available in an immediate-release tablet formulation (6 mg, 18 mg, 30 mg, and 36 mg) as well as an oral suspension formulation (22.75 mg/mL). In a multicenter, randomized, double-blind, placebo-controlled study of 196 male pediatric patients, patients who received deflazacort had improved muscle strength at 12 weeks, compared with patients who received placebo. Through the 52-week study, an overall stability in average muscle strength was maintained in patients who received deflazacort. Results on several timed measures of patient function (eg, time to stand from supine, time to climb four stairs, and time to walk or run 30 feet) also numerically favored deflazacort 0.9 mg/kg/day at week 12. Marathon Pharmaceuticals, headquartered in Northbrook, Illinois, markets Emflaza.

—Kimberly Williams

Serum levels of ubiquitin C-terminal hydrolase-L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were unable to distinguish between patients with mild traumatic brain injury (mTBI) and patients with orthopedic trauma, according to a study published online ahead of print January 27 in the Journal of Neurotrauma. The results cast doubt on the value of these proposed biomarkers in diagnosing mTBI, the researchers said. Serum UCH-L1 and GFAP were longitudinally measured in 73 patients with acute orthopedic injury and in 93 patients with CT-negative mTBI when they arrived at the hospital and one, two, three, and seven days after admission, as well as at a follow-up visit between three and 10 months after injury. Levels of GFAP were higher in patients with orthopedic trauma than in patients with mTBI on arrival, but subsequent levels did not differ between groups. Levels of UCH-L1 did not significantly differ between the groups.

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation without maintenance therapy is effective for inducing long-term sustained remission of active relapsing-remitting multiple sclerosis at five years, according to a study published online ahead of print February 1 in Neurology. Twenty-five participants were evaluated for transplant, and 24 participants underwent high-dose immunosuppressive therapy and hematopoietic cell transplantation. Median follow-up was 62 months. Event-free survival (ie, survival without disability progression, relapse, or new lesions on MRI) was 69.2%. Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3%, 86.9%, and 86.3%, respectively. Adverse events were consistent with toxic effects associated with high-dose immunosuppressive therapy and hematopoietic cell transplantation, including cytopenia and infection. Neurologic disability improved among participants who survived and completed the study, with a median change in Expanded Disability Status Scale score of -0.5.

Estimated glomerular filtration rate on admission is an important predictor of poststroke short-term outcomes, according to a cohort study published in the February issue of Stroke. Investigators analyzed data from 232,236 patients with ischemic stroke in Get With The Guidelines-Stroke. Patients were age 65 or older. In all, 11.8% of patients died during hospitalization or were discharged to hospice, and 38.6% were discharged home. Renal dysfunction was independently associated with an increased risk of in-hospital mortality that was highest among those with an estimated glomerular filtration rate of less than 15 mL/min/1.73 m2 without dialysis (odds ratio, 2.52). In addition, receiving dialysis and having an estimated glomerular filtration rate of less than 29 mL/min/1.73 m2 were associated with lower odds of being discharged home.

Habitual sleep duration in monozygotic twins may be associated with distinct patterns of differential gene expression and pathway enrichment that affect immune response, according to a study published in the January issue of Sleep. Investigators selected 11 healthy monozygotic twin pairs (82% female; mean age, 42.7) based on subjective sleep duration discordance and then monitored participants' habitual sleep duration with two weeks of wrist actigraphy. Peripheral blood leukocyte RNA from fasting blood samples was obtained on the final day of actigraphic measurement and hybridized to Illumina humanHT-12 microarrays. The mean 24-hour sleep duration of the total sample was 439.2 minutes. Mean within-pair sleep duration difference per 24 hours was 64.4 minutes. The researchers observed distinctive pathway enrichment based on sleep duration differences. Habitual short sleep was associated with upregulation of genes involved in transcription, ribosome, translation, and oxidative phosphorylation. Genes that were downregulated with short sleep were highly enriched in immunoinfammatory pathways, as well as developmental programs, coagulation cascade, and cell adhesion.

A brain-computer interface that can decipher the thoughts of people who are unable to communicate may help people with completely locked-in syndrome, according to a study published January 31 in PLOS Biology. Researchers studied a brain-computer interface in four patients with advanced amyotrophic lateral sclerosis and completely locked-in syndrome. Patients responded to "yes" or "no" questions by thinking their answers. The noninvasive brain-computer interface assessed changes in frontocentral cortical oxygenation, measured using functional near-infrared spectroscopy, to determine patients' answers. Patients communicated with an above-chance-level correct response rate over 70%. EEG oscillations and electrooculographic signals did not exceed the chance-level threshold for correct communication.  

 
Using a new noninvasive fMRI method, physicians may be able to predict who is more likely to continue experiencing symptoms months or years after concussion, according to a study published online ahead of print January 13 in the Journal of Neurotrauma. Investigators recruited 75 patients with mild traumatic brain injury (mTBI) and 47 healthy subjects as part of the prospective, multicenter Transforming Research and Clinical Knowledge in TBI pilot study. Researchers compared the functional connectivity of the resting-state networks between patients and controls, and group differences in the interactions between resting-state networks. They assessed patients' cognitive and behavioral performance at six months post injury. Spatial maps of resting-state networks involved in behavioral and cognitive processes differed between patients with mTBI and healthy controls, and these differences were predictive of patients' outcomes at six months post injury.

 
Among patients with Alzheimer's disease, lifelong bilingualism correlates with functional modulations in crucial neural networks, suggesting neural reserve and compensatory mechanisms, according to a study published online ahead of print January 30 in the Proceedings of the National Academy of Sciences. Eighty-five patients with Alzheimer's disease (45 German-Italian bilingual speakers and 40 monolingual speakers) matched for disease duration were included in this study. Bilingual individuals were on average five years older than people who did not speak another language. Consistent with models of cognitive reserve, cerebral hypometabolism was more severe in the group of bilingual individuals with Alzheimer's disease. Metabolic connectivity analyses supported a neuroprotective effect of bilingualism by showing increased connectivity in the executive control and the default mode networks in bilingual patients, compared with monolingual patients.

 
The Huntington's Disease Society of America (HDSA), in conjunction with the FDA, conducted two surveys to gather the perspectives of patients with Huntington's disease and juvenile Huntington's disease and their caregivers. Findings from the surveys were published online ahead of print January 24 in the Journal of Huntington's Disease. One survey covered disease symptoms that matter most to people with Huntington's disease, and the other covered current approaches to treatment. The surveys received a total of 3,631 responses. "The frequency and impact of symptoms appear to be felt more by caregivers than individuals with Huntington's Disease, especially when it comes to loss of abilities," said lead investigator George J. Yohrling, PhD, Senior Director of Mission and Scientific Affairs for the HDSA. "There was also a large difference in the perception of symptom frequency between caregivers and individuals with Huntington's disease."

 
Intentional and unintentional head impacts are independently associated with moderate to severe CNS symptoms in adult amateur soccer players, according to a study published online ahead of print February 1 in Neurology. Soccer players completed an online questionnaire about how often they played soccer during the previous two weeks, how many times they had unintentional head impacts, how many times they headed the ball, and the frequency and severity of CNS symptoms. A total of 222 players completed 470 questionnaires. Heading-related symptoms were reported in 20% of the questionnaires. Heading in the highest quartile was significantly associated with CNS symptoms when controlling for unintentional head impacts. People with unintentional head impacts were at increased risk for CNS symptoms when controlling for heading.

