Doctor and patient

Credit: CDC

The 2500-year-old Pythagorean theorem could be the most effective way to identify the point at which a patient’s health begins to improve, a new study suggests.

Researchers made the discovery while examining receiver operating characteristic (ROC) curves, which are used to measure changes in a patient’s health status.

“It all comes down to choosing a point on a curve to determine when recovery has occurred,” said study author Rob Froud, PhD, of the University of Warwick in Coventry, UK.

“For many chronic conditions, epidemiologists agree that the correct point to choose is that which is closest to the top-left corner of the plot containing the curve. As we stopped to think about it, it struck us as obvious that the way to choose this point was by using Pythagoras’s theorem.”

The theorem states that, in a right-angled triangle, the sum of the squares of the 2 right-angled sides is equal to the square of the hypotenuse (the longer diagonal that joins the 2 right-angled sides).

With this formula (a²+b²=c²), a person can determine the length of the hypotenuse when given the length of the other 2 sides.

“We set about exploring the implications of this and how it might change conclusions in research,” Dr Froud said. “We conducted several experiments using real trial data, and it seems using Pythagoras’s theorem makes a material difference.”

“It helps to identify the point at which a patient has improved with more consistency and accuracy than other methods commonly used. The moral of the story is that, before you throw out the old stuff in the attic, just go through it one last time, as there may be something in there that is still relevant and useful.”

Dr Froud and his colleague Gary Abel, PhD, of the University of Cambridge in the UK, described this research in PLOS ONE.

Doctor and patient

Credit: CDC

The 2500-year-old Pythagorean theorem could be the most effective way to identify the point at which a patient’s health begins to improve, a new study suggests.

Researchers made the discovery while examining receiver operating characteristic (ROC) curves, which are used to measure changes in a patient’s health status.

“It all comes down to choosing a point on a curve to determine when recovery has occurred,” said study author Rob Froud, PhD, of the University of Warwick in Coventry, UK.

“For many chronic conditions, epidemiologists agree that the correct point to choose is that which is closest to the top-left corner of the plot containing the curve. As we stopped to think about it, it struck us as obvious that the way to choose this point was by using Pythagoras’s theorem.”

The theorem states that, in a right-angled triangle, the sum of the squares of the 2 right-angled sides is equal to the square of the hypotenuse (the longer diagonal that joins the 2 right-angled sides).

With this formula (a²+b²=c²), a person can determine the length of the hypotenuse when given the length of the other 2 sides.

“We set about exploring the implications of this and how it might change conclusions in research,” Dr Froud said. “We conducted several experiments using real trial data, and it seems using Pythagoras’s theorem makes a material difference.”

“It helps to identify the point at which a patient has improved with more consistency and accuracy than other methods commonly used. The moral of the story is that, before you throw out the old stuff in the attic, just go through it one last time, as there may be something in there that is still relevant and useful.”

Dr Froud and his colleague Gary Abel, PhD, of the University of Cambridge in the UK, described this research in PLOS ONE.

Doctor and patient

Credit: CDC

The 2500-year-old Pythagorean theorem could be the most effective way to identify the point at which a patient’s health begins to improve, a new study suggests.

Researchers made the discovery while examining receiver operating characteristic (ROC) curves, which are used to measure changes in a patient’s health status.

“It all comes down to choosing a point on a curve to determine when recovery has occurred,” said study author Rob Froud, PhD, of the University of Warwick in Coventry, UK.

“For many chronic conditions, epidemiologists agree that the correct point to choose is that which is closest to the top-left corner of the plot containing the curve. As we stopped to think about it, it struck us as obvious that the way to choose this point was by using Pythagoras’s theorem.”

The theorem states that, in a right-angled triangle, the sum of the squares of the 2 right-angled sides is equal to the square of the hypotenuse (the longer diagonal that joins the 2 right-angled sides).

With this formula (a²+b²=c²), a person can determine the length of the hypotenuse when given the length of the other 2 sides.

“We set about exploring the implications of this and how it might change conclusions in research,” Dr Froud said. “We conducted several experiments using real trial data, and it seems using Pythagoras’s theorem makes a material difference.”

“It helps to identify the point at which a patient has improved with more consistency and accuracy than other methods commonly used. The moral of the story is that, before you throw out the old stuff in the attic, just go through it one last time, as there may be something in there that is still relevant and useful.”

Dr Froud and his colleague Gary Abel, PhD, of the University of Cambridge in the UK, described this research in PLOS ONE.

In November last year, one of the highly prestigious National Medals of Technology and Innovation was presented to Thomas J. Fogarty, Fogarty Institute for Innovation, for his innovations in minimally invasive medical devices. U.S. President Obama presided at the ceremony and presented the award.

Dr. Fogarty is chairman, director and founder of the Fogarty Institute for Innovation, and has served as a founder, chairman, or board member of over 30 business and research companies. During the past 40 years, he acquired 135 surgical patents, including the Fogarty balloon catheter and the Aneurx Stent Graft, an endovascular device that replaces open surgery for aortic aneurysm.

Courtesy of the National Science and Technology Medals

Along with the recently awarded National Medal of Technology and Innovation, he has received the Jacobson Innovation Award of the American College of Surgeons and the 2000 Lemelson-MIT prize for Invention and Innovation. He was inducted into the Inventors Hall of Fame in 2001.

Surgeon who saved Pope’s life thanked

Dr. Juan Carlos Parodi today is a prominent figure in the world vascular community, one famous for his work in the development of endovascular aortic aneurysm repair (EVAR) several decades ago.

But it was an emergency gall bladder operation many years ago, which he performed in his native Argentina, that caused him to rise to a unique prominence, illustrated in a more recent visit to Vatican City, where he had a 40-minute private audience with Pope Francis.

Courtesy of Marta Di Gaetano

Dr. Parodi explained: “In 1980 I was called to treat a poor priest with a gangrenous cholecystitis caused by Clostridium. I took care of him without charging him, and after days of dialysis he survived. I forgot the experience until one day I received a call telling me that the poor priest I took care of became the Pope Francis. He invited me to visit him in the Vatican, and I went to visit him last year.

“Pope Francis received me saying: Welcome the surgeon who saved my life coming in the middle of the night to do an operation without asking for any compensation! I told him that as a physician we help people who need us, regardless of the lack of payment capacity. I was honored by being invited by him,” Dr. Parodi added.

Currently, Dr. Parodi is a professor of surgery at the University of Buenos Aires, and chief of vascular surgery at the Sanatorio Trinidad, Buenos Aires.

In November last year, one of the highly prestigious National Medals of Technology and Innovation was presented to Thomas J. Fogarty, Fogarty Institute for Innovation, for his innovations in minimally invasive medical devices. U.S. President Obama presided at the ceremony and presented the award.

Dr. Fogarty is chairman, director and founder of the Fogarty Institute for Innovation, and has served as a founder, chairman, or board member of over 30 business and research companies. During the past 40 years, he acquired 135 surgical patents, including the Fogarty balloon catheter and the Aneurx Stent Graft, an endovascular device that replaces open surgery for aortic aneurysm.

Courtesy of the National Science and Technology Medals

Along with the recently awarded National Medal of Technology and Innovation, he has received the Jacobson Innovation Award of the American College of Surgeons and the 2000 Lemelson-MIT prize for Invention and Innovation. He was inducted into the Inventors Hall of Fame in 2001.

Surgeon who saved Pope’s life thanked

Dr. Juan Carlos Parodi today is a prominent figure in the world vascular community, one famous for his work in the development of endovascular aortic aneurysm repair (EVAR) several decades ago.

But it was an emergency gall bladder operation many years ago, which he performed in his native Argentina, that caused him to rise to a unique prominence, illustrated in a more recent visit to Vatican City, where he had a 40-minute private audience with Pope Francis.

Courtesy of Marta Di Gaetano

Dr. Parodi explained: “In 1980 I was called to treat a poor priest with a gangrenous cholecystitis caused by Clostridium. I took care of him without charging him, and after days of dialysis he survived. I forgot the experience until one day I received a call telling me that the poor priest I took care of became the Pope Francis. He invited me to visit him in the Vatican, and I went to visit him last year.

“Pope Francis received me saying: Welcome the surgeon who saved my life coming in the middle of the night to do an operation without asking for any compensation! I told him that as a physician we help people who need us, regardless of the lack of payment capacity. I was honored by being invited by him,” Dr. Parodi added.

Currently, Dr. Parodi is a professor of surgery at the University of Buenos Aires, and chief of vascular surgery at the Sanatorio Trinidad, Buenos Aires.

In November last year, one of the highly prestigious National Medals of Technology and Innovation was presented to Thomas J. Fogarty, Fogarty Institute for Innovation, for his innovations in minimally invasive medical devices. U.S. President Obama presided at the ceremony and presented the award.

Dr. Fogarty is chairman, director and founder of the Fogarty Institute for Innovation, and has served as a founder, chairman, or board member of over 30 business and research companies. During the past 40 years, he acquired 135 surgical patents, including the Fogarty balloon catheter and the Aneurx Stent Graft, an endovascular device that replaces open surgery for aortic aneurysm.

Courtesy of the National Science and Technology Medals

Along with the recently awarded National Medal of Technology and Innovation, he has received the Jacobson Innovation Award of the American College of Surgeons and the 2000 Lemelson-MIT prize for Invention and Innovation. He was inducted into the Inventors Hall of Fame in 2001.

Surgeon who saved Pope’s life thanked

Dr. Juan Carlos Parodi today is a prominent figure in the world vascular community, one famous for his work in the development of endovascular aortic aneurysm repair (EVAR) several decades ago.

But it was an emergency gall bladder operation many years ago, which he performed in his native Argentina, that caused him to rise to a unique prominence, illustrated in a more recent visit to Vatican City, where he had a 40-minute private audience with Pope Francis.

Courtesy of Marta Di Gaetano

Dr. Parodi explained: “In 1980 I was called to treat a poor priest with a gangrenous cholecystitis caused by Clostridium. I took care of him without charging him, and after days of dialysis he survived. I forgot the experience until one day I received a call telling me that the poor priest I took care of became the Pope Francis. He invited me to visit him in the Vatican, and I went to visit him last year.

“Pope Francis received me saying: Welcome the surgeon who saved my life coming in the middle of the night to do an operation without asking for any compensation! I told him that as a physician we help people who need us, regardless of the lack of payment capacity. I was honored by being invited by him,” Dr. Parodi added.

Currently, Dr. Parodi is a professor of surgery at the University of Buenos Aires, and chief of vascular surgery at the Sanatorio Trinidad, Buenos Aires.

As an experienced clinician who has seen tics and habits in your patients come and go, you may be surprised by the amount of concern parents express about them. At times, it seems, and may be, that the parent’s attention to the habit actually keeps it going! This does not always mean that the child keeps doing the habit to aggravate the parent, as parental correction may amp up the child’s anxiety, which may make the habit worse.

As with other parent concerns, both empathizing with their worry and providing evidence-based information is helpful in relieving their distress.

Habits are complex behaviors done the same way repeatedly. Habits can have a strong protective effect on our lives and be a foundation for success when they ensure that we wash our hands (protection from infection), help us know where the keys are (efficiency), or soothe us to sleep (bedtime routines).

Tics are “involuntary” (meaning often, but not always, suppressible), brief, abrupt, repeated movements usually of the face, head, or neck. More complex, apparently meaningless movements may fall into the category of stereotypies. If they last more than 4 weeks, are driven, and cause marked dysfunction or significant self-injury, they may even qualify as stereotypic movement disorder.

It is good to know that repeated behaviors such as thumb sucking, nail/lip biting, hair twirling, body rocking, self biting, and head banging are relatively common in childhood, and often (but not mostly) disappear after age 4. I like to set the expectation that one habit or tic often evolves to another to reduce panic when this happens. Thumb and hand sucking at a younger developmental age may be replaced by body rocking and head banging, and later by nail biting and finger and foot tapping.

Even in college, habits are common and stress-related such as touching the face; playing with hair, pens, or jewelry; shaking a leg; tapping fingers; or scratching the head. Parents may connect some of these to acne or poor hygiene (a good opening for coaching!) but more importantly they may be accompanied by general distress, anxiety, obsessive-compulsive symptoms, and impulsive aggressive symptoms, which need to be looked for and addressed.