 
Meditation or music listening may significantly enhance subjective memory function and objective cognitive performance in adults with subjective cognitive decline, according to a study published February 3 in the Journal of Alzheimer's Disease. A total of 60 participants with subjective cognitive decline were randomized to a Kirtan Kriya meditation program or a music listening program. The researchers asked participants to practice 12 minutes each day for three months, then at their discretion for the ensuing three months. At baseline, three months, and six months, researchers measured memory and cognitive functioning. Fifty-three participants completed the study. Both groups showed marked and significant improvements at three months in memory and cognitive performance. At six months, overall gains were maintained or improved, with effect sizes ranging from medium to large.

 
Yoga and aerobic exercise interventions do not significantly reduce objectively measured sleep disturbances among midlife women who are experiencing hot flashes, according to a study published January 15 in the Journal of Clinical Sleep Medicine. Researchers conducted secondary analyses of a randomized controlled trial in the Menopause Strategies: Finding Lasting Answers for Symptoms and Health network. In the trial, 186 late transition and postmenopausal women ages 40 to 62 with hot flashes were randomized to 12 weeks of yoga, supervised aerobic exercise, or usual activity. Changes in the actigraphic sleep outcomes from baseline to weeks 11 to 12 were small and did not differ between groups. An exploratory analysis suggested that women with poor self-reported sleep quality at baseline potentially had improved sleep stability following yoga.

 
Longitudinal data provide strong evidence of cognitive aging in midlife women, with substantial within-woman declines in processing speed and memory, according to a study published January 3 in PLoS One. Researchers used data from 2,124 participants from the Study of Women's Health Across the Nation. Participants completed annual tests of processing speed, verbal episodic memory, and working memory. Average age at baseline was 54. There were 7,185 cognitive assessments with a median follow-up time of 6.5 years. In mixed effects regression, adjusted for practice effects, retention, menopause symptoms, and covariates, scores on two of four cognition tests declined. Mean decline in cognitive speed was 0.28 per year or 4.9% in 10 years, and mean decline in verbal episodic memory (delayed testing) was 0.02 per year or 2% in 10 years.  

 
The FDA has approved Emflaza (deflazacort) for the treatment of Duchenne muscular dystrophy in patients age 5 and older. The corticosteroid is available in an immediate-release tablet formulation (6 mg, 18 mg, 30 mg, and 36 mg) as well as an oral suspension formulation (22.75 mg/mL). In a multicenter, randomized, double-blind, placebo-controlled study of 196 male pediatric patients, patients who received deflazacort had improved muscle strength at 12 weeks, compared with patients who received placebo. Through the 52-week study, an overall stability in average muscle strength was maintained in patients who received deflazacort. Results on several timed measures of patient function (eg, time to stand from supine, time to climb four stairs, and time to walk or run 30 feet) also numerically favored deflazacort 0.9 mg/kg/day at week 12. Marathon Pharmaceuticals, headquartered in Northbrook, Illinois, markets Emflaza.

—Kimberly Williams

Nearly half of patients in the general population who test positive for hepatitis C virus (HCV) do not have the disease, according to Dr. Anne Moorman and her associates.

From a sample of 22,359 National Health and Nutrition Examination Study participants, 479 people received positive HCV antibody test results from 2007 to 2012. Of this group, 477 participants underwent further follow-up testing using a recombinant immunoblot assay. RIBA testing confirmed positive test results for 323 participants, while 105 patients received negative test results and 49 received indeterminate test results.

Jarun011/Thinkstock

[email protected]

Nearly half of patients in the general population who test positive for hepatitis C virus (HCV) do not have the disease, according to Dr. Anne Moorman and her associates.

From a sample of 22,359 National Health and Nutrition Examination Study participants, 479 people received positive HCV antibody test results from 2007 to 2012. Of this group, 477 participants underwent further follow-up testing using a recombinant immunoblot assay. RIBA testing confirmed positive test results for 323 participants, while 105 patients received negative test results and 49 received indeterminate test results.

Jarun011/Thinkstock

[email protected]

Nearly half of patients in the general population who test positive for hepatitis C virus (HCV) do not have the disease, according to Dr. Anne Moorman and her associates.

From a sample of 22,359 National Health and Nutrition Examination Study participants, 479 people received positive HCV antibody test results from 2007 to 2012. Of this group, 477 participants underwent further follow-up testing using a recombinant immunoblot assay. RIBA testing confirmed positive test results for 323 participants, while 105 patients received negative test results and 49 received indeterminate test results.

Jarun011/Thinkstock

[email protected]

In extensive new clinical practice guidelines, the Endocrine Society and two others offer updated recommendations about the treatment of pediatric obesity. Among other things, the guidelines offer new insight into the role of genetics in childhood obesity, provide more extensive guidance regarding bariatric surgery in adolescents, and suggest that measurements of insulin concentrations aren’t useful barometers.

The guidelines also point to research gaps in several areas and call for more studies.

Why issue new guidelines now? “Eight years have passed since the last publication. We did a very thorough job, but there’s been an incredible amount of interest in child obesity, and more information is available,” lead author Dennis M. Styne, MD, professor of pediatrics and the Yocha Dehe endowed chair in pediatric endocrinology at the University of California at Davis, said in an interview. Indeed, recent years have produced hundreds of studies into pediatric obesity, he noted.

The 49-page guidelines are cosponsored by the European Society of Endocrinology and the Pediatric Endocrine Society (J Clin Endocrinol Metab. 2017 March;102[3]:1-49).

Pediatric obesity is of special interest to endocrinologists, Dr. Styne said. “While there’s interest from many specialists now, we are at the forefront of evaluation and treatment of complications like polycystic ovary syndrome, metabolic syndrome, dyslipidemia, and type 2 diabetes.”

The guidelines provide recommendations about a wide variety of obesity-related topics including screening, diagnosis, and treatment. The Endocrine Society commissioned two systematic reviews to support the guidelines: One examined longer randomized controlled trials into medication, surgery, lifestyle, and community-based intervention treatments. The other examined how changing body mass index levels corresponded to cardiometabolic changes.

Several updated areas in the guidelines should be of special interest to endocrinologists: guidance regarding the genetic causes of pediatric obesity, the use of weight-loss medication and surgery, and the roles of insulin tests and breast-feeding, according to Dr. Styne.

In regard to genetics, the guidelines note that research suggests 7% of patients with extreme pediatric obesity “may have rare chromosomal abnormalities and/or highly penetrant genetic mutations that drive their obesity. This percentage is likely to increase with newer methods for genetic testing.”

Dr. Styne calls this finding “remarkable.” As he put it, “we didn’t appreciate that so much in the past.”

The guidelines suggest genetic testing for patients who become obese before the age of 5 years, have a family history of extreme obesity, or show clinical signs of genetic obesity syndromes, especially extreme hyperphagia.

As for the most extreme treatments for the most obese children, the guidelines recommend against weight-loss medication outside of clinical trials and note that “increasing evidence” supports bariatric surgery in teens who haven’t been able to lose enough pounds through lifestyle modification. However, “the use of surgery requires experienced teams with resources for long-term follow-up.”