Stereotypies occur in about 20% of typically developing children (called “primary”) and are classified into:

• Common behaviors (such as, rocking, head banging, finger drumming, pencil tapping, hair twisting),

• Head nodding.

• Complex motor movements (such as hand and arm flapping/waving).

Habits – including nail biting, lip chewing, and nose picking – also may be diagnosed as stereotypic movement disorders, although ICD-10 lists includes them as “other specified behavioral and emotional disorders.”

For both conditions, the behavior must not be better accounted for by a compulsion, a tic disorder, part of autism, hair pulling (trichotillomania), or paroxysmal dyskinesias.

So what is the difference between motor stereotypies and tics (and why do you care)? Motor stereotypies begin before 3 years in more than 60%, whereas tics appear later (mean 5-7 years). Stereotypies are more fixed in their pattern, compared with tics that keep shifting form, disappearing, and reappearing. Stereotypies frequently involve the arms, hands, or the entire body, while tics involve the eyes, face, head, and shoulders. Stereotypies are more fixed, rhythmic, and prolonged (most more than 10 seconds) than tics, which are mostly brief, rapid, random, and fluctuating.

One key distinguishing factor is that tics have a premonitory urge and result in a sense of relief after the tic is performed. This also means that they can be suppressed to some extent when the situation requires. While both may occur more during anxiety, excitement, or fatigue, stereotypic movements, unlike tics, also are common when the child is engrossed.

Tics can occur as a side effect of medications such as stimulants and may decrease by lowering the dose, but tics also come and go, so the impact of a medication can be hard to sort out.

One vocal or multiple motor tics occurring many times per day starting before age 18 years and lasting more than 1 year are considered chronic; those occurring less than 1 year are transient. Chronic multiple motor tics accompanied by vocalizations, even sniffing or throat clearing, qualify as Tourette syndrome. The feared component of Tourette of coprolalia (saying bad words or gestures) is fortunately rare. These diagnoses can only be made after ruling out the effects of medication or another neurological condition such as Sydenham’s chorea (resulting from infection via group A beta-hemolytic streptococcus, the bacterium that causes rheumatic fever) or PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).

The importance of distinguishing tics from stereotypies is in the treatment options, differential diagnosis, and prognosis. Some families (and certainly the kids themselves) do not even notice that they are moving abnormally even though 25% have at least one family member with a similar behavior. But many parents are upset about the potential for teasing and stigmatization. When you ask them directly what they are afraid of, they often admit fearing an underlying diagnosis such as intellectual disability, autism, or Tourette syndrome. The first two are straightforward to rule in or out, but Tourette can be subtle. If parents don’t bring up the possibilities, it is worth telling them directly which underlying conditions can be ruled out.

There are many conditions comorbid with tics including attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), learning disorder (LD), behavioral, developmental or social problems, and mood or anxiety disorders. This clearly means that a comprehensive evaluation looking specifically for these conditions is needed when a child has chronic tics. Typically developing children with complex arm or hand movements also are more likely to have ADHD (30%), LD (20%), obsessive-compulsive behaviors (10%), or tics (18%).

Tics and stereotypies may be annoying, but generally are not harmful or progressive, although repeated movements such as skin or nose picking may result in scars or infections, and severe head banging can lead to eye injuries. Frequently repeated motor acts can cause significant muscle pain and fatigue. The most common problems are probably injury to self-esteem or oppositional behavior as a result of repeated (and fruitless) nagging or punishment by parents, even if well-meaning.

Since they occur so often along with comorbid conditions, our job includes determining the most problematic aspect before advising on a treatment. Both tics and stereotypies may be reduced by distraction, but the effect on stereotypies is faster and more certain. You can make this intervention in the office by simply asking how the child can tell when they make the movement and have them plan out what they could do instead. An example might be to shift a hand flapping movement (that makes peers think of autism) into more acceptable fist clenching. Habit reversal training or differential reinforcement based on a functional analysis can be taught by psychologists when this simple suggestion is not effective. When tics are severe, teacher education and school accommodations (504 Plan with extended time, scribe, private location for tic breaks) may be needed.

Medication is not indicated for most tics because most are mild. If ADHD is present, tics may actually be reduced by stimulants or atomoxetine rather than worsened. If the tic is severe and habit reversal training has not been successful, alpha agonists such as clonidine or guanfacine, or typical or atypical neuroleptics may be helpful. Even baclofen, benzodiazepines, anticonvulsants, nicotine, and Botox have been used. These require consultation with a specialist.

As for other chronic medical conditions, tics and persisting stereotypies deserve a comprehensive approach, including repeated education of the parent and child, evaluation for comorbidity, school accommodations, building other strengths and social support, and only rarely pulling out your prescription pad.

Dr. Howard is an assistant professor of pediatrics at The Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline. E-mail her at pdnews@frontlinemedcom.com.

As an experienced clinician who has seen tics and habits in your patients come and go, you may be surprised by the amount of concern parents express about them. At times, it seems, and may be, that the parent’s attention to the habit actually keeps it going! This does not always mean that the child keeps doing the habit to aggravate the parent, as parental correction may amp up the child’s anxiety, which may make the habit worse.

As with other parent concerns, both empathizing with their worry and providing evidence-based information is helpful in relieving their distress.

Habits are complex behaviors done the same way repeatedly. Habits can have a strong protective effect on our lives and be a foundation for success when they ensure that we wash our hands (protection from infection), help us know where the keys are (efficiency), or soothe us to sleep (bedtime routines).

Tics are “involuntary” (meaning often, but not always, suppressible), brief, abrupt, repeated movements usually of the face, head, or neck. More complex, apparently meaningless movements may fall into the category of stereotypies. If they last more than 4 weeks, are driven, and cause marked dysfunction or significant self-injury, they may even qualify as stereotypic movement disorder.

It is good to know that repeated behaviors such as thumb sucking, nail/lip biting, hair twirling, body rocking, self biting, and head banging are relatively common in childhood, and often (but not mostly) disappear after age 4. I like to set the expectation that one habit or tic often evolves to another to reduce panic when this happens. Thumb and hand sucking at a younger developmental age may be replaced by body rocking and head banging, and later by nail biting and finger and foot tapping.

Even in college, habits are common and stress-related such as touching the face; playing with hair, pens, or jewelry; shaking a leg; tapping fingers; or scratching the head. Parents may connect some of these to acne or poor hygiene (a good opening for coaching!) but more importantly they may be accompanied by general distress, anxiety, obsessive-compulsive symptoms, and impulsive aggressive symptoms, which need to be looked for and addressed.

Stereotypies occur in about 20% of typically developing children (called “primary”) and are classified into:

• Common behaviors (such as, rocking, head banging, finger drumming, pencil tapping, hair twisting),

• Head nodding.

• Complex motor movements (such as hand and arm flapping/waving).

Habits – including nail biting, lip chewing, and nose picking – also may be diagnosed as stereotypic movement disorders, although ICD-10 lists includes them as “other specified behavioral and emotional disorders.”

For both conditions, the behavior must not be better accounted for by a compulsion, a tic disorder, part of autism, hair pulling (trichotillomania), or paroxysmal dyskinesias.

So what is the difference between motor stereotypies and tics (and why do you care)? Motor stereotypies begin before 3 years in more than 60%, whereas tics appear later (mean 5-7 years). Stereotypies are more fixed in their pattern, compared with tics that keep shifting form, disappearing, and reappearing. Stereotypies frequently involve the arms, hands, or the entire body, while tics involve the eyes, face, head, and shoulders. Stereotypies are more fixed, rhythmic, and prolonged (most more than 10 seconds) than tics, which are mostly brief, rapid, random, and fluctuating.

One key distinguishing factor is that tics have a premonitory urge and result in a sense of relief after the tic is performed. This also means that they can be suppressed to some extent when the situation requires. While both may occur more during anxiety, excitement, or fatigue, stereotypic movements, unlike tics, also are common when the child is engrossed.

Tics can occur as a side effect of medications such as stimulants and may decrease by lowering the dose, but tics also come and go, so the impact of a medication can be hard to sort out.

One vocal or multiple motor tics occurring many times per day starting before age 18 years and lasting more than 1 year are considered chronic; those occurring less than 1 year are transient. Chronic multiple motor tics accompanied by vocalizations, even sniffing or throat clearing, qualify as Tourette syndrome. The feared component of Tourette of coprolalia (saying bad words or gestures) is fortunately rare. These diagnoses can only be made after ruling out the effects of medication or another neurological condition such as Sydenham’s chorea (resulting from infection via group A beta-hemolytic streptococcus, the bacterium that causes rheumatic fever) or PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).

The importance of distinguishing tics from stereotypies is in the treatment options, differential diagnosis, and prognosis. Some families (and certainly the kids themselves) do not even notice that they are moving abnormally even though 25% have at least one family member with a similar behavior. But many parents are upset about the potential for teasing and stigmatization. When you ask them directly what they are afraid of, they often admit fearing an underlying diagnosis such as intellectual disability, autism, or Tourette syndrome. The first two are straightforward to rule in or out, but Tourette can be subtle. If parents don’t bring up the possibilities, it is worth telling them directly which underlying conditions can be ruled out.

There are many conditions comorbid with tics including attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), learning disorder (LD), behavioral, developmental or social problems, and mood or anxiety disorders. This clearly means that a comprehensive evaluation looking specifically for these conditions is needed when a child has chronic tics. Typically developing children with complex arm or hand movements also are more likely to have ADHD (30%), LD (20%), obsessive-compulsive behaviors (10%), or tics (18%).

Tics and stereotypies may be annoying, but generally are not harmful or progressive, although repeated movements such as skin or nose picking may result in scars or infections, and severe head banging can lead to eye injuries. Frequently repeated motor acts can cause significant muscle pain and fatigue. The most common problems are probably injury to self-esteem or oppositional behavior as a result of repeated (and fruitless) nagging or punishment by parents, even if well-meaning.

Since they occur so often along with comorbid conditions, our job includes determining the most problematic aspect before advising on a treatment. Both tics and stereotypies may be reduced by distraction, but the effect on stereotypies is faster and more certain. You can make this intervention in the office by simply asking how the child can tell when they make the movement and have them plan out what they could do instead. An example might be to shift a hand flapping movement (that makes peers think of autism) into more acceptable fist clenching. Habit reversal training or differential reinforcement based on a functional analysis can be taught by psychologists when this simple suggestion is not effective. When tics are severe, teacher education and school accommodations (504 Plan with extended time, scribe, private location for tic breaks) may be needed.

Medication is not indicated for most tics because most are mild. If ADHD is present, tics may actually be reduced by stimulants or atomoxetine rather than worsened. If the tic is severe and habit reversal training has not been successful, alpha agonists such as clonidine or guanfacine, or typical or atypical neuroleptics may be helpful. Even baclofen, benzodiazepines, anticonvulsants, nicotine, and Botox have been used. These require consultation with a specialist.

As for other chronic medical conditions, tics and persisting stereotypies deserve a comprehensive approach, including repeated education of the parent and child, evaluation for comorbidity, school accommodations, building other strengths and social support, and only rarely pulling out your prescription pad.

Dr. Howard is an assistant professor of pediatrics at The Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline. E-mail her at pdnews@frontlinemedcom.com.

As an experienced clinician who has seen tics and habits in your patients come and go, you may be surprised by the amount of concern parents express about them. At times, it seems, and may be, that the parent’s attention to the habit actually keeps it going! This does not always mean that the child keeps doing the habit to aggravate the parent, as parental correction may amp up the child’s anxiety, which may make the habit worse.

As with other parent concerns, both empathizing with their worry and providing evidence-based information is helpful in relieving their distress.

Habits are complex behaviors done the same way repeatedly. Habits can have a strong protective effect on our lives and be a foundation for success when they ensure that we wash our hands (protection from infection), help us know where the keys are (efficiency), or soothe us to sleep (bedtime routines).

Tics are “involuntary” (meaning often, but not always, suppressible), brief, abrupt, repeated movements usually of the face, head, or neck. More complex, apparently meaningless movements may fall into the category of stereotypies. If they last more than 4 weeks, are driven, and cause marked dysfunction or significant self-injury, they may even qualify as stereotypic movement disorder.

It is good to know that repeated behaviors such as thumb sucking, nail/lip biting, hair twirling, body rocking, self biting, and head banging are relatively common in childhood, and often (but not mostly) disappear after age 4. I like to set the expectation that one habit or tic often evolves to another to reduce panic when this happens. Thumb and hand sucking at a younger developmental age may be replaced by body rocking and head banging, and later by nail biting and finger and foot tapping.

Even in college, habits are common and stress-related such as touching the face; playing with hair, pens, or jewelry; shaking a leg; tapping fingers; or scratching the head. Parents may connect some of these to acne or poor hygiene (a good opening for coaching!) but more importantly they may be accompanied by general distress, anxiety, obsessive-compulsive symptoms, and impulsive aggressive symptoms, which need to be looked for and addressed.

Stereotypies occur in about 20% of typically developing children (called “primary”) and are classified into:

• Common behaviors (such as, rocking, head banging, finger drumming, pencil tapping, hair twisting),

• Head nodding.

• Complex motor movements (such as hand and arm flapping/waving).

Habits – including nail biting, lip chewing, and nose picking – also may be diagnosed as stereotypic movement disorders, although ICD-10 lists includes them as “other specified behavioral and emotional disorders.”

For both conditions, the behavior must not be better accounted for by a compulsion, a tic disorder, part of autism, hair pulling (trichotillomania), or paroxysmal dyskinesias.

So what is the difference between motor stereotypies and tics (and why do you care)? Motor stereotypies begin before 3 years in more than 60%, whereas tics appear later (mean 5-7 years). Stereotypies are more fixed in their pattern, compared with tics that keep shifting form, disappearing, and reappearing. Stereotypies frequently involve the arms, hands, or the entire body, while tics involve the eyes, face, head, and shoulders. Stereotypies are more fixed, rhythmic, and prolonged (most more than 10 seconds) than tics, which are mostly brief, rapid, random, and fluctuating.

One key distinguishing factor is that tics have a premonitory urge and result in a sense of relief after the tic is performed. This also means that they can be suppressed to some extent when the situation requires. While both may occur more during anxiety, excitement, or fatigue, stereotypic movements, unlike tics, also are common when the child is engrossed.

Tics can occur as a side effect of medications such as stimulants and may decrease by lowering the dose, but tics also come and go, so the impact of a medication can be hard to sort out.

One vocal or multiple motor tics occurring many times per day starting before age 18 years and lasting more than 1 year are considered chronic; those occurring less than 1 year are transient. Chronic multiple motor tics accompanied by vocalizations, even sniffing or throat clearing, qualify as Tourette syndrome. The feared component of Tourette of coprolalia (saying bad words or gestures) is fortunately rare. These diagnoses can only be made after ruling out the effects of medication or another neurological condition such as Sydenham’s chorea (resulting from infection via group A beta-hemolytic streptococcus, the bacterium that causes rheumatic fever) or PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections).

The importance of distinguishing tics from stereotypies is in the treatment options, differential diagnosis, and prognosis. Some families (and certainly the kids themselves) do not even notice that they are moving abnormally even though 25% have at least one family member with a similar behavior. But many parents are upset about the potential for teasing and stigmatization. When you ask them directly what they are afraid of, they often admit fearing an underlying diagnosis such as intellectual disability, autism, or Tourette syndrome. The first two are straightforward to rule in or out, but Tourette can be subtle. If parents don’t bring up the possibilities, it is worth telling them directly which underlying conditions can be ruled out.

There are many conditions comorbid with tics including attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), learning disorder (LD), behavioral, developmental or social problems, and mood or anxiety disorders. This clearly means that a comprehensive evaluation looking specifically for these conditions is needed when a child has chronic tics. Typically developing children with complex arm or hand movements also are more likely to have ADHD (30%), LD (20%), obsessive-compulsive behaviors (10%), or tics (18%).

Tics and stereotypies may be annoying, but generally are not harmful or progressive, although repeated movements such as skin or nose picking may result in scars or infections, and severe head banging can lead to eye injuries. Frequently repeated motor acts can cause significant muscle pain and fatigue. The most common problems are probably injury to self-esteem or oppositional behavior as a result of repeated (and fruitless) nagging or punishment by parents, even if well-meaning.

Since they occur so often along with comorbid conditions, our job includes determining the most problematic aspect before advising on a treatment. Both tics and stereotypies may be reduced by distraction, but the effect on stereotypies is faster and more certain. You can make this intervention in the office by simply asking how the child can tell when they make the movement and have them plan out what they could do instead. An example might be to shift a hand flapping movement (that makes peers think of autism) into more acceptable fist clenching. Habit reversal training or differential reinforcement based on a functional analysis can be taught by psychologists when this simple suggestion is not effective. When tics are severe, teacher education and school accommodations (504 Plan with extended time, scribe, private location for tic breaks) may be needed.

Medication is not indicated for most tics because most are mild. If ADHD is present, tics may actually be reduced by stimulants or atomoxetine rather than worsened. If the tic is severe and habit reversal training has not been successful, alpha agonists such as clonidine or guanfacine, or typical or atypical neuroleptics may be helpful. Even baclofen, benzodiazepines, anticonvulsants, nicotine, and Botox have been used. These require consultation with a specialist.

As for other chronic medical conditions, tics and persisting stereotypies deserve a comprehensive approach, including repeated education of the parent and child, evaluation for comorbidity, school accommodations, building other strengths and social support, and only rarely pulling out your prescription pad.

Dr. Howard is an assistant professor of pediatrics at The Johns Hopkins University, Baltimore, and creator of CHADIS (www.CHADIS.com). She has no other relevant disclosures. Dr. Howard’s contribution to this publication was as a paid expert to Frontline. E-mail her at pdnews@frontlinemedcom.com.

A new Committee Opinion published by the American College of Obstetricians and Gynecologists (ACOG) in Obstetrics & Gynecology outlines the current barriers women face when attempting to obtain contraception and provides strategies to overcome these barriers.

Unintended pregnancy and abortion rates are higher in the United States than in most other developed countries, says ACOG; the most recent data report that 49% of US pregnancies are unintended.¹

The cost of unintended pregnancy
The human cost of unintended pregnancy is high, says ACOG, because women must choose to carry the pregnancy to term and keep the baby, decide for adoption, or undergo abortion. Women and their families struggle with this challenge for medical, ethical, social, legal, and financial reasons. US births from unintended pregnancies resulted in approximately $12.5 billion in government expenditures in 2008. Affordable access to contraceptives would not only improve health but also reduce costs, as each dollar spent on publicly funded contraceptive services saves the US health-care system nearly $6.¹

“The most effective way to reduce abortion rates is to prevent unintended pregnancy by improving access to consistent, effective, and affordable contraception,” states the Committee Opinion.¹

What are barriers to use?
Major barriers to contraceptive use include lack of knowledge, misperceptions, and exaggerated concerns about safety among patients and health-care professionals, says the Committee.

Patients are concerned that oral contraceptives are linked to major health problems, that intrauterine devices (IUDs) carry a high risk of infection, and that certain contraceptives are abortifacients (although no FDA-approved contraceptive is an abortifacient).

Health-care professionals also may have knowledge deficits: some are uncertain about the risks and benefits of IUDs and lack knowledge about correct patient selection and contraindications.¹ 

What strategies does ACOG support?
One in four American women who obtain contraceptive services seek them at publicly funded family planning clinics, cites ACOG.¹ The Affordable Care Act (ACA) provides that all FDA-approved contraceptive methods, sterilization procedures, and patient contraceptive education and counseling are covered for women without cost sharing for all new and revised health plans and Medicaid. However, many employers are now exempt. Women covered by exempted employers and those who remain uninsured will not benefit from ACA coverage. For these women, cost barriers persist and the most effective methods (IUDs, contraceptive implant) likely will be unattainable, says ACOG.¹

Insurance companies, clinic systems, or pharmacy and therapeutics committees create additional barriers, including the number of products dispensed at one time. Insurance plans prevent 73% of women from receiving more than a 1 month supply of contraception at a time, yet most women are unable to obtain refills on a timely basis. Some systems require that women “fail” certain contraceptive methods before a more expensive method (IUD, implant) will be covered. ACOG states: “All FDA-approved contraceptive methods should be available to all insured women without cost sharing and without the need to ‘fail’ certain methods first. In the absence of contraindications, patient choice and efficacy should be the principal factors in choosing one method of contraception over another.”¹

Additional strategies ACOG supports and recommends to ensure affordable and accessible contraception include:

To see all of ACOG’s recommendations, access the full report. 

A new Committee Opinion published by the American College of Obstetricians and Gynecologists (ACOG) in Obstetrics & Gynecology outlines the current barriers women face when attempting to obtain contraception and provides strategies to overcome these barriers.

Unintended pregnancy and abortion rates are higher in the United States than in most other developed countries, says ACOG; the most recent data report that 49% of US pregnancies are unintended.¹

The cost of unintended pregnancy
The human cost of unintended pregnancy is high, says ACOG, because women must choose to carry the pregnancy to term and keep the baby, decide for adoption, or undergo abortion. Women and their families struggle with this challenge for medical, ethical, social, legal, and financial reasons. US births from unintended pregnancies resulted in approximately $12.5 billion in government expenditures in 2008. Affordable access to contraceptives would not only improve health but also reduce costs, as each dollar spent on publicly funded contraceptive services saves the US health-care system nearly $6.¹

“The most effective way to reduce abortion rates is to prevent unintended pregnancy by improving access to consistent, effective, and affordable contraception,” states the Committee Opinion.¹

What are barriers to use?
Major barriers to contraceptive use include lack of knowledge, misperceptions, and exaggerated concerns about safety among patients and health-care professionals, says the Committee.

Patients are concerned that oral contraceptives are linked to major health problems, that intrauterine devices (IUDs) carry a high risk of infection, and that certain contraceptives are abortifacients (although no FDA-approved contraceptive is an abortifacient).

Health-care professionals also may have knowledge deficits: some are uncertain about the risks and benefits of IUDs and lack knowledge about correct patient selection and contraindications.¹ 

What strategies does ACOG support?
One in four American women who obtain contraceptive services seek them at publicly funded family planning clinics, cites ACOG.¹ The Affordable Care Act (ACA) provides that all FDA-approved contraceptive methods, sterilization procedures, and patient contraceptive education and counseling are covered for women without cost sharing for all new and revised health plans and Medicaid. However, many employers are now exempt. Women covered by exempted employers and those who remain uninsured will not benefit from ACA coverage. For these women, cost barriers persist and the most effective methods (IUDs, contraceptive implant) likely will be unattainable, says ACOG.¹

Insurance companies, clinic systems, or pharmacy and therapeutics committees create additional barriers, including the number of products dispensed at one time. Insurance plans prevent 73% of women from receiving more than a 1 month supply of contraception at a time, yet most women are unable to obtain refills on a timely basis. Some systems require that women “fail” certain contraceptive methods before a more expensive method (IUD, implant) will be covered. ACOG states: “All FDA-approved contraceptive methods should be available to all insured women without cost sharing and without the need to ‘fail’ certain methods first. In the absence of contraindications, patient choice and efficacy should be the principal factors in choosing one method of contraception over another.”¹

Additional strategies ACOG supports and recommends to ensure affordable and accessible contraception include:

To see all of ACOG’s recommendations, access the full report. 

A new Committee Opinion published by the American College of Obstetricians and Gynecologists (ACOG) in Obstetrics & Gynecology outlines the current barriers women face when attempting to obtain contraception and provides strategies to overcome these barriers.

Unintended pregnancy and abortion rates are higher in the United States than in most other developed countries, says ACOG; the most recent data report that 49% of US pregnancies are unintended.¹

The cost of unintended pregnancy
The human cost of unintended pregnancy is high, says ACOG, because women must choose to carry the pregnancy to term and keep the baby, decide for adoption, or undergo abortion. Women and their families struggle with this challenge for medical, ethical, social, legal, and financial reasons. US births from unintended pregnancies resulted in approximately $12.5 billion in government expenditures in 2008. Affordable access to contraceptives would not only improve health but also reduce costs, as each dollar spent on publicly funded contraceptive services saves the US health-care system nearly $6.¹

“The most effective way to reduce abortion rates is to prevent unintended pregnancy by improving access to consistent, effective, and affordable contraception,” states the Committee Opinion.¹

What are barriers to use?
Major barriers to contraceptive use include lack of knowledge, misperceptions, and exaggerated concerns about safety among patients and health-care professionals, says the Committee.