The guidelines also recommend against measuring serum insulin concentrations as part of pediatric screening for obesity. “A lot of people like to get insulin levels and think it tells them about the future of the child,” Dr. Styne said. “But it doesn’t work very well.”

In another area that reflects new information, the guidelines note that breast-feeding hasn’t been definitively shown to be effective in reducing childhood obesity. “The literature is contradictory,” Dr. Styne said, although he noted that breast-feeding still has many other benefits.

The guidelines point to research gaps in several areas, including the prevention and treatment of pediatric obesity. There’s also “uncharted territory” regarding how to “effectively transition to adult care, with continued necessary monitoring, support, and intervention.”

In regard to the best treatment programs, “we didn’t come up with an answer regarding overall effectiveness,” Dr. Styne said. “School- and community-based programs have promise, but I can’t give you the percentage of success.”

As for the overall picture of pediatric obesity in the United States, “we’re in a better situation than we were 8 years ago,” he said. “Everyone is talking about the problem, and when you talk to families, they’re more aware of it.”

Still, he said, the prevalence of obesity in kids is high, estimated at 17% of those aged 2-19 years in 2014. “That’s not a good place to be,” he said. “We still have to work harder.”

The Endocrine Society funded the guidelines. Dr. Styne reports ownership interests in Teva, Bristol Myers and Organovo. Other authors report various disclosures.

In extensive new clinical practice guidelines, the Endocrine Society and two others offer updated recommendations about the treatment of pediatric obesity. Among other things, the guidelines offer new insight into the role of genetics in childhood obesity, provide more extensive guidance regarding bariatric surgery in adolescents, and suggest that measurements of insulin concentrations aren’t useful barometers.

The guidelines also point to research gaps in several areas and call for more studies.

Why issue new guidelines now? “Eight years have passed since the last publication. We did a very thorough job, but there’s been an incredible amount of interest in child obesity, and more information is available,” lead author Dennis M. Styne, MD, professor of pediatrics and the Yocha Dehe endowed chair in pediatric endocrinology at the University of California at Davis, said in an interview. Indeed, recent years have produced hundreds of studies into pediatric obesity, he noted.

The 49-page guidelines are cosponsored by the European Society of Endocrinology and the Pediatric Endocrine Society (J Clin Endocrinol Metab. 2017 March;102[3]:1-49).

Pediatric obesity is of special interest to endocrinologists, Dr. Styne said. “While there’s interest from many specialists now, we are at the forefront of evaluation and treatment of complications like polycystic ovary syndrome, metabolic syndrome, dyslipidemia, and type 2 diabetes.”

The guidelines provide recommendations about a wide variety of obesity-related topics including screening, diagnosis, and treatment. The Endocrine Society commissioned two systematic reviews to support the guidelines: One examined longer randomized controlled trials into medication, surgery, lifestyle, and community-based intervention treatments. The other examined how changing body mass index levels corresponded to cardiometabolic changes.

Several updated areas in the guidelines should be of special interest to endocrinologists: guidance regarding the genetic causes of pediatric obesity, the use of weight-loss medication and surgery, and the roles of insulin tests and breast-feeding, according to Dr. Styne.

In regard to genetics, the guidelines note that research suggests 7% of patients with extreme pediatric obesity “may have rare chromosomal abnormalities and/or highly penetrant genetic mutations that drive their obesity. This percentage is likely to increase with newer methods for genetic testing.”

Dr. Styne calls this finding “remarkable.” As he put it, “we didn’t appreciate that so much in the past.”

The guidelines suggest genetic testing for patients who become obese before the age of 5 years, have a family history of extreme obesity, or show clinical signs of genetic obesity syndromes, especially extreme hyperphagia.

As for the most extreme treatments for the most obese children, the guidelines recommend against weight-loss medication outside of clinical trials and note that “increasing evidence” supports bariatric surgery in teens who haven’t been able to lose enough pounds through lifestyle modification. However, “the use of surgery requires experienced teams with resources for long-term follow-up.”

The guidelines also recommend against measuring serum insulin concentrations as part of pediatric screening for obesity. “A lot of people like to get insulin levels and think it tells them about the future of the child,” Dr. Styne said. “But it doesn’t work very well.”

In another area that reflects new information, the guidelines note that breast-feeding hasn’t been definitively shown to be effective in reducing childhood obesity. “The literature is contradictory,” Dr. Styne said, although he noted that breast-feeding still has many other benefits.

The guidelines point to research gaps in several areas, including the prevention and treatment of pediatric obesity. There’s also “uncharted territory” regarding how to “effectively transition to adult care, with continued necessary monitoring, support, and intervention.”

In regard to the best treatment programs, “we didn’t come up with an answer regarding overall effectiveness,” Dr. Styne said. “School- and community-based programs have promise, but I can’t give you the percentage of success.”

As for the overall picture of pediatric obesity in the United States, “we’re in a better situation than we were 8 years ago,” he said. “Everyone is talking about the problem, and when you talk to families, they’re more aware of it.”

Still, he said, the prevalence of obesity in kids is high, estimated at 17% of those aged 2-19 years in 2014. “That’s not a good place to be,” he said. “We still have to work harder.”

The Endocrine Society funded the guidelines. Dr. Styne reports ownership interests in Teva, Bristol Myers and Organovo. Other authors report various disclosures.

In extensive new clinical practice guidelines, the Endocrine Society and two others offer updated recommendations about the treatment of pediatric obesity. Among other things, the guidelines offer new insight into the role of genetics in childhood obesity, provide more extensive guidance regarding bariatric surgery in adolescents, and suggest that measurements of insulin concentrations aren’t useful barometers.

The guidelines also point to research gaps in several areas and call for more studies.

Why issue new guidelines now? “Eight years have passed since the last publication. We did a very thorough job, but there’s been an incredible amount of interest in child obesity, and more information is available,” lead author Dennis M. Styne, MD, professor of pediatrics and the Yocha Dehe endowed chair in pediatric endocrinology at the University of California at Davis, said in an interview. Indeed, recent years have produced hundreds of studies into pediatric obesity, he noted.

The 49-page guidelines are cosponsored by the European Society of Endocrinology and the Pediatric Endocrine Society (J Clin Endocrinol Metab. 2017 March;102[3]:1-49).

Pediatric obesity is of special interest to endocrinologists, Dr. Styne said. “While there’s interest from many specialists now, we are at the forefront of evaluation and treatment of complications like polycystic ovary syndrome, metabolic syndrome, dyslipidemia, and type 2 diabetes.”

The guidelines provide recommendations about a wide variety of obesity-related topics including screening, diagnosis, and treatment. The Endocrine Society commissioned two systematic reviews to support the guidelines: One examined longer randomized controlled trials into medication, surgery, lifestyle, and community-based intervention treatments. The other examined how changing body mass index levels corresponded to cardiometabolic changes.

Several updated areas in the guidelines should be of special interest to endocrinologists: guidance regarding the genetic causes of pediatric obesity, the use of weight-loss medication and surgery, and the roles of insulin tests and breast-feeding, according to Dr. Styne.

In regard to genetics, the guidelines note that research suggests 7% of patients with extreme pediatric obesity “may have rare chromosomal abnormalities and/or highly penetrant genetic mutations that drive their obesity. This percentage is likely to increase with newer methods for genetic testing.”

Dr. Styne calls this finding “remarkable.” As he put it, “we didn’t appreciate that so much in the past.”

The guidelines suggest genetic testing for patients who become obese before the age of 5 years, have a family history of extreme obesity, or show clinical signs of genetic obesity syndromes, especially extreme hyperphagia.

As for the most extreme treatments for the most obese children, the guidelines recommend against weight-loss medication outside of clinical trials and note that “increasing evidence” supports bariatric surgery in teens who haven’t been able to lose enough pounds through lifestyle modification. However, “the use of surgery requires experienced teams with resources for long-term follow-up.”

The guidelines also recommend against measuring serum insulin concentrations as part of pediatric screening for obesity. “A lot of people like to get insulin levels and think it tells them about the future of the child,” Dr. Styne said. “But it doesn’t work very well.”

In another area that reflects new information, the guidelines note that breast-feeding hasn’t been definitively shown to be effective in reducing childhood obesity. “The literature is contradictory,” Dr. Styne said, although he noted that breast-feeding still has many other benefits.

The guidelines point to research gaps in several areas, including the prevention and treatment of pediatric obesity. There’s also “uncharted territory” regarding how to “effectively transition to adult care, with continued necessary monitoring, support, and intervention.”

In regard to the best treatment programs, “we didn’t come up with an answer regarding overall effectiveness,” Dr. Styne said. “School- and community-based programs have promise, but I can’t give you the percentage of success.”

As for the overall picture of pediatric obesity in the United States, “we’re in a better situation than we were 8 years ago,” he said. “Everyone is talking about the problem, and when you talk to families, they’re more aware of it.”

Still, he said, the prevalence of obesity in kids is high, estimated at 17% of those aged 2-19 years in 2014. “That’s not a good place to be,” he said. “We still have to work harder.”

The Endocrine Society funded the guidelines. Dr. Styne reports ownership interests in Teva, Bristol Myers and Organovo. Other authors report various disclosures.

HOLLYWOOD, FLA. – A three-parameter scoring system predicts which patients are likely to experience complications from surgery for a small bowel obstruction.

The new tool – dubbed FAS (Functional status, American Society of Anesthesiologists [ASA] classification, and Sepsis) – focuses mostly on preoperative functional status and the presence of preoperative sepsis. It’s as accurate as a time-consuming 10-item Margenthaler system published in 2006, which requires data on blood chemistry, neurologic status, and cardiac and lung function as well as age, sepsis, and preoperative functional measures.

Michele G. Sullivan/Frontline Medical News

• History of congestive heart failure

• Neurological deficit or stroke

• Chronic obstructive pulmonary disease

• Elevated white cell count

• Preoperative functional health status

• Surgery type

• Preoperative creatinine

• Wound classification

• ASA class

• Age

Dr. Asuzu and his mentor, Kevin Y. Pei, MD, FACS, wanted to come up with a more user-friendly risk assessment tool for patients undergoing open small bowel adhesiolysis. They focused on two measures of preoperative functional status: dependent vs. independent and ASA classification. Another measure – preoperative sepsis – estimated the impact of the patient’s current medical problem.

The tool was tested retrospectively in two independent cohorts extracted from the ACS National Surgery Quality Improvement Project (NSQIP) database. The initial discovery cohort comprised 6,036 patients; the replication cohort, 9,000. These patients had a mean age of 60 years and were relatively healthy, with low rates of congestive obstructive pulmonary disease, renal failure, cancer, bleeding disorders, and ascites. About half were taking antihypertensive medications and 5%, steroids.

Using multivariable regression, the authors developed a scoring system as follows:

• 6 points for each level of preoperative functional status (1 – independent, 2 – partially dependent, 3 – totally dependent)

• 6 points for each level of ASA classification (1 – no disturbance, 2 – mild disturbance, 3 – severe disturbance, 4 – life-threatening disturbance, and 5 – moribund state)

• 4 points for each level of perioperative sepsis (1 – systemic inflammatory response syndrome [SIRS], 2 – sepsis, 3 – septic shock)

In the discovery cohort, the three-item FAS tool was just as accurate as the Margenthaler tool, with an odds ratio of 1.11 vs 1.10 for any complication. The areas under the curve were 0.69 vs. 0.68. These results were virtually identical in the replication cohort.

With a combined total score of 32 as the cutoff, FAS yielded a specificity of 93% for predicting any complication and 92% for any of the six most common complications (ventilator dependence greater than 48 hours, pneumonia, superficial surgical site infection, postoperative sepsis, urinary tract infection, or unplanned intubation) in the replication cohort. The positive predictive value was 50% for any complication and 45% for the six most common complications, and the negative predictive values were 81% and nearly 85%, respectively.

“We are very pleased with how this performs,” Dr. Asuzu said in an interview. “It’s apparent that these three parameters are sufficient to tell us with a high level of specificity which patients could benefit from a more conservative approach. The next step is to prospectively validate it in a single center dataset.”

He said discriminating the most meaningful risk factors plainly showed that preoperative physical status is the best indicator of how well a patient will handle the surgery.

“It turns out that the biggest predictor of you how do after surgery is how you are doing before surgery. We can look at it as the how big the hit is, and the patient’s ability to take that hit. If their ability is already compromised, it’s a sign they might not do well.”

The “functional status” parameter may seem overly simplistic at first glance, he said. “But it really takes into account everything: the gout, the hypertension, the smoking, heart and respiratory and kidney function. All of this plays a role in functional status. I think this is why some of these more complex scores suffer. They’re not clear because there is so much overlap there.”

Dr. Asuzu had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

HOLLYWOOD, FLA. – A three-parameter scoring system predicts which patients are likely to experience complications from surgery for a small bowel obstruction.

The new tool – dubbed FAS (Functional status, American Society of Anesthesiologists [ASA] classification, and Sepsis) – focuses mostly on preoperative functional status and the presence of preoperative sepsis. It’s as accurate as a time-consuming 10-item Margenthaler system published in 2006, which requires data on blood chemistry, neurologic status, and cardiac and lung function as well as age, sepsis, and preoperative functional measures.

Michele G. Sullivan/Frontline Medical News

• History of congestive heart failure

• Neurological deficit or stroke

• Chronic obstructive pulmonary disease

• Elevated white cell count

• Preoperative functional health status

• Surgery type

• Preoperative creatinine

• Wound classification

• ASA class

• Age

Dr. Asuzu and his mentor, Kevin Y. Pei, MD, FACS, wanted to come up with a more user-friendly risk assessment tool for patients undergoing open small bowel adhesiolysis. They focused on two measures of preoperative functional status: dependent vs. independent and ASA classification. Another measure – preoperative sepsis – estimated the impact of the patient’s current medical problem.

The tool was tested retrospectively in two independent cohorts extracted from the ACS National Surgery Quality Improvement Project (NSQIP) database. The initial discovery cohort comprised 6,036 patients; the replication cohort, 9,000. These patients had a mean age of 60 years and were relatively healthy, with low rates of congestive obstructive pulmonary disease, renal failure, cancer, bleeding disorders, and ascites. About half were taking antihypertensive medications and 5%, steroids.