Patients are concerned that oral contraceptives are linked to major health problems, that intrauterine devices (IUDs) carry a high risk of infection, and that certain contraceptives are abortifacients (although no FDA-approved contraceptive is an abortifacient).

Health-care professionals also may have knowledge deficits: some are uncertain about the risks and benefits of IUDs and lack knowledge about correct patient selection and contraindications.¹ 

What strategies does ACOG support?
One in four American women who obtain contraceptive services seek them at publicly funded family planning clinics, cites ACOG.¹ The Affordable Care Act (ACA) provides that all FDA-approved contraceptive methods, sterilization procedures, and patient contraceptive education and counseling are covered for women without cost sharing for all new and revised health plans and Medicaid. However, many employers are now exempt. Women covered by exempted employers and those who remain uninsured will not benefit from ACA coverage. For these women, cost barriers persist and the most effective methods (IUDs, contraceptive implant) likely will be unattainable, says ACOG.¹

Insurance companies, clinic systems, or pharmacy and therapeutics committees create additional barriers, including the number of products dispensed at one time. Insurance plans prevent 73% of women from receiving more than a 1 month supply of contraception at a time, yet most women are unable to obtain refills on a timely basis. Some systems require that women “fail” certain contraceptive methods before a more expensive method (IUD, implant) will be covered. ACOG states: “All FDA-approved contraceptive methods should be available to all insured women without cost sharing and without the need to ‘fail’ certain methods first. In the absence of contraindications, patient choice and efficacy should be the principal factors in choosing one method of contraception over another.”¹

Additional strategies ACOG supports and recommends to ensure affordable and accessible contraception include:

To see all of ACOG’s recommendations, access the full report. 

Although DNA strain type switches are known to be a natural occurrence in patients with onychomycosis, increases in strain type switching that follow treatment failure could be an antifungal-induced response, according to the results of a study published in the British Journal of Dermatology.

“The dermatophyte Trichophyton rubrum is responsible for the majority (~80%) of [onychomycosis] cases, many of which frequently relapse after successful antifungal treatment,” noted the study authors, led by Dr. Aditya K. Gupta of the University of Toronto. Despite several previous studies of various facets related to onychomycosis, “data outlining onychomycosis infections of T. rubrum with DNA strain type, treatments, outcome and geographical location are still warranted,” they added (Br. J. Dermatol. 2015;172:74-80).

© Metin Cengiz Bar??/Thinkstock

Dr. Gupta and his associates examined 50 adults infected with T. rubrum, determined via analysis of toenail specimens from onychomycosis patients in southwest Ontario. The patients were divided into cohorts based on the treatment they received: oral terbinafine, laser, or placebo (no terbinafine and no laser). Typing of DNA strains was done only in culture-positive samples before and after treatment, leaving a study population of six in the terbinafine group, nine in the laser group, and eight in the placebo group.

Half of the terbinafine subjects were prescribed oral terbinafine 250 mg/day for 12 weeks, while the other three received oral terbinafine 250 mg/day pulse therapy at on/off intervals of 2 weeks up to 12 weeks.

The investigators also used three DNA strains known to be common in Europe for comparison and found that six distinct strains, labeled A-F, accounted for 94% of the T. rubrum strains – these strains corresponded to the European ones. However, three other strains (6% of strains) were found that investigators concluded were native to North America.

Strain type switching occurred in five (83%) of the terbinafine subjects, five (56%) of the laser cohort subjects, and two (25%) of those in the placebo cohort. Roughly half of the type switches noted in the terbinafine cohort were associated with mycological cures and were followed by relapse shortly thereafter. Dr. Gupta and his associates also found that all DNA strains in this cohort were susceptible to terbinafine while in vitro. Strain types in the laser and placebo cohorts did not show any signs of intermittent cures.

The patients were sampled at intervals of 0, 12, 24, 36, 48, 60, and 72 weeks of treatment, and T. rubrum DNA strain types were determined at week 0 (n = 6) and week 48 (n = 1) or 72 (n = 5). Patients in the laser cohort were treated at weeks 0, 8, and 16 and sampled at weeks 0, 8, 16, 24, and 48, with T. rubrum DNA strain types determined at week 0 (n = 9) and week 24 (n = 5) or 48 (n = 4). Finally, placebo patients were sampled at the same regularity as those in the laser cohort, with T. rubrum DNA strain types determined at week 0 (n = 8) and week 24 (n = 1) or 48 (n = 7), they reported.

“The T. rubrum DNA strain type switches observed in ongoing infections among all treatment groups could be attributed to microevolution or coinfections of DNA strains,” the researchers noted. “The presence of coinfecting T. rubrum DNA strains that flux with environmental conditions or local niches could account for the DNA strain type switches observed in all treatment groups, where only the relatively stable types are able to propagate in culture,” they added.

Dr. Gupta and his associates did not disclose any source of funding or any relevant conflicts of interest.

dchitnis@frontlinemedcom.com

Although DNA strain type switches are known to be a natural occurrence in patients with onychomycosis, increases in strain type switching that follow treatment failure could be an antifungal-induced response, according to the results of a study published in the British Journal of Dermatology.

“The dermatophyte Trichophyton rubrum is responsible for the majority (~80%) of [onychomycosis] cases, many of which frequently relapse after successful antifungal treatment,” noted the study authors, led by Dr. Aditya K. Gupta of the University of Toronto. Despite several previous studies of various facets related to onychomycosis, “data outlining onychomycosis infections of T. rubrum with DNA strain type, treatments, outcome and geographical location are still warranted,” they added (Br. J. Dermatol. 2015;172:74-80).

© Metin Cengiz Bar??/Thinkstock

Dr. Gupta and his associates examined 50 adults infected with T. rubrum, determined via analysis of toenail specimens from onychomycosis patients in southwest Ontario. The patients were divided into cohorts based on the treatment they received: oral terbinafine, laser, or placebo (no terbinafine and no laser). Typing of DNA strains was done only in culture-positive samples before and after treatment, leaving a study population of six in the terbinafine group, nine in the laser group, and eight in the placebo group.

Half of the terbinafine subjects were prescribed oral terbinafine 250 mg/day for 12 weeks, while the other three received oral terbinafine 250 mg/day pulse therapy at on/off intervals of 2 weeks up to 12 weeks.

The investigators also used three DNA strains known to be common in Europe for comparison and found that six distinct strains, labeled A-F, accounted for 94% of the T. rubrum strains – these strains corresponded to the European ones. However, three other strains (6% of strains) were found that investigators concluded were native to North America.

Strain type switching occurred in five (83%) of the terbinafine subjects, five (56%) of the laser cohort subjects, and two (25%) of those in the placebo cohort. Roughly half of the type switches noted in the terbinafine cohort were associated with mycological cures and were followed by relapse shortly thereafter. Dr. Gupta and his associates also found that all DNA strains in this cohort were susceptible to terbinafine while in vitro. Strain types in the laser and placebo cohorts did not show any signs of intermittent cures.

The patients were sampled at intervals of 0, 12, 24, 36, 48, 60, and 72 weeks of treatment, and T. rubrum DNA strain types were determined at week 0 (n = 6) and week 48 (n = 1) or 72 (n = 5). Patients in the laser cohort were treated at weeks 0, 8, and 16 and sampled at weeks 0, 8, 16, 24, and 48, with T. rubrum DNA strain types determined at week 0 (n = 9) and week 24 (n = 5) or 48 (n = 4). Finally, placebo patients were sampled at the same regularity as those in the laser cohort, with T. rubrum DNA strain types determined at week 0 (n = 8) and week 24 (n = 1) or 48 (n = 7), they reported.

“The T. rubrum DNA strain type switches observed in ongoing infections among all treatment groups could be attributed to microevolution or coinfections of DNA strains,” the researchers noted. “The presence of coinfecting T. rubrum DNA strains that flux with environmental conditions or local niches could account for the DNA strain type switches observed in all treatment groups, where only the relatively stable types are able to propagate in culture,” they added.

Dr. Gupta and his associates did not disclose any source of funding or any relevant conflicts of interest.

dchitnis@frontlinemedcom.com

Although DNA strain type switches are known to be a natural occurrence in patients with onychomycosis, increases in strain type switching that follow treatment failure could be an antifungal-induced response, according to the results of a study published in the British Journal of Dermatology.

“The dermatophyte Trichophyton rubrum is responsible for the majority (~80%) of [onychomycosis] cases, many of which frequently relapse after successful antifungal treatment,” noted the study authors, led by Dr. Aditya K. Gupta of the University of Toronto. Despite several previous studies of various facets related to onychomycosis, “data outlining onychomycosis infections of T. rubrum with DNA strain type, treatments, outcome and geographical location are still warranted,” they added (Br. J. Dermatol. 2015;172:74-80).

© Metin Cengiz Bar??/Thinkstock

Dr. Gupta and his associates examined 50 adults infected with T. rubrum, determined via analysis of toenail specimens from onychomycosis patients in southwest Ontario. The patients were divided into cohorts based on the treatment they received: oral terbinafine, laser, or placebo (no terbinafine and no laser). Typing of DNA strains was done only in culture-positive samples before and after treatment, leaving a study population of six in the terbinafine group, nine in the laser group, and eight in the placebo group.

Half of the terbinafine subjects were prescribed oral terbinafine 250 mg/day for 12 weeks, while the other three received oral terbinafine 250 mg/day pulse therapy at on/off intervals of 2 weeks up to 12 weeks.

The investigators also used three DNA strains known to be common in Europe for comparison and found that six distinct strains, labeled A-F, accounted for 94% of the T. rubrum strains – these strains corresponded to the European ones. However, three other strains (6% of strains) were found that investigators concluded were native to North America.

Strain type switching occurred in five (83%) of the terbinafine subjects, five (56%) of the laser cohort subjects, and two (25%) of those in the placebo cohort. Roughly half of the type switches noted in the terbinafine cohort were associated with mycological cures and were followed by relapse shortly thereafter. Dr. Gupta and his associates also found that all DNA strains in this cohort were susceptible to terbinafine while in vitro. Strain types in the laser and placebo cohorts did not show any signs of intermittent cures.

The patients were sampled at intervals of 0, 12, 24, 36, 48, 60, and 72 weeks of treatment, and T. rubrum DNA strain types were determined at week 0 (n = 6) and week 48 (n = 1) or 72 (n = 5). Patients in the laser cohort were treated at weeks 0, 8, and 16 and sampled at weeks 0, 8, 16, 24, and 48, with T. rubrum DNA strain types determined at week 0 (n = 9) and week 24 (n = 5) or 48 (n = 4). Finally, placebo patients were sampled at the same regularity as those in the laser cohort, with T. rubrum DNA strain types determined at week 0 (n = 8) and week 24 (n = 1) or 48 (n = 7), they reported.

“The T. rubrum DNA strain type switches observed in ongoing infections among all treatment groups could be attributed to microevolution or coinfections of DNA strains,” the researchers noted. “The presence of coinfecting T. rubrum DNA strains that flux with environmental conditions or local niches could account for the DNA strain type switches observed in all treatment groups, where only the relatively stable types are able to propagate in culture,” they added.

Dr. Gupta and his associates did not disclose any source of funding or any relevant conflicts of interest.

dchitnis@frontlinemedcom.com

Doctor consults with patient

Credit: NIH

The “transformation” of treatment for chronic lymphocytic leukemia (CLL) is the “Advance of the Year” for 2015, according to a report by the American Society of Clinical Oncology (ASCO).

The report said 4 therapies that were recently approved in the US fill a major unmet need for CLL patients—obinutuzumab and ofatumumab for patients with previously untreated CLL and idelalisib and ibrutinib for patients with relapsed or refractory CLL.

“For many older patients, especially, these drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle,” said Gregory Masters, MD, ASCO expert and co-executive editor of the report.

The report, “Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress Against Cancer,” is available in the Journal of Clinical Oncology and on ASCO’s cancer research advocacy website, CancerProgress.net.

The report was developed under the direction of an 18-person editorial board of experts from a wide range of oncology specialties. It features:

• The top cancer research advances of the past year: Identifying major trends in cancer prevention and screening, treatment, quality of life, survivorship, and tumor biology
• A Decade in Review: Recounting improvements in cancer care since the first issue of Clinical Cancer Advances
• The 10-Year Horizon: Previewing trends likely to shape the next decade of cancer care, including genomic technology, nanomedicine, and health information technologies
• Progress in Rare Cancers: Highlighting promising early achievements in treating certain uncommon but devastating cancers.