Using multivariable regression, the authors developed a scoring system as follows:

• 6 points for each level of preoperative functional status (1 – independent, 2 – partially dependent, 3 – totally dependent)

• 6 points for each level of ASA classification (1 – no disturbance, 2 – mild disturbance, 3 – severe disturbance, 4 – life-threatening disturbance, and 5 – moribund state)

• 4 points for each level of perioperative sepsis (1 – systemic inflammatory response syndrome [SIRS], 2 – sepsis, 3 – septic shock)

In the discovery cohort, the three-item FAS tool was just as accurate as the Margenthaler tool, with an odds ratio of 1.11 vs 1.10 for any complication. The areas under the curve were 0.69 vs. 0.68. These results were virtually identical in the replication cohort.

With a combined total score of 32 as the cutoff, FAS yielded a specificity of 93% for predicting any complication and 92% for any of the six most common complications (ventilator dependence greater than 48 hours, pneumonia, superficial surgical site infection, postoperative sepsis, urinary tract infection, or unplanned intubation) in the replication cohort. The positive predictive value was 50% for any complication and 45% for the six most common complications, and the negative predictive values were 81% and nearly 85%, respectively.

“We are very pleased with how this performs,” Dr. Asuzu said in an interview. “It’s apparent that these three parameters are sufficient to tell us with a high level of specificity which patients could benefit from a more conservative approach. The next step is to prospectively validate it in a single center dataset.”

He said discriminating the most meaningful risk factors plainly showed that preoperative physical status is the best indicator of how well a patient will handle the surgery.

“It turns out that the biggest predictor of you how do after surgery is how you are doing before surgery. We can look at it as the how big the hit is, and the patient’s ability to take that hit. If their ability is already compromised, it’s a sign they might not do well.”

The “functional status” parameter may seem overly simplistic at first glance, he said. “But it really takes into account everything: the gout, the hypertension, the smoking, heart and respiratory and kidney function. All of this plays a role in functional status. I think this is why some of these more complex scores suffer. They’re not clear because there is so much overlap there.”

Dr. Asuzu had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

HOLLYWOOD, FLA. – A three-parameter scoring system predicts which patients are likely to experience complications from surgery for a small bowel obstruction.

The new tool – dubbed FAS (Functional status, American Society of Anesthesiologists [ASA] classification, and Sepsis) – focuses mostly on preoperative functional status and the presence of preoperative sepsis. It’s as accurate as a time-consuming 10-item Margenthaler system published in 2006, which requires data on blood chemistry, neurologic status, and cardiac and lung function as well as age, sepsis, and preoperative functional measures.

Michele G. Sullivan/Frontline Medical News

• History of congestive heart failure

• Neurological deficit or stroke

• Chronic obstructive pulmonary disease

• Elevated white cell count

• Preoperative functional health status

• Surgery type

• Preoperative creatinine

• Wound classification

• ASA class

• Age

Dr. Asuzu and his mentor, Kevin Y. Pei, MD, FACS, wanted to come up with a more user-friendly risk assessment tool for patients undergoing open small bowel adhesiolysis. They focused on two measures of preoperative functional status: dependent vs. independent and ASA classification. Another measure – preoperative sepsis – estimated the impact of the patient’s current medical problem.

The tool was tested retrospectively in two independent cohorts extracted from the ACS National Surgery Quality Improvement Project (NSQIP) database. The initial discovery cohort comprised 6,036 patients; the replication cohort, 9,000. These patients had a mean age of 60 years and were relatively healthy, with low rates of congestive obstructive pulmonary disease, renal failure, cancer, bleeding disorders, and ascites. About half were taking antihypertensive medications and 5%, steroids.

Using multivariable regression, the authors developed a scoring system as follows:

• 6 points for each level of preoperative functional status (1 – independent, 2 – partially dependent, 3 – totally dependent)

• 6 points for each level of ASA classification (1 – no disturbance, 2 – mild disturbance, 3 – severe disturbance, 4 – life-threatening disturbance, and 5 – moribund state)

• 4 points for each level of perioperative sepsis (1 – systemic inflammatory response syndrome [SIRS], 2 – sepsis, 3 – septic shock)

In the discovery cohort, the three-item FAS tool was just as accurate as the Margenthaler tool, with an odds ratio of 1.11 vs 1.10 for any complication. The areas under the curve were 0.69 vs. 0.68. These results were virtually identical in the replication cohort.

With a combined total score of 32 as the cutoff, FAS yielded a specificity of 93% for predicting any complication and 92% for any of the six most common complications (ventilator dependence greater than 48 hours, pneumonia, superficial surgical site infection, postoperative sepsis, urinary tract infection, or unplanned intubation) in the replication cohort. The positive predictive value was 50% for any complication and 45% for the six most common complications, and the negative predictive values were 81% and nearly 85%, respectively.

“We are very pleased with how this performs,” Dr. Asuzu said in an interview. “It’s apparent that these three parameters are sufficient to tell us with a high level of specificity which patients could benefit from a more conservative approach. The next step is to prospectively validate it in a single center dataset.”

He said discriminating the most meaningful risk factors plainly showed that preoperative physical status is the best indicator of how well a patient will handle the surgery.

“It turns out that the biggest predictor of you how do after surgery is how you are doing before surgery. We can look at it as the how big the hit is, and the patient’s ability to take that hit. If their ability is already compromised, it’s a sign they might not do well.”

The “functional status” parameter may seem overly simplistic at first glance, he said. “But it really takes into account everything: the gout, the hypertension, the smoking, heart and respiratory and kidney function. All of this plays a role in functional status. I think this is why some of these more complex scores suffer. They’re not clear because there is so much overlap there.”

Dr. Asuzu had no financial disclosures.

[email protected]

On Twitter @Alz_Gal

AMSTERDAM – Incretin-based antidiabetic drugs do not appear to increase risk for pancreatic cancer, but the acute need for these drugs because of rapid worsening of type 2 diabetes may be a marker for early, occult pancreatic adenocarcinoma, investigators cautioned.

Results of a study of nearly 825,000 patients with type 2 diabetes in Belgium and northern Italy showed that patients who required a first-time prescription for an incretin-based antidiabetic drug had a 3.5-fold greater risk of being diagnosed with pancreatic cancer within 3 months, compared with patients who could be safely maintained on an oral noninsulin, nonincretin antidiabetic drug (NIAD), reported Alice Koechlin of the International Prevention Research Institute in Lyon, France, on behalf of coauthor Phillipe Autier, MD, also of the institute.

[email protected]

AMSTERDAM – Incretin-based antidiabetic drugs do not appear to increase risk for pancreatic cancer, but the acute need for these drugs because of rapid worsening of type 2 diabetes may be a marker for early, occult pancreatic adenocarcinoma, investigators cautioned.

Results of a study of nearly 825,000 patients with type 2 diabetes in Belgium and northern Italy showed that patients who required a first-time prescription for an incretin-based antidiabetic drug had a 3.5-fold greater risk of being diagnosed with pancreatic cancer within 3 months, compared with patients who could be safely maintained on an oral noninsulin, nonincretin antidiabetic drug (NIAD), reported Alice Koechlin of the International Prevention Research Institute in Lyon, France, on behalf of coauthor Phillipe Autier, MD, also of the institute.

[email protected]

AMSTERDAM – Incretin-based antidiabetic drugs do not appear to increase risk for pancreatic cancer, but the acute need for these drugs because of rapid worsening of type 2 diabetes may be a marker for early, occult pancreatic adenocarcinoma, investigators cautioned.

Results of a study of nearly 825,000 patients with type 2 diabetes in Belgium and northern Italy showed that patients who required a first-time prescription for an incretin-based antidiabetic drug had a 3.5-fold greater risk of being diagnosed with pancreatic cancer within 3 months, compared with patients who could be safely maintained on an oral noninsulin, nonincretin antidiabetic drug (NIAD), reported Alice Koechlin of the International Prevention Research Institute in Lyon, France, on behalf of coauthor Phillipe Autier, MD, also of the institute.

[email protected]

Updated guidelines for the diagnosis and treatment of cystic fibrosis (CF) include two major changes.

The first important update is that clinicians use the latest classifications of the specific CF transmembrane conductance regulator (CFTR) gene mutations, from the Clinical and Functional TRanslation of CFTR (CFTR2) database, to aid with making a CF diagnosis in any patient, newborn to adult. The other of these changes relates to the chloride concentration level used to confirm CF diagnosis through a sweat test. Under the new guidelines, the sweat chloride threshold for “possible” CF or a CF-related disease was reduced to 30 mmol/L of chloride concentration from 40 mmol/L across all ages. The guidelines, written by an international team of collaborators and published by the Cystic Fibrosis Foundation, are available online in the Journal of Pediatrics (J Pediatr 2017 Feb;181(suppl):S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064).

Since its inception in 2008, the CFTR2 project has described 300 of the 2,000 known CF-related mutations and their various functional and clinical impacts. The project involves amassing phenotypic and genotypic information from patient registries to collect, quantify, and describe mutations reported in individuals with CF. Such mutations are categorized as CF-causing, carrying a variety of potential clinical consequences, non–cystic fibrosis causing, or unknown. The previous guidelines, written in 2008, relied on a 23-mutation panel from the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists.

“We’ve more precisely defined what cystic fibrosis is,” Patrick R. Sosnay, MD, assistant professor of medicine at Johns Hopkins University, Baltimore, and coauthor of the guidelines, said in a statement. “The stakes in categorizing a mutation are particularly high. For example, claiming that a mutation 100% causes cystic fibrosis may affect people’s reproductive decisions if they believe their child will have the mutation.”

In the CFTR2 project, the “disease-liability” of each mutation is evaluated through a combination of sweat chloride and functional activity identified in cell-based systems, according to a supplement published simultaneously with the updated guidelines (J Pediatr 2017 Feb;181(suppl):S52-S57.e2. doi: 10.1016/j.jpeds.2016.09.068). Data from this project led to the discovery of a cohort of 746 persons diagnosed with CF despite sweat chloride levels less than 60 mmol/L. These findings were the basis for the guideline authors’ decision to lower the threshold of chloride concentration in sweat in order for an individual to be considered having a possible CF diagnosis, according to the supplement.

The guidelines include 27 approved consensus statements spanning four overlapping categories, and applying to screened and nonscreened populations; newborn screened populations and fetuses undergoing prenatal testing; infants with an uncertain diagnosis and designated as having either CFTR gene-related metabolic syndrome or being CF-screen positive, inconclusive diagnosis; and nonscreened patients who present with symptoms, including children before newborn screening implementation, those with false negative tests and older, nonscreened patients.

Although not specified in the consensus statements, the authors of a second supplement published simultaneously with the updated guidelines (J Pediatr 2017;181(suppl):S27-S32.e1. doi: 10.1016/j.jpeds.2016.09.063), wrote that they supported genotyping all individuals diagnosed with CF, even if physiologic tests establish the diagnosis, to better understand the disease’s genetic epidemiology and to refine future therapies. “If the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help,” this supplement’s authors concluded.

The updated guideline authors recommend avoiding the use of terms such as “atypical” or “nonclassical” CF, as there is no consensus on the specific taxonomy of CF, since the genetic data are still emerging.

When administering a newborn test, the guidelines warn that the heterogenous nature of newborn screening often leads to false positive results, thus the need for the sweat test. Although obtaining an adequate sweat specimen for chloride measurements can be difficult, the authors say it is possible, especially in full-term infants aged 1 month. Repeat sweat testing is recommended, as is nasal potential difference (NPD) and intestinal current measurement (ICM) in some cases.

Another change to the guidelines is that newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may now be designated as having CFTR-related metabolic syndrome/CF screen positive inconclusive diagnosis (CRMS/CFSPID), instead of CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis. Regarding changes to screening for CRMS/CFSPID, the older guidelines called for such an assessment by age 2 months, repeated every 6-12 months, while the new guidelines say their recommendation on the duration and frequency of follow-up “remains to be determined.”

The authors of the first supplement decry the lack of standardized CF diagnostic criteria for those diagnosed with CF outside of the neonatal period, and urge clinicians to rely on clinical evidence including organ pathologies typical in CF, such as bronchiectasis or pancreatic insufficiency, along with testing for the presence of CFTR dysfunction with sweat chloride testing, CFTR molecular genetic analysis, or CFTR physiologic tests.

In contrast, the second supplement states that “clinical suspicion should always take precedence” in making a CF diagnoses for individuals in this age group.

Dr. Sosnay and Philip M. Farrell, MD, PhD, a coauthor of the guidelines, received funds from the Cystic Fibrosis Foundation, where guideline coauthor Terry B. White, PhD, is an employee. Kris De Boeck, MD, a coauthor of the first supplement, receives funding from Vertex Pharmaceuticals, Ablynx, Aptalis, Galapagos, Gilead, Pharmaxis, and PTC Therapeutics. The guideline and supplements’ other authors have no disclosures.

[email protected]

On Twitter @whitneymcknight

Updated guidelines for the diagnosis and treatment of cystic fibrosis (CF) include two major changes.

The first important update is that clinicians use the latest classifications of the specific CF transmembrane conductance regulator (CFTR) gene mutations, from the Clinical and Functional TRanslation of CFTR (CFTR2) database, to aid with making a CF diagnosis in any patient, newborn to adult. The other of these changes relates to the chloride concentration level used to confirm CF diagnosis through a sweat test. Under the new guidelines, the sweat chloride threshold for “possible” CF or a CF-related disease was reduced to 30 mmol/L of chloride concentration from 40 mmol/L across all ages. The guidelines, written by an international team of collaborators and published by the Cystic Fibrosis Foundation, are available online in the Journal of Pediatrics (J Pediatr 2017 Feb;181(suppl):S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064).

Since its inception in 2008, the CFTR2 project has described 300 of the 2,000 known CF-related mutations and their various functional and clinical impacts. The project involves amassing phenotypic and genotypic information from patient registries to collect, quantify, and describe mutations reported in individuals with CF. Such mutations are categorized as CF-causing, carrying a variety of potential clinical consequences, non–cystic fibrosis causing, or unknown. The previous guidelines, written in 2008, relied on a 23-mutation panel from the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists.

“We’ve more precisely defined what cystic fibrosis is,” Patrick R. Sosnay, MD, assistant professor of medicine at Johns Hopkins University, Baltimore, and coauthor of the guidelines, said in a statement. “The stakes in categorizing a mutation are particularly high. For example, claiming that a mutation 100% causes cystic fibrosis may affect people’s reproductive decisions if they believe their child will have the mutation.”