“This has truly been a banner year for CLL and for clinical cancer research as a whole,” said ASCO President Peter P. Yu, MD. “Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients.”

Doctor consults with patient

Credit: NIH

The “transformation” of treatment for chronic lymphocytic leukemia (CLL) is the “Advance of the Year” for 2015, according to a report by the American Society of Clinical Oncology (ASCO).

The report said 4 therapies that were recently approved in the US fill a major unmet need for CLL patients—obinutuzumab and ofatumumab for patients with previously untreated CLL and idelalisib and ibrutinib for patients with relapsed or refractory CLL.

“For many older patients, especially, these drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle,” said Gregory Masters, MD, ASCO expert and co-executive editor of the report.

The report, “Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress Against Cancer,” is available in the Journal of Clinical Oncology and on ASCO’s cancer research advocacy website, CancerProgress.net.

The report was developed under the direction of an 18-person editorial board of experts from a wide range of oncology specialties. It features:

• The top cancer research advances of the past year: Identifying major trends in cancer prevention and screening, treatment, quality of life, survivorship, and tumor biology
• A Decade in Review: Recounting improvements in cancer care since the first issue of Clinical Cancer Advances
• The 10-Year Horizon: Previewing trends likely to shape the next decade of cancer care, including genomic technology, nanomedicine, and health information technologies
• Progress in Rare Cancers: Highlighting promising early achievements in treating certain uncommon but devastating cancers.

“This has truly been a banner year for CLL and for clinical cancer research as a whole,” said ASCO President Peter P. Yu, MD. “Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients.”

Doctor consults with patient

Credit: NIH

The “transformation” of treatment for chronic lymphocytic leukemia (CLL) is the “Advance of the Year” for 2015, according to a report by the American Society of Clinical Oncology (ASCO).

The report said 4 therapies that were recently approved in the US fill a major unmet need for CLL patients—obinutuzumab and ofatumumab for patients with previously untreated CLL and idelalisib and ibrutinib for patients with relapsed or refractory CLL.

“For many older patients, especially, these drugs essentially offer the first chance at effective treatment, since the side effects of earlier options were simply too toxic for many to handle,” said Gregory Masters, MD, ASCO expert and co-executive editor of the report.

The report, “Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress Against Cancer,” is available in the Journal of Clinical Oncology and on ASCO’s cancer research advocacy website, CancerProgress.net.

The report was developed under the direction of an 18-person editorial board of experts from a wide range of oncology specialties. It features:

• The top cancer research advances of the past year: Identifying major trends in cancer prevention and screening, treatment, quality of life, survivorship, and tumor biology
• A Decade in Review: Recounting improvements in cancer care since the first issue of Clinical Cancer Advances
• The 10-Year Horizon: Previewing trends likely to shape the next decade of cancer care, including genomic technology, nanomedicine, and health information technologies
• Progress in Rare Cancers: Highlighting promising early achievements in treating certain uncommon but devastating cancers.

“This has truly been a banner year for CLL and for clinical cancer research as a whole,” said ASCO President Peter P. Yu, MD. “Advances in cancer prevention and care, especially those in precision medicine, are offering stunning new possibilities for patients.”

AML in the bone marrow

The US Food and Drug Administration (FDA) has granted fast track designation for CPX-351, a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle, to treat elderly patients with secondary acute myeloid leukemia (AML).

In a phase 2 study of elderly AML patients, there was no significant difference in response or survival rates between patients who received CPX-351 and those who received cytarabine and daunorubicin.

However, CPX-351 conferred a significant response benefit among patients with poor cytogenetics and a significant survival benefit in patients with secondary AML.

“We are pleased that FDA has granted fast track status for CPX-351 for the treatment of elderly patients with secondary AML,” said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals, the company developing CPX-351.

“Our ongoing phase 3 study in these patients has completed enrollment, and we expect induction response rate data to be available in the second quarter of this year, and to have overall survival data, the primary endpoint of the study, in the first quarter of 2016.”

“If our phase 3 study comparing CPX-351 to the current standard of care is successful, the fast track designation may provide an added benefit of facilitating the [new drug application] review process.”

The FDA established the fast track designation process to expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

The designation allows a drug’s developer to submit sections of a new drug application (NDA) on a rolling basis, so the FDA can review portions of the NDA as they are received instead of waiting for the entire NDA submission. A fast-track-designated product could be eligible for priority review if supported by clinical data at the time of NDA submission.

Phase 2 trial

In an article published in Blood last April, researchers reported results with CPX-351 in elderly patients with newly diagnosed AML. The study enrolled 126 patients who were 60 to 75 years of age.

They were randomized to receive CPX-351 (n=85) or “control” treatment consisting of cytarabine and daunorubicin (n=41). The treatment groups were well-balanced for disease and patient characteristics at baseline.

Overall, the response rate was 66.7% in the CPX-351 arm and 51.2% in the control arm (P=0.07). Among patients with adverse cytogenetics, the response rates were 77.3% and 38.5%, respectively (P=0.03). And among patients with secondary AML, response rates were 57.6% and 31.6%, respectively (P=0.06).

The median overall survival was 14.7 months in the CPX-351 arm and 12.9 months in the control arm. The median event-free survival was 6.5 months and 2.0 months, respectively. These differences were not statistically significant.

However, secondary AML patients treated with CPX-351 had significantly better overall survival than secondary AML patients in the control arm. The median overall survival was 12.1 months and 6.1 months, respectively (P=0.01). The median event-free survival was 4.5 months and 1.3 months, respectively (P=0.08).

Common adverse events included febrile neutropenia, infection, rash, diarrhea, nausea, edema, and constipation. There were minimal differences between the treatment arms in the incidence of these events.

The median time to neutrophil recovery was longer in the CPX-351 arm than in the control arm—36 days and 32 days, respectively. And the same was true for platelet recovery—37 days and 28 days, respectively.

Patients in the CPX-351 arm had a higher incidence of grade 3-4 infection than controls—70.6% and 43.9%, respectively—but not infection-related deaths—3.5% and 7.3%, respectively.

By day 60, 4.7% of patients in the CPX-351 arm and 14.6% of patients in the control arm had died. All of these deaths occurred in high-risk patients, particularly those with secondary AML.

AML in the bone marrow

The US Food and Drug Administration (FDA) has granted fast track designation for CPX-351, a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle, to treat elderly patients with secondary acute myeloid leukemia (AML).

In a phase 2 study of elderly AML patients, there was no significant difference in response or survival rates between patients who received CPX-351 and those who received cytarabine and daunorubicin.

However, CPX-351 conferred a significant response benefit among patients with poor cytogenetics and a significant survival benefit in patients with secondary AML.

“We are pleased that FDA has granted fast track status for CPX-351 for the treatment of elderly patients with secondary AML,” said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals, the company developing CPX-351.

“Our ongoing phase 3 study in these patients has completed enrollment, and we expect induction response rate data to be available in the second quarter of this year, and to have overall survival data, the primary endpoint of the study, in the first quarter of 2016.”

“If our phase 3 study comparing CPX-351 to the current standard of care is successful, the fast track designation may provide an added benefit of facilitating the [new drug application] review process.”

The FDA established the fast track designation process to expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

The designation allows a drug’s developer to submit sections of a new drug application (NDA) on a rolling basis, so the FDA can review portions of the NDA as they are received instead of waiting for the entire NDA submission. A fast-track-designated product could be eligible for priority review if supported by clinical data at the time of NDA submission.

Phase 2 trial

In an article published in Blood last April, researchers reported results with CPX-351 in elderly patients with newly diagnosed AML. The study enrolled 126 patients who were 60 to 75 years of age.

They were randomized to receive CPX-351 (n=85) or “control” treatment consisting of cytarabine and daunorubicin (n=41). The treatment groups were well-balanced for disease and patient characteristics at baseline.

Overall, the response rate was 66.7% in the CPX-351 arm and 51.2% in the control arm (P=0.07). Among patients with adverse cytogenetics, the response rates were 77.3% and 38.5%, respectively (P=0.03). And among patients with secondary AML, response rates were 57.6% and 31.6%, respectively (P=0.06).

The median overall survival was 14.7 months in the CPX-351 arm and 12.9 months in the control arm. The median event-free survival was 6.5 months and 2.0 months, respectively. These differences were not statistically significant.

However, secondary AML patients treated with CPX-351 had significantly better overall survival than secondary AML patients in the control arm. The median overall survival was 12.1 months and 6.1 months, respectively (P=0.01). The median event-free survival was 4.5 months and 1.3 months, respectively (P=0.08).

Common adverse events included febrile neutropenia, infection, rash, diarrhea, nausea, edema, and constipation. There were minimal differences between the treatment arms in the incidence of these events.

The median time to neutrophil recovery was longer in the CPX-351 arm than in the control arm—36 days and 32 days, respectively. And the same was true for platelet recovery—37 days and 28 days, respectively.

Patients in the CPX-351 arm had a higher incidence of grade 3-4 infection than controls—70.6% and 43.9%, respectively—but not infection-related deaths—3.5% and 7.3%, respectively.

By day 60, 4.7% of patients in the CPX-351 arm and 14.6% of patients in the control arm had died. All of these deaths occurred in high-risk patients, particularly those with secondary AML.

AML in the bone marrow

The US Food and Drug Administration (FDA) has granted fast track designation for CPX-351, a fixed-ratio combination of cytarabine and daunorubicin inside a lipid vesicle, to treat elderly patients with secondary acute myeloid leukemia (AML).

In a phase 2 study of elderly AML patients, there was no significant difference in response or survival rates between patients who received CPX-351 and those who received cytarabine and daunorubicin.

However, CPX-351 conferred a significant response benefit among patients with poor cytogenetics and a significant survival benefit in patients with secondary AML.

“We are pleased that FDA has granted fast track status for CPX-351 for the treatment of elderly patients with secondary AML,” said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals, the company developing CPX-351.

“Our ongoing phase 3 study in these patients has completed enrollment, and we expect induction response rate data to be available in the second quarter of this year, and to have overall survival data, the primary endpoint of the study, in the first quarter of 2016.”

“If our phase 3 study comparing CPX-351 to the current standard of care is successful, the fast track designation may provide an added benefit of facilitating the [new drug application] review process.”

The FDA established the fast track designation process to expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs.

The designation allows a drug’s developer to submit sections of a new drug application (NDA) on a rolling basis, so the FDA can review portions of the NDA as they are received instead of waiting for the entire NDA submission. A fast-track-designated product could be eligible for priority review if supported by clinical data at the time of NDA submission.

Phase 2 trial

In an article published in Blood last April, researchers reported results with CPX-351 in elderly patients with newly diagnosed AML. The study enrolled 126 patients who were 60 to 75 years of age.

They were randomized to receive CPX-351 (n=85) or “control” treatment consisting of cytarabine and daunorubicin (n=41). The treatment groups were well-balanced for disease and patient characteristics at baseline.

Overall, the response rate was 66.7% in the CPX-351 arm and 51.2% in the control arm (P=0.07). Among patients with adverse cytogenetics, the response rates were 77.3% and 38.5%, respectively (P=0.03). And among patients with secondary AML, response rates were 57.6% and 31.6%, respectively (P=0.06).

The median overall survival was 14.7 months in the CPX-351 arm and 12.9 months in the control arm. The median event-free survival was 6.5 months and 2.0 months, respectively. These differences were not statistically significant.

However, secondary AML patients treated with CPX-351 had significantly better overall survival than secondary AML patients in the control arm. The median overall survival was 12.1 months and 6.1 months, respectively (P=0.01). The median event-free survival was 4.5 months and 1.3 months, respectively (P=0.08).

Common adverse events included febrile neutropenia, infection, rash, diarrhea, nausea, edema, and constipation. There were minimal differences between the treatment arms in the incidence of these events.

The median time to neutrophil recovery was longer in the CPX-351 arm than in the control arm—36 days and 32 days, respectively. And the same was true for platelet recovery—37 days and 28 days, respectively.

Patients in the CPX-351 arm had a higher incidence of grade 3-4 infection than controls—70.6% and 43.9%, respectively—but not infection-related deaths—3.5% and 7.3%, respectively.