In the CFTR2 project, the “disease-liability” of each mutation is evaluated through a combination of sweat chloride and functional activity identified in cell-based systems, according to a supplement published simultaneously with the updated guidelines (J Pediatr 2017 Feb;181(suppl):S52-S57.e2. doi: 10.1016/j.jpeds.2016.09.068). Data from this project led to the discovery of a cohort of 746 persons diagnosed with CF despite sweat chloride levels less than 60 mmol/L. These findings were the basis for the guideline authors’ decision to lower the threshold of chloride concentration in sweat in order for an individual to be considered having a possible CF diagnosis, according to the supplement.

The guidelines include 27 approved consensus statements spanning four overlapping categories, and applying to screened and nonscreened populations; newborn screened populations and fetuses undergoing prenatal testing; infants with an uncertain diagnosis and designated as having either CFTR gene-related metabolic syndrome or being CF-screen positive, inconclusive diagnosis; and nonscreened patients who present with symptoms, including children before newborn screening implementation, those with false negative tests and older, nonscreened patients.

Although not specified in the consensus statements, the authors of a second supplement published simultaneously with the updated guidelines (J Pediatr 2017;181(suppl):S27-S32.e1. doi: 10.1016/j.jpeds.2016.09.063), wrote that they supported genotyping all individuals diagnosed with CF, even if physiologic tests establish the diagnosis, to better understand the disease’s genetic epidemiology and to refine future therapies. “If the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help,” this supplement’s authors concluded.

The updated guideline authors recommend avoiding the use of terms such as “atypical” or “nonclassical” CF, as there is no consensus on the specific taxonomy of CF, since the genetic data are still emerging.

When administering a newborn test, the guidelines warn that the heterogenous nature of newborn screening often leads to false positive results, thus the need for the sweat test. Although obtaining an adequate sweat specimen for chloride measurements can be difficult, the authors say it is possible, especially in full-term infants aged 1 month. Repeat sweat testing is recommended, as is nasal potential difference (NPD) and intestinal current measurement (ICM) in some cases.

Another change to the guidelines is that newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may now be designated as having CFTR-related metabolic syndrome/CF screen positive inconclusive diagnosis (CRMS/CFSPID), instead of CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis. Regarding changes to screening for CRMS/CFSPID, the older guidelines called for such an assessment by age 2 months, repeated every 6-12 months, while the new guidelines say their recommendation on the duration and frequency of follow-up “remains to be determined.”

The authors of the first supplement decry the lack of standardized CF diagnostic criteria for those diagnosed with CF outside of the neonatal period, and urge clinicians to rely on clinical evidence including organ pathologies typical in CF, such as bronchiectasis or pancreatic insufficiency, along with testing for the presence of CFTR dysfunction with sweat chloride testing, CFTR molecular genetic analysis, or CFTR physiologic tests.

In contrast, the second supplement states that “clinical suspicion should always take precedence” in making a CF diagnoses for individuals in this age group.

Dr. Sosnay and Philip M. Farrell, MD, PhD, a coauthor of the guidelines, received funds from the Cystic Fibrosis Foundation, where guideline coauthor Terry B. White, PhD, is an employee. Kris De Boeck, MD, a coauthor of the first supplement, receives funding from Vertex Pharmaceuticals, Ablynx, Aptalis, Galapagos, Gilead, Pharmaxis, and PTC Therapeutics. The guideline and supplements’ other authors have no disclosures.

[email protected]

On Twitter @whitneymcknight

Updated guidelines for the diagnosis and treatment of cystic fibrosis (CF) include two major changes.

The first important update is that clinicians use the latest classifications of the specific CF transmembrane conductance regulator (CFTR) gene mutations, from the Clinical and Functional TRanslation of CFTR (CFTR2) database, to aid with making a CF diagnosis in any patient, newborn to adult. The other of these changes relates to the chloride concentration level used to confirm CF diagnosis through a sweat test. Under the new guidelines, the sweat chloride threshold for “possible” CF or a CF-related disease was reduced to 30 mmol/L of chloride concentration from 40 mmol/L across all ages. The guidelines, written by an international team of collaborators and published by the Cystic Fibrosis Foundation, are available online in the Journal of Pediatrics (J Pediatr 2017 Feb;181(suppl):S4-S15.e1. doi: 10.1016/j.jpeds.2016.09.064).

Since its inception in 2008, the CFTR2 project has described 300 of the 2,000 known CF-related mutations and their various functional and clinical impacts. The project involves amassing phenotypic and genotypic information from patient registries to collect, quantify, and describe mutations reported in individuals with CF. Such mutations are categorized as CF-causing, carrying a variety of potential clinical consequences, non–cystic fibrosis causing, or unknown. The previous guidelines, written in 2008, relied on a 23-mutation panel from the American College of Medical Genetics and Genomics and the American Congress of Obstetricians and Gynecologists.

“We’ve more precisely defined what cystic fibrosis is,” Patrick R. Sosnay, MD, assistant professor of medicine at Johns Hopkins University, Baltimore, and coauthor of the guidelines, said in a statement. “The stakes in categorizing a mutation are particularly high. For example, claiming that a mutation 100% causes cystic fibrosis may affect people’s reproductive decisions if they believe their child will have the mutation.”

In the CFTR2 project, the “disease-liability” of each mutation is evaluated through a combination of sweat chloride and functional activity identified in cell-based systems, according to a supplement published simultaneously with the updated guidelines (J Pediatr 2017 Feb;181(suppl):S52-S57.e2. doi: 10.1016/j.jpeds.2016.09.068). Data from this project led to the discovery of a cohort of 746 persons diagnosed with CF despite sweat chloride levels less than 60 mmol/L. These findings were the basis for the guideline authors’ decision to lower the threshold of chloride concentration in sweat in order for an individual to be considered having a possible CF diagnosis, according to the supplement.

The guidelines include 27 approved consensus statements spanning four overlapping categories, and applying to screened and nonscreened populations; newborn screened populations and fetuses undergoing prenatal testing; infants with an uncertain diagnosis and designated as having either CFTR gene-related metabolic syndrome or being CF-screen positive, inconclusive diagnosis; and nonscreened patients who present with symptoms, including children before newborn screening implementation, those with false negative tests and older, nonscreened patients.

Although not specified in the consensus statements, the authors of a second supplement published simultaneously with the updated guidelines (J Pediatr 2017;181(suppl):S27-S32.e1. doi: 10.1016/j.jpeds.2016.09.063), wrote that they supported genotyping all individuals diagnosed with CF, even if physiologic tests establish the diagnosis, to better understand the disease’s genetic epidemiology and to refine future therapies. “If the identified mutations are known to be associated with variable outcomes, or have unknown consequence, that genotype may not result in a CF phenotype. In these cases, other tests of CFTR function may help,” this supplement’s authors concluded.

The updated guideline authors recommend avoiding the use of terms such as “atypical” or “nonclassical” CF, as there is no consensus on the specific taxonomy of CF, since the genetic data are still emerging.

When administering a newborn test, the guidelines warn that the heterogenous nature of newborn screening often leads to false positive results, thus the need for the sweat test. Although obtaining an adequate sweat specimen for chloride measurements can be difficult, the authors say it is possible, especially in full-term infants aged 1 month. Repeat sweat testing is recommended, as is nasal potential difference (NPD) and intestinal current measurement (ICM) in some cases.