By day 60, 4.7% of patients in the CPX-351 arm and 14.6% of patients in the control arm had died. All of these deaths occurred in high-risk patients, particularly those with secondary AML.

The nanoparticles

Credit: Jonathan Lovell

A new type of nanoparticle can be used with 6 different imaging techniques, according to research published in Advanced Materials.

Investigators found they could detect these nanoparticles via CT and PET scans, as well as photoacoustic, fluorescence, upconversion, and Cerenkov luminescence imaging.

A machine capable of performing all 6 imaging techniques at once has not yet been invented, to the researchers’ knowledge.

But they hope the creation of their nanoparticles and related work will spur the development of such technology.

That way, patients could receive a single injection of the nanoparticles and have several types of imaging done, which would provide a clearer picture of organs and tissues than a single imaging method alone.

For instance, when the investigators used their nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the

deepest tissue penetration, while the photoacoustic imaging showed blood vessel details the first 2 techniques missed.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” said study author Jonathan Lovell, PhD, of the University of Buffalo in New York.

“Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

Dr Lovell and his colleagues designed their nanoparticles to have 2 components: a core that glows blue when struck by near-infrared light and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium, and thulium. The ytterbium is dense in electrons—a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer is also adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these 2 biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful new tool for medical imaging,” said Paras Prasad, PhD, also of the University of Buffalo.

“More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals, such as cadmium, that are known to pose potential risks and are found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” added Guanying Chen, PhD, of the University of Buffalo and Harbin Institute of Technology in China.

Dr Lovell said the next step for this research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end.

The nanoparticles

Credit: Jonathan Lovell

A new type of nanoparticle can be used with 6 different imaging techniques, according to research published in Advanced Materials.

Investigators found they could detect these nanoparticles via CT and PET scans, as well as photoacoustic, fluorescence, upconversion, and Cerenkov luminescence imaging.

A machine capable of performing all 6 imaging techniques at once has not yet been invented, to the researchers’ knowledge.

But they hope the creation of their nanoparticles and related work will spur the development of such technology.

That way, patients could receive a single injection of the nanoparticles and have several types of imaging done, which would provide a clearer picture of organs and tissues than a single imaging method alone.

For instance, when the investigators used their nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the

deepest tissue penetration, while the photoacoustic imaging showed blood vessel details the first 2 techniques missed.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” said study author Jonathan Lovell, PhD, of the University of Buffalo in New York.

“Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

Dr Lovell and his colleagues designed their nanoparticles to have 2 components: a core that glows blue when struck by near-infrared light and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium, and thulium. The ytterbium is dense in electrons—a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer is also adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these 2 biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful new tool for medical imaging,” said Paras Prasad, PhD, also of the University of Buffalo.

“More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals, such as cadmium, that are known to pose potential risks and are found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” added Guanying Chen, PhD, of the University of Buffalo and Harbin Institute of Technology in China.

Dr Lovell said the next step for this research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end.

The nanoparticles

Credit: Jonathan Lovell

A new type of nanoparticle can be used with 6 different imaging techniques, according to research published in Advanced Materials.

Investigators found they could detect these nanoparticles via CT and PET scans, as well as photoacoustic, fluorescence, upconversion, and Cerenkov luminescence imaging.

A machine capable of performing all 6 imaging techniques at once has not yet been invented, to the researchers’ knowledge.

But they hope the creation of their nanoparticles and related work will spur the development of such technology.

That way, patients could receive a single injection of the nanoparticles and have several types of imaging done, which would provide a clearer picture of organs and tissues than a single imaging method alone.

For instance, when the investigators used their nanoparticles to examine the lymph nodes of mice, they found that CT and PET scans provided the

deepest tissue penetration, while the photoacoustic imaging showed blood vessel details the first 2 techniques missed.

“This nanoparticle may open the door for new ‘hypermodal’ imaging systems that allow a lot of new information to be obtained using just one contrast agent,” said study author Jonathan Lovell, PhD, of the University of Buffalo in New York.

“Once such systems are developed, a patient could theoretically go in for one scan with one machine instead of multiple scans with multiple machines.”

Dr Lovell and his colleagues designed their nanoparticles to have 2 components: a core that glows blue when struck by near-infrared light and an outer fabric of porphyrin-phospholipids (PoP) that wraps around the core.

Each part has unique characteristics that make it ideal for certain types of imaging.

The core, initially designed for upconversion imaging, is made from sodium, ytterbium, fluorine, yttrium, and thulium. The ytterbium is dense in electrons—a property that facilitates detection by CT scans.

The PoP wrapper has biophotonic qualities that make it a great match for fluorescence and photoacoustic imagining. The PoP layer is also adept at attracting copper, which is used in PET and Cerenkov luminescence imaging.

“Combining these 2 biocompatible components into a single nanoparticle could give tomorrow’s doctors a powerful new tool for medical imaging,” said Paras Prasad, PhD, also of the University of Buffalo.

“More studies would have to be done to determine whether the nanoparticle is safe to use for such purposes, but it does not contain toxic metals, such as cadmium, that are known to pose potential risks and are found in some other nanoparticles.”

“Another advantage of this core/shell imaging contrast agent is that it could enable biomedical imaging at multiple scales, from single-molecule to cell imaging, as well as from vascular and organ imaging to whole-body bioimaging,” added Guanying Chen, PhD, of the University of Buffalo and Harbin Institute of Technology in China.

Dr Lovell said the next step for this research is to explore additional uses for the technology.

For example, it might be possible to attach a targeting molecule to the PoP surface that would enable cancer cells to take up the particles, something that photoacoustic and fluorescence imaging can detect due to the properties of the smart PoP coating. This would enable doctors to better see where tumors begin and end.

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.

The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.

The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.

To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.

The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.

“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”

The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.

“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.

“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.

Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.

Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”

“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”

Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.

“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.

The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.

The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.

To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.

The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.

“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”

The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.

“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.

“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.

Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.

Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”

“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”

Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.

“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

Researchers say they’ve uncovered the complex genetic architecture that enables the malaria parasite Plasmodium falciparum to develop resistance to the antimalarial drug artemisinin.

The team found evidence to suggest that 20 mutations in a single gene work with background mutations in 4 other genes to promote resistance.

The group believes their findings, published in Nature Genetics, could help improve early detection of emerging artemisinin resistance.

To make their discovery, the researchers analyzed 1612 samples from subjects at 15 locations in Southeast Asia and Africa. The team performed P falciparum genome sequencing and genotype calling at more than 600,000 single-nucleotide polymorphism positions on all samples.

The work revealed 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in 4 other genes—fd, arps10, mdr2, and crt—to support artemisinin resistance.

“Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance—until mutations occurred in the kelch13 gene,” said Roberto Amato, PhD, of the Wellcome Trust Sanger Institute in Oxford, UK.

“It’s similar to what we see with precancerous cells, which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick off growth.”

The variety of kelch13 mutations associated with artemisinin resistance makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background—in this case, a fixed set of 4 well-defined mutations in fd, arps10, mdr2, and crt—could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions before resistant parasites take hold.

“We are at a pivotal point for malaria control,” said Nick Day, MBBS, of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand.

“While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective. We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.”

The researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar, and Bangladesh, the team found that the distribution of different kelch13 mutations is localized within relatively well-defined geographical areas.

Although artemisinin-resistant parasites appear to have migrated across national borders, this only happened on a limited scale. In fact, the most widespread kelch13 mutation, C580Y, seems to have emerged independently on several occasions.

Parasites along the Thailand-Myanmar border appear to have acquired C580Y separately from those in Cambodia and Vietnam. But parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

“We don’t yet know the role of these background mutations,” said Olivo Miotto, PhD, also of MORU. “Some may not affect drug resistance directly but, rather, provide an environment where drug-resistance mutations are tolerated.”

“Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.”

Mutations in the kelch13 gene were present, yet rare, in Africa. But they weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa, where most malaria deaths occur.

“These data serve as a reminder of how crucial surveillance and elimination programs are,” said Dominic Kwiatkowski, MBBS, of the Wellcome Trust Sanger Institute.

“At present, artemisinin resistance appears to be largely confined to Southeast Asia, but the situation might change as the parasite population continues to evolve. By linking genomic data with clinical data, we’re developing a better understanding of the multiple genetic factors involved in the emergence of resistance, and that is starting to provide vital clues about how to prevent its spread.”

One day in 1986, a medical school classmate handed Dr. Robert P. Bright a gun that she intended to use to kill herself. She asked him to hold on to it for her and to keep quiet about her sense of hopelessness.

“She didn’t want anybody in the medical school to know; it was all hidden and hush-hushed,” recalled Dr. Bright, who is now a psychiatrist at the Mayo Clinic, Scottsdale, Ariz. “I was trying to juggle that with the issue of safety.”

He honored his classmate’s request for confidentiality, but he sought advice from the medical school dean about what to do. Before long, his classmate sought help from a psychiatrist and got better with medication and psychotherapy. “It turned out well, thank goodness,” Dr. Bright said.

Similar stories of despair among medical students and physicians don’t always end well. The American Foundation for Suicide Prevention estimates that 300-400 U.S. physicians commit suicide each year, about one per day. Suicide deaths are 250%-400% higher among female physicians, compared with women in other professions, and 70% higher among male physicians, compared with men in other professions. Major depression is a common risk factor, along with bipolar disorder and substance abuse.

Depression and other mood disorders may be underrecognized and inadequately treated in physicians because they may be reluctant to seek treatment, may attempt to diagnose and treat themselves, or may seek and receive “VIP treatment” from health care providers, according to a review article coauthored by Dr. Bright (Current Psych. 2011;10:16-30).

“Physicians struggling with these things are very much in the closet about it,” he said. “It’s a sad reflection on the stigma that’s still in our country that people can’t come forth and say, ‘I’m struggling with depression or anxiety.’ ”

Researchers led by Dr. Katherine J. Gold at the University of Michigan used data from the National Violent Death Reporting System to evaluate suicide among physicians and found that job stressors “may impact physician identity and be a particular risk factor for which more attention is warranted” (Gen. Hosp. Psychiatry 2013;35:45-9).

Work dissatisfaction sent Dr. Pamela Wible into a tailspin early in her career. In 2004 she found herself in a suicidal state for about 6 weeks, “I stayed at home, crying myself into my pillow and I never sought help from my colleagues,” recalled Dr. Wible, a family physician in Eugene, Ore., who currently leads training sessions in medical student and physician suicide prevention. “I was not depressed before entering the medical profession, but [I had developed] constant thoughts of ‘Can I just disappear? What’s the easiest way to do this?’ I got to a place of complete surrender but I didn’t have the gun. I didn’t have the stockpile of pills. I didn’t have a follow-through on the plan.”

Instead of taking her own life, she “had an epiphany” and changed the way she practiced medicine. She said that owning her own clinic empowered her to “become the doctor I had originally described on my personal statement when I entered medical school.”

According to Dr. Charles F. Reynolds III, a psychiatrist at the University of Pittsburgh, reluctance to seek treatment can also be driven by concerns about the amount of time that treatment could take.

“As physicians, we often don’t appropriately take care of ourselves when it comes to issues like depression,” said Dr. Reynolds, who also directs the National Institute of Mental Health–sponsored Center of Excellence in the Prevention and Treatment of Late Life Mood Disorders. “We may still see it as a character weakness rather than as a medical illness that can be diagnosed and appropriately treated. Concerns about privacy also figure into the concerns of some physicians as well.”

Practicing in a rural area or small community can also be an obstacle to treatment, not only because of limited access to psychiatrists, but because the “patient” may be the only physician in town.

“As much as there’s stigma for everybody being voluntarily or involuntarily admitted [for suicidal ideation], it’s a little different when you’re a provider within the hospital where you’re seeking care,” Dr. Bright noted.

He said that if he had the opportunity to counsel physicians experiencing suicidal thoughts, he would “remind them of the medical nature of depression, that the brain is just another organ and the organ is not making chemicals just like the pancreas doesn’t make insulin in diabetes,” he said. “I’d also encourage them to get the treatment that they need. I would encourage compassion for themselves that they would give to anybody else in the same situation.”

He said that he would advise them to find a mental health provider “that they trust with confidentiality, and to reach out to other people for support. I would also let them know about the physician assistance programs that are available. There’s one through Vanderbilt (the Vanderbilt Center for Professional Health) and several others that specialize in working with physicians who are struggling with mental health or substance abuse or disruptive behavior.”

Dr. Reynolds’ core message to distressed physicians is that “you’re a better doctor for your patients, and a better father or mother for your family, if you’re taking good care of yourself,” he said. “It’s hard for you to take care of your patients if you’re not also taking care of yourself, if you’re burning out. Get help. Treatment works.”

Dr. Christine Moutier, chief medical officer of the American Foundation for Suicide Prevention, added that troubled physicians “should feel no shame for the fact that they’re in distress. Any of us can get there through a whole variety of different pathways that life presents. There’s science and data to support this experience as commonplace and having underpinnings that are of no fault to anyone. That’s the reality.”

Dr. Wible, who has lost several colleagues and physician friends to suicide, said that she hopes for a more transparent discussion of the topic by the medical profession. She presented on the topic at the 2014 annual scientific assembly of the American Academy of Family Physicians.

“The talk before mine was on Ebola, and every seat was taken” in the 900-seat room. When it came time for her presentation, “I maybe had 100 people in the room. Now, are physicians more likely to die from Ebola or from suicide? We are in a state of denial. If we don’t talk about suicide, we will continue to lose one or two medical students or doctors every day. The sooner we talk about this and connect with each other outside of a PowerPoint presentation, the sooner we’re going to solve this.”

After a physician in a large clinical department at the University of Pittsburgh took his own life several years ago, the chair of that department invited Dr. Reynolds to speak with his staff. The meeting “was primarily educational in nature, so we talked about the topic, to try to destigmatize and to educate people about the need for appropriate help-seeking,” recalled Dr. Reynolds, who is a former president of the American College of Psychiatrists. “If the leadership of a medical institution appropriately sanctions help-seeking behavior and treatment of mental disorders like depression, that’s going to make it okay for people to reach out and seek help rather than pushing it under the rug, so to speak. If the leadership says ‘this is a key thing and we don’t think you can function adequately as a medical student or as a physician if you’re not taking appropriate care of yourself,’ that helps to shift the culture.”

The ripple effect of that kind of message from health care administrators can’t be underestimated, said Dr. Moutier, who helped launch a suicide and depression awareness program at the University of California, San Diego (Acad. Med. 2012;87:320-6). She encouraged health care leaders to stage periodic grand rounds and lectures for their medical staff about physician well-being, burnout, and the risk of suicide. “If the leader is uncomfortable talking about these things, that’s a sign they should get a little education for themselves about [these topics],” she said.

Dr. Reynolds noted that certain state medical licensure boards including those for Arkansas and Pennsylvania have incorporated destigmatizing language into relicensure exams. “Some of them previously would ask questions such as whether the applicants had a history of a mental disorder like depression,” he said. “What you’re beginning to see now increasingly is that the state medical board will ask more generic questions, like ‘Do you have any conditions that would interfere with the practice of your specialty in medicine?’ This is a good thing.”

He said that he is optimistic about future of physician well-being, noting that the University of Pittsburgh and other medical schools have incorporated wellness principles into first-year curriculum. “We underscore the importance of students becoming sensitive to one another, learning how to recognize depression in each other and creating a culture in which students can encourage each other to engage in appropriate help-seeking,” Dr. Reynolds explained. “I think we are witnessing a shift in the culture of institutional medicine as we bring along new generations of physicians who are better educated about mental disorders and their treatment and issues related to suicide as we reach out to students, make counseling services available to them, educate them about these issues. That supports a cultural shift that gradually erodes the issue of stigma that has so long plagued appropriate help-seeking in medical institutions.”

Still, Dr. Wible said that she worries about the disaffected colleagues who reach out to her almost every day. “Just yesterday I got an e-mail from a physician in Oklahoma who told me they just lost three physicians to suicide in 1 month who were on probation with the medical board,” she said. “These are not defective physicians. These people need to be helped.”

Dr. Wible said that she favors holding periodic panel discussions on the topics of depression and physician suicide for medical students and physicians alike. “Let other physicians who’ve been depressed and suicidal sit in front of the room on the first week of medical school, or in a hospital once in a while, mandatory, where you listen to other well-respected physicians say, ‘yeah. I cried myself to sleep after I lost this patient,’ or ‘I had suicidal thoughts during a malpractice case.’ There are lots of reasons why physicians could be sad. They need to start talking about it publicly. Other medical students and physicians would then feel comfortable to raise their hands in the audience and say, ‘I felt the same way.’ ”

Suggested resources for help

American Foundation for Suicide Prevention (www.afsp.org/).

24-hour crisis line: 1-800-273-TALK (8255).

In 2008 the AFSP released a documentary about the problem of physician depression and suicide titled “Struggling in Silence,” which aired on public television stations nationwide and is available on DVD for $24.99.

Center for Patient and Professional Advocacy (www.mc.vanderbilt.edu/centers/cppa/index.php)

Depression and Bipolar Support Alliance (www.dbsalliance.org).

Federation of State Physician Health Programs Inc. (www.fsphp.org).

Vanderbilt Center for Professional Health (www.mc.vanderbilt.edu/cph).

The Mayo Clinic Program on Physician Well-Being (http://www.mayo.edu/research/centers-programs/physician-well-being-program/overview).

ePhysicianHealth.com, a program of the Ontario Medical Association (http://php.oma.org/ePhysicianHealth.html)

The Academic Medicine Handbook: A Guide to Achievement and Fulfillment for Academic Faculty, New York: Springer, 2013 (http://www.springer.com/medicine/internal/book/978-1-4614-5692-6)

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

One day in 1986, a medical school classmate handed Dr. Robert P. Bright a gun that she intended to use to kill herself. She asked him to hold on to it for her and to keep quiet about her sense of hopelessness.

“She didn’t want anybody in the medical school to know; it was all hidden and hush-hushed,” recalled Dr. Bright, who is now a psychiatrist at the Mayo Clinic, Scottsdale, Ariz. “I was trying to juggle that with the issue of safety.”

He honored his classmate’s request for confidentiality, but he sought advice from the medical school dean about what to do. Before long, his classmate sought help from a psychiatrist and got better with medication and psychotherapy. “It turned out well, thank goodness,” Dr. Bright said.

Similar stories of despair among medical students and physicians don’t always end well. The American Foundation for Suicide Prevention estimates that 300-400 U.S. physicians commit suicide each year, about one per day. Suicide deaths are 250%-400% higher among female physicians, compared with women in other professions, and 70% higher among male physicians, compared with men in other professions. Major depression is a common risk factor, along with bipolar disorder and substance abuse.

Depression and other mood disorders may be underrecognized and inadequately treated in physicians because they may be reluctant to seek treatment, may attempt to diagnose and treat themselves, or may seek and receive “VIP treatment” from health care providers, according to a review article coauthored by Dr. Bright (Current Psych. 2011;10:16-30).

“Physicians struggling with these things are very much in the closet about it,” he said. “It’s a sad reflection on the stigma that’s still in our country that people can’t come forth and say, ‘I’m struggling with depression or anxiety.’ ”

Researchers led by Dr. Katherine J. Gold at the University of Michigan used data from the National Violent Death Reporting System to evaluate suicide among physicians and found that job stressors “may impact physician identity and be a particular risk factor for which more attention is warranted” (Gen. Hosp. Psychiatry 2013;35:45-9).

Work dissatisfaction sent Dr. Pamela Wible into a tailspin early in her career. In 2004 she found herself in a suicidal state for about 6 weeks, “I stayed at home, crying myself into my pillow and I never sought help from my colleagues,” recalled Dr. Wible, a family physician in Eugene, Ore., who currently leads training sessions in medical student and physician suicide prevention. “I was not depressed before entering the medical profession, but [I had developed] constant thoughts of ‘Can I just disappear? What’s the easiest way to do this?’ I got to a place of complete surrender but I didn’t have the gun. I didn’t have the stockpile of pills. I didn’t have a follow-through on the plan.”

Instead of taking her own life, she “had an epiphany” and changed the way she practiced medicine. She said that owning her own clinic empowered her to “become the doctor I had originally described on my personal statement when I entered medical school.”

According to Dr. Charles F. Reynolds III, a psychiatrist at the University of Pittsburgh, reluctance to seek treatment can also be driven by concerns about the amount of time that treatment could take.

“As physicians, we often don’t appropriately take care of ourselves when it comes to issues like depression,” said Dr. Reynolds, who also directs the National Institute of Mental Health–sponsored Center of Excellence in the Prevention and Treatment of Late Life Mood Disorders. “We may still see it as a character weakness rather than as a medical illness that can be diagnosed and appropriately treated. Concerns about privacy also figure into the concerns of some physicians as well.”

Practicing in a rural area or small community can also be an obstacle to treatment, not only because of limited access to psychiatrists, but because the “patient” may be the only physician in town.

“As much as there’s stigma for everybody being voluntarily or involuntarily admitted [for suicidal ideation], it’s a little different when you’re a provider within the hospital where you’re seeking care,” Dr. Bright noted.

He said that if he had the opportunity to counsel physicians experiencing suicidal thoughts, he would “remind them of the medical nature of depression, that the brain is just another organ and the organ is not making chemicals just like the pancreas doesn’t make insulin in diabetes,” he said. “I’d also encourage them to get the treatment that they need. I would encourage compassion for themselves that they would give to anybody else in the same situation.”

He said that he would advise them to find a mental health provider “that they trust with confidentiality, and to reach out to other people for support. I would also let them know about the physician assistance programs that are available. There’s one through Vanderbilt (the Vanderbilt Center for Professional Health) and several others that specialize in working with physicians who are struggling with mental health or substance abuse or disruptive behavior.”

Dr. Reynolds’ core message to distressed physicians is that “you’re a better doctor for your patients, and a better father or mother for your family, if you’re taking good care of yourself,” he said. “It’s hard for you to take care of your patients if you’re not also taking care of yourself, if you’re burning out. Get help. Treatment works.”

Dr. Christine Moutier, chief medical officer of the American Foundation for Suicide Prevention, added that troubled physicians “should feel no shame for the fact that they’re in distress. Any of us can get there through a whole variety of different pathways that life presents. There’s science and data to support this experience as commonplace and having underpinnings that are of no fault to anyone. That’s the reality.”

Dr. Wible, who has lost several colleagues and physician friends to suicide, said that she hopes for a more transparent discussion of the topic by the medical profession. She presented on the topic at the 2014 annual scientific assembly of the American Academy of Family Physicians.

“The talk before mine was on Ebola, and every seat was taken” in the 900-seat room. When it came time for her presentation, “I maybe had 100 people in the room. Now, are physicians more likely to die from Ebola or from suicide? We are in a state of denial. If we don’t talk about suicide, we will continue to lose one or two medical students or doctors every day. The sooner we talk about this and connect with each other outside of a PowerPoint presentation, the sooner we’re going to solve this.”

After a physician in a large clinical department at the University of Pittsburgh took his own life several years ago, the chair of that department invited Dr. Reynolds to speak with his staff. The meeting “was primarily educational in nature, so we talked about the topic, to try to destigmatize and to educate people about the need for appropriate help-seeking,” recalled Dr. Reynolds, who is a former president of the American College of Psychiatrists. “If the leadership of a medical institution appropriately sanctions help-seeking behavior and treatment of mental disorders like depression, that’s going to make it okay for people to reach out and seek help rather than pushing it under the rug, so to speak. If the leadership says ‘this is a key thing and we don’t think you can function adequately as a medical student or as a physician if you’re not taking appropriate care of yourself,’ that helps to shift the culture.”

The ripple effect of that kind of message from health care administrators can’t be underestimated, said Dr. Moutier, who helped launch a suicide and depression awareness program at the University of California, San Diego (Acad. Med. 2012;87:320-6). She encouraged health care leaders to stage periodic grand rounds and lectures for their medical staff about physician well-being, burnout, and the risk of suicide. “If the leader is uncomfortable talking about these things, that’s a sign they should get a little education for themselves about [these topics],” she said.

Dr. Reynolds noted that certain state medical licensure boards including those for Arkansas and Pennsylvania have incorporated destigmatizing language into relicensure exams. “Some of them previously would ask questions such as whether the applicants had a history of a mental disorder like depression,” he said. “What you’re beginning to see now increasingly is that the state medical board will ask more generic questions, like ‘Do you have any conditions that would interfere with the practice of your specialty in medicine?’ This is a good thing.”