Another change to the guidelines is that newborns with a high immunoreactive trypsinogen level and inconclusive CFTR functional and genetic testing may now be designated as having CFTR-related metabolic syndrome/CF screen positive inconclusive diagnosis (CRMS/CFSPID), instead of CFTR-related metabolic syndrome or CF screen positive, inconclusive diagnosis. Regarding changes to screening for CRMS/CFSPID, the older guidelines called for such an assessment by age 2 months, repeated every 6-12 months, while the new guidelines say their recommendation on the duration and frequency of follow-up “remains to be determined.”

The authors of the first supplement decry the lack of standardized CF diagnostic criteria for those diagnosed with CF outside of the neonatal period, and urge clinicians to rely on clinical evidence including organ pathologies typical in CF, such as bronchiectasis or pancreatic insufficiency, along with testing for the presence of CFTR dysfunction with sweat chloride testing, CFTR molecular genetic analysis, or CFTR physiologic tests.

In contrast, the second supplement states that “clinical suspicion should always take precedence” in making a CF diagnoses for individuals in this age group.

Dr. Sosnay and Philip M. Farrell, MD, PhD, a coauthor of the guidelines, received funds from the Cystic Fibrosis Foundation, where guideline coauthor Terry B. White, PhD, is an employee. Kris De Boeck, MD, a coauthor of the first supplement, receives funding from Vertex Pharmaceuticals, Ablynx, Aptalis, Galapagos, Gilead, Pharmaxis, and PTC Therapeutics. The guideline and supplements’ other authors have no disclosures.

[email protected]

On Twitter @whitneymcknight

African Americans who have sickle cell trait show lower hemoglobin A_1c levels at any given concentration of fasting glucose than do those who don’t have sickle cell trait, according to a report published online Feb. 7 in JAMA.

This suggests that HbA_1c levels systematically underestimate glucose levels in black patients who carry the trait, who comprise approximately 10% of the African American population, said Mary E. Lacy, a doctoral candidate in the department of epidemiology, Brown University School of Public Health, Providence, R.I., and her associates.

The investigators examined a possible link between HbA_1c and sickle cell trait, which affects hemoglobin even though it doesn’t confer sickle cell disease, by analyzing data from two cohort studies involving African American adults. They focused on 4,620 participants who underwent serial HbA_1c and plasma glucose measurements during 5-25 years of follow-up. A total of 367 of them had sickle cell trait.

Analysis of 9,062 concurrent assessments of fasting glucose and HbA_1c plus 2,001 concurrent assessments of 2-hour postprandial glucose and HbA_1c showed mean HbA_1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.

“Our results suggest that currently accepted clinical measures of HbA_1c do not reflect recent past glycemia in the same way in African Americans with and without sickle cell trait,” Ms. Lacy and her associates said (JAMA 2017 Feb 7. doi: 10.1001/jama.2016.21035).

When used as a screen for prediabetes or diabetes, HbA_1c values “systematically underestimate long-term glucose levels,” which means a significant proportion of African American patients will miss the opportunity for treatment. In this study, “using standard clinical HbA_1c criteria to identify prediabetes and diabetes resulted in identifying 40% fewer cases of prediabetes and 48% fewer cases of diabetes among participants with sickle cell trait, compared to those without sickle cell trait,” the investigators noted.

“Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than [those of] white people, the cost of inaccurately assessing risk and treatment response is high,” they added.

The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.

African Americans who have sickle cell trait show lower hemoglobin A_1c levels at any given concentration of fasting glucose than do those who don’t have sickle cell trait, according to a report published online Feb. 7 in JAMA.

This suggests that HbA_1c levels systematically underestimate glucose levels in black patients who carry the trait, who comprise approximately 10% of the African American population, said Mary E. Lacy, a doctoral candidate in the department of epidemiology, Brown University School of Public Health, Providence, R.I., and her associates.

The investigators examined a possible link between HbA_1c and sickle cell trait, which affects hemoglobin even though it doesn’t confer sickle cell disease, by analyzing data from two cohort studies involving African American adults. They focused on 4,620 participants who underwent serial HbA_1c and plasma glucose measurements during 5-25 years of follow-up. A total of 367 of them had sickle cell trait.

Analysis of 9,062 concurrent assessments of fasting glucose and HbA_1c plus 2,001 concurrent assessments of 2-hour postprandial glucose and HbA_1c showed mean HbA_1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.

“Our results suggest that currently accepted clinical measures of HbA_1c do not reflect recent past glycemia in the same way in African Americans with and without sickle cell trait,” Ms. Lacy and her associates said (JAMA 2017 Feb 7. doi: 10.1001/jama.2016.21035).

When used as a screen for prediabetes or diabetes, HbA_1c values “systematically underestimate long-term glucose levels,” which means a significant proportion of African American patients will miss the opportunity for treatment. In this study, “using standard clinical HbA_1c criteria to identify prediabetes and diabetes resulted in identifying 40% fewer cases of prediabetes and 48% fewer cases of diabetes among participants with sickle cell trait, compared to those without sickle cell trait,” the investigators noted.

“Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than [those of] white people, the cost of inaccurately assessing risk and treatment response is high,” they added.

The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.

African Americans who have sickle cell trait show lower hemoglobin A_1c levels at any given concentration of fasting glucose than do those who don’t have sickle cell trait, according to a report published online Feb. 7 in JAMA.

This suggests that HbA_1c levels systematically underestimate glucose levels in black patients who carry the trait, who comprise approximately 10% of the African American population, said Mary E. Lacy, a doctoral candidate in the department of epidemiology, Brown University School of Public Health, Providence, R.I., and her associates.

The investigators examined a possible link between HbA_1c and sickle cell trait, which affects hemoglobin even though it doesn’t confer sickle cell disease, by analyzing data from two cohort studies involving African American adults. They focused on 4,620 participants who underwent serial HbA_1c and plasma glucose measurements during 5-25 years of follow-up. A total of 367 of them had sickle cell trait.

Analysis of 9,062 concurrent assessments of fasting glucose and HbA_1c plus 2,001 concurrent assessments of 2-hour postprandial glucose and HbA_1c showed mean HbA_1c was consistently significantly lower in people with sickle cell trait (mean level, 5.7%) than in those without the trait (mean level, 6%) despite similar glucose values.

“Our results suggest that currently accepted clinical measures of HbA_1c do not reflect recent past glycemia in the same way in African Americans with and without sickle cell trait,” Ms. Lacy and her associates said (JAMA 2017 Feb 7. doi: 10.1001/jama.2016.21035).

When used as a screen for prediabetes or diabetes, HbA_1c values “systematically underestimate long-term glucose levels,” which means a significant proportion of African American patients will miss the opportunity for treatment. In this study, “using standard clinical HbA_1c criteria to identify prediabetes and diabetes resulted in identifying 40% fewer cases of prediabetes and 48% fewer cases of diabetes among participants with sickle cell trait, compared to those without sickle cell trait,” the investigators noted.

“Because black people typically have a higher prevalence of diabetes and experience a number of diabetic complications at higher rates than [those of] white people, the cost of inaccurately assessing risk and treatment response is high,” they added.

The National Heart, Lung, and Blood Institute, the National Institute on Aging, the National Institute on Minority Health Disparities, the Providence VA Medical Center, and the National Institute of Diabetes and Digestive and Kidney Diseases supported the study. Ms. Lacy and her associates reported having no relevant financial disclosures.