He said that he is optimistic about future of physician well-being, noting that the University of Pittsburgh and other medical schools have incorporated wellness principles into first-year curriculum. “We underscore the importance of students becoming sensitive to one another, learning how to recognize depression in each other and creating a culture in which students can encourage each other to engage in appropriate help-seeking,” Dr. Reynolds explained. “I think we are witnessing a shift in the culture of institutional medicine as we bring along new generations of physicians who are better educated about mental disorders and their treatment and issues related to suicide as we reach out to students, make counseling services available to them, educate them about these issues. That supports a cultural shift that gradually erodes the issue of stigma that has so long plagued appropriate help-seeking in medical institutions.”

Still, Dr. Wible said that she worries about the disaffected colleagues who reach out to her almost every day. “Just yesterday I got an e-mail from a physician in Oklahoma who told me they just lost three physicians to suicide in 1 month who were on probation with the medical board,” she said. “These are not defective physicians. These people need to be helped.”

Dr. Wible said that she favors holding periodic panel discussions on the topics of depression and physician suicide for medical students and physicians alike. “Let other physicians who’ve been depressed and suicidal sit in front of the room on the first week of medical school, or in a hospital once in a while, mandatory, where you listen to other well-respected physicians say, ‘yeah. I cried myself to sleep after I lost this patient,’ or ‘I had suicidal thoughts during a malpractice case.’ There are lots of reasons why physicians could be sad. They need to start talking about it publicly. Other medical students and physicians would then feel comfortable to raise their hands in the audience and say, ‘I felt the same way.’ ”

Suggested resources for help

American Foundation for Suicide Prevention (www.afsp.org/).

24-hour crisis line: 1-800-273-TALK (8255).

In 2008 the AFSP released a documentary about the problem of physician depression and suicide titled “Struggling in Silence,” which aired on public television stations nationwide and is available on DVD for $24.99.

Center for Patient and Professional Advocacy (www.mc.vanderbilt.edu/centers/cppa/index.php)

Depression and Bipolar Support Alliance (www.dbsalliance.org).

Federation of State Physician Health Programs Inc. (www.fsphp.org).

Vanderbilt Center for Professional Health (www.mc.vanderbilt.edu/cph).

The Mayo Clinic Program on Physician Well-Being (http://www.mayo.edu/research/centers-programs/physician-well-being-program/overview).

ePhysicianHealth.com, a program of the Ontario Medical Association (http://php.oma.org/ePhysicianHealth.html)

The Academic Medicine Handbook: A Guide to Achievement and Fulfillment for Academic Faculty, New York: Springer, 2013 (http://www.springer.com/medicine/internal/book/978-1-4614-5692-6)

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

One day in 1986, a medical school classmate handed Dr. Robert P. Bright a gun that she intended to use to kill herself. She asked him to hold on to it for her and to keep quiet about her sense of hopelessness.

“She didn’t want anybody in the medical school to know; it was all hidden and hush-hushed,” recalled Dr. Bright, who is now a psychiatrist at the Mayo Clinic, Scottsdale, Ariz. “I was trying to juggle that with the issue of safety.”

He honored his classmate’s request for confidentiality, but he sought advice from the medical school dean about what to do. Before long, his classmate sought help from a psychiatrist and got better with medication and psychotherapy. “It turned out well, thank goodness,” Dr. Bright said.

Similar stories of despair among medical students and physicians don’t always end well. The American Foundation for Suicide Prevention estimates that 300-400 U.S. physicians commit suicide each year, about one per day. Suicide deaths are 250%-400% higher among female physicians, compared with women in other professions, and 70% higher among male physicians, compared with men in other professions. Major depression is a common risk factor, along with bipolar disorder and substance abuse.

Depression and other mood disorders may be underrecognized and inadequately treated in physicians because they may be reluctant to seek treatment, may attempt to diagnose and treat themselves, or may seek and receive “VIP treatment” from health care providers, according to a review article coauthored by Dr. Bright (Current Psych. 2011;10:16-30).

“Physicians struggling with these things are very much in the closet about it,” he said. “It’s a sad reflection on the stigma that’s still in our country that people can’t come forth and say, ‘I’m struggling with depression or anxiety.’ ”

Researchers led by Dr. Katherine J. Gold at the University of Michigan used data from the National Violent Death Reporting System to evaluate suicide among physicians and found that job stressors “may impact physician identity and be a particular risk factor for which more attention is warranted” (Gen. Hosp. Psychiatry 2013;35:45-9).

Work dissatisfaction sent Dr. Pamela Wible into a tailspin early in her career. In 2004 she found herself in a suicidal state for about 6 weeks, “I stayed at home, crying myself into my pillow and I never sought help from my colleagues,” recalled Dr. Wible, a family physician in Eugene, Ore., who currently leads training sessions in medical student and physician suicide prevention. “I was not depressed before entering the medical profession, but [I had developed] constant thoughts of ‘Can I just disappear? What’s the easiest way to do this?’ I got to a place of complete surrender but I didn’t have the gun. I didn’t have the stockpile of pills. I didn’t have a follow-through on the plan.”

Instead of taking her own life, she “had an epiphany” and changed the way she practiced medicine. She said that owning her own clinic empowered her to “become the doctor I had originally described on my personal statement when I entered medical school.”

According to Dr. Charles F. Reynolds III, a psychiatrist at the University of Pittsburgh, reluctance to seek treatment can also be driven by concerns about the amount of time that treatment could take.

“As physicians, we often don’t appropriately take care of ourselves when it comes to issues like depression,” said Dr. Reynolds, who also directs the National Institute of Mental Health–sponsored Center of Excellence in the Prevention and Treatment of Late Life Mood Disorders. “We may still see it as a character weakness rather than as a medical illness that can be diagnosed and appropriately treated. Concerns about privacy also figure into the concerns of some physicians as well.”

Practicing in a rural area or small community can also be an obstacle to treatment, not only because of limited access to psychiatrists, but because the “patient” may be the only physician in town.

“As much as there’s stigma for everybody being voluntarily or involuntarily admitted [for suicidal ideation], it’s a little different when you’re a provider within the hospital where you’re seeking care,” Dr. Bright noted.

He said that if he had the opportunity to counsel physicians experiencing suicidal thoughts, he would “remind them of the medical nature of depression, that the brain is just another organ and the organ is not making chemicals just like the pancreas doesn’t make insulin in diabetes,” he said. “I’d also encourage them to get the treatment that they need. I would encourage compassion for themselves that they would give to anybody else in the same situation.”

He said that he would advise them to find a mental health provider “that they trust with confidentiality, and to reach out to other people for support. I would also let them know about the physician assistance programs that are available. There’s one through Vanderbilt (the Vanderbilt Center for Professional Health) and several others that specialize in working with physicians who are struggling with mental health or substance abuse or disruptive behavior.”

Dr. Reynolds’ core message to distressed physicians is that “you’re a better doctor for your patients, and a better father or mother for your family, if you’re taking good care of yourself,” he said. “It’s hard for you to take care of your patients if you’re not also taking care of yourself, if you’re burning out. Get help. Treatment works.”

Dr. Christine Moutier, chief medical officer of the American Foundation for Suicide Prevention, added that troubled physicians “should feel no shame for the fact that they’re in distress. Any of us can get there through a whole variety of different pathways that life presents. There’s science and data to support this experience as commonplace and having underpinnings that are of no fault to anyone. That’s the reality.”

Dr. Wible, who has lost several colleagues and physician friends to suicide, said that she hopes for a more transparent discussion of the topic by the medical profession. She presented on the topic at the 2014 annual scientific assembly of the American Academy of Family Physicians.

“The talk before mine was on Ebola, and every seat was taken” in the 900-seat room. When it came time for her presentation, “I maybe had 100 people in the room. Now, are physicians more likely to die from Ebola or from suicide? We are in a state of denial. If we don’t talk about suicide, we will continue to lose one or two medical students or doctors every day. The sooner we talk about this and connect with each other outside of a PowerPoint presentation, the sooner we’re going to solve this.”

After a physician in a large clinical department at the University of Pittsburgh took his own life several years ago, the chair of that department invited Dr. Reynolds to speak with his staff. The meeting “was primarily educational in nature, so we talked about the topic, to try to destigmatize and to educate people about the need for appropriate help-seeking,” recalled Dr. Reynolds, who is a former president of the American College of Psychiatrists. “If the leadership of a medical institution appropriately sanctions help-seeking behavior and treatment of mental disorders like depression, that’s going to make it okay for people to reach out and seek help rather than pushing it under the rug, so to speak. If the leadership says ‘this is a key thing and we don’t think you can function adequately as a medical student or as a physician if you’re not taking appropriate care of yourself,’ that helps to shift the culture.”

The ripple effect of that kind of message from health care administrators can’t be underestimated, said Dr. Moutier, who helped launch a suicide and depression awareness program at the University of California, San Diego (Acad. Med. 2012;87:320-6). She encouraged health care leaders to stage periodic grand rounds and lectures for their medical staff about physician well-being, burnout, and the risk of suicide. “If the leader is uncomfortable talking about these things, that’s a sign they should get a little education for themselves about [these topics],” she said.

Dr. Reynolds noted that certain state medical licensure boards including those for Arkansas and Pennsylvania have incorporated destigmatizing language into relicensure exams. “Some of them previously would ask questions such as whether the applicants had a history of a mental disorder like depression,” he said. “What you’re beginning to see now increasingly is that the state medical board will ask more generic questions, like ‘Do you have any conditions that would interfere with the practice of your specialty in medicine?’ This is a good thing.”

He said that he is optimistic about future of physician well-being, noting that the University of Pittsburgh and other medical schools have incorporated wellness principles into first-year curriculum. “We underscore the importance of students becoming sensitive to one another, learning how to recognize depression in each other and creating a culture in which students can encourage each other to engage in appropriate help-seeking,” Dr. Reynolds explained. “I think we are witnessing a shift in the culture of institutional medicine as we bring along new generations of physicians who are better educated about mental disorders and their treatment and issues related to suicide as we reach out to students, make counseling services available to them, educate them about these issues. That supports a cultural shift that gradually erodes the issue of stigma that has so long plagued appropriate help-seeking in medical institutions.”

Still, Dr. Wible said that she worries about the disaffected colleagues who reach out to her almost every day. “Just yesterday I got an e-mail from a physician in Oklahoma who told me they just lost three physicians to suicide in 1 month who were on probation with the medical board,” she said. “These are not defective physicians. These people need to be helped.”

Dr. Wible said that she favors holding periodic panel discussions on the topics of depression and physician suicide for medical students and physicians alike. “Let other physicians who’ve been depressed and suicidal sit in front of the room on the first week of medical school, or in a hospital once in a while, mandatory, where you listen to other well-respected physicians say, ‘yeah. I cried myself to sleep after I lost this patient,’ or ‘I had suicidal thoughts during a malpractice case.’ There are lots of reasons why physicians could be sad. They need to start talking about it publicly. Other medical students and physicians would then feel comfortable to raise their hands in the audience and say, ‘I felt the same way.’ ”

Suggested resources for help

American Foundation for Suicide Prevention (www.afsp.org/).

24-hour crisis line: 1-800-273-TALK (8255).

In 2008 the AFSP released a documentary about the problem of physician depression and suicide titled “Struggling in Silence,” which aired on public television stations nationwide and is available on DVD for $24.99.

Center for Patient and Professional Advocacy (www.mc.vanderbilt.edu/centers/cppa/index.php)

Depression and Bipolar Support Alliance (www.dbsalliance.org).

Federation of State Physician Health Programs Inc. (www.fsphp.org).

Vanderbilt Center for Professional Health (www.mc.vanderbilt.edu/cph).

The Mayo Clinic Program on Physician Well-Being (http://www.mayo.edu/research/centers-programs/physician-well-being-program/overview).

ePhysicianHealth.com, a program of the Ontario Medical Association (http://php.oma.org/ePhysicianHealth.html)

The Academic Medicine Handbook: A Guide to Achievement and Fulfillment for Academic Faculty, New York: Springer, 2013 (http://www.springer.com/medicine/internal/book/978-1-4614-5692-6)

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